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    June 2022

    Micro-Learning CE Associated - Click Here For Details

    Seasonal Allergies are coming At-Choo Soon

    Key Terms
    • Anticholinergics: act locally on nasal mucosa to inhibit serous and seromucous gland secretions
    • Antihistamines: selectively block peripheral histamine-1 receptors, to minimize response to triggers
    • IgE: immunoglobulin E, antibodies produced by the immune system as part of the body’s defense against specific triggers
    • Leukotriene receptor antagonists: inhibits activation of receptors that are correlated with pathophysiology of asthma, airway edema, smooth muscle contraction, and inflammatory responses
    • Mast cell stabilizers:act locally to reduce histamine degranulation from mast cells
    • Rhinitis medicamentosa: chronic nasal congestion associated with overuse of vasoconstrictor nasal medications, sometimes referred to as “rebound” nasal congestion
    Shifting Trends
    Springtime brings with it warmer weather, baseball games, and budding trees. In the Fall, we enjoy Friday night football games and pumpkin-flavored everything. For many, these seasonal changes also bring unrelenting watery eyes, runny noses, and scratchy throats. And it is only getting worse.

    In 2010, the Asthma and Allergy Foundation of America (jointly with the National Wildlife Federation) released a report on the effect of a warming climate on allergies and asthma.1 Ragweed is the chief Fall trigger for many patients’ allergies. According to the report, it grows faster and produces more pollen in an environment with more carbon dioxide. Longer growing seasons as a result of warmer weather allow ragweed plants to grow larger, releasing more pollen. In the Spring, budding trees and flowers are the primary pollen producers. A warmer climate means their habitat will expand to previously inhospitable areas. Fungal allergens, too, could be more problematic as the planet warms.

    Review of Allergic Pathophysiology
    Allergic rhinitis is characterized by sneezing, runny nose, nasal obstruction, and often accompanied by itchy, watery eyes. The physiological response to seasonal allergens is an IgE antibody-mediated inflammatory response.2 The severity of this response can be mild to severe and varies with trigger type, the extent of exposure, and patient-specific factors.

    The Pharmacist’s Role in Treating Seasonal Allergies
    Allergic rhinitis is likely a condition that affects many of your patients. Indeed, surveys indicate physician-diagnosed allergic rhinitis affects upwards of 20% of adults and 13% of children in the United States. The functional and economic toll of seasonal allergies is immense. Impaired physical and social functioning and daytime somnolence can lead to lost days of work and lower quality of life.

    As patients reach for over-the-counter allergy medications, the incidence of potentially harmful drug interactions increases as well. It is in this capacity that pharmacists can play a key role in alleviating patients’ symptoms while helping them minimize the effects of medications.

    Cornerstones of Treatment for Seasonal Allergies
    The most common medications used to treat allergic conditions are antihistamines, decongestants, and glucocorticoids. Leukotriene inhibitors, mast cell stabilizers, and anticholinergics can be useful in some cases, too. In recommending a medication to a patient, we should maximize symptom reduction and improve patient productivity while minimizing adverse effects and drug-drug interactions. The latest treatment guidelines were published in 2020 by the American Academy of Allergy, Asthma, and Immunology (AAAAI).3

    Antihistamines
    Oral antihistamines have long been the standard for seasonal allergies. They can be used proactively to minimize symptoms prior to trigger exposure, or reactively post-exposure. First-generation agents tend to be more sedating and require multiple daily doses. Second-generation agents, conversely, tend to cause less sedation and are taken once daily. These second-generation agents are sometimes called “non-sedating” antihistamines, but a more accurate label is “less-sedating.” Medications in both generations are available without a prescription.

    Oral AntihistaminesGenerationRecommended Adult Dose
    (≥12 years)
    Recommended Pediatric Dose
    (6≥11 years)
    Chlorpheniramine14mg every 4-6 hours2mg every 4-6 hours
    Clemastine fumarate11.34mg BID, or 2.68mg daily0.67mg BID, or 1.34mg daily
    Diphenhydramine125mg every 4-6 hoursNot recommended3
    Hydroxyzine110-25mg at bedtime12.5-25mg at bedtime
    Triprolidine12.5mg every 4-6 hours1.25mg every 4-6 hours
    Cetirizine (Zyrtec®)210mg daily5-10mg daily
    Desloratadine (Clarinex®)25mg daily2.5mg daily
    Fexofenadine (Allegra®)260mg BID, or 180mg daily30mg BID, or 60mg daily
    Levocetirizine (Xyzal®)25mg daily2.5mg daily
    Loratadine (Claritin®)25mg BID, or 10mg daily5-10mg daily


    Many of the agents listed above (and several other medications) are also available in ophthalmic and nasal dosage forms. The topical formulations generally cause little to no sedation. With all antihistamines, it is important that the patient use caution when drug-induced sedation would interfere with activities.

    Glucocorticoids
    Nasal steroids are now the gold standard for allergic rhinitis. They are the single most effective maintenance therapy and cause very few adverse effects. They can successfully treat both nasal and ophthalmic symptoms of seasonal allergies. Antihistamines often do little to relieve allergic nasal congestion; nasal steroids are particularly effective in these cases. Many of nasal steroids are available over the counter. The choice of agent is generally patient preference. Dose and frequency of these agents is product specific. Generally, though, the recommended dose for most products is 1 or 2 inhalations in both nostrils once or twice daily.

    It is important that patients be counseled on correct dosing technique with nasal steroids. Proper positioning of the head will ensure the medication is distributed to the nasal tissues rather than draining down the throat. The patient should tilt the head slightly downward, while pointing the spray upward, away from the septum.

    Older, first-generation agents are associated with higher systemic bioavailability. Second-generation agents are typically undetectable at the systemic level, which is preferable especially for children and when using year-round. The maximum effect of nasal steroids usually arrives after one to two weeks of daily use. In the interim, oral antihistamines can be used concurrently to treat allergy symptoms.

    Nasal SteroidGenerationOTC/Rx
    Beclomethasone (Beconase®, Qnasl®)1Rx
    Budesonide (Rhinocort®)1OTC
    Flunisolide (Nasarel®)1Rx
    Triamcinolone (Nasacort®)1Rx and OTC
    Ciclesonide (Omnaris®, Zetonna®)2Rx
    Fluticasone furoate (Flonase Sensimist®)2OTC
    Fluticasone propionate (Flonase®)2Rx and OTC
    Mometasone (Nasonex®)2Rx


    Two of the above products – beclomethasone and ciclesonide – are delivered via dry aerosol. This delivery form may be preferable for patients put off by the scent or taste effects of the other aqueous solutions.

    Anticholinergics and Mast Cell Stabilizers
    The anticholinergic ipratropium bromide, in nasal spray form, can be useful for treating rhinorrhea (runny nose), but it is still less effective than the nasal glucocorticoids for sneezing, itching, and nasal obstruction.4 If runny nose is still not well controlled on nasal steroids, it can be used concurrently. Ipratropium requires frequent dosing. Because of its inferiority to nasal steroids, ipratropium is not considered first-line treatment for seasonal allergies.

    Cromolyn sodium, a mast cell stabilizer, is particularly useful for people who have episodic symptoms that can be anticipated. For example, a patient who is allergic to cats can use cromolyn nasal spray about 30 minutes prior to visiting a friend who has a cat to minimize nasal allergen triggering. In the same way, cromolyn can be initiated 1-2 weeks prior to environmental pollen peaks as a prophylactic measure. This agent does require frequent daily dosing when used for seasonal allergies. Cromolyn is also considered second-line treatment to nasal steroids but can be useful when other agents are not- well tolerated.5

    Second-Line AgentsOTC/RxTypical Dose and Frequency
    Ipratropium (Atrovent Nasal®)Rx2 sprays in each nostril 2-3 times daily
    Cromolyn (NasalCrom®)OTC1 spray in each nostril 3-4 times daily


    Nasal Decongestants
    Nasal decongestants work by causing local vasoconstriction. Phenylephrine, oxymetazoline, xylometazoline, and naphazoline are the agents in this class. While they are very effective for nasal congestion, they are not recommended for allergic rhinitis monotherapy. Chronic use of nasal decongestants can give rise to rhinitis medicamentosa or “rebound” congestion. Downregulation of alpha-adrenergic receptors in the nasal tissues can occur in as little as 3 days of use. Patients who use nasal decongestants frequently often find themselves in a cycle of nasal congestion both caused by and relieved by the medication. Therefore, patients should be warned against using any of these singly agents for more than 72 hours.

    Patients with congestion-dominant seasonal nasal symptoms may find benefit from a combination of once-daily nasal steroid plus the long-acting nasal decongestant agent oxymetazoline. A study that evaluated this combination found that nasal symptoms were less than in the placebo group, and even less in the group using a steroid alone.6 Moreover, the study found that the once-daily dosing with the steroid did not bring on rhinitis medicamentosa. Still, it is still advisable to discontinue use of a nasal decongestant once symptoms are well-controlled.

    Leukotriene Receptor Antagonists
    One medication in this class, montelukast (Singulair®), was used for patients who could not tolerate nasal sprays. However, recent trials revealed troubling neuropsychiatric changes associated with the drug. As a result, the FDA issued a boxed warning for montelukast, citing its link to insomnia, anxiety, depression, and suicidal ideation.7, 8 With this new information, the risk/benefit ratio of montelukast increased significantly. Given the number of other safer alternatives for treating seasonal allergies, montelukast (and other agents in its class) should be avoided.

    When to Refer at Patient to a Specialist
    If a patient fails multiple courses of the recommended agents, an evaluation for non-allergic etiologies is advisable. A specialist should rule out other conditions before initiating allergen immunotherapy. Adult and pediatric patients who have prolonged, severe symptoms, co-existing asthma or nasal polyps should also be referred for further evaluation.

    Summary
    Seasonal allergy symptoms and allergic rhinitis are very common conditions, affecting 10-30 percent of adults and children in industrialized countries. Prevalence is increasing. Medications to treat allergic nasal symptoms are numerous, many available without a prescription. As such, pharmacists play a key role in advising patients on safe use of these medications.

    The treatment of choice for most patients is a nasal glucocorticoid. These agents offer safety, minimal systemic absorption, convenient once-daily dosing, and over-the-counter availability. Nasal steroids can also be combined with oral antihistamines when symptoms are most severe. For some patients, targeted therapy with ipratropium or cromolyn may be beneficial. Nasal decongestants offer some short-term relief but should be used very cautiously – and briefly – to avoid “rebound” vasoconstriction. Recent warnings about serious neuropsychiatric adverse effects of leukotriene receptor antagonists have taken montelukast off the recommended list of allergy treatments. If patients have other pulmonary conditions, or fail multiple trials of the standard agents, an immunologist or otolaryngologist consult is warranted.

    References
    • National Wildlife Federation. Extreme Allergies and Global Warming.; 2010. Accessed March 22, 2022. https://www.aafa.org/media/1634/extreme-allergies-global-warming-report-2010.pdf
    • Dykewicz MS, Wallace DV, Baroody F, et al. Treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2017;119(6):489-511.e41. doi:10.1016/j.anai.2017.08.012
    • Dykewicz MS, Wallace DV, Amrol DJ, et al. Rhinitis 2020: A practice parameter update. J Allergy Clin Immunol. 2020;146(4):721-767. doi:10.1016/j.jaci.2020.07.007
    • Milgrom H, Biondi R, Georgitis JW, et al. Comparison of ipratropium bromide 0.03% with beclomethasone dipropionate in the treatment of perennial rhinitis in children. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 1999;83(2):105-111. doi:10.1016/S1081- 1206(10)62620-8
    • Pitsios C, Papadopoulos D, Kompoti E, et al. Efficacy and safety of mometasone furoate vs nedocromil sodium as prophylactic treatment for moderate/severe seasonal allergic rhinitis. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2006;96(5):673-678. doi:10.1016/S1081-1206(10)61064-2
    • Baroody FM, Brown D, Gavanescu L, DeTineo M, Naclerio RM. Oxymetazoline adds to the effectiveness of fluticasone furoate in the treatment of perennial allergic rhinitis. J Allergy Clin Immunol. 2011;127(4):927-934. doi:10.1016/j.jaci.2011.01.037
    • Druss B, Pincus H. Suicidal ideation and suicide attempts in general medical illnesses. Arch Intern Med. 2000;160(10):1522-1526. doi:10.1001/archinte.160.10.1522
    • Federal Drug Administration. FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis. Drug Safety and Availability. Published March 4, 2020. Accessed April 10, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-boxed-warning-about-serious- mental-health-side-effects-asthma-and-allergy-drug


    Section

    Mechanism:

    Initial Therapy:

    Precautions:

    Cost:




    May 2022

    Micro-Learning CE Associated - Click Here For Details

    New Updates to Asthma Treatment

    Key Terms
    DPI: dry powder inhaler
    ICS: inhaled corticosteroid
    LABA: long-acting beta-2 adrenergic agonist
    MART: maintenance and reliever therapy
    MDI: metered-dose inhaler
    OCS: oral corticosteroids
    SABA: short-acting beta-2 adrenergic agonist


    Have you met GINA?
    The Global Initiative for Asthma (GINA) guidelines were established in 1993 and are now considered the gold standard for best practices in treating patients with asthma. The GINA report is updated every year, with cumulative reviews of new evidence twice yearly. The newest update was issued in 2021. It expounds on a significant change in the standard of care for most patients that was first suggested in 2019. The 2021 update also addresses many aspects of asthma treatment relative to COVID-19 risk and management. A free download of the GINA reports is available for personal use at http://ginasthma.org.

    Review of Asthma Step Treatment The standard of care for treating adults and adolescents with asthma follows a stepwise approach, based on symptom severity.
    • Step 1: symptoms less than twice per month
    • Step 2: symptoms twice a month or more
    • Step 3: symptoms most days, or waking at night once or more per week
    • Step 4: daily symptoms, waking at night once or more per week, and low lung function
    • Step 5: persistent exacerbations and worsening symptoms despite aggressive treatment
    In the 2021 GINA report, treatment recommendations for each step were updated to reflect the most recent studies. Of all patients with asthma, almost one-quarter will require high-intensity treatment (high-dose ICS-LABA or medium-dose ICS-LABA plus OCS). Of those, about 17% have multiple treatment failures on high-intensity regimens. And, furthermore, about 4% of patients with difficult-to-treat asthma will be classified as having severe-refractory disease, with poor symptom control despite good inhaler technique and medication adherence.1 These patients fall in Step 5, and should always be managed by a pulmonologist and/or immunologist.

    A Sea-Change in Asthma Treatment
    In 2019, the GINA guidelines changed the recommendation for medication therapy in Step 1 asthma patients.2 Until then, patients who had infrequent symptoms (less than two exacerbations per month) and no risk factors for exacerbations were given a single medication – a SABA (e.g., albuterol or levalbuterol) for as-needed use. At that time, the GINA report recommended treatment with either symptom-driven (as needed) or daily low-dose ICS inhaler regimens. Monotherapy with a SABA had been first-line for fifty years. However, the GINA report clearly stated a SABA-only regimen was no longer recommended for adults and adolescents.

    In making this fundamental change, the report cited safety evidence that SABA-only treatment increased the risk of severe exacerbations, and that adding any ICS significantly reduced that risk. A study in 2007 found of patients with infrequent asthma symptoms (less than weekly), up to 20% of those were at risk of dying during an acute exacerbation.3 More recent studies demonstrated higher uses of SABA inhalers were associated with adverse clinical outcomes like severe exacerbations and death.4, 5

    At that time, GINA did not alter its recommendations for more severe asthma (Step 2 and above). Patients with more frequent asthma symptoms, or who have more risk factors for exacerbations, were to continue the standard combination LABA-ICS inhaler on a scheduled-dose basis, along with a SABA as a “rescue” inhaler.

    The GINA 2021 update built upon the 2019 guidelines.6 This report states the new preferred mild asthma treatment strategy is a low-dose ICS, specifically combined with inhaled formoterol. Formoterol is classified as a LABA, but it has a similar onset of action to SABAs (5-15 minutes).

    GINA 2021 also established two “tracks,” based on evidence gleaned since the 2019 change. Track 1 (the preferred approach) is a low-dose ICS-formoterol combination inhaler, either as-needed or scheduled based on the patient’s disease severity. Track 2 is the use of a single-drug SABA plus a separate ICS inhaler used immediately after SABA. This sequential inhaler use can be as-needed for symptom control for milder-severity asthma patients. Patients with more severe and frequent symptoms should use the ICS on a schedule and the SABA as needed. Track 1 is preferred because using low-dose ICS as a symptom reliever has been shown to reduce the risk of severe exacerbations compared to the use of a SABA as the reliever. The latest GINA report named this type of therapy “maintenance and rescue therapy” (MART).

    For patients requiring high-intensity treatment (Steps 3-5), GINA acknowledged that MART would require modification. A medium dose ICS, oral corticosteroids, or biologic therapy should be considered to reduce the risk of exacerbations.

    Classification of Medication Intensity
    The following tables classify the recommended total daily dose ranges into low, medium, and high-intensity treatment options. These tables do not represent drug-dose equivalence.

    Adults and Adolescents
    ICSDaily ICS Dose in Micrograms
    LowMediumHigh
    Beclomethasone diprop. DPI100-200>200-400>400
    Budesonide MDI or DPI200-400>400-800>800
    Ciclesonide MDI80-160>160-320>320
    Fluticasone fur. DPI100100200
    Fluticasone prop. MDI or DPI100-250>250-500>500
    Mometasone fur. MDI200-400200-400>400
    **Adapted from GINA 2021, Box 3-6A6

    Children Ages 6-11 Years
    ICSDaily ICS Dose in Micrograms
    LowMediumHigh
    Beclomethasone diprop. DPI50-100>100-200>200
    Budesonide MDI or DPI100-200>200-400>400
    Budesonide nebules250-500>500-1000>1000
    Ciclesonide MDI80>80-160>160
    Fluticasone fur. DPI5050n/a
    Fluticasone prop. MDI or DPI40-100>100-200>200
    Mometasone fur. MDI100100200
    *Adapted from GINA 2021, Box 6-66

    GINA Recommendations for Children
    The 2021 GINA update saw similar treatment recommendations for children under age 12. As always, adherence and inhaler technique should be closely assessed in children before increasing asthma medication doses. For young patients in Steps 1-2, the use of an ICS whenever the SABA is used is the standard. Step 3 patients should follow MART using a very low-dose ICS-formoterol combination inhaler. Those in Steps 4-5 should use a medium-dose or high-dose ICS-LABA (or low-dose ICS-formoterol MART) and be referred to a pediatric pulmonologist.6

    COVID-19 Implications on Asthma Treatment
    We now have two years of data on the risk and complications of coronavirus infection on asthma sufferers. First, people with asthma are not at higher risk for acquiring COVID-19, nor are those with well-controlled asthma more likely to die if infected.7 However, studies have shown asthma patients who recently required oral glucocorticoids8 or hospitalization9 to treat an exacerbation were more likely to die after acquiring COVID-19. For these reasons, it is critical to select asthma medications that maximize symptom control to prevent fatal COVID-19 complications. There is one caveat to this recommendation: nebulized medications should be avoided to minimize COVID virus transmission.

    Vaccination Recommendations
    The COVID-19 vaccines available in the U.S. have been successfully tested on patients with asthma. Generally, adverse events related to the various COVID-19 vaccine products are very rare. With current data in this population, GINA recommends COVID-19 vaccination for all patients with asthma who do not have contraindications.6 The vaccines should be given in a healthcare setting where severe reactions can be addressed quickly if they occur. Any patient who has a history of a severe allergy to polyethylene glycol, or any other vaccine ingredient, should not receive a product with these ingredients. The other standard vaccine precautions apply to patients with asthma.

    The CDC’s Advisory Committee on Immunization Practices (ACIP) also recommends patients with asthma receive an annual influenza vaccine, along with appropriately-timed Tdap, pneumococcal, and zoster immunizations.10

    Summary
    • Asthma guidelines for adults, adolescents, and children were updated in 2021 based on safety data that showed adding an ICS for even mild asthma reduced the risk of death, hospitalization, and exacerbations.
    • Low-dose ICS treatment provides the most clinical benefit for most patients with asthma.
    • Two treatment “tracks” were established by GINA in 2021. Track 1 involves the use of a low-dose ICS-formoterol combination inhaler, either as-needed or scheduled. Track 2 is comprised of a single-drug SABA plus a separate ICS inhaler used immediately after the SABA. This new recommendation is called “maintenance and reliever therapy,” or MART.
    • A scheduled ICS-formoterol regimen is preferred for patients with more frequent symptoms, or risk factors for exacerbations. The ICS strength should be titrated to adequate symptom control.
    • Regimens that offer optimal symptom control are crucial to reducing the complications of and hospitalizations for COVID-19.
    • Asthma patients should receive COVID-19, influenza, Tdap, and pneumococcal vaccinations on schedule unless they have contraindications to these products
    References
    1. Hekking PPW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135(4):896-902. doi:10.1016/j.jaci.2014.08.042
    2. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2019. Published online 2019. http://www.ginasthma.org
    3. Dusser D, Montani D, Chanez P, et. al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Eur J Allergy Clin Immunol. 2007;62(6):591-604.
    4. Nwaru B, Ekström M, Hasvold P, et. al. Overuse of short-acting β2-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme. Eur Respir J. 2020;55(5):1901872. doi:10.1183/13993003.01872-2019
    5. Stanford RH, Shah MB, D’Souza AO, Dhamane AD, Schatz M. Short-acting β-agonist use and its ability to predict future asthma-related outcomes. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2012;109(6):403-407. doi:10.1016/j.anai.2012.08.014
    6. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2021. Published online 2021. http://www.ginasthma.org
    7. Wu T, Yu P, Li Y, et al. Asthma does not influence the severity of COVID-19: a meta-analysis. J Asthma. Published online April 23, 2021:1-7. doi:10.1080/02770903.2021.1917603
    8. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430-436. doi:10.1038/s41586-020-2521-4
    9. Bloom CI, Drake TM, Docherty AB, et al. Risk of adverse outcomes in patients with underlying respiratory conditions admitted to hospital with COVID-19: a national, multicentre prospective cohort study using the ISARIC WHO Clinical Characterisation Protocol UK. Lancet Respir Med. 2021;9(7):699-711. doi:10.1016/S2213-2600(21)00013-8
    10. Centers for Disease Control and Prevention. Lung Disease Including Asthma and Adult Vaccination. Accessed March 21, 2022. https://www.cdc.gov/vaccines/adults/rec-vac/health-conditions/lung-disease.html

    Micro-Learning CE Associated - Click Here For Details

    Overview of Lithium: What to know when you didn’t remember what you needed to know!

    The use of lithium in psychiatry goes back to the mid 1800s, however more scientific rigor in examining its role in mania began in the mid 20th century.1 Fast forward ahead to today where lithium is FDA approved for the treatment of bipolar disorder (i.e., Bipolar I Disorder), including acute mania and maintenance therapy.

    Although the FDA has approved lithium for this condition, different guidelines recommend the use of lithium in different ways. Therefore, pharmacists should not expect a rigid “cookie cutter approach” to its use. For example CANMAT (Canadian Network for Mood and Anxiety Treatments) and BAP (British Association for Psychopharmacology) recommend lithium as a 1st line intervention for acute mania and mixed episodes whereas NICE (National Institute for Health and Care Excellence) and WFSBP (World Federation of Societies of Biological Psychiatry) suggest the use of other agents such as second generation antipsychotics (SGA) with what might be perceived as less adverse effects when compared to lithium, first.

    Our case for consideration
    TS is a 32-year-old patient who returns monthly to your community pharmacy for refills on lithium along with a few other medications. According to his most recent lab report, his lithium levels are appropriate and no other monitoring parameter are out of range. Here is TS’s complete medication list:
    • Lithium 600mg twice daily for bipolar disorder x 10 years
    • Metformin 1000mg twice daily for T2DM x 2 years
    • Lisinopril 20mg daily for hypertension x 5 years
    • Melatonin 3mg daily at bedtime for sleep
    • Multivitamin daily for nutritional supplementation
    TS expresses concern over a recent emergence of acne that has caused distress and embarrassment.

    What is Bipolar Disorder (BP)? Although there is a specific criteria list of symptoms and duration of illness for formal diagnosis, typical symptoms include a rotation and range of extreme moods including elevated (mania) and depression. Both the duration and severity of the mood episodes are different based on the type of BP the individual is diagnosed with, however the presence of mania and whether or not hospitalization is required generally leads clinician’s towards making the more severe BP I diagnosis. Typical symptoms of mania include hyperactivity, decreased need for sleep, poor judgement, flight of ideas, grandiosity (exuding unrealistic pompous superiority) and possible aggression. Sometimes individuals can experience a “mixed state” and have both depression and mania occurring at the same time.

    Clinical pearls for safe and effective Lithium use

    Dosing is just one part of the program! Lithium is generally dosed to a target serum concentration range somewhere between 0.6mEQ/L to 1.2mEQ/L. In some severe cases, targets can be as high as 1.5mEq/L but anything over this threshold is considered potentially toxic and should be avoided. Because there is a very narrow range between therapeutic and toxic, lithium is a narrow therapeutic range medication and is often considered a “high alert” medication in medication safety organizations and communities. Also, it should be noted that some prescribers may opt for lower dosing thresholds purposefully. Routine ongoing therapeutic drug concentration monitoring, in addition to other regular tests to prevent adverse outcomes, is a necessary part of lithium therapy.

    A good starting dose for most healthy adults is 300 mg by mouth 3 times per day with serum lithium concentrations measured after 3 days with labs drawn 12 hours after the last oral dose and regularly until the patient is stabilized which takes about 5 days after given a steady scheduled dose. Dose changes are best if implemented by 300 mg doses every 3 days until the desired outcome is achieved. There has also been a liquid formulation available with 8mEq lithium citrate = 300mg lithium carbonate, however the recent supply chain disruption has been associated with raw ingredient shortage and lack of availability and uncertain future access of the lithium liquid.

    Basic pharmacokinetics:
    • No hepatic metabolism and no CYP450 drug interactions
    • Renal excretion; avoid using in patients with pre-existing renal compromise as evidenced with CrCl less than 30ml/min but cautious dosing is permitted for patients with CrCl above 30mL/min
    • Susceptible to drug interactions that result from impact on kidney function
    • Linear and predictable. Double the oral dose and expect that serum concentration to double too. Pregnant women may require higher doses during pregnancy but dose decreases prior to delivery to accommodate for normalization of volume of distribution that occurs late in 3rd term.
    Drug interactions
    Let’s review an illustrative summary to refresh your memory. Refer to the package label for a complete list of drug interactions! There are times when drug interactions may be present, but when combined use is medically necessary, can be managed with appropriate monitoring and vigilance.

    Blood pressure:
    • Ace inhibitors/ARBs: decreased sodium reabsorption, sodium loss and reduced GFR leading to a compensatory reabsorption of lithium and increased lithium concentrations
    • Diuretics: thiazide diuretics are the main problem-can result in 50% increase in lithium concentration and thus should be avoided; loop diuretics when used judiciously, generally result in less clinically significant consequences if over-diuresis can be avoided. Other diuretics should be considered on a case-by case basis.
    • Non-dihydropyridine Calcium channel blockers (such as diltiazem, and verapamil): increased risk of neurotoxicity when combined with lithium
    NSAIDS: thought to be result of inhibited prostaglandin synthesis, decreased renal blood flow and increased lithium concentrations

    Other: although rare, reported increased risk of neuroleptic malignant syndrome when combined with antipsychotics. Reports of serotonin syndrome are even more rare.

    What about the adverse effects we should expect with lithium treatment?
    Let’s review an illustrative summary to refresh your memory but always remember to refer to the package label for a complete list of adverse effects reported and recommendations to mitigate these risks!

    Genitourinary-can occur in up to 33% of patients but mitigated with once daily dosing and targeting the lowest effective serum concentration.
    • Polyuria
    • Acute more common versus chronic kidney disease
    Endocrine/metabolic- monitor thyroid panels-exogenous thyroid supplementation generally preferred over lithium discontinuation when clinically appropriate. Monitor bone density based on prescribers’ clinical judgement and patient specific clinical risks
    • Hypothyroidism
    • Hyperparathyroidism
    • Weight gain
    Cardiovascular
    • QT prolongation, ECG changes and arrhythmias-avoid in patients with underlying cardiac conditions (avoid entirely in patients with 3rd degree block and if family history of sudden death in young adults).
    Gastrointestinal- tends to be transient early in treatment; emergence of later episodes could be suggestive of lithium toxicity (evaluation needed)
    • Nausea
    • Thirst/dry mouth
    Neurologic
    • Muscle weakness and lethargy, tremor
    Hematologic
    • Leukocytosis reported (generally benign)
    Dermatologic
    Acne, psoriasis and alopecia-both newly emergent or exacerbated preexisting condition (may resolve with lower doses; addressing the dermatologic side effect is the preferred mitigation versus discontinuing lithium whenever clinically appropriate and possible). These seemingly “cosmetic” problems can be personally distressing and may result in non-adherence therefore addressing these adverse effects with appropriate concern and subsequent pharmacologic recommendations is essential.

    Patients are best positioned to “see something and to say something” when it comes to adverse effects. Please give lithium a fair shake and keep my tip sheet for future use when you encounter new prescriptions and opportunities to educate prescribers and patients on safe, effective and appropriate use of this oldie but goodie medication!

    So what about TS?
    1. What pharmacologic intervention should be recommended when a patient reports a new emergence or worsening of a dermatologic condition such as acne?
      1. Acne usually occurs due to a drug interaction with lithium so discontinue other drugs that can interact with lithium
      2. Acne is usually a sign of a bigger problem and lithium should be discontinued immediately
      3. Acne can be personally distressing and should not be ignored; initiate a topical acne product as a first line intervention
      4. Acne is not a big deal; explain that the patient should be more worried about the mental health condition and just continue lithium
    2. You are concerned that TS is on an ACE inhibitor for blood pressure along with lithium since this can represent a significant drug interaction. Looking in TS’s history, he has had intolerable adverse reactions to almost all other blood pressure medications and his lisinopril is resulting in improved blood pressure control without complaints of side effects. What action do you take when advising pharmacotherapeutic recommendations?
      1. TS should not be on lisinopril; it is contraindicated with lithium therapy
      2. TS can remain on lisinopril provided TS’s renal function remains acceptable and lithium levels are appropriate
      3. TS can only remain on lisinopril at half dose to prevent complications resulting from hepatic metabolism
      4. TS should not be on lithium if he needs lisinopril


    I have had the privilege of developing and presenting programs that have covered a wide range of mental health topics. And, while I love this part of the CE experience, it is really the Q & A with you that I treasure the most. After each Q & A session I reflect back on the questions asked and felt compelled to circle back to these and use them in future updates._Viola! Perfect for the new launch of the micro CE mini-blog based on Tammie Lee Demler’s BEST in the classroom series..

    During my psychiatric updates, I am often asked how lithium fits in. I have become an increasing fan of lithium and I observe that many prescribers are hesitant to use this very effective medication because of fear of side effects. Here I share some basics and clinical pearls to refresh you in your advocacy for the safe use of lithium!

    Have a Great Day on the Bench!!

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    Overview of Drugs Requiring Renal Monitoring

    Drugs contraindicated in renal failure: Mnemonic

    Students often find the following amusing and memorable mnemonic helpful in recalling the major drugs that fall into this category:
    • Many (Metformin)
    • People (Potassium sparing diuretics)
    • Like (Lithium)
    • Napping (Nitrofurantoin)
    • Naked (N-SAIDS)
    In no particular order, then, let’s tackle some of the ‘big ones’:

    NSAID/COX-2 Inhibitors

    No difference in the safety profile of these two classes for drugs in renal insufficiency. Both can lead to edema, hypertension, acute and chronic renal failure.

    Acetaminophen is by far the safest analgesic in patients in renal failure. Use colchicine, renal adjusted dose joint injection or brief course of corticosteroids for episodic gout in renal failure.

    Lithium

    Withdrawal of lithium therapy can be associated with disastrous consequences and should only be done under the supervision of a physician experienced in the management of bipolar affective disorder. Because lithium is almost entirely renally excreted, monitor BUN, creatinine and TSH before and while a patient is on therapy. Use caution if the patient is sodium depleted or taking diuretic therapy. Maintenance lithium level is 0.6-1mEq/liter to minimize side effects.
    • Draw blood levels 12 hours after last dose.
    • Check blood levels: 5-7 days after initiation & any change in dosage.
    • Maintenance: every 1-2 months. In stable patients, every 6-12 months.
    • Monitor more frequently if volume depletion, or diuretic use, diarrhea or vomiting.
    • Check thyroid and renal function before starting lithium and every 6-12 months.
    • Hypothyroidism can occur and contribute to bipolar exacerbations
    IV contrast dye

    At least 5 percent of patients who undergo cardiac catheterization experience a transient rise in the plasma creatinine concentration of more than 1.0 mg/dL due to contrast-induced renal dysfunction. This risk is greater in patients who have diabetes. The plasma creatinine concentration usually returns to baseline within seven days, and less than 1 percent of patients, usually patients who have diabetes with underlying severe chronic kidney disease, go on to require chronic hemodialysis.

    High molecular weight/ ionic contrast dye can cause severe vasospasm in the afferent arteriole and acute renal failure. Risk factors include: diabetes, myeloma, chronic renal failure, dehydration, diuretic therapy and CHF. Less common with newer lower molecular weight/ nonionic contrast dyes. Best to avoid all together by utilizing MRI, ultrasound, CT scans.

    Acetylcysteine (Mucomyst®) can also be given orally to prevent nephrotoxicity caused by radio contrast dye. Usually administered orally the day before and the day of the procedure.

    Statin have also been shown to be protective of kidneys during cath procedures. At some institutions, it is now standard of care to put acute coronary syndrome (ACS) patients who are a candidate for percutaneous coronary intervention (PCI) on statins to prevent contrasted-induced acute kidney injury. High-dose rosuvastatin given on admission to statin-naïve patients with ACS who are scheduled for an early invasive procedure can prevent CI-AKI (contrast induced acute kidney injury) and improve short-term clinical outcome. (Statin Contrast Induced Nephropathy Prevention [PRATO-ACS]. Rosuvastatin (Crestor®) was given to statin naïve patients at a dose of 40mg for the first dose, then 20mg daily. https://www.jacc.org/doi/abs/10.1016/j.jacc.2013.04.105

    Antibiotics that do NOT require Dosage adjustment in Renal impaired:
    • Azithromycin (Zithromax®)
    • Cephtriaxone (Rocephin®)
    • Ciprofloxacin XL (Cipro-XL)
    • Clindamycin (Cleocin®)
    • Doxycycline Vibramycin®)
    • Linezolid (Zyvox®)
    • Minocycline (Minocin®)
    • Moxifloxin (Avelox®)
    For an excellent reference, consult the latest edition of the Sanford Guide. It features 23 pages of renally adjusted antibiotic/antiviral medications.

    Factor Xa inhibitors
    Pay attention to CrCl when dosing these anticoagulants. Even though they don’t require INR monitoring, renal function needs to be checked before prescribing.

    Rivaroxaban (Xarelto®): Nonvalvular Atrial Fibrillation (NVAF):
    • For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal
    • For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily with the evening meal
    Apixaban (Eliquis®)
    • Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation:
      • The recommended dose is 5 mg orally twice daily.
      • In patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily.
    Edoxaban (Savaysa®)
    Treatment of NVAF: Assess CrCL before initiating therapy. The recommended dose is 60 mg once daily in patients with CrCL >50 to ≤ 95 mL/min.
    • Do not use edoxaban in patients with CrCL > 95 mL/min (sorry, your kidneys are “too” good for this drug!)
    • Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min
    Metformin (Glucophage®)
    • Metformin medications should be stopped at the time of or prior to CT studies with IV Contrast and withheld for 48 hours after the procedure.
    • Most experts prefer using creatinine clearance because it's adjusted for the patient's age, weight, and gender. (Cockcroft-Gault equation). When using creatinine clearance, avoid in patients with clearance less than 30 mL/minute.
    Allopurinol (Zyloprim®):
    Requires renal dosage adjustments: Titrate to dosage to lower uric acid to 6mg/dL. Decrease dose if renal impaired for maintenance.
    • If Creatinine clearance: 20mL/min= 200mg daily.
    • If Creatinine clearance: 10mL/min = 100mg daily
    STATINS: All statins require renal dosing adjustments except for Atorvastatin (Lipitor®)

    BETA-BLOCKERS:
    • The lipophilic beta blockers labetalol (Normodyne®), metoprolol (Toprol-XL®, Lopressor®) and Carvedilol (Coreg®) are the best options.
    • Most references recommend Carvedilol as the best choice due to its renal protective effect. Carvedilol with its alpha blocking ability blocks the unopposed alpha vasoconstriction.
    BISPHOSPHONATES: Should be avoided in CKD. AVOID: Renal insufficiency—do not use if CrCl is less than 35ml/minute


    When we look at the laundry list of medications in this piece, these drugs are most frequently used in patients at risk for renal impairment. Patients with metabolic syndrome, Type-2 diabetes, heart failure and hypertension are most likely to take these medications.

    Lithium is not a favorite among most family practitioners for bipolar disorder. Most family practice clinicians leave monitoring of this drug to the psychiatrists. At the clinic I helped staff two days a week we had a 20-year-old patient come in with his caregiver.

    It was in the summer and as I do with all of my lithium patients, reminded them of the need for adequate hydration. His caregiver alerted me that the kid was drinking a 2-liter bottle of water about every half hour. My ears perked up. When I see any lithium patient, I think thyroid and kidneys. I alerted our very astute PA, and the patient was diagnosed with lithium induced nephrogenic diabetes insipidus.

    This condition is rather common, occurring between 20-40% of all lithium patients. Especially during summer months, it is important for all pharmacists to caution lithium patients. While you are at it, remind your topiramate and zonisamide patients to drink up as well!

    Have a Great Day on the Bench!!

    April 2022

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    Overview of ACEs and ARBs

    The TRIPLE WHAMMY! ACE/ARB + DIURETIC + NSAID = TROUBLE

    ACE inhibitors are not nephrotoxic per se, or at least not in the manner that cyclosporine or aminoglycosides are. By inhibition of ACE (angiotensin converting enzyme) they alter the hemodynamics within the glomerulus. ACEI prevents the conversion of Angiotensin-I to Angiotensin II thus releasing the vasoconstriction of the efferent glomerular arterioles, with a subsequent decrease in the glomerular hydrostatic pressure. With less glomerular hydrostatic pressure, there is less glomerular filtration.

    How ACEI has beneficial renal effects: they decrease proteinuria possibly by selectively decreasing the permeability of the glomerular membrane to protein by stabilization of basement membrane of glomerulus. There is a risk of renal impairment in patients taking an ACE inhibitor (or ARB), diuretic, and NSAID. Combining any two of these drugs can lead to acute renal failure (Acute Kidney Injury) in susceptible patients. Combining all three is a "triple whammy."

    Mechanism: In the normal kidney, glomerular filtration is related to glomerular blood flow. In school we learned that the glomerulus is like a coffee filter. However, I would propose that the glomerulus is more like an espresso machine. An espresso machine is dependent on PRESSURE. If we INCREASE the flow into the vessel, and INHIBIT the outflow, pressure builds and filtration occurs.

    Endogenous prostaglandins are responsible for vasodilatation of the afferent arterioles, which allows increased blood flow to the glomerulus. When these prostaglandins are blocked, perfusion is reduced and filtration is inhibited.

    Angiotensin II is responsible for the vasoconstriction in the efferent arterioles, which is necessary to drive up pressure. We think of Angiotensin-II as a “bad guy” since it is responsible for elevating blood pressure. HOWEVER, this vasoconstriction in the efferent arterioles facilitates filtration, by essentially blocking the outflow.
    • NSAIDS: block prostaglandin mediated afferent arteriolar VASODILATION. (Allows blood to perfuse into the glomerulus)
    • ACE/ARB: blocks Angiotensin-2 mediated efferent arteriolar VASOCONSTRICTION (increases pressure for filtration)
    • DIURETICS: decrease plasma volume

    WHO’s AT RISK?
    Is a problem in patients who already have impaired renal function or at risk due to:
    • older age
    • heart failure
    • dehydration
    It is best to avoid chronic NSAIDs or aspirin for pain, including COX-2 inhibitors like celecoxib (Celebrex®).

    DON'T stop low-dose aspirin (doses of 325 mg/day or less aren't likely to cause renal problems)

    What to do:
    Monitor susceptible patients for worsening renal function:
    • increased blood pressure
    • elevated potassium (hyperkalemia)
    • edema
      • Don't reduce the dose or stop an ACE /ARB unless serum creatinine increases more than 30% within 2 months of starting the drug.
      • Stop (or reduce) ACE/ARB if serum potassium exceeds 5.5 mEq/L.
    ACE’s /ARB ‘s for diabetes
    Treatment with ACE inhibitors (or Angiotensin Receptor Blockers) results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes mellitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients.
    Source: https://pubmed.ncbi.nlm.nih.gov/9036682/#:~:text=Treatment%20with%20ACE%20inhibitors%20results,to%20reduction%20of%20protein%20excretion

    Between 33% and 50% of patients with renal artery stenosis will usually have a mild decline in GFR, occurring within a few days after the administration of an ACE/ARB. A large decline in kidney function occurs in less than 5 to 10 percent of cases. The ACE inhibitor-induced reduction in GFR in renovascular disease almost always resolves after cessation of therapy. For renal protection in diabetics, it is always best to “start low and go slow.” If a patient has an elevated serum creatinine of more than 30% within one week of initiation of ACE/ARB therapy, bilateral renovascular disease should be strongly suspected.

    One of the toughest questions I answer from students is this: “Why do we give a drug like an ACE inhibitor or ARB to diabetics for renal protection when, in fact, they can be nephrotoxic?” My students love the analogy of the espresso machine, which is dependent on PRESSURE. If we INCREASE the flow into the vessel, and INHIBIT the outflow, pressure builds, and filtration occurs.

    Except for one student. One of my students was a family practice physician who just came to the United States. All throughout this segment he would shake his head. At the end of class he said, I understand everything you said, I just don’t believe it!

    Some find it hard to believe, since ACE inhibitors are revered for their effects on the kidneys and STAR ratings for Medicare. STAR ratings are based on patients with diabetes taking “RAS” drugs, including ACE inhibitors or ARBs. Physicians and pharmacists get “dinged” if their patients are not taking an ACEi or an ARB… regardless of the reason.

    That is unfortunate too, because we always need to be looking at the entire patient. Medicare plans look at numbers, while we look at patients!!!

    Have a Great Day on the Bench!!

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    Overview of Nephrotoxicity

    NEPHROTOXICITY

    Acute kidney injury (formerly known as acute renal failure) occurs in the hospital setting at a rate of 22% worldwide. Half of all the acute kidney injury cases occur in critically ill patients.
    https://pubmed.ncbi.nlm.nih.gov/30388976/

    Drugs Causing Tubular Epithelial Cell Damage:
    • Aminoglycoside antibiotics
    • Radiographic contrast media
    • Cisplatin & Carboplatin
    • Amphotericin-B: both tubular injury and renal vasoconstriction contribute to this drug’s nephrotoxicity
    • Tacrolimus and cyclosporine
    Hemodynamically mediated Renal Failure:
    • ACE inhibitors & ARBS
    • NSAIDS
    Obstructive Nephropathy: Drugs can cause renal stone formation either by raising excretion rates of naturally occurring stone components or by directly precipitating within the urinary tract. Seen in patients with volume depletion and renal insufficiency.
    • Acyclovir
    • Sulfadiazine
    • Indinavir & Foscarnet
    • Tricyclic Antidepressants
    • Triamterene (Potassium sparing diuretic)
    • Ciprofloxacin
    Glomerular disease:
    • NSAIDS
    • Hydralazine
    • Avoid potassium sparing diuretics if CrCl is less than 30
    Tubulointerstitial disease:
    • Methicillin
    • NSAIDS
    • Cyclosporine
    • Lithium
    • Methotrexate
    Pseudo-renal failure:
    • Corticosteroids
    • Trimethoprim
    • Cimetidine


    Selected antimicrobial agents causing nephrotoxicity:

    Aminoglycosides - examples:
    • neomycin –most nephrotoxic
    • Tobramycin and Gentamycin are about the same nephrotoxicity
    • Streptomycin is the least nephrotoxic.
    • Tetracyclines are nephrotoxic—(Doxycycline is safe, as it is fecally excreted)
    Mechanism: they accumulate in the proximal tubule, causing acute tubular necrosis.

    Cephalosporins: Keflex ® (cephalexin) may be nephrotoxic, use with caution in patients with CrCl less than 50mL/min.


    Selected antineoplastic agents causing nephrotoxicity:

    Cisplatin & Carboplatin: Proximal tubular damage occurs acutely after administration as a result of impairment of cell energy and production, possibly by binding to proximal tubular cellular proteins and sulfhydryl groups. Nephrotoxicity was 50-100% in the 1980’s but has been decreased to 6-13% by limiting total drug dose, and reducing the rate of administration. Contributes to acute renal failure if used with other nephrotoxins.

    Selected immunosuppressant drugs causing nephrotoxicity

    Cyclosporine (Neoral®) and Tacrolimus (Prograf®): Toxicity is usually dose dependent. It causes distal tubular dysfunction from severe vasoconstriction. Causes reversible vasoconstriction and injury to glomerular afferent arterioles, possibly because of increased activity of vasoconstrictors. Regular blood monitoring is necessary to prevent nephrotoxicity. Kidney biopsy is necessary in transplant patients to distinguish rejection from toxicity. Calcium channel blockers are useful, blocking the vasoconstrictive effects of cyclosporine.

    Tacrolimus and cyclosporine: calcineurin inhibitors with a high risk of developing kidney injury either as acute kidney injury, which is largely reversible after reducing the dose, or as chronic progressive kidney disease, which is usually irreversible.

    Managed with dose reduction and/or discontinuing interacting drugs.

    Renal failure is insidious, and frequently slips by prescribers. Many drugs that are in our fast-moving section require a lot of respect. Drugs like ibuprofen, lisinopril, hydrochlorothiazide, metformin, cephalexin, and allopurinol are purchased in bottles of 500 or 1000, and we dispense them frequently. All of them can cause problems with kidney function.

    A “triple whammy” is sometimes observed, featuring ACE’s/ ARBS when given with a diuretic and an NSAID. Numerous drugs we frequently dispense require renal dosing from antibiotics to gabapentin and the Factor Xa inhibitors for anticoagulation.

    These fast movers deserve our respect.

    Have a Great Day on the Bench!!

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    Overview of Beta-3 Receptor Agonists for Overactive Bladder & Agents for Female Sexual Function Disorder

    Mechanism of Action: By stimulating beta-3 receptors, these drugs relax the detrusor muscle during the storage phase of the urinary bladder fill-void cycle thereby increasing bladder capacity.

    Mirabegron (Myrbetriq®) $420/month (FDA approved:2013)
    • Available as extended-release tablets: 25mg or 50mg
    • Available as extended release suspension 8mg/mL 100mL bottles (28 day expiration)
    Advantages: does NOT cause anticholinergic side effects. Less likely to cause prolongation of QT on EKG. Disadvantages:
    • Moderate blocker of CYP2D6 pathway (increases metoprolol and digoxin levels)
    • May cause increases in blood pressure (8-10% incidence).
    • Allow 8 weeks to see full benefit.
    • Don’t exceed 25mg/day if patient has renal impairment
    Vibegron (Gemtesa®) $480/month April-2021
    • Available as 75mg tablets
    Advantages:
    • Being a Beta-3 agonist, it does not cause anticholinergic side effects.
    • Less increases in blood pressure than seen with mirabegron
    • Does not block CYP-2D6
    • Less discontinuation- significantly less side effects
    Female Sexual Dysfunction:

    Women have very limited treatment options in the realm of sexual dysfunction, with the available options (flibanserin (Addyi®) and bremelanotide (Vyleesi®) being grossly cost prohibitive. A year’s worth of flibanserin would be $6,600 for six sexual encounters per year, while the same $6,600 would buy approximately a months’ worth of bremelanotide.

    The Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition (DSM-V) defines Female Sexual Disorders (FSD) as disturbances in the female sexual response cycle, resulting in marked distress and interpersonal difficulties. In particular, female sexual arousal disorder (FSAD) belongs to the subcategory “female sexual interest/arousal disorder” and is one of the most prevalent subcategories of FSDs.

    - Includes lack of sexual desire, impaired arousal, inability to achieve orgasm, anxiety about sexual performance, not finding sex pleasurable or pain with sexual activity - Approximately 40% of women in the U.S. have sexual concerns - Sexual response cycle: Desire (libido) → Arousal (excitement) → Orgasm → Resolution

    Risk Factors: depression, anxiety, psychotic disorders, benzodiazepines, SSRIs

    Treatment: treat underlying cause, lifestyle modifications (weight loss, diet, sleep), lubrication, therapy

    Female Hypoactive Sexual Desire Disorder (HSDD):
    • Estrogen - (alone or in combination with progestin) for peri/postmenopausal atrophic vaginitis
      • May improve vaginal environment - less dryness, improved mucosa, reduced pH
    • Testosterone - NOT FDA approved, often prescribed off label w/ or w/o estrogen
      • May be effective for short-term treatment but limited evidence for treatment >6 months
      • Increases # sexually satisfying events by around 1.2 events/month
      • Formulations: tablet, transdermal spray, patch
      • Contraindications: presence/high risk of breast/endometrial cancer, VTE, CV disease
      • Adverse events: hirsutism/virilization, acne, CV complications, breast cancer
    • Bupropion - norepinephrine-dopamine reuptake inhibitor
      • May increase sexual arousal and orgasm (may or may not improve desire) in HSDD
    Flibanserin (Addyi®)- serotonin receptor 1A agonist/serotonin receptor 2A antagonist, 2015
    • Cost for 30 tablets is ~$550.00
    • 100 mg tablet, once daily at bedtime (NOT PRN) in premenopausal women
    • Increases number of sexually satisfying events by approximately 0.5 events/month
    • Can cause dizziness, somnolence, nausea, fatigue, insomnia, dry mouth
    • Interacts with CYP3A4 inhibitors, alcohol CONTRAINDICATED with use (can cause severe hypotension/syncope), must enroll in REMS program to prescribe
    • Not for those with HSDD due to medical/psych conditions, medications or other drug substance, or relationship problems
    Female Orgasmic Disorder: mainstay of treatment is psychotherapy

    Sexual Pain Disorder: conduct pelvic exam, consider hormonal treatments (estrogen, ospemifene)

    Bremelanotide (Vyleesi®) (approved June 21,2019)

    Cost: ~$6,667.00 per month (9 autoinjectors)

    Mechanism: Activates melanocortin receptors, but the mechanism by which it improves sexual desire and related distress is unknown.
    • The First FDA-Approved As-Needed Treatment for premenopausal women experiencing distress or interpersonal difficulty due to low sexual desire
    • 1 in 10 Premenopausal Women in the U.S. (Approximately 6 Million Women) suffer From HSDD
    EFFICACY: There was no difference between treatment groups in the change from the start of the study to end of the study in the number of satisfying sexual events. Bremelanotide does not enhance sexual performance. (source: FDA)
    • 25% of patients treated with bremelanotide had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire) compared to about 17% of those who took placebo
    DOSING: Inject SQ at least 45 minutes prior to sex
    • Only one dose per 24 hours
    • Maximum of 8 doses per month
    • Only for use in pre-menopausal women
    • Available as an auto-injector 1.75mg dose (per 0.3mL)
    • STOP: treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.
    SIDE EFFECTS:
    • nausea (40%) and vomiting, (13% needed meds to control nausea and vomiting)
    • flushing
    • injection site reactions
    • headache
    • hypertension- usually resolves in 12 hours, not recommended for uncontrolled hypertension or cardiac patients
    MAJOR DRUG INTERACTION: Naltrexone (Revia®) if taken by mouth, bremelanotide may significantly decrease the levels of naltrexone in the blood. Patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use bremelanotide because it could lead to naltrexone treatment failure.

    CHECK THE MED LIST!
    Watch for female sexual dysfunction caused by meds - review medication list for SSRIs/benzodiazepines
    • Highest risk antidepressants (>30%): fluoxetine, fluvoxamine, paroxetine, sertraline
    • Medium risk (10-30%): citalopram, duloxetine, escitalopram, venlafaxine
    • Lowest risk: bupropion, mirtazapine, desvenlafaxine, vilazodone, vortioxetine
    NOTE: In one study, the incidence of individuals who spontaneously reported sexual side effects was 14% compared with 58% of individuals who reported sexual side effects when asked directly by their physicians. It is fair to say, it is an issue worth bringing up. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007725/

    Management strategies for SSRI-induced sexual dysfunction:
    1. Consider decreasing dose of offending medication.
    2. Switching to another SSRI or antidepressant, augmenting therapy with bupropion.
    Remember to taper, cross-taper, or leave wash-out periods when switching between SSRIs/antidepressants as appropriate!

    The distinct side effect profiles of anticholinergics and beta-3 receptor agonists, is a “no-brainer.” All of the peripheral side effects of the anticholinergics, along with the increase chance for dementia, make them no competition for the beta-3 agonists. Beta-3 agonists are as efficacious, albeit more expensive.

    Beta-3 receptor agonists appear to be at least effective as the anticholinergic medications, without the side effects of dry mouth, constipation, cardiac issues and possibly dementia. Reduced discontinuance rates may favor these products, however due to their expense, might require prior authorizations from insurance companies.

    Have a Great Day on the Bench!!

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    Overview of Anticholinergics for the Pharmacological Management of Overactive Bladder

    Mechanism: Drugs with anticholinergic activity are often the first drug used for Urge Urinary Incontinence (UUI). Drugs with anticholinergic activity act by antagonizing muscarinic cholinergic receptors, through which efferent parasympathetic nerve impulses evoke detrusor contraction. The detrusor muscle is responsible for urine flow. The net effect of cholinergic blockade is increased bladder capacity and decreased urgency. In addition, women with mixed Urinary Incontinence (UI) or UUI plus urethritis or vaginitis may benefit from topical or systemic estrogen (alone or in combination with an anticholinergic.)

    General Distribution of Muscarinic Receptor Subtypes

    M1Brain (cortex, hippocampus), glands, sympathetic ganglia
    M2Heart, smooth muscle (including detrusor), hindbrain
    M3Smooth muscle (detrusor), salivary and excretory glands
    M4Brain (cerebral cortex, striatum), lung
    M5Brain (substantia nigra) eye
    COMPARISON of ANTICHOLINERGICS

    Brand NameGenericM3 selectivityDosage
    Ditropan 5mgOxybutynin+(5mg) 2 to 4 times daily
    Ditropan XL 5mg, 10mg , 15mg tabsOxybutynin+(5 to 30mg) once daily
    Detrol 1mg,2mgTolterodine+(1mg –2mg) BID
    Detrol LA 2mg, 4mgTolterodine+(2mg-4mg) once daily
    Sanctura 20mgTrospiumleast(20-40mg) BID
    Sanctura XR 60mg capsTrospiumleast60mg once daily in am
    Enabelex 7.5 & 15mgDarifenicin+++(30mg) daily
    Vesicare 5mg & 10mgSolifenacin++(5mg-10mg) once daily
    Toviaz® 4mg & 8mgFesoterodine++4-8mg daily (use 4mg if on CYP450 blocker)


    Differences in the available products:

    Sanctura ® (trospium), although is the least M3 selective is most commonly used in Europe. It is a quaternary amine/anticholinergic. Not as lipid soluble and minimal blood brain barrier penetration, and less sedation. Improves OAB symptoms in 3 days. Negligible amount metabolized by P450, therefore minimal drug interactions. Give on empty stomach.

    Detrol (oxybutnin) and Detrol LA (oxybutynin ER) are the most commonly used anticholinergics at this time.

    Toviaz ® (fesoterodine) is a prodrug, with the same active metabolite as tolterodine (Detrol). Cost is over $400/month. Topical anticholinergic for bladder control. Avoids first metabolism and less anticholinergic side effects.

    Oxytrol® Oxybutynin patch (3.9 mg/24 hr patch) dose 3.9mg twice a WEEK Available Rx cost approximately $740.00 per box of 8 patches. Over the Counter (retail $29.99) per box of 8 patches.

    Gelnique® available in one gram foil packets. Apply 1 gel-packet once daily. Cost is around $450.00/month

    Oral oxybutynin is available as a generic, and is dosed 3 times daily. This is often the first choice of the insurance companies due to costs. Sanctura® (trospium) is also generically available. Many insurance companies require a patient to “try and fail” on generic oxybutynin before approving the more expensive ($120-$430/month) brand name products.

    Anticholinergics: Even a single anticholinergic medication can increase the risk of cognitive impairment by up to 50%...even more in patients who've had a stroke or have a family history of dementia. Anticholinergics are also linked to higher hospitalization rates. Anticholinergics are sometimes added for incontinence that's caused or exacerbated by a cholinesterase inhibitor, used for Alzheimer’s. These cholinesterase inhibitors increase cholinergic activity and may lead to OAB symptoms.

    The more potent the anticholinergic, the more likely it will cause memory loss. The potent anticholinergics were most often associated with poorer memory and executive function, brain hypometabolism, brain atrophy, and increased risk of clinical conversion to cognitive impairment. Source: JAMA Neurol. 2016;73(6):721-732. doi:10.1001/jamaneurol.2016.0580


    Other anticholinergics: Drugs with significant anticholinergic adverse effects decrease urinary bladder detrusor muscle contractility, resulting in urinary retention (examples: antihistamines, tricyclic antidepressants, phenothiazines).

    Drugs like Detrol® (tolterodine) poses little risk of urinary retention, IF there is good flow. Antimuscarinics work during storage, rather than voiding.

    This category of drugs is frustrating as a community pharmacist. Third party payers sometimes demand that patients try and fail anticholinergics, potentially causing a whole boatload of problems. We give drugs for Alzheimer’s that increase cholinergic activity (donepezil) and others. Then, a prescriber must prescribe an ANTI-cholinergic if the patient has overactive bladder. These payers sometimes insist that prescribers give cholinergics and ANTI-cholinergics to the same patient!

    I was also amazed to see that our warehouse (McKesson) still has oxybutynin (Oxytrol®) over the counter. The cost difference is nearly $700!

    Have a Great Day on the Bench!!

    March 2022

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    OVERACTIVE BLADDER- THE BASICS

    Overactive Bladder (OAB) is characterized by the presence of involuntary bladder contractions that occur during bladder filling, despite the patients attempt to suppress them. An individual presenting with OAB is likely to present with several of the following symptoms:
    • Increased daytime frequency: individual believes that he or she voids too often during the day.
    • Urgency: the sudden compelling desire to pass urine, which is difficult to defer.
    • Urinary incontinence: any involuntary leakage of urine. Should be described further by specifying other relevant factors, such as type, frequency and severity.
    Additional symptoms of OAB may include:
    • Urge Urinary Incontinence (UUI): involuntary leakage accompanied by or immediately preceded by urgency. Can present in different symptomatic forms, for example small losses between micturition or complete bladder emptying. UUI is most commonly found in older women and believed to be from detrusor muscle overactivity.
    • Stress Urinary Incontinence (SUI): involuntary leakage on effort or exertion or sneezing or coughing or anything that builds up abdominal pressure. Believed to be due to the lack of mechanical support of the urethra which leads to insufficient resistance to outflow of urine during increased abdominal pressures. Seen most commonly in women ages 45 to 49 years.
    • Mixed Urinary Incontinence (MUI): involuntary leakage associated with urgency, and also with exertion, effort sneezing or coughing.
    • Overflow Urinary Incontinence: can be due to detrusor muscle underactivity and is characterized by a loss of urine with no warning or triggers. The volume leaked may be small or large and can occur with a change of position or activity.
    • Nocturia: waking to void at night 2 or more times.
    Drugs that can affect bladder contractility:
    • Anticholinergics
      • Tricyclic antidepressants such as amitriptyline (Elavil®)
      • First generation antihistamines such as diphenhydramine (Benadryl®), chlorpheniramine (Chlor-trimeton®)
      • GI spasmolytics: dicyclomine (Bentyl®), hyoscyamine (Levsin®), glycopyrrolate (Robinul®)
      • Anticholinergics for Parkinson’s: trihexyphenidyl (Artane®) and benztropine (Cogentin®)
    • ACE inhibitors: (lisinopril etc.) decreases contractility, as well as potentially causing an increased frequency of cough.
    • Benzodiazepines: (diazepam, lorazepam etc) their muscle relaxation effect may impair bladder emptying.
    • Alpha blockers like Tamsulosin (Flomax®) terazosin (Hytrin®) and all members in this class decrease urethral sphincter tone.
    • Any antipsychotic, antidepressant or muscle relaxants with anticholinergic effects will decrease bladder contractility
    • Alcohol: decreases contractility
    • Caffeine: increases contractility and rate of emptying. Diuretic effect increases urine volume.


    Non-Pharmacological Management: There is no cure for OAB, so management techniques are essential. Keep a bladder diary. Keep a record of ins & outs.
    • Education about lifestyle interventions
    • Regulate fluid intake
    • Eliminate bladder irritants (alcohol & caffeine, carbonated beverages, artificial sweeteners, citrus juices, tomato-based products, chocolate)
    • Maintain bowel regularity
    • Kegel exercises- Pelvic muscle rehab. Strengthens muscles in pelvic floor which support the bladder neck & urethra. Method:
      • Find the right muscles: imagine you are trying to stop yourself from passing gas. Squeeze the muscles you would use, if you sense a “pulling feeling” those are the right muscles.
      • It is important not to squeeze other muscles, at the same time, and NOT to hold your breath. Be careful not to tighten your stomach, leg, or buttock muscles. Squeezing the wrong muscles can put undue pressure on bladder control muscles.
      • Pull in muscles, hold for count of 3. Relax for a count of 3. Work up to 3 sets of 10 repeats.
      • Start doing these exercises lying down, this is easiest because muscles do not need to work against gravity. When muscles get stronger, do them sitting or standing. Working against gravity is like adding more weight.
      • Repeat but don’t overdo it
    • Bladder training-void regularly every hour on the hour. Then increase duration between voids by 15 minutes each week, until comfortable with urinary frequency. This helps with control by suppressing involuntary detrusor contractions. Check out: https://medlineplus.gov/ency/patientinstructions/000141.htm


    According to the Agency for Healthcare Research and Quality, approximately 15.1 % of US women report overactive bladder (OAB) and 11.0 % report OAB with urge urinary incontinence.

    When we see the selection of incontinence products in our over-the-counter space and the number of OAB meds on our shelves, we can make a definite difference in this population.

    Most of the treatment options for OAB, with the exception of two, are taking advantage of the “side effects” caused by anticholinergic therapy. This represents a huge market where patient consultation is a must.

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    Overview of Treatment Options for Interstitial Cystitis (Bladder Pain Syndrome)

    Pentosan polysulfate sodium (Elmiron®) 100mg caps
    Recommended dose: 300 mg/day taken as one 100 mg capsule orally three times daily. The capsules should be taken with water at least 1 hour before meals or 2 hours after meals.
    Patients should be reassessed after 3 months. May take 3-6 months for improvement.



    WARNINGS
    Weak anticoagulant effect: This drug is a heparin-like compound, with approximately 1/15th the effect of heparin. It is in the low-molecular weight heparin family. Mechanism of action for IC is unknown. Pregnancy Category-B (inform clinician if pregnant) FDA WARNING 2020: Retinal pigmentary changes
    • A detailed ophthalmologic history before starting therapy.
    • For patients with preexisting ophthalmologic conditions, get a baseline before starting therapy for future comparison.
    • A retinal examination is suggested for all patients within six months of initiating treatment and periodically while continuing treatment. If pigmentary changes in the retina develop, access risk versus benefits.
    • May be a cumulative effect.
    ADVERSE EFFECTS:
    The most common side effects are hair loss (almost always limited to a single area of the scalp), diarrhea, nausea, blood in the stool, headache, rash, upset stomach, abnormal liver function tests, dizziness, and bruising.

    DIETARY APPROACH:
    Some foods are well known for causing interstitial cystitis (IC): Start by eliminating the top offenders: citrus (Vitamin-C), spicy hot foods, Mono Sodium Glutamate (MSG), soy, caffeine, coffee, tea, sodas, alcohol, tomatoes, cranberry juice, and chocolate.

    There are lists of: “Most bothersome”, “IC friendly” and “Foods worth trying”. Each individual should maintain a food diary. A useful website that I recommend is:
    http://www.ichelp.org/living-with-ic/interstitial-cystitis-and-diet/elimination-diet/least-and-most-bothersome-foods/

    WORTH CONSIDERATION:
    • Bladder training with “urge suppression" may be helpful.
    • Patients might also get relief from OTC therapy such as ibuprofen, acetaminophen, or naproxen.
    • Tricyclic Antidepressants, such as amitriptyline might be helpful to relieve the neurogenic pain component as well as help manage the depressant symptoms of the disease state.



    Phenazopyridine (Pyridium®) 100mg & 200mg tablets
    available OTC: Azo-standard® 95mg and 97.5mg
    • Mechanism: Phenazopyridine is an “azo” excreted in the urine, where it exerts a direct topical analgesic effect, on urinary tract mucosa. 65% remains unchanged in the urine.
    • Phenazopyridine has been marketed since 1925 and since 1951 has had a dual status of prescription and over-the-counter
    • status of prescription and over-the-counter Indication: symptomatic relief of discomfort and pain
    OTC Dosage:
    • 97.5mg (maximum strength) three times daily with meals.
    • 95mg (regular strength) three times daily with meals
    • Do not administer for more than 2 days with antibacterial agents (no benefit if longer). May mask symptoms of inappropriate antibiotic choice.
    Indication: symptomatic relief of discomfort and pain, before antibacterial therapy becomes effective.

    Prescription dosage: Phenazopyridine (Pyridium®) 100-200mg three times daily with meals. Do not administer for more than 2 days with antibacterial agents. (no benefit if longer). May mask symptoms of inappropriate antibiotic choice.

    Warnings, precautions, adverse effects:
    • Headache/ rash /pruritis
    • Staining of contact lens
    • Discoloration of urine – reddish-orange in color
    • Patient information
    • Avoid if glucose-6-phosphate dehydrogenase deficient
    • Avoid if kidney function is less than 50mL/minute.
    Patient education:
    • This medicine will change the color of your urine to red or orange. This is temporary and harmless, but it can stain clothing and towels. Other body fluids may be discolored as well. Recommend mini-pads to minimize staining.
    • Don't wear soft contact lenses while taking this medicine. It can permanently stain your lenses.
    • Take with food
    • May mask symptoms of active infections


    I met a patient a few years back, a 30-year-old female with interstitial cystitis (IC), or what is commonly known as ‘bladder pain syndrome’. She kept track of her IC triggers, which included smoked foods, soda, especially “citrus based soda”, iced tea, and sports drinks.

    It is also advisable that the patient maintain a bladder diary, as patients truly suffer with this disease state. Many patients seem to get the most benefit from dietary restriction. This incurable inflammatory bladder condition affects up to half a million people, primarily women (10:1 females:males) . It causes severe pain and urinary frequency, similar to the symptoms caused by a severe bladder infection. Unlike infections, however, bacteria are not usually found.

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    Prophylaxis of Urinary Tract Infections

    Prophylaxis is indicated for:
    Women with 3 or more episodes per year (or 2 or more in 6 months). Be sure to exclude abnormalities: stones, reflux, fistula etc.
    Agents must eliminate pathogenic bacteria from the fecal or introital reservoirs, and not cause bacterial resistance. Prophylaxis is appropriate if recurrent cystitis episodes have no association to coitus.

    ANTIBIOTIC PROPHYLAXIS:
    ANTIBIOTIC PROPHYLAXIS: Once daily dosing-usually at bedtime
    • Trimeth/Sulfa SS (400/80): ½ tablet daily at bedtime
    • Trimethoprim 100mg daily
    • Cephalexin (Keflex®)? 250mg daily
    • Nitrofurantoin (Macrodantin®)? 50mg or 100mg daily
    Note : this product is?NOT?MacroBID®.? It is an immediate release product. Take with food or milk to prevent GI upset.

    Post coital dosing for prophylaxis:
    • Trimeth/Sulfa SS (400/80) one tablet once
    • Trimethoprim 100mg one tablet once
    • Cephalexin 250mg one capsule once
    • Nitrofurantoin: 50mg or 100mg one capsule once
    Self-administered antibiotic therapy:
    • Self-administered single dose of Trimeth/Sulfa DS two tablets at onset of symptoms
    UTI prevention tips that actually work:
    • Urinate immediately after having sexual intercourse. Urinating flushes out bacteria that may have entered the urethra during intercourse.
    • Use proper hygiene. Wipe front to back.?
    • Rinse the vulva after sex.
    • Keep well hydrated with water and avoid “holding it” throughout the day
    • Wear regular cotton underwear. Thong underwear can lead to UTI’s by tracking bacteria from the rectal area into the urethra via the vagina.
    • Don’t smoke; it lowers immunity.
    • Avoid condoms coated with nonoxynol-9
    • In post-menopausal women, topically administer estrogen cream.? It decreases the colonization of the E.coli.
      • Nitrofurantoin is more effective; however, clinicians worry about pulmonary fibrosis with long term nitrofurantoin use.
    URINARY TRACT ANTISEPTICS:
    • Methenamine Hippurate (Hiprex®) FDA approved 1967: 1,000 mg twice daily
    • Methenamine Mandelate (Mandelamine®): 1,000 mg 4 times daily
    Urinary tract infection, prophylaxis/suppression. Prophylaxis or suppression of recurrent urinary tract infections when long-term therapy is indicated, and infection has been eradicated by appropriate antimicrobial treatment.? Needs acidic urine for maximum efficacy. Restrict alkalinizing foods and medications to maintain urine pH ≤5.5.

    Mechanism: methenamine component is hydrolyzed to formaldehyde in acidic urine. Hippuric or mandelic acid, has some antibacterial activity and also acts to keep the urine acidic.

    Note: should only be used?after?eradication of the infection by other appropriate antimicrobial agents.

    CRANBERRY SUPPLEMENTS:
    Cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated uropathogens (e.g. uropathogenic E. coli) to the uroepithelium, thus impairing colonization and subsequent infection.? It seems to work in the lab, but there is no compelling data to “push” these products.

    Because of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be recommended for the prophylaxis of recurrent UTIs at this time.

    Cranberry tablets- (AZO Cranberry®) no data to support its use, and causes significant GI upset and heartburn.

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    Overview of Treatment Options for Urinary Tract Infections in Pregnancy

    DRUGS to AVOID:
    Tetracyclines, Sulfonamides (1st and late 3rd trimester), fluoroquinolones.

    OPTIONS FOR CONSIDERATION:

    Cephalosporins: Cephalexin (Keflex®) 250-500mg every 6 hours for 7 days.
    Cefpodoxime (Vantin®) 100mg BID for 5-7 days (third-generation cephalosporin)
    Penicillins: Amox/clav (Augmentin®) 500mg every 8 hours OR Amox/clav 875/125 twice daily for 7 days.
    Nitrofurantoin: MacroBID® 100mg twice daily for 7-10 days (avoid if G-6-PD & at term).
    • Historically marked as ‘Pregnancy Category B’. Recommended that nitrofurantoin be AVOIDED during the first trimester and late last trimester of pregnancy due to potential for hemolytic anemia in newborns.
    Trimeth/Sulfa (Bactrim DS®): 1 tablet BID x 7days.
    • Avoid Trimeth/Sulfa during 1st trimester and 3rd trimester near term. Avoid if G-6-PD.
    • Remember, trimethoprim is a folic acid antagonist, and should be avoided during the first trimester.
    • Avoid all sulfonamides in the last days before delivery because they can displace bilirubin from plasma binding sites in the newborn, which may possibly increase risk for kernicterus.
    Fosfomycin (Monurol®) only indicated for UTI

    Mechanism: broad spectrum bactericidal antibiotic, that interrupts cell wall synthesis. It also reduces bacterial adherence to the uroepithelial cells.

    Dosage: 1 packet (3gm of granules) mixed with 3-4 oz. cool water and dissolve. Drink at once.
    May see diarrhea (9%) and Headache (4%) and nausea (4%)
    Pregnancy category-B

    Patient information:
    • May take with or without food.
    • Symptoms should improve in 2 or 3 days. If not, call clinician. Do not repeat dose.
    • Always mix with water. Do not ingest in dry form.
    • Clinician note: this drug is seldom used, so call the pharmacy to see if it is in stock.
    • Good choice if the patient is pregnant.
    • Good choice if the patient is sulfa allergic, or if local E.coli are over 20% resistant.
    • Approximate cost: $75.00 for 1 packet (1 dose)
    Fluconazole: For yeast infections, high dose fluconazole (400mg-800mg/day) is teratogenic. However, the 150mg dose for vaginal yeast infections has data that is not so clear. Best to avoid since topical azole antifungals such as clotrimazole and miconazole are so safe and effective.

    I would have to think that the toughest job for any OB/GYN would be prescribing any medication in pregnancy. I remember when Bendectin® was pulled from the market in 1983, due to lawsuits. Bendectin® was a combination of doxylamine and pyridoxine, both which were Pregnancy Category A drugs at the time. Today, we have Diclegis® and Bonjesta®, which contain the same ingredients for nausea of pregnancy.

    One day when my wife Denise was working the bench, the OB/Gyn department called with a question. They had a patient with a UTI and were not sure what to give. The patient was pregnant (so, no fluoroquinolones/tetracyclines). The culture showed resistance to penicillins (so, no cephalexin/penicillins), and the patient was from the Middle East and had Glucose-6 Phosphate deficiency (so, no nitrofurantoin or Trimeth/sulfa)! Of course, my wife knew the only answer...Fosfomycin (Monurol®), which the practitioners had never heard of!

    Denise ordered in the drug for the patient, who recovered without incident. As I always tell my student pharmacists, yes those patients are REAL and many times come to our pharmacies. We have to be the drug experts!

    Have a Great Day on the Bench!!

    February 2022

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    Treatment of Uncomplicated Cystitis

    MICROBIOLOGY

    UTI’s are the most common bacterial infection in women. The most common bacteria found in acute uncomplicated cystitis is E.coli, which is responsible for 75% to 95% of all cases. The remainder of the cases are caused by Proteus mirabilis, Klebsiella pneumoniae, and Staphylococcus saprophyticus. Most cases can be treated with short course therapy.

    I highly recommend that pharmacists call the inpatient pharmacies at their local hospitals, as resistance rates may vary significantly by region. Hospital pharmacists are the keepers of the antibiograms.

    THE ‘GO TO’ DRUGS FOR UNCOMPLICATED UTI:

    TRIMETHOPRIM/SULFAMETHOXAZOLE DOUBLE STRENGTH
    Sanford Guide recommends use only if local E.coli resistance is less than 20%, and patient has no allergy.
    Watch for drug interactions, especially with warfarin.
    Pregnancy Category D
    • TRIMETH/SULFA (Bactrim DS®) (1) TABLET TWICE DAILY FOR 3 DAYS
    Complicated: Trimeth/Sulfa DS: Give BID for 7-10 days

    FLUOROQUINOLONES
    Sanford Guide recommends use of fluoroquinolones if local resistance patterns for E. coli are 10% or less and patients can’t take SMX/TMP.

    Watch for drug interactions.
    Absorption can be blocked with di and trivalent cations such as calcium, iron, magnesium etc.
    May cause fluctuations in blood sugars.
    Is an alternative choice for patients with sulfa allergy or contraindications (G6P-dehydrogenase).
    (Note: moxifloxacin does not achieve high enough levels in the kidney/bladder for treatment of UTI’s)

    • CIPROFLOXACIN (Cipro® 250mg) (1) TABLET TWICE DAILY FOR 3 DAYS
    Complicated: Ciprofloxacin 250-500mg BID for 7 to 10 days.
    • LEVOFLOXACIN (Levaquin 250mg) (1) TABLET DAILY FOR 3 DAYS
    Complicated: Levofloxacin 250mg daily for 7 to 10 days

    NITROFURANTOINS

    NITROFURANTOIN MACROCRYSTALS MONOHYDRATE
    Recommended writing for “MacroBID” do not confuse for “Macrodantin”.
    Avoid if G6P-dehydrogenase. Pregnancy Category B
    • NITROFURANTOIN MAC/MONO: (MacroBID 100mg) (1) CAP TWICE DAILY FOR 5 DAYS
    Prescribing tips:
    • AVOID nitrofurantoin in patients with creatinine clearance less than 60mL/minute. However, there is a bit of a controversy, with some references saying 30-40mL per minute. The newest Beers list allows for nitrofurantoin use down to 30mL/minute.
    • AVOID nitrofurantoin if early pyelonephritis is suspected, because serum concentrations don’t get high enough to treat systemic infections.
    • AVOID last week of pregnancy due to potential for hemolytic anemia in newborns.
    • WATCH for: increased risk for pulmonary toxicity, neuropathy, hepatotoxicity.
    • AVOID in complicated UTI

    Fosfomycin (Monurol®) only indicated for UTI

    Mechanism: broad spectrum bactericidal antibiotic, that interrupts cell wall synthesis. It also reduces bacterial adherence to the uroepithelial cells.

    Dosage: 1 packet (3gm of granules) mixed with 3-4 oz. cool water and dissolved. Drink at once.

    May see diarrhea (9%) and Headache (4%) and nausea (4%) Pregnancy category-B

    Patient information:
    • May take with or without food
    • Symptoms should improve in 2 or 3 days. If not, call the clinician. Do not repeat dose
    • Always mix with water. Do not ingest in dry form.
    • Clinician note: this drug is rarely used, so call the pharmacy to see if it is in stock
    • May be a good choice if patient is pregnant
    • May be a good choice if the patient is sulfa allergic, or if local E.coli resistance rates are over 20%.
    • Approximate cost: $75.00 for 1 packet (1 dose)


    I am always impressed with the bacterial resistance rates in the areas that I practice. It makes sense to me that nitrofurantoin resistance rates are always less than 10% for E.coli.

    Given the fact that trimethoprim/sulfamethoxazole and the fluoroquinolones can be used for a variety of infections, there is more potential for overuse of these medications. Nitrofurantoin has limited use, and therefore, is much less likely to be “overprescribed.”

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    Overview of Acute Pyelonephritis

    ACUTE PYELONEPHRITIS--- OUTPATIENT

    Is an infectious inflammatory disease involving the kidney parenchyma and renal pelvis. Gram negative bacteria (most likely: E.coli) are most common. Infection usually ascends from the lower urinary tract, with the exception of Staph aureus, which is spread hematogenously. Usually occurs in women 18-40 years of age.

    Clinical presentation:
    • Temperature over 102F
    • Definite costovertebral tenderness (flank pain)
    • Voiding symptoms
    • Positive urine culture.
    Mild cases can be treated with oral medication. Severe cases should be hospitalized.
    • ALWAYS perform culture and sensitivity!
    • Monitor for drug interactions if using SMZ-TMP or fluoroquinolones.
    Antibiotics should be dosed for at least 2 weeks. Highly active agents such as fluoroquinolones can be given for 7 days.

    Sanford guide recommends:
    Ceftriaxone 1gm IV, then may transition to:
    fluroquinolones for 5-7 days.
    • Ciprofloxacin (Cipro®) 500mg BID x 7 days OR
    • Levofloxacin (Levaquin®) 750mg Daily for 7 days
    Other Options:
    • SMZ/TMP (Bactrim-DS®) should not be used for initial empiric therapy because of high rates of resistance, SMZ/TMP 160/800 mg (one DS tablet) PO twice daily x 14 days is appropriate treatment of uncomplicated cystitis for pathogens known to be sensitive.
      • Watch for warfarin interactions and hyperkalemia
    • Oral Cephalosporins for 14 days. (Oral beta-lactams are less effective for acute pyelonephritis and frequently relapse.)
    • Amoxicillin/Clavulanic acid (Augmentin®) for 14 days. (Oral beta-lactams are less effective for acute pyelonephritis and frequently relapse.)
    • Nitrofurantoins (MacroBid®) are not recommended for acute pyelonephritis as it does not attain therapeutic levels in renal parenchyma.
    Hopkins Antibiotic Guide recommends: consider an initial dose of a parenteral agent, particularly if fluoroquinolone resistance is >10%. Then complete treatment as guided by antimicrobial sensitivity results.
    • Ceftriaxone 1 gm IM or IV x 1
    • Gentamicin 5 mg/kg IM or IV x 1
    • Ciprofloxacin 400 mg IV x 1
    If hospitalized: treat until patient is afebrile for 24-48 hours, then complete a 2-week course with oral drugs. Follow up with urine culture 2 weeks after course of antibiotic therapy is completed, to ensure response and to prevent relapse.

    Chronic pyelonephritis: recommended treatment is 3 to 6 months of therapy.

    Pharmacists occasionally see patients coming into our practice sites seeking something for bladder burning and head to the phenazopyridine section.

    I make it a point to ask about having any back pain (flank pain) and if they have a fever. Acute pyelonephritis is a condition that phenazopyridine has no role in its treatment.

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    Urinary Tract Infections: The Basics 

    Causative Agents

    Pathogens most likely to cause urinary tract infections include primarily Escherichia coli, but also other Enterobacteriaceae (Klebsiella). Other gram-negative bacilli such as Pseudomonas aeruginosa may be involved. Staphylococci, enterococci, Proteus, and Candida species can also be implicated in urinary tract infections.

    Female Anatomy and the Risk of UTI
    • Short urethra facilitates ascent of organisms from the introitus into the bladder
    • Frequency of UTI increases after puberty due to sexual activity
      • Approximately 50% of women will develop at least one UTI within their lifetime, with 1 in 3 women having a UTI by the age of 24
    • Women with recurrent UTI may have more adhesive receptors on GU mucosa—allowing more binding sites for pathogens
    • Women whose mucosal secretions lack fucosyltransferase activity are more prone to recurrent UTI, as this enzyme keeps bacteria from adhering to the urethra
    • The female urethra is usually colonized with bacteria believed to originate from the fecal flora
      • Bacteria reach the bladder by a “massaging action” during sexual intercourse
    • Use of spermicides and diaphragms increase the risk of UTI
    • Risk factors include pregnancy, mechanical instrumentation, catheterization
    • Lactobacilli which produce lactic acid & decrease E. coli colonization in the vaginal flora help to prevent UTI, as well as circulating estrogen levels. Use of beta-lactam antibiotics (penicillins and cephalosporins) will destroy Lactobacillus, which is protective for UTI
    • In elderly females, poor bladder emptying due to prolapse may increase risk

    Male UTIs
    • Higher incidence in uncircumcised men has been observed
      • Over their lifetime, uncircumcised men are four times more likely to experience a UTI than circumcised men
    • The prostate secretes zinc, a potent antibacterial that stops the ascent of infection
    • Lower zinc levels in prostatic secretions of men with bacterial prostatitis
    • In elderly males, prostatic hypertrophy causes obstruction
    • Therapy is more difficult than in females. Treatment should last 10 to 14 days.
    • Uncomplicated infections are rare. Most infections are complicated, because of structural or functional abnormality which disrupts normal defense mechanisms.

    Age
    • Elderly population (over 65) equal ratio between male and female UTI
    • Most age-related UTI are asymptomatic
    • In patients with dementia, fecal incontinence causes increased incidence if UTI
    • Neuromuscular disease, such as strokes, may cause increased incidence
    • Catheterization is more common in elderly
    • Residual urine volume due to anticholinergic use, prostatic hypertrophy, urethral stricture, calculi, tumors, and bladder diverticula

    Treatment of Elderly Patients
    • Make sure there are symptoms, and that urine is abnormal, not just a positive culture
      • Treatment of asymptomatic UTI in the elderly is not advised. It is said to be a benign disease and treatment is not warranted.
    • Asymptomatic Bacteriuria is dependent on age. Check for obstruction if there are recurrent symptoms. Don’t treat chronic bacteriuria in elderly females; this is often due to diverticuli in the bladder.
    • Males: most common cause of infection is due to bladder outlet obstruction, because of prostatic hypertrophy
      • Obtain culture before treatment... because cause of infection is NOT as predictable in men as they are in women

    Treatment of Pediatric Patients

    If the child is under 5 with a positive urine culture, he/she should be treated even if asymptomatic with conventional courses of therapy used for symptomatic infections. In children, there is a greater risk of developing renal scarring and long-standing renal damage during the first five years of life.

    Urinary tract infections are common depending on the age group. We see most UTIs in young, sexually active females. Back in the day, the condition was referred to “honeymooner’s cystitis.” Urinary tract infections can also be common on the other end of the spectrum, affecting older women who have issues with incomplete bladder emptying.

    When I see my patients reaching for those urinary tract medications, such as phenazopyridine, I make sure they understand this is for symptomatic relief. Appropriate treatment for the UTI is still needed.

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    Overview of Testosterone Replacement Options

    Warnings/Precautions and/ Adverse effects: Traditional oral tablets: may cause GI upset and are of little value because of extensive first pass metabolism. May also cause hepatotoxicity. However, there is a newer formulation which bypasses these traditional issues caused by oral testosterone.
    • Edema, weight gain
    • Hypertension, CHF
    • LABS to be checked: hematocrit (red blood cell levels) (D/C if over 55%), serum testosterone, lipid profile every 6-12 months. PSA yearly and digital rectal exam twice yearly.
    • CANCER: men over 50 years who begin testosterone treatment should be reevaluated for prostate cancer three months and one year after beginning treatment
    • Acne can be exacerbated
    • Exacerbate benign prostatic hyperplasia, or enhanced growth of prostate cancer
    • Avoid testosterone in males with breast cancer, as testosterone can be converted to estradiol by aromatase.
    • Caution in patients with sleep apnea
    Drug Interactions:
    • May increase insulin requirements.
    • Increased clearance of propranolol.
    Chronic drugs that LOWER testosterone levels:
    • Prednisone 5mg/day and greater, or
    • Morphine 100mg/day or greater AND their equivalents.



    Representative Products and Dosages (Testosterone replacement):
    • • Delatestryl® (testosterone enanthate) 200mg/mL & Depo-Testosterone (Testosterone cypionate) 100 & 200mg/mL. Administered intramuscularly (IM) (generics are very inexpensive)
    Dosage: 200mg every 2-4 weeks. Generally, doses of over 400mg/month are not necessary.
    • Androderm® 2.5mg and 5mg patches. Apply to arm, back, abdomen or thighs. Change every 24 hours. Do NOT apply to the scrotum. Cost approx. $600/month
    TESTOSTERONE topical gels:

    Advantages: Provides therapeutic testosterone levels without large fluctuations, easier to use and less skin irritation than patches.

    Disadvantages: Transfer of gel or solution from one person to another --avoid this by washing hands after application and wearing clothing over application site.

    Comments: Do not apply to genitals.

    Testosterone Monitoring: Check testosterone level at least 7 to 14 days after initiation of therapy.
    • Androgel® testosterone gel 1.62% packets and pump ($650/month) generic available Apply once daily to upper arm, shoulders or abdomen. One study showed a 30 percent lower bioavailability when it was applied to the abdomen as opposed to the arms and shoulders.
    • Fortesta®: testosterone gel 2% 10mg per pump ($490/month) generic is available Dosage: Start with 40 mg (4 pump actuations) once daily in the morning applied to thighs to minimize product transfer. Max dose is 70 mg per day.
    • Testim® gel (1%) ($710.00/month) generic is available Start with 5 g (50 mg of testosterone) once daily applied to shoulders or upper arms. Increase to 10 g if needed. Do not apply to abdomen.

    Oral Testosterone: Testosterone undecanoate (Jatenzo®) : 158mg, 198mg and 237mg

    Mechanism: Jatenzo® is lipophilic, absorbed through the intestinal lymphatic system, which then eliminates first pass metabolism. Previous oral testosterone therapies (methyltestosterone) saw first pass metabolism and associated liver issues.

    Dose: 1-2 capsules twice daily with food.

    Dose range: minimum of 158 mg twice daily and a maximum of 396 mg twice daily based on serum testostxerone drawn 6 hours after the morning dose at least 7 days after starting treatment or following dose adjustment and periodically thereafter

    Advantages:
    • No liver function issues
    • No topical transfer
    • Ease of use

    Warnings: May cause hypertension and cardiovascular events such as myocardial infarction and stroke

    Cost: for the two lower strengths around $950/month. Highest strength is $1900/month. Bottles of 120 capsules


    TESTOSTERONE MONITORING
    • Check a morning TOTAL testosterone...and repeat to confirm. FREE testosterone: check if the total is borderline especially if the patient has factors that can alter levels, such as: obesity, diabetes, cirrhosis, hypo- or hyperthyroidism, etc
    • Check serum testosterone 4 to 12 weeks after starting therapy. In older men, aim for the low end of normal, such as 400 to 500 ng/dL.
    • Measure midway between injections for testosterone enanthate and cypionate
    • Also monitor for increased hematocrit and PSA and do a digital rectal exam at baseline, 3 to 6 months, and then yearly.


    Direct to consumer advertising is a real thing when it comes to testosterone replacement. One of the physician assistants I had the privilege to work with directly said he seldom complies with an older male’s request to do testosterone levels. For the most part, they are low! And when the guy finds out they are low he wants a supplement.

    Direct to consumer advertising for testosterone replacement in males really works.

    Between 2009 and 2013 among US men residing in 75 United States direct marketing areas, regional exposure to televised direct to consumer advertising was associated with greater testosterone testing, new initiation, and initiation without recent testing. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471355/

    Testosterone levels are rarely identified as a cause of erectile dysfunction. Must do an endocrine workup, must also exclude prostate cancer by PSA and digital rectal exam. Testosterone should only ever be administered to hypogonadal men, with documented low testosterone levels.

    Testosterone requires conversion to dihydrotestosterone (DHT) for its action on the external genitalia, sexual hair, and of course the prostate gland. Testosterone requires conversion to estradiol to have its effects on bone strength. If a male has aromatase deficiency, osteoporosis occurs.

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    January 2022

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    Treatment of Premature Ejaculation (PE)

    IELT: Intravaginal Ejaculatory Latency Time (time from intromission until ejaculation)
    Prevalence is consistently around 30% in men age 18-59 in the U.S.
    In the Diagnostic and Statistical Manual of Mental Disorders V (DSM-V), PE is defined as a sexual disorder with:
    • consistent ejaculation within 1 minute or less of vaginal penetration
    • duration over a period of at least 6 months
    • experienced 75–100% of the time
    • the condition results in clinically significant distress, sexual frustration, dissatisfaction, or tension between partners
    • this condition is not better accounted for by another non-sexual mental disorder, medication or illicit substance use, or medical condition
    Topical anesthetics
    Mechanism: contain benzocaine or lidocaine, a local anesthetic, causing a decreased sensation. Promoted to decrease premature ejaculation.

    There are desensitizing gels with 7.5% lidocaine, as well as condoms with benzocaine (4-5%) to cause desensitization

    Warnings/Precautions and/ Adverse effects:
    • Sensitivity to this product/ or benzocaine or lidocaine
    • Apply 10-15 minutes before intercourse
    • Use a condom to prevent transfer to partner.
    Dapoxetine
    Is a SSRI and meets many of the ideal treatment criteria, including oral administration, pharmacokinetic profile suitable for PRN administration, and a good side effects profile.'

    Can be taken with a PDE5 inhibitor or alcohol without any significant interactions. Compared to placebo, the 60mg to 100mg produced statistically significant improvement in the men’s IELT generating an approximately 3 fold increase in average IELTs from just under 1 minute at baseline, to 2.91 minutes (60mg) and 3.1 minutes (100mg).

    Nausea is the most common side effect at approximately 9%

    In October of 2005, the FDA sent a non-approvable letter to Johnson & Johnson. The drug “Priligy” by Jaansen Pharmaceuticals is available in Europe.

    SSRI’s
    Paroxetine is far superior to fluoxetine and other SSRIs within this realm, with one study showing an increase of IELT of 9 minutes. For improvement of IELT, it requires chronic daily dosing which patients find inconvenient and laden with unpleasant side effects. SSRIs have a slow onset of action and adverse effects including nausea, drowsiness, cognitive impairment, and sexual side effects. With any SSRI, start with a low dose and gradually increase at monthly intervals. Will take at least 2-3 weeks of therapy to see desired effect.

    Clomipramine
    In one study, off label use of clomipramine was shown to be more effective in prolonging IELT than sertraline and fluoxetine. Side effects were more common than other agents.

    Dose: clomipramine 25mg taken 4 to 6 hours before intercourse.

    Substantially prolonged ejaculation time in about half of the men, although was of little benefit with short initial IELT’s.

    Tramadol
    Considered a third line agent, due to its effects with serotonin and norepinephrine. Because of the potential for opioid abuse, this therapy is not recommended.

    Ejaculatory dysfunction
    Frequently seen with tamsulosin, switching to alfuzosin provides relief from ejaculatory dysfunction from other alpha blockers.

    Getting your patients comfortable to discuss sexual dysfunction does require a lot of trust. When I notice that a guy is not being adherent to his tamsulosin, I will inquire if he is having sexual dysfunction. I have had four male patients admit to me that they were having painful ejaculation while taking tamsulosin. I recommended to their physician to switch to alfuzosin, which the physician made the change. All four patients were quite pleased with the results of the switch.

    On another occasion, a young couple come to the pharmacy and wanted to talk with me. She was complaining that he was "taking too long” and was it the clonazepam or sertraline causing this problem. Of course, it was the sertraline, and I explained to them that any of the SSRI's can cause this problem. He was changed to bupropion for his depression, and the issue resolved.

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    Overview of Nontraditional Options for Erectile Dysfunction

    Alprostadil Intracavernosal injection (FDA approved 1995)

    Mechanism: direct injection of vasoactive prostaglandins onto the corpora cavernosum.

    Warnings/Precautions and/ Adverse effects: First injection should be done in a clinician’s office with trained personnel. Must stay in office until complete detumescence occurs. If there is no response, the next higher dose may be given in 1
    • Generally reserved for patients who have failed other regimens.
    • May be used only twice a week.
    • May cause: Penile fibrosis, priapism, penile pain. hematoma, ecchymosis
    Contraindications: sickle cell anemia, leukemia, (any condition predisposing patient to priapism), penile angulation, Peyronies disease , cavernosal fibrosis & penile implants.

    Representative Products and Dosages:
    • Alprostadil (Caverject®) 5mcg/ml , 10mcg/ml, 20mcg/ml, 40mcg/ml injection
    • Alprostadil (Edex®) 10mcg/ml, 20mcg/ml
    For purely neurogenic dysfunction, start with 1.25mcg. If other etiologies, start with 2.5mcg. Final dose should not exceed 60mcg, should produce an erection adequate for intercourse within 5 to 20 minutes ideally to last no longer than 1 hour. (Mean dose at end of 6 months- 20mcg) (cost about $90.00 per injection)


    Alprostadil urethral suppository (FDA approved 1996)

    Mechanism: alprostadil inserted via suppository into the urethra. Apply post urination, residual urine disperses the medicated pellet permitting alprostadil to be absorbed by the urethral mucosa. Then transported through the erectile bodies by communicating vessels between corpus spongiosum and corpora cavernosa. Induces vasodilatation in the vascular beds.

    Erection occurs in 5 to 10 minutes and lasts 30-60 minutes. Can be used up to twice daily.

    Warnings/Precautions and/ Adverse effects:
    • May cause transient penile pain, and hypotension
    • NOT priapism
    • Headache and dizziness, testicular pain
    • Possible urethral abrasions and bleeding
    • Do NOT use if partner is pregnant, unless using a condom


    Representative Products and Dosages:

    Alprostadil (Muse®): 125mcg, 250mcg, 500mcg, and 1000mcg urethral suppositories. Are small pellets one time use applicator/injector containing the alprostadil dose, about 30mm into the urethra. (cost= about $75/dose)

    Papaverine penile injection
    Mechanism: Smooth muscle relaxer
    Relaxes blood vessels and allows increased blood flow to the penis.
    Possibly inhibits phosphodiesterases and it may have direct actions on calcium channels.
    A natural opiate from the poppy plant.
    • Onset: 10 minutes. Intercourse should be attempted within 2 hours. Maximum 3 times per week.
    • Dose: 30 to 60mg: slowly inject over one or two minutes to completely inject the dose. This minimizes serious adverse effects such as arrhythmias.
    Yohimbine
    Mechanism: blocks presynaptic alpha-2 adrenergic receptors. Increases parasympathetic and decreases sympathetic activity. Erection is linked to cholinergic activity, and alpha-2 blockade, which theoretically results in increased penile blood inflow, decreased outflow or both.

    Widely used as an aphrodisiac to improve sexual drive. Frequently seen in herbal or “natural” remedies for erectile dysfunction.

    Warnings/Precautions and/ Adverse effects/Drug Interactions
    May cause: anxiety, insomnia, tachycardia and hypertension.
    • American Urological Society has cautioned against the use of yohimbine.
    • HAS NO FDA sanctioned indications
    • Contraindicated with antidepressants
    Alprostadil (Prostaglandin E1, PGE1) is used in the management and treatment of erectile dysfunction in males and for temporary patency of ductus arteriosus in newborns with congenital heart diseases before surgical intervention. PGE1 causes smooth muscle relaxation, leading to vasodilation, increasing peripheral blood flow and helping with erectile dysfunction.

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    Overview of 5-PDE Inhibitors for Erectile Dysfunction

    Phosphodiesterase type-5 inhibitors:

    sildenafil (Viagra®)-approved 1998
    vardenafil (Levitra®) approved 2003
    tadalafil (Cialis®) approved 2003

    Mechanism: Works by enhancing the effect of nitric oxide by inhibiting phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by Phosphodiesterase-5 inhibitors produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, which in turn produces an erection.

    Warnings/Precautions and/ Adverse effects:
    • Color disturbances: (blue/green) important for pilots (PDE-6 found in retina) can be affected at higher doses.
    • Headache (16%), facial flushing, dyspepsia
    • Hypotension: 8-10mm decrease in systolic & 5-6 mm in diastolic.
    • Hearing loss: ISMP-2016: reports a strong association between PDE5 drugs and hearing loss. PDE5 caused hearing loss 21.5 times higher than similar comparators.
    • In 1998, there were 123 sildenafil related deaths, 67% were MI and 36% developed CV symptoms within 5 hours of administration. Interestingly, less than 20% of these patients took nitrates.
    Drug Interactions (5-PDE inhibitors)
    • CONTRAINDICATED with nitrate use.
    • CONTRAINDICATED with alpha blockers due to hypotension.
    • Caution with all blood pressure medications.
    • Metabolized by Cytochrome P450 3A4. Cimetidine increases sildenafil levels by 56%. Also increased with ketoconazole and erythromycin (180% increase)
    • Give lower doses to men who take potent CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, or indinavir.
    Representative Products and Dosages

    BrandGenericDose mgOnset min.Duration
    Viagra®sildenafil25,50,10030 min4 hours
    Levitra ®vardenafil2.5,5,10,2020 min4 to 5 hours
    Cialis®tadalafil5, 10, 2030 min36 hours (weekend)
    Cialis®tadalafil2.5mg or 5mgTaken once daily
    Stendra®avanafil50,100,200mg15 min4 hours


    Dosage: On demand dosing - Taken on an as needed basis, usually ½ to 1 hour before sexual activity

    Cialis® tadalafil continuous dosing The low-dose daily dosing provides an option for men with ED who want a medication that can be taken without regard to timing of sexual activity and who anticipate sexual activity at least twice weekly. Men will take 2.5 or 5 mg tadalafil daily instead of 5 to 20 mg as needed. The long half-life of tadalafil allows for continuous daily dosing, so men do not need to plan ahead.

    Revatio® (sildenafil) 20mg: treatment of pulmonary arterial hypertension. Retails for $.50- 2.00/tablet…
    • Dose: 20mg 3 times daily, spaced 6 hours apart.
    • May improve exercise tolerance
    • May slow down worsening changes in physical condition
    • NOTE: all strengths of sildenafil (25,50 and 100mg) are available as GENERICS. Prices are less than 10% of the cost of the brand name Viagra®


    OTHER POTENTIAL USES FOR 5-PDE INHIBITORS:

    ALZHEIMER's PREVENTION: Cleveland Clinic’s Genomic Medicine Institute examined a database of more than seven million patients, finding that the ED medication performed significantly better at Alzheimer’s prevention than high blood pressure and diabetes drugs like losartan and metformin. Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate. Based on retrospective case–control pharmacoepidemiologic analyses of insurance claims data for 7.23 million individuals, it was found that sildenafil usage was significantly associated with a 69% reduced risk of AD.
    https://www.nature.com/articles/s43587-021-00138-z

    High Altitude Pulmonary Edema (HAPE) is the abnormal accumulation of plasma and some red blood cells in the lung air sacs due to a breakdown in the pulmonary blood-gas barrier, triggered by “thin oxygen” seen at higher altitudes. PDE-5 inhibitors sildenafil and tadalafil prevented hypoxic pulmonary hypertension and the development of HAPE.
    • • Sildenafil: single dose of 50 or 100 mg just prior to exposure for acute ascent, or give 50 mg every eight hours if staying 2-6 days.
    • • Tadalafil: 10 mg every 12 hours
    I am amazed with the numerous uses for the 5-PDE inhibitors. Their side effects of hypotension can be so bothersome, that pilots cannot fly, according to FAA regulations, for 8 hours after using sildenafil and vardenafil. For tadalafil on ‘as needed’ basis, pilots have to wait 24 hours!

    https://www.faa.gov/about/office_org/headquarters_offices/avs/offices/aam/ame/guide/pharm/ed/ Have a Great Day on the Bench!!

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    Broad Overview of Erectile Dysfunction

    Erectile dysfunction: (DSM IV- American Psychiatric Association)
    • The consistent inability to achieve and/or maintain an erection adequate for satisfactory sexual intercourse
    • Cause is marked by distress or interpersonal difficulty
    • Cause is not better accounted for by a drug of abuse or medication or direct physical effects of a substance
    It’s complicated---both physical and psychological components are at play. Most men experience spontaneous erections during rapid eye movement sleep and often wake up with an erection during the night. Complete loss of nocturnal erections is present in men with neurologic or vascular disease and may help rule out a psychogenic component. Parasympathetic nerves mediate an erection, while sympathetic nerves are responsible for ejaculation and penile stiffening. Nitrous oxide and other chemicals cause vasodilation, which leads to venous occlusion, rigidity and erection.

    INCIDENCE OF ERECTILE DYSFUNCTION (ED) IN MEN WITH OTHER DISEASES:
    • Cerebrovascular disease 70%
    • Coronary artery disease 60%
    • Coronary artery bypass graft 60%
    • Diabetes mellitus 50%
    • Peripheral vascular disease 70%
    • Untreated hypertension 10%
    Complete erectile dysfunction: About 5 percent of men (1/20) that are 40 years old have complete erectile dysfunction. About 15 percent of men at age 70 have complete ED.

    Mild and moderate erectile dysfunction affects approximately 10 percent of men per decade of life:
    • 50 percent of men in their 50’s
    • 60 percent of men in their 60’s.
    • 70 percent of men in their 70’s
    Classes of Drugs implicated with ED
    • Major antipsychotics (typical)
    • Tricyclic antidepressants
    • SSRI antidepressants
    • Anxiolytics (benzodiazepines)
    • Anticholinergics (as antispasmodics & anti-Parkinson’s drugs)
    • Antihistamines (especially sedating)
    • Muscle relaxants
    • Antiarrhythmic (disopyramide) (amiodarone) (mexiletine)
    • ANTIHYPERTENSIVES
    • Diuretics: thiazides and spironolactone
    • Central sympatholytics: methyldopa and clonidine
    • Beta-Blockers (propranolol & metoprolol)
    OTHERS:
    • Cimetidine
    • Digoxin
    • Indomethacin
    • Lithium
    • Metoclopramide
    • Phenytoin
    • Ketoconazole
    • Anti-androgenic agents (bicalutamide, flutamide, leuprolide)
    DRUGS WITH ABUSE POTENTIAL
    • Amphetamines
    • Barbiturates
    • Cocaine
    • Marijuana
    • Narcotics/Opiates (especially if over 100 MME per day)
    • Nicotine
    Cost:

    MECHANISMS for medications causing ERECTILE DYSFUNCTION

    Medication:Mechanism Proposed:Modified Libido/Sexual Response:
    Antihypertensives, anxiolytics, ethanol, muscle relaxants, narcotics, neuroleptics sedativesSEDATIONDecreased libido
    Cimetidine, Marijuana, Digoxin, excess Ethanol, Ketoconazole, SpironolactoneTestosterone antagonismLibido
    Metoclopramide, Narcotics, AntipsychoticsProlactin elevationLibido
    Anticholinergic Agents, TCAs, antihistamines (1st generation)Parasympathetic dysfunctionPenile tumescence
    Diuretics, methyldopa, beta-blockersDecreased arteriolar flow to corporaPenile tumescence


    DRUG causing sexual dysfunction:Possible alternative:
    AnticonvulsantsValproic acid
    AntidepressantsBupropion
    AntihypertensivesACE inhibitors & Calcium Channel Blockers, ARBS, alpha-blockers
    AntipsychoticsLoxapine
    DiureticsFurosemide
    Anti-ulcer drugsFamotidine
    Nonsteroidal anti-inflammatoryDiclofenac
    Antihistamines (1st generation)Second generation antihistamines




    I remember as a teenager watching an episode of M*A*S*H where “Hawkeye” was out with a nurse and was having “difficulties”. He was talking with BJ, his tentmate and told him the “couldn’t”. BJ responded, “couldn’t what?”. Hawkeye said, “you know, the big couldn’t.” That was the only reference that I ever remember seeing on TV until sildenafil (Viagra®) came out in 1998.

    Now, guys walk into the pharmacy and say, “Hey doc, I need a refill on my Viagra”. Wow how times have changed. Before the three PDE-5 inhibitors became generic, the Super Bowl was overrun with ads for ED drugs. Remember Bears Coach Mike Ditka (Pitt alumnus) promoting ED products? Now that these generics are cheap, more and more men are buying them on a regular basis.

    Have a Great Day on the Bench!!

    December 2021

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    Benign Prostatic Hyperplasia (BPH): Complicating Medications & Related Conditions

    Benign Prostatic Hypertrophy
    • Most common benign neoplasm of American men.
    • Nearly ubiquitous condition among all elderly men. Nearly 80% of men who live to be 80 have BPH. 50% will be symptomatic. 50% of the symptomatic patients require treatment.
    Irritative symptoms:
    • Dysuria (discomfort when urinating)
    • Nocturia (frequent urination at night)
    • Urgency
    • Frequency
    • Burning
    Obstructive:
    • Hesitancy
    • Straining
    • Dribbling
    • Weak stream
    • Incomplete emptying
    MEDICATIONS to Avoid with BHP
    • Testosterone: causes prostate enlargement and growth. Although the television is chocked full of commercials for men with “low T”, care must be exercised in the older population so as not to exacerbate prostate issues
    • Sympathomimetic agents may cause or worsen urinary difficulty in patients with prostate enlargement due to smooth muscle contraction in the bladder neck via stimulation of alpha-1 adrenergic receptors. Therapy with sympathomimetic agents should be administered cautiously in patients with hypertrophy or neoplasm of the prostate. Avoid all amphetamine products as well as pseudoephedrine (Sudafed®) in the older population.
    • Drugs with significant anticholinergic adverse effects: decrease urinary bladder detrusor muscle contractility, resulting in urinary retention.Avoid first generation antihistamines, tricyclic antidepressants, phenothiazines. However, drugs like tolterodine (Detrol®) poses little risk of urinary retention, if there is good flow. Antimuscarinics work during storage, rather than voiding.
    • Anticholinergics: Avoid anticholinergics such as benztropine, hyoscyamine and trihexyphenidyl.
    • Diuretics: polyuria secondary to high dose therapy may present as urinary frequency.

    Be sure to rule out Bacterial Prostatitis:
    Inflammation of prostate gland and surround tissue as a result of infection. Pathogenic bacteria, usually gram-negative organisms, must be present in prostatic secretions and in urine. A urine gram stain is indicated in any patient with suspected bacterial prostatitis.

    Clinical appearance:
    • Sudden onset of fever, chills, myalgia, malaise, cloudy urine
    • Localized pain: perineal and or suprapubic regions.
    • Digital palpitation of the prostate via the rectum may reveal a swollen, tender, warm, tense or indurated gland.


    TREATMENT:
    Prostatitis Usual etiologyTreatment
    Less than age 35 years oldN. gonorrhoeae, C.trachomatisceftriaxone 250mg IM + doxycycline 100 BID x10 days
    Over 35 years of ageEnterobacteriacae (coliforms)Fluoroquinolones OR Trimeth/Sulfa DS BID for 10-14 days
    Chronic bacterialEnterobacteriaceae (80%)
    Enterococci
    Proteus
    Pseudomonas aeruginosa
    Ciproflox 500 BID x 4 weeks or Levoflox 750mg daily x 4 weeks. Trimeth/Sulfa DS BID for 1-3 months.


    Patients frequently inquire about getting something for their cold symptoms that is safe for hypertensive patients. Although pseudoephedrine is safe for most patients with controlled blood pressure (it raises blood pressure by about 3mm Hg), we need to be cautious in patients with prostate issues.

    I always ask any patients with as much gray hair as I have if they have any issues with their prostate. Most of us are aware that first generation antihistamines (such as diphenhydramine) should be avoided, but we also need to avoid pseudoephedrine. Although phenylephrine may be safer, it’s practicality as a decongestant is limited.

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    Overview of 5-Alpha Reductase Inhibitors for Benign Prostatic Hyperplasia (BPH)

    Getting to know the prostate:
    • At birth, it is pea-sized and weighs 1gm. The prostate stays pea sized until puberty, reaching “adult size” by age 25 to 30.
    • The prostate typically remains that size until patient is 40. At that time, a second growth spurt begins and continues until the man is 70 or 80. During this time, the prostate can double or triple in size.
    5-Alpha Reductase Inhibitors

    Mechanism: Inhibits the production of dihydrotestosterone. Most useful in male patients whose prostates are very large. Minimal benefit in patients with normal or moderately enlarged prostate gland, and whose BPH symptoms are caused primarily by muscle cell overgrowth.

    Indications: Patients with large prostates (50-60 gm), who are not good surgical candidates, those who wish to avoid surgery, and those who cannot tolerate the side effects of alpha-adrenergic antagonists.

    Warnings/Precautions/Adverse effects:
    • Pregnancy Category-X
    • Women who are of childbearing age should not handle tablets, crushed or broken.
    • Erectile dysfunction in about 4%
    • Decreased libido, decreased ejaculate volume.
    • Breast tenderness and enlargement
    • Testicular pain
    Dosages:
    • Dutasteride (Avodart®) : 0.5mg capsules : one capsule daily
    • Finasteride (Proscar®) : 5mg tablets : 1 tablet daily.
    • Finasteride (Propecia®): 1mg tablets-------for alopecia, not for BPH
    Prescriber notes: Finasteride and Dutasteride are available generically and decrease the need for surgery by 50% compared to alpha blockers. Dutasteride is three times more potent of an inhibitor of 5-alpha-reductase type 2 and 100 times more potent of an inhibitor of 5-alpha-reductase type 1, when compared to finasteride. Dutasteride 0.5mg reduces serum DHT by 94% compared to Finasteride 5mg at around 70%.

    Drug interactions: Dutasteride is metabolized by CYP450-3A4. According to in vitro data, blood concentrations of dutasteride might increase in the presence of CYP3A4 inhibitors such as ritonavir, ketoconazole, verapamil, diltiazem, cimetidine, and ciprofloxacin. These are considered to be moderate drug-drug interactions.


    Natural remedies—Saw palmetto

    Many previous studies suggest that saw palmetto leads to mild to moderate improvement of urinary symptoms of BPH. Some studies suggest that it's comparable to finasteride, but probably less effective than alpha-blockers. A well-designed NIH trial shows no significant improvement in men with moderate to severe BPH who took saw palmetto for a year.

    The difference might be: patient study group had more severe symptoms, or different formulation of saw palmetto. Typical dose 160mg twice daily. Always expect different results from different formulations. More rigorous studies suggest that saw palmetto isn't better than placebo for BPH symptoms.

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    Overview of Alpha Blockers for Benign Prostatic Hyperplasia (BPH)

    ALPHA BLOCKERS---for BPH

    Mechanism: Relaxes smooth muscles, especially in the urinary tract and prostate. By relaxing muscles around the prostate, they increase urinary flow. Minimal effect on sex drive.

    Alpha blockers are classified according to selectivity and half-life. Alpha-1a receptors are localized to the prostate and bladder neck, and selective blockade results in fewer systemic side effects (orthostatic hypertension, dizziness, tiredness, headache & rhinitis). These agents work quickly and may exhibit symptomatic relief when appropriately dosed, within 2 weeks. Approximately 70% of patients will respond.

    Nonselective alpha blockers: Terazosin (Hytrin®), Doxazosin (Cardura®), Prazosin (Minipress®). Prazosin is not approved for BPH.

    Selective alpha-1a blockers: Tamsulosin (Flomax®) and Alfuzosin (Uroxatral®) Silodosin (Rapaflo®)

    Warnings/precautions (alpha blockers): Orthostatic hypotension may occur with the first few doses. Minimize by slow titration. Watch for syncope. Best to have patient take at bedtime to minimize dizziness.

    Significantly less side effects with the selective alpha-1a blockers. Titration not required for Alfuzosin (Uroxatrol®)

    Adverse effects: (alpha blockers):
    • Orthostatic hypotension
    • Dry mouth
    • Urinary urgency
    • Constipation
    • Priapism, ejaculatory problems
    Intraoperative Floppy Iris Syndrome: ALL Alpha-1 Blockers cause intraoperative floppy iris syndrome (IFIS). The iris becomes flaccid and billows in response to intraoperative irrigation currents, causing the potential prolapse of the iris toward phacoemulsification incisions. Ophthalmologists can modify their surgical techniques including using iris hooks, iris dilation rings, viscoelastic devices. Ophthalmologists MUST know before surgery that patient has been on alpha blocker therapy.

    Drug interactions:
    NSAIDs decrease antihypertensive effects
    Beta Blockers and Diuretics increase the antihypertensive effects of these agents

    Patient Education:
    • Watch for postural hypotension
    • Watch for drowsiness
    • If priapism occurs, seek medical treatment immediately.
    ALPHA BLOCKERS - ALPHA NON-SELECTIVE
    GENERICBRANDINDICATIONSTARTING DAILY DOSEUSUAL DAILY DOSEMAXIMUM DAILY DOSE
    DOXAZOSINCARDURA®BPH1mg at bedtime1-16mg/day16mg=HTN
    8mg=BPH
    PRAZOSINMINIPRESS®1mg at bedtime2-20mg (in 2-3 doses)40mg
    TERAZOSINHYTRIN®BPH1mg at bedtime1-20mg20mg/day


    ALPHA BLOCKERS - ALPHA –1a SELECTIVE
    GENERICBRANDINDICATIONSTARTING DAILY DOSEUSUAL DAILY DOSEMAXIMUM DAILY DOSE
    TAMSULOSINFLOMAX®BPH0.4 mg at bedtime0.4- 0.8mg0.8mg
    ALFUZOSINUROXATRAL®BPH10mg10mg10mg
    SILODOSINRAPAFLO®BPH8mg with food8mg with food (4mg if CrCl=30-50)


    Prescriber notes:
    • Alfuzosin (Uroxatral®) is least likely of alpha blockers to cause ejaculatory problems. Does not require dosage titration.
    • Silodosin (Rapaflo®) : Contraindicated with potent CYP3A4 inhibitors
    • Tamsulosin (Flomax®) is least likely of alpha blockers to cause orthostatic hypotension, and MOST likely to cause ejaculatory problems


    One of my favorite stories I share with students occurred in the family practice office I worked at two days a week. A patient was not being adherent to his terazosin (Flomax®) and, when I questioned him, he was experiencing sexual side effects. We changed his medication to alfuzosin (Uroxatrol®). Three months later when I saw him at a Christmas party, I got the biggest hug! He was so pleased with the change in therapy. The truth is we had at least 4 other gentlemen at the clinic with the same issues and changed with good results.

    At the same office, we had a patient in for a simple physical for cataract surgery. The patient did not understand the ophthalmologist’s instructions and continued to take his tamsulosin and was scheduled for surgery in just two days. I called the eye doctor’s office and informed them, and the nurse said they would inform the surgeon doing the surgery. He simply used iris hooks to stabilize the iris, and the surgery was uneventful. When we get prescriptions for eye drops for a patient preparing for cataract surgery, if it is a male, I always check for alpha blockers on their chart.

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    Prescriptions That May Contribute to Hair Loss

    DRUG CLASSExamplesComments
    ACE inhibitorsCaptopril, Lisinopril, RamiprilUp to 5% of Ramipril patients may experience hair loss
    AndrogensTestosteroneMay cause androgenic alopecia
    Blood ThinnersWarfarin especially high doses HeparinOver 5% of warfarin patients see hair loss; up to 50% if on high doses
    AntifungalsFluconazole, Terbinafine, KetoconazoleUp to 20% with fluconazole / Over 5% for terbinafine
    Anti-ThyroidMethimazole & PropylthiouracilAlso, check thyroid levels for any hair loss
    Aromatase inhibitorsExemestane, Anastrozole, LetrozoleThey block estrogen formation / Frequency: Exemestane-15% ; Anastrozole-5%
    BuspironeBuspar®May cause hair loss 5%
    Calcium Channel BlockersNifedipine (Procardia)May cause hair loss up to 5%
    Chemotherapeutic agentsDepends on drug. Antimitotic agents are the worstCauses anagen effluvium. (Active follicles)
    AntidepressantsbupropionBupropion had highest risk; paroxetine had lowest
    Estrogen blockerTamoxifenCauses androgenic alopecia
    ImmunosuppressantsLeflunomide mycophenolate tacrolimus Leflunomide- 15% ; mycophenolate=15% tacrolimus =28%
    InterferonsFor MS and HepatitisMay cause hair loss 50% of the time
    Mood StabilizersLithium; Divalproex & Carbamazepine can be used for seizuresLithium up to 20% / Divalproex up to 28%- may treat with zinc and selenium / Carbamazepine up to 6%
    Oral ContraceptivesThe more androgenic progestins are most likely to cause TE. Desogestrel, norgestimate, drospirenone are LEAST androgenic progestins
    Vitamin-A analogsAcitretin and isotretinoinIsotretinoin for acne -5% / Acitretin for psoriasis up to 75%
    StatinsAtorvastatin and SimvastatinRosuvastatin does not cause hair loss


    Treatment of Hair Loss

    Finasteride: Although we are accustomed to dispensing Finasteride (Proscar®) at a dose of 5mg per day for treatment of benign prostatic hypertrophy, the dose for treatment of male patterned is finasteride 1mg (Propecia 1mg). 1mg per day inhibits the production of dihydrotestosterone in the scalp by more than 60%. Finasteride does not have any affinity for androgen receptors. Long term treatment is necessary; hair count showed a 9% increase after 1 year and showed a 24% increase after 4 years. Hair regrowth will be lost 9-12 months after drug discontinuation.

    Minoxidil (topical) 2% and 5%: Product works directly on the hair follicles by promoting hair growth by increasing the duration of anagen, shortening telogen, and enlarging miniaturized follicles. The 5% strength shows greater efficacy. Initially, hair shedding may occur at the initiation of treatment possibly due to stimulation of telogen follicles to reenter the anagen phase. Apply to the scalp twice daily, not to the hair. Combination therapy with finasteride plus minoxidil produces better results than either agent alone. These hair loss treatments seem to work best in patients that have shorter duration of baldness and more limited areas of baldness seem to do better with finasteride or minoxidil treatment.

    Biotin: Biotin deficiency is very rare and occurs from drinking raw egg whites. Supplementation for the purposes of hair loss is not beneficial for most patients.


    Last week we discussed the three phases that our hair cycles through. The telogen phase is when the hair is “at rest”. Telogen effluvium (TE) results from changes in follicular cycling that leads to the excessive shedding of telogen hairs. A wide variety of endogenous and exogenous factors have been linked to induction of telogen effluvium. Serious illness, major surgery, childbirth, rapid weight loss, nutritional deficiency, profound emotional stress, and drug exposure have been implicated in causing TE. Always recommend checking the thyroid!

    Telogen hair loss develops within two to three months after the inciting factor, and reverses once the inciting factor is eliminated. The cause of telogen effluvium may be multifactorial in patients who have multiple medical problems or who are taking multiple drugs. In some cases, an inciting factor cannot be identified. But, let’s look at medications implicated in causing hair loss. I’ve included the most common culprits (causing hair loss more than 5% of the time)

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    Hair Loss---The basics

    Our hair growth undergoes three distinct cycles. 90% of our hair follicles are in the “anagen” hair growth phase. In this cycle our hair grows about 0.3mm per day, which translated would be 9mm (1/3 inch) per month. Activation of the androgen receptor in the hair follicles shortens the anagen or growth phase in the normal hair growth cycle.

    The other 10% are in the “transformation” and “resting” phases. We lose about 50-150 hairs per day on average. Infrequent shampooing will show increased losses on days that the patient shampoos, due to manual dislodging, but the average is the same. A common cause of hair breakage is prolonged tension of hair by tight braids & ponytails. Ask the patient when they look at the lost hairs, do they see the follicular “bulb” at the bottom, to rule out hair breakage. If they are seeing the distinct white bulb, this indicates hair loss of the shaft in the resting or “telogen” phase.

    Thanks Mom: It's not ALL Mom’s fault! Baldness is strongly associated with the AR gene found on the “X” chromosome, but other chromosomes are at play too. A large study looking at 12,806 men of European ancestry found that people with the gene had more than twice the risk of developing male patterned baldness than people without it. However, factors from the father’s side, as well as other external factors can be implicated in male pattern baldness. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364959/)


    Patterned baldness- where genetics and aging meet:

    Male pattern hair loss or androgenetic alopecia in men is characterized by the slow, progressive loss of hair in a characteristic distribution. The condition is mediated by the action of androgens on androgen-sensitive hair follicles in genetically susceptible males. Drugs like low dose finasteride (Propecia®/Proscar®) are used to block the testosterone, which affects the androgen sensitive follicles. Finasteride and dutasteride, commonly used for enlarged prostate, are 5-alpha reductase inhibitors that block the conversion of testosterone to the more potent dihydrotestosterone. Interestingly, no one can find a link between baldness and prostatic hypertrophy.

    Female pattern hair loss most frequently presents as hair thinning on the frontal and vertex areas of the scalp. The frequency of this condition increases with age and is most commonly seen in women that are post-menopausal. It will affect as high as 19% of Caucasian women. Again, testosterone is the villain in our female patients, although most ladies have normal levels. Topical minoxidil (Rogaine®) is the first line treatment. If they poorly respond to minoxidil or have elevated testosterone levels, the anti-androgens like spironolactone (Aldactone®) or finasteride (Proscar®/Propecia®) can be tried. Allow at least a 4–6-month trial of minoxidil, finasteride or spironolactone to see benefits.

    Polycystic ovary syndrome is a common cause of excessive androgen production in women. Common dermatologic manifestations of elevated testosterone include excessive hair growth (hirsutism), acne, brown patches on the neck (acanthosis nigricans), and male patterned baldness (androgenic alopecia). Hirsute women often have increased activity of 5 alpha-reductase. Androgens affect the formation of acne by increasing sebum production from sebaceous glands in the skin. The diagnosis of polycystic ovary syndrome includes a complete history, physical examination with emphasis on evidence of androgen excess, and appropriate laboratory investigation to exclude other causes of hyperandrogenism. Treatments for the dermatologic conditions of hyperandrogenism include: diet and exercise, oral contraceptives, antiandrogens, and insulin-sensitizing medications, such as metformin.

    Vitamins?? Excess vitamin A from supplements (retinoids, isotretinoin, etc.) may cause hair to fall out. Deficiencies of zinc, iron, biotin, or vitamin D can also cause hair to thin. Supplementing these vitamins is only beneficial if there is a deficiency of that vitamin.

    Foods? Green tea, onions, pumpkin seeds, and edamame, among other foods and beverages, contain nutrients that may lower DHT levels and prevent hair loss. Obviously, this needs more study, but these foods are healthy additions to anyone’s diet regardless of their effect on hair loss.

    As this seasoned pharmacist gets older a lot of changes in the hairline have occurred. When my barber cuts my hair, the trimmings are a lot whiter and the pile seems to be smaller. We get questions about hair loss: could some of the drugs we dispense cause hair loss? could biotin or “Hair/Skin/Nails” formula help? Biotin deficiency, after all, is implicated in hair loss. Biotin deficiency, though, is very rare, and supplementation does little to restore hair growth.

    Have a Great Day on the Bench!!

    November 2021

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    Running out of Options: Now What? A Review of Rarely Used Epilepsy Drugs



    Felbamate (Felbatol®) ??(approved 1993)
    Rarely used due to extreme side effect profile. Parent or legal guardian should sign a legal consent form before administration.

    Mechanism: Blockade of NMDA ( n-methyl-d-aspartate)

    Dosage: 1200-3600mg in 3 divided doses. Days to steady state: 4 to 5 days

    Adverse effects: aplastic anemia, hepatotoxicity, blurred vision, diplopia, photosensitivity anorexia

    Contraindications: last resort therapy

    Drug Monitoring:? ?Aplastic anemia: rates of 20 to 30% may be as high as 70%. Liver failure is common; administer liver function tests every 1 – 2 weeks.

    Patient education: Report signs of infection, easy bruising, weakness, or fatigue


    Tiagabine (Gabitril®)?????(approved 1997)
    Available as tablets= 2, 4, 12 & 16mg

    Mechanism: selective GABA reuptake inhibitor (SGRI

    Use: adjunctive treatment for focal seizures in patients 12 years of age and older

    Dosage: Adults: (over 18yrs)= 4mg daily. May increase by 4mg per day at weekly intervals. Take in divided doses 2-4 times per day. Time to steady state is 2 days. Usual adult maintenance: 32-56mg in 2 to 4 divided doses. (max=80mg)

    Adverse effects: dizziness (27%), asthenia, somnolence, nervousness & nausea.

    Patient education: Take with food to minimize GI upset. Exercise caution when driving or operating dangerous machinery.


    Rufinamide (Banzel®)?(approved 2008)
    Available as 200 mg, 400 mg tablets

    Mechanism: modulates activity of sodium channels

    Use: Adjunctive treatment of Lennox-Gastaut syndrome in adults and children 4 years and older

    Adults Dose: Initial: 400-800 mg/day, divided twice daily (Max/day: 3200 mg--divided twice daily)

    Adverse effects: QT interval shortening, multiorgan hypersensitivity reaction, including rash
    • Drug interactions: CYP2E1 inhibitor (weak) andCYP3A4 inducer (weak). Watch for drug interactions with inducers and inhibitors of CYP450.
    • Take with food
    • Serum level monitoring not needed


    Perampanel (Fycompa®)? ??????????(approved 2012)
    Available as: 2mg,4mg,6mg,8mg,10mg,12mg tablets

    Mechanism: first?glutamate?receptor antagonist. Remember that glutamate is the most prevalent?excitatory?neurotransmitter. (GABA is an inhibitory transmitter).

    Use: Approved for the treatment of focal-onset seizures (four years of age and older), and as adjunctive treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older. Maximum dose is 12mg/day.

    Schedule III controlled substance: possible euphoria and abuse.? Watch for mood changes such as anger, hostility.

    Drug interactions:
    • CYP450-3A4;? perampanel? 12 mg/day reduces the efficacy of levonorgestrel contraceptives. Select an additional or alternate contraceptive
    • Perampanel undergoes extensive liver metabolism.? Its effect will be decreased by CYP inducers like phenobarbital, carbamazepine and phenytoin.

    Cannabidiol (Epidiolex®) oral solution? 100mg/mL ?(Schedule-V)? (June-2018)
    Available as: 12.5mg, 25mg, 50mg, 100mg, 150mg and 200mg tablets
    • CBD is a chemical constituent of the cannabis plant
    • CBD does not cause intoxication or the euphoria that comes from tetrahydrocannabinol (THC), the primary psychoactive component of marijuana
    Inication: For the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.

    Dose: Administered orally.
    • The starting dosage is 2.5 mg/kg twice daily (5 mg/kg/day).
    • After one week, the dosage can be increased to a maintenance dosage of 5 mg/kg twice daily.

    Pushing the dose to 20 mg/kg/day dosage resulted in somewhat greater reductions in seizure rates than the recommended maintenance dosage of 10 mg/kg/day, but with an increase in adverse reactions.

    Precautions: be sure to order liver function tests (ALT and AST) before starting therapy.
    • 32% of treated patients experienced drowsiness and sedation.
    • can cause decreases in hemoglobin and hematocrit
    • metabolized by CYP3A4 and CYP2C19
      • Inducers will lower blood levels.
      • Blockers will raise blood levels.

    Cenobamate (Xcopri®)?(approved 2019)
    Available as: 12.5mg, 25mg, 50mg, 100mg, 150mg and 200mg tablets

    Mechanism: inhibits voltage-dependent sodium channels and enhancing gamma-aminobutyric acid (GABA) inhibition through the GABA-A receptor.

    Use: focal (partial-onset) seizures in adults. Should be used in adults with treatment-resistant focal seizures.

    Dosing: Long titration schedule, starting with 12.5mg per day, escalating the dose every 2 weeks until the maintenance dose of 200mg per day is reached.? Maximum daily dose is 400mg.

    Drug interactions: expect lots, due to metabolism by CYP2E1, CYP2A6, CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5, and glucuronide conjugation. May increase concentration of clobazam, phenobarbital and phenytoin.?

    Avoid in patients with hepatic or renal impairment.

    Our discussions on seizure medications shows us that our understanding of epilepsy is still in its infancy. Although we don’t see a lot of phenytoin and phenobarbital dispensed, we see even less of the drugs in today’s discussion dispensed. Newer agents are equally effective, and in most cases, better tolerated than older agents.

    Some of the newer drugs are only approved for adjunct therapy, while others may be appropriate for monotherapy. Many older drugs (carbamazepine, phenobarbital, phenytoin, primidone, valproic acid) have significant side effects, requiring serum monitoring, as well as tolerance developing. Also, some are enzyme blockers and inducers, having lots of drug interactions.

    I had a patient on felbamate 30 years ago, when the patient’s doctor ran out of options for seizure treatment. Just recently I dispensed a prescription of cerobamate.? One of the readers of Clinicians Corner has a family member who has benefited immensely with CBD for seizure control.

    We have a long way to go in neurology, as the neurons have yet to be completely understood!

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    Overview of Gabapentinoids

    Gabapentin (Neurontin®) FDA approved in 1993
    capsules 100mg, 300mg, 400mg; tablets 600mg & 800mg (available generically) Mechanism: A GABA analog, with no GABA receptor interaction, or GABA effects. Binds to the voltage-gated calcium channels at the alpha 2-delta subunit in the central nervous system. Seems to block excitatory neurotransmitters, as well as modulating the release of several neurotransmitters including glutamate, noradrenaline, and substance P.

    Indications:
    • Postherpetic neuralgia in adults
    • Adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalization, in adults and pediatric patients 3 years and older with epilepsy
    • ‘Off Label’ Uses: restless leg syndrome, hot flashes, diabetic peripheral neuropathy, back pain, paresthesia, anxiety in bipolar disease, alcohol withdrawal etc.
      • These are NOT FDA approved indications.
    Dosage:
    • ADULT: initial: 300mg at bedtime, increase to 900mg over 3 days.
    • Maintenance 1,800 to 2,400mg/day in divided doses.
    • Most clinicians are using 2,400 to 4,800mg/day for epilepsy
    • For neuropathic pain don’t exceed 3,600mg per day.
    • CHILD: start 10 to 15mg/kg/day in 3 divided doses. Maintenance dose of up to 50mg/kg /day
    Renally impaired patients require dosage adjustment: GABAPENTIN
    Renal clearance CrCl in mL/minTotal Daily dosage range (mg/day)
    Over 60900-3,600mg
    30-59400-1,400
    15-29200-700
    15 and less100-300mg (reduce proportionally)

    Adverse effects: Fatigue, dizziness, headache drowsiness, ataxia, nystagmus, aggressive behavior in children.

    Contraindications: None

    Drug Monitoring: No optimal level given. Titrate to therapeutic effect, takes about one day to reach steady state.

    Drug interactions:
    • Antacids reduce bioavailability by 20%
    • Cimetidine reduces renal excretion of Gabapentin, causing increase in Gabapentin effect.
      • Separate by 2 or 3 hours.
    • Gabapentin does NOT induce or inhibit liver enzymes.
    • Elimination half-life is 5-7 hours; takes 2 days to completely clear the body
    • Takes at least 7 days to taper a patient off of gabapentin
    Patient education:
    • Watch for drowsiness-caution driving.
    • Avoid cimetidine & antacids by 2 hours.
    Abuse potential: especially with alcohol and high doses. Be on the lookout for frequent requests for early refills. Some states now have Gabapentin in Schedule-V
    • States where gabapentin is classified as a controlled substance: Alabama, Kentucky, Michigan, North Dakota, Tennessee, Virginia, and West Virginia.
    • Not controlled but mandated reporting: Connecticut, Washington DC, Indiana, Kansas, Massachusetts, Minnesota, Nebraska, New Jersey, Ohio, Oregon, Utah, and Wyoming.
    • States thinking about mandatory reporting: Delaware, New York, and Wisconsin.


    Pregabalin (Lyrica®) FDA Approved 2004
    available as capsules: 25, 50, 75, 100,150, 200, 225, 300mg
    Lyrica CR® : Extended-release tablets: 82.5 mg, 165 mg, and 330 mg

    Schedule-V controlled substance

    Mechanism: Not well understood. Looks like GABA but has no effect on GABA or BZ receptors. Pregabalin binds to the voltage-gated calcium channels at the alpha 2-delta subunit in the central nervous system, resulting modulation in the release of several neurotransmitters including glutamate, noradrenaline, and substance P.

    Dosage and Administration: May give with or without food. Immediate release is FDA Approved for:
    • Epilepsy: for adjunctive treatment of partial onset seizures.
    • Diabetic peripheral neuropathy
    • Post herpetic neuralgia
    • Fibromyalgia
    • Neuropathic pain associated with spinal cord injury
    • Once-daily dosing (CR) for diabetic peripheral neuropathy and post-herpetic neuralgia, but not for fibromyalgia.
    • When converting from IR twice daily to CR once daily, take the daily dose in the morning. Add 10% to total IR dose to get CR dose. (75mg IR= 82.5CR; 150mgIR=165mgCR; 600mgIR=660mg ER, etc.)
    Warnings/ Precautions/Adverse Effects:
    • Weight gain and edema (especially if given with thiazolidinediones)
    • Visual disturbances (notify clinician if occurs)
    • Report any muscle pain, tenderness, or weakness & fever
    • May see additive effects with CNS depressants (opioids & benzodiazepines).
    • Avoid alcohol
    • Pregnancy Category-C
    • May cause male mediated teratogenicity. (inform clinician if planning to father a child)
    • Dizziness and somnolence
    • MUST taper drug over a 1-week period. Do NOT stop abruptly.
    • In clinical practice, this drug is used for post herpetic neuralgia, and diabetic neuropathy.
    GABAPENTINOID WARNING: Dec-2019
    The U.S. Food and Drug Administration (FDA) is warning that serious breathing difficulties may occur in patients using gabapentin (Neurontin®) or pregabalin (Lyrica®, Lyrica CR®) who have respiratory risk factors. These include the use of opioid pain medicines and other drugs that suppress the central nervous system, and conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function. The elderly are also at higher risk.

    Gabapentinoids are often being combined with CNS depressants, which increases the risk of respiratory depression. CNS depressants include opioids, anti-anxiety medicines, antidepressants, and antihistamines. There is less evidence supporting the risk of serious breathing difficulties in healthy individuals taking gabapentinoids alone.

    Be aware of the potential additive effects of all these CNS depressants and plan accordingly, by starting with low doses, titrating carefully, and informing patients of the potential for CNS and respiratory depression and their symptoms. The gabapentinoid prescribing information already includes guidance for health care professionals to caution patients about dizziness, somnolence, and the potential for impaired ability to operate a car or complex machinery. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin

    Is there a drug in the pharmacy that we dispense more inappropriately than gabapentin? It seems to be part of most pain management doctors regimen, also including tizanidine or cyclobenzaprine, and an opioid.

    I have yet to ask a student pharmacist what the FDA approved indications are for gabapentin and received a correct answer. I most often get “neuropathic pain” or “diabetic peripheral neuropathy” as the answer. The truth is gabapentin is only FDA approved for post herpetic neuralgia and seizure management.

    Many physicians see gabapentin as “not as bad as” opioids, but we as pharmacists still need to warn our patients about the dangers of this drug, especially given the fact it is frequently prescribed in conjunction with opioids, and other CNS suppressants such as tizanidine, tricyclic antidepressants and cyclobenzaprine.

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    Overview of Topiramate and Lacosamide Use in Seizure Disorders

    Topiramate (Topamax®) FDA approved:1996
    tablets: 25mg, 50mg, 100mg, 200mg.
    Sprinkle caps: 15mg,25mg (available generically)
    • Qsymia®: phentermine/ topiramate: 3.75 mg/23 mg; 7.5 mg/46 mg; 11.25 mg/69 mg; 15 mg/92 mg. Approved 2012 for weight loss (BMI over 30 or BMI over 27 with other risk factors.)
      • This drug requires a REMS program that is available on the website at https://qsymiarems.com/information-for-pharmacists.htm
    Mechanism: blocks voltage dependent sodium and calcium channels, augments the activity of the neurotransmitter GABA at some subtypes of the GABA-a receptor and antagonizes the kainate subtype of the glutamate receptor.

    Indications for use:
    • Partial onset seizures
    • Tonic-clonic seizures
    • Unlabeled use: alcohol dependence, binge eating, bulimia nervosa, cluster headache, infantile spasms, migraine prevention, weight loss in obesity.
    Dosage: Recommended dose: 200mg-400mg /day in 2 divided doses. 400mg/day as adjunct for tonic clonic seizures. Start with 25-50mg/ day; then may increase by 25mg-50mg increase per week. Pediatrics: 5-9mg/kg/ day (ages 2-16; Not approved for use under age 2.)

    Adverse effects: 28% of patients taking this drug discontinued therapy because of the following side effects: anorexia (2.7%); ataxia (2.1%); confusion (3.1%; depression (2.6%); difficulty with concentration (2.9%); fatigue, mental difficulty & somnolence (3.2%). Most of the side effects are dose dependent. Impaired cognition.

    Pregnancy Category: D (was changed March 2011 from Cat-C): causes oral clefts and low birth weight.

    Drug interactions:
    • Avoid alcohol (increases drowsiness)
    • Avoid carbonic anhydrase inhibitors (promotes stone formation by reducing urinary citrate excretion, and by increasing urinary pH. Topiramate is a weak carbonic anhydrase inhibitor. Be sure patients are adequately hydrated in summer months.
    • Mild inducer of CYP-450--- caution with oral contraceptives.
    Patient education:
    • Monitor weight, may cause weight loss
    • Maintain adequate fluid intake to minimize renal stone formation
    • Watch for drowsiness- caution driving
    • Reduces effectiveness of oral contraceptives. Decreases plasma concentrations of ethinyl estradiol by 25%. Consider alternate method or increase estrogen dose.


    Lacosamide (Vimpat®) FDA approved: 2008
    Tablets: 50mg, 100mg 150mg & 200mg tabs; solution and injection 200mg/20mL.
    Schedule-V controlled substance

    Indications for Use:
    • An adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy who are 17 years and older.
    • Injection is indicated as short-term replacement when oral administration is temporarily not feasible in these patients.
    Dosage: Initially, give 50 mg twice daily (100 mg/day). The dose may be increased, based on clinical response and tolerability, at weekly intervals by 100 mg/day given as two divided doses to a daily dose of 200 to 400 mg/day.

    Mechanism: In vitro electrophysiological studies show selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

    Adverse effects:
    • Most common side effects: double vision, headache, nausea, dizziness
    • Suicidal ideation
    • Dizziness and ataxia
    • Schedule V controlled substance; can cause euphoria or "drunk" feeling
    Monitoring:
    • Check EKG at baseline and after dose titration in patients with cardiac conduction problems, heart disease, or heart failure.
    • Serum level monitoring not needed.
    • Minimal interactions with CYP 450 ---is a CYP2C19 substrate and inhibitor (same as omeprazole). Elimination may be decreased by coadministration of divalproex.


    One of my patients that was taken Topiramate and said he stopped taking it because he was feeling lightheaded and fuzzy, he referred to the drug a “Dope-a-max”. We use a fair amount of topiramate for migraine prevention, and I always warn my patients in the summer to be sure they are adequately hydrated because of the risk of oligohidrosis (lack of sweating).

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    Overview of Levetiracetam and Brivaracetam



    Levetiracetam (Keppra 250mg, 500mg, 750mg (available generically) FDA approved in 1999

    Mechanism: has a most unusual mechanism of action described as binding to the synaptic vesicle protein SV2A; binding at this site may modulate synaptic transmission through alteration of vesicle fusion. SV2a does not cause immediate seizures but may contribute to a state of heightened epileptogenicity. SV2A dysfunction is linked to seizure activity.

    Indications: Most neurologists will start new patients on this medication, due to efficacy and low generic cost, and lack of drug interactions. Levetiracetam has a broad spectrum of use.
    • adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.
    • adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.
    • adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.
    Dosage: initial dose: 500mg twice daily. Titrate by 1000mg/day increments every 2 weeks. Maximum = 3000mg/day

    Adverse effects: drowsiness, headache & dizziness.

    Drug Monitoring: None necessary. Time to steady state: 2 days.

    Drug interactions: Not extensively metabolized. Not dependent on P450 isoenzymes.

    Patient education:
    • Swallow tablets whole. Do not chew or crush
    • May cause drowsiness. Use caution when driving or operating dangerous machinery.
    • Report any behavioral changes to practitioner, such as: hostility, irritability, hallucinations, thoughts of suicide.
    • Considered to be weight neutral. Some reports show significant weight loss.
    Oct-2021: Study results showed that individuals treated with levetiracetam showed improvement in cognitive function, and those with silent epileptic activity showed a clear benefit from the drug. There’s a subtype of Alzheimer’s disease, consider it an epileptic variant, that’s quite common, occurring in approximately 60% of patients. Patients with this form of Alzheimer's disease show symptomatic improvement with levetiracetam, by improved cognitive function.
    https://jamanetwork.com/journals/jamaneurology/article-abstract/2784539
    Among Alzheimer’s patients, an estimated 10-22% develop seizures, while an additional 22-54% exhibit silent epileptic activity.

    Brivaracetam (BRIVIACT®) FDA approved in 2016 Schedule-V
    Available as Tablets: 10 mg, 25 mg, 50 mg, 75 mg, and 100 mg and oral solution: 10 mg/mL. cost $1,200/ month

    Indications: approved as monotherapy or adjunctive therapy for focal-onset seizures in patients one month of age and older.

    Mechanism: same as Levetiracetam, binding to SV2A protein.

    Dosage: Monotherapy or adjunctive therapy is 50 mg twice daily. Dose can be adjusted dosage may be adjusted down to 25 mg twice daily (50 mg per day) or up to 100 mg twice daily (200 mg per day), based on patient tolerability..

    Drug interactions: Brivaracetam is 60% metabolized by CYP450-2C19 (same isoenzyme that activates clopidogrel) Weak metabolizers of CYP2C19 might experience excess levels of brivaracetam, causing toxicity. Best to avoid inducers of CYP2C19, such as phenytoin, carbamazepine, and phenobarbital as they may increase metabolism of brivaracetam. Adverse effects: Sleepiness, dizziness, fatigue and nausea.

    I’m always amazed with the new information coming out with old established drugs. Such was the case this past week, when I read about levetiracetam being used in Alzheimer’s patients. I was never aware that Alzheimer’s patient exhibited increases in seizure activity.

    As we discussed in a previous column, the cholinesterase inhibitors helped 1/12 Alzheimer’s patients. It shows our very rudimentary knowledge of Alzheimer’s, seizures and function of the CNS.

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    Overview of Lamotrigine for Seizure Disorders

    Lamotrigine (Lamictal®)
    FDA approved 1994
    Available as: chew: 2mg, 5mg & 25mg, tablets: 25, 100, 150 & 200mg

    Mechanism: is unknown but may interfere with sodium channels and stabilize neuronal membranes, modulation presynaptic excitatory amino acid release (glutamate & aspartate). Also, may have a slight effect on calcium channels.

    Lamotrigine is FDA-approved for adjunct therapy for Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures (adjunctive), and focal onset seizures (monotherapy or adjunctive therapy); may be used off-label for other seizure types.

    The investigators at the SANAD (Standard and New Antiepileptic Drugs) trials concluded that lamotrigine should be the first drug of choice for use in focal seizures.

    Although we think of lamotrigine as being a seizure medication, it is more commonly used for bipolar disease. Lamotrigine has better evidence of efficacy than lithium for monotherapy for bipolar depression. Lamotrigine is the best choice for prevention of recurrent depressive episodes. Lamotrigine does not have great efficacy for mania. Dosage:

    Adults: read and follow all package instructions concerning dosing.
    Because of risk for Stevens-Johnson Syndrome, slow titration is a must. The incidence of rash, which has included Stevens-Johnson syndrome, is approximately 0.3% to 0.8% in pediatric patients (2 to 17 years of age) and 0.08% to 0.3% in adults receiving lamotrigine. Rash, if it occurs, is almost always seen in the first 8 weeks of therapy.
    There are different dosage regimens to follow:
    • Adding lamotrigine to AED regimen containing Valproic acid (Depakote®)
      • 25mg every other day, for 2 weeks. Then 25mg every day for 2 weeks.
    • Adding lamotrigine to EIAED (enzyme inducing anti-epileptic drug). CBZ, DPH, PBARB without valproic acid.
      • 50mg daily for 2 weeks. Then 100mg daily in 2 divided doses for 2 weeks.
    • Start lamotrigine without any inducers/ inhibitors:
      • 25mg daily for 2 weeks. Then 50mg daily for 2 weeks.
    Adverse effects: skin rash (discontinue if it appears)-Black box warning. Titrate slowly, especially if taking Valproic acid.


    Lamotrigine Safety Alert April 2021
    The FDA has issued a drug safety communication after a review of study findings showed a potential increased risk of arrhythmias in patients with heart disease who are taking lamotrigine (Lamictal®)

    Drug interactions: many drug interactions between enzyme blockers and inducers. Although lamotrigine does not induce or inhibit other drugs, its metabolism is affected. Adding valproic acid to lamotrigine, will double lamotrigine steady state concentration.

    Half-life for lamotrigine is 6-8 hours.

    Drug Monitoring: optimal blood level: 4 to 20 mcg. Days to steady state: 4 to 5 days

    Patient care points:
    • Be sure to follow titration guidelines.
    • If rash should occur, stop the drug and immediately contact your prescriber.
    • Inhibits dihydrofolate reductase. Folic acid supplementation may be necessary.
    • May also cause nausea, dizziness, tremor, diplopia.
    • Lamotrigine may reduce the effectiveness of combined estrogen-progestin contraceptives
    • Pregnancy may cause an increase in seizures by increasing lamotrigine clearance by 65%. It quickly reverts to pre-pregnancy levels after delivery.


    Lamotrigine dosing is a textbook example of drug interactions. I included this drug as an example in my intro to Pharmacology lectures. If a patient is on a CYP3A4 blocker, you cut the dose in half. If a patient is on a CYP3A4 inducer you double the dose.

    We frequently see lamotrigine used for bipolar, especially in patients that lean to the depressive side. This drug, like carbamazepine, does require that patients be warned of the potential for rash, which could be Stevens Johnson Syndrome, “The Mother of all Rashes.” For lamotrigine, a benign rash may occur in up to 10% of patients; the rate for SJS is 1/1,000 patients.

    Unlike carbamazepine, there is no blood or genetic test to determine who is at risk for SJS. Slow titration and good counseling need to be standard processes with each patient.

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    Overview of Valproic Acid and Divalproex for Seizure Disorders

    Depakene® (approved 1978), Depakote® (approved 1983), Depakote ER® (approved 2000)

    Mechanism:
    • Increases levels of GABA by potentiating post synaptic GABA response by inhibiting the enzymatic response for the catabolism of GABA
    • Valproate is considered the most effective antiseizure medication for idiopathic generalized epilepsy with generalized tonic-clonic seizures
    • Affects potassium channel creating direct membrane stabilizing effect
    Depakene capsules, Depakote tablets, Depakote-ER DOSING: Adults: 1000 to 3000mg daily in divided doses. (Depakote ER as a single dose). Maximum is 60mg/kg/day.
    Child: start with 10-15mg/kg per day. Divided into 2 or 3 doses. Expect dose to escalate. Don’t exceed 60mg/kg/day.
    • Depakote® (divalproex sodium) is an enteric coated valproic acid derivative.
    • Written as “Depakote® 500mg” implies the enteric coated but multiple dosed.
    • Only Depakote ER 500mg should be given as a single dose (Multiple tablets given together)
    • Depakote is available as 125mg enteric coated tablets, 250mg tablets & 500mg tablets. Also available as 125mg sprinkle capsules.
    • Depakote ER® is available as 250mg and 500mg tablet (these are silver colored)
    • Divalproex ER (Depakote-ER) is used for epilepsy, mania, and migraine prophylaxis. Effective in preventing depressive recurrences in mania by 30
    • Divalproex DR (Depakote) is used for epilepsy. Divide doses if over 250mg.
    • Depakene® is valproic acid capsules and is available as a generic. Depakote and Depakote ER are available generically:
      • Depakote= divalproex delayed release
      • Depakote-ER= divalproex extended release
    Adverse effects: Hepatotoxicity, Teratogenicity, Pancreatitis are in the Black Box Warning.

    Stomach upset, alopecia, weight gain, tremor, easy bruising, thrombocytopenia.

    Blocker of P4503A4

    Teratogenicity: Divalproex has the highest risk for teratogenicity of all available anti-epileptic drugs.

    Contraindications: Hepatic disease and known urea cycle disorders

    May cause hyperammonemic encephalopathy which can lead to seizures, coma and death.

    Drug Monitoring:
    • Optimal blood level is 50-125mcg/mL. May take 2- 4 days for steady state blood levels.
    • Liver function tests are necessary: initial therapy: every 1 to 2 weeks, then periodically
    Patient education:
    • Take with food to minimize stomach upset.
    • Swallow tablets whole. Do not chew or crush.
    • Will cause weight gain. Monitor weight.
    • Watch for drug interactions, as this is a blocker of P450 3A4 metabolism


    Primidone (Mysoline®) 50 and 250mg tablets (approved 1954)

    Mechanism: Metabolized to Phenobarbital and PEMA (phenylethylmalonamide)
    Used for focal seizures and generalized tonic-clonic seizures.
    In some refractory patients, the PEMA potentiates the activity of phenobarbital.


    Essential tremor: Low dose primidone (start with 25mg) may also be effective when used intermittently for essential tremor that is exacerbated by situational stress or anxiety. Frequently used with propranolol.

    Dosage:
    • Maintenance: 250mg three to four times daily. Maximum 500mg four times daily (2 grams/day)
    • Children under age 8: days 1-3= 50mg at bedtime; days 4-6 = 50mg twice daily. Days 7-9: 100mg twice daily. Maintenance: 125 to 250mg three times daily
    Adverse effects:
    • CNS: drowsiness, alteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, tolerance, dependence
    • Children: hyperactivity
    Drug Monitoring: optimal blood level: 10-40mcg/mL. Days to steady state: 10 days

    Drug interactions: Inducer of CYP-3A4 (similar to phenobarbital, one of the metabolites).

    Patient education:
    • Watch for drowsiness.
    • Report multiple drug therapy to practitioner.


    Both divalproex and primidone, although effective for seizure management, are more commonly used for other conditions. Most of the divalproex I dispense is written by mental health professionals. We also see a good bit of divalproex used for migraine prophylaxis.

    Divalproex is a drug that be challenging to prescribe, given the delineation between ER and DR. It was not such a challenge when we were dispensing brand Depakote versus Depakote-ER.

    Now that it is available generically, the confusion may occur between Divalproex ER versus Divalproex DR. I advise my prescribers to write it by the brand name, and we pharmacists will dispense the generic.

    Although divalproex and primidone have lots of side effects and drug interactions, sometimes divalproex is the best choice for migraine, bipolar and epilepsy.

    Primidone seems, at low dose, to be effective for essential tremor, along with propranolol. Chances are that if you see a prescription for primidone, it probably is for essential tremor.

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    Overview of Carbamazepine

    Carbamazepine (Tegretol®, Carbatrol®)
    Tegretol: FDA approved 1968
    • Tegetol® available as : 100mg chew, 200mg tablets, & XR 100,200 ,400mg. Tegretol suspension=100mg/5mL. Generic equivalents available for susp, chew tabs and 200mg tablets
    • Carbatrol®: extended release capsules 100, 200 & 400mg
    Mechanism: thought to act by reducing polysynaptic responses and blocking post-tetanic potentiation.

    Uses:
    • treatment of focal and generalized seizures
    • affective illnesses such as bipolar disorder
    • chronic pain syndromes such as trigeminal neuralgia.
    Dosage:
    • Adults: initial-200mg twice daily. May increase to 800 to 1600mg daily in divided doses.
      • May increase at weekly intervals of no more than 200mg/day.
      • Maintenance level: 800-1200 per day
    • Child: 10-20mg/kg/day in 2 or 3 divided doses. Max dose 35mg/kg/day.
      • May increase at weekly intervals of no more than 100mg/day
    USE: For newly diagnosed, new onset, and refractory epilepsy

    Adverse effects:
    • Bone marrow suppression –FDA box warning: Aplastic anemia, agranulocytosis, pregnancy category-D, hyponatremia.
    • Men may have higher rates of sexual dysfunction due to lowering of testosterone.
    • May cause aggression! Slow titration minimizes adverse effects.
    Contraindications: Drug interactions - extensively metabolized by the P450 3A4 isoenzyme. The metabolism of carbamazepine is blocked by: cimetidine, erythromycin, clarithromycin, fluoxetine & azole antifungals.

    Is a potent enzyme inducer: it will speed the metabolism of drugs metabolized by the P450 enzyme system. Will decrease the effect of: oral contraceptives (recommend another method), doxycycline, haloperidol, anticoagulants, benzodiazepines, theophylline. It . Carbamazepine induces its own metabolism!
    • Half-life after chronic therapy decreases. Autoinduction occurs 3-4 weeks after starting carbamazepine, resulting in a decrease in carbamazepine levels
    • Phenytoin and phenobarbital may lower carbamazepine levels but increase levels of its active metabolite carbamazepine 10,11-epoxide
    HYPERLIPIDEMIA: Enzyme-inducing antiseizure drugs have been associated with increased hyperlipidemia. Order lipid panels for patients who require long-term therapy with enzyme-inducing drugs.

    Drug Monitoring: target serum concentration: 4 to 12 micromol/mL. Carbamazepine 10,11-epoxide is the metabolite that is measured. Measure at 3, 6 and 9 weeks, then every 60 days until constant levels. Time to steady state: 3-4 days.
    • Perform blood counts and liver function at baseline.
    • Monitor sodium levels
    • Do CBC and LFT (liver function testing) monthly
    • Monitor blood level of drug closely every 2 weeks, for first 2 months
    • After patient titrated, do CBC and LFT every 6-12 months.
    • Check blood levels every 3-6 months and after each dosage change
    Carbamazepine

    Patient education:
    • May cause drowsiness, dizziness and blurred vision.
    • Report any unusual bleeding or bruising, fever, sore throat rash or ulcers
    • Report liver reactions: anorexia, N/V, or jaundice
    -Note: minimal cognitive impairment compared with other antiepileptic drugs.



    Genetic Testing
    It is recommended to genetically test many Asians BEFORE starting carbamazepine to predict risk of a serious drug reaction. This is the first time that genetic testing is recommended before using a rather common drug.

    Carbamazepine carries a FDA box warning recommending that patients of Asian descent be screened for the HLA-B*1502 (HLA=Human Leukocyte antigen) gene before starting carbamazepine.

    HLA-B*1502 is seen almost exclusively in Asian populations (Chinese & South Asian Indian). About 5% of patients who have it will develop Stevens-Johnson syndrome or toxic epidermal necrolysis with carbamazepine.


    Symptoms of Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis:
    Both Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis can start with non-specific symptoms such as: coughing, aching, headache, fever, vomiting, diarrhea. Symptoms usually occur within the first 8 weeks to therapy.

    This is usually followed by a red rash across the face and the trunk of the body, which can continue to spread to other parts of the body. Blisters then form across the body in places such as the nose, mouth, eyes, and genital areas, and the mucous membrane becomes inflamed. With some people, the nails and hair begin to come out as well. In the case of Toxic Epidermal Necrolysis patients, the skin can start to come away in sheets leaving exposed flesh that could be likened to serious burning and is very susceptible to infection.

    Both disease variations are potentially deadly. In drug related cases, the symptoms for both diseases can take one or two weeks to manifest from the first time the patient takes the drug.


    Treatment for Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis
    If the cause is drug related, doctors can stop the drug immediately. In the case of a new infection on top of the condition or a bacterial infection, select a suitable antibiotic. In severe cases, the patient is treated in a burn unit. Patients have to be treated in meticulously hygienic environments to alleviate the risk of further infection, which could result in death. In cases where the patients have lost a lot of fluid through seeping areas where the skin has come away, intravenous fluid replacement may be required. The hospital may also use topical and oral corticosteroids to treat affected areas.
    Reference: http://www.skinassn.org/stevens-johnson-syndrome-symptoms-treatment.html



    Carbamazepine is another 50 plus year old drug. When I taught students in the neurology component of pharmacology, seizure meds seem to be the most challenging. For us older practitioners, we simply divide them into “old drugs” those that we had on the shelves when we started practicing: phenobarbital, phenytoin, primidone, valproic acid, and carbamazepine were the go-to drugs for seizure management until the early 1990’s. Then came a landslide of seizure medications in the 1990’s with more introduced every couple of years.

    These drugs are a hodge-podge of drug interactions and needs for frequent lab monitoring. Neurologists seldom use these five drugs, but psychiatrists frequently use divalproex and carbamazepine for mood stabilization.

    Carbamazepine with its drug interactions and potential drug interactions deserves special attention. Be sure to look at the “entire patient” and if the patient is of Asian descent, genetic testing for HLA-B*1502 antigen is a must. Stevens-Johnson syndrome is frequently referred to as “the Mother of all Skin Rashes.”

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    Overview of Phenobarbital and Phenytoin

    PHENOBARBITAL

    Phenobarbital tablets 15mg,30mg,60mg,90mg, 100mg

    20mg/5cc elixir
    Phenobarbital was first marketed in 1912 by Bayer under the brand name Luminal®.

    Mechanism: binds to GABA receptors and intensifies the effects of GABA.
    INCREASES the duration of the GABA mediated chloride channel opening. Chloride is the major inhibitory ion in the central nervous system.

    Use: partial and generalized seizure

    Dosage:
    Child: 3-6mg/kg/ day in divided doses.
    Adult: 60-100mg/day

    Neonates: is drug of choice for seizures. May cause delayed intellectual development. Adverse effects: drowsiness, depression, and confusion

    Contraindications: drug abusers, alcohol abusers, depressed patients

    Drug interactions: Phenobarbital is a potent p450 enzyme inducer.
    Decreased serum levels of: Warfarin, OC’s, propranolol, lamotrigine, and theophylline (speeds up metabolism)

    HYPERLIPIDEMIA: Enzyme-inducing antiseizure drugs have been associated with an increased incidence of hyperlipidemia. Order lipid panels for patients who require long-term therapy with enzyme-inducing drugs.

    Drug Monitoring: therapeutic blood level 10 to 40mcg/mL, Time to steady state: 14 to 21 days

    Patient education:
    • withdraw slowly from drug, under a practitioner’s advice
    • Schedule IV drug

    • NET EFFECT on the GABA receptor
    • Barbiturates increase the duration of chloride ion channel opening at the GABA receptor, to increase the efficacy of GABA.
    • Benzodiazepines increase the frequency of the chloride ion channel opening at the GABA receptor to increase the potency of GABA.
    Other Uses:
    • To prevent seizures in newborns, who are born to mothers with a history of heroin use during pregnancy
    • To increase breakdown of bilirubin in neonates to prevent jaundice. (Gilberts syndrome)


    Phenytoin, “Diphenylhydantoin, DPH (Dilantin®)

    History: In 1908, phenytoin was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. In 1938, it was discovered to be an effective anti-seizure medication.

    Available as capsules: 100mg, chew tabs 50mg, suspension 125mg/5cc and Phenytek® 200mg & 300mg

    Mechanism: stabilizes neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of sodium ions.

    Use: simple/complex partial, generalized tonic-clonic.

    Dosage: Adult: 300mg-700mg/day

    Adverse effects: nystagmus, ataxia, sedation, confusion, gingival hyperplasia, hirsutism, blood dyscrasia, vitamin K deficiency, osteomalacia, & folate deficiency. Can cause megaloblastic anemia.

    Contrandications: do not use in sinus bradycardia, or cardiomyopathies

    Drug Interactions
    • Drugs increasing the effect of phenytoin - inhibit metabolism: Allopurinol, benzodiazepines, cimetidine, alcohol, fluconazole, metronidazole, omeprazole, sulfonamides, valproic acid, and trimethoprim. Alcohol-acute ingestion
    • Drugs decreasing effect of phenytoin - increase metabolism: Barbiturates, carbamazepine, alcohol- (chronic), theophylline
    • Phenytoin is also an enzyme inducer- it will decrease the effectiveness of oral contraceptives. It also decreases the effectiveness of: Acetaminophen, amiodarone, carbamazepine, quinidine, theophylline & valproic acid.
    Hyperlipidemia: Enzyme-inducing antiseizure drugs have been associated with an increased incidence of hyperlipidemia. Order lipid panels for patients who require long-term therapy with enzyme-inducing drugs.

    Drug Monitoring: optimal blood level 10-20mcg/mL. Time to steady state: 5-10 days

    Patient Education (Phenytoin):
    • Practice good oral hygiene to decrease gingival hyperplasia/li>
    • Take with food to decrease GI upset.
    • Avoid alcohol
    • Watch for drowsiness, dizziness, blurred vision. Exercise caution when driving.
    • Encourage use of another method of birth control


    Both phenytoin and phenobarbital have been available for over 100 years. From the folks who brought us aspirin and heroin, Bayer Pharmaceuticals also brought phenobarbital to market in the early 1900’s, under the brand name Luminal®. Luminal® was used as a sedative and also as an anti-seizure medication.

    Phenobarbital also has a very dark side. In the 1940’s Adolph Hitler used Luminal® as part of his child euthanasia plan to kill mentally and physically handicapped children. Over 5,000 children were killed as part of Nazi Germany’s Kinder-Euthanasie program which led to the extermination of even more children in the concentration camps. It all started with Luminal® being administered to 50 intellectually disabled children in 1940 at a clinic in Ansbach Germany.

    Phenytoin also has a story line, albeit not as tragic as phenobarbital. It was described that Richard Nixon was given phenytoin to stabilize his mood swings when he was in the White House. Jack Dreyfus of the Dreyfus Fund fame, was reported to give Richard Nixon large doses of phenytoin after he was elected in 1968, as Dreyfus felt it helped with mood swings and depression.

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    Overview of Seizure Disorders

    Seizure Basics:: What type of seizure the patient experiences is important to the selection of pharmacotherapy. The purpose of this piece is not to make us amateur neurologists, but to cover the basics:

    Seizures can be divided into two classes: focal or generalized
    • Focal (partial) seizures involve only a portion of the brain and are broken down to their impairment of awareness.
    • Generalized seizures are broken down into motor and non-motor seizures. The most obvious generalized seizure is the tonic-clonic variety.
    Seizures by the numbers: (source: International League Against Epilepsy (ILAE)
    • 90% of people with epilepsy are aware of their diagnosis as a treatable brain disorder
    • 80% of people with epilepsy have available to them safe, effective and affordable medications
    • 70% of patients with epilepsy experience adequate seizure management
    • 10% of the world’s population will experience a seizure in their lifetime
    What meds to choose: Treatment for the first seizure is not immediately recommended if what provoked the seizure can be resolved. Usually, 50% of patients with a new diagnosis of epilepsy will become seizure free with the first antiseizure medication prescribed. Treatment for the first seizure depends on the following:
    • Seizure type
    • Patient preference
    • Risk benefit ratio: side effect profile
    • Patient’s age
    • Potential for pregnancy
    FDA Requires Warnings about Risk of Suicidal Thoughts and Behavior for Antiepileptic Medications. (2008)
    The U.S. Food and Drug Administration announced it will require the manufacturers of antiepileptic drugs to add to these products' prescribing information, or labeling, a warning that their use increases risk of suicidal thoughts and behaviors (suicidality). The action includes all antiepileptic drugs including those used to treat psychiatric disorders, migraine headaches and other conditions, as well as epilepsy.

    The FDA is also requiring the manufacturers to submit for each of these products a Risk Evaluation and Mitigation Strategy, including a Medication Guide for patients. Medication Guides are manufacturer-developed handouts that are given to patients, their families and caregivers when a medicine is dispensed. The guides contain FDA-approved information about the risks of suicidal thoughts and behaviors associated with the class of antiepileptic medications.

    OK, so what about the newer anti-epileptic drugs approved since 2008?
    The August 2, 2021 edition of JAMA Neurology states that “suicidality was evaluated prospectively in trials of 5 antiseizure medications eslicarbazepine (Aptiom®), perampanel (Fycompa®), brivaracetam (Briviact®), cannabidiol (Epidiolex), and cenobamate (Xcopri®), including 17 trials involving 5996 patients, including 4000 patients treated with antiseizure medications and 1996 treated with placebo. There was no evidence of increased risk of suicidality (ideation or behavior) overall or for any individual drug.”

    Basically the study shows: “There is no current evidence that newer antiseizure medications increase suicidality in epilepsy; therefore, a suicidality class warning is not warranted.”
    JAMA Neurol. Published online August 2, 2021. doi:10.1001/jamaneurol.2021.2480

    Background:

    Older agents: Before 1990, we only had 6 drugs to treat all forms of epilepsy: These agents included carbamazepine (Tegretol®), ethosuximide (Zarontin®), phenobarbital, phenytoin (Dilantin®), primidone (Primidone®), and valproic acid (Depakote®/Depakene®). These drugs were used as monotherapy and in combined regimens in newly diagnosed and refractory cases, yet 20% to 30% of epileptic patients are refractory to these drugs.

    All six had in common:
    • Drug interactions (very complex pharmacokinetic parameters)
    • Need for blood level monitoring
    • Teratogenic potential


    I have witnessed four seizures and all four times I was scared to death. I have seen a middle-aged woman have a seizure in church, a 20 something year old female who was waiting for her levetiracetam prescription to be filled, and a 24-year-old who had a seizure as a result of hypoglycemia.

    The lady in the store handed me her empty bottle of levetiracetam and asked “How long is this going to take? I have been out of this for a couple of days.” Within minutes, she was on the floor with a clonic tonic seizure.

    Every time, after every seizure I called 911 to summon help, especially when it happens in the store. Sometimes your most important job is keeping the spectators away from “gawking”, by moving them to the next aisle and allowing the patient some level of dignity.

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    Overview of NMDA Receptor Antagonists in the Management of Alzheimer’s Disease

    NMDA receptor antagonists
    “neuroprotective”

    Memantine (Namenda®): tablets 5mg & 10mg (approved 2003) generic available Namenda-XR®: once daily available as 7mg,14mg, 21mg, 28mg XR capsules (approved 2010) generic available

    Mechanism: Persistent activation of CNS n-methyl-d-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been postulated to contribute to symptoms of Alzheimer’s. The drug memantine (Namenda®) has low to moderate affinity for the NMDA receptor. In the presence of memantine, an open channel antagonist, excessive calcium is prevented from entering, effectively lowering background noise. Memantine binds deep inside the channel, not at the glutamate receptor. This helps memantine discriminately block abnormal glutamate activity.

    Memantine remotely modulates the receptor, preventing excessive flow, BUT allowing normal function. The abnormal glutamate activity that leads to neuronal loss is prevented, but physiological activation that produces learning and memory is preserved. Memantine (Namenda®) blocks neuronal toxicity and has a neuro-protective effect on the glutaminergic and cholinergic neurons.

    Dosage: start 5mg daily, increase to 5mg BID, then 5mg in am and 10mg in PM, then 10mg BID. Wait 1 week between dosage interval increases. For XR capsules, start with 7mg/day titrating to 28mg max. Separate dosage increases by 7 days.

    NOTE: this drug is often used in combination with the cholinesterase inhibitors. Is used for moderate to severe Alzheimer’s disease. This drug is said to improve behavior.

    Adverse Effects: generally, well tolerated.

    Contraindication: drugs that make urine alkaline- sodium bicarbonate, carbonic anhydrase inhibitors or severe UTI’s

    Drug Interactions: Clearance of memantine is reduced by 80% in alkaline urine conditions pH=8. May also interact with drugs secreted by tubular secretion (HCTZ, ranitidine, cimetidine, triamterene, quinidine)

    Memantine and Donepezil Extended Release (Namzaric®) 28/10 and 14/10
    (cost= $507.00/month)
    Treatment of moderate to severe dementia of the Alzheimer's type in patients stabilized on:
    • Memantine (10 mg twice a day or 28 mg ER once a day) and donepezil 10 mg once a day, or
    • Memantine (5 mg twice a day or 14 mg ER once a day) and donepezil 10 mg once a day in patients with severe renal impairment
    Lecithin Lecithin is a major dietary source of choline, so extra consumption may reduce the progression of dementia. After multiple studies it showed no more effect than placebo in the treatment of Alzheimer’s disease. Has no therapeutic effect in early onset Alzheimer’s.

    CROSSWORD PUZZLES — possibly the most efficacious prevention for Alzheimer's https://www.alzinfo.org/articles/crossword-puzzles-alzheimers/
    “We report a direct association between cognitive activity and Pittsburgh compound B uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of beta-amyloid, perhaps influencing the onset and progression of Alzheimer’s disease,” the researchers write.”

    Pittsburgh compound B binds to beta-amyloid, a toxic protein that builds up in the brains of those with Alzheimer’s and is the main component of the brain plaques that characterize the disease.

    The researchers found that the more often someone engaged in mentally stimulating activities, the less buildup of beta-amyloid they were likely to have in the brain. Other tips to reduce the risk of cognitive decline or dementia, some evidence (not high-level) supports the following:
    • For adults who smoke, offer interventions to facilitate smoking cessation.
    • Reduce or stop excessive alcohol consumption
    • Mediterranean-like diet may be beneficial
    • Offer cognitive training for mild to moderate impairment.
    • Hypertension, diabetes, dyslipidemia (at mid-life), and weight (at mid-life) management may be offered.


    Alzheimer’s disease affects 1 in 9 older Americans, with 2/3 of them being women. Currently there are 6 million people living with Alzheimer’s disease, and that number is expected to double by the year 2050. Currently, this disease costs the nation $355 billion dollars. Between 2000 and 2019, deaths from heart disease have decreased 7.3% while deaths from Alzheimer’s have increased 145%.

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    An Overview of Cholinesterase Inhibitors in Alzheimer’s Disease

    Cholinesterase Inhibitors

    Donepezil (Aricept®) 5mg and 10 mg tablets; 23mg tablets (approved 1996) Dosage: initial: 5mg at bedtime. May increase to 10mg 4 to 6 weeks later. Take in the evening, just prior to retiring.
    • 5mg: mild to moderate AD
    • 10mg: mild, moderate, severe AD
    • 23mg: moderate and severe AD (only increased score 2 points out of 100)
    Donepezil® (Aricept) 23mg tablet: For moderate to severe dementia. Must be stabilized on 10mg dose for 3 months before instituting the 23mg dose. Causes significant GI distress. Adverse effects: insomnia, dizziness, nausea, diarrhea, headache. (all less than 10%). Much higher incidence of GI upset and weight loss with 23mg dose.

    Contraindications: increases gastric secretions. Watch for GI bleeding especially if on NSAIDS

    Drug interactions: P450 inhibitors could increase blood levels. Anticholinergics (such as those of IBS and Overactive bladder) will decrease effectiveness.

    Patient education: Take right before bedtime. May take with food. Generally, well tolerated.

    Rivastigmine (Exelon®) caps: 1.5, 3,4.5 & 6mg (approved 2000)
    Dosage: initial: 1.5mg BID. May increase to 3.0mg BID after 2 weeks.
    • May increase to 4.5mg BID after two weeks, and to 6mg BID in 2 weeks.
    • Usual maintenance dose is 3 to 6 mg BID.
    • Take with food in divided doses in the morning & evening.
    Adverse effects: nausea (47%), vomiting (31%), diarrhea (31%), headache (17%), dizziness (21%) anorexia (17%)

    Contraindications: cholinergics increase gastric secretions. Watch for GI bleeding especially if on NSAID

    Drug interactions: not metabolized by P450. Anticholinergic drugs will decrease effectiveness.
    Patient education: High incidence of nausea, vomiting and diarrhea
    NOTE: Rivastigmine is the only cholinesterase inhibitor approved for dementia in Parkinson’s Disease

    Rivastigmine (Exelon®) patch:
    Dosage available: 4.6mg and 9.5mg/day patch
    • For patients who have trouble swallowing
    • Once daily dosing instead of the BID oral formulations increases compliance.
    • Less nausea and vomiting because drug levels are lower and steadier than with caps
    • New start: 4.6 mg patch, then increase to 9.5 mg after 4 weeks if tolerated.
    Switching from oral: prescribe the 4.6 mg patch for those taking less than 6 mg/day of oral or the 9.5 mg patch for patients on higher doses.



    Galantamine (Razadyne®) 4, 8, 12mg tabs. ER caps available. (approved 2001)
    {name was originally Reminyl, but was changed due to confusion with Amaryl®}
    An anticholinesterase, but also has activity as a nicotinic receptor agonist

    Dosage: start: 4mg twice daily for 4 weeks. Then 8mg twice for 4 weeks. Then increase to 12mg twice daily for 4 weeks, then 16mg twice daily.

    Maintenance dose: 8 to 16mg BID

    Adverse effects: Pregnancy Category B

    Contraindications: Cholinesterase inhibitors increase gastric secretions. Watch for GI bleeding if on NSAID

    Drug interactions: Anticholinergics will reduce its effect.

    Drug monitoring: dosage adjustments are necessary in hepatic impairment and renal impairment.

    Patient education: if therapy is interrupted for several days, the patient must be re-titrated. Starting on the lowest dose and escalated to maintenance dose.

    Class side effects: donepezil, rivastigmine, galantamine)
    • There is an increased risk of bradycardia and fainting in patients taking cholinesterase inhibitors
    • Remember: cholinergic stimulation can slow heart rate which can to a higher risk of fainting, falls, hip fractures, and pacemaker insertion.
    • Cholinesterase inhibitors increase gastric secretions. Watch for GI bleeding if on NSAID
    Bottom Line: One in 12 patients will experience side effects (mostly GI) with cholinesterase inhibitors. Conversely, only 1 in 12 patients show any improvement. No good evidence that drugs delay nursing home placement. Rate of functional and cognitive decline do not improve with drug therapy.



    Alzheimer's drugs have always been expensive. Back in 2010 the chief financial officer called me for some advice. He was curious as to how the Long-Term Care unit of the business had drastically decreased their monthly wholesaler bill.

    He said, “I know they are good, but they cut over $240,000 off last month’s bill.” I explained that donepezil (Aricept®) went from being $240.00 for thirty tablets per patient per month to the generic being around $6.00 per patient per month.

    Most of us seasoned pharmacists remember the first Alzheimer’s drug tacrine (Cognex®) by Parke Davis. It was dosed four times daily. When I first dispensed it and explained the dosing to the patient’s husband he quipped “If she can remember to take this medicine four times a day, does she really have Alzheimers?!!”

    Efficacy of these drugs is questionable, at best. We indeed are treating the caregiver and not so much the patient.

    Have a Great Day on the Bench!!

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    Overview of Alzheimer’s Disease

    Signs and symptoms of Alzheimer’s Disease (AD):

    MILD ADMODERATE ADSEVERE AD
    ForgetfulnessDisorientationAgnosia* (more pronounced)
    Word-finding difficultyIncreased memory lossApraxia*
    ApathyConfusionAggression
    Poor attentionInsomniaAgitation
    Difficulty with complex tasksWanderingIncontinence
    DepressionSpeech difficultyPoor Basic ADL
    Work TroubleRestlessGait disturbance
    Difficulty with IADL


    Definitions:
    • Apraxia: inability to carry out purposeful movements in the absence of paralysis or other motor/sensory impairment
    • Agnosia: loss of the power to recognize the import of sensory stimuli
    • ADL: activities of daily living
    • IADL: instrumental activities of daily living
    RULE OUT:
    • Vitamin B12 deficiency
    • Depression, which is a treatable comorbid condition.
    Incidence:
    • The incidence and prevalence of Alzheimer’s disease increases with age, essentially doubling in prevalence every 5 years after the age of 65 years.
    • Onset of AD before age 60 has been associated with a genetic disposition (less than 1% of patients.)
    • Patients with Down Syndrome can develop signs of AD 10-20 years earlier than their counterparts.


    Cholinesterase inhibitors
    The cholinergic system is the system MOST often associated with the early degeneration of Alzheimer’s Disease (AD). Large numbers of cholinergic neurons in the basal forebrain innervate the cortex and hippocampus and are intricately involved in normal learning and memory. In addition to loss of these neurons, cholinergic impairments observed in patients with AD also include:
    • Decline in choline acetyltransferase activity
    • Depletion of acetylcholine (Ach)
    • Acetylcholine in CNS: COGNITION
    • Acetylcholine in PNS: MUSCLES and AUTONOMIC nervous system
    • Decline in acetylcholinesterase activity
    Site of dysfunction is also important:
    • Cortex: loss of cholinergic output contributes to attention deficits
    • Amygdala: cholinergic loss is associated with emotional changes.
    Cholinesterase inhibitors function by blocking ACh destruction and increasing the lifespan of the neurotransmitter in the synaptic cleft, therefore compensating for the loss of ACh containing neurons. While they may enhance cognitive function, they do not slow the degenerative process that underlies the disease.

    Mechanism: enhances cholinergic function by reversible inhibition of acetycholinesterase.


    Aducanumab (Aduhelm®)
    Since aducanumab has been in the news and has caused a lot of controversy, lets discuss it first. Mechanism: Aducanumab is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease. The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. Treatment with aducanumab should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials

    Dose: given as a one-hour infusion, given every 4 weeks. Must be titrated, starting with 1mg/kg ending at 10mg/kg. MRI’s need to be obtained before the 7th and 12th infusion.

    Cost and controversy: $56,000 per year. If all 6 million Alzheimer’s Disease patients were treated with aducanumab, we could significantly strain Medicare funds, to the tune of $336 BILLION. For comparison, Medicare Part B, the hospital insurance plan for seniors, spent $37 billion total on ALL drugs in 2019! This amounts to a 10-fold increase for just ONE drug. (Don’t forget the cost of infusion, as well as those MRI’s required by the package insert)

    Efficacy: Efficacy: Biogen states it slows the progression of AD, but only showed a reduction in the number of amyloid plaques, but there is not a direct correlation to the severity of Alzheimer’s.

    Alzheimer’s is indeed a devastating disease. The drug therapy we have isn’t very robust at all. The cholinesterase inhibitors seem to cause lots of side effects and have issues with efficacy. The NMDA antagonist memantine does not show much efficacy either. In short, our toolbox is limited.

    I always use the analogy with my patients of jumping out of an airplane when discussing AD drug therapy. If they jump out of an airplane with a parachute, and I jump out without one, what happens? We both will hit the ground, me a lot faster. Even with the parachute you will eventually hit the ground, just a lot longer time. At their very best, therapies we have for AD are parachutes, not cures.

    I truly feel with the lack of efficacy of the AD drugs, we are treating the caregiver… just by showing we do care about their loved one with AD.

    Have a Great Day on the Bench!!

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    Overview of Treatment Considerations for Patients with Parkinson’s Disease

    Parkinson's Disease

    Parkinson’s Disease has more surgical and pharmacological treatments than any other disease of the central nervous system. The effect on activities of daily living (ADL) are the primary determining factor for selection of pharmacological treatment options. The current belief is that the choice and timing of initial therapy for PD, regardless of mechanism of action, has little impact on the long-term outcome of PD in terms of motor fluctuations.

    Holding off treatment unnecessarily deprives patients of therapeutic benefit early in the disease, when the potential for sustained improvement is greatest. This needs to be a shared clinical decision with the patient and their family.

    Hoehn & Yahr Scale (used to describe severity of Parkinson’s)
    • Stage 1 : unilateral involvement
    • Stage:2 bilateral involvement, no postural abnormalities
    • Stage 3: Bilateral involvement , mild postural imbalance, patient is independent
    • Stage 4: Bilateral involvement postural instability, patient requires much help
    • Stage 5: Severe, fully developed disease, patient restricted to bed or chair
    Wehn to start levodopa treatment...
    • Delay treatment: evidence suggests long term L-dopa therapy can cause response fluctuations, dementia, and loss of L-dopa efficacy.
    • Dyskinesias are more likely the longer patients are on levodopa. (window keeps getting smaller)
    • Start ASAP: counter-argument that response fluctuations is due to disease progression and not L-dopa therapy. In a 3-year multicenter study, mortality doubled if L-dopa therapy is delayed.
    • Current thinking is to initiate treatment when disease interferes with person’s occupation or activities of daily living. The former belief of holding off levodopa therapy (think rationing levodopa therapy) has been unfounded.
    MOTOR FLUCTUATIONS and POSSIBLE INTERVENTIONS IN PARKINSONS DISEASE

    For end-of dose deterioration (“wearing off”) consider:
    • Increase frequency of carbidopa-levodopa doses.
    • Use controlled release carbidopa-levodopa
    • Add dopamine agonists, selegiline, tolcapone or amantadine.
    • Add apomorphine
    For delayed onset of response consider:
    • Giving on an empty stomach before meals
    • Crushing or chewing with a full glass of water
    • Reducing protein intake and antacids
    • Adding dopamine agonists
    • Using morning standard release carbidopa-levodopa instead of sustained release
    For drug-resistant “off periods” consider:
    • Increasing dose and/or frequency of carbidopa-levodopa
    • Crushing or chewing and take with a full glass of water
    • Adding dopamine agonists, and or apomorphine
    For treatment of random oscillations (“on-off”), consider:
    • Adding dopamine agonists, selegiline, or tolcapone
    • Using ‘drug holidays’
    For treatment of start hesitation (“freezing”), consider:
    • Increasing dose of carbidopa-levodopa
    • Adding dopamine agonists
    Treatment of Parkinson’s Disease Dementia
    • Parkinson's disease dementia: dementia that occurs more than a year after onset of Parkinson's
    • Hallucinations or delusions can occur in as many as 50 percent of patients with Parkinson’s disease at some time during the course of their illness.
    • Lewy body dementia
      • cause: abnormal protein deposits in brain
      • deficient in BOTH acetylcholine (like Alzheimer’s) and dopamine (like Parkinson’s).
      • challenge: Treating one symptom worsens the other. (cholinesterase inhibitors help dementia but makes Parkinson’s worse). L-dopa helps motor movements but makes dementia worse.
    • L-dopa and dopamine agonists may cause psychiatric symptoms including delirium, agitation, paranoia, delusions, or hallucinations.
    Treatment choices for dementia:
    • Pimavancerin (Nuplazid®): first and only medication indicated for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
      • What makes it different: doesn’t block dopamine receptors; it is an “inverse agonist” at the 5-HT2a receptor.
      • Dose=34mg/day
      • Reduce dose by ½ if strong CYP450-3A4 inhibitor. Dose= 17mg/day
      • Potential for QT prolongation. Caution with other drugs
    • Clozapine (Clozaril®) at low doses is effective but requires monitoring for neutropenia. (only available at specialized pharmacies)
    • Quetiapine (Seroquel® started at 12.5mg / week and titrated upward by 12.5mg/week is also safe and effective and doesn’t require the monitoring for neutropenia that Clozaril® requires.
    • Rivastigamine (Exelon®) the only cholinesterase inhibitor approved


    Stepwise Approach to Drug-Induced Psychosis in Parkinson’s Disease:
    1. Simplify regimen. Stop medications with highest risk to benefit first.
      1. Stop anticholinergics and antidepressants with anticholinergic activity
      2. Stop Selegiline
      3. Taper and stop dopamine agonists
      4. Taper and stop amantadine (watch for amantadine withdrawal)
      5. Stop COMT inhibitors.
    2. Start quetiapine (Seroquel®) or pimavancerin (Nuplazid®) or rivastigamine (Exelon®) therapy.
    Dextromethorphan=20mg + quinidine=10mg (Nuedexta®):
    Used for treatment of pseudobulbar effect, which is emotional lability manifested by laughter or crying outbursts in neurological conditions such as MS, ALS, neurological conditions. Pseudobulbar effect has been treated by TCA’s, and SSRI. Quinidine (antiarrhythmic) blocks the first pass metabolism of DM and causes an increase of 25 fold in the AUC of DM.

    Drug interactions: stop SSRI, SNRI or TCA or MAOI.

    Parkinson’s Disease is arguably the worst of the neurological diseases. Patients experience their own decline every single week; they are worse this week than they were last week, and next work will be even worse. If the physical manifestations of Parkinson’s Disease are challenging enough, the psychological manifestations of the disease can be equally disabling.

    Have a Great Day on the Bench!!

    August 2021

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    An Overview of Carbidopa/Levodopa Therapy for the Management of Parkinson’s Disease

    Levodopa therapy

    Mechanism: Dopamine does not cross the blood brain barrier (BBB), however Levodopa the metabolic precursor, does cross the BBB. It is decarboxylated into dopamine in the basal ganglia and in the periphery by dopa-decarboxylase. Hence the blood dopamine is increased.
    • Sinemet® (carbidopa/levodopa):10/100, 25/100, 25/250 immediate release.
    Controlled release: 25/100 and CR 50/200
    • Rytary® (carbidopa/levodopa): Extended-release capsules: Carbidopa and levodopa 23.75 mg / 95 mg, 36.25 mg / 145 mg, 48.75 mg / 195 mg, 61.25 mg / 245 mg. Immediate release beads, coupled with extended-release beads. Released at different intervals in the gastrointestinal tract.
    • Stalevo®: (carbidopa/levodopa and entacapone)
      • Stalevo® 50: 12.5mg carbidopa/ 50mg levodopa/ 200mg entacapone
      • Stalevo® 100: 25mg carbidopa/ 100mg levodopa/ 200mg entacapone
      • Stalevo® 150: 37.5 carbidopa/ 150mg levodopa/ 200mg entacapone
    • Inbrija®: Levodopa for inhalation: Is a dry powder for inhalation containing 84mg per dose (2 capsules at 42mg each), for breakthrough freezing episodes. Can be used up to 5 times a day for a maximum of 420mg/day. Works within 10 minutes of inhalation.
    I watched the video, and can’t imagine how a Parkinson’s patient could load this device. It is similar to the Spiriva Handihaler®, where a capsule gets punctured, and the dry powder gets inhaled. Check out the video: https://www.inbrija.com/how-to-use

    Effects of carbidopa:
    • decreases peripheral conversion of levodopa to dopamine by blocking dopa-decarboxylase
    • increases amount of levodopa to cross blood brain barrier
    • carbidopa does NOT cross blood brain barrier.
    • carbidopa has a levodopa sparing effect, decreasing the amount of Levodopa necessary to obtain a clinical response by 75%
    Dosage: must be individualized.
    Start with Sinemet 25/100 three times daily, or 10/100 three or four times daily
    Ideal carbidopa range =70 to 100mg. (over 125mg has no more effect)
    • Adjust carbidopa dose based on side effects. When more carbidopa is required, move up to 25/100.
    • Adjust levodopa dose based on desired effects. If more levodopa is required move up to 25/250. Maximum daily dose of levodopa is 3g.
    May increase by one tablet daily or every other day.
    NOTE: sustained release formulations may cause more erratic absorption.

    Adverse effects: When used alone, L-Dopa effects are common: nausea & vomiting (80%), cardiac arrhythmias (10%) postural hypotension (25%). These all occur secondary to the peripheral conversion of levodopa to dopamine. Therefore, carbidopa is added, based on side effects.

    Challenges with Levodopa therapy
    • Medication dosages taking too long to “kick in” and start working
    • Medication wearing off before the next scheduled medication dose
    • Severe on-off medication fluctuation periods (e.g. rapid cycling during the day ranging from feeling completely on medication to completely off medication)
    • Dyskinesia (too much movement, usually resulting from too high of a blood level of dopamine)
    • Too many pills
    • Too many medication dosage intervals; such as taking medications every 1-2 hours throughout the waking day
    Wearing off: 2/3 of patients will experience loss of efficacy after 5 years.

    ON/OFF: wide fluctuations between hyperkinetic to hypokinetic state, potentially occurring several times a day.

    “ On” period: : is characterized by dyskinesias of face, neck & limbs, augmented by stress or movement at a time of maximal levodopa benefit. They appear as abnormal, choreiform movements, usually involving the neck, trunk and upper extremities.

    Dyskinesias can be thought of as too much movement secondary to the extension of the pharmacologic effect or too much striatal dopamine stimulation. Dyskinesias are more likely to occur with L dopa therapy (D1 and D2 agonism) suggesting that the D1 receptor is involved in producing dyskinesia. Most patients however will tolerate these mild dyskinesias as a trade-off for good mobility.

    “Off” period: characterized by akinesia & dystonia. Can be painful and immobilizing generalized to limb, face & trunk. This can be very debilitating as it can cause a freezing of gait. Rock hard spasms of abdominal musculature may occur.
    Can address this concern of on/off by using Sinemet SR®. May also add COMT or MAO-b inhibitors.

    Other Adverse effects: akathisia, delirium, depression, hallucinations, paranoia & dementia.

    Contraindications: levodopa may activate malignant melanoma. Rule out any suspicious skin lesions before therapy.

    Food interactions: Competes with protein for absorption. Lower protein meals during the day and main protein at dinner.

    Drug interactions: MAOI (antidepressants). Stop for 2 weeks before initiating therapy. Pyridoxine (B-6) decreases Levodopa effect; however, this is seen less often with carbidopa/levodopa combinations. Chelation (Iron, Calcium, multivitamins) can affect absorption.

    Drug Monitoring: Clinical response drives the therapy and dosing. Notify practitioner if uncontrollable movements of face, tongue, limbs, mood or mental changes, irregular heartbeat, difficult urination, or persistent nausea and vomiting.

    Patient Education Levodopa therapy:
    • May take a few weeks for optimal results.
    • Avoid vitamins with B-6 (pyridoxine)
    • Exercise caution when driving.
    • Watch for orthostatic hypotension.
    • Take medication with food.
    • Do not crush SR tablets
    Other Drugs:
    • Levodopa (Larodopa®): is available as 100mg & 500mg tablets
    • Carbidopa (Lodosyn®): is available as 25mg tablets.


    There seems to be a shortage of neurologists in most areas, so primary care physicians, nurse practitioners and physician assistants will become more engaged in the management of Parkinson’s disease and drug therapy. One of my favorite neurologists several years ago was resistant to hiring physician assistants and CRNP’s because neurology patients are such a challenge. After he finally broke down and had to hire two physician assistants, he said it was one of the best decisions he ever made. He said, “I finally get to be a doctor again, and my PA’s help keep the loose ends tied together.” The pharmacist, as the drug expert, will be called upon to guide family practice physicians and their mid-level prescribers to provide advice for their Parkinson's patients.

    Most neurologists at one time held off on Levodopa therapy until after all of the other treatment options were exhausted. Today’s recommendations are to start when the patient needs it. Shared clinical decision making is the best approach for starting any Parkinson’s therapy.

    Have a great day on the bench!!

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    An Overview of Adjunctive Therapies for Parkinson’s Disease

    Adjunctive therapies for Parkinson’s Disease

    COMT inhibitors: (catecholamine-o-methyl-transferase)
    • Entacapone (Comtan®) 200mg tablets (approved 1999)
    • Tolcapone (Tasmar®) 100mg & 200mg tablets (approved 1998)
    • Opicapone (Ongentys®) – 2020 available as 25mg and 50mg capsules (approved 2020)
    Mechanism: no effect on Parkinson’s disease as monotherapy. They are used with carbidopa/levodopa to prevent peripheral conversion. Inhibits COMT, increasing dopamine levels. When carbidopa blocks dopa decarboxylase as with carbidopa/levodopa (Sinemet®), COMT is the main metabolizing enzyme for levodopa.

    Significantly decreases off times and decreases levodopa requirements. Prolongs and potentiates the levodopa effect and thereby reduce "off" time when used as add-on therapy with levodopa.

    Increases blood levels (AUC), but does not increase Cmax or Tmax.

    May theoretically be better than CR products because they don’t delay time to maximal effect. Overall help simplify carbidopa/levodopa (Sinemet®) dosing, may reduce Levadopa requirements and decrease time in “off” period.

    Dosage: decrease the dose of levodopa 10 to 30 percent to avoid exacerbating peak-dose dyskinesia and other dopaminergic side effect
    • Entacapone (Comtan®): 200mg with each dose of carbidopa/levodopa max=1600mg/day
    • Opicapone (Ongentys®): The recommended dosage is 50 mg once daily at bedtime
    • Tolcapone (Tasmar®): 100mg three times daily. (May cause severe liver failure, making it a last line choice)
    Adverse effects: dizziness, drowsiness, diarrhea, orange discolored urine (tolcapone, entacapone). Because of increased dopaminergic stimulation, patients might see dyskinesia, psychiatric effects (such as visual hallucinations), nausea, orthostatic hypotension, and somnolence.

    Contraindications: tolcapone (Tasmar®): liver disease

    Drug interactions: COMT also breaks down sympathomimetics. May increase BP & HR, possible arrhythmias

    Drug Monitoring: tolcapone (Tasmar®): liver enzymes. D/C at once if ALT or AST is above ULN.


    Carbidopa/ Levodopa/ Entacapone:
    • Stalevo® 50: 12.5mg carbidopa/ 50mg levodopa/ 200mg entacapone
    • Stalevo® 100: 25mg carbidopa/ 100mg levodopa/ 200mg entacapone
    • Stalevo® 150: 37.5 carbidopa/ 150mg levodopa/ 200mg entacapon
    Istradefylline (Nourianz®) approved 2019

    Mechanism: Istradefylline is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes

    Dosage: 20mg daily, up to a maximum of 40mg daily.
    Note: Patients who smoke 20 or more cigarettes per day (or the equivalent of another tobacco product), recommended dosage is 40 mg once daily

    Adverse effects: The most common adverse reactions were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia. Patient Education: avoid OTC sympathomimetics. Watch for postural hypotension. Exercise caution when driving.

    I love the brand name for entacapone (Comtan®); it’s nice to have a brand name that describes the mechanism of action, like Namenda®, which is an NMDA receptor antagonist for Alzheimer’s.

    Istradefylline intrigues me. It is a methylxanthine like caffeine, theobromine, theophylline and pentoxifylline.

    So, this class of drugs contains a stimulant (caffeine), an ingredient in chocolate (theobromine), an asthma/COPD medication (theophylline), a drug to improve blood flow for intermittent claudication (pentoxifylline) and a Parkinson's drug (istradefylline). Now that is diversity in a family!!

    Lots of mechanisms of action for Parkinson’s treatment, all based on providing sufficient dopamine to the brain. I tell my students to remember the three big enzymes for dopamine metabolism: catecholamine-o-methyl-transferase (COMT), monoamine oxidase (MAO) and dopa-decarboxylase (DDC).

    Have a great day on the bench!!

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    An Overview of Monoamine-B Oxidase Inhibitors

    Monamine Oxidase Inhibitors (MAO-b)

    Monoamine oxidase-B (MAO-b) is an enzyme responsible for the chemical breakdown of dopamine in the brain. MAO-B inhibitors act by inhibiting the activity of this enzyme and therefore slowing the breakdown of dopamine, which allows for increased levels of dopamine in the brain.

    MAO-b inhibitors can be given either as a monotherapy or they can be combined with carbidopa-levodopa therapy. They are considered to be modestly effective as early symptomatic treatment for Parkinson’s disease. Although MAO-b inhibitors have been shown to bring about only a modest decrease in the severity of Parkinson’s symptoms, initiation for MAO-b therapy can delay the reliance on levodopa.

    Selegiline (L-deprenyl) brand: Eldepryl® (1989) or Carbex®/ Zelapar(ODT) 5mg caps (now generic)

    Mechanism: irreversible inhibitor of MAO-b

    Dosage for Selegiline: Parkinsonian patients receiving levodopa/carbidopa therapy who demonstrate a deteriorating response to this treatment:
    Dose: 5mg at breakfast and at lunch (gets metabolized to an “amphetamine like” metabolite). Don’t exceed max daily dose of 10mg, because of non-selective inhibition of MAO over that dose.

    Adverse effects: Dosing over 10mg per day puts patients at risk for dietary reactions with tyramine containing foods, referred to as “cheese reaction”.

    Contraindications: No dietary restrictions are required due to selective MAO-b inhibition

    Drug interactions: Although no interactions with fluoxetine & meperidine have been reported with this medication, it is prudent not to administer these drugs.
    • Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin Norepinephrine Reuptake Inhibitors (SNRI) , Buspirone, and mirtazapine may cause Serotonin Syndrome (excessive levels of serotonin): Confusion, agitation, tremor, seizures & death.
    Drug Monitoring: clinical presentation

    Patient Education: Don’t exceed 10mg. Take at breakfast & lunch. Report severe headache or elevated blood pressure

    Selegiline oral disintegrating tablets (Zelapar®) 1.25mg
    • Designed to minimize first pass metabolism, increase bioavailability, and reduce amphetamine-like metabolites.
    • Start with 1.25mg dissolved in mouth. After 6 weeks, may increase to maximum dose of 2.5mg.
    Rasagiline (Azilect®) Teva Neuroscience ,2006 0.5mg, 1mg (now generic)
    • Approved for initial monotherapy, as well as adjunct therapy in moderate to advanced disease.
    • Is a MAO-B inhibitor that blocks the breakdown of dopamine, primarily in the brain.
    • Adverse effects: hallucinations, headache arthralgia, dyspepsia, depression, falls and flu-like symptoms
    • Dosage:
      • Monotherapy: 1mg daily
      • Combination therapy: initial dose 0.5mg daily. May increase to 1mg if inadequate response. May potentiate adverse effects of L-dopa (hallucinations and dyskinesias)
    Safinamide (Xadago®) 50mg & 100mg ($800/month) new-2017
    • A reversible (new class of drugs) MAO-B inhibitor as an adjunct to carbidopa/levodopa therapy in patients that experience on/off motor fluctuations.
    • Currently not approved as monotherapy.
    • Used in mid-late-stage Parkinson’s and increases ON time without causing dyskinesias.
    • Not known if there are any advantages over the older irreversible MAO-B inhibitors.
    I don’t think anyone waited more anxiously for the introduction of Selegiline (L-deprenyl) than my wife’s family. My mother-in-law as I described in the first unit of this Neurology section, was a robust and brilliant reading supervisor. She had been afflicted with Parkinson’s in her early 50’s. We waited anxiously for Selegiline to become available, as we heard about its success in Europe.

    As I described at the beginning of this letter, MAO-b inhibitors are lightweights. Once the drug became available in the US, I’m sure my mother-in-law was one of the first to have it prescribed for her. Unfortunately, it provided no benefit as her condition was so advanced.

    Have a great day on the bench!!

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    An Overview of Dopamine Receptor Agonists

    Dopamine Receptor Agonists

    Mechanism: Dopamine agonists are ineffective in patients who have shown no therapeutic response to levodopa. Seems to be more efficacious in early Parkinson’s disease.
    • Direct stimulation of dopamine receptors
      • Although they do not “look” like dopamine, they stimulate the dopamine receptor.
    Class effects:
    • Associated with pathologic gambling, compulsive sexual behavior, binge eating or compulsive buying, in up to 50 percent of patients with long-term use.
      • Remember, dopamine is known as the “pleasure hormone”/li>
      • Dopamine agonist withdrawal syndrome (DAWS): If stopped suddenly, anxiety, panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving, like cocaine withdrawal may occur.
      • Class adverse effects: watch for dizziness, hallucinations can occur, may all cause drowsiness, may cause nausea, vomiting, headache, dry mouth and fatigue. Vivid dreams are common leading to sleep disturbances.
    Bromocriptine (Parlodel®) tablets: 2.5mg caps: 5mg
    Classification: Ergot Dopamine Receptor Agonist

    Start with 1.25mg BID with meals. May increase dose by 2.5mg /day every 2 to 4 weeks.
    Usual dosage range: 10 to 40mg/day. Don’t exceed 100mg/day. Seldom used for Parkinson’s disease, mostly used as second line therapy for hyperprolactinemia. Patients unresponsive to L-dopa therapy are poor candidates for bromocriptine.

    CAUTION: CAUSES stiffening of heart valves. Causes significant nausea.

    Cycloset® (Bromocriptine) is an add on treatment for Type-2 diabetes. Initial dose is one tablet (0.8 mg) daily increased weekly by one tablet until maximal tolerated daily dose of 1.6 to 4.8 mg is achieved.



    NON-Ergot dopamine receptor agonists: Pramipexole & Ropinirole

    Pramipexole (Mirapex®) (non-ergot) 0.125mg, 0.25mg, 0.5mg 1mg and 1.5mg (available generically)
    MIRAPEX ER® 0.375, 0.75, 1.5mg, 3.0mg, 4.5mg (available generically)
    • tablets are taken once daily, with or without food
    • Is approved as monotherapy
    • Usually dosed three times daily for Parkinson’s disease
    • Maintenance dose: 1.5 to 4.5mg/day
    • If used with Levodopa, may decrease L-dopa dosage. (May see average decrease of 27%)
    Ropinirole (Requip®) (non-ergot) 0.25mg, 0.5mg 1mg,2mg, 4mg (available generically)
    REQUIP XL: once daily : Tablets: 2 mg, 4 mg, 6 mg, 8 mg, and 12 mg
    Approved for monotherapy--(generics are available)
    • Take 3 times daily with or without food.
    • Starting dose is 0.25mg three times daily
    • Increase dose by 0.25mg thee times daily for each week for 4 weeks.
    • When used as an adjunct to levodopa, the levodopa dose can be decreased gradually as tolerated.
    Contraindications: may need to reduce levodopa based on clinical response

    Drug interactions: Ropinirole: CYP1A2 is the major enzyme responsible for the metabolism of ropinirole. Thus inhibitors (ciprofloxacin, fluvoxamine) or inducers (omeprazole or smoking) of CYP1A2 may alter the clearance of ropinirole.

    Drug Monitoring: clinical management of symptoms

    Patient Education:
    • Exercise caution when driving
    • Take with food or milk to reduce GI upset
    • Report mood changes and uncontrolled movements
    USE (Parkinson’s disease): :
    • may be used as monotherapy early on, so as to delay L-dopa therapy.
    • less effective for motor symptoms but do cause less dyskinesias and motor fluctuations.
    • less effective for motor symptoms but do cause less dyskinesias and motor fluctuations. May be effective as add-on treatment to L-dopa therapy induced motor fluctuations.
    USE (restless leg syndrome): :
    • • Requip® (ropinirole) is approved for restless legs syndrome. Begin therapy for RLS: Ropinirole 0.25mg daily 1 to 3 hours before bedtime, with increased doses as needed (by 0.5mg/ week), and as tolerated to a maximum of 4mg/ day. Median dose studied was 2mg.
    • • Mirapex® (pramipexole) is approved for restless legs syndrome as of December. Begin therapy for RLS: Pramipexole 0.125mg once daily 2-3 hours before bedtime. Can be titrated every 4-7 days if needed. 3 strengths available for RLS 0.125mg, 0.25mg and 0.5mg for convenient titration. 75% of patients will have relief at 0.25mg 2-3 hours before bedtime.
    Key diagnostic Criteria for Restless Legs Syndrome (RLS) :
    • Urge to move the legs (usually caused by uncomfortable leg sensations- may be described as aching, burning or painful)
    • Temporary relief with movement – partial or total relief from discomfort by walking or stretching.
    • Onset or worsening of symptoms in the evening or at night.
    • During evaluation, rule out pregnancy, renal failure, or iron deficiency.
    Apomorphine hydrochloride (Apokyn®) injection 10mg/ml (non-ergot)

    Indication: for acute intermittent hypo mobility on “off” or “end of dose wearing off” episodes through stimulation of postsynaptic dopamine D2-type receptors within the caudate-putamen in the brain. Associated with advanced Parkinson’s disease. Helpful for freezing episodes

    Kynmobi® (apomorphine hydrochloride) for the acute, intermittent treatment of off episodes in patients with Parkinson disease (PD)
    • a sublingual film formulation (doses 10mg, 15mg, 20mg, 25mg, and 30mg ) of apomorphine, a non-ergoline dopamine agonist.
    • Adverse reactions: nausea, oral/pharyngeal soft tissue swelling, oral/pharyngeal soft tissue pain and paresthesia, dizziness, and somnolence.
      • Because of the high incidence of nausea and vomiting, an antiemetic starting 3 days prior to the initial dose of Kynmobi is recommended. Avoid ondansetron (Zofran®) for nausea due to hypotension.
    Rotigotine (Neupro®) is a patch. Approved May 2007 (non-ergot).
    Available strengths: 1 mg/24 hr.; 2 mg/24 hr.; 3 mg/24 hr.; 4 mg/24 hr.; 6 mg/24 hr.; 8 mg/24 hr.
    • For early-stage idiopathic Parkinson’s disease and restless legs syndrome. Rotigotine is a dopamine agonist, mimicking the effects of dopamine.


    “Who is the most famous Parkinson’s Disease patient of all?” I would ask my class and the response was usually “Michael J. Foxx”. Wrong! The next answer invariably was “Mohammed Ali”. I would remind the students they are at St. Francis University and this guy’s image could be found anywhere! That’s right “Pope John Paul II” was the answer I would be looking for.

    Exactly 20 years ago we were in Rome Italy, on a pilgrimage with our beloved priest as our tour guide. We went to outdoor Mass at St. Peter’s Square for St Peter and Paul’s Feast Day, which is a holiday in Italy. At the beginning, Pope John Paul walked out with his Cardinals, he read his sermon while he was sitting. By the end of Mass (about 1.5 hours after the start), he was wheeled off in a wheelchair.

    How could he deteriorate so quickly? I later read that before any big event, the Pope’s physician would give him an injection of apomorphine, that would enable him to participate for a while. Unfortunately, it wore off quickly.

    Have a great day on the bench!!

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    An Overview of Drugs Used in the Management of Parkinson’s Disease

    Initial therapy for Parkinson's Disease--manage the symptoms!

    Amantadine:
    • Symmetrel® 100mg capsules, syrup 50mg/5mL
      • Dose is usually 100mg twice daily. Never exceed 400mg.
    • Gocovri® 68.5mg and 137mg ER capsules. /li>
      • The initial daily dosage is 137 mg; after 1 week, increase to the recommended daily dosage of 274 mg .
      • Dosed at bedtime
    • Osmolex ER® Extended-release tablets containing 129 mg, 193 mg, or 258 mg amantadine.
      • Start with 129mg in morning; titrate to a max of 322mg.
    History: Initially developed as an antiviral medication to treat influenza. Was approved in 1968, but later found to be useful as a treatment for Parkinson’s Disease. Because of resistance, amantadine is no longer recommended for prophylaxis or treatment of influenza A, as of 2006.

    Mechanism: Decreases pre-synaptic uptake of dopamine. And enhances dopamine synthesis and release from presynaptic storage granules

    Dosage: 100mg BID max= 300mg/day (dosage adjustment required if renal impaired)
    Response is rapid and is effective in 50% of patients.

    Adverse effects: hyper excitability, tremor, confusion, livedo reticularis (rose colored mottling of skin), slight anticholinergic effects.

    Patient educations:
    • Tolerance develops in 6 to 12 weeks of the initiation of therapy.
    • Take last dose well before bedtime to decrease insomnia.
    Use: To treat early Parkinson’s Disease or as adjunctive treatment in later stages. May be effective in treating tremor which can be resistant to dopamine treatment. Effect may last only a few weeks. Withdraw slowly so as not exacerbate symptoms.



    Anticholinergics:

    Mechanism: Decreases cholinergic function, thereby increasing relative activity of the remaining dopamine. Monotherapy for patients with Parkinson Disease who are less than 65 years of age and have disturbing tremor but do not have significant bradykinesia or gait disturbance. Used for management of symptoms only.

    Drugs and dosage:
    • Benztropine (Cogentin®): tablets = 0.5mg, 1mg & 2mg (generic available)
      • 1 to 2 mg at bedtime, may also divide doses. Up to 6mg/day
    • Trihexyphenidyl (Artane®) : tablets 2mg & 5mg (generic available)
      • Start 1 –2mg first day. May increase by 2mg/day every 3 to 5 days. Max= 15mg
      • Give in divided doses.
    Adverse effects:
    • Minor: you know the big 4 anticholinergic side effects! With apologies for the crudeness here, I will offer a reminder of the popular memory tool here:
      • Can’t see, can’t pee, can’t spit, can’t s**t!
    • Major: delirium, disorientation hallucinations, agitation & anxiety
    • Disease State Interactions: decreased gastric motility, may cause gastric deactivation of L-Dopa
    Patient Educations:
    • if GI upset is a problem, take with food
    • Exercise caution with drowsiness/dizziness, especially during dangerous tasks & driving
    • Hard candy may help relieve symptoms of dry mouth
    • Avoid alcohol
    Use: May be most useful in treatment of tremor and drooling. Withdraw slowly so as not to exacerbate these symptoms.

    Treatment of Parkinson’s Disease can be challenging. Most neurologists usually start with ‘symptom management drugs’ such as amantadine and the anticholinergics. I always found it interesting that benztropine (Cogentin®) was always prescribed by psychiatrists primarily to prevent the adverse effects caused by the first-generation antipsychotics like perphenazine, trifluoperazine, thiothixene etc.

    Neurologists always prescribed trihexyphenidyl (Artane®) for Parkinson’s disease. I asked a neurologist once why trihexyphenidyl was written for by neurologists, and he responded “Gee, I don’t really know; that’s just how we were trained!” Simply explained as “tradition.”

    Most neurologists hold off on treatment with dopamine agonists and levodopa until the patients see impact on their activities of daily living. This is truly when “shared decision making” is a must for treatment of Parkinson’s disease.

    Have a great day on the bench!!

    July 2021

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    An Overview of Idiopathic Parkinson’s Disease

    Idiopathic Parkinson’s Disease (IPD)
    • A progressive and irreversible degeneration of melan-containing dopaminergic neurons within the pars compacta of the substantia nigra.
    • The severity of IPD generally correlates with the degree of cell loss. Neural degeneration also correlates with a decrease in dopaminergic neurotransmission.
    • Loss of dopamine results in a deficiency of dopamine relative to other neurotransmitters, particularly acetylcholine (ACH). Typically, noticeable symptoms for diagnosis do not arise until 80% of neurons are gone.
    Incidence: Parkinson’s impacts over 1 million people in North America. Parkinson’s disease is uncommon in those under age 40, with a rapid increase at age 60. Mean age of diagnosis is 70 years, with men being diagnosed twice as frequently as women.

    Smoking: interestingly enough, smokers have a lower rate of Parkinson’s disease.

    Hoehn & Yahr Scale: (used to describe severity of Parkinson’s)

    Stage 1: unilateral involvement
    Stage 2: bilateral involvement, no postural abnormalities
    Stage 3: Bilateral involvement, mild postural imbalance, patient is independent.
    Stage 4: Bilateral involvement postural instability, patient requires much help
    Stage 5: Severe, fully developed disease, patient restricted to bed or chair.


    Parkinson symptoms
    • Micrographia (small writing)
    • Hypomimia (“Masked faces”)
      • caused by rigid movement of facial muscles, creating an expression that appears to lack emotion
    • Tremor at rest
      • begins unilaterally and are present in 70%
    • Tremors (not during sleep)
      • may worsen with stress
    • Rigidity of limbs trunk and face
    • Bradykinesia (slow movement when walking)
    • Soft or low voice
    • Some people report loss of smell many years before onset of tremor/symptoms
    • Depression is reported in up to 50% of Parkinson’s patients
    • Abulia: loss of the impulse, will, or motivation to think, speak, and act, usually due to presence of a disease


    Secondary Parkinson’s Disease: May be precipitated by trauma, neoplasms or severe ischemic vessel disease, medications. Need MRI to rule out.

    Drug induced Parkinsonism:
    • May be indistinguishable from idiopathic Parkinsonism. /li>
    • Drug-induced symptoms are often symmetrical and occur within weeks to months after starting an offending medication.
    • About 10% of Parkinson-like motor symptoms are caused by mediations.
    • Drug induced is reversible, occurs later in treatment than the preceding extrapyramidal symptoms.
    High potency neuroleptics (antipsychotics), especially first-generation antipsychotics, frequently require anti-Parkinsonism drugs.

    Treatment: decrease dose of antipsychotic. Use anti-Parkinson drugs. After 4 to 6 weeks, these anti-Parkinson drugs may be stopped.

    Common drugs causing Parkinson-like effects:
    • Metoclopramide (Reglan®) (very significant)
    • Prochlorperazine (Compazine®)
    • Haloperidol: Haldol® (block dopamine receptors)
    • Phenothiazine: Chlorpromazine, Trifluperazine etc. (block dopamine receptors)
    • Second generation antipsychotics: risperidone, paliperidone, and olanzapine
      • (quetiapine and clozapine are considered safest in this regard)
    • Cholinesterase inhibitors: donepezil, rivastigmine
    • Amitriptyline
    • Carbamazepine
    • Reserpine
    • Less common: valproate, lithium and SSRI’s
    • Other Agents: Carbon monoxide, Cyanide, Lead, Mercury, Methyl chloride, photographic dyes.
    NOTE: Drug Induced Parkinsonism is most commonly seen in elderly women, who are taking higher doses of the offending drug.

    Of the all the neurological diseases, none hit home for me like Parkinson’s disease. My beautiful mother-in-law, Dolores succumbed to this dreaded disease at age 61. She presented with symptoms in her early fifties, and we saw her gradual decline. She was a vibrant, attractive and brilliant woman who raised 6 kids. She was a reading supervisor and was loved by her students and her colleagues in the elementary schools she visited.

    I once had a nurse at a long-term care facility tell me that she thought Parkinson’s disease was the cruelest of the neurological diseases because the patients were able to see firsthand their own decline. Parkinson patients are very cognizant of the fact that they get a little worse every day.

    I remember seeing Denise’s mom deteriorate every time we saw her. My daughters in elementary school, when asked what their favorite food was didn’t respond “pizza” or “chicken nuggets”. It was chicken gravy over waffles, because we seemed to eat that once a week because it was Grandma’s favorite. It was a staple meal for quite a few years in our home, because it was something she could enjoy, as she had difficulty chewing and swallowing.

    None of Denise’s four sisters have seen any sign of this dreaded disease. I’ve combed through pages of genetic studies with regard to the PARK2 gene, and there doesn’t seem to be a strong genetic generational link. For that, our entire family is thankful

    Have a great day on the bench!!

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    An Overview of Antiarrhythmics

    CLASS I AGENTS: Sodium Channel Blockers

    CLASS Ia AGENTS

    Indications for Use:
    • Treatment of: Supraventricular tachycardia, ventricular tachycardia, prevent ventricular fibrillation, symptomatic ventricular premature beats.
    • Delay the recurrence of occasional atrial fibrillation
    Mechanism of Action: Sodium channel blocker- depresses phase 0 depolarization, slows conduction, prolongs repolarization. Increases QRS interval and increases QT interval.
    Examples: disopyramide (Norpace®) and quinidine (Quinaglute®)

    CLASS Ib AGENTS

    Indications for Use: ventricular tachycardia, prevention of v-fib, symptomatic ventricular beats.
    Mechanism of Action: Sodium channel blocker; modest depression of conduction, shortening of repolarization, decrease in QT interval.
    Examples: Lidocaine®, Mexiletine (Mexitil®), tocainide (Tonocard®)

    CLASS Ic AGENTS
    Indications for Use: life threatening ventricular tachycardia, or v-fib, refractory supraventricular tachycardia Mechanism of Action: Sodium channel blocker. Markedly depress phase 0 repolarization, slows conduction

    Examples: Flecainide (Tambocor®); Morcozine (Ethmozine®), Propafenone (Rythmol®)


    CLASS II AGENTS: BETA BLOCKERS

    Indications for Use: Supraventricular tachycardia, may prevent v-fib, digitalis induced ventricular arrhythmias Mechanism of Action:
    • Beta blockers- suppress phase 4 depolarization. Slows AV conduction. Decreases heart rate.
    • Reduces sympathetic stimulation of the heart (beta-1). Slows sinus rhythm without significantly changing the QT or QRS interval. Decreases HR and myocardial oxygen demand.


    CLASS III AGENTS: Potassium channel blockers

    Amiodarone (Cordarone®, Pacerone®) 100mg, 200mg & 400mg tablets (approved 1985)

    Mechanism of Action: potassium channel blockers. Causes prolonged action potential (QT prolongation). refractory v-tach, suprav-tach, prevention of v-tach, a-fib, v-fib
    Indications for Use: For atrial and ventricular tachycardia. Has been shown to decrease patient arrhythmic deaths in patients after a myocardial infarction.
    • Should only be initiated in the hospital setting.
    • Is the most effective for prevention of a-fib and v-tach or v-fib.
    • More effective than sotalol or drugs in reducing recurrent tachycardia.
    • Most effective drug for atrial fibrillation.
    • The most effective antiarrhythmic drug for maintenance of normal sinus rhythm.
    Dosage: loading dose of 800-1600mg/day for 1 to 3 weeks. When control is achieved dose can be decreased to 600-800mg/day for 1 month. Maintenance dose is usually 400mg/day.

    Warning/Precautions & Adverse Effects
    • Life threatening pulmonary toxicity (especially if over 400mg/day)
    • Most patients develop corneal micro deposits, 1 to 4 months after therapy.
    • Monitor for hypotension and brady arrhythmias
    • Monitor for hepatic dysfunction, thyroid disorders (hypo & hyper), and photosensitivity
    • May cause blue/gray skin discoloration
    • Half-life is 65 days....drug interactions may continue after drug is discontinued (May have adverse reactions for 4 months after therapy has ended!)
    Patient Information:
    • Watch for photosensitivity
    • Take consistently with regard to meals (food affects absorption)
    • Choose amiodarone over dronedarone for patients with paroxysmal or persistent atrial fib who need rhythm control, especially if they have heart failure or severe left ventricular hypertrophy.
    Dronedarone (Multaq®) available as 400mg tabs (approved 2009)
    • Evidence suggests that patients with permanent atrial fibrillation actually have a higher risk of death and cardiovascular events, when on dronedarone.
    • Avoid dronedarone or other antiarrhythmics for permanent atrial fibrillation. None of them improve outcomes.
    Sotalol (Betapace®) approved 1992

    Indications:
    • Treatment of life-threatening, documented ventricular arrhythmias, such as sustained ventricular tachycardia
    • Maintenance of normal sinus rhythm (delay in time to recurrence of AFIB/AFL) in patients with symptomatic AFIB/AFL who are currently in sinus rhythm.
    Mechanism of Action: non-selective beta blocker
    • methanesulfonanilide, is a class III antiarrhythmic drug that is used for the treatment of both atrial and ventricular arrhythmias.
    Dosage: Hospitalized patients initiated or re-initiated on sotalol for at least 3 days or until steady-state drug levels are achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring.
    Typical Dose: 80mg twice daily.
    Adverse Effects:
    • Renal dosing is required. Dosing frequency is determined by renal clearance.
    • Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol

    Dofetilide (Tikosyn®) approved 1999
    • Use: conversion or prevention of a-fib and a-flutter. Not considered first line. Use only if patient is not a candidate for amiodarone or sotalol
    • Dosage calculated by creatinine clearance and QTc interval
    • Watch patients for Torsades
    • Monitor closely for CYP4503Ar4 drug interactions
    • Patients initiated on this therapy must be placed in a facility that can provide calculations for creatinine clearance, continuous ECG monitoring, and cardiac resuscitation for a minimum of 3 days


    CLASS IV AGENTS---Calcium channel blockers

    Indications for Use:
    • treatment and prevention of supraventricular tachycardia
    • first line agent for prevention of PSVT (paroxysmal supraventricular tachycardia)
    Mechanism of Action: CCB inhibit the influx of calcium through its channels causing slower conduction through the SA and AV nodes. They slow ventricular rates, in atrial flutter, atrial fibrillation, and PSVT. Only diltiazem (Cardizem®) and verapamil (Isoptin®) are indicated for heart dysrhythmias.



    GENERAL PATIENT COUNSELING INFORMATION
    • Inform patients that complete remission is unlikely, notify if you have increase in arrhythmias
    • Patients with a-fib or a-flutter should be educated about importance of antithrombic therapy, as well as signs and symptoms of stroke:
      • Drooping of mouth, sudden onset of slurred speech, muscle weakness. FAST!!!!
    • Monitor drug interactions. Carefully change therapies.
    • Periodic ECG and lab assessments are necessary.
    KEY POINTS:
    • All antiarrhythmics are proarrhythmic
    • Cardiac arrhythmias may range from benign to lethal
    • Use anticoagulation to help prevent strokes...and rate control with a beta-blocker, verapamil, diltiazem, or digoxin.
    • Tell patients that it is often okay to stay in atrial fib especially if they don't have symptoms.
    • Most antiarrhythmics are hepatically eliminated, thus drug interactions are common
    • Non-Pharmacological therapies are necessary for life threatening v-tach & v-fib
    • Treatment of a-fib should include assessment of antithrombic therapy
    • Direct current cardioversion is typically treatment of choice for severe arrhythmias
    • The ICD is the most highly effective method in preventing sudden death due to recurrent ventricular tachycardia or ventricular fibrillation.
    I remember in the early 1980’s we bought procainamide (Procan SR®) and quinidine (Quinaglute Duratabs®) in bottles of 500 and moved them. We were excited when tocainide (Tonocard®) and flecainide (Tambocor®) came out in 1985, as new and improved antiarrhythmics. Then, the bottom fell out of that market. It was discovered that rhythm control was not as important as rate control.

    Today we seldom use antiarrhythmics, maybe an occasional flecainide and mostly amiodarone. Amiodarone is a great drug to discuss with student pharmacists. Most are taught that after 5 half-lives there is minimal drug in the body (actually 3.125%).

    With a half-life of 65 days, it takes amiodarone 1 year (5 x 65 days) to clear out of the patient. I would tell my PA students to make sure they have done every test necessary before initiating amiodarone therapy. I have had a couple of patients have thyroid issues (usually hypothyroid) while on amiodarone therapy. I spell it out amIODarone, and notice the presence of iodine in the compound. Remind your patients to have their physicians to do a yearly TSH.

    Have a Great Day on the Bench!!

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    An Overview of ARNIs in Heart Failure

    ANGIOTENSIN RECEPTOR BLOCKER / NEPRILYSIN INHIBITOR (“ARNI’s”)

    Sacubitril/valsartan (Entresto®):Approved 2015
    Sacubitril= neprilysin inhibitor AND
    Valsartan=angiotensin II receptor blocker (ARB)

    Indications: reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

    Mechanism:
    • Sacubitril blocks neprilysin, which degrades the beneficial compounds in the Renin-Angiotensin Aldosterone system. By increasing the levels of natriuretic peptides, bradykinin and adrenomedullin, sodium is lowered, vasoconstriction is decreased as well as decreases in maladaptive remodeling.
    • Valsartan is an Angiotensin-1 receptor blocker. By blocking the effects of Angiotensin-2, vasoconstriction is decreased, along with decreasing sodium retention.
    Entresto®: available as tablets: (sacubitril/valsartan) 24/26 mg; 49/51 mg; 97/103 mg

    Initial Therapy:
    • Allow a 36 hour “washout” period if switching from a previous ACE or ARB
    • Starting dose: 49/51 mg (sacubitril/valsartan) twice daily
    • Double the dose after 2-4 weeks, to a maintenance dose 97/103 mg (sacubitril/valsartan) twice daily, as tolerated by the patient.
    Precautions:
    • Caution patients about the risk for angioedema, and hypotension. Avoid for severe hepatic impairment.
    • Be aware of hypotension and avoid Entresto® when systolic BP < 100 mmHg. Watch for syncope!
    Bad News for Entresto® (sacubitril/valsartan)
    • In the phase 3 Paradise-MI trial, Entresto® missed its primary endpoint to reduce the risk of cardiovascular death and heart failure after an acute myocardial infarction. Basically, Entresto® (sacubitril/valsartan) lost to an ACE inhibitor. Although Entresto® fared better than ramipril (Altace®), the outcome was not statistically significant.
    • There was a 6% rate of heart failure hospitalizations in the Entresto® arm, versus 6.9% in the ramipril cohort. And 1.4% of Entresto® patients developed outpatient heart failure compared to 2% in subjects who received ramipril.
    • Reference: https://www.acc.org/latest-in-cardiology/clinical-trials/2021/05/14/01/22/paradise-mi
    Cost:
    • Wholesale acquisition cost of Entresto®, is nearly $600/month.
    • Wholesale acquisition cost for Ramipril= $6.00/ month
    • Adherence: Entresto® requires twice daily dosing, while ramipril and most ACE inhibitors/ARBs are dosed once a day.


    HEART FAILURE WRAP-UP:

    MORTALITY REDUCING DRUGS (best options in parentheses)
    • ACEI’s: (ramipril, enalapril)
      • ARB’s (losartan, valsartan, candesartan)
    • Beta-Blockers: (metoprolol-XL, carvedilol, bisoprolol)
    • Aldosterone Antagonists:
    • ARNI’s: (sacubitril/valsartan)
    • Hydralazine/BiDil:
    • SGLT2 inhibitors: Dapagliflozin (Farxiga®) was shown to prolong survival in heart failure. Canagliflozin (Invokana®) Empagliflozin (Jardiance®), were shown to have benefits in cardiovascular disease, to varying degrees.
    MORBIDITY REDUCING DRUGS
    • Diuretics
    • Digoxin
    • Ivabradine
    The pharmacist is critical for the following:
    • Watch for drugs that can worsen heart failure, such as nonsteroidal anti-inflammatory drugs, antiarrhythmic drugs, calcium channel blockers like diltiazem (Cardizem®) and verapamil (Isoptin®), thiazolidinediones like rosiglitazone (Avandia®), pioglitazone (Actos®).
    • Patient Education for self-management
      • Weighing daily and reporting significant weight gain
      • Limiting fluids
      • Watching salt intake and diet
      • Monitoring shortness of breath, especially at night
      • Adherence to prescribed medication
      • Monitoring pulse
      • Caution with dizziness
      • Providing pill boxes, especially for multiple dosing regimens
    References:
    ARBS:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947116/
    ACE: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753869/

    “New and improved” ---we see it from automobiles to dishwashing soap. I have to admit for the longest time, I thought Entresto® (sacubitril/valsartan) was in a class by itself. The latest data from May, though, doesn’t seem to support that.

    As Entresto® hones in on the 5-billion-dollar annual sales mark, I have to wonder how many of those patients would have had similar outcomes with an ACE inhibitor, given the information from the latest trials. The average prescription for Entresto® approaches $600.00 per month versus $6.00 for a month supply of ramipril!

    I can easily tell the difference in my original dish soap, versus the ‘new and improved’. I am not so sure we can see significant differences between these two drugs, and certainly when the cost is 100 times more.

    Have a great day on the bench!!

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      An Overview of Heart Failure Drugs Isosorbide dinitrate/hydralazine and Ivabradine


    VASODILATORS

    Isosorbide DN 20mg/Hydralazine 37.5mg (BiDIL®) FDA approved:2005
    • Hydralazine: reduces afterload + dilates arterioles
    • Nitrate: reduces preload + dilates veins
    • Dose: start with 1 tablet three times daily, with a maximum dosage of 2 tablets three times daily
    Use:
    • There are no large-scale studies that support their use as monotherapy
    • Have been used in combination with nitrates
    Effects:
    • Reduces pulmonary congestion
    • Increases CO, by reduction of preload and afterload.
    Indications:
    • Adjunct to standard therapy in self-identified African American patients to improve survival, improve time to hospitalization for heart failure, and to improve patient reported functional status. This is the first “race specific” drug approved by the FDA.
    • Is added on with ACEI/ARBs , diuretics, digoxin
    • The African American Heart Failure trial was terminated early because at 12 months the BiDil® group showed a 43% reduction in overall mortality.
    Warnings/Precautions:
    • May cause lupus like symptoms
    • May cause symptomatic hypotension
    • Hydralazine may cause myocardial ischemia and anginal attacks
    • May cause headache (50%), dizziness (32%)
    • May cause GI upset
    Drug interactions
    • Caution with erectile dysfunction PDE-5 inhibitors (i.e. sildenafil, vardenafil, etc.)
    • Caution with alcohol & MAOI

    HYPEROLARIZATION ACTIVATED CYCLIC NEUCLEOTIDE GATED CHANNEL BLOCKER

    Ivabradine (Corlanor®) FDA approved 2015
    • Available as tablets 5mg, 7.5mg

    Indications:
    • Reduces the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use
    • No effect on myocardial contractility or ventricular repolarization
    • Beta-blockers are STILL first line treatment in heart failure. Treat to target doses (Carvedilol 25mg twice daily, or Metoprolol succinate 200mg/day or Bisoprolol 10mg/day)
    Dosing Schedule:
    • Starting dose is 5 mg twice daily
    • After 2 weeks of treatment, adjust dose based on heart rate
    • Maximum dose is 7.5 mg twice daily
    • In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, initiate dosing at 2.5 mg twice daily
    Effects
    • Prevents 1:25 patients being hospitalized.
    • Lowers heart rate without decreasing blood pressure; elevated plasma norepinephrine concentration is a marker for poor survival in these patients. An elevated heart rate contributes to adverse outcomes in patients with HFrEF
    Mechanism:
    • Inhibits the sinoatrial modulating pacemaker If (“I sub f”) or "funny” current in the heart. This in turn lowers heart rate without decreasing blood pressure. High heart rates reflect adverse effect of heart failure.
    Warnings/Precautions: Avoid ivabradine in patients with:
    • Acute decompensated heart failure
    • Avoid in A-fib or other arrhythmias
    • Blood pressure less than 90/50 mmHg
    • Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present
    • Resting heart rate less than 60 bpm prior to treatment
    • Severe hepatic impairment
    • Pacemaker dependence (heart rate maintained exclusively by the pacemaker)


    BiDil® (hydralazine/isosorbide) was the first race specific drug. This points to the fact that we are all different in the ways we metabolize drugs, as well as their efficacy among various populations. A lot of talk has been around for years about “precision medicine”. Hopefully the day will soon get here that we see more and more benefits of precision medicine.

    About 5 years ago Denise and I were at our alma mater, the University of Pittsburgh, where they did some genetic tests. We both found out that we are intermediate metabolizers of CYP 450-2C19. This is the enzyme system that activates clopidogrel to its active metabolite. Denise and I would not see much benefit from clopidogrel if it were prescribed, because of our inability to activate the drug.

    Asian patients should not be started on more than 5mg of rosuvastatin. Chinese patients are more susceptible to Stevens-Johnson-Syndrome caused by carbamazepine. Chinese patients also have a significantly higher incidence of closed angle glaucoma.

    We’re all different and I look forward to the day that our genomic sequence will be part of our charts. That will be precision medicine!

    Have a great day on the bench!!


    June 2021

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    An Overview of Digoxin

    DIGOXIN??

    ?Although digitalis glycosides have been in use for over 250 years, it was not until the 1920s were they clearly demonstrated to have a positive ionotropic effect on the heart. The efficacy of digoxin in heart failure and supraventricular tachyarrhythmias such as a-fib, is well established and widely accepted. The role in heart failure patients with normal sinus rhythm is more controversial.

    Current recommendations are:
    • Patients with LV systolic dysfunction & supraventricular tachyarrhythmias (a-fib)
      • consider early in therapy to control ventricular response rate
    • Patients with normal sinus rhythm
      • digoxin does not improve survival, but its positive ionotropic effects, symptom reduction, and quality of life improvement are evident in patients with mild to severe heart failure
      • should be used with other heart failure therapies (DIUR, ACEI, BB)
    Mechanism:
    • Inhibits the Na/K APTase pump. This results in an increase of intracellular calcium and in turn causes a positive inotropic effect.
    • Recent evidence indicates it decreases sympathetic outflow from the CNS thus blunting excessive sympathetic activation that occurs in heart failure.
    • Recent evidence suggests digoxin acts by furthering the activation of neurohormonal systems; this results in deactivation of renin-angiotensin-aldosterone compensation which promotes diuresis, decreases fluid volume, decreases renal sodium reabsorption and diminishes edema
    • Overall, it increases force of cardiac contraction
    Indications:
    • Heart failure: Mild to moderate heart failure
      • increases left ventricular ejection fraction, and improves heart failure symptoms, as evidenced by exercise capacity, and heart failure related hospitalizations, emergency care.
    • Atrial fibrillation: controls ventricular response rate in patients with chronic a-fib.
      • less effective than beta-blockers or calcium channel blockers
    Warnings/Precautions/Adverse Effects:
    • Cardiac: arrhythmias, bradycardia, heart block
    • GI: anorexia, abdominal pain, nausea and vomiting
    • Neurological: visual disturbances, disorientation, confusion, fatigue
    Toxicity:
    • Current target range: 0.5-1 nanogram/mL
    • Toxicity occurs over 2 nanogram/mL but may occur at lower levels if the patient has hypokalemia, hypomagnesemia, or is elderly.?
      • Be sure to monitor for blood levels of potassium and magnesium, especially if patient takes loop diuretics.
      • Digoxin has a narrow therapeutic range
        • Toxicity can be fatal in a significant percentage of patients experiencing toxicity
    Drug interactions

    INCREASES the Digoxin effect: (increased serum concentrations):
    • Quinidine, Verapamil, Amiodarone: decrease dose of digoxin by 50% if added.
    • Propafenone (Rhythmol®), Flecanide (Tambocor®)
    • Macrolide antibiotics (Erythromycin, Clarithromycin)
    • Itraconazole (Sporanox®)
    • Spironolactone (Aldactone®)
    • Cyclosporine
    DECREASES the effect of Digoxin (decreased serum concentrations):
    • Antacids
    • Cholestyramine (Questran®), Colestipol (Colestid®),
    • Metoclopramide (Reglan®)
    • Bupropion (Wellbutrin®)
    • Inducers of p-glycoprotein, such as rifampin, phenytoin (Dilantin®), carbamazepine (Tegretol®), phenobarbital, St. John’s Wort
    OTHER concerns:
    • Diuretics: increases the risk of digoxin toxicity when hypokalemia and hypomagnesemia are present. (Be sure to keep potassium levels at 4- 5.5mmol/L)
    • Renal insufficiency: Digoxin clearance is reduced, therefore monitor closely for toxicity.
    • Biotin: can interfere with the assay for digoxin by interfering with lab test.? This may appear as an artificial increase in digoxin levels
    Products:
    • Lanoxin® (digoxin) tablets 0.125mg (yellow), 0.25mg (white)
    • Lanoxin® (digoxin) elixir 0.05mg/mL (pediatric)
    • Lanoxin ® (digoxin) injection 0.25mg/mL
    Dosage:
    • Based on clinical response. There are several tables in the literature for rapid digitalizing in the hospital setting based on age, lean body weight, renal function, and concomitant disease state.? Also, there are regimens for slow and fast initiation of therapy.
    Initiation Dose:
    • 0.25mg/day in patients less than age 70 with good renal function?
    • 0.125mg in patients greater than age 70 or with impaired renal function.
    • 0.0625mg in patients with marked renal impairment.?
    Maintenance Dose:
    • 0.125 to 0.5mg daily
    • Doses may be increased every 2 weeks
    • Remember: 0.25mg= 250mcg; 0.125mg= 125mcg
    Patient Education:
    1. Know the SIGNS of Digoxin Toxicity
      • Anorexia: common and early sign
      • Fatigue, headache and malaise
      • Nausea and vomiting
      • Mental confusion, disorientation
      • Alterations in visual perceptions (halos around lights)
      • Cardiac effects: premature ventricular contractions, ventricular tachycardia, SA/AV block, atrial tachycardia with AV block.
    2. Eat small frequent meals (4-6/day) to decrease metabolic demands
    3. Moderate sodium restriction may be helpful as well.
    Treatment of Digitalis Toxicity:
    • DigiFab® (40mg per vial) or DigiBind® (38mg/vial)
    • Each vial binds approximately 0.5mg of digoxin
    Indications:
    • Treatment of life threatening or potentially life-threatening digoxin toxicity or overdose. Not indicated for milder cases of digitalis toxicity.
    • Known suicidal or accidental consumption of more than 10mg of Digoxin in healthy adults or 4mg in previously healthy children or ingestion causing steady state serum concentrations greater than 10 nanograms/mL
    Maechanism:
    • Binds the molecules of digoxin making them unavailable for binding at their site of action. The Fab fragment/digoxin complex accumulates in the blood and is excreted by the kidney.? It shifts the equilibrium away from binding digoxin to its receptors and reverses its effects.
    Dosage/Administration:
    • Infused IV through a 0.22micron filter


    We seasoned pharmacists love digoxin, but don’t dispense it as much as we did in previous years.? I remember as a student pharmacist in the 1980’s working for a small independent pharmacy selling Lanoxin® (digoxin) by Burroughs Wellcome for $1.89 for 30 tablets.?

    Back then, pharmacists charged a 40% mark-up on medications, and actually made money without filling hundreds of prescriptions per day! This was before the Angiotensin Converting Enzyme Inhibitors (ACEI’s) were introduced, and quickly became first line therapy for heart failure.

    This evening, I checked our warehouse site, and the current price is $1,372.61 per 100 tablets, which would be a 400-fold increase from the price paid back in 1981.? The digitalis glycosides were first isolated from the foxglove plant (Digitalis lanata) by William Withering an English Physician in 1785.? Before the United States became a country, digitalis glycosides were being used to treat “dropsy”, so a 400-fold increase in a 40 year seems drastic at best.?

    If automobiles had increased at the same rate, the Datsun 210 that Denise and I bought in 1981, would now cost 1.6 million dollars!

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    A Broad Overview of Medications Used in Heart Failure

    HEART FAILURE--- the Basics
    Heart Failure: a clinical syndrome resulting from a variety of cardiac disorders that impairs the ability of the ventricle to fill with or eject blood.
    • Heart failure is the only major cardiovascular disease increasing in prevalence.
    • Heart failure is the most common hospital discharge diagnosis for Medicare patients. More Medicare dollars are spent for the diagnosis and treatment of heart failure than any other disorder.
    • Symptom management and reduction of hospitalization are the primary goals of treatment
    DRUG THERAPY FOR HEART FAILURE:

    Improvement in symptoms (improved morbidity) can be achieved with the use of diuretics, beta blockers, ACE inhibitors, ARBs, ARNI, hydralazine plus nitrate, digoxin, and aldosterone antagonists.

    Prolongation of patient survival (improved mortality) has been documented with the use of beta blockers, ACE inhibitors, ARNI, hydralazine plus nitrate, and aldosterone antagonists. More limited evidence of survival benefit is available for diuretic therapy

    MANIFESTATIONS OF HEART FAILURE:
    The primary manifestations of heart failure are dyspnea (shortness of breath) and fatigue, which may limit exercise tolerance and fluid retention, which may lead to pulmonary edema and peripheral edema. Some patients have marked exercise intolerance and little fluid retention, whereas others have prominent edema and few symptoms of fatigue or dyspnea.

    Ejection fraction: Patients with a left ventricular ejection fraction less than 40% are considered to have systolic dysfunction. In general, there is poor correlation between ejection fraction and symptoms. Most patients will present with Heart Failure with Reduced Ejection Fraction (HFReF)

    NON-PHARMACOLOGIC MEASURES
    smoking cessation
    restriction of alcohol consumption
    salt restriction
    weight reduction if obese (BMI >30.0)
    monitor weight every day to detect fluid accumulation before it becomes symptomatic.

    DRUGS that can precipitate or worsen heart failure:
    Antiarrhythmics: disopyramide, flecainide, propafenone
    Beta blockers
    Calcium Channel Blockers: Verapamil & Diltiazem (non-dihydropyridine)

    Role of Calcium Channel Blockers:
    First generation CCB (verapamil & diltiazem) may accelerate progression of CHF
    Amlodipine (Norvasc®) is safe with severe heart failure. (No better than placebo)

    Avoid CCB unless treating angina or hypertension. If needed, use amlodipine.

    Classification Based on Patient Symptoms: NYHA

    Class-1: patients with cardiac disease, but without limitations of physical activity. Ordinary physical activity does not cause undue fatigue, dyspnea, or palpitations. (no limitations)
    • Described as Ejection Fraction <40% with no signs of dyspnea
    • TREATMENT: ACEI; may consider BB
    Class-2: patients with cardiac disease, that results in slight limitations of physical activity. Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. (can climb 2 flights of stairs)
    • Described as mild dyspnea on exertion.
    • Treatment: Volume Overload: diuretic, ACEI or ARB or ARNI and digoxin. Later, consider Spironolactone.
    • Treatment: No Volume Overload: ACEI or ARB or ARNI and BB
    Class-3: patients with cardiac disease that results in marked limitations of physical activity, although patient is comfortable at rest, less than ordinary activity leads to symptoms. (climbs ½ flight of stairs)
    • Described as moderate dyspnea on exertion
    • Initiate and titrate diuretic, ACEI or ARB or ARNI; Add digoxin then initiate BB (if not already done), consider spironolactone.
    Class-4: patients with cardiac disease that results in an inability to carry on physical activity without discomfort. Symptoms of CHF are present even at rest. With any physical activity increased discomfort is experienced. (won’t even look at a flight of stairs) (Source: American Heart Association)
    • Described as severe dyspnea on exertion
    • Consider hospitalization. Initiate diuretic, ACEI or ARB or ARNI, add digoxin & titrate BB
    • Add spironolactone later. If no improvement, add IV ionotropes.

    HEART FAILURE MEDICATIONS
    MORTALITY REDUCINGMORBIDITY REDUCING
    ACE-inhibitors or ARBSDiuretics (prefer-loop)
    Beta-blockersthiazides are ok
    Aldosterone antagonistsDigoxin
    ARNI’s (Entresto®)vabradine
    Hydralazine/ISDN (BiDil) – if African American
    Dapagliflozin (Farxiga) SGLT2 inhibitor for diabetes.


    When I would teach heart failure to my class I would throw in a little history and use the British term “dropsy”. One of my students from Jamaica came up after class and was pleased that I used the term “dropsy” in class. He said as a boy in Jamaica he would see several old people sitting around with their feet elevated, and he was told that they had “dropsy.” He shared with me that he often wondered about this disease, and what the medical term was.

    Heart failure treatment has come a l-o-n-g way since I graduated in 1981. Ace inhibitors were not available yet, and the standard treatment was digoxin (Lanoxin®), furosemide (Lasix) and potassium because of the furosemide.

    Today, ACE inhibitors or Angiotensin Receptor Blockers (ARB’s) are first line treatment as they do reduce mortality. Community pharmacists have a huge role in treatment of heart failure by making sure patient adherence is optimal, to reduce hospitalizations.

    Next we will discuss drugs specific for the treatment of heart failure. Kind of interesting to see a diabetes drug , dapagaflozin (Farxiga®) being used for heart failure!

    Have a great day on the bench!!

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    Hypertension: A Glance at Special Patient Populations

    Treatment of SPECIFIC PATIENTS

    I. PREGNANCY Methyldopa (Aldomet®) during all trimesters of pregnancy is traditionally the “go to” due to remote chance of fetal harm. Use only if clearly needed.
    • Methyldopa is Category-B; watch for fatigue and dizziness.
    • Nifedipine-ER (a CCB) – is considered safe
    • Labetalol (Normodyne®): appears to be better able to prevent the appearance of fetal growth retardation.
    AVOID: ACEI, ARB, Aliskiren, Eplerenone, Spironolactone

    II. COPD/ASTHMA
    Drug of Choice: Calcium Channel Blockers
    AVOID: BB, especially if non-selective beta-blockers

    III. DIABETES MELLITUS
    Drug of Choice: Angiotensin Converting Enzyme Inhibitors (ACEI’s)/ Angiotensin Receptor Blockers (ARB’s); CCB (2nd choice)
    AVOID: Beta Blockers (BB) & diuretics

    IV. ANGINA
    Drug of Choice: Beta Blockers (non-ISA) and CCB
    AVOID: peripheral vasodilators

    V. HEART FAILURE
    Drug of Choice: ACEI/ARB and diuretic
    Also, non-Dihydropyridine (diltiazem, verapamil) and low dose BB

    VI. AFRICAN AMERICANS Drug of Choice: Diuretic or CCB Monotherapy with BB or ACEI are often ineffective. May add ACEI—40% of blacks have good response to ACEI May add BB: BB plus diuretics are equally efficacious in blacks and whites.

    VII. ELDERLY
    Drug of Choice:
    • Thiazide plus ACEI, (preferred if diabetic or HF)
    • BB if hypertensive with angina
    • Men with BPH: use alpha blockers
    • AVOID: central acting alpha agonist
    VIII. DEPRESSION
    AVOID: central alpha agonists & beta-blockers

    IX. SEXUAL DYSFUNCTION
    Drugs of choice: ACEI, ARBs and CCB
    Avoid BB and alpha agonists, and diuretics


    X. RENAL INSUFFICIENCY
    Drug of Choice: ACE & ARBS; Loop Diuretics
    CAUTION: ACE if bi-renal arterial stenosis.
    AVOID: Thiazides



    TREATMENT of RESISTANT HYPERTENSION- Top 10 Considerations
    1. ALWAYS check with the pharmacy to see if poor adherence is the problem before proceeding with additional hypertensive medications.
    2. Simplify regimens such as using combination products to decrease the number of pills per day, and lower number of copays. (Lisinopril/hctz) (Diovan/HCT) (Amlodipine/benazepril). Will see additive effect and decrease in side effects.
    3. Bedtime dosing may be helpful if early morning hypertension is a problem
    4. Secondary causes of resistance include: obstructive sleep apnea, renal artery stenosis, primary aldosteronism. Screen for these conditions.
    5. Check for drugs that can elevate blood pressure such as NSAIDs and COX-2 inhibitors, sympathomimetics amines (pseudoephedrine)
    6. Many experts feel a diuretic should be used. Chlorthalidone (Hygroton®) and indapamide (Lozol®) two old diuretics, seldom used today are usually more effective than HCTZ for blood pressure reduction.
    7. Use Loop diuretics if impaired renal function
    8. Most patients need an ACE/ARB plus CCB or BB.
    9. Next step is to use an aldosterone blocker (spironolactone, eplerenone), because these patients (20%) have elevated aldosterone levels.
    10. Watch potassium levels, with aldosterone blockers, especially if combined with ACE or ARBs
    COMBINATION therapy:
    Start 2 drug therapy if patients are over 20mmHg(systolic) or 10mmHg(diastolic).
    Pick combos for UNCOMPLICATED hypertension using this summary.
    Preferred Combos
    • ACEI + thiazide
    • ACEI + dihydropyridine CCB
    • ARB + thiazide
    • ARB + dihydropyridine CCB
    • CCB + thiazide
    Acceptable Combo
    • Thiazide + potassium-sparing diuretic
    • Aliskiren + thiazide or CCB
    • B-blocker + diuretic or dihydro CCB
    • B-blocker + ACEI or ARB
    • Dihydropyridine CCB + non-dihydropyridine CCB
    NOT Preferred Combos
    • ACEI + ARB
    • Aliskiren + ACE or ARB
    • B-blocker + Nondihydropyridine CCB
    • B-blocker + Central acting (clonidine, methyldopa, etc)


    Only a gray-haired pharmacist like me and my colleagues would remember SER-AP-ES® which was a combination product for treating high blood pressure (Serpasil-Apresoline-Esidrex). It contained three drugs: reserpine (an adrenergic uptake inhibitor), hydralazine (vasodilator) and hydrochlorothiazide (diuretic).

    After we graduated in 1981, the ACE inhibitors took over. Combination therapy went out the window, as clinicians were told to push the dose of monotherapy, so you knew where the side effects were coming from.

    Now the pendulum has swung in the opposite direction, using low doses of combination therapy to minimize side effects, and to maximize the additive benefit of mechanisms of action. “The more things change, the more they remain the same!”

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    Hydralazine, Aliskiren, and Minoxidil: The Lesser Known Antihypertensives

    In this session, we cover three drugs that are not frequently used. Of the three, I have dispensed hydralazine the most. It has been years since I’ve dispensed aliskiren (Tekturna®) or minoxidil (Loniten®). I think most clinicians associate minoxidil with hair growth more often than with hypertension!

    Hydralazine remains a relevant player, as we will discuss its use when we cover heart failure. Hydralazine is part of BiDil®, along with isosorbide, for heart failure in self-described African American patients. I was amazed to discover that hydralazine (Apresoline®) was first approved in 1953.

    RENIN INHIBITOR
    Tekturna (aliskiren) --approved 2007
    cost: $290 (Generic now available at around $180/month)
    Mechanism: is the first direct renin inhibitor.
    Available as 150mg or 300 mg and is dosed once a day.
    It works earlier in the renin-angiotensin-aldosterone system than ACE inhibitors or ARBs.

    Indications: is approved only for hypertension.
    • Works as well as: ARBs, ACE inhibitors, and thiazides.
    Do not add to an ACE or an ARB, provides no cardiovascular benefit, and causes an increase in adverse events, such as angioedema and hyperkalemia.

    Adverse effects
    • can cause diarrhea especially at the higher dose. Use a lower dose or a different drug if this is bothersome.
    • may also cause cough and angioedema, but probably less often than ACE inhibitors. Considered to be third- or fourth-line for hypertension, not considered monotherapy.
    Pregnancy: Categories C (first trimester) and D (second and third trimesters)

    RENIN INHIBITOR
    NOTE: Avoid this class of drugs, unless necessary, to treat refractory hypertension unresponsive to all other agents. They should not be used alone, secondary to increases in plasma renin activity, cardiac output & heart rate. Use only with beta-blockers and diuretics (usually Loop diuretics). BB will block the baroreceptor reflex response, and decrease the likelihood or precipitating an angina attack.

    Mechanism: Direct relaxation of peripheral arterial smooth muscle, and therefore significantly decreases peripheral resistance, possibly by inhibition of calcium release from the sarcoplasmic reticulum and inhibition of myosin phosphorylation in arterial smooth muscle cells

    Indications: severe hypertension that has been refractory to other agents.

    Warnings/precautions:
    • Monitor for fluid accumulation
    • Hydralazine: may cause drug induced systemic lupus
    • Caution with pulmonary hypertension
    • Caution with significant renal failure or CHF
    Adverse effects
    • Dizziness, hypotension, fatigue, malaise, joint ache
    • Minoxidil: hirsutism—(Remember Rogaine®?)
    • Peripheral neuropathy
    • Headache
    Patient Education: Notify physician immediately if: HR over 20 bpm over baseline, rapid weight gain (over 5lb) unusual swelling of extremities, face or abdomen, breathing difficulty, new or aggravated angina, severe indigestion, lightheadedness.

    VASODILATORS

    GENERIC
    (Year)
    BRANDSTARTING DAILY DOSEUSUAL DAILY DOSEMAXIMUM DAILY DOSE
    Hydralazine (1953)Apresoline®25mg BID50-300mg (2-4 doses)300mg
    Minoxidil (1979)Loniten®5mg /day5mg /day 5-40mg/day40mg


    Have a great day on the bench!!


    May 2021

    Micro-Learning CE Associated - Click Here For Details

    Overview of Angiotensin Receptor Blockers (ARB's)

    Mechanism: AT1 receptors are normally acted upon by Angiotensin II to produce to produce vasoconstriction & aldosterone release. When the AT1 receptor is blocked, aldosterone secretion is blocked, and vascular smooth muscle is relaxed (vasodilation)

    Indications:
    • Nephropathy in Type II diabetics
    • Heart failure
    • Hypertension
      • Can be used alone but are frequently combined with a diuretic
      • Less cough, and reduced incidence of angioedema than ACEI’s
    Warnings/precautions:
    • May cause hyperkalemia
    • (ARBS) Pregnancy category D; report pregnancy ASAP
    • May be nephrotoxic if combined with HCTZ/NSAIDS
    Drug interactions
    • Watch potassium levels monitor for HYPERkalemia (excessive potassium levels)
    • Caution with drugs that elevate potassium (K+ supplements, spironolactone)
    Patient Education:
    • Report pregnancy as soon as possible. Stop drug.
    • WATCH Potassium Levels! Avoid salt substitutes, K+ sparing diuretics.
    • May be NEPHROTOXIC (especially if combined with HCTZ/NSAID)
    Prescribing information:
    Generic nameBrand nameStarting doseAverage daily doseMaximum daily doseHalf life
    Irbesartan
    **generic**
    1997
    Avapro®
    75,150,300
    150mg/day150-300mg300mg12-20hours
    Losartan
    **generic**
    1995
    Cozaar®
    25, 50, 100mg
    50mg/day25-100mg100mg2hrs. Metabolite=6-9 hrs
    Valsartan
    **generic**
    1998
    Diovan®
    80, 160, 320mg
    80mg/day80-320mg320mg6 hrs
    Telmisartan
    *generic**
    2000
    Micardis
    40, 80mg
    40mg/day20-80mg80mg24 hrs
    Candesartan
    **generic**
    1998
    Atacand®
    4.8.16.32mg
    16mg/day monotherapy2mg-32mg80mg9hrs
    Olmesartan
    **generic**
    2003
    Benicar®
    5, 20, 40mg
    20mg/day20-40mg40mg13hrs
    Azilsartan
    (2011)
    Edarbi®40-80mg80mg80mg, then combo11hr


    Because ACEI’s and ARBS affect different steps in the Renin-Angiotensin-II pathway, what value would they have if used in combination?
    • Heart Failure:
    An ARB (valsartan-Diovan®) or (candesartan- Atacand®) can be added to a HF regimen containing an ACE, and a BB for further symptom relief, and possible reduction in mortality.
    • Acute MI
    Although ACEI’s are first line, if patient is intolerant, valsartan (Diovan®) is a viable alternative. However, combination therapy of ACEI and ARB are NOT recommended.
    • Renal impairment
    Combination therapy of ACEI and ARB has been shown to reduce microalbuminuria, compared with monotherapy, in patients with diabetic and nondiabetic renal disease. The reduction in proteinuria seen in patients in the combination therapy group came at a cost of increased renal impairment. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183919/

    ARBs practice points:

    Olmesartan: in 2013 the FDA announced Olmesartan (Benicar®) can produce a "sprue-like enteropathy" characterized by severe chronic diarrhea and weight loss. This may occur months to years after starting drug therapy.
    Irbesartan, Olmesartan and Telmisartan: have the longest half-lives and are available as generics.
    Losartan: has shown a decrease in serum uric acid levels by 1-2mg/dl. It is the only ARB with the ability to significantly lower uric acid levels.

    Stopping the ACEI cough:
    • ARBs have about 1/3 of the incidence of cough versus ACEI’s.
    • May occur with 1 or two weeks of therapy but may take up to 6 months.
    • Women experience the ACEI cough more than men.
    • It usually begins within one to two weeks of instituting therapy, but it can be delayed up to six months.
    • Chinese have the highest ethnic prevalence.
    • May take up to 4 weeks to resolve after discontinuation.


    When I practiced in Altoona, we used a lot of irbesartan (Avapro®) at the clinic because the Physician Assistants were former students. Losartan (Cozaar®) was the first ARB approved, and hence the first generic approved, and the insurance companies jumped on Losartan as the preferred drug.

    Most people take a once-a-day blood pressure medication in the morning. You may recall that after 5 half-lives, there is minimal drug in the body. With a 2-hour half-life, that 7am dose of Losartan is negligible after 5pm! This is concerning, because patients are most likely to have a stroke at 4:00am, when there is virtually no losartan available for the receptors. For this reason, ARBs with a longer half-life, such as irbesartan, are preferred.

    The most in-depth discussion I ever had about ARBs was last February when a local pulmonologist quizzed me about the specificity of the ARBs for the AT-2 receptor. After a bunch of research, I found that none of the ARBS covered the AT2 receptor. As you can guess he was looking to block the AT2 receptor to prevent attachment of the SARS-COV2 virus.

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    Overview of ACE Inhibitors

    Indications: for specific populations, ACE inhibitors are first line choice for these compelling indications:
    • Diabetes, post MI, high coronary disease risk, chronic kidney disease, recurrent stroke prevention.
    • Decreases or stabilizes microalbuminuria. Are nephroprotective in diabetics and patients with renal disease.
    • Decreases incidence of new onset diabetes.
    Prescribing Notes:
    • Captopril and enalapril are considered to be the shortest acting, all of the other ACE inhibitors are long acting and should be used once a day.
    • ACE inhibitors are less effective in African American patients unless prescribed with a thiazide diuretic or calcium channel blocker
    Warnings/precautions: Pregnancy category C (1st trimester); Category-D (2nd & 3rd trimester): report pregnancy ASAP. Watch for HYPERkalemia (Excessive potassium levels)

    Adverse effects
    • Neutropenia is rare, but serious
    • Proteinuria
    • May be NEPHROTOXIC (especially if combined with hydrochlorothiazide)
    • Dry, non-productive cough. Possibly due to bradykinin formation in the lungs
    • Altered sense of taste (captopril)
    • Angioedema (rare)
    • NO adverse effect on Erectile dysfunction
    Drug interactions
    • NSAIDs may diminish their effectiveness.
    • WATCH potassium levels
    • Use caution with potassium sparing diuretics
    • Use caution potassium supplements (salt substitutes)
    • Yaz® or Yazmin® oral contraceptives have drosperidone (spironolactone relative)
    Patient Education:
    • Watch for signs of angioedema: swelling of lips, tongue, lips, difficulty in swallowing or breathing.
    • May cause rash or impaired taste perception (captopril)
    • Report pregnancy to practitioners ASAP
    SELECTED ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI’s)
    Generic nameBrand nameOther indications
    (all are indicated for hypertension)
    Starting doseUsual
    hypertensive dose
    Maximum daily dose
    Captopril
    (1981)
    Capoten®
    12.5,25,50,100mg
    HF, post MI, diabetic nephropathy25mg BID50mg-two to four times daily450mg
    Enalapril
    (1985)
    Vasotec®
    2.5, 5. 10.20mg
    HF, asymptomatic LV dysfunction5mg10-40mg daily (divide doses)40mg
    Lisinopril
    (1987)
    Prinivil® or Zestril®
    2.5,5,10,20,30,40
    HF, post MI5-10mg /daily20-40mg daily40mg
    Quinapril
    (1991)
    Accupril®
    5,10,20,40
    HF10mg/day20-80mg/d or BID80mg
    Ramipril
    (1991)
    Altace®
    2.5,5,10mg
    HF, post MI2.5mg/day5-20mg/d or BID20mg


    SMACK DOWN on ACE inhibitors: ACE inhibitors have a worse adverse effect profile than angiotensin receptor blockers (ARBS). We’re all aware of the dry, irritating cough that is the most common adverse effect of ACE inhibitors. I’ve seen percentages range from 5 to 20%. This ACE inhibitor cough is particularly pronounced in Asian patients. Angioedema, a more serious adverse effect that is sometimes fatal, is more common in those using ACE inhibitors than in those using angiotensin receptor blockers.

    With efficacy for cardiac outcomes being similar, the authors find no reason to prescribe ACE inhibitors. The Angiotensin Receptor Blockers (ARBs) are now as cheap as ACE inhibitors and have equal to or better outcomes for stroke, cardiac and diabetic nephropathy. The author feels that ARB's (which we will discuss in the next session) should be first line.

    https://www.healio.com/news/cardiology/20180326/review-no-reason-to-use-ace-inhibitors-for-hypertension


    I share this story with my student pharmacists, especially if they tell me they were told in class not to warn patients of the ACE inhibitor cough. Students at one university were told not to warn patients of the potential for an ACE inhibitor cough, because it “puts ideas in patient’s heads”.

    Some years ago, a patient transferred to my store. I went over to talk to her about her lisinopril prescription. She stated she has taking it for years. Regardless, I went over the side effects such as cough and angioedema. Four weeks later she came in with her husband and pointed to me and said, “He’s the guy who told me about my blood pressure pill, and the cough.”

    Turned out she had this persistent cough that was treated with an Azithromycin pack, promethazine/codeine cough syrup, and prednisone. Previously she saw her PCP and was ultimately referred to an ENT specialist.

    She was scheduled for a throat biopsy, because of the concern for esophageal cancer. She discussed my ACE inhibitor cough concern with her PCP, who changed her to valsartan, and the cough went away! I always discuss ACE inhibitor coughs, especially with any new start.

    Have a great day on the bench!!

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    Review of the Renin-Angiotensin-Aldosterone System (RAAS)

    Most of us, including me, have wondered what the purpose of the Renin-Angiotensin-Aldosterone-System (RAAS) has other than to cause hypertension and heart and kidney failure. I was fascinated to read that the activation of this system was a critical adaptation for survival of mammals that migrated from sea to land. It protected against life-threatening circumstances like salt and water deprivation, diarrhea, or hemorrhage. While we seem to no longer need this protection, activation of the system in many patients leads to disease, most commonly hypertension and heart failure. Sodium retention, coupled with hyperaldosteronism, results in vascular remodeling of the heart and disease progression. When we block this system and its effects, we can prevent or at least manage heart failure, chronic kidney disease, myocardial infarction, and hypertension. This system plays a vital role in cardiac, renal and vascular diseases, primarily causing renal failure, hypertension and heart failure.

    1) ANGIOTENSINOGEN : GETS CONVERTED TO ANGIOTENSIN-1 BY RENIN
    2) ANGIOTENSIN-1 GETS CONVERTED TO ANGIOTENSIN-2 BY ANGIOTENSIN CONVERTING ENZYME
    3) ANGIOTENSIN-2 BINDS TO THE AT-1 RECEPTOR SITE
    • Renin inhibitors block the first step. They inhibit ACTIVATION of the whole system.
    • Angiotensin Converting Enzyme (ACE) inhibitors work further down. They inhibit the PRODUCTION of angiotensin II, but some is still produced by other routes.
    • Angiotensin Receptor Blockers (ARBs) inhibit BINDING of angiotensin II at the receptors; but don't inhibit the cascade at all. Also, keep in mind ARBs block only type 1 receptors; angiotensin II can still bind to other receptors.


    “GOOD GUYS”“BAD GUYS”
    Naturetic peptidesAngiotensin II (vasoconstrictor)
    bradykininAldosterone (sodium retention)
    adrenomedullin“Bad guys” cause sodium retention and vasoconstriction, driving up blood pressure.
    Positive effects of the “good guys”: lowers sodium, decreases vasoconstriction, decreases “maladaptive remodeling”“Bad guys” are made by Angiotensinogen, Renin, Antiotensin-I, Angiotensin-II. Their effects are blocked by ACE-I, ARBS, Renin Blockers.
    DEGRADED by neprilysin, which can be blocked by sacubitril. Blocking neprilysin increases the “good guys”.
    Renin: Is released by the kidneys in response to reduced renal arterial pressure, sympathetic neural stimulation, or reduced sodium delivery to the distal tubule.

    Angiotensin II: Is a potent peripheral vasoconstrictor, and also stimulates aldosterone release from the adrenal glands.
    • Elevated aldosterone causes an increase in sodium reabsorption, which leads to an increased blood volume, thereby increasing blood pressure.
    • Therefore, ACE inhibition results in decreased Angiotensin II production which leads to decreased sodium & water retention, decreased potassium excretion, and arterial vasodilation.
    • Angiotensin Converting enzyme is also responsible for the metabolism of bradykinin, a vasodilator.
    • ACE inhibitors cause bradykinin levels to increase because of decreased breakdown.
    • The vasodilation caused by increased bradykinin levels may contribute to the hypotensive effects of the ACE inhibitors.
    • It has been postulated that elevated levels of bradykinin in the lungs may be responsible for the cough that ACEI’s induce in patients.
    Adrenomedullin: Identified as a potent vasodilator considered by some to be the most potent endogenous vasodilatory peptide found in the body. It is metabolized by neprilysin.

    Bradykinin: also a vasodilator, and also affects vascular permeability. It is metabolized by neprilysin and angiotensin converting enzyme.

    Natriuretic peptides: enhances sodium output in the kidneys, and plays a role in heart remodeling in congestive heart failure. It is metabolized by neprilysin.

    Aldosterone: Aldosterone binds to the mineralocorticoid receptor in various tissues. Its main actions occur in the distal tubule of the kidney where it causes sodium and water reabsorption and potassium secretion. This potassium excretion occurs in the urine, as well as the feces, sweat, and saliva.

    There is probably not another system that points out the need for continuing education more than the Renin-Angiotensin-Aldosterone System (RAAS). I remember in pharmacology back in 1980 our professor mentioning this system and this new drug he was studying called captopril. Captopril was released just as we were graduating in 1981.

    Before we continue our conversation in subsequent sessions about three classes of drugs, the Angiotensin Converting Inhibitors (ACEi), Angiotensin Receptor Blockers (ARBs) and the seldom used Renin Inhibitor, it is important to review the basics of where they work and the enzymes and hormones they affect.

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    Focus on Dihydropyridine Calcium Channel Blockers

    Mechanism: inhibits the influx of calcium through slow channels in vascular smooth muscle, and causes relaxation. In the vascular system, arterioles appear to be more sensitive than veins; therefore, postural hypotension seldom is an adverse effect. Generally, the dihydropyridines have a greater ratio of vascular smooth effects relative to the cardiac effects than do verapamil and diltiazem. From a patient population perspective, black and elderly patients tend to respond well to these drugs.

    Indications:
    • Alternative drugs in patients unable to take beta blockers such as angina patients, bronchospastic patients, and patients with Raynaud’s.
    • CCB differ in degrees of systemic and coronary arterial vasodilation, SA node and AV node depression, and decrease in myocardial contractility.
    Dihydropyridines: [Amlodipine (Norvasc®), Felodipine (Plendil®), Nifedipine (Procardia®) , Isradipine (Dynacirc®), Nisoldipine (Sular®), and Nicardipine (Cardene®)]
    • have greater affinity for vascular, versus myocardial channels (potent vasodilators)
    • watch for vasodilatory side effects: edema, headache, flushing, rarely orthostatic hypotension
    • Minimal effect on heart conduction: not useful for supraventricular tachycardias
    • Can be used with Beta Blockers or in patients with heart block
    • Minimal drug interactions. Caution with amlodipine (weak inhibitor of CYP-450-3A4) and higher doses of amlodipine may see two-fold increase in simvastatin levels.
    • Grapefruit juice may increase levels of dihydropyridines: amlodipine, felodipine and nifedipine
    Patient Education:
    • Notify physician if any of the following occur: irregular heartbeat, shortness of breath, swelling of hands and feet, constipation, dizziness, hypotension.
    • Instruct patient in postural hypotension
    • Avoid grapefruit juice in dihydropyridines
    • Most of the products in this class are sustained release. Do not open capsules, or chew or crush tablets.


    GenericBrandDate of IntroductionComments
    AmlodipineNorvasc® 2.5, 5mg 10mg (Pfizer)1992
    NifedipineNifedipine Procardia-XL® -30, 60, 90mg (Pfizer)1981 (caps)Don’t use capsules for hypertension
    FelodipinePlendil® 2.5, 5, 10mg (Merck)1991
    NisoldipineSular® 20,30, 40mg (Zeneca)1995
    NimodipineNimotop® 30mg (Bayer)1988Used for subarachnoid hemorrhage
    NicardipineCardene® 20, 30mg1988Longer half-life than amlodipine
    IsradipineDynacirc® 2.5, 5mg (SKB)1990


    Other than hypertension, uses for dihydropyridine CCBs include:
    • Nifedipine has some efficacy in treatment of preterm labor.
    • Nimodipine (Nimotop®) has affinity for cerebral blood vessels and appears to reduce morbidity after a subarachnoid hemorrhage.
    • Nicardipine is used IV to prevent cerebral vasospasm associated with stroke. It has higher affinity for vessels in the heart and in the brain.


    The 1990's were filled with "me too" drugs: the benzodiazepines, cephalosporins, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers came onto the market by the droves!

    Of all of these new classes of drugs, none completely dominated the class like amlodipine dominates the dihydropyridine CCB's. It's been years, actually decades, since I have dispensed isradipine (Dynacirc®), nicardipine (Cardene®), and nisoldipine (Sular®), but interestingly enough I've dispensed nimodipine a few times for patients this past year with subarachnoid hemorrhages, due to accidents

    The physician from the rehab hospital was amazed that a local pharmacy had it in stock. Lately, it is amlodipine being dispensed ... by a landslide.

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    NON-Dihydropyridine Calcium Channel Blockers

    Mechanism:
    CCBs inhibit the influx of calcium through its channels causing slower conduction through the SA and AV nodes. They slow ventricular rates, in atrial flutter, atrial fibrillation, and PSVT.

    Only diltiazem and verapamil are indicated for heart dysrhythmias. Cardiac muscle is highly dependent on the influx of calcium during each action potential for normal function and rhythm. Impulse generation in the sinoatrial node and conduction in the atrioventricular node may be reduced or blocked by calcium channel blockers

    Angina
    • Indicated for reduction in symptoms where beta blockers are contraindicated. The reduction in mechanical function reduces oxygen demand in patients with angina.
    • Combination with beta blockers when a beta blocker therapy is not successful
    • Slow release long acting dihydropyridines & non-dihydropyridines are effective in stable angina
    • Decrease systemic vascular resistance and arterial BP by vasodilation of systemic arteries
    • Decreased contractility and oxygen requirements
    • Verapamil & Diltiazem decrease MV02 (myocardial oxygen demand) by decreasing conduction through the AV node, and decreasing heart rate

    Antiarrhythmic
    Indications for use: treatment and prevention of supraventricular tachycardia. First line agent for prevention of PSVT (paroxysmal supraventricular tachycardia). Also useful for treatment of atrial fibrillation, especially when beta blocker therapy is not tolerated. Diltiazem and Verapamil are more selective for cardiac tissue than are the dihydropyridines. They block tachycardias in the calcium dependent cells especially in the AV node

    Hypertension: In the absence of cardiac disease, there is no compelling reason to consider non-dihydropyridine CCB to be first line therapy. Are useful in patients with obstructive airway disease and in the African American population. They are also useful in patients with angina and atrial fibrillation, with hypertension.

    Diltiazem (Cardizem®, Dilacor®, Tiazac®, Taztia®, Cartia XT®) (tablets approved 1982)
    Available as tablets: 30, 60, 90 and 120mg
    • SR-Capsules: dosed BID : 60-90-120mg
    • CD-capsules: once daily 120,180,240,300,360mg
    • LA –tablets : 120,180,240,300,360,420 mg tablets

    Dosage 120mg- 360mg / day

    Drug Interactions: inhibits cytochrome P-450 enzymes in the liver.
    • Administration with a beta blocker may precipitate heart failure.
    • Quinidine increases the risk of hypotension.
    • May increase digoxin concentration.

    Verapamil (Isoptin®, Calan®, Verelan®, Covera HS®)
    • Immediate release tablets: 40mg, 80mg 120mg tablets dosed 3 times daily.
    • Sustained release tablets: 120,180,240mg
    • Sustained release capsules: 120,180,240,360mg
    • PM capsules: 100, 200, 300mg
    • Dosage:120mg-360mg /day

    Drug Interactions / Special Notes: inhibits cytochrome P-450 enzymes in the liver
    • Administration with a beta blocker may precipitate heart failure
    • Quinidine increases the risk of hypotension
    • May increase digoxin concentration
    • May cause nausea and constipation

    Diltiazem (Cardizem-CD®) & Verapamil (Isoptin® , Calan®, Verelan®)
    • More potent coronary vasodilators (verapamil more than diltiazem)
    • Good choice for supraventricular tachycardias
    • Minimal peripheral vasodilation & side effects
    • May cause bradycardia, and heart block
    • Avoid in patients with LV systolic dysfunction (EF less than 30%), conduction abnormalities or combined with beta blockers.
    • Indicated for angina
    • Indicated for migraine headache prophylaxis
    • Verapamil is indicated for prevention of cluster headache
    • First generation CCB (verapamil & diltiazem) may accelerate progression of heart failure

    Warnings/precautions/ adverse effects (CCB's)
    • May worsen conduction defects, systolic dysfunction
    • Gingival hyperplasia
    • May cause nausea & headache
    • Verapamil: may cause constipation

    Calcium channel blockers and rash:
    • Calcium channel blockers may cause eczema and other skin problems. About 1% of patients get minor skin reactions (rash, itching, photosensitivity) Calcium blockers can cause a delayed eczema rash occurring about 3 months after starting the drug.

    • Patient Education CCB
      • Notify physician if any of the following occur: irregular heartbeat, shortness of breath, swelling of hands and feet, constipation, dizziness, hypotension.
      • Instruct patient in postural hypotension
      • Most of the products in this class are sustained release. Do not open capsules, or chew or crush tablets



      Calcium channel blockers (CCBs) can be divided into two distinct classes, even though they “block calcium”. We have the dihydropyridines and the “non-dihydropyridines”. This session will explore the two non-dihydropyridine calcium channel blockers, diltiazem, and verapamil. These two drugs were very popular in the 1980's when they came out. We had Calan® by Searle and Isoptin® by Knoll that were the verapamil products. On the verapamil front, Marion Merrell Dow had Cardizem®, first as tablets, then SR capsules then CD capsules then LA tablets. Other branded products followed as well, including Taztia®, Dilacor® and Tiazac®.

      Prescribers may be advised to write diltiazem by the brand name to decrease confusion. "Diltiazem 120" can be interpreted as 120mg immediate release tablets (3-4 times daily); SR capsules (twice daily), CD once a day capsules, or LA once a day tablets. This is a potential for medication error with which pharmacists and pharmacy technicians must be keenly aware.

      Have a great day on the bench!!


    April 2021

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    ALPHA BLOCKERS

    Mechanism: blocks peripheral alpha-1 receptors (post-synaptic)- causes vasodilation of arteries and veins. Alpha-1 receptors are also abundant in the smooth muscle of the bladder neck and prostate. Causes less reflex tachycardia than direct vasodilators (like minoxidil & hydralazine).

    Indications: for patients who have not responded to initial hypertensive therapy. Ideal for older men with BPH.

    Warnings/precautions: Orthostatic hypotension may occur after the first few doses. Minimize by slow titration. Watch for syncope. In the ALLHAT study, the doxazosin arm was discontinued prematurely due an increase of 25% in CV disease outcomes. Caused increase in risk of stroke, CHF and CHD. An alpha blocker is not recommended for initial monotherapy, with the possible exception of older men with symptoms of prostatism and if they are not at high cardiovascular risk.

    Adverse effects
    • Orthostatic hypotension
    • Dry mouth
    • Urinary urgency
    • Constipation
    • Priapism
    Drug interactions

    NSAIDs decrease antihypertensive effects
    Beta blockers and Diuretics increase antihypertensive effects of these agents

    Patient Education:
    • Watch for postural hypotension. Start low. Give dose at bedtime.
    • Watch for drowsiness
    • If priapism occurs seek medical treatment immediately.


    ALPHA BLOCKERS
    GENERICBRAND (year)OTHER INDICATIONSSTARTING DAILY DOSEUSUAL DAILY DOSEMAXIMUM DAILY DOSE
    DOXAZOSINCARDURA®
    (1990)
    BPH1mg at bedtime1-16mg/day16=HTN
    8mg=BPH
    PRAZOSINMINIPRESS®
    (1976)
    1mg at bedtime2-20mg
    (in 2-3 doses)
    40mg
    TERAZOSINHYTRIN®
    (1987)
    BPH1mg at bedtime1-20mg20mg/day


    Prescribing information:

    PRAZOSIN: Always a test question for my PA students...which alpha blocker is NOT to be used for BPH. The answer is prazosin (Minipress®), as it has too short of a duration of action. We dispense more prazosin than doxazosin or terazosin!

    Prazosin is used frequently for improving sleep and decreasing nightmares for patients suffering from PTSD (post-traumatic stress disorder). Nearly 20% of veterans who suffer from PTSD are treated with prazosin. There have been studies proving and disproving its efficacy. Although one rigorous study found it no more effective than placebo, it is recommended NOT to change its clinical use, since there is little else for treatment of nightmares.

    Prazosin blocks the alpha1 receptor for norepinephrine, which becomes more sensitive in combat settings (or any trauma). This up-regulation doesn't seem to go away once the stimulus is removed, and nightmares can become problematic.

    Drugs causing Intraoperative Floppy Iris Syndrome:

    Alpha-1 Blockers: both selective and non-selective The iris becomes flaccid and billows in response to intraoperative irrigation currents, causing the potential prolapse of the iris toward phacoemulsification incisions. Ophthalmologists can modify their surgical techniques including using iris hooks, iris dilation rings, viscoelastic devices.

    Ophthalmologists MUST know before surgery that patient has been on alpha blocker therapy. Usual protocol is to stop the medication 7-10 days pre-op. Be sure to check for alpha blocker use with pre-op physicals for cataract surgery!

    Alpha blockers have been mostly reserved for treatment of Benign Prostatic Hypertrophy (BPH), thanks to the ALLHAT study (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial). We use lots of alpha blockers, but mostly for treatment of BPH. The selective alpha blockers (tamsulosin, alfuzosin, silodosin) were purposely excluded from this discussion, as they are not for treatment of hypertension.

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    ALPHA AGONISTS (CENTRALLY ACTING)

    Mechanism: decreases sympathetic outflow to the cardiovascular system.
    • Clonidine: stimulates alpha-adrenoceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure.
    • Guanfacine: stimulation of central a2-adrenergic receptors. By stimulating these receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels.
    • Methyldopa: conversion into alpha-methylnorepinephrine, which is a potent alpha-2 adrenergic agonist that binds to and stimulates potent central inhibitory alpha-2 adrenergic receptors.
    Indications: use in mild to moderate hypertension has been reduced due to availability of other agents with less side effects.
    • Methyldopa: is primarily used for hypertension during pregnancy.
    Warnings/precautions:
    • Methyldopa: flu like symptoms. Monitor for hepatic dysfunction. Anemia
    Class adverse effects:
    • Drowsiness, dizziness, dry mouth
    • Depression and sleep disturbances
    • Impotence
    • Orthostatic hypotension
    • Bradycardia
    Drug interactions:
    • Caution with other sedating medications
    • Caution with angina, recent myocardial infarction, and cerebrovascular accident.
    Patient Education: Gradually taper dose. Do not suddenly stop. (rebound hypertension)

    CENTRAL ACTIVE ALPHA-2 AGONISTS

    GENERICBRANDYEARSTARTING DAILY DOSEUSUAL DAILY DOSEMAXIMUM DAILY DOSE
    ClonidineCatapres®
    Catapres TTS®
    19740.1mg BID 0.1mg/day patch weekly 0.2-0.6mg (2 divided doses)
    patch 0.1-0.3mg/day
    Tabs=0.8mg
    patch=0.3mg
    GuanfacineTenex®19861mg/day1-3mg/day3mg
    MethyldopaAldomet®1962250mg BID500-2000 in 2 doses2000mg

    Clonidine has been used for the following:
    • Atrial fib
    • alcohol withdrawal
    • ADD
    • Constitutional growth delay in children
    • Cyclosporin associated nephrotoxicity
    • Diabetic diarrhea
    • Hyperhidrosis
    • Hypertensive urgencies
    • Mania
    • Menopausal flushing
    • Methadone/opiate detox
    • Pheochromocytoma diagnosis
    • Post Herpetic neuralgia
    • Psychosis
    • Reduction of allergen induced inflammatory reaction
    • Restless legs syndrome
    • Smoking cessation facilitation
    • Ulcerative colitis


    My son-in-law, Mark Garofoli and I attended PAINWEEK in Las Vegas a couple of years ago, where Mark did several presentations. We went to the exhibit hall and spoke with the pharmaceutical representatives. One was extolling the wonderful benefits of a new medication for opioid withdrawal disorder, and how effective it was when compared to placebo. Both of us being pharmacists and understanding the mechanisms of action asked the reps, “How did it stand up against clonidine?” The silence was deafening! This product costs $20 per tablet; the cost of clonidine is negligible.

    I remember in the 1980’s dispensing alpha-methyl-dopa (Aldomet®) as the “go to” drug for hypertension. We older pharmacists remember buying Aldomet® 250, Aldomet® 500, and Aldoril® 15 and Aldoril® 25 in bottles of 500! Today when we see methyldopa prescribed, it is usually for pregnant women with hypertension.

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    Overview of Potassium Sparing Diuretics

    POTASSIUM SPARING DIURETICS

    Mechanism of action:
    • Amiloride (Midamor®) and triamterene (Dyrenium®) are cations that directly block sodium channels but do not affect the mineralocorticoid receptor, thus preserving potassium.
    • Spironolactone (Aldactone®) and eplerenone (Inspra®) competitively inhibit the mineralocorticoid receptor, with eplerenone being more specific for that receptor. Eplerenone has less endocrine side effects, especially gynecomastia in males.
    Uses: All four potassium sparing diuretics are weak with respect to diuresis. They are frequently combined with loop diuretics to minimize potassium loss. Years ago, they were combined with thiazide diuretics to enhance hypertension control.
    • Spironolactone and eplerenone: by blocking the mineralocorticoid receptor, these drugs may reduce the adverse effects of excess aldosterone on the heart, making them useful for heart failure. Growing evidence shows that they may mediate some major effects of the Renin-Angiotensin-Aldosterone system activation, such as myocardial remodeling and fibrosis as well as sodium retention and potassium loss at the distal tubules. Aldosterone promotes sodium retention, potassium and magnesium loss, sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, and vascular damage and impairs arterial compliance. The RALES study showed a 29% relative risk reduction in heart failure. Should be considered as a “neurohormonal antagonist” rather than a potassium sparing diuretic.
    • Amiloride: useful for treatment of lithium induced diabetic nephrogenic diabetes insipidus
    Adverse effects: Monitor for hyperkalemia, especially if taking potassium supplementation or ACE inhibitors or ARBS. Triamterene is a potential nephrotoxin, possibly leading to crystalluria and cast formation. Causes kidney stones, which can be oxalate or triamterene stones.

    GenericBrandYearStartAverageMaximum
    AmilorideMidamor®Oct 19815mg/day5mg/day20mg
    TriamtereneDyrenium®Aug 196450mg/day50-100mg300mg
    SpironolactoneAldactone®Jan 196012.5-25mg50-100N/A
    EplerenoneInspra®Sep 200212.5-25mg50mg50mg
    Amiloride/HCTZModuretic® 5/50Oct 1981One dailyOne daily2 tabs daily
    Triamterene/HCTZDyazide® 37.5Dec 1965One dailyOne daily2 caps daily
    Spironolactone/HCTZAldactazide 25Jan 1961One dailyTwo daily8 daily


    I remember early on in my career when spironolactone, amiloride, triamterene were the go-to drugs for hypertension. In 1983, we dispensed so much spironolactone (Aldactone®) and spironolactone/HCTZ (Aldactazide®), that we got a free Hoover sweeper!

    We bought potassium sparing diuretics in bottles of 1000 and turned them over in a couple of weeks. We seldom dispense triamterene and amiloride today, and spironolactone is used by cardiologists for heart failure and dermatologists to suppress testosterone in women to help control acne and poly cystic ovary syndrome.

    One of my favorite patients came to the pharmacy a few years back. He was taking spironolactone for heart failure and complained that he was suffering from gynecomastia. He said the pain was so annoying he was ready to try on one of his wife’s bras!

    I wrote the drug name “eplerenone” on a sheet of paper, as he was seeing his endocrinologist the next day. The endocrinologist refused saying it would not help. Being persistent he approached his family doctor, and she made the change to eplerenone. Within a month the gynecomastia resolved, while still maintaining good control of his heart failure.

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    Overview of Loop Diuretics

    LOOP DIURETICS: The “big guns” for edema

    Mechanism:Inhibits the NKCC2 (the luminal Na/K/2Cl co-transporter) in the thick ascending limb of the loop of Henle. This leads to a decrease in total fluid volume through inhibition of sodium and chloride resorption, which causes increased excretion of water, sodium, chloride, magnesium and calcium. Loop diuretics are several times more potent than thiazides, cause less vasodilatation, and are not usually as effective for treating hypertension.

    Indications:
    • When patients are unable to tolerate thiazide diuretics, when they lose effectiveness, and in patients with impaired renal function (less than 30mL/min).
    • Most heart failure patients require more potent Loop diuretics rather than thiazide diuretics.
    • Loops primary agents used to increase excretion of sodium and water
    Dosing:
    • Take daily in the morning.
    • If dosed twice daily, take in AM and afternoon.
    • Ideally, furosemide should be taken on an empty stomach (food decreases absorption), Torsemide (Demadex®) is not affected by food.
    Warnings/precautions/ adverse effects:
    • Same effects as thiazides, additionally:
      • monitor for hypovolemia
      • check BUN and serum creatinine
      • watch for ototoxicity (especially if on an ototoxic drug)
      • may cause postural hypotension
      • may cause photosensitivity
    Drug interactions:
    • NSAIDS: blunt loop diuretics response
    • Antiarrhythmics: depleted K+ may cause Torsade’s de Pointes
    • May cause hyperuricemia, and precipitate gout attacks
    • Lithium: diuresis may spike lithium levels
    Patient Education/Counseling:
    • Report muscle cramps, dizziness, excessive thirst, weakness and confusion as these may be signs of over diuresis.
    • Patients should weigh themselves daily (fluid retention)
    • May be allergic if are allergic to sulfa antibiotics.
    • Caution for photosensitivity—recommend sunscreen
    • Potassium supplements may not be needed if taking an ACE inhibitor (lisinopril, etc.)
    • May need to change to potassium-sparing diuretic if hypokalemia persists
    • Control sodium intake
    • Take in the morning. Take with food
    • Notify practitioner if muscle cramps occur
    • Monitor blood sugar levels in diabetics
    Monitoring:
    • Weight
    • Urine output
    • Blood pressure
    • Blood levels for sodium, potassium, magnesium, creatinine, BUN
    GENERICBRANDSTARTING DOSEUSUAL DOSEMAXIMUM DOSE**SEVERE CKD LESS THAN 30ML/MIN
    BumetanideBumex®0.25mg BID1mg BID-TID10mg8-10mg
    FurosemideLasix®20mg BID40mg 3-4/day320mg200mg
    TorsemideDemadex®2.5mg/day5mg/day15-20mg50-100mg
    Ethacrynic acidEdecrin®50mg/day50mg-200mg/ day (divided dose)400mg400mg


    **MAXIMUM DOSE: dose that when exceeded, does not produce additional diuresis in healthy subjects.

    CHEAT SHEET: bumetanide 1 mg = furosemide 40 mg= torsemide 20 mg = Ethacrynic acid 50 mg

    Hypersensitivity reactions: Furosemide (Lasix®), bumetanide (Bumex®), and torsemide (Demadex®), which are in the sulfonamide class, can cause hypersensitivity reactions, usually manifested as a rash or rarely acute interstitial nephritis, similar to those produced by other sulfonamide drugs. Caution if severely allergic to Sulfa antibiotics, such as Bactrim® or Septra®.
    • Ethacrynic Acid (Edecrin®)- is the “go to” for patients that are refractory to the sulfonamide loop diuretics, or patients that are extremely allergic to the sulfa class (including celecoxib, sulfonylureas, thiazides, etc.). This product is expensive, one tablet of ethacrynic acid costs about as much as 100 tablets of the other loop diuretics!


    In the 1920's while treating syphilis with mercury-based compounds, clinicians noted that they caused excretion of excess fluid. Until the discovery of azetazolamide (a carbonic anhydrase inhibitor) in 1950, the toxic mercury-based compounds were all that was available!

    Chlorothiazide (Diuril®) (1958), yet another sulfa derivative, became the mainstay for heart failure and hypertension. In 1966, the FDA approval of furosemide (Lasix®) took over the treatment of kidney failure and pulmonary edema. Ethacrynic acid (Edecrin®) was approved in 1967 and marketed by Merck.

    In 1983, bumetanide (Bumex®) became the third loop diuretic to be approved. In 1993, torsemide (Demadex®) was FDA approved and marketed by Roche.

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    Overview of Thiazid Diuretics

    THIAZIDE DIURETICS

    Mechanism:
    • direct arteriole dilation
    • Reduction in total fluid volume, through the inhibition of sodium resorption in the distal tubules of the nephron
    • Prominent diuretic effect fades over time; however, the antihypertensive effect is persistent.
    • Increases effectiveness of other antihypertensive agents by preventing the re-expansion of plasma volume.
    Indications:
    • Currently recommended for initial therapy of hypertension.
      Diuretics are more effective in African Americans and elderly patients because they are more renin dependent than Caucasians. Thiazide diuretics are preferred over “loop” diuretics because of their extended action.
    Warnings/precautions:
    • Thiazides are filtration dependent, and only effective in patients with a creatine clearance (CrCl) greater than 30mL per minute.
    • Take early in the day to avoid nocturia
    • Photosensitivity—use SPF >15
    • May increase blood glucose in diabetics
    • Report muscle cramps, may indicate depleted potassium
    • Caution if allergic to sulfonamide drugs.
    Adverse effects
    • May cause hypokalemia, and hypomagnesemia
    • May cause orthostatic hypotension.
    Drug interactions
    • Steroids: cause salt retention and antagonize the actions of thiazides
    • NSAIDS: blunt thiazides response
    • Calcium: increases calcium levels, is protective for osteoporosis
    • Antiarrhythmias: depleted K+ may cause Torasades de Pointes
    • May cause hyperuricemia, and precipitate gout attacks
    • Lithium: thiazides decrease lithium clearance and increase risk of toxicity
    Patient Education: Thiazide diuretics
    • Be sure to monitor: BUN/ creatinine; cholesterol levels, K+ levels, uric acid levels, weight and BP
    • Take in the morning. Take with food
    • Notify practitioner if muscle cramps occur
    • Use sunscreen due to photosensitivity
    • Monitor blood sugar levels in diabetics
    • Watch alcohol intake for OTC drugs
    • May cause gout attacks, notify physician of sudden joint pain.
    Prescribing information: Thiazide diuretics
    • Flattened dose response curve for hypotensive effect. Blood pressure reduction plateaus at 25mg for HCTZ , while adverse potential increases with increasing doses (50mg, 100mg). Full antihypertensive effect may take up to 4 weeks or longer.
    • Very, very inexpensive therapy. 100 tablets less than $8.00
    • Pregnancy: Category-B: indicated when edema is due to pathological causes. Dependent edema resulting from restriction of venous return by the gravid uterus is NOT properly treated with diuretics.
    • The combination of an Angiotensin Converting Inhibitor (ACEI)/ or Angiotensin Receptor Blocker (ARB) with a thiazide diuretic reduces risk of thiazide-induced hypokalemia. Most common combinations are Lisinopril/HCTZ, Losartan/HCTZ and Irbesartan/HCTZ
    • ACEI/ARB ameliorates diuretic-induced activation of the renin-angiotensin-aldosterone system, caused by a thiazide diuretic. This leads to an additive blood pressure reduction
    • Chlorthalidone and indapamide, both thiazide-like diuretics in the same class as HCTZ, have been shown to provide greater antihypertensive efficacy. Both chlorthalidone and indapamide reduce cardiovascular events and mortality compared with hydrochlorothiazide. So that begs the question why do most pharmacists buy HCTZ in bottles of 1000, and we “blow the dust off” the indapamide and chlorthalidone?
    • Metolazone (Zaroxolyn®) is frequently prescribed by nephrologists because it may be effective in patients with renal impairment. Most often used as a “kicker” two or three times a week to augment the diuretic effects of loop diuretics like furosemide (Lasix®).


    Generic/BrandDosage formsTypical adult doseHalf life
    Chlorthalidone (Hygroton®) 25, 50mg tablets12.5- 25mg once daily.50-60 hours
    Chlorothiazide (Diuril®)500mg tablets 250mg/5ml susp 500mg-1000mg per day or divided BID1-2 hours/td>
    Hydrochlorothiazide (HydroDiuril®, Esidrex®) 12.5mg caps; 12.5mg, 25mg, 50mg tabs12.5-50mg/day5.6-14hrs
    Indapamide (Lozol®) 1.25mg, 2.5mg tabs1.25-2.5mg daily16hrs
    Metolazone (Zaroxolyn®)2.5mg, 5mg 10mg tablets2.5-5mg once daily14 hours



    THIAZIDE DIURETIC TIMELINE:

    GENERICBRANDAPPROVAL DATEMANUFACTURER
    ChlorothiazideDiuril®9/4/1958Merck
    HydrochlorothiazideEsidrix®
    HydroDiuril®
    Oretic®
    2/12/1959
    2/24/1959
    7/6/1959
    Ciba-Geigy
    Merck
    Abbott
    HydroflumethiazideSaluron®7/22/1959Shire LLC
    BendroflumethiazideNaturetin-10®12/7/1959Apothecon
    ChlorthalidoneHygroton®4/7/1960USV
    MethyclothiazideEnduron®10/21/1960Abbott
    PolythiazideRenese®9/26/1961Pfizer
    MetolazoneZaroxolyn®11/27/1973Pennwalt
    IndapamideLozol®7/6/1983USV

    BODY STOP

    Thiazide diuretics are 63 years old and still going strong! These agents are timeless, with only three of them used at all today, namely hydrochlorothiazide (HCTZ), metolazone and chlorthalidone.

    With all of the evidence for indapamide and metolazone being superior to HCTZ, we have the HCTZ 12.5mg and 25mg in our "fast moving" section of the pharmacy.

    I can’t think of more than 2 or 3 current patients taking chlorthalidone or indapamide. I remember 40 years ago, when we would buy Enduron® (methyclothiazide) in bottles of 1000 and move them right off the shelf. I also remember buying bulk bottles of Diuril® 500mg as well as HydroDiuril® 100mg tablets.

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    Hypertension and Beyond: A Glance at the Wide Utility of Beta Blockers

    BETA-ADRENERGIC BLOCKERS (Beta Blockers) for HEART FAILURE

    Mechanism: Interfere with sympathetic nervous system to decreases peripheral vasoconstriction
    • Protect heart from over-stimulation by sympathetic nervous system. Blockade of beta receptors antagonizes the increase in sympathetic nervous system activity responsible for the progression of heart failure
    • Over a period of 3-6 months BB produce substantial rises in ejection fraction (averaging 10% absolute increase) and reducing LV size and mass
    • Current guidelines recommend BB with all patients with stable HF due to LV dysfunction unless unable to tolerate. Patients MUST be stable before treatment is initiated
    Beta blockers most effective for heart failure
    • Carvedilol (Coreg®) target dose: 25mg BID
    • Metoprolol succinate (Toprol-XL) target dose 200mg/day
    • Bisoprolol (Zebeta®) 10mg daily
    Titrate all beta blockers slowly (increase dose every two weeks), but try to get patient to target doses.

    BETA-ADRENERGIC BLOCKERS (Beta Blockers) for HYPERTENSION
    • Unless a patient has Coronary Artery Disease (CAD), atrial fibrillation, angina or heart failure, beta-blockers are considered second line therapy for hypertension, especially in patients over age 60.
    • Atenolol has NOT been shown to improve outcomes in hypertension, heart failure, or after a myocardial infarction.
    • Non vasodilating beta blockers are also associated with impaired glucose tolerance, which may lead to an increase risk of new onset Type-2 diabetes. (Carvedilol, labetalol and nebivolol are VASOdilating beta blockers)
    BETA-ADRENERGIC BLOCKER (Beta Blocker) for HYPERTENSION IN PREGNANCY
    • Labetalol is the preferred antihypertensive in pregnancy. Low concentrations of labetalol appear in breast milk
    BETA-ADRENERGIC BLOCKERS (Beta Blockers) for MIGRAINE PROPHYLAXIS
    • Metoprolol tartrate (Lopressor), propranolol (Inderal) and timolol (Blocadren) penetrate the blood brain barrier, and have proven efficacy for migraine prevention.


    I tell my new heart failure patients that are just starting out on carvedilol (Coreg), that “if I have a miracle drug on my shelf it is carvedilol.”Back in the early 1990’s one of my patients came in with a sheet of paper from his cardiologist. Turns out his cardiologist was Pittsburgh’s most renown heart failure specialist.

    He asked me to review the side effects about carvedilol.The drug was not even on the market yet, and the patient was to be enrolled in a study.He was on the heart transplant list, and this was the last-ditch effort using medication.

    The patient responded well, lived another 20 years, and never needed a heart transplant.The efficacy of that drug is amazing, just getting the patients to have good adherence is the biggest challenge.Every two weeks when the dose is increased, the patient feels wiped out, and many fall short of the 25mg twice daily goal. Keep encouraging their patients to tolerate the initial side effects, because the benefits are amazing!

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    Exploring Differences Between Common Beta Blockers

    Eighteen beta blockers are listed in Up-To-Date's website. I find it beneficial to sort them out into the most common ones on the community pharmacist's shelves.

    I remember early on in my career when propranolol (Inderal®) changed from the round orange, blue, green tablets to hexagonal tablets because the manufacturer's patent expired in July 1985. Now, nebivolol (Bystolic®) is the only branded beta-blocker left on our shelves, and a prior authorization is usually the case if a clinician needs to prescribe it. Over time, beta blockers have proven to be cheap and effective.

    BETA BLOCKERS- The differences...

    Cardioselectivity for Beta-1: All Beta blockers lose their cardio-selectivity at higher doses. Avoid beta blockers in patients with asthma, COPD, and peripheral vascular disease and diabetes unless there are compelling indications, such as ischemic heart disease and prevention of second myocardial infarction (MI).
    • Beta-1 selective drugs include: Acebutalol (Sectral®), Atenolol (Tenormin®), Bisoprolol (Zebeta®), Metoprolol (Lopressor® or Toprol-XL®)
    ISA (intrinsic sympathomimetic activity) in theory may have advantages in beta blockers in patients with borderline CHF, sinus bradycardia or peripheral vascular disease. These agents do not appear to be as protective against cardiovascular events as other beta blockers. They may increase the risk of MI, thus should not be used.
    • Penbutalol (Levatol®) and Pindolol (Visken®) and Acebutalol (Sectral®) have ISA, causing less resting bradycardia and lipid changes
    Lipophilic Beta Blockers: All Beta Blockers cross the Blood Brain Barrier, but the extent to which they enter the brain depends on the lipophilicity. Propranolol (Inderal®) (least cardio selective BB) and Metoprolol (Lopressor®/Toprol-XL®) are relatively lipophilic. More lipophilic BB cause more CNS side effects such as depression.

    Hydrophilic Beta Blockers:
    • Atenolol (Tenormin®) and Nadolol (Corgard®) are more water soluble (weakly lipophilic). Less likely to cause sedation.
    Non-Vasodilating beta blockers:
    • Propranolol (Inderal®), Metoprolol (Lopressor®, Toprol-XL®), Atenolol (Tenormin®), are associated with insulin resistance, and decreased insulin secretion.
    Vasodilating beta-blockers:
    • Carvedilol (Coreg®), Nebivolol (Bystolic®), Labetalol (Normodyne®) do not cause hyperglycemia. Are the best choice for a diabetic patient.

    Mechanism: Beta blockers
    Beta-blockers slow heart rate and reduce myocardial contractility. In hypertensive patients, they reduce total peripheral resistance.

    Proposed mechanisms include:
    • -stimulation of renin secretion is blocked
    • -cardiac contractility is decreased, thus decreasing cardiac output
    • -central sympathetic output is decreased
    • -decrease in heart rate decreases cardiac output
    • -Beta blocker action may combine all the above mechanisms
    Indications for beta blockers:
    • Patients with rapid resting heart rate (a-fib, paroxysmal supraventricular tachycardia)
    • Heart failure, post-MI
    • High coronary disease risk
    • Angina
    • Hypertension
    • Prevention of migraine (propranolol). Documentation of efficacy is less clear for metoprolol, atenolol, and nadolol.
    Warnings/precautions
    • Caution with diabetics: Diabetes (watch for “masking” of hypoglycemic symptoms)
    • Caution in patients with Raynauds or peripheral vascular disease
    • Caution in COPD/ asthma or bronchospastic disease
    • Caution in depressed patients—avoid lipid soluble BB (propranolol & metoprolol)
    • Caution in hyperlipidemia; increases LDL and decreases HDL
    Patient Education
    • Report dizziness or hypotension
    • Sedation with lipid soluble beta blockers (propranolol & metoprolol)
    • Avoid rapid withdrawal: taper dose over 14 days.
    • Sexual dysfunctions (impotence & decreased libido)
    NOTES: Beta Blockers:
    • • All beta blockers lower blood pressure to a similar extent, and can be dosed once or twice daily.
    • • Cardioselectivity is dose dependent
    • • May increase triglycerides
    • Carvedilol (Coreg®), Metoprolol (Toprol-XL®), and Bisoprolol (Zebeta®) are the only beta-blockers with mortality evidence for use in heart failure. (However, the COMET study showed that carvedilol is the most effective)
    BETA BLOCKERS— MOST COMMON Non-Selective Beta Blockers
    (beta-1 and beta-2 activity – are more likely to cause peripheral vasoconstriction, bronchoconstriction, delayed recovery from hypoglycemia in Type-1 diabetes, and impair exercise performance. Not a good choice for patients with asthma/COPD)
    DrugLipophilicityHalf LifeIndicationDoseComments
    Nadolol (Corgard®)LOWLONGAngina, HTN, A-fib10-240mg/day
    Propranolol (Inderal®) HIGHShort, but LA formula availableAngina, HTN, tremor, Migraine PxTabs: 10-40mg QID LA-CAPs: 80-160/day max=320mg High risk of fatigue. Low concentrations in breast milk

    BETA BLOCKERS- MOST COMMON beta-1 selective
    (remember beta selectivity is lost at higher doses)

    DrugLipophilicityHalf LifeIndicationDoseComments
    Atenolol (Tenormin®)LOWLONGA-fib for rate control. HTN: no improvement in mortality 25-100mgRenal elimination
    Metoprolol tartrate Immediate release (Lopressor®) ModerateMediumAngina, hypertension, post MI25-400mg
    Metoprolol Succinate extended release (Toprol-XL®) ModerateLONG (once a day) Heart failure, HTN, angina, a-fib12.5-400mgSuccinate is long acting
    Nebivolol (Bystolic®) LOWLONGHTN,5-40mgNot indicated for HF in USA

    BETA-BLOCKERS MOST COMMON alpha-1 antagonist activity
    (these cause peripheral vasodilation)

    DrugLipophilicityHalf LifeIndicationDoseComments
    Carvedilol (Coreg®) Moderate1st-pass metabolism. Moderate Heart Failure, Hypertension, LVD after MI 3.125mg BID to 25mg BID maximum of 50 mg BIDNOT cardioselective
    Labetalol (Trandate®) (Normodyne®)LOWModerateHypertension100mg-400mg BIDNOT cardioselective. Preferred BB in PREGNANCY. Low concentration in breast milk.


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    Overview of Statins for Hyperlipidemia

    Statins: what would we ever do without them? At one time, diet and exercise and anion exchange resins were all we had to combat hyperlipidemia.

    One of the biggest challenges we all have as community pharmacists is KEEPING patients on statin therapy. We all know that our star ratings are based on diabetics being prescribed statins, as well as adherence to statin therapy. Everyone complains of muscle pain, but a patient along with their doctor should decide based on liver function tests as to whether they should continue therapy.

    STATINS

    Mechanism of Action: HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids.

    Indication: Overwhelmingly the best choice for elevated LDL cholesterol, providing safe and effective LDL lowering by 18- 55%. Also, lower triglycerides, and increase HDL.

    The primary target of lipid-lowering therapy is LDL because there is a strong relationship between elevated LDL and coronary heart disease. Moderate doses of statins, which primarily target LDL, decrease cardiovascular morbidity and mortality by 25% to 35% within five years’ use. Although low HDL and high triglycerides are associated with increased risk for coronary heart disease, evidence of cardiovascular benefit from treating low HDL or high triglycerides is less compelling.

    Warnings/Precautions/Adverse effects:
    • GI adverse effects
    • Headache & dyspepsia
    • Elevated liver enzymes AST and ALT.
      • Do LFT initially, at 12 weeks, then annually.
    • Myopathy: is believed to be low 0.08% (8 per 10,000)
    • Check CK (creatine kinase) before starting therapy. Do not stop statins if less than 3 times upper-limit of normal.
    • Evaluate for increased/excess exercise.
    • 30% of patients on placebo experience muscle pain
    • Evaluate in 6-12 weeks as per the scheme outlined previously
    • May be worse if other drugs are taken concurrently (erythromycin, cyclosporine, niacin, fibrates, antifungals)
    • May lead to rhabdomyolysis: disintegration of dissolution of muscle
    Drug Interactions:
    • Pravastatin (Pravachol®) and Rosuvastatin (Crestor®) are not metabolized by CYP450.
    • Pitavastatin (Livalo®): Not significantly metabolized by CYP450 and may be less likely to be involved in drug interactions.
    • Other statins (simvastatin/lovastatin) have potential for significant drug interactions.
    • Grapefruit juice: co administration with grapefruit juice (8oz or 1 grapefruit)) may increase simvastatin, & lovastatin levels. Separation for food and drug does NOT work. Grapefruit primarily affects intestinal, not hepatic enzymes.
    STATIN COMPARISONS: to get 41% LDL-C lowering:
    Rosuvastatin 5mg= Atorvastatin 20mg= Simvastatin 40mg=Pravastatin 80mg


    Contraindications for statins:
    Itraconazole, Ketoconazole, Posaconazole, Erythromycin, Clarithromycin, Telithromycin, HIV protease inhibitors, Nefazodone, Gemfibrozil, Cyclosporine, Danazol

    Simvastatin dose should not exceed 10 mg with amiodarone, verapamil, or diltiazem. Simvastatin dose should not exceed 20 mg with amlodipine or ranolazine.

    Cholesterol medications are ideally dosed after supper & before bedtime, due to increased cholesterol synthesis during the night. Although rosuvastatin (Crestor®) and atorvastatin (Lipitor®), because of their long half-lives, can be dosed any time, most clinicians advise that all statins be given in the evening for maximum benefit. Pravastatin (Pravachol®), Fluvastatin (Lescol®), Simvastatin (Zocor®) and Lovastatin (Mevacor®) must be dosed in the evening.

    May cause photosensitivity reactions.

    Pregnancy category-X.

    Asian patients may require lower doses of the statins.

    All statins except pitavastatin (Livalo®) are available generically.

    Statins are no longer recommended to be combined with niacin for hyperlipidemia. The FDA pulled approval of this combo to treat hyperlipidemia.

    Statins inhibit CoQ10 formation and many theorize low CoQ10 levels might lead to myopathy. There's no conclusive proof that CoQ10 works for statin induced myopathy but some anecdotal reports suggest it might be helpful. Dosage: If patients want to try CoQ10, suggest starting low and dividing doses over 100 mg. Take two to three times daily to minimize nausea and diarrhea. Interestingly enough, a meta-analysis of 2400 patients showed significant lower levels of Vitamin-D in patients who had statin associated muscle pain.

    Muscle complaints defined:

    Myopathy - a general term related to any muscle complaint

    Myalgia - muscle complaints (i.e., ache, weakness) without elevations in CK. This is the most common myopathy reported with statins

    Myositis - muscle complaints with elevation of CK Rhabdomyolysis - markedly elevated levels of CK, usually greater than ten times the upper limit of normal; usually accompanied by creatinine elevation, brown urine, and urinary myoglobin.

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    February 2021

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    Beyond the Statins: An Overview of PCSK9 Inhibitor Antibodies

    Monoclonal antibodies are notoriously expensive. Whether for the treatment of rheumatoid arthritis or multiple sclerosis, the costs are incredibly high. I smile when I think of these drugs, because they were first introduced at around $1,200 per month.

    Due to poor sales because of formulary coverage, both companies reduced the price of these drugs by 60%. It shows that monoclonal antibody therapy for COMMON diseases needs to be reasonably priced.

    We are seeing more of these drugs being used, thanks to decreased costs. They are highly efficacious, but certainly do not take the place of statin therapy for most patients, with a cost of around $10 per month.

    PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibitor Antibodies
    (Both drugs approved in 2015)


    HOW THEY WORK: The PCSK9 protein interferes with the clearance of LDL-C from the blood. LDL receptors on liver cells remove LDL-C from the blood by binding it and then moving it into the cell for elimination. The lipid-free receptors then return to the surface of the cell. When PCSK9 binds to the LDL receptor, however, the receptor is unable to re-emerge on to the cell surface to remove more LDL-C, which then remains in the blood. By inhibiting the PCSK9 protein, PCSK9 inhibitors essentially improve the liver’s ability to recycle LDL receptors, resulting in a greater number of receptors on the cell surface and enabling more LDL-C to be removed from circulation.

    BENEFITS
    • They can lower LDL-C by as much as 60% in patients on statin therapy.
    • Reductions in the rates of stroke or myocardial infarction by 50%.
    • Lowers triglyceride levels by 12 to 31 percent
    • Slight increase in high density lipoprotein cholesterol by 5 to 9 percent
    Alirocumab (Praluent®): (approx. $500/month): Indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL- C

    Storage: keep in a refrigerator at 36°F to 46°F in the outer carton in order to protect from light. Warm up to room temperature before injection. Don’t exceed 24 hours of time out of refrigerator. May take up to 20 seconds for injection to be complete.

    Dose: 75mg SQ every 2 weeks. This is usually enough to achieve max lowering of LDL-C. Maximum dose is 150mg every 2 weeks. Available as pre-filled single dose pens, 75mg or 150mg.

    Evolocumab (Repatha®): (approx. $500/month) is used along with diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia, (an inherited condition that causes high levels of LDL), or atherosclerotic heart or blood vessel problems, who need additional LDL lowering.

    Keep refrigerated. May be stored at room temperature for up to 30 days.

    Dose: Primary hyperlipidemia with established clinical atherosclerotic CVD or heterozygous familial hypercholesterolemia: 140 mg every 2 weeks or 420 mg once monthly in abdomen, thigh, or upper arm.

    For both products “maximally tolerated statin therapy” can be interpreted as no statin at all if patients can’t tolerate statins.

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    Beyond the Statins: Overview of Fibric Acid Derivatives

    For most of our patients elevated triglycerides seem to be directly connected to their poor diet of refined carbohydrates. Pizza, pasta, bread, sugar drinks, cookies, donuts, virtually anything that tastes good can drive up triglycerides. Fibrates are of not much value. Treatment of elevated triglycerides is better left to the dietician, rather than reaching for the fibrates! Diet and exercise are the cornerstone for hyperlipidemia, cardiovascular disease, and diabetes.

    Tricor was first introduced in 1993 (67mg, 134mg, 200mg), and reformulated in 2001 (54mg and 160mg), and again in 2004 (48mg and 145mg), just to protect the patent. To follow up, they introduced Trilipix (fenofibric acid) in 2008, which was their last attempt to breathe life into this product. It bombed.

    Fibrates for High Triglycerides... not so fast

    Triglyceride overview:

    ASCVD: Elevated fasting plasma triglycerides levels are associated with atherosclerotic cardiovascular disease (ASCVD) burden and events such as myocardial infarction and stroke. Triglycerides over 150mg/dl seems to increase the risk of ASCVD. Elevated triglycerides are also associated with insulin resistance, metabolic syndrome, platelet aggregation and low HDL. Lowering TG’s has not been proven to reduce ASCVD events.

    Acute pancreatitis: The risk for acute pancreatitis rises when serum TG levels exceed 500 mg/dL. The risk of developing acute pancreatitis is approximately 5 percent when TG’s exceed 1000mg/dl and up to 20 percent with TGs exceed 2000 mg/dL.

    Medications that can exacerbate hypertriglyceridemia:
    • Oral estrogens
    • Bile-acid sequestrants (Cholestyramine, Colestipol, Colesevelam)
    • Antiretroviral regimens, especially for HIV (especially Protease inhibitors)
    • Second-generation antipsychotic medications such as clozapine (Clozaril) and olanzapine (Zyprexa
    • Nonselective beta blockers (propranolol)
    • Thiazide Diuretics
    • Glucocorticoids
    • Increased consumption of alcohol, sugar-containing beverages and simple carbohydrates


    FIBRIC ACID DERIVITIVES

    Mechanism of Action:
    Bind to and stimulate peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor which increases lipoprotein lipase activity, which hydrolyzes triglycerides from VLDL. Other effects include decreased hepatic cholesterol synthesis, and increased cholesterol secretion in the bile \

    Indication: 20 to 50% reduction in triglycerides

    Warnings/ Precautions/Adverse effects:
    • Caution if combined with statins (watch CK, rhabdomyolysis)
    • Take with food to minimize GI upset
    • May increase gallstones - don’t give if patient has gallbladder disease.

    Drug Interactions: Fibrates will increase warfarin effect- reduce warfarin dose by 30%

    Patient Education: Take with food to minimize GI effects

    Products of this Class (Fibrates)
    • Gemfibrozil (Lopid®)
      • 600mg tablets
      • Dosage: 1 tablet BID
      • Prescriber note: Avoid combining Gemfibrozil with statins CONTRAINDICATED.
    • Fenofibrate (Tricor®)
      • Tablets 48mg and 145mg (new formulations)
      • Dosage: 1 tablet daily
      • Other fenofibrate formulations: 54mg, 67mg, 134mg, 150mg, 160mg, 200mg


    Fibric acid derivatives have fallen out of favor.

    NOTE: Statins typically lower TG levels by 5 to 15 percent; however, high-intensity statin therapy can lower TGs by 25 to 30 percent. Most clinicians will increase the statin dose rather than add a fibrate. Fibrates, when combined with statins did not lower risk of non-fatal MI, non-fatal stroke, or CV death. Gemfibrozil is the only fibrate with demonstrated beneficial effects on cardiovascular outcomes, but its use with statins can increase the risk of myopathy and is not recommended. Fenofibrate is not proven, gemfibrozil with statins causes high risk of myopathy and is not recommended.

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    Beyond the Statins: Overview of Ezetimibe and Bempedoic Acid

    Ezetimibe (Zetia®- approved October-2002)

    >Mechanism: works by blocking NCP1L1 (Niemann-Pick C1-Like 1), which blocks intestinal absorption of cholesterol and phytosterols. It is effective in absence of dietary cholesterol because it blocks absorption of cholesterol in the bile.

    Indication:
    It lowers LDL by 18%, and triglycerides by 8%, and raises HDL by 1-5% by itself. When combined with statins it lowers LDL 25%, triglycerides by 14%, and raises HDL by 3%.

    Prescribers Note:
    Most clinicians will try to get a statin on board even if the patient complains of muscle pain. Even giving Atorvastatin 5mg 3 or 4 times a week greatly improves the lipid profile over that of ezetimibe (Zetia®) alone. Ezetimibe may be helpful for avoiding high doses of statins, and therefore possibly decreasing risk of myopathy in patients who do not meet cholesterol goals on low-dose statin therapy alone.

    Warnings/Precautions/Adverse Effects:
    Well tolerated. May see increase in liver transaminases when combined with statins.

    Pregnancy Category-C


    Bempedoic Acid (Nexletol®-approved 2020)

    Mechanism: the first ATPcitrate lyase (ACL) inhibitor, indicated for use as adjunct to diet and maximally tolerated statin therapy. This enzyme is “upstream” from HMG reductase, the enzyme that statins block. First oral, once daily, non-statin in 20 years since ezetimibe. Lowered LDL-C by 17% on background therapy.

    Dose: 180mg once daily, with or without food.
    • Simvastatin: Avoid concomitant use with simvastatin greater than 20 mg.
    • Pravastatin: Avoid concomitant use with pravastatin greater than 40 mg
      • Practice Point: other statins such as rosuvastatin and atorvastatin do not seem to be affected by bempedoic acid and may be a more rational choice./li>
    Warning: may increase blood uric acid levels. Hyperuricemia may occur early in treatment and persist throughout treatment and may lead to the development of gout.
    • Practice Point: Check the profile for allopurinol, febuxostat or colchicine which indicate potential for gout flares. Be sure to contact the prescriber and patient.
    Tendinopathies: bempedoic acid increases the risk for tendon rupture, especially in the rotator cuff, biceps, and Achilles tendons.
    • Practice point: Check patient profile for the following that can increase the risk of tendon rupture: patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders..
    Pennsylvania Medicaid Formulary requires: “Is being prescribed the ACL inhibitor by or in consultation with an appropriate specialist (e.g., cardiologist, endocrinologist, or other provider specializing in lipid disorders.”

    Do not consider Bempedoic acid to be as safe as the PCSK-9 inhibitors (alirocumab (Praluent®), evolocumab (Repatha®). The potential for gout as well as tendinopathies makes it necessary for the prescriber and pharmacist to provide a more intense patient counseling effort. This is especially important for patients with commercial insurance or Medicare-D plans where the prescriber might not need to be a specialist as required for the state Medicaid plans, such as Pennsylvania's.

    Nexletol (bempedoic acid) and Nexlizet (bempedoic acid + ezetimibe) are being detailed to family practice offices as well as the specialists.

    Make sure you are monitoring the uric acid levels, as bempedoic acid might precipitate a gout attack. Most recommendations say check uric acid (and get it under control) before prescribing bempedoic acid.

    Have a great day on the bench!!

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    An Overview of Bile Acid Resins

    At the beginning of my career, all we had to lower cholesterol was diet, exercise, and cholestyramine (Questran®). One of my colleagues had a heart attack at the age of 42 years. His wife went to a cooking school in the early 1980’s to learn how to cook heart healthy meals.

    The statins came along about 1987 and for the most part displaced cholestyramine as treatment of hyperlipidemia. Now I see that most of the cholestyramine prescriptions are written by gastroenterologists, and the colesevelam prescriptions are written by endocrinologists!

    BILE ACID-RESINS
    Mechanism of Action: Anion exchange resin that binds bile acids in the intestine. Resins are insoluble and non-absorbable. Bile acids are synthesized from cholesterol, and by their removal more cholesterol is taken up from the bloodstream. Bile acids and resins are excreted in the stool.

    Indication: Usually used as adjuncts to statin therapy requiring further lowering of LDL, reduces LDL by 15-30%.

    Warnings/ Precautions/Adverse effects:
    • Constipation- major side effect (30%)
    • Taken right before meals.
    • ELEVATES Triglycerides (negative feedback with liver)
    • Vitamin deficiencies: Bind fat soluble vitamins (A, D, E, K); be sure to monitor for Vitamin-K deficiency
    Drug interactions:
    • Will bind other drugs and decrease their absorption. Colestipol and cholestyramine bind digoxin, warfarin, statins and other ionic charged drugs can be bound
    • Other drugs should be taken 1 hour before, or 4-6 hours after the resins
    Patient Education:
    • Other drugs should be taken 1 hour before, or 4-6 hours after the resins
    • Increase fluid intake and fiber in order to better cope with constipation
    • Large tablet load, unpalatable taste and side effects will impact adherence to this class of drugs
    Products of this Class:
    • Cholestyramine (Questran®, Prevalite®) available in regular and sugar free. Scoop is included
      • Dose = 4gm 1 –2 times daily
      • Dissolve granules in water or juice
    • Colestipol (Colestid®)
      • Tablets (1gm): 2 to 16 tablets daily
      • Granules: 5gm packets, 5 to 30gm/day
    • Colesevelam (Welchol® 625mg)
      • Also used as add-on therapy for Type-2 diabetes. Used along with Metformin, sulfonylureas, and insulin. Bile acids play a role in cholesterol and glucose metabolism (FXR receptor). Reducing bile acid absorption can improve both. Lowers HbA1c about 0.5%- 0.8%; Lowers LDL up to 20%.
      • CAUTION: in patients with triglycerides over 300 mg/dL. Avoid use if triglycerides exceed 500 mg/dL. May increase triglycerides up to 10% especially when combined with insulin or sulfonylureas.
      • Dose: 3 tablets BID or 6 tablets as a single dose or 3.75gm packets once daily
      • Colesevelam does NOT bind digoxin, warfarin, or statins


    ITCHING:
    Pruritus may develop in patients with cholestasis due to any cause. Elevated bile acids in the skin can cause itching. Cholestyramine (4-16 grams per day) can be considered as first line therapy. Colestipol can also be considered. Best if dosed before and after breakfast in patients with an intact gallbladder to enhance the excretion of the bile pruritogens, which seem to accumulate in the gallbladder during the overnight fast.

    CLOSTRIDIUM DIFFICILE:
    Cholestyramine binds toxins A and B excreted by Clostridium difficile. Cholestyramine does not alter the gut flora but may be helpful as adjunctive therapy. Now that vancomycin is considered first line therapy for C. dif, caution must be exercised when using cholestyramine, as it may bind vancomycin rendering it less effective. If both are given together, be sure to separate by at least 2-3 hours.

    DIAPER RASH:
    Some diaper rash compounds include cholestyramine to bind up bile acids, which can cause direct irritation. Nationwide Children’s Hospital uses a 20% Cholestyramine/Petrolatum preparation, consisting of cholestyramine light (80%) [25grams] combined with petrolatum base [75grams]. Shelf life was 180 days.

    Para Have a great day on the bench!!

    January 2021

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    Role of Niacin in the Management of Hyperlipidemia

    Understanding Niacin therapy always gives me a better appreciation for treating hyperlipidemia. I always tell my students that “Niacin makes the numbers look pretty but does nothing to extend life.”

    Niacin raises HLD, lowers LDL and triglycerides, but doesn’t do anything to decrease CV events. You have to wonder what it is that the statins do that is so “magical”. When statins make the numbers look pretty, patients live longer. I have to wonder if further research will show that statins do more than play the numbers game. Hyperlipidemia is clearly more than a numbers game!

    The goal of treating hyperlipidemia is to decrease the concentration of free LDL in the blood that can cause fatty streaks and plaques and to increase HDL which works to reverse the formation of fatty streaks and plaques.

    LDL: low density lipoprotein –a genetic link exists (bad cholesterol)
    • Oxidized LDL becomes atherogenic
    HDL: high density lipoprotein- no genetic link (“good cholesterol”)
    TG: triglycerides-a genetic link exists.
    • Oxidizes LDL, lowers LDL clearance, causes inflammation—a genetic link exists
    The overall goal is to decrease the risk for a cardiac event or a stroke.
    • For every 1% reduction in total cholesterol, total CV mortality is reduced by 1.5%
    • For each 1% decrease in LDL there is a 2% decrease in risk of CV events
    • For each 1% increase in HDL there is a 3% decrease in risk of CV events
    Major risk factors that modify LDL goals:
    • Cigarette smoking
    • Hypertension (BP >140/90 mmHg or on antihypertensive medications)
    • Low HDL cholesterol
    • Family history of premature CHD
      1. Male first degree relative <55 years old
      2. Female first degree relative <65 years old
    • Age
      1. Men > 55 years old
      2. Women > 55 years old

    NICOTINIC ACID (Niacin) Vitamin B3
    Mechanism of Action for hyperlipidemia
    Decreases the production and release of very low-density lipoprotein (VLDL). Niacin also decreases the release of free fatty acids from adipose tissue into the circulation, which is the primary producer of circulating FFA’s.

    Indication:
    • Niacin (1.5-4.5gm/day) - lowers LDL by 5-25%, increases HDL 15-35%, and decreases triglycerides by 10-50%. Sounds like a winning combination… except…
    • Never monotherapy (low-cholesterol, low-fat diet)
    Warnings/ Precautions/Adverse effects:
    • Although Niacin is arguably the most effective drug for improving the entire lipid profile it is difficult for patients to tolerate.
    • Causes cutaneous flushing
      • Can be overcome by one Aspirin 325mg 30 minutes before niacin (enteric coating 1 hour).
    • Start low and go slow with niacin dosing
    • Take with food
    • GI upset
    • Liver toxicity
    • May cause mild worsening of glucose intolerance.
      • Diabetics may experience a 25% increase in serum glucose levels.
    • May raise uric levels and precipitate gout.
    Patient Education:
    • Major side effect is cutaneous flushing.
    • Take with food to decrease GI upset, right before bed..
    • Swallow whole, with cold water.
    • Avoid sudden changes in posture. May cause dizziness.
    • Avoid alcohol and hot drinks during administration.
    • Increase blood glucose monitoring if diabetic.
    • Watch niacin content in multivitamin.
    Products of this Class:
    • Niaspan® 500, 750 and 1000 (generic available, but still expensive)
    • gen=$60/90 tablets
    • brand= 990.00/90 tablets
    • Adult dose: start at 500mg at bedtime for 1-4 weeks. Then 1000mg at bedtime for 5-8 weeks then titrate to response and tolerance. Doses over 2000mg/day are not recommended
    Other forms of Niacin:
    • Can be either nicotinic acid or nicotinamide
    • Nicotinic acid is the only form proven to lower LDL
    • Immediate Release Niacin
      • Over-the-counter
    • Niaspan ER®
      • Less flushing, but long-term effects unknown
    • “Slow” Niacin- over the counter
      • Not used for the treatment of Dyslipidemia
      • Typically, nicotinamide
      • Hepatotoxicity


    BAD PRESS FOR NIACIN! (September 2014): “Added to a statin Niacin does NOT improve cardiovascular outcomes more than a statin alone when LDL is around 70 mg/dL. Adding niacin to bump up HDL makes number look better but doesn’t improve outcomes.” (AIM-HIGH study)

    SAFETY: For every 1000 patients treated for about 4 years with a statin plus niacin and an anti-flushing agent, about 18 more will develop diabetes and 37 more diabetics will have worse glycemic control...compared to patients on a statin alone.

    RECOMMENDATION: Niacin is associated with dyspepsia, diarrhea, rash, muscle pain, and flushing with possibly more infections and GI bleeding. If they have low LDL and stable CV disease, recommend stopping the Niacin

    URBAN LEGEND: Niacin to flush THC for drug testing? Doesn’t work, high doses lead to liver toxicity. Have a great day on the bench!!

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    Overview of Anticoagulation Management

    A lot of noise was made when the Factor Xa drugs came out and there was no reversal agent. We all feel comfortable with Vitamin-K reversing the effects of warfarin, but that can take a couple of days. Just simply stopping the Factor Xa inhibitors will produce similar results! Now that we have monoclonal antibodies to reverse dabigatran and the Xa inhibitors that worry should be gone.

    A common question, though, in the family practice setting is when someone should stop their anticoagulant or antiplatelet therapy. The chart below provides guidance on that front:

    Drug NameHALF LIFEWhen to STOP BEFORE PROCEDURE
    Asprin7-10 days before
    Prasugrel (Effient®)7-10 days before
    Clopidogrel (Plavix®)5 days before
    Ticagrelor (Brilinta®)5 days before
    Warfarin (Coumadin®)5 days before
    Dabigatran (Pradaxa®)12-17 hours1-2 days before
    3-5 days if CRCl is less than 50
    Rivaroxaban (Xarelto®)5-9 hoursAt least 24 hours (ideal=48hr)High risk= 2 days
    Apixaban (Eliquis®)8-15 hoursAt least 24 hours (ideal-48hr)High risk= 2 days
    Edoxaban (Savaysa®)6-11 hoursAt least 24 hours (ideal-48hr)High risk= 2 days


    WHEN to RESTART: Most experts say to restart therapy 24 hours after a low bleeding risk procedure. Most agree that the anti-platelet drugs cannot be reversed.

    ASPIRIN reversal… sort of
    Intravenous DDAVP may be beneficial in some cardiac surgical patients with intractable microvascular bleeding due to platelet dysfunction that may be caused by aspirin use.

    Vitamin-K: Reversal agent for Warfarin Treatment: Stop drug.
    • If minor bleeding progresses to major bleeding: Administer Vitamin-K at 5 to 25mg parenterally. May cause prolonged resistance to warfarin.
    • If INR is between 5 to 9, a low dose of oral Vitamin K (2.5mg) is given
    • Greater than 9 with no bleeding: give 5 mg orally. Will reduce the INR within 12 to 24 hours.
    Idarucizumab (Praxbind®)- reversal agent for dabigatran
    • Idarucizumab is a humanized monoclonal antibody fragment (Fab) indicated in patients treated with idarucizumab when reversal of the anticoagulant effects of dabigatran is needed:
      • For emergency surgery/urgent procedures
      • In life-threatening or uncontrolled bleeding
    Coagulation factor Xa (recombinant), inactivated-zhzo) (Andexxa®)
    • ANDEXXA® is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
    • This indication is approved under accelerated approval based on the change from baseline in anti-Factor Xa activity in healthy volunteers. An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies to demonstrate an improvement in hemostasis.
    Limitation of use:
    • ANDEXXA® has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any Factor Xa inhibitors other than apixaban (Eliquis®) and rivaroxaban (Xarelto®).
    Prothrombin Complex Concentrate (PCC) (Kcentra®)

    Kcentra® is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure..

    Administration route: intravenous use only. Online dosing calculator available.
    • Administer Vitamin-K to maintain Vitamin K-dependent clotting factor levels once the effects of Kcentra® have diminished
    Source: human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (mad cow disease), is possible

    FRESH FROZEN PLASMA
    Plasma is frozen within hours after donation in order to preserve the clotting factors. The shelf life of FFP is 12 months, but it can be extended to 7 years if stored at − 65 °C (-85°F). Most often used to treat bleeding disorders when a clotting factor or multiple factors are deficient, and no factor specific concentrate is available.
    A unit of FFP contains near normal levels of all factors, including 400mg of fibrinogen. It increases factor levels by 3%

    Indications for use for FFP
    • Treatment of multiple or specific coagulation factor deficiency, with abnormal PT or APPT. Either congenital or acquired (related to drug treatment)
    • Can be used for prophylaxis for planned surgical procedures.
    • Patients with massive transfusion who have clinically significant coagulation deficiencies.
    Patients on warfarin who are bleeding or need to undergo an invasive procedure before Vitamin-K could reverse the warfarin effect or who need to have anticoagulation therapy after the procedure.

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    OVERVIEW OF DIRECT ORAL ANTICOAGULANTS (DOACs)

    Virchow’s Triad—risk factors for venous thrombosis
    STASIS OF BLOOD FLOWENDOTHELIAL INJURYHYPERCOAGUABILITY
    Atrial fibrillationSmokingObesity
    Varicose veinsCholesterol plaquesPregnancy
    Prolonged immobilizationChronic high BPCancer/Chemotherapy
    Genetic factors (Factor-V)
    Oral contraceptives


    DOAC-NOAC- TSOAC?
    Direct oral anticoagulants (DOACs) are oral medications that specifically inhibit factors IIa or Xa. They are also known as new (or novel) oral anticoagulants (NOACs) or target-specific oral anticoagulants (TSOACs). DOACs are the preferred name according to the International Society of Thrombosis and Haemostasias

    Where DOAC’s work:
    Prothrombin---- ((Xa))------ Thrombin (Rivaroxaban works here)
    Fibrinogen----((Thrombin))-----Fibrin (Dabigatran works here)
    Fibrin does the cross linking to stabilize the clot that is formed


    DABIGATRAN (PRADAXA®) (released- November 2010)

    Mechanism: Direct Thrombin Inhibitor. Dabigatran was the first ORAL anticoagulant to be introduced in over 50 years!! Referred to as a “univalent direct thrombin inhibitor” that binds directly to the active site on factor IIa (thrombin). Thrombin is a naturally occurring enzyme in our circulatory system that converts fibrinogen into fibrin, which is an important step in clot formation. By tying up thrombin, clots are not so readily formed.

    Dosage: 150mg BID / 75mg BID if CrCl is 15-30mL/min
    Advantages compared to warfarin:
    • Prevents more strokes, including hemorrhagic (5/1000 a/fib patients/year)
    • Extensive monitoring not necessary
    • Fewer food and drug interactions
    • Less intracranial bleeding
    Disadvantages compared to warfarin:
    • COST: $15/day costs more than warfarin + monitoring
    • TWICE DAILY DOSING must have excellent patient compliance
    • GI upset- give with food. Increase GI bleed
    Prescribing info: Make sure INR is below 2 before starting therapy.
    • Some drug interactions with P-glycoprotein inhibitors (Ketoconazole, Clarithromycin, others)
    • Rifampin speeds metabolism.
    • Due to costs, this drug is ideal for patients with uncontrolled INR on warfarin therapy.

    FACTOR Xa INHIBITORS
    Role of Factor Xa: Factor Xa is responsible for the conversion of prothrombin to thrombin. Blocking Xa blocks that conversion to thrombin and clot formation is impeded.

    Rivaroxaban (Xarelto®) available August-2011 (490.00/month)
    The first oral, selective inhibitor of Factor Xa approved by the FDA

    Nonvalvular Atrial Fibrillation:
    • For patients with CrCl >50 mL/min: 20 mg orally, once daily with the evening meal
    • For patients with CrCl 15 - 50 mL/min: 15 mg orally, once daily with the evening meal
    Treatment of DVT, PE, and Reduction in the Risk of Recurrence of DVT and of PE:
    • 15 mg orally twice daily with food for the first 21 days for the initial treatment of acute DVT or PE. After the initial treatment period, 20 mg orally once daily with food for the remaining treatment and the long-term reduction in the risk of recurrence of DVT and of PE. Reduce to 10mg after 1 year.
    • Prophylaxis of DVT Following Hip or Knee Replacement Surgery: 10 mg orally, once daily with or without food
    Indications:
    • to reduce risk of stroke and systemic embolism in nonvalvular atrial fibrillation
    • for treatment of deep vein thrombosis (DVT)
    • for treatment of pulmonary embolism (PE)
    • for reduction in the risk of recurrence of DVT or PE
    • for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery (10mg daily)
    • for prophylaxis of venous thromboembolism (VTE) in acutely ill
    • to reduce the risk of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease
    ADVANTAGES:
    • Convenient once-daily, oral dosing
    • No routine monitoring of INR or other coagulation parameters is required. Fast onset.
    • AVOID use in severe renal impairment (creatinine clearance <30 mL/min).
    • AVOID in patients with hepatic impairment
    • AVOID drugs that Inhibit Cytochrome P450 CYP3A4 Enzymes and Drug Transport Systems such as P-gp and strong CYP3A4 inhibitors, which cause significant increases in rivaroxaban exposure. May double dose if giving concurrently with P4503A4 inducer.
    • for prophylaxis of venous thromboembolism (VTE) in acutely ill
    • to reduce the risk of major cardiovascular events in patients with chronic coronary artery disease (CAD) or peripheral artery disease
    (October 2018) Rivaroxaban XARELTO® is indicated, in combination with aspirin, to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in patients with chronic coronary artery disease (CAD) or peripheral artery disease (PAD).
    • • Dose is 2.5mg BID + 81mg aspirin/day
    Apixaban (Eliquis®) (approved Dec 28, 2012) ($485.00/month)

    Indications
    ELIQUIS® is a factor Xa inhibitor anticoagulant indicated:
    • to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
    • for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
    Apixaban Indications and Dosages: Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation (NVAF): The recommended dose is 5 mg orally twice daily.

    In patients with at least 2 of the following characteristics reduce dose to 2.5mg twice daily:
    • Age: over age 80,
    • body weight less than 60kg (132lbs),
    • serum creatinine ≥1.5 mg/dL
    • Greater than 9: give 5 mg orally.? Will reduce the?INR within 12 to 24 hours
    Indications and dosage:
    • Prophylaxis of DVT following hip or knee replacement surgery: The recommended dose is 2.5 mg orally twice daily.
    • Treatment of DVT and PE: The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
    • serum creatinine ≥1.5 mg/dL
    • Reduction in the risk of recurrent DVT and PE following initial therapy: The recommended dose is 2.5 mg taken orally twice daily.

    Drug interactions: Warfarin is metabolized by the P450 enzyme system.? Lots of drug interactions.
    • P450 inhibitors (blockers): Azole-antifungals, some HMG CoA reductase drugs, erythromycins, etc.
    • P450 inducers: carbamazepine, barbiturates, phenytoin
    • Can be displaced from binding sites: loop diuretics, valproate
    • Platelet aggregation: NSAIDS can enhance warfarin’s effect.


    A fib: for every 1000 patients treated per year, apixaban prevents three more strokes, avoids ten major bleeds, and prevents four deaths compared to warfarin


    Edoxaban (Savaysa®) (2015) ($400/month)

    Treatment of NVAF: Assess CrCL before initiating therapy. The recommended dose is 60 mg once daily in patients with CrCL >50 to ≤ 95 mL/min.
    • Do not use SAVAYSA in patients with CrCL over 95 mL/min (sorry, your kidneys are “too” good for this drug!)
    • Reduce dose to 30 mg once daily in patients with creatinine clearance 15 to 50 mL/min
    Treatment of DVT and PE: The recommended dose is 60 mg once daily. The recommended dose is 30 mg once daily for patients with CrCL 15 to 50 mL/min or body weight less than or equal to 60 kg or who use certain P-gp inhibitors.

    With nearly 50% of our warfarin patients having uncontrolled INR's, DOACs have been a Godsend. They do not require extensive monitoring, do not hang around very long in the body, and have excellent efficacy.

    One of the biggest challenges we see, however, is the cost of these medications. Adherence becomes a challenge when patients struggle to pay even a percentage of the costs of these medications.

    Rudolf Virchow (1821-1902) was a German physician who is credited for elucidating the origins of thromboembolism. In fact, he coined the term “thrombosis” which is the process by which a clot forms in a blood vessel as well as the term “embolism”, which is a clot that has moved and blocks off a vessel. Virchow also had a brilliant career in which he clarified how cells divide, as well being a strong social medicine advocate. Considered by many to be the most brilliant physician of the 1800’s and the ‘father of cell pathology’, he even has a lymph node named after him!

    In the next session, we will discuss when to stop these drugs before elective surgical procedures. Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    Anticoagulation Overview: Vitamin-K Antagonists (Warfarin)

    Warfarin? (Coumadin®) tablets: (approved by FDA June 8, 1954)
    Mechanism of Action: Vitamin K antagonist: produces its pharmacological effect by interfering with the interconversion of Vitamin-K and its 2,3 epoxide.? Leads to depletion of Factors: II, VII, IX and X (produced in liver)?and anticoagulant proteins C & S.?

    Dosage: at least 4 to 5 days are necessary before a patient is anti-coagulated.
    Initial Dosage: 5mg / day in normal patients.? The INR should be 2 in four to five days.
    • 2.5 to 4mg for elderly or patients with liver disease
    • 7.5 to 10mg for young, healthy or obese patients
    • Most clinicians titrate warfarin doses by trial and error
    • Now the FDA is suggesting lower doses for patients with certain genetic variations.
    Genetic Variations in Warfarin:
    • CYP2C9 activity indicates a slow or fast metabolizer. A slow metabolizer may need a lower maintenance dose and take longer for their INR to get to steady state
    • Vitamin K epoxide reductase activity (VKORC1) tells whether a patient is sensitive or resistant to warfarin’s effects.
    Adverse effects bleeding
    Treatment stop the drug
    • If minor bleeding progresses to major bleeding: Administer Vitamin-K 5 to 25mg parenterally. May cause prolonged resistance to warfarin.
    • 7.5 to 10mg for young, healthy or obese patients
    • MIf INR is between 5 to 9, a low dose of oral Vitamin K (2.5mg) is given
    • Greater than 9: give 5 mg orally.? Will reduce the?INR within 12 to 24 hours
    Contraindications: pregnancy Category X
    Drug interactions: Warfarin is metabolized by the P450 enzyme system.? Lots of drug interactions.
    • P450 inhibitors (blockers): Azole-antifungals, some HMG CoA reductase drugs, erythromycins, etc.
    • P450 inducers: carbamazepine, barbiturates, phenytoin
    • Can be displaced from binding sites: loop diuretics, valproate
    • Platelet aggregation: NSAIDS can enhance warfarin’s effect.
    Drug monitoring: Warfarin is metabolized by the P450 enzyme system.? Lots of drug interactions.
    • Initial: INR should be done daily while in the hospital.
    • Every 2 or 3 days if not hospitalized
    • Once stabilized, monitor every 4 to 6 weeks
    • TARGET INR is between 2 and 3 for most conditions requiring anticoagulation therapy

    TEACHING POINTS FOR Warfarin ) Consult pharmacist or practitioner for recommendations for OTC medications?
    Bleeding:? have lots of Band-Aids; use electric razors
    FOOD–drug interactions:? Be careful with diets and Vitamin K rich foods.?? Patients are often told to avoid foods high in vitamin K because of warfarin antagonism. A diet too low in vitamin K makes it MORE difficult to manage INR, because any change in dietary vitamin K can cause large fluctuations in INR. Encourage patients to eat a well-balanced consistent diet.
    Note: Warfarin patients are at the goal INR only 55% of the time (yikes!)
    –BEFAST: teach your patients signs and symptoms of a stroke, pulmonary embolism, deep vein thrombosis and heart attack:

    Signs and symptoms of a Stroke—BE FAST!
    • B -Balance: sudden loss of balance, headache, or dizziness
    • E -Eyes: trouble seeing out of one or both eyes
    • F -Face: Uneven smile or expression, facial droop or numbness in the face
    • A -Arms: weakness, numbness, one arm drifts down
    • S -Speech: slurred, mute, inappropriate words or strange speech
    • T– Time: seek help immediately. Immediately call 9-1-1.
    Signs and Symptoms of Pulmonary Embolism (PE)
    • Dyspnea: Difficulty breathing or shortness of breath. Usually sudden and severe
    • Hemoptysis: Coughing up blood
    • Diaphoresis: Abnormal?sweating
    • Cyanosis: Nails or lips turning blue
    • Tachycardia: Rapid heartbeat
    • Pain: Unexplained sharp, severe?pain in the chest?and/or back
    • Syncope: Loss of consciousness
    Signs and Symptom of Deep Vein Thrombus (DVT)
    • throbbing or cramping pain in 1 leg (rarely both legs), usually in the calf or thigh
    • swelling in 1 leg (rarely both legs)
    • warm skin around the painful area
    • red or darkened skin around the painful area
    • swollen veins that are hard or sore to the touch

    Signs and symptoms of Heart Attack in WOMEN
    Usually in female patients multiple symptoms may occur:
    • Chest pain: or fullness in the chest (an elephant sitting on my chest!)
    • Nausea or stomach pain: feeling like the need to vomit. More commonly seen in women
    • Anxiety: feeling like something is wrong, but cannot put your finger on it
    • Arm pain: pain in the arm, leg, or jaw. A woman may feel numbness radiating down the left arm, and this pain or sensation can pread elsewhere in the body, especially the shoulders
    • Dyspnea: shortness of breath or difficulty with breathing
    • Cold sweats: resulting in cold clammy skin
    • Dizziness: sudden onset of lightheadedness, room spinning is usually combined with other symptoms on this list
    • Extreme fatigue: unexpected sluggishness or exhaustion
    • Heart palpitations: heart skips a beat or fluttering sensation

    Signs and symptoms of Heart Attack in Men
    Usually in male patients the following symptoms occur:
    • Pain or tingling in back, neck, shoulder, or jaw
    • Chest pain
    • Sweating
    • Shortness of breath

    The history of the discovery and marketing of warfarin (Coumadin®) is a most fascinating story that begins in the pastures of the northeast:

    Numerous cows in the 1920’s died after routine minor surgical procedures such as castration or dehorning. A Canadian veterinarian named Frank Shofield astutely reasoned that this hemorrhaging could be attributed to animals that ate silage that had rotten sweet clover.? This hemorrhaging became known as “sweet clover disease.”

    Dr Karl Paul Link, a chemist from Wisconsin, started his own investigation into the curious problem in 1933. He published an article in Circulation describing the effects of the rotted sweet clover. Dr Link’s work was supported by the Wisconsin Alumni Research Foundation (WARF), which is the root name for warfarin.? Dr Link’s student Harold Campbell isolated the anticoagulant dicoumarol in 1939.?At first this compound was sold as a rat poison, and it wasn’t until the 1950’s that Endo Pharmaceutical began marketing warfarin for human use.

    While on vacation in 1955, President Eisenhower was given warfarin after a heart attack, which vaulted this drug to national prominence.? Warfarin poisoning was also postulated to have caused the cerebral hemorrhage and gastrointestinal bleed that lead to the demise of Russian dictator Josef Stalin.

    My daughter Gretchen gave me a 1959 drug handbook, which listed the available strengths of Coumadin as 1mg, 5mg and 25mg!

    Have a great day on the bench!!

    December 2020

    Micro-Learning CE Associated - Click Here For Details

    A Overview of Heparin and Low Molecular Weight Heparins

    HEPARIN First available 1936
    Mechanism of Action: derived from bovine lung or porcine intestinal mucosa. Heparin binds to Antithrombin III and results in an inactivation of clotting factors IXa, Xa, XIIa and Thrombin (IIa). By inactivating thrombin, it inhibits the thrombin induced factors V and VIII. Not only does Heparin prevent the growth and propagation of the formed thrombus, but it also allows the patient’s own thrombolytic system to degrade the clot. Heparin may also have a direct effect on thrombolysis.

    Dosage: each hospital develops its own nomograms that are specific for the reagent and instrument used to validate that nomogram. Is administered IV or SC.
    Adverse effects & contraindications: bleeding is the primary adverse effect. Watch for nosebleeds, hematuria, or tarry stools. Minimal renal elimination, can be used for renal insufficiency or renal failure.

    HIT: Most common cause of DRUG INDUCED neutropenia. Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of exposure to heparin (ie, unfractionated heparin, low molecular weight [LMW] heparin) that occurs in up to 5 percent of patients exposed, regardless of the dose, schedule, or route of administration. More common with heparin.

    Reversal: Protamine sulfate 1% solution will neutralize heparin. Each mg of protamine neutralizes about 100 USP heparin units. Works in 5 minutes and is active for 2 hours. Should give via slow IV infusion over 10 minutes. Heparin also has a very short half-life of 60-90 minutes.

    Contraindications:
    • Use caution with elderly women; they are twice as likely to experience major bleeding than men.
    • Severe uncontrolled hypertension is a contraindication.
    • Pregnancy category-C

    Drug interactions: interactions do occur with NSAIDS, digitalis etc. Since tight monitoring is required, dosage adjustments are easily made.

    Drug monitoring: most common: APTT (Activated Partial Thromboplastin Time), is widely used, quickly done and reproducible. Do APTT six hour after bolus dose, or after any dosage change then every 6 hours until a therapeutic APTT is reached. Then evaluate every 24 hours. APTT= normal range is 25-35 seconds. Ranges vary from lab to lab. Heparin induced APTT is 1.5 to 2.5 times normal.


    LOW MOLECULAR WEIGHT HEPARINS (LMWH)

    Enoxaparin (Lovenox®) approved 1993
    injection 30mg/0.3ml, 40/0.4ml, 60/0.6ml, 80/0.8ml, 100/1ml, 120/0.8ml, 150/ml & 300mg/3ml

    Mechanism: inhibits factor IIa and to a much greater extent Xa.
    • DVT surgical prophylaxis: (dose dependent on surgical site)
    • DVT treatment with or without PE:
    • Outpatient treatment: patients with acute DVT without PE who can be treated at home. Typical outpatient dose: is 1mg/kg subcutaneously every 12 hours.
    Adverse effects & contraindications: minor bleeding, gingival bleeding, watch for GI or urogenital bleeding.

    Reversal: Protamine: give 1mg for every 1mg of enoxaparin. Protamine neutralizes only 60-75% of antithrombotic activity. Not recommended if LMWH was given more than 12 hours earlier.

    Pregnancy category B. LMW does not cross placenta. Appears to be safe to use during pregnancy. Good alternative to heparin when long term anticoagulation is necessary.

    Caution with NSAIDS, they can increase bleeding.

    Drug Monitoring: because of predictable responses, routine monitoring of APTT is not necessary. Have baseline PT, CBC, Creatinine then periodic monitoring of platelets and fecal occult blood. Patient education: (enoxaparin)
    • Contact practitioner if bleeding, bruising, dizziness itching, rash or fever occurs
    • Injections are given around the navel, upper thigh, or buttocks. Change site daily
    • Inject under skin not into muscle
    • If excessive bruising occurs at injection site it may be lessened by an ice cube massage on the site prior to injection.
    NOTE: other low molecular weight heparins are available, but enoxaparin (Lovenox®) is the most commonly used. Here are the others:
    • Dalteparin (Fragmin®)
    • Tinzaparin (Innohep®)
    • Fondaparinux (Arixtra®)


    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    A Broad Overview of Antiplatelet Therapy

    ASPIRIN (patented: 1899)
    Mechanism: Acetylation of platelet cyclooxygenase prevents synthesis of Thromboxane A2, (a prostaglandin derivative) which is a potent vasoconstrictor, and inducer of platelet aggregation and platelet release reaction. Aspirin inhibits platelet aggregation for the life of the platelet (7 to 10 days).

    Men benefit more: cardiovascular protection
    Women benefit more: stroke prevention

    Dosage: American Heart Assn. Recommends 75mg to 325mg/ day
    Adverse effects & contraindications: GI bleeding. Avoid with asthma.
    Drug interactions: Warfarin (however, this may be beneficial)
    Drug monitoring: check for signs and symptoms of bleeding such as dark stools
    Patient education: Take with food. Use enteric coated tablets. Take low dose


    Thienopyridines
    Mechanism: inhibits platelet aggregation and activation by blocking the P2Y12 adenosine diphosphate (ADP) receptor on the platelet surface. This inhibition is irreversible and lasts throughout the lifespan of the platelet (5-7 days).

    Clopidogrel (Plavix®)
    75mg tablets (FDA approved 1997)
    Dosage: one tablet (75mg) daily, with or without food.
    Clopidogrel is a pro-drug needing activation by the CYP450-2C19 pathway.
    • Indicated for recent MI, or stroke, or established peripheral arterial disease. Reduces the rate of new ischemic stroke, new MI and other vascular deaths.
    • Acute coronary Syndrome (ACS): for patients with acute coronary syndrome (unstable angina, non-Q-wave MI) including patients who are managed medically and those to be managed with percutaneous coronary intervention (with or without stent) or Coronary Artery Bypass Grafting (CABG)
    Mechanism: inhibits platelet aggregation for the life of the platelet (5-7 days)
    Adverse effects: increased bleeding risk
    Contraindications: active bleeding (GI) or intracranial hemorrhage
    Drug interactions: administer with caution for NSAID patients (increased GI bleeding risk)
    • About 30% of Caucasians are poor CYP450- 2C19 metabolizers
    • Omeprazole (Prilosec®) blocks this pathway and may reduce effectiveness of clopidogrel. Pantoprazole (Protonix®) is the least likely in this drug class to interact
    Patient education: Discontinue 7-10 days before surgery if so directed. Most clinicians when combining with aspirin, will use the 81mg (low dose).

    In some cases, there is no benefit to aspirin/clopidogrel than aspirin therapy alone:
    • Cardiovascular risk factors only: aspirin + clopidogrel: combo NOT beneficial
    • Established cardiovascular disease: aspirin + clopidogrel: combo NOT beneficial
    • Acute coronary syndrome: aspirin + clopidogrel: combo is beneficial
    • After a stent: aspirin + clopidogrel: combo is beneficial

    Prasugrel (Effient®)
    FDA approved in 2009. Prasugrel seems to be more effective than clopidogrel for reducing cardiovascular events in some acute coronary syndrome patients undergoing angioplasty. Carries a higher bleeding risk than clopidogrel.

    Compared to clopidogrel:
    • Higher bleeding risk. Avoid in patients with prior TIA or prior stroke.
    • Not affected by 2C19 activation (minimal drug interactions with omeprazole)
    • Combine with aspirin after angioplasty
    • Avoid if over 75, unless high risk
    • More effective than clopidogrel after angioplasty-more bleeding!
    • Discontinue 7 days before surgery
    Dosage: 5mg per day if under 60kg / 10mg if over 60kg


    WHEN A PATIENT RUNS OUT OF REFILLS. MAJOR RISK!!

    What about STOPPING aspirin, clopidogrel, prasugrel, and ticagrelor? The first challenge is no clear evidence determines the most effective duration for dual antiplatelet therapy (DAPT) after drug-eluting stents.

    Risk of stopping aspirin, clopidogrel, or other antiplatelet drugs too soon:
    NOTE: serious consequences can occur for patients on aspirin for secondary prevention, or on aspirin plus clopidogrel for acute coronary syndrome or after a stent, if they stop their drug therapy too soon.

    Platelet rebound effect-Stopping Aspirin therapy:
    • Stopping aspirin even short-term may increase the risk of heart attack and stroke possibly due to a rebound effect.
    • Stopping aspirin seems to stimulate the production of new platelets and increase binding of fibrinogen. This rebound effect lasts at least 8 to 10 days after stopping therapy.
    • More surgeons will continue aspirin if bleeding risk is low especially if the patient's risk of thrombosis is high.
    • Aspirin prevents clotting while it is being taken, but abruptly stopping it triples the risk of stroke and increases the risk of other cardiovascular adverse effects.
    • Stopping aspirin in patients with a prior MI leads to 4 extra MIs per 1000 patients per year.
    • Stopping clopidogrel (Plavix®) within 30 days after a drug-eluting stent results in 25% of patients having a stent thrombosis instead of just 1%.
    • For stents, continue aspirin plus clopidogrel (Plavix®), prasugrel (Effient®), or ticagrelor (Brilinta®):
      • 30 days after a bare metal stentl
      • 1 year after a drug eluting stent
      • Many clinicians will keep patients on dual therapy longer if the bleeding risk is low

    CONTINUE ASPIRIN INDEFINITELY!
    • Surgery: If the drug must be stopped, stop clopidogrel, ticagrelor, or aspirin 5 days prior and prasugrel 7 days before surgery. Continue aspirin for all but the riskiest surgery.

    TALKING POINTS, WE WANT TO SHARE WITH OUR PATIENTS:
    • Adherence is critical for all antiplatelet therapy. Triple risk of heart attack if stopped too soon.
    • Aspirin is serious medicine, do not stop without talking to your doctor


    Aspirin is serious therapy. As such, prescribers are encouraged to actually write prescriptions for aspirin therapy. First, prescribed aspirin therapies are covered on many state Medicaid programs. Secondly, it underscores the importance of this therapy and provides valuable adherence data with respect to refills.

    I often wonder how long it would take to get Aspirin through the FDA approval process today, given its side effect profile. Most pharmacists are aware that Aspirin is really the trade name that Bayer gave acetyl salicylic acid, which had its origins from willow bark. Interestingly enough, aspirin came onto the market one year after heroin was marketed, also by the Bayer company in Germany.

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    An Overview of Platelets and Coagulation

    Antiplatelet Therapy
    As pharmacists, we provide prescription therapy directed at clot prevention. Many of us older pharmacists remember a 60-Minute “hatchet job” done to our profession in the 1980’s when a staged patient was buying a bottle of aspirin, while the pharmacist dispensed his warfarin prescription.

    I remember an expert saying that this was a big “no-no”. We all learned in pharmacy school that warfarin and aspirin should never be given together… those were the days!! Today, it is rather commonplace to see triple therapy consisting of an anticoagulant, and two antiplatelets (aspirin/clopidogrel). It just depends on the source of the clot.

    TRIPLE THERAPY for ANTI-COAGULATION
    Some older patients are at higher risk for conditions that require two antiplatelet drugs plus anticoagulation.

    An example of such a patient:
    • coronary stent patient (needs Aspirin + clopidogrel (Plaxix®)
    • plus has atrial fibrillation or mechanical valve or Venous thromboembolism (VTE) (needs Warfarin)


    In this case, TRIPLE therapy is warranted because there are 2 different kinds of clots:


    White clot:
    • Mostly platelets
    • Usually forms in the arteries (high pressure)
    • Use antiplatelet therapy such as Aspirin, Clopidogrel, prasugrel, or ticagrelor
    • Protective against MI and stroke
    Red clot:
    • Rich in red blood cells and fibrin
    • Usually forms in the veins or atrium (low pressure)
    • Use Anticoagulant therapy such as warfarin
    • Protects against DVT (deep vein thrombosis) and PE (pulmonary emboli)


    PLATELETS: stop the bleeding!
    Platelets initiate hemostatic mechanisms that repair injured blood vessels. The platelet is a circulating disc-shaped cell that does not contain a nucleus. Many references refer to them as “blood cell fragments.”

    ROLE OF PLATELETS: As pharmacists, we provide prescription therapy directed at clot prevention. Many of us older pharmacists remember a 60-Minute “hatchet job” done to our profession in the 1980’s when a staged patient was buying a bottle of aspirin, while the pharmacist dispensed his warfarin prescription.

    Activated platelets do the following:
    • Adhesion to the site of injury
    • Activation and secretion
    • Aggregation- form clumps to “plug the leaks”
    • Interaction with coagulation factors especially with factor VIIa to promote local coagulation, and ultimately the generation of thrombin, the most potent of the platelet agonists.
    Antiplatelet mechanisms of action… ways to block platelet activity:
    • Blocking the thrombin receptor (PAR-1): think vorapaxar (Zontivity®), which was removed from the US market
    • Blocking ADP binding at the P2Y1 and P2Y12 receptors: think clopidogrel (Plavix®), prasugrel (Effient®) and ticagrelor (Brilinta®)
    • Blocking prostaglandin synthesis: think aspirin and other non-selective COX-1 inhibitors
    • Blocking cyclic AMP: think dipyridamole

    How many?
    A normal platelet count ranges from 150,000 to 450,000 platelets per microliter of blood.
    • Having more than 450,000 platelets is a condition called thrombocytosis or thrombocythemia
    • Having fewer than 150,000 is known as thrombocytopenia.


    Last week my 4-year-old grandson Luke and I were out for a walk. He said, “Let’s take a shortcut over to the other road.” We walked through some brush, and Luke got scratched by a briar. He looked at his scratch and saw the blood and said, “We need to go home and have Mom put a Band-aid on it.”

    I told him, “You’ll be fine; your platelets will take care of it.” He asked me what a platelet was, and I explained that was like your body’s own Band-aid that stops the bleeding. For the next 3 days we watched every platelet video on YouTube! He sustained another scratch, and told me it was so big that he needed “two platelets” to fix it… I guess my Band-aid analogy painted the wrong picture.

    We are beginning to cover Cardiology meds, which would seem appropriate given the sudden interest in platelets in my family!

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    An Overview of Herpes and Zoster Treatment

    Acyclovir (Zovirax®)
    Available as: capsules 200mg; tablets 400mg & 800mg and 200mg/5ml
    Mechanism: requires 3 phosphorylation steps for activation. Is selectively activated and accumulates only in infected cells. It inactivates DNA polymerase.
    Indication for Use:
    • Initial and recurrent HSV I and II
    • Treatment of herpes Zoster (shingles)
    • Treatment of varicella (chickenpox)
    • IV used for treatment of herpes simplex encephalitis, neonatal HSV and serious HSV or VZV infections
    Dosages:
    • Initial genital: 400mg 5 times daily for 7-10
    • Mucocutaneous oral labial: 400 mg 5 times daily for 5 days
    • Recurrent: 800mg three times daily for 2 days or 400mg three times daily for 5 days
    • Suppression: 400mg twice daily
    • Zoster: 800mg 5 times daily for 7 days. (start within 24 hours of rash)
    • Varicella: 20mg/kg (800mg MAX) four times daily for 5 days. (generally, treatment not recommended)
    Warnings/Precautions:
    • Pregnancy: Category-B
    • Treatment for Zoster is MOST effective when initiated within 48 hours of onset of rash. After 72 hours of onset, minimal benefit.
    • Renal impairment: dosage adjustment required
    Adverse Effects:
    • Photosensitivity may occur
    • Stevens-Johnson syndrome
    • GI: diarrhea and nausea
    Drug Interactions:
    • May elevate theophylline
    • May lower levels of Phenytoin and Valproic acid
    Patient Education:
    • Avoid sexual intercourse when visible herpes lesions are present.
    • Oral Acyclovir does NOT eliminate latent HSV, and is not a cure
    • May cause photosensitivity, wear sunscreens and protective clothing.
    • May take with or without food


    Famvir® (Famciclovir)
    Available as: tablets 125mg, 250mg & 500mg
    Mechanism: Gets bio-transformed to penciclovir which is active against HSV I & II, and VZV. Inhibits viral DNA synthesis.
    Indication for Use:
    • Zoster: 500mg every 8 hours for 7 days
    • Recurrent genital herpes: 1GM twice daily for 1 day
    • Herpes Simplex (oral or genital) 250mg three times daily for 7-10 days
    • Suppression: 250mg twice daily for up to 1 year
    • Mucocutaneous oral labial: 500mg twice daily for 7 days
    • Famciclovir has been approved as the first and only antiviral to shorten duration of cold sore outbreak with a single dose:
    Dosage: Famciclovir 500mg: Three tablets (1500mg) as a single dose at earliest sign or symptom of a cold sore.

    Warnings/Precautions:
    • Pregnancy: Category-B
    • Initiate therapy ASAP
    Adverse Effects:
    • Headache
    • Nausea & vomiting
    Patient Education:
    • Initiate therapy ASAP (within 6 hours of outbreak)
    • May take with or without food

    Epithelial Keratitis dosing for oral antiviral agents.
    Click Here for AAO Treatment Guide
    • Acyclovir (Zovirax®): 400mg 3-5 times daily for 7-10 days OR
    • Valacyclovir (Valtrex®): 500mg twice daily for 7-10 days OR
    • Famciclovir (Famvir®) 250mg BID for 7-10 days


    Viruses are non-living particles that require a host cell in order to replicate. They must be inside a host cell to cause infection, by overtaking that cells ‘machinery’. The virus is surrounded by a protein coat or capsid and contains only a few dozen genes either in the form of RNA or DNA that contain the information necessary for replication.

    Some viruses such as the common cold are self-limiting, resolving in 7 to 10 days. Other viruses such as HIV can cause serious and sometimes fatal disease and require aggressive therapy. Challenges in drug therapy are due to rapid mutation which can quickly render drugs ineffective. Due to the intracellular nature of the viruses, it is difficult for medications to find their “targets” inside normal living cells.

    Depending upon whether the HSV-1 virus attacks the oral mucosa, or HSV-2 attacks the genital mucosa, the doses for the three antivirals are different.

    For Zoster (shingles), caused by a varicella virus, think highest dose for longest duration. Most important with the treatment of these viral infections, start treatment early, ideally within 48 hours of onset of symptoms.

    Didn’t you forget something?? Topical treatment of Herpes infections.
    The short answer is no I didn’t. All of the topical products whether for cold sores, genital herpes or herpes eye infections are expensive and need to be applied frequently, at least 5 times per day.

    With the oral dosage forms being available as generics, there is no need whatsoever to prescribe these less than effective and overpriced products.

    Have a great day on the bench!!



    November 2020

    Micro-Learning CE Associated - Click Here For Details

    An Overview of Influenza Treatment

    TREATMENT OF ACUTE FLU

    ADAMANTANES
    • Amantadine (Symmetrel®) not recommended
    • Rimantadine (Flumadine®) not recommended
    At one time these drugs were recommended for treatment of Influenza-A. Since 2006, the CDC has not recommend using these drugs due to resistance to Type-A flu strains.

    NEURAMINIDASE INHIBITORS

    Zanamavir (Relenza®) approved July 1999 (WAC=$59.00)
    Mechanism:
    inhibits neuraminidase, with the possibility of alteration of virus particle aggregation and release.

    Indications for use:
    Treatment of both Type A and Type-B influenza. Will decrease symptoms by 1.3 days if started within 48 hours of viral symptoms.

    Warnings / Precautions / Adverse effects:
    May see pulmonary effects in asthma and COPD patients. Have albuterol ready for rescue as this drug may induce bronchospasm. Not recommended for this patient group. May see mild gastrointestinal distress such as nausea, vomiting and diarrhea.

    Patient Education:
    • If asthmatic or COPD, have Albuterol inhaler ready.
    • Instruct patient on use of delivery system.
    • Must complete 5-day course even is symptoms disappear
    • Does not reduce the transmission of virus to others.
    • Take 2 doses first day of treatment, if there are 2 hours between doses. Then every 12 hours.

    Representative Products:
    Relenza® (zanamivir) diskhaler: Adults: 2 inhalations twice daily. Age 7 years to adult.

    OSELTAMIVIR (Tamiflu®) approved 1999
    Mechanism:
    Inhibits neuraminidase, with the possibility of alteration of virus particle aggregation and release. Is a prodrug, is pharmacologically similar to zanamivir

    Indications for use:
    Influenza type A and B. Begin within 48 hours of symptoms. May reduce symptoms by 1 day.

    Warnings / Precautions / Adverse effects:
    Nausea, vomiting, vertigo and insomnia

    NOTE: CDC warning: November 13, 2006
    The FDA approved a labeling supplement to include a precaution about neuropsychiatric events for Tamiflu®. Self-injury and delirium have been observed in Japan primarily among pediatric patients. Monitor pediatric patients for signs of unusual behavior.

    Patient Education:
    Start therapy as soon as possible.
    Not a substitute for the vaccine

    Representative Products:
    Tamiflu® 75mg capsules and powder for suspension 12mg/mL (available generically) Adults: 75mg twice daily for 5 days.
    Adults: 75mg twice daily for 5 days.
    Children: based on body weight:
    • If younger than 1 yr old: 3 mg/kg/dose twice daily

    If 1 yr or older, dose varies by child’s weight:
    • 15 kg or less, the dose is 30 mg twice a day
    • >15 to 23 kg, the dose is 45 mg twice a day
    • >23 to 40 kg, the dose is 60 mg twice a day
    • >40 kg, the dose is 75 mg twice a day


    CHEMOPROPHYLAXIS with Tamiflu and Relenza
    FormulationsAdult DosePediatric dose
    Oseltamivir (Tamiflu)30,45,75mg caps and 6mg/ml oral suspProphylaxis: 75mg/day Treatment: 75mg BIDProphylaxis: 30-75mg/day Treatment 30-75mg BID
    Zanamivir (Relenza)5mg/blister inhalerProph: 2 inh once daily Treat: 2 inh BID x5Proph: over 5yrs: 2 inh QD Treat over 7 yo: 2 inh BID

    COST of Tamiflu: $180.00/ 10 capsules 75mg
    Cost of generic (oseltamivir): $40.00/10 caps 75mg


    Baloxavir marboxil tablets (XOFLUZA® ) approved 2018 Cost: $180.00/dose
    Mechanism of action:
    is a polymerase acidic (PA) endonuclease inhibitor, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication

    Indications for use:
    for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours. Shortens flu symptoms versus placebo by about one day.

    Dose:
    Take a single dose of XOFLUZA® orally within 48 hours of symptom onset with or without food
    • 80kg and over: take 80mg dose.
    • 40kg-80kg: take 40mg as a single dose.
    • On average, patients recovered from flu symptoms in 2.3 days---(54 hours versus 80 hours) by about one day.
    • Does not reduce the transmission of virus to others.
    • Reduces viral load faster than oseltamivir, but not sure that reduces spread of flu.

    Warnings / Precautions / Adverse effects:
    • No changes at QT interval, even at twice the dose.
    • Avoid co-administration of XOFLUZA® with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, magnesium, selenium, or zinc).
    • The dose of XOFLUZA® depends on weight
    • Avoid if pregnant
    • Reduces viral load faster than oseltamivir, but not sure that reduces spread of flu.


    CANDIDATES for PHARMACOLOGICAL TREATMENT (per 2018 IDSA guidelines)

    HIGH RISK PATIENTS:: Clinicians should start antiviral treatment as soon as possible for adults and children with documented or suspected influenza, vaccinated or not, who meet the following criteria:
    • Persons of any age who are hospitalized with influenza.
    • Outpatients of any age with severe or progressive illness, regardless of illness duration.
    • Outpatients who are at high risk of complications from influenza, including those with chronic medical conditions and immunocompromised patients. Think diabetes, obesity, chronic kidney disease, chronic heart disease, chronic lung disease (asthma, COPD)
    • Children younger than 2 years and adults ≥65 years.
    • Pregnant women and those within 2 weeks postpartum

    LOW RISK PATIENTS:: Outpatients with illness onset ≤2 days before presentation (C-I).
    • Symptomatic outpatients who are household contacts of persons who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised (C-III).
    • Symptomatic healthcare providers who care for patients who are at high risk of developing complications from influenza, particularly those who are severely immunocompromised

    NON-PHARMACOLOGICAL TREATMENT MEASURES
    (Of course, PREVENTION is the best approach)
    • Vaccination: best if given in October and November
    • Avoid close contact with sick people
    • Stay home if you are sick
    • Cover mouth and nose when coughing or sneezing
    • Wash your hands---OFTEN! Viruses can survive on surfaces for 2-8 hours.
    • Avoid touching eyes, nose, mouth
    • Looks like we need to add masking and social distancing to this list given the low transmission rate in the Southern Hemisphere in 2020.

    TREATMENT MEASURES
    • Bedrest
    • Fluids
    • Humidification of air

    PHARMACOLOGICAL MANAGEMENT
    • Cough suppressants, analgesic. Symptom management.
    • Absolutely no aspirin in patients under age 18.

    We’ve seen a significant decrease in the influenza spread in the southern hemisphere, most likely due to social distancing, masking, working from home and on-line learning. All of the efforts made to decrease the spread of the COVID-19 virus are greatly impacting the spread of the seasonal influenza virus. Patients seem a lot more interested in getting their flu vaccinations this year. I’ve noticed a huge uptick in patient who were “first timers”.

    Many universities will end their fall term before Thanksgiving, and the students will not return to campus until 2021. This should greatly help decrease the “holiday germ exchange” where students would go home collect their Thanksgiving germs, bring them back to campus, spread them around, and everyone could bring home fresh germs for Christmas.

    All of the efforts made to decrease the spread of the COVID-19 virus are greatly impacting the spread of the seasonal influenza virus. Patients seem a lot more interested in getting their flu vaccinations this year. I’ve noticed a huge uptick in patient who were “first timers”.

    Finally, some good news for 2020! But patients will inevitably be diagnosed with influenza in the coming season. So, what do we do?

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    Flu shots? Did you get yours?

    Who should get the flu vaccine?
    That’s easy… virtually everyone from age six months and up, regardless of pregnancy status. Patients with laboratory confirmed COVID 19 infection, symptomatic or not, should not get the influenza vaccination until they are no longer acutely and do not require isolation.

    On average, about 45% of the United States citizens get their annual flu shot.
    Healthcare workers: last year 80.6% of all healthcare workers got the vaccine. By occupation, flu vaccination coverage was highest among physicians (98%), nurses (92%), pharmacists (90.6%), and nurse practitioners and physician assistants (88.8%). (source: CDC.gov)

    Efficacy of last year’s vaccine:was estimated to be 45% with 50% accuracy for the Influenza-B and 37% for Influenza-A

    For 2020-2021, trivalent (three-strain) egg-based vaccines are recommended to contain:
  • A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus (updated)
  • FA/Hong Kong/2671/2019 (H3N2)-like virus (updated)
  • B/Washington/02/2019 (B/Victoria lineage)-like virus (updated)

  • Quadrivalent (four-strain) egg-based vaccines, which protect against a second lineage of B viruses, are recommended to contain:
  • the three recommended viruses above, plus B/Phuket/3073/2013-like (Yamagata lineage) virus. (remains unchanged from 2019-2020 vaccine)


  • US DRUG NAMES (egg based):Afluria Quadrivalent; Fluad Trivalent; Fluad Quadrivalent; Fluarix Quadrivalent; Flucelvax Quadrivalent; FluLaval Quadrivalent; Fluvirin; Fluzone High-Dose; Fluzone Quadrivalent

    For 2020-2021, cell- or recombinant-based vaccines are recommended to contain:
    • A/Hawaii/70/2019 (H1N1)pdm09-like virus (updated)
    • A/Hong Kong/2671/2019 (H3N2)-like virus
    • B/Washington/02/2019 (B/Victoria lineage)-like virus
    • BB/Phuket/3073/2013-like (Yamagata lineage) virus

    There are two egg-free vaccines available in the US. Flublok Quadrivalent is recombinant and Flucelvax Quadrivalent is cell-based.


    Flu vaccines for patients over age 65:
    • Fluzone High-Dose Quadrivalent® contains four times the amount of antigen as the standard-dose inactivated flu vaccine, producing better protection in the elderly population. In a NEJM study Fluzone High Dose was found to be 24% more effective in preventing flu in adults 65 years and older relative to a standard-dose vaccine.
    • FLUAD® Influenza Vaccine, Adjuvanted: For active immunization of persons 65 years of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. (Source: fda.com) Medicare beneficiaries 65 years and older found that trivalent FLUAD provided greater protection against flu-related hospitalizations than standard-dose, egg-based flu vaccine.

    Adjuvants are ingredients of a vaccine that elicits a more robust immune response. Adjuvants also can reduce the amount of virus needed for production of a vaccine and still give adequate immune response.


    Share the following talking points with your patients:
    • During the preparation of inactivated influenza vaccines, the vaccine viruses are made noninfectious (inactivated or killed). Therefore, it cannot cause influenza.
    • The flu vaccine is administered intramuscularly by injection.
    • The flu vaccine takes two weeks to provide a full immune response.
    • The flu vaccine is licensed for use among persons aged >6 months, including those who are healthy, pregnant, and those with chronic medical conditions.

    What will this year’s flu season look like?
    • Flu season: influenza activity remained at lower levels than expected for this time of the year, though increased detections were reported in some countries. In the temperate zones of the southern hemisphere, the influenza season remained low or below baseline. Despite continued or even increased testing for influenza in some countries in the southern hemisphere, very few influenza detections were reported.
    • In the temperate zone of the northern hemisphere, influenza activity remained below inter-seasonal levels. (Source: World Health Organization)
    • It appears that all of the mitigation efforts to stop the spread of COVID-19 are having a significant impact on influenza spread. Children naturally spread influenza, and with many of them staying at home and attending school virtually, it seems to have impact on the decreased spreading of influenza. Social distancing, wearing face masks, limiting size of gatherings and travel restrictions all have impacted the rates of influenza illness.
    Once again, I relied heavily on my daughter Dr. Gretchen Garofoli to do the proofreading and additions to this column. She does outstanding presentations for her students as well as freeCE.com.

    I was amazed that the physicians and nurses had a higher immunization rate than did the pharmacists. Whenever you call most chain pharmacies, they answer the phone “Hi this is “Big Box Drug store, we are offering flu shots.” Every pharmacy is actively promoting flu shots to their patients, with increased availability and flu shot clinics. Certainly, we as pharmacists know of the availability of flu shots.

    I’m hoping that the very mild flu season is a harbinger of what we have in the Northern Hemisphere this flu season. Most agree we need a break from viruses. Wear your mask, wash your hands, and social distance!

    As Gretchen is doing, I would encourage you to get actively in your community and pharmacies providing flu shots, especially as patients are more concerned than ever with vaccinations. Throw in a Tdap, and a pneumonia shot while you're at it!!

    Have a great day on the bench!!

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    Influenza: The Basics

    FLU SEASON: starts in October and November and greatly increases in December and January with the highest peak occurring in February in the Northern Hemisphere. Here are some flu basics that we clinicians need to become familiar with:
    • Flu is caused by an RNA virus of the orthomyxovirus family.
    • Antigenic drift: Frequent minor changes in antigenic structure of the virus. This can reach epidemic proportions, but not every year. This is what requires minor adjustments in the vaccine formulation.
    • Antigenic shift: Major change in one or both major antigens in Influenza-A resulting in different subtype. This can result in major pandemics in all ages.
    Influenza-A
    • Subtypes based on 2 surface antigens hemagglutinin (H) and neuraminidase (N).
    • Four types of hemagglutinins cause disease in humans and virus attachment to cells (H1, H2, H3, H5). There are 16 known hemagglutinin proteins (Labeled H1- H16).
    • Two types of neuraminidase cause disease in humans and have a role in viral penetration of cells. (N1, N2) There are 9 known variants of the neuraminidase proteins.
    • Causes moderate to severe disease in all ages and can be transmitted in other animals.
    • Most commonly associated with global pandemics
    • Three subtypes of Influenza A have maintained a presence in the human population:
      • H1N1, H1N2, and H3N2
      • *Note: Avian flu is the H5N1 subtype which is infamous for its transmission from infected fowl to humans.
    EGG BASED FLU VACCINE:
    For 2020-2021, trivalent (three-component) egg-based vaccines are recommended to contain:
    • A/Guangdong-Maonan/SWL1536/2019 (H1N1)pdm09-like virus
    • A/Hong Kong/2671/2019 (H3N2)-like virus
    • B/Washington/02/2019 (B/Victoria lineage)-like virus
    Quadrivalent (four-component) egg-based vaccines, which protect against a second lineage of B viruses, are recommended to contain:
    • the three recommended viruses above, plus B/Phuket/3073/2013-like (Yamagata lineage) virus.
    • US DRUG NAMES (egg based): Afluria®; Afluria Quadrivalent®; Fluad®; Fluarix Quadrivalent®; Flucelvax Quadrivalent®; Flucelvax [DSC]®; FluLaval Quadrivalent®; Fluvirin®; Fluzone High-Dose®; Fluzone Intradermal Quadrivalent®; Fluzone Quadrivalent®; Fluzone [DSC]®
    For 2020-2021, cell- or recombinant-based vaccines are recommended to contain:
    • A/Hawaii/70/2019 (H1N1)pdm09-like virus (updated)
    • A/Hong Kong/45/2019 (H3N2)-like virus (updated)
    • B/Washington/02/2019 (B/Victoria lineage)-like virus (updated)
    • B/Phuket/3073/2013-like (Yamagata lineage) virus
    The only product available for this flu season is Flublok Quadrivalent®. There are no egg proteins in this product.

    Medication Guide and/or Vaccine Information Statement (VIS) In the U.S, the appropriate CDC-approved Vaccine Information Statement (VIS) must be provided to the patient prior to administering each dose of this vaccine; VIS is available at http://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.html.

    WHO IS THE ACIP?: ACIP comprises medical and public health experts. The ACIP meets three times a year to develop recommendations on how to use vaccines to control disease in the United States. The recommendations include the age(s) when the vaccines should be given, the number of doses needed, and the amount of time between doses.
    • Oseltamivir-resistant influenza A (H1N1) strains have been identified in the United States and some other countries. However, oseltamivir or zanamivir continue to be the recommended antivirals for treatment of influenza because other influenza virus strains remain sensitive to oseltamivir, and resistance levels to other antiviral medications remain high.
    Influenza –B
    No subgroups.
    Only affects humans and causes a milder disease usually in children.

    Influenza-C
    Rarely reported in humans. Does not cause significant infections in humans.

    INFLUENZA:
    • Major complication is pneumonia, Reyes syndrome, worsening of chronic bronchitis and death.
    • One of the leading causes of vaccine-preventable disease. 20-40K deaths during epidemics.
    • Rates of disease highest in elderly (over 65 years old), less than 2 years of age, and people of any age with medical conditions.
    • Penetrates the epithelial cells of the respiratory tract and destroys the host cell.
    • Virus is shed in respiratory secretions for 5 to 10 days, and transmission is through direct person to person droplet contamination or contact.
    • Incubation period is approx. 2 days
    • Clinical features: abrupt onset, fever, myalgia, sore throat, nonproductive cough, headache.
    • Disease peaks between December and March in the Northern Hemisphere.
    Comparison of Symptoms Between Common Cold and Influenza
    Symptom/ParameterCommon ColdInfluenza
    FeverUncommon (low grade)Common 100-104F
    Myalgia, arthralgiaUncommonCommon and severe
    AnorexiaUncommonCommon
    HeadacheUncommon and mildCommon and severe
    Dry coughMild to moderateCommon and severe
    Malaise and weaknessMildSevere
    Fatigue LevelMild, short livedSevere long lasting 2-3 wks
    Nasal congestionCommonOccasional
    Sore throatCommonOccasional
    Vaccine availablenoYes (yearly)
    Incubation period12 hours to 5 days (avg=2d)1-4 days (average=2 days)
    Contagious period1 day before & 5 days after1 day before & 5 days after
    ComplicationsSinus congestionBronchitis, pneumonia

    My daughter Gretchen Garofoli sits as the Coordinator of the American Pharmacists Association Immunizing Pharmacists SIG Community. She is very active at West Virginia University teaching and promoting immunization. She lectures across several platforms, especially FreeCE.com where she is their immunizing expert.

    As Gretchen is doing, I would encourage you to get actively in your community and pharmacies providing flu shots, especially as patients are more concerned than ever with vaccinations. Throw in a Tdap, and a pneumonia shot while you're at it!!

    Have a great day on the bench!!

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    Overview of Antibiotic-Induced Clostridioides difficile Infection

    C. dif infections... what a way to wrap up antibiotics!

    Clostridioides (Clostridium) difficile is an anaerobic gram-positive spore and toxin producing bacillus first discovered in 1935. In the 1970’s, its role was elucidated in antibiotic associated diarrhea. It is one of the most common and problematic nosocomial infections to contain. As “C. diff” multiplies, it produces two toxins (A and B) that cause diarrhea and colitis. 027/NAP1/BI isolates are the most virulent and produce 20 times more A and B toxins in vitro.

    Incidence: Between 2001-2010, the CDC analyzed data from 2.2 million hospital discharges. 700,000 patients were admitted for Clostridioides difficile infection (CDI) and nearly 1.5 million others acquired the infection while hospitalized for other reasons. CDIs increased from 4.5 to 8.2 per 1,000 discharges across the study period. Overall, 7.1% of infected patients died. Additionally, patients who acquired the infection while hospitalized were more than twice as likely to die than patients who were admitted for treatment of principal infection, a trend that increased during the study.

    Risk factors for developing CDAD (Clostridioides difficile associated diarrhea) include:
    • Antacid drugs (especially Proton pump inhibitors—omeprazole, esomeprazole)
    • Previous exposure to antimicrobial agents: Virtually all antibiotics have been associated with CDAD, but historically these drugs have posed the greatest risk. Aminopenicillins, cephalosporins, clindamycin and fluoroquinolones are frequently being implicated as risk factors. Fluoroquinolone administration for as short as 1-3 days whereas most antibiotics associated with CDAD take more than 3 days to occur. Remember this major side effect when counseling patients when dispensing levofloxacin (Levaquin®) ciprofloxacin (Cipro®), and moxifloxacin (Avelox®)
    Treatment of C. difficile (source: Sanford guide 2020)
    • First line: Vancomycin (Vancocin®) 125mg capsules four times daily for 10-14 days
    • Second line: Fidaxomicin (Dificid®) 200mg twice daily for 10 days (cost:$4100)
    • Third line: Metronidazole 500mg three times daily is only to be used if patient is not able to afford vancomycin or fidaxomicin
    • Adjunct therapy: Some clinicians use cholestyramine (Questran) 4gm 3 or 4 times daily to bind the toxins released by C.dif. Be sure to separate from vancomycin therapy by 2-3 hours to avoid binding.
    • Adjunct therapy: Saccharomyces boulardii (Florastar/ Stabile-GI) has the best efficacy of all probiotics for C. dif diarrhea.
    • Fecal transplant can be tried if reoccurrence, where an infusion of stool from a healthy donor is usually given rectally by enema or colonoscope. Some success has occurred when given by NG tube. Has the highest rate of efficacy.
    Zinplava® bezlotoxumab: approved 2016
    • human monoclonal antibody that binds to Clostridioides difficile toxin B, indicated to reduce recurrence of Clostridioides difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at a high risk for CDI recurrence.
    • Limitation of Use: ZINPLAVA is not indicated for the treatment of CDI because it is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI
    Prevention of Difficile:
    • Alcohol wipes and gels do not stop the spread. C. difficile is spread by spores, and the spores are relatively resistant to alcohol and other antiseptics. Wash hands with soap and water. Artificial fingernails are impossible to clean adequately, even after vigorous scrubbing or use of an antimicrobial soap. Healthcare workers are advised not to wear artificial nails, if in contact with C. dif patients.
    • Bleach wipes: good bathroom hygiene is effective in controlling C. dif. Patients should wipe down the toilet seat after each use with bleach wipes. Note that commercially available Clorox® wipes (yellow and green can) do not contain bleach. However, Clorox® “HealthCare” wipes contain bleach, and can be used for disinfection in the bathroom. See www.clorox.com for recipes to make your own solution. Don’t use paper towels, as they degrade the solution. https://www.clorox.com/resources/coronavirus/how-to-make-your-own-disinfecting-solution/
    • Antibiotic stewardship is a must! Use antibiotics only when absolutely necessary to avoid potential for C. dif.
    We pharmacists frequently dispense antibiotics, and sometimes we question the rationale. Now that the fluoroquinolones are very cheap, clinicians seem to jump on them. The current resistance rate for Strep pneumo (respiratory infections) for azithromycin (Z-pak) is around 47%. The current resistance rate for E. coli (urinary tract infections) for Trimeth/Sulfa is 21% and for Cipro/Levofloxacin is 27%.
    Besides the huge problem of antibiotic resistance, the development of Clostridioides difficile infection (CDI) is yet another problem that can be created with indiscriminate antibiotic use.

    Have a great day on the bench!!

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    Clindamycin Overview

    CLINDAMYCIN

    Mechanism:
    Binds exclusively to the 50S ribosomal subunit and suppresses protein synthesis. Clindamycin is 90% bioavailable after oral administration.

    Indications for use:
    Treatment of serious infections due to susceptible strains of streptococcus & staphylococcus. Very effective for Gram positive and Anaerobes. Penetrates well into the bone even in absence of inflammation.

    Common use: dental infections, anaerobic intra-abdominal infections, Methicillin resistant staph aureus (CA-MRSA).
    2nd choice for dental prophylaxis: adults 600mg one hour before appointment. Toxic shock syndrome: inhibits production of staphylococcal toxin associated with the toxic shock syndrome, used along with vancomycin.

    Warnings/Precautions:
    PSEUDOMEMBRANOUS COLITIS: fatal colitis characterized by severe persistent diarrhea. Toxins caused by Clostridioides difficile cause antibiotic associated colitis. When significant diarrhea occurs, STOP the drug. Don’t give anti-peristaltic meds. This condition can begin even after the cessation of Clindamycin.
    This condition is treated with Vancomycin, Fidaxomicin or Metronidazole.

    Pregnancy Category: B

    Side effects:
    Colitis & diarrhea

    Drug Monitoring:
    Watch for pseudomembranous colitis.

    Patient Education:
    Do not treat diarrhea without notifying the prescriber
    May take Clindamycin with food and full glass of water

    Most common Drugs & dosage of this class
    Clindamycin (Cleocin®)
    Available as capsules: 150mg, 300mg. Suspension: 75mg/5ml
    Suspension needs to be reconstituted. Do NOT refrigerate. Good for 14 days.
    Dosage: Serious infections: 150mg- 300mg every 6 hours
    More serious: 300mg-450mg every 6 hours.
    Child 8-16mg/kg divided in 3 or 4 equal doses.
    Dental prophylaxis: 600mg 1 hour before appointment

    Clindamycin is also used topically for treatment of acne.
    Available as 1% lotion, cream, gel and solutions. Apply twice daily.
    Also available as: Cleocin® Vaginal cream and suppositories.

    Clindamycin (Cleocin®), we learned in Pharmacy School back in the late 1970’s, was a most welcome addition to the infectious disease clinician’s armamentarium because it penetrated the vasculature of infected bone. It was pretty well elucidated at that time that there was a significant risk of Clostridioides difficile infection, and abundant caution was recommended.

    To quote the American Association of Endodontists (AAE) for patients that cannot take penicillins or cephalosporins, they offer this warning:

    “For patients with a true allergy to penicillin, the primary alternative antibiotic recommendation has changed. It is now azithromycin with a loading dose of 500 mg, and then 250 mg for four additional days.”

    “Clindamycin now has a U.S. Food and Drug Administration black box warning for Clostridioides difficile infection, which can be fatal. Therefore, it is only indicated if the patient cannot take azithromycin.”

    “For all patients on antibiotics, the antibiotic treatment is discontinued as soon as definitive treatment and improvement of the condition occurs (as short as three days), rather than to the full course of the prescription.”

    With the dental warnings from the AAE, I suspect we will be seeing a lot less oral clindamycin.

    Clindamycin, which was derived from lincomycin was approved by the FDA in the late 1960’s. Lincomycin (Lincocin®) is a natural product made by Streptomyces lincolnensis, an actinobacterium. Generic Clindamycin capsules became available in 1989.

    Have a great day on the bench!!


    October 2020

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    Role of Nitroimidazoles in Practice

    NITROIMIDAZOLES

    METRONIDAZOLE (Flagyl®) (1963)

    Mechanism:
    Disrupts structure of RNA and DNA, and cellular proteins of organism.

    Indications for use
    • Highly effective against ANAEROBES (mostly gram negative)
    • 3 types of protozoal infections: giardiasis, amebiasis, trichomoniasis
    • Clostridium difficile (C.dif) infections if cost is a concern, however we are seeing more resistance, and metronidazole is no longer considered first line therapy.
    • used in combination for H. pylori infections
    • bacterial vaginosis
    • used for intra-abdominal infections
    • “They clean-up what the big classes of drugs (FQ, ceph, pen, macrolides) miss!”
    Most common uses:
    • Abdominal infections, vaginosis, trichomoniasis, GI infections such as amebiasis, Giardia duodenalis (also termed G. lamblia) Helicobacter pylori, C.dif
    • Topical therapy can be used for treatment of acne rosacea and bacterial vaginosis
    Warnings/Precautions
    Pregnancy Category B (however, some references say don’t use 1st trimester)
    Disulfram reactions (nausea, flushing, vomiting with alcohol)
    Neurological effects (rare) seizures, peripheral neuropathy
    Headache
    Metallic taste
    Nausea, vomiting & diarrhea

    Side effects:
    Headache
    Metallic taste
    Nausea, vomiting & diarrhea

    Patient Education:
    Avoid alcohol
    Report any neurological effects to prescriber
    Complete course of therapy as prescribed
    May darken urine
    May cause unpleasant metallic taste.

    Most common Drugs & dosage of this class
    Metronidazole (Flagyl®)
    Dosage: Adult 250- 500mg every 6 to 8 hours for 7 to 10 days.
    Trichomoniasis: 1- day treatment: 2GM in one day, as a single or divided dose.
    Child dose: consult literature. Based on type of infection.

    Metrocream® & Metrogel®
    Used topically once or twice daily.
    Used for rosacea

    Metrogel Vaginal®
    Bacterial vaginosis: 1 applicatorful once or twice daily for 5 days. Be sure to specify route of administration when prescribing topical therapy.

    TINIDAZOLE (Tindamax®) 2004
    Is a second generation nitroimidazole
    Indications:
    • Treatment of trichomoniasis caused by Trichomonas vaginalis. (2GM single dose)
    • Treatment of giardiasis caused by Giardia duodenalis (also termed G. lamblia) (2gm single dose)
    • Treatment of intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica (2gm daily for 3-5 days)
    • Treatment of bacterial vaginosis (Gardnerella vaginitis) (2gm daily for 2 days)
    Side effects: like metronidazole; also avoid first trimester of pregnancy, avoid alcohol.

    SECNIDAZOLE (Solosec®) (2017)
    Indications:
    • Bacterial vaginosis. Dose one single gram packet of granules taken with food.
    Side effects: The most common side effects of secnidazole include yeast infection, headache, nausea, altered taste, vomiting, diarrhea, abdominal pain, and vaginal itching

    Note: does not seem to affect alcohol metabolism like tinidazole and metronidazole. There are no restrictions on alcohol use with secnidazole.

    Nitroimidazoles have been available since 1963. Metronidazole counseling is a must and most of us are well engrained to counsel patients about the absolute need to avoid alcohol. Often, people are bothered by the metallic taste from metronidazole.

    Even though tinidazole is available generically, and costs less than $30 per course of therapy it never got much attention, because metronidazole is so effective and cheap.

    One use of the metronidazole is for giardiasis. Giardiasis is extremely common, with 95% of all fresh surface water being contaminated. I remember as a kid going fishing with my Grandpa and we always drank out of a spring or creek, as long as it “didn’t smell bad”! Today, all fresh water needs to be purified before drinking. Here in Central Pennsylvania you’ll still see people with their plastic water jugs getting “fresh mountain spring water.” Keep the metronidazole handy!!

    Have a great day on the bench!!

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    Role of Nitrofurantoins in the Treatment of Urinary Tract Infections

    NITROFURANTOINS for UTI

    Nitrofurantoin history
    Approved by the FDA in 1953, nitrofurantoin became standard therapy for lower urinary tract infections (UTI) until the late 1970s. Other antibiotics, such as the fluoroquinolones, became available and its use decreased substantially. Since 2011, nitrofurantoin was again recommended as first-line therapy for lower UTI due to increasing resistance to fluoroquinolones.

    Mechanism
    MAY disrupt carbohydrate metabolism. May inhibit cell wall synthesis. Low doses are bacteriostatic; high doses are bactericidal. Therapeutic serum & tissue concentrations are not achieved, except in the urinary tract. Poorly absorbed. 90% is renally eliminated, achieving high urine concentrations.

    Indications for use
    Effective against many Gram (+) and Gram (-) including some strains of E.coli, P.mirab, Klebsiella, S.aureus, Enterobacter. Nitrofurantoin macrocrystals (Macrodantin®) may also be used for prevention of urinary tract infections. Dose is one capsule at bedtime or one capsule after each act of intercourse.

    Prescribing tips or more like “when not to prescribe”:
    • AVOID nitrofurantoin in patients with creatinine clearance less than 60mL/minute due to an increased risk for pulmonary toxicity, neuropathy, hepatotoxicity.
    • AVOID nitrofurantoin if early pyelonephritis is suspected, because serum concentrations doesn’t get high enough to treat systemic infections.
    • AVOID in the first trimester of pregnancy
    • AVOID last week of pregnancy due to potential for hemolytic anemia in newborn. Neonates had a higher rate of neonatal jaundice.
    • AVOID in complicated UTI
    Warnings/Precautions
    Pulmonary reactions: manifested by sudden onset of dyspnea, chest pains, cough, fever & chills. Prolonged use can cause pulmonary fibrosis.
    Hemolysis can occur if the patient is Glucose-6-phosphate dehydrogenase (G-6-PD) deficient.

    Pregnancy Category B: AVOID last week of pregnancy due to potential for hemolytic anemia in newborn.

    Side effects
    GI upset is common. Give with food.
    Headache, dizziness, confusion.
    Dermatologic: exfoliative dermatitis

    Patient Education-Nitrofurantoins:
    Complete full course of therapy.
    Take with food or milk
    May cause brown discoloration of urine
    Notify physician if breathing difficulties, skin rashes or tingling in fingers & toes.

    Most common Drugs & dosage of this class
    • MacroBid (nitrofurantoin macrocrystals monohydrate)
      Dosage: 100mg BID with food.
    • Macrodantin (nitrofurantoin macrocrystals) 50mg and 100mg
      Dosage: QID with food. (is most commonly used for Urinary Tract Infection prophylaxis)
    Other Urinary Tract Antiseptics:
    • Methenamine Hippurate (Hiprex®)- is the salt of hippuric acid and methenamine. Available as 1 gram tablets.
    • Methenamine Mandelate (Mandelamine®)- is the salt of mandelic acid and methenamine, available as 500mg and 1gm tablets. Dose 1gm four times daily.
    Mechanism: an inactive weak base, slowly hydrolyzes in acidic urine to ammonia and the nonspecific antibacterial, formaldehyde. Formaldehyde is thought to act by denaturation of protein. It becomes effective when urinary pH is less than 5.5, so frequently Vitamin-C (ascorbic acid) 4-12 grams may be given to acidify the urine and increase efficacy.

    Used only for prophylaxis of UTI, not treatment.

    Of course, I always recommend generic drugs be prescribed. However, I tell my students that this drug should be prescribed by brand name and let the pharmacist substitute to the generic equivalent.

    We frequently get prescriptions for “Nitrofurantoin macrocrystals 100mg-one capsule BID” which is Macrodantin® which is dosed four times daily, or once daily for prophylaxis. We have to call the doctor’s office for clarification.

    We also get “Nitrofurantoin Macrocrystals Monohydrate 100mg HS for prevention” which is MacroBID®, which is not used for prophylaxis, but treatment. When prescribing on an EMR or Pharmacy software it is best to search by “MacroBID®” or “Macrodantin®”

    I had not dispensed any methenamine for at least 30 years, and currently I have 2 women on this drug for prevention. For treatment/prevention of UTI, it seems the “antique drugs” are more efficacious. Our local resistance rates for nitrofurantoin for E. Coli is 7%, where the resistance to fluroquinolones is 27% and resistance to Sulfamethoxazole/Trimethoprim is 25%.

    Sanford guide recommends NOT using fluoroquinolones if resistance rates are over 10%, and not using Sulfa if the resistance rate is over 20%. At the clinic our “go to” is Macrobid® (nitrofurantoinMM) 100mg twice daily for 7 days, once the risk of pyelonephritis is ruled out.

    Have a great day on the bench!!

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    Overview of Fluroquinolones

    FLUOROQUINOLONES
    Mechanism: involves inhibition of DNA topoisomerase. Disrupts DNA cell replication.
    Fluoroquinolones are considered bactericidal.

    Indications for use:
    Excellent Gram positive & gram-negative coverage. Activity against Pseudomonas. Coverage of Anaerobes is poor.

    Warnings/Precautions:
    • May cause QT prolongation. Caution with elderly or any patient taking drugs that prolong the QTc interval. (FDA Black Box warning)
    • Photosensitivity reactions can occur. Use a sunscreen.
    • Mental health: may cause mood or behavior changes such as nervousness, confusion, agitation, paranoia, hallucinations. (FDA Black Box warning)
    • May worsen symptoms of myasthenia gravis. (FDA Black Box warning)
    • Tendonitis: may not give to patients under 18! (FDA Black Box warning)
    • Avoid in pregnant women, nursing women & children due cartilage erosion in growing bone tissue. (FDA Black Box warning) Pregnancy Category D
    • Pseudomembranous colitis (Clostridium difficile associated diarrhea) FQ have been implicated in causing surges of the highly toxic 027/BI/NAP1strain of C. dif.
    • May affect blood sugar levels, especially in diabetics (esp. renal impaired). HYPOglycemia can occur within the first 3 days. HYPERglycemia usually doesn't show up until after 3 days. Advise extra blood sugar monitoring. (FDA Black Box warning)
    • 2018: increased risk of the aorta (the main artery of body) rupturing, causing massive bleeding and potentially, death.
    Side effects: rash, urticaria, photosensitivity

    Drug Interactions:
    Do not take with antacids, multivitamins, iron, calcium, magnesium, for at least 2 hours.
    Increases theophylline levels
    May increase prothrombin time or INR (warfarin interaction)

    Patient Education:
    • Use sunscreen if outside.
    • May take with food to decrease GI upset.
    • Avoid iron, magnesium, calcium, zinc or any divalent or trivalent ions.
    • Finish the entire course of therapy.
    Most common Drugs & dosage:

    Ciprofloxacin (Cipro®) FDA initial approval 1987
    Available as: 250mg, 500mg 750mg and XR 500mg & XR 1000mg tablets

    Typical dosage: 500mg every 12 hours
    • Primary use today is for urinary tract infections, skin/soft tissue and GI infections. Not for respiratory infections. Not for gonorrhea infections.
    • Historical note: In August 2000, the FDA approved ciprofloxacin for management of postexposure inhalational anthrax. First antimicrobial drug approved by the FDA for use in treating an infection due to a biological weapon.
    Levofloxacin (Levaquin®) (FDA approved: 12/1998)
    Available as: tablets 250, 500mg & 750mg also available as liquid (25mg/ml)
    Dosage: 500mg q24 hours for 10 days
    • Can be used for both UTI and respiratory infections
    • For sinusitis, may give 750mg daily for 5 days. The higher peak concentrations of levofloxacin provide more rapid and complete killing of pathogens, which may decrease the emergence of resistance.
    • Hospital discharge: IV to PO mg for mg
    Moxifloxin (Avelox®) (FDA approved 1999)
    available as 400mg tablets
    Dose: 400mg every 24 hours
    • Little renal penetration, used only for respiratory infection, and skin and soft tissue infections. Minimal value for urinary tract infections.
    • Does NOT cover pseudomonas.
    Delafloxacin (Baxdela®) --- FDA approved 2018
    “the exception to all of the fluoroquinolone rules”
    Dosage: 450mg orally every 12 hours ($675.00/ 5 days therapy) or 300mg IV q12h

    Uses:
    • Is an anionic fluoroquinolone antibiotic for treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI’s)
    • More active than other FQ’s against Gram positive organisms such as multi drug resistant
      Strep pneumo and MRSA (methicillin resistant S. aureus).
    • Like other FQ: May cause tendinopathy.
    • Avoid polyvalent cations with administration.
    Special Notes:
    • Does not prolong QTc interval
    • Does not cause photosensitivity
    Gemifloxacin (Factive) – FDA approved 2003
    Was used for exacerbations of chronic bronchitis but is seldom used due to causing red exfoliative rash.

    And, you seasoned pharmacists remember the FIRST fluoroquinolone:

    Norfloxacin (Noroxin®) by Merck October 1986
    Only used for urinary tract infections, rarely used today.

    FLUROQUINOLONE RESISTANCE:
    We see major resistance to fluoroquinolones. Here are some resistance stats from my backyard: Escherichia coli accounts for 75-95% of urinary tract infections.
    Streptococcus pneumoniae was a big player in the pre-antibiotic era, thanks to child immunizations it is seen less frequently. However, is the most common agent in hospitalizations.

    USA 2017UPMC Altoona
    Altoona, PA
    Mount Nittany,
    State College PA
    E. coli resistance25%27%16%
    Strep pneumo resistance1%5%0%

    Altoona, PA where I practice is a community with an older population. State College PA, home of Penn State is a more affluent, healthier, younger, and better educated community, less likely to demand or need antibiotic therapy. There is a distance of about 35 miles between the two municipalities, but a major gap in fluoroquinolone resistance.

    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220265
    https://www-uptodate-com
    Special thanks to Ukwen Akpoji, from the Cleveland Veterans Hospital, John Rossi from Mount Nittany and the staff at UPMC Altoona Pharmacy.

    Once again, my fellow pharmacists, including my wife Denise, were helpful in guiding me through this overview. Ukwen Akpoji, Pharm D. provided some interesting data about the prevalence of resistance in the United States. He commented, “E. coli resistance to fluoroquinolones is about 30% at our VA (we have a unique population which may not be relatable to community).” With Ukwen’s population being much older and sicker, we might expect to see even higher resistance rates in other patient populations. Is there any wonder that the Cleveland Veterans Hospital needs a pharmacist specialized in antibiotic stewardship?

    At the clinic that I staff, we have changed our protocol for treatment of urinary tract infections, making nitrofurantoin the agent of choice for uncomplicated UTI’s due to resistance as well as the significant adverse effects of the fluoroquinolones.

    I remember as a young pharmacist when Noroxin® and Cipro® became available in the late 1980’s. They were a Godsend, as the patients no longer needed to be hospitalized to be treated with aminoglycosides for Pseudomonas infections. After 30 years of use, we have seen numerous side effects that require us to reign in overuse.

    Have a great day on the bench!!

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    Overview of Sulfonamide Antibiotics

    Sulfonamides

    Sulfonamide mechanism:
    • Sulfa drugs compete with para-amino-benzoic-acid (PABA) to block its conversion to dihydrofolic acid (DHFA)
    • Trimethoprim: block conversion of dihydrofolate to tetrahydrofolate
    Bacteria are obligate folic acid synthesizers, while humans obtain folate through dietary sources.

    Septra DS®, Bactrim DS® 800/160 and Bactrim® & Septra® (single strength) 400/80
    Liquid: 200mg SMZ/ 40mg TMP

    Adults: Septra DS®, BID for 7-10 days
    Child: 40mg/kg SMZ divided BID for 10 days.

    Indications for use:
    • Acute and chronic cystitis.
    • UTI caused by E.coli.
    • Used to treat P. Carinii infections (PCP pneumonia)
    • Also, for post-transplant antibiotic prophylaxis of PCP pneumonia
    • Methicillin resistant Staph aureus
    • Upper Respiratory Infections, Acute bronchitis
    • Acute otitis media (second line)
    • Lice- the combination of topical permethrin (Nix®) and oral (TMP/SMX) was a better second line treatment for head lice infestation than was PER alone. Monitor for adverse effects
    Warnings/Precautions: sulfonamides are perhaps the most allergenic of all antibiotics.
    About 3% - 4% of patients develop allergic reactions to sulfonamide antibiotics, also popularly known as "sulfa" antibiotics.
    • Sulfonylarylamines (the sulfa antibiotics: sulfamethoxazole, sulfisoxazole) along with the HIV protease inhibitors amprenavir and fosamprenavir)
    • NONsulfonylarylamines (loop diuretics, thiazide diuretics, sulfonylureas, celecoxib (Celebrex), acetazolamide, etc)
    • Sulfonamide moiety-containing drugs (e.g., sumatriptan, sotalol, and topiramate, etc)
    NONsulfonylarylamine and sulfonamide moiety-containing drugs need NOT be routinely avoided in patients with a history of allergy to sulfonylarylamines. However, these warning flags appear on most computer systems, and gently warn patients to watch for rash etc.

    Carries the highest risk of toxic epidermal necrolysis of the antibiotic classes. Can cause Stevens Johnson syndrome, hepatic necrosis, agranulocytosis. More likely to occur in HIV patients.

    Pregnancy Category-C:
    • Avoid in the first trimester of pregnancy since trimethoprim is a folic acid antagonist, and may have an association with folate-sensitive birth defects
    • Avoid at term. Can cause jaundice, hemolytic anemia and kernicterus. Both sulfa and trimethoprim easily cross placenta. Premature infants and infants with hyperbilirubinemia.
    Glucose-phosphate dehydrogenase deficiency: Any patient with G-6-PD (glucose-6- phosphate dehydrogenase) deficiency is at increased risk for adverse effects.

    Side effects:
    Photosensitivity (wear sunscreen!)
    GI upset including Nausea, Vomiting, Diarrhea
    Crystaluria— encourage patient to drink plenty of fluids.

    Drug Interactions: (Sulfa drugs)
    Warfarin: may prolong prothrombin time---significant drug interaction (increasing warfarin effect)
    Diuretics: in elderly can cause thrombocytopenia
    Potassium: may cause elevated potassium (hyperkalemia):
    Trimethoprim is structurally like the potassium-sparing diuretic amiloride. It competitively inhibits the sodium channels of the epithelium in the distal nephron, thereby impairing renal potassium excretion.

    Drug Monitoring:
    Watch for blood dyscrasias.
    Don’t give to patients with G-6-PD deficiency
    Watch for hypersensitivity reactions
    Adjust dose for a creatinine clearance of less than 30 mL/min
    Patient Education:
    Take full course of therapy. Drink large glass of water with each dose.

    Most Common Drugs & Dosage of This Class:
    Septra SS®, Septra DS®, Bactrim SS®, Bactrim DS® are most commonly used.
    5:1 ratio SMX to TMP
    • Double strength: 800mg sulfamethoxazole +160mg trimethoprim
    • Single strength: 400mg sulfamethoxazole + 80mg trimethoprim
    • Suspension: 200mg sulfamethoxazole + 40mg trimethoprim per teaspoonful

    The sulfonamides have a most interesting history. In the 1930’s sulfonamides became popular as one of the first true antibacterial agents, an outcropping from the dye industry. Demand for this product in a liquid form was met by the Massengil company by dissolving the powdered antibiotic in diethylene glycol—anti-freeze. Lethal kidney failure ensued.

    In just two months during September and October 1937, this drug was responsible for the deaths of more than 100 people in 15 states, from Virginia to California. The drug and the deaths led to the passage of the 1938 Food, Drug, and Cosmetic Act, which increased FDA’s authority to regulate drugs. Up until that point, drugs did not need to be proven safe, just labeled correctly.

    It was not until the Kefauver Harris Amendment in 1962 that assured efficacy. It took until I was 4 years old until the government made the drug companies show that their drugs worked! The Kefauver-Harris amendments were necessary due to the thalidomide tragedy that devastated Great Britain but was never approved in the United States.

    We seasoned pharmacists remember Gantrisin® (sulfasoxazole), Gantanol® (Sulfamethoxazole) and AZO-Gantanol®(phenazopyridine/Sulfamethoxazole). Today, most of us see only Trimeth/Sulfa, which early on in my career was co-marketed by Burrough Wellcome (Septra®) and Roche (Bactrim®).

    Have a great day on the bench!!


    September 2020

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    Overview of Macrolide Antibiotics

    MACROLIDES
    Erythromycin was first isolated in 1952 from the bacteria Saccharopolyspora erythraea
    Mechanism: may be bactericidal OR bacteriostatic. It binds to the 50S ribosomal subunit of the 70S ribosomal unit, thus inhibiting protein synthesis

    Indications for use: effective against many gram-positive bacteria, including strep (Streptococcus pneumonea) Corynebacterium, Neisseria & some strains of Mycoplasma, Legionella, Treponema & Bordetella. Some penicillin-G resistant S. aureus are susceptible to erythromycins. Are preferred drugs for Mycoplasma pneumoniae, Campylobacter, Legionnaires, Chlamydia, diphtheria & pertussis.

    Most common uses: Upper Respiratory Infection, Community Acquired Pneumonia, Chlamydia, atypicals.

    Warnings/Precautions
    Gastrointestinal distress (nausea, vomiting & diarrhea) occurs with all Erythromycins
    Allergies are rare, may see skin eruptions, fever, and eosinophilia
    Cholestatic hepatitis can occur (rare)
    Hepatotoxicity can develop with estolate salts of Erythromycin
    P450 blockers (except Azithromycin). Therefore, they may increase the effects of warfarin, digoxin & theophylline, some cholesterol drugs (simvastatin, atorvastatin).

    Side effects:
    Pseudomembranous colitis
    GI upset because it stimulates GI motility & increase pain and cramping

    Drug Interactions: Erythromycin and clarithromycin are CYP-P450 inhibitors. Both are 14 membered macrolides. Azithromycin is a 15 membered ring NOT metabolized by P-450 system, but excreted in the bile and then the feces, with very little unchanged drug appearing in the urine

    Patient Education:
    Take with food
    Take course until completed
    Watch for signs of liver dysfunction (pale stools, muscle cramps, yellowing of skin etc.)

    Most common Drugs & dosage of this class:

    Erythromycin base (Erytab®) (Erythrocin®) (old drug—extremely expensive $10-$17/tablet)

    Azithromycin (Zithromax®)
    Azithromycin was discovered by Pliva a Yugoslavian drug company. Pliva cross licensed azithromycin to Pfizer who launched it under the brand name Zithromax® in 1991
    Available as tablets: 250mg & 500mg. Suspension 100mg/5ml & 200mg/5ml
    Adults:
    Zithromax TriPack: 500mg tablets – one daily for 3 days
    Zithromax Zpack 250mg: Take 2 tablets first day. Then 1 tablet daily days 2—5.
    Child: 10mg/kg on day 1 then 5mg/kg on days 2-5.
    Otitis media can be given as 30mg/kg as a single dose.
    Pregnancy Category B

    Azithromycin has a half-life of 63 hours so coverage occurs for 5 days after the last dose.
    Once day doses (1gm) are also indicated for : Chlamydia, Chancroid, Non-gonococcal urethritis. Gonococcal is a 2gm dose.
    • NOT metabolized by cytochrome-p450 enzyme system
    • No dosage adjustment needed if renally impaired
    • Caution: may prolong QT interval—caution with heart patients especially if bradycardia, or other QT-prolonging drugs.
    • RESISTANCE: is a major problem with azithromycin. The current resistance rate for Strep pneumo (respiratory infections) for azithromycin (Z-pak) is around 47% in Altoona, PA.
    Clarithromycin (Biaxin®)
    Clarithromycin was developed by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s. Clarithromycin was developed to overcome the acid instability of erythromycin.
    Available as tablets: 250mg, 500mg and XL-500mg. Suspension 125 & 250/5cc
    Adults: 500mg twice daily with food or Biaxin XL 500mg: 2 tablets once daily.
    Child: 15mg/kg/day divided twice daily, every 12 hours for 10 days. Nasty bitter taste.

    Pregnancy Category: C
    ** more effective than Erythromycins against staph & strep. Also effective against Toxoplasmosis & Cryptosporidium species.
    Given with lansoprazole & omeprazole to eradicate Helicobacter pylori.
    • Cut dose in half if creatinine clearance is less than 30ml/min
    • Causes metallic taste in mouth
    • Caution: may prolong QT interval—caution with heart patients especially if bradycardia, or other QT-prolonging drugs.
    POTENT blocker of CYP450-3A4, and P-glycoprotein
    Increases warfarin (Coumadin®) levels—may cause increased bleeding risk.

    I remember in pharmacy school (now 40 years ago) one of my professors saying that the safest group of drugs were the erythromycins. They were reportedly “easy to dose, did not have drug interactions and didn’t cause resistance!” One out of three is correct.

    Macrolide resistance is a real problem. I spend a fair amount of time discussing macrolide resistance with my students, because azithromycin is “designed” to cause resistance.

    The package insert states that it is 5 days’ worth of meds that fights infections for 10 days. Using our simple pharmacokinetics, we see that after 10 days, the azithromycin levels would fall below the minimum inhibitory concentration (MIC), which is where resistance occurs.

    Since azithromycin has a half-life of 63 hours, and it takes 5 half-lives to get to a negligible amount, it would take 13 days after the last dose (day-5) to have a negligible amount (day-18). At a minimum, the levels of azithromycin fall under the MIC for at least 8 days! Simple pharmacokinetics show us why it is a flip of the coin whether an azithromycin pack will benefit our patients.

    Have a great day on the bench!!

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    Tetracycline Overview

    TETRACYCLINES

    Mechanism: Tetracyclines are bacteriostatic. They inhibit bacterial protein synthesis, working on ribosomal RNA.

    Indications for use:
    Covers most staph & strep strains, enterics, mycoplasma, spirochetes, rickettsiae, Chlamydia

    Drug of choice: acne & chlamydia, Rocky Mountain Spotted Fever, and Borrelia burgdorferi (Lymes)
    Doxycyline is approved for malaria prophylaxis.
    Doxycyline is less nephrotoxic and may be preferred in patients with renal disorders, as the drug is almost entirely excreted through the feces.
    Both Minocycline and Doxycycline are long acting with a half-life of 16 hours.

    Warnings/Precautions:
    • do not give with antacids, calcium, iron. (drug will not get absorbed)
    • photosensitivity
    • dental staining (not to be used in prepubertal children) ***
    • do not use in pregnant women or if breast feeding
    • May cause pseudotumor cerebri, a condition in which intracranial pressures increase
    Drug Interactions: any divalent or trivalent cations (magnesium, calcium, iron etc)
    • Decreases effectiveness of bactericidal antibiotics
    • May decrease effectiveness of oral contraceptives
    • Warfarin: increases effect. Increased bleeding risk.
    Class Side effect of tetracyclines: hepatotoxicity, nephrotoxicity, photosensitivity, dental staining, Pseudomembranous colitis is rare for this class of drugs

    Patient Education:
    • Avoid dairy products if using tetracycline. Does not seem to affect doxycycline.
    • May take with food to decrease GI upset
    • Wear sunscreen
    Most common Drugs & dosage of this class
    Tetracycline:
    Available as capsules 250mg & 500mg
    Dosage 250-500mg four times daily

    Doxycycline hyclate (Vibramycin®) Doxycycline monohydrate (Monodox®):
    Available as capsule=50mg & 100mg & 100mg tablets
    Dosage: 200mg first day, then 100mg daily for 10days. May use 100mg BID for 10 days.
    Minimal food drug interaction with doxycycline. Absorption is delayed.
    Common uses: Acne, Lyme disease, Upper Respiratory Infection, Community Acquired Pneumonia, Chlamydia, Community Acquired Methicillin Resistant Staph Aureus (CA-MRSA) Rocky Mountain Spotted Fever (RMSF)
    Not so common uses: bioterrorism: plague, anthrax, tularemia.

    ***Doxycycline is the most effective antibiotic for the treatment of suspected rickettsial infections, including Rocky Mountain spotted fever (RMSF). Delay in treatment of rickettsial diseases may lead to severe illness or death. Children are five times more likely than adults to die from RMSF.
    Misperceptions about the use of doxycycline for children prevent kids from getting lifesaving treatment. The old tetracyclines indeed cause dental staining and that warning in 1970 was given to the tetracycline family, even though it is NOT appropriate for doxycycline.
    Smile and take your DOXYCYCLINE: Doctors often avoid prescribing doxycycline to young children because of a warning that tooth staining may occur when used in children less than 8 years old. In a recent study, experts at the CDC and Indian Health Service (IHS) found that short courses of the antibiotic doxycycline can be used in children without causing tooth staining or weakening of tooth enamel.
    https://www.cdc.gov/rmsf/doxycycline/index.html#:~:text=Despite%20the%20current%20label%20warning,severe%20illness%20and%20save%20lives

    Doxycycline capsules: I always recommend and dispense doxycycline hyclate tablets. The doxycycline 100 mg capsules are huge and a potential choking hazard. I have had a couple of students who shared with me that had esophageal varices from doxycycline capsules getting stuck in their throat. My wife had a GI doctor share with her that he has seen this happen all to frequently and can be greatly reduced by exclusively dispensing the tablets.

    Doxycycline monohydrate (Monodox®):
    Available as tablets and capsules. Were believed to cause less GI upset. Not really proven.

    Minocycline (Minocin®):
    Available as capsules 50mg, 75mg & 100mg
    Dosage: 200mg stat; then 100mg BID q12h
    Minocycline may cause vestibular disorders, resulting in dizziness.
    Minocycline may cause pigmentation of skin & mucus membranes.

    How well I remember Achromycin-V® being dispensed for $4.00 for 100 capsules when I first started my career. Today the wholesale acquisition cost is almost $4.00 PER CAPSULE, and that price has dropped in half since last year! Remember 6 years ago when doxycycline was $4 per tablet cost, and now it is inexpensive again?

    Here’s an unusual use for tetracycline: It can be used as a biomarker in animals (and humans too!) The bait can be fed to the animal and then an allotted portion of time is allowed to pass. The critter (bear, raccoon etc) is given a second dose of tetracycline containing bait.

    A tooth is then extracted, sectioned in half and the “rings” of tetracycline can be measured and the animal’s growth can be measured. Tetracycline can also be used to measure vaccine distribution in wildlife, using tetracycline as a biomarker.
    Chlortetracycline was the first member of the tetracycline family, discovered in 1948. Aureomycin ophthalmic ointment was FDA approved in 1950. Tetracycline was first approved by the FDA in 1953, the patent given to Lederle Labs for the brand name of Achromycin-V®. Doxycycline was approved by the FDA in 1967 with the brand name of Vibramycin®. Minocycline (Minocin®) was approved by the FDA in 1971, the last tetracycline to be approved.

    Have a great day on the bench!!

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    Penicillin Allergy? Let’s Make Sure!

    Table 1. Classifications of β-lactam Reactions
    Levine ClassificationGell & Coombs ClassificationTime to Onset, hMediator(s)MechanismClinical Signs
    ImmediateType I≤1PCN-specific IgE antibodiesHistamine and vasoactive stormAnaphylaxis; angioedema; bronchospasm; urticaria (hives)
    Non-immediateType II≥72IgG, complementAntigen bound to hapten and fixed in tissue; increased clearance of RBCs, PltsGoodpasture's syndrome; PCN-related hemolytic anemia
    Type IIIIgG, IgM immune complexesTissue deposition of immune complexesSystemic Lupus; Penicillin-induced serum sickness
    Type IVT-cellsActivated T-cellsMorbilliform eruptions, contact dermatitis; Rarely more serious: e.g., Stevens-Johnson Syndrome
    So, penicillin allergies come in variations, with the Immediate Type-1 being the most serious. Those are the ones that physicians and pharmacists need to be most concerned about.

    So what’s the Big Deal… we have clindamycin and fluoroquinolones. From head to heart to skin infections (notably methicillin-susceptible Staphylococcus aureus or MSSA), beta-lactams like cephalosporins and penicillins are the drugs of choice. If they are “taken off the table,” we are forced to use broad-spectrum antibiotics like clindamycin and fluoroquinolones. Fluoroquinolones and clindamycin may not only be less effective for eradicating the bacteria (leading to antibiotic resistance), but also are a major cause of Clostridium difficile diarrheal infections!
    First-generation cephalosporins are commonly prescribed for surgical site infection (SSI) prophylaxis for almost all surgeries, either as monotherapy or as combination therapy. Preserving first-generation cephalosporins through antibiotic stewardship is critical to future patient care.

    Beta-lactam Cross-Reactivity: An OChem Rerun
    Cephalosporins are related to the structure and antimicrobial activity of penicillins. Both groups of antibiotics possess the core four-membered β-lactam ring. Cephalosporin cross-reactivity potential is related to the structural R1 side chain.
    For example, amoxicillin shares the same R1 side chain as ampicillin, cephalexin (Keflex®), cefadroxil (Duricef®), and cefaclor (Ceclor®). Patients allergic to penicillins should avoid cephalosporins with identical R1-group side chains. The third-generation cephalosporins, such as cefdinir (Omnicef®), cefpodoxime (Vantin®) and ceftriaxone (Rocephin IM/IV®), do not have R1 side chains that match the penicillins, so there is minimal chance of cross-reactivity.

    You Can Help to Set the [Allergy] Record Straight! Almost 80% of patients with IgE-mediated reactions lose their hypersensitivity after 10 years! Asking questions about their reaction symptoms, time since the initial reaction and whether they have taken other beta-lactam antibiotics since can be useful to “de-label” and remove allergies from the patients’ records. As pharmacists, we have a unique opportunity to ensure accurate documentation! We must make sure that when we document a patient-reported “allergy,” we delineate between allergies and side effects:
    • Allergy is an adverse drug reaction mediated by an immune response (e.g., rash, hives).
    • A side effect is an expected and known effect of a drug that is not the intended therapeutic outcome (GI upset, diarrhea).
    I've precepted 65 students now and am amazed with their success. Last week Ukwen Akpoji reached out to me and offered a guiding hand through the challenges of antibiotic stewardship, as well as navigating through patient reported allergies.

    With his experiences in that field, I am able to provide you some very useful information with regards to antibiotic use.

    “I’m allergic to penicillins. The last time I took Augmentin, I got horrible upset stomach and diarrhea. I can’t take penicillins.”

    How many times does that happen in our primary care and community pharmacy settings? Fortunately for me, I’ve precepted 65 students now, and some have become experts in their respective fields. Student #34 Ukwen Akpoji is such a superstar in the field of antibiotic stewardship. He shared the following with me for this session:

    Over 30 million people in the United States report a penicillin drug allergy. Less than 5% of these patients mount a type I hypersensitivity reaction mediated by IgE antibodies (i.e. anaphylaxis, angioedema, bronchospasm, etc.). These are histamine-related mechanisms, which is why diphenhydramine (Benadryl) usually helps relieve symptoms.

    Have a great day on the bench!!

    Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA. 2019;321(2):188-99. https://pubmed.ncbi.nlm.nih.gov/30644987/
    Chaudhry SB, Veve MP, Wagner JL. Cephalosporins: A Focus on Side Chains and β-Lactam Cross-Reactivity. Pharmacy (Basel). 2019;7(3):103. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789778/

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    Cephalosporins Overview

    CEPHALOSPORINS
    Mechanism: like their closest cousins the penicillins, cephalosporins bind to proteins in the cell wall, enabling it to inhibit cell wall synthesis of the bacteria, causing cell wall lysis and cell death (bactericidal).

    Indications for use:
    Differs between 1st, 2nd, and 3rd generation cephalosporins.

    1st GENERATION CEPHALOSPORINS:
    Gram positive activity, staph aureus, S.epidermidis, Strep pyogenes, Strep pneumoniae.
    Not active against MRSA/ MRSE.
    Some strains of Klebsiella, P.mirabilis, E.coli, Shigella (Gram Negatives)
    Primarily cover gram positive organisms: methicillin-sensitive S. aureus, group A strep
    Some gram-negative coverage: E. coli, Klebsiella species, P. mirabilis
    Poor anaerobic coverage

    Most Common 1st Generation Cephalosporins
    Cephalexin (Keflex®)
    • Available as: capsules 250mg & 500mg. Suspension: 125mg/5ml & 250mg/5ml
    • Adult dosage: 250- 500mg every six hours
    Cefadroxil (Duricef®)
    • Available as 500mg capsules & 1GM tablets. Suspension: 125/5ml; 250/5; 500mg/5ml
    • Adult dose: 1 to 2 gm per day in single or divided doses
    Most Common use: Methicillin Sensitive Staph Aureus (MSSA) skin/soft tissue. Urinary Tract Infection. Surgical prophylaxis

    2nd Generation
    Gram positive: same as above
    Gram negative: more extensive including: Acinetobacter, Citrobacter, Enterobacter, Neisseria, Proteus, E.coli & Klebsiella, Haemophilus influenza,

    Cefuroxime and cefprozil cover S. pneumoniae.
    Enhanced coverage of gram negative organisms: H. influenza, M. catarrhalis, Neisseria species
    Some anaerobic coverage. Cefoxitin and cefotetan cover B. fragilis.

    2nd Generation Cephalosporins
    Cefaclor (Ceclor®)

    Cefuroxime (Ceftin®) is a second-generation cephalosporin that maintains gram-positive activity of first-generation cephalosporins and adds activity against Proteus mirabilis, Hemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Moraxella catarrhalis
    Available tablets 125mg, 250mg, 500mg. Suspension: 125mg & 250mg/5cc
    Dosage: Adults 250mg-500mg every 12 hours, with meals
    Common use: Cefuroxime: Upper Respiratory Infection (URI), UTI, Lyme early stage, Otitis media, sinusitis.

    FIRST AND SECOND GENERATION cephalosporins have no activity against Listeria, Atypicals, MRSA, and Enterococci!

    3rd Generation: broad spectrum, most resistant to cephalosporinases.
    Some penetrate the CSF
    Gram positive: decreased compared to first & second generation
    Gram Negative: extensive coverage for Citrobacter, Enterobacter, Neisseria, Hemophilus, Serratia, with some Pseudomonas activity.
    Third-generation agents have enhanced activity against both gram-positive and gram-negative bacteria compared to 1st and 2nd generation.

    3rd Generation Cephalosporins
    Cefdinir (Omnicef®)
    Available as 300mg capsules susp:125mg/5cc & 250mg/5cc
    Dosage: Adults 300mg q12
    Child: 14mg/kg/day divided BID Suspension good for 10 days after reconstitution.
    Major Counseling point: Will turn stools red! occurs when cefdinir
    combines with iron to form a precipitate that gives stool a characteristic discoloration

    Cefpodoxime (Vantin®)
    Available as tablets: 100mg & 200mg. Suspension: 50mg/5cc & 100mg/5cc
    Dosage: Adults: 200-400mg/day divided BID. For skin may increase to 800mg/day

    Ceftriaxone (Rocephin®)
    Available only as injection: 500mg and 1gm injection GIVE IM or IV
    Adults: 1-2 gm daily. Pediatrics 50-75mg/kg. Max=2gm/day
    Dosed once a day. Avoid injection with calcium salts, precipitates in lungs and kidneys.

    COMMON USES: Third Generation Cephalosporins
    • Cefdinir: otitis media; upper respiratory infection.
    • Ceftriaxone: Lyme’s, otitis media, gonorrhea, upper and lower respiratory infections. skin infections
    • Some anaerobic coverage. No agents cover B. fragilis
    Warnings/Precaution: Crossover Allergy
    Cross-reactivity between penicillins and cephalosporins is less than 1%, (instead of 10% as previously thought) which is less likely with second- and third generation cephalosporins than first-generation cephalosporins.
    • Cefdinir (Omnicef®), cefuroxime (Ceftin®), cefpodoxime (Vantin®) or ceftriaxone (Rocephin®), are a safe choice because they do not have the “penicillin-like” side chains.
    Side effects: Cephalosporins
    Hematologic abnormalities: Some cephalosporins contain a methlythiotetrazole (MTT) side chain that increase risk of bleeding (hypoprothrombinemia)
    Rare: nephrotoxicity & hepatic enzyme abnormalities

    Drug Interactions
    Possible disulfiram reaction
    Probenecid inhibits tubular secretion

    Patient Education:
    Watch for severe penicillin allergy patients
    Take with food or milk
    Complete course of therapy

    As we previously discussed with the onset of penicillin therapy, bacterial resistance rapidly became problematic. Penicillinase producing staphylococci were wreaking havoc in the hospitals.

    Fortunately, in 1945 an Italian pharmacologist named Giuseppe Brotzu discovered an antibiotic-producing species of Cephalosporium (now Acremonium), isolated from a sewage outfall in Sardinia! Dr. Brotzu’s visit to a sewer pipe led to the discovery of one of the most used antibiotic classes today.

    As far as my historical experiences go, I remember when Eli Lilly’s brand of cephalosporin (Keflex®) was the first $1.00 per capsule back in 1979. As an intern, I remember Louie Rinovato, my preceptor, saying he doubts that the prices can go much higher! We were just at the beginning. Thanks to generics today, you can buy 100 capsules for what ten capsules of Keflex cost back in 1979!

    Have a great day on the bench!!

    August 2020

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    Penicillin: Still in Use 75 Years Later!

    PENICILLINS
    Mechanism: penicillin binds to proteins in the cell wall, enabling it to inhibit cell wall synthesis of the bacteria, causing cell wall lysis and cell death. Beta-lactam antibiotics (penicillins and cephalosporins) inhibit the growth of sensitive bacteria by inactivating penicillin binding proteins, which are involved in cell wall synthesis. Penicillins are bactericidal.
    Resistance: has been a problem since the introduction of penicillin in the 1940’s.
    • The binding sites can adapt and alter the permeability of the outer membrane
    • Decreasing affinity of the target site can be altered.
    • Resistance to the beta-lactam antibiotics is also due to production of enzymes that cleave penicillins (penicillinases), cephalosporins (cephalosporinases), or both (beta-lactamases)
    Indications for use
    Are highly effective against gram positive cocci and some gram-negative cocci. Little effect on GM- rods.
    • Penicillin-G is 5 to 10 times more active than Penicillin-V against gram negatives & some anaerobes.
    • Are ineffective against Staph aureus, due to beta-lactamase produced by staph.
    • Penicillinase resistant penicillins are not hydrolyzed by beta-lactamase.
    • Are drugs of choice for non-resistant Staph & strep. N. meningitidis, B. Anthracis.
    • Most common use: syphilis, susceptible pharyngitis and endocarditis and dental infections.
    • C. tetani, C. Perfringens, Listeria, Syphilis.
    Warnings/Precautions
    * Hypersensitivity reactions in 3 to 10 % (rash 4-8%) ; Anaphylaxis in 0.01% to 0.05% Rarely N/V with oral use

    Side effects: very rare- neurotoxicity at high doses. Neutropenia & nephrotoxicity. Broader spectrum penicillins: Amoxicillin can cause diarrhea due to disruption of normal GI flora.

    Drug Interactions: Probenecid increases blood levels.

    Patient Education: Finish entire prescribed dose. Report any rash to practitioner

    Most common Drugs & dosage of this class:

    Penicillin VK (PenVeeK® & V-Cillin-K®)
    Available as tablets: 250mg & 500mg. Liquid= 125mg/5ml & 250mg/5ml
    Liquid is reconstituted by pharmacist. Good for 14 days after mixing. Does have a bitter taste after reconstitution.

    Dose: 250mg-500mg two to four times daily.
    Pediatric:25-50mg/kg/day divided in 4 doses, every 6 hours.

    Penicillin parenteral is still measured in units.
    One unit of penicillin represents the specific activity in 0.6 mcg of sodium penicillin.
    1 mg of penicillin sodium represents approximately 1667 units of penicillin.
    Therefore, 250mg of Penicillin- 400,000iu

    Penicillin G (Pen G & Bicillin L-A)
    Penicillin G is a natural penicillin that is most commonly given intramuscularly (IM)
    • Penicillin G comes in two unique IM formulations: Benzathine Pen G and Procaine Pen G
    • These IM Repository formulations allow for steady release of medications at therapeutic doses for extended intervals
    • Great option for kids that a practitioner is worried that a caregiver may forget doses or non-compliant patients
    • Most common formulation/use: Benzathine Pen G 2.4 million units IM as a single dose for syphilis
    Penicillinase resistant Penicillins (“anti-staph penicillins”):
    Examples: methicillin, oxacillin (1971), cloxacillin (1971) & dicloxacillin (1968).
    Good for methicillin sensitive strep and staph. (not good for enterococci)
    Are not affected by beta-lactamase.
    Generally used for skin and soft tissue infection

    Extended Spectrum Penicillins
    Have a broad spectrum of coverage, but most importantly … Pseudomonas aeruginosa
    Because extended spectrum penicillins are sensitive to Beta-lactamase, they are coupled with Beta-lactamase inhibitors
    Examples: Piperacillin/tazobactam (Zosyn®) and Ticarcillin/clavulanate (Timentin®)
    Piperacillin/tazobactam (Zosyn®) is the safer option that is most commonly used
    Ticarcillin has been associated with electrolyte abnormalities and platelet inhibition Dosing and dosing intervals vary based organism/location of infection.

    I am amazed to read the stories of how the United States “ramped up” the manufacturing of penicillin to meet the demands of World War Two.

    It was indeed an international effort between the United States and Great Britain. Great Britain had the scientists and the technology, but their industrial complex was leveled due to the bombings.

    The US had the land and the fermentation tanks and equipment; with the help of British scientists, penicillin was rapidly produced. The most interesting part of the account I read, was in their search for a penicillin strain they spent most of their efforts with soil screenings.

    The big breakthrough came when the most productive strain was isolated on a rotten cantaloupe in the Peoria fruit market! My wife who describes cantaloupe as smelling like “dirty gym socks” was pleased to learn that her least favorite fruit has an extremely useful purpose!

    Have a great day on the bench!!

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    Anti-Infective Prescribing: The Ground Rules

    ANTI-INFECTIVE STEWARDSHIP IS A MUST!
    • Antibiotics are the only drug where use in one patient can impact the effectiveness in another.
    • If everyone does not use antibiotics well, we will all suffer the consequences.
    • Antibiotics are a shared resource, (and becoming a scarce resource).
    • Using antibiotics properly is analogous to developing and maintaining good roads.
    • Available data demonstrates that we are not doing a good job of using antibiotics in in-patient settings.
    • Several studies show that a substantial percentage (up to 50%) of in-patient antibiotic use is either unnecessary or inappropriate.
    Definitions
    • anti-infective: applies to any drug that is effective against pathogens.
    • antibiotic: technically refers to natural substances produced by a micro-organism that can kill other micro-organisms. However, most of us use antibiotic, anti-infective and antimicrobial interchangeably.
    • bacteriostatic: do not actually kill the bacteria but slow the growth of the organism. The body’s immune system can then dispose of the bacteria. Most bacteriostatic antibiotics disrupt protein synthesis.
    • bactericidal: kill the bacteria outright, usually by interruption of cell wall synthesis
    • minimum inhibitory concentration (MIC): concentration of an antibiotic which prevents growth of the culture.
    • minimum bactericidal concentration (MBC): the concentration that kills 99.9% of the inoculum. Often the MBC is 2 to 8 times that of the MIC
      • Antibiotics for which achievable blood concentrations regularly exceed the MBC of common pathogens are classified as BACTERICIDAL.
      • Antibiotics whose blood concentrations readily exceed MIC but usually do not exceed the MBC are classified as BACTERIOSTATIC.
      • Antibiotics whose blood concentrations do not reach MIC are RESISTANT.
    • time/kill curve: time dependent killing: little or no enhancement of bactericidal activity with drug concentrations above the MBC. Killing depends on maintaining the concentrations above the MBC for as much of the dosing interval as possible. Time kill curves are used to determine whether an antimicrobial is bactericidal or bacteriostatic.
    • post-antibiotic effect: when bacteria are exposed to an antibiotic at concentrations above MIC, the antibiotic is then removed.Bacterial replication does not resume as normal, for a variable period of time (usually hours) after removal of the antibiotic. The post antibiotic effect provides a rationale for pulse dosing of antibiotics. Serum antibiotic concentration falls below the MIC, for part of the dosing interval, the PAE may prevent bacterial multiplication during the brief time when the serum antibiotic concentration falls below the MIC before the next antibiotic dose.
    • superinfection: secondary infections caused when microorganisms normally present in the body are killed by the antibiotic. These normal organisms called host flora (or normal flora) inhabit the skin, upper respiratory, GU, and GI tract.
      • Examples: candida vulvovaginitis after amoxicillin therapy
      • C. difficile: after clindamycin therapy (or any broad-spectrum antibiotic)
    BACTERIOSTATIC ANTI-INFECTIVES
    DNA synthesis inhibitor:
    Fluoroquinolones
    RNA Synthesis inhibitor:
    Rifampin

    Protein synthesis inhibitors:
    Macrolides
    Tetracyclines
    Clindamycin
    Chloramphenicol

    Antimetabolites:
    Sulfonamides

    BACTERICIDAL ANTI-INFECTIVES
    Cell wall synthesis inhibitors:
    Penicillins
    Cephalosporins
    Vancomycin
    Carbapenems

    Cell membrane inhibitors:
    Isoniazid (bacteriostatic if stationary phase; bactericidal if growing) Amphotericin-B (fungicidal or fungistatic depending on concentration & organism)

    Protein synthesis inhibitors:
    Aminoglycosides

    I teach anti-infective therapy in the Summer semester at St. Francis in the Physician Assistant program. Knowing how much information is crammed in the Physician Assistant’s heads that year, I thought it would be prudent to cover antibiotic therapy.

    What do oxycodone, diazepam, penicillin, and ciprofloxacin have in common? I tell my students that antibiotics, benzodiazepines and opioids are drugs that we not only prescribe for the individual patient, but for society as well.

    Because benzos and opioids are considered as drugs with potential abuse, we must take precautions to minimize dependence and addiction and make certain that these drugs are not diverted. Diversion of opioids and benzos can become a societal problem.

    We must also be prudent in prescribing antibiotic therapy for our patients because they can create resistance to bacteria. Increasing bacterial resistance through reckless prescribing can cause an increase in resistant organisms in which current antibiotics can be futile.

    We have to look no further than the infamous “Z-pak” (Azithromycin) which, in our area, has a 48% resistance rate for Strep pneumo, a very common respiratory pathogen. It is a “flip of the coin” as to whether the “Z-pak” will cure your next community acquired pneumonia. Not being able to cure pneumonias in our patients is a societal problem as well.

    Have a great day on the bench!!

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    Migraine Headache Prevention is Easy…Unless We Are Looking at Real Patients!

    MIGRAINE COMORBIDITY AND COEXISTING CONDITIONS

    DISORDERCONSIDERAVOID OR CAUTION
    DepressionTCA, SSRI, SNRIBeta-blockers
    Bi-Polar disorderValproate, TopiramateTCA, SSRI, SNRI
    AnxietyTCA, SNRI, BB
    Sleep disturbancesTCABB
    StrokeAspirinErgot
    FibromyalgiaTCA, SSRI, SNRIBB
    ObesityTopiramate, SNRITCA, Valproate, SSRI
    EpilepsyTopiramate, ValproateTCA, SSRI, SNRI
    RaynaudsCCBBB, Ergots
    Over Age 60BB (due to stroke risk)
    SmokersBB (due to stroke risk)
    Uninsured patientsCGRP blockers $$$
    PregnancyCaution with all therapies. CCB seem to be safestTopiramate, Valproate

    TCA= Tricyclic Antidepressants such as Amitriptyline (Elavil) and Nortriptyline (Pamelor)
    SSRI= Selective Serotonin Reuptake Inhibitors such as fluoxetine (Prozac®), sertraline (Zoloft®)
    SNRI= Serotonin-norepinephrine reuptake Inhibitor such as venlafaxine (Effexor®), duloxetine (Cymbalta®)
    BB= Beta blockers such as metoprolol (Toprol-XL®, Lopressor®) and propranolol (Inderal®)
    CCB= Calcium Channel Blockers such as verapamil (Isoptin®)
    CGRP= Calcitonin gene-related peptide blockers such as Ajovy®, Aimovig®, Emgality®

    OPTIMIZING MIGRAINE MANAGEMENT
    Evidence based guidelines adopted by the AAFP, AAN
    • NSAIDS as FIRST LINE Therapy
    • Triptans (or Dihydroergotamine???) indicated for those who fail to tolerate or respond to NSAIDS
    • NO evidence to support the use of butalbital compounds (Fioricet®)
    • Little evidence to support use of isometheptene compounds (Midrin®)
    • Opioids reserved for use when other medications cannot be used. (Cardio patients)
    Remember when prescribing:
    • Drug overuse is a problem with sub-optimal therapy. Best to use the “one and done” approach. Think of using only Sumatriptan 100mg or Rizatriptan 10mg, rather than redosing with a lower strength.
    • Don’t take acute drugs more frequently than 5 half lives. Sumatriptan and Rizatriptan’s half-life is 2.5 hours.
    QUESTIONS to ASK
    • How often do you experience a headache of any severity per month?
    • How often do you experience severe or disabling headaches per month?
    • Has there been any change in either of these headaches over the past six months?
    • How often do you take Rx or OTC meds per month?
    Questions that don't work:
    • How many migraines per month?
    • On a scale of 1-10 how severe?
    As we health care professionals can attest, very seldom does a patient come in with only one chief complaint with no comorbidities. If that were the case, patients could go to a vending machine hit the migraine prevention button and the pills would magically drop out!

    Because of these complex patients, providers such as PA’s and physicians as well as pharmacists must always look at the entire patient and their comorbidities before selecting any therapy.

    Beta blockers are first line therapy for migraine prevention, unless the patient has bradycardia, hypotension, erectile dysfunction, fibromyalgia, depression, a smoker, or over 60 years of age. Hardly qualifies as “first line therapy” in a significant portion of the population.

    As one of the professors at St. Francis says, “Patients don’t come into the clinic with A, B, C or D selections on their forehead!”

    Have a great day on the bench!!

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    Treatment of Cluster Headaches

    TREATMENT OF CLUSTER HEADACHES

    Cluster headache: a form of migraine often characterized by brief, but frequently recurrent bouts of severe headache. Frequently referred to as “suicide headaches”. Headaches may last from 45 minutes to 3 hours, maximum. May occur every other day or up to 8 times per day, even the same time each day known as circadian periodicity.
    • Patients will not lie down; they are extremely agitated and incapacitated. They walk and pace and have been known to bang their head off a wall to deflect the pain.
    • Clusters may occur in groups of up to 8 a day lasting for weeks or months.
    • Pain is intense, concentrate on 1 side of head, accompanied by “Cranial autonomic symptoms” such as tearing of the eye, runny nose, fullness of the ear and a droopy eye on the same side.
    Origin: hypothalamus, near where circadian rhythm is governed.
    Typical patient: is a middle-aged male who smokes.

    TREATMENT of CLUSTER HEADACHE
    Oxygen: Flow rate is 12 liters per minute inhaled through a mask, sitting upright is safe and inexpensive, and works within 15 minutes. However, Medicare will NOT pay for oxygen for treatment of episodic cluster headache, even though it is the standard of care. (Fortunately for most, oxygen therapy is affordable.)

    Fast acting triptans: such as injectable sumatriptan (Imitrex®) 6mg subcutaneously, or sumatriptan 20mg nasal spray, or zolmitriptan (Zomig®) nasal spray 5mg. Sumatriptan injection and nasal spray are available as generics. Zomig® is brand only.

    Ergotamine preps: same as migraine dosage. Will help some patients. Save for patients who can’t use a triptan. Same dosage as migraines
    dihydroergotamine:
    Migranal® nasal spray 4mg/ml. ($315.00/dose)
    • Dosage: 1 spray (0.5mg) each nostril every 15 minutes for a maximum of 4 sprays.
    • Don’t exceed 3mg/day (6 sprays)
    • Don’t exceed 4mg/week (8 sprays)
    D.H.E.® injection: ($250.00/dose) DHE is usually given as a 1 mg intravenous bolus and may be repeated at one hour, with a maximum dose of 3 mg in 24 hours. Maximum= 3ml per 24hr if SC or IM. 2ml max if IV =6ml per week.

    Octreotide (Sandostatin®): may be effective in the treatment of acute cluster headaches.
    Dose: single dose of subcutaneous octreotide (100 mcg)

    Butorphanol (Staldol®) nasal spray: C-IV
    • Narcotic administered as a nasal spray. May provide relief esp. if nausea.
    • One nasal spray; wait 90-120 minutes before deciding to administer another dose.
    • Side effects: watch for drowsiness, may be habit forming.
    Lidocaine: Some success with intranasal Lidocaine. Lidocaine is hard to administer, and mixed results (33% efficacy).

    MEDICATIONS USED FOR PROPHYLACTIC THERAPY FOR CLUSTER HEADACHE

    Calcium channel blockers: Verapamil is the drug of choice. Use highest tolerable dose, (max=320mg/day). Watch for: incidence of electrocardiographic (ECG) abnormalities, including heart block and bradycardia. Best to do an ECG before starting therapy, and with dosage increases over 480mg.
    Watch for: edema, gastrointestinal discomfort, constipation, dull headache, and gingival hyperplasia

    Lithium: can be used but save for patients not responding to verapamil.
    Be sure to inform patient about side effects:
    • Drink 8 to 12 glasses of water a day. Watch for dehydration.
    • Take with food to minimize GI upset.
    • Therapeutic blood levels: maintenance 0.6 to 1.2 mEq/L
    Ergotamine preparations: are of limited value for prevention

    Corticosteroids- can be effective. Reserve for patients who don’t respond to verapamil. Usual dose: oral prednisone 60 to 100 mg once a day for at least five days, and then tapering by decreasing the dose 10 mg every day

    Melatonin: can help some patients. 10mg in the evening. This makes sense because melatonin levels are decreased in some patients with cluster headache.

    Anticonvulsants: Gabapentin (Neurontin®), Topiramate (Topamax®), and Divalproex (Depakote ER®) have all shown promise. Use doses as for migraine prophylaxis.

    Galcanezumab (Emgality®) Galcanezumab is a calcitonin gene-related peptide (CGRP) antagonist indicated in adults for
    • Preventive treatment of migraine AND
    • Treatment of episodic cluster headache (approved June 2019)
    • ligand antagonist a with a 25- to 30-day half-life
    NOTE: inform patients continue preventative treatment for 4 to 6 weeks after remission, to make sure cycle has ended
    Good resource: American Migraine Foundation

    I asked my neighbor at the pharmacy, Curt, who owns Penn-Med, what a non-rebreathing mask was, and he told me it was a typical oxygen mask. A rebreathing mask has the bag attached to the mask. When I asked him about providing oxygen to patients who suffered from cluster headaches, he told me of the reimbursement challenges of providing this service to patients who had normal pulse-ox readings. Yet another time when bureaucracy gets in the way of providing optimal care.

    Curt has a son who is a physical therapist, who specializes in treating migraine headaches by using physical therapy. His son can tell within three visits whether PT is going to be of any help or not. A lot of women are getting much needed relief with this specialized form of physical therapy.

    Have a great day on the bench!!

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    Herbal and Complementary Therapy for Migraine Prevention

    COMPLEMENTARY MEDICATIONS FOR MIGRAINE PREVENTION

    Butterbur: well-studied natural medicine. Treatment of both allergic rhinitis and for preventing migraine headache.
    Postulated mechanism: antispasmodic effects on smooth muscle and vascular walls. Possible anti-inflammatory effects by inhibiting leukotriene synthesis. The American Academy of Neurology (AAN) and American Headache Society (AHS) recommends petasites butterbur (50-75 mg bid), with a Level-A recommendation.
    Side effects: May cause GI upset, primarily burping as well as headache, itchy eyes, diarrhea, breathing difficulties, fatigue, and drowsiness.
    Caution: The raw, unprocessed butterbur plant contains chemicals called pyrrolizidine alkaloids (PAs). PAs can cause liver damage and possibly cancer. Only butterbur products that have been processed to remove PAs and are labeled or certified as PA-free should be used, for up to 16 weeks.

    Feverfew: reduces the frequency of migraines, and when migraines do occur, they tend to have less severe symptoms of pain, nausea, vomiting, and sensitivity to light and noise. AVOID if allergic to ragweed. AAN recommends feverfew (50-300 mg bid) with a Level-B recommendation. There is conflicting evidence about the efficacy of feverfew for migraine prevention.
    Side effects: nausea, digestive problems, and bloating; if the fresh leaves are chewed, sores and irritation of the mouth may occur. Avoid if pregnant. May interact with anticoagulants.

    Riboflavin: migraine prevention is its role in mitochondrial function because migraines could be partly due to mitochondrial dysfunction. Riboflavin is required as a precursor for factors needed for electron transport in mitochondria. Needs to be dosed at 400mg per day and takes at least 3 months to show efficacy. Vitamin B-2 is available in 100mg tablets, over the counter. In one study, the number needed to treat (NNT) for efficacy was 2.3 University of Pittsburgh. Well tolerated, discolors urine bright yellow.

    Magnesium: has been used for treatment and prevention of migraine headache. Some research shows that taking high-dose oral magnesium reduces the frequency and severity of migraine. Magnesium deficiency is related to factors that promote headaches, and people who get migraines seem to have lower levels of magnesium. The strongest evidence for magnesium’s effectiveness is in patients who have migraines with aura. It is believed magnesium may prevent the wave of brain signaling, which produces visual and sensory changes seen with aura. The guidelines from the AAN and the AHS say that magnesium is probably effective and should be considered for migraine prevention. Good choice for menstrual migraine.

    Dose is 400mg by mouth of Magnesium Oxide per day. IV magnesium can be used to abort an irretractable headache. Is in Pregnancy Category-A.
    Side effect: No surprise that diarrhea was the most common side effect.

    Coenzyme Q10 also affects mitochondrial function. Impaired oxygen metabolism and low cellular energy levels caused by faulty mitochondrial function might play a role in migraine headache pathogenesis. Coenzyme Q10 taken in a dose of 100 mg of three times daily appears to reduce migraine attack frequency, headache-days, and days-with-nausea. According to recent clinical research, the number needed to treat for one person to experience a 50% reduction in migraine attack frequency is three. Depending on the brand, it may cost up to $30 per month.

    Just because I know one of my most attentive readers wants to know...

    What About Medical Marijuana?
    Here are the highlights from an article in the Journal of Pain:
    Headache and migraine ratings were reduced by nearly 50% after using cannabis. Men reported larger reductions in headache after cannabis use than women. Cannabis concentrates were related to larger reductions in headache than flower. Evidence for tolerance to effects of cannabis on headache and migraine was detected. Evidence for medication overuse headache was not detected. This article shows a reduction in number of headaches and frequency. 40% of patients for whom medical cannabis was recommended for migraine reported a positive effect, with a decrease in migraine frequency from 10.4 to 4.6 migraines/month. Journal of Pain

    My students of St. Francis frequently hear me downplay complementary medications to treat or prevent disease. Especially with herbal therapy, there is no standardization in the United States.

    Products can vary from store to store since we do not have any system like the Komission-E monographs like Germany has, that spells out everything about purity and safety of herbal products. The only government help we have is just with the labeling of the products.

    When I see that butterbur must have the pyrrolizidine alkaloids removed to prevent liver toxicity and cancers, it makes me very reluctant to recommend the product given the lack of standardization of herbs.

    I am amazed, though, with the levels of efficacy shown by using riboflavin in the 400mg dose along with the magnesium oxide 400mg dose. The key is to have our patients use it for at least 3 months. Ah, the challenges of medication prescribing… getting our patients to “buy into” therapies that don’t show immediate benefit!

    Have a great day on the bench!!

    July 2020

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    Migraine Prophylaxis: Commonly Used Agents

    MIGRAINE PROPHYLAXIS: COMMONLY USED AGENTS

    BEHAVIORIAL MANAGEMENT

    Risk Factors
    • Stress (Note: Neurology April 2014 says stress reduction INCREASES migraine)
    • Menses
    Sensory Stimuli
    • Foods/stimulants
    • Weather fronts
    • Chronobiologic changes
    • Protective Factors
    • Stress management
    • Biofeedback
    • Regular Sleep & meals
    • Regular exercise
    • Adequate Hydration
    • Regular work/ school
    Indications for Pharmacological prevention
    Headache Frequency: greater than 8 days/ month or 2 days/week
    Significant disability MIDAS (Migraine Disability Assessment) > 10 or HIT-6 > 60 (measures of headache disability)
    Complications with Migraines
    Acute therapies are ineffective
    Migraine related complications

    Success: is defined as working in 50% of the patients to decrease headaches by 50%
    Expect at least 6 weeks to see benefit from migraine prophylaxis

    NEURONAL HYPEREXCITABILITY IN MIGRAINE
    Neuronal hyperexcitability predisposes individuals to migraine
    Increased neuronal hyperexcitability may be multi factorial
    Abnormal glutamate metabolism
    Deficiency of systemic and brain magnesium
    Abnormal calcium channels that influence presynaptic neurotransmitter release.
    Migraine may be prevented by reducing neuronal hyperexcitability.

    Encourage patients to identify and avoid triggers... skipping meals, disrupted sleep, stress, alcohol, wine, cheese, aspartame, etc. Men are 35% more likely to report overexertion as a migraine trigger. Men are more sensitive to light. Women are more sensitive to triggers of smell and are more likely to become nauseous.

    a) Beta blockers (considered first line for prophylaxis)
    These beta-blockers are lipid soluble and can penetrate the blood brain barrier
    • Propranolol (Inderal®)
    Dosage: 60mg to 360mg daily
    Side effects: fatigue, lassitude, depression, insomnia, postural symptoms
    • Metoprolol tartrate (Lopressor®) or metoprolol succinate (Toprol-XL®)
    Dosage: 50-200mg daily
    Side effects: same as propranolol

    Best to avoid beta blockers in smokers and patients over age 60

    b) General analgesics/NSAIDs (second line)
    • Aspirin 650-1950mg per day.
    • Naproxen 250mg to 550mg –twice daily
    Caution: regular use might lead to chronic headache.
    Avoid: CV disease, GI risk, hypertension

    c) Antidepressants (second line)
    • Amitriptyline (Elavil®) tablets
    Dosage: 25-75mg at bedtime (up to 150mg)
    Side effects: drowsiness, anticholinergic side effects, weight gain.
    Contraindicated in cardiac patients. Amitriptyline is the only tricyclic that has proven efficacy for migraine. No data on using other TCA’s
    • Venlafaxine (Effexor®) (second line)
    Side effects: headache, nervousness, insomnia, weight gain, GI disturbances.
    Caution: if hypertensive or recent heart attack.

    d) Calcium channel blockers (3rd line)
    • Diltiazem (Cardizem®, Cardizem CD®, Cardizem LA®)
    Dosage: 90-180mg daily
    Side effects: headache
    • Verapamil (Isoptin® or Calan SR®)
    Dosage: 80-160mg daily (up to 320mg/day)
    Side effects: Constipation, peripheral edema & cardiac conduction disturbances.

    Dr Robert Kaniecki: Headache Seminar: “Calcium channel blockers are not very effective”

    e) Anticonvulsants:
    • Topiramate (Topamax®) 25mg, 50mg , 100mg, 200mg
    Dosage: 25 to 150mg (Latest information suggests 50mg BID is sufficient)
    Side effects: confusion, weight loss, paresthesia, kidney stones
    Caution: over 200mg a day might decrease effectiveness of oral contraceptives
    • Divalproex (Depakote ER®)
    Dosage: Depakote ER® 500mg once daily for 7 days. Then increase to 1000 mg once daily. Do not crush or chew tablets.
    Side effects: weight gain, hair loss, tremor, diarrhea, and abdominal pain. During first 6 months of treatment watch for thrombocytopenia & hepatic failure.
    • Gabapentin (Neurontin®) -NOT effective- no better than placebo
    Dr. Robert Kaniecki: Headache Seminar:
    • Phenytoin, carbamazepine, phenobarbital are ineffective
    • Give 20% to 25% of maximum daily dose.
    f) Cyproheptadine (Periactin®)

    Often used for children

    4mg tablets, syrup: 2mg/teaspoon
    An antihistamine, with anti-serotonin properties
    Side effects: drowsiness, weight gain.
    Dosage: 4mg three times daily. Maximum 32mg/day

    Migraine headaches are disabling. Patients often want relief to not only get rid of them (with ‘-ditans’, ‘-triptans’ and ‘-gepants’) but also to keep the headaches from occurring in the first place. I find it amazing that success is defined as this: Half of your patients have half of the intensity/frequency of their headaches!

    Two weeks ago, we covered the CGRP inhibitors, all which cost around $725.00 per month. Virtually everything in this week's column is usually less than $20.00 per month.

    Have a great day on the bench!!

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    Treatment of Migraine Headache in Special Populations

    TREATMENT OF MIGRAINE HEADACHE IN SPECIAL POPULATIONS

    Treatment of Migraine Headache in Children

    In children, the pain is most often bilateral. Symptoms include photophobia (sensitivity to light), phonophobia (sensitivity to sounds), nausea, vomiting, and movement sensitivity.
    • Treatment (acute): Ibuprofen (7.5 - 10 mg/kg) max=800 mg.
    • Acetaminophen (2nd choice). Dose: 15 mg/kg up to 1000 mg.
    • If not effective, try sumatriptan (Imitrex®) nasal spray. Use 10 mg for kids weighing 44 -85lb. Use 20 mg for kids over 85 pounds.
    • Children age 6 to 10 years old weighing less than 110 lbs. should begin with the smallest available dose of triptan. (Sumatriptan-25mg)
    • Treat early for maximum effectiveness.
    Treatment of migraine headache in Pregnancy
    Migraine treatment of choice for pregnant patient: 1000mg Acetaminophen + 10mg metoclopramide.
    Second line: May also use butalbital/APAP/caffeine or Acetaminophen/codeine #3.

    REBOUND HEADACHES (MOH: Medication Overuse Headache) Key points:

    Diagnostic criteria include:
    • Headache - 15 or more days per month in a patient with a pre-existing headache disorder
    • Regular overuse for more than three months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache:
    Overuse of headache medications whether Rx or OTCs for just a few months can make their headaches worse when patients take meds frequently for migraine or tension headaches.

    Here are the drugs most likely to cause medication overuse headaches (MOH) and their % of reported incidence.

    Caution patients to avoid using:
    • butalbital/ acetaminophen (Fioricet®) for 5-8 or more days/month (causes 48% of MOH)
    • acetaminophen (Tylenol®) (causes 46% of MOH)
    • an opioid for 8 or more days/month (causes 33% of MOH)
    • aspirin analgesics (Excedrin®, Bufferin®), (aspirin causes 32% of MOH)
    • Triptans: do not use more than 10-14 days per month. That is why drugs like sumatriptan are packaged in 9 tablet boxes. (Triptans cause 18% of MOH)
    • NSAIDs (Motrin®, Aleve®) for 10 or more days/month. (10% of MOH)
    • Strategy for treating medication overuse headache:
      • Stop abruptly the over-used meds like NSAIDS and triptans
      • Taper butalbital and opioids.
    Treatment of withdrawal headaches:
    symptoms: worsening headache, anxiety, nausea or vomiting, disturbed sleep present for several days or longer.
    Select a drug from another class
    Antiemetic if needed- prochlorperazine (Compazine®) or metoclopramide (Reglan®) helps with nausea AND headache pain.
    Prednisone 100 mg/day for 5 days helps with inflammation but not pain.

    KEEP A HEADACHE DIARY
    • Chart your symptoms, even those that seem unrelated to headaches.
    • Be sure to include dates, times, and weather.
    • Chart what you were doing, eating, or drinking before the headache began. Log the duration of the headache.
    • Log the medications you took to treat the headache and their efficacy
    AVOID opioids and butalbital for headache treatment!!
    USE prophylactic therapy, which will be discussed in the next session.

    I was a leader of a Boy Scout Troop for almost 20 years. When I think of migraine headaches in kids one of my Scouts stands out. He got a migraine at almost every campout. Whether it was the smoke from the fire or just fatigue, he frequently went home with a massive headache.

    It taught me to remind every patient to keep a good headache diary and to isolate the trigger and do your best to avoid them.

    Rebound headaches can be challenging too. Sometimes the very therapies that are prescribed can be the most important contributory factor to causing rebound headaches.

    Have a great day on the bench!!

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    Acute Relief of Migraine Without ‘Triptans’

    GEPANTS AND DITANS

    CGRP Antagonists for TREATMENT of ACUTE MIGRAINE HEADACHE
    ‘Gepants’ are small molecule drugs which block the CGRP receptor and are effective at both relieving migraines and preventing them. ‘Gepants’, unlike the heavier monoclonal antibodies, rapidly penetrate the brain, so they work quickly; however, they are metabolized in the liver so there is a higher potential for interactions and possibly liver damage. Consider use after patients fail on two triptans, or can’t take triptans due to cardiovascular issues. Two have been approved to date:

    Ubrogepant (Obrelvy®) 50mg and 100mg tablets: Approved Dec 23, 2019
    Dose: 50 to 100mg with or without food, at first sign of migraine headache. If needed a second dose can be taken after 2 hours. Maximum daily dose is 200mg.
    Can be used to treat up to 8 migraines a month.
    Drug interactions: caution with strong CYP450-3A4 inhibitors or inducers. See package insert for liver failure, strong and moderate inducers or inhibitors of CYP450-3A4. Avoid in renal failure.
    Adverse effects: nausea, somnolence, dry mouth, dizziness, or upper respiratory tract infections between 2-5% of patients.
    Good news: no cardiovascular warnings, not controlled, not habit forming, savings card program.
    Bad news: cost is over $90 per pill

    Rimegepant sulfate (Nurtec ODT®): Approved Feb 27, 2020.
    Dose: 75mg one tablet as a single dose. Maximum is one tablet daily.
    Drug interactions: Avoid with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers. Refer to package insert.
    Adverse effects: Nausea and vomiting
    Good news: no cardiovascular warnings, not controlled, not habit forming, savings card program.
    Bad news: cost is over $90 per pill

    Atogepant: A third ‘gepant’, atogepant, is currently being studied for use as a migraine preventive.

    ‘DITANS’
    Lasmiditan (Reyvow®) is a newly approved (October 2019) migraine abortive tablet. Available: 50- and 100-mg tablets, is a controlled (Schedule V) substance.
    Ditans: Referred to as a Neurally Active Anti- Migraine Agent (NAAMA); it is a specific 5HT1F agonist. Lasmiditan has much higher affinity for the 5-HT1F receptor than for the vasoconstrictor 5-HT1B receptor. No constriction of the coronary or cerebral vessels and offers an alternative for those who cannot take the triptans. No better or no worse with respect to efficacy compared to triptans.
    Warnings: do not drive for 8 hours after dosing, due to drowsiness even if not feeling impaired. Watch for serotonin syndrome.
    Take home: The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology.

    I tell my student pharmacists of a quote I once heard about health care. "Five years after you graduate, 50% of what you learned in pharmacy school will be obsolete." Neurology, more than any other discipline, supports that quote.

    In just the past 18 months we have had 7 drugs approved for the treatment of migraine headache. There are 4 CGRP monoclonals we discussed last week, 2 ‘gepants’ and one ‘ditan’!

    What fascinates me with this class of drugs is their lack of influence on the blood vessels. We all believed that the vasodilation was the cause of migraines and by "shrinking" those vessels we stopped the process. If that is the case, how do we explain ‘ditans’, ‘gepants’ and non-steroidal anti-inflammatory drugs having such efficacy in migraine treatment?

    As far as the brain goes, we are still in the infancy stage of our understanding of this amazing organ!

    Have a great day on the bench!!

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    Headache Prevention with CGRP Therapy

    CGRP BLOCKERS-- JUST WHAT OUR PATIENTS HAVE BEEN WAITING FOR? MAYBE SOME.

    CGRP (calcitonin-gene-related peptide) when released causes intense inflammation in the coverings of the brain (the meninges), and for most migraine patients, causes the pain of a migraine attack. This peptide causes vasodilatation which causes several pain processes, most notably migraine headache.

    Mechanism: drug therapy is directed against calcitonin gene related peptide (CGRP) or its receptor for the preventive treatment of migraine and cluster headache. Calcitonin gene-related peptide (CGRP) is a vasoactive peptide, involved in dilation of cerebral and dural blood vessels. Widely distributed throughout the body, CGRP levels in serum increase during migraine or cluster headache.

    MONOCLONAL ANTIBODIES----Prevention

    Erenumab-aooe (Aimovig®) 70mg ------cost $725/month approved April-2018
    Dosing: Recommended dosage for migraine prophylaxis is 70 mg once monthly given as a subcutaneous injection; some patients may benefit from a dosage of 140 mg once monthly. The 140 mg dose is administered once monthly as two consecutive injections of 70 mg each.
    Mechanism: CGRP-receptor antagonist (it blocks the CGRP receptor)
    Efficacy: the number of migraine days per month was reduced by 3.2 in the 70 mg erenumab-aooe group; 3.7 in the 140 mg erenumab-aooe group, and 1.8 in the placebo group.
    Half-life: 28 days
    Time to peak: 6 days
    Side effects: injection site reaction and constipation. Constipation may be significant, best to avoid in patients already suffering from constipation, or taking constipation inducing meds (TCA’s, opioids)
    Storage: Store under refrigeration. Allow to come to room temperature for 30 minutes before administration

    Fremanezumab-vfrm (Ajovy®) ----cost 725.00 per month. Approved Sept-2018
    Dosing: For migraine prophylaxis: Two subcutaneous dosing options are available to administer the recommended dosage:
    • 225 mg monthly, or
    • 675 mg every 3 months (quarterly) Given as 3 consecutive injections.
    Mechanism: Fremanezumab-vfrm attaches to the CGRP molecule, preventing it from activating CGRP receptors by distorting the CGRP protein so that less of it can connect to the receptors.
    Half-life: Estimated at 31- to 39-days Storage: Remove from the refrigerator. Prior to use, allow AJOVY to sit at room temperature for 30 minutes protected from direct sunlight.

    Galcanezumab (Emgality®) cost= $725/month Sept 2018
    Mechanism: calcitonin gene-related peptide (CGRP) antagonist that attaches to the CGRP molecule, preventing it from activating CGRP receptors by distorting the CGRP protein so that less of it can connect to the receptors. Galcanezuman is ligand antagonist.
    Half-life: 25- to 30-days
    Administration: SC injection.
    Indications and Dosage:
    Two adult indications:
    • Preventive treatment of migraine: First dose is a loading dose of 240 mg, or 2 injections of 120 mg each, which may be administered in the doctor’s office, or by the patient. After that inject 1 dose each month.
    • Treatment of episodic cluster headache (approved June 2019) The recommended dosage is 300 mg (three consecutive subcutaneous injections of 100 mg each) at the onset of the cluster period, and then monthly until the end of the cluster period.
    Aimovig®, Ajovy®, Emgality®:
    • All thee were approved between May and September 2018
    • All three cost the same $725.00 per injection. All have copay coupons for commercial insurance.
    • All three can be injected in the abdomen, upper thigh, or upper arm. All list injection site reactions as side effects
    • Aimovig® contains latex, the others are latex-free.
    • Only Emgality®, thus far is approved for cluster headache treatment. It also is available as an auto-injector (like the Trulicity® device)
    Eptinezumab-jjmr (Vyepti®) approved February 2020
    Mechanism: attaches to the CGRP molecule, preventing it from activating CGRP receptors by distorting the CGRP protein so that less of it can connect to the receptors.
    Administration & Dosage: IV infusion in a health care setting, every 3 months. Do not push IV.
    The recommended dosage is 100 mg administered by IV every 3 months; however, some patients may benefit from a dosage of 300 mg administered by IV every 3 months. No loading dose needed. Infuse over a 30-minute period.

    How well I remember in the early 1990’s when sumatriptan became available! Migraine sufferers before that time had Fioricet®, Fiorinal®, Midrin®, and Cafergot®. None of these products are recommended today. Now we have the CGRP blockers for acute migraine relief as well as prophylaxis.

    Will this new class of drugs be the wonder drugs of migraine therapy? So far patients either love them or hate them. I had one patient who had not met his deductible and had a $450 copay. He said, “for this ability to have a normal month I’m fine with paying $15 per day.” Now that he met his deductible his copay is $35 and both pharmacist and patient are a lot happier!

    Have a great day on the bench!!

    June 2020

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    The Use of Selective Serotonin Receptor Agonists in the Management of Migraine Headache

    TRIPTANS- THE GAME CHANGER IN MIGRAINE HEADACHE RELIEF

    TRIPTANS: The medications we discussed last week that we are not supposed to use for migraine headache treatment, were the mainstay of therapy until the early 1990’s. In December of 1992 Imitrex (sumatriptan) injection was approved by the FDA, and the oral dosage form was approved in June of 1995. This profoundly changed acute migraine headache treatment. No more caffeine/ergotamine and oxycodone for migraine treatment, and doctors stopped prescribing both of these drugs in the mid 1990’s for headache.

    Mechanism: activate 5HT1b and 5HT1d and 5HT1f, which make them laser focused for migraine treatment. The net effect of triptans is to constrict cranial blood vessels and suppress inflammatory neuropeptides.
    Even though these drugs are laser focused for migraine treatment, 7-30% of patients will not respond to triptans. When this occurs consider allodynia, where triptans are used after aggressive dosing of non-steroidal anti-inflammatories (NSAIDs).

    Adverse effects: tingling, paresthesias, sensation of warmth in neck & head chest and limbs. Do not use triptans within 24 hours of ergots or other triptans.

    Contraindications: ischemic heart disease, myocardial infarction, uncontrolled hypertension, other heart disease. To reduce the potential for angina, do not give if risk factors: obesity, diabetes, hypercholesterolemia, as well as smokers, men over 40 and post-menopausal women.

    Selective Serotonin Receptor Agonists (Triptans):
    BRAND NAMEGENERIC NAMEAVAILABLE STRENGTHDOSAGEMAX DAILY DOSAGEHALF-LIFEONSET(in minutes)
    Axert®AlmotriptanTablets 6.25, 12.512.5mg; repeat in 2 hours25mg3.5 hours60 min
    Imitrex®SumatriptanAvailable StrengthTablets 25, 50, & 100mg200mg2.5hr60-120 min
    Nasal spray 5mg, 20mg5 or 20mg. Repeat in 2 hours40mg15-20 min
    Inject 6mg/.5ml New:4mg/.5ml6mg, repeat in 1 hour12mg10-15 min
    Treximet®Sumatriptan + naproxen85/5001 tablet; may repeat in 2 hours. Max 2/day170/1000mg60-120 min
    Relpax®EletriptanTablets 20 & 40mg20mg-40 Repeat in 2 hours80mg5hr60 min
    Frova®Frovatriptan2.5mg2.5mg repeat in 2 hours7.5mg25 hours (longest)60-120 min
    Maxalt®RizatriptanTablet/wafer 5mg, 10mg5 or 10mg. Repeat in 2 hours30mg2-3 hours30 min
    Zomig®ZolmitriptanTablet/wafer 2.5mg, 5mg2.5-5mg repeat in 2 hours10mg2.5-4 hours45 min
    Amerge®Naratriptan1mg & 2.5mg1mg or 2.5mg repeat in 4 hours5mg6 hours60 min


    COST: all the products above are available as generics. However due to competition, or lack thereof, there is great variability in pricing of the generics. Sumatriptan and Rizatriptan are the cheapest, with almotriptan and frovatriptan being the most expensive.

    OK I give up why do we need 7 different triptans??????
    • If you fail on a triptan, the second choice might work better
    • Faster onset—injections work quicker (10-15 minutes) so do nasal sprays (15 minutes). Also, good if patient is vomiting. (note that orally disintegrating tablets do NOT work faster).
    • Long half-life drugs like Frovatriptan and Naratriptan may be more useful for menstrual migraines—more useful for prevention than to abort a headache.
    The Headache Specialist says, “Using TRIPTANS for Migraines”:
    • Reduces all aspects of migraine disability
    • Minimal or no sedation
    • Intrinsic antiemetic properties
    • Drug induced headache is uncommon if use optimally. (Use high dose early)
    • Use 1 pill per headache
    One of the best pieces of advice we can give our patients came from a headache seminar I attended was “Take one and you are done.” The specialist also advised to take the maximum dose available to get rid of the headache. “Hit the headache hard and early on.”

    Most patients know when a migraine is coming, and at the first sign they should take a full dose of a triptan. The specialist stated he had no time for sumatriptan 25mg or the 50mg.

    He also recommended “cleaning up” the inflammatory neuro peptides with NSAID therapy, such as ibuprofen or naproxen, both high doses. Triptans have indeed changed the management of migraine headaches, especially now that the class is very affordable.

    Have a great day on the bench!!

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    Ergots and Opioids: No Place in Migraine Management

    WHAT NOT TO USE FOR MIGRAINE HEADACHE RELIEF
    Ergotamine preparations
    Mechanism: in the cranial arteries, it promotes constriction and decreases pulsation.
    Migraine activity might be due to agonist activity at serotonin receptor subtypes
    5-HT1b and 5HT1d
    Adverse effects: can stimulate the chemoreceptor trigger zone and cause nausea and vomiting in 10% of patients. Weakness in legs, myalgia, numbness & tingling in periphery. May also cause angina-like pain.
    Ergotism from chronic or acute overdosage. Symptoms include hallucinations, severe gastrointestinal upset, abortions, dry gangrene, and a painful burning sensation in the limbs and extremities commonly known as “St. Anthony’s Fire”. Ergotism was commonly seen in the middle ages as a fungal infestation of grains, especially rye grains.
    Contraindications: ischemic heart disease, myocardial infarction, uncontrolled hypertension, other heart disease and pregnancy.
    To reduce angina: do not give if risk factors: obesity, diabetes, hypercholesterolemia, smokers, men over 40, post-menopausal women.

    Drug therapy:
    Ergotamine + caffeine:
    Cafergot®: tablets: 1mg ergotamine + 100mg caffeine.
    Dosage: Take 2 tablets at onset. Then every 30 minutes as needed.
    • Maximum daily dose: 6 tablets per day.
    • Maximum weekly dose: 10 tablets per week
    Dihydroergotamine:
    Migranal® nasal spray 4mg/ml.
    Dosage: 1 spray (0.5mg) each nostril every 15 minutes for a maximum of 4 sprays.
    Don’t exceed 3mg/day (6 sprays)
    Don’t exceed 4mg/week (8 sprays)

    D.H.E.® injection: Dosage 1ml IM, IV or SC every 1 hour to a maximum of 3ml per 24 hours. (2ml if IV)
    • Maximum= 3ml per 24hr if SC or IM. 2ml max if IV. max =6ml per week.
    • Best to combine with metoclopramide (Reglan) for nausea
    Dr Robert Kaniecki: headache seminar:
    • Ergotamines are “hopelessly outdated”.
    • All ergots are pharmacologically non-selective.
    • Narrow window of opportunity
    • Enhances Nausea
    • Modest efficacy (little difference from NSAIDS)
    • Cardiovascular effects
    OPIOIDS : GENERAL PRINCIPLES

    Side effects for opioids:
    Lightheadedness, dizziness, drowsiness, shortness of breath, nausea, vomiting, CONSTIPATION
    Contraindications for opioids:
    Alcoholics, heart failure, patients with opioid abuse potential
    Patient information for opioids:
    • Watch for drowsiness, caution driving. Avoid alcohol
    • Caution abuse potential, using and storage.
    • Do NOT adjust dose without consulting prescriber.
    • Caution if used in pregnancy
    REMEMBER: Patients treated with opioids as first-line therapy are significantly more likely to return to the emergency department with a headache within seven days of the original visit

    Dr Robert Kaniecki stated at the headache seminar:
    Use of opioids for migraine treatment:
    • Pro-inflammatory! (migraine is an inflammatory disorder)
    • Vasodilator
    • Increases nausea and vomiting
    • Sedating
    • Drug seeking behavior
    • (No contraindications with vascular disease: benefit)
    I was so frustrated when I saw a student pharmacist’s notes that had 29 pages of ergot alkaloids. Discussion of ergot alkaloids has a rich history that dates to known cases in the Middle Ages, that caused gangrene and hallucinations. The Salem witch trials were believed to be due to ergotism.

    It has been postulated that the 10th plague of the Egyptians was also due to wheat being infected by the ergot fungi (Claviceps purpurea) which caused ergotism, and then death of the first-born Egyptians. Yes, history is fun, but there is so much to learn about treatment of disease states with pharmacotherapies that are actually used.

    Dr Kaniecki with many years of headache management hit the nail on the head… “Ergots are hopelessly outdated.” I say they belong in the history books, and not occupy 29 pages in a student pharmacist’s lecture notes!

    Have a great day on the bench!!

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    First Line Therapy for Tension and Migraine Headaches

    USE OF GENERAL ANALGESICS FOR MANAGEMENT OF ACUTE HEADACHES
    (tension or migraine)

    For mild to moderate migraine attacks not associated with vomiting or severe nausea, simple analgesics (NSAIDs, acetaminophen) or combination analgesics are first choice agents because they are effective, less expensive, and less likely to cause adverse effects than migraine-specific agents such as triptans or ergots.

    ACETAMINOPHEN: Mechanism: possibly decreases central prostaglandin synthesis (?). (mechanism unknown)

    Acetaminophen dosing:
    • max: 4000mg /day in healthy patient
    • max: 3000mg if drinking alcohol (social)
    • max: 2000mg if an alcoholic- best to limit acetaminophen use
    Drug interactions/Adverse Effects:
    Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure in the U.S. Around 30,000 patients are hospitalized each year in the U.S. to undergo treatment for this condition.

    Acetaminophen: warfarin- may result in significant elevations of international normalized ratio (INR), putting patients at increased risk for hemorrhage. If acetaminophen is necessary at doses near or greater than 2 g/day for more than 1 day, an extra INR measurement should be considered.

    NONSTEROIDIAL ANTI-INFLAMMATORIES:
    Mechanism: NSAIDS inhibit cyclooxygenase (COX-1 & COX-2) which are enzymes that catalyzes the synthesis of prostaglandins, which are hormone-like substances that participate in a wide range of body functions such: as the contraction and relaxation of smooth muscle, the dilation and constriction of blood vessels, control of blood pressure, and modulation of inflammation. Prostaglandins are derived from a chemical called arachidonic acid.
    • Blocking COX-1 : causes blood thinning (good) and stomach ulcers (bad)
    • Blocking COX-2: causes coagulation (bad) and protects stomach (good)
    RX NSAIDS: Short-acting NSAIDS, with a duration of less than six hours include: ibuprofen (Motrin), diclofenac (Voltaren), etodolac (Lodine) and indomethacin (Indocin)

    Long-acting NSAIDS, with a duration of action over six hours including naproxen (Naprosyn), meloxicam (Mobic), celecoxib (Celebrex), nabumetone (Relafen)

    OTC NSAIDS:
    Aspirin: 325mg tablets, 165mg & 81mg tablets (Ecotrin max strength 500mg & 650mg)
    • Dosage: 1 or 2 tablets every 4 hours as needed for pain
    • Monitor for increased bleeding with warfarin and aspirin
    • May cause tinnitus.
    Ibuprofen (Advil®, Motrin®) 200mg tablets OTC 400,600,800mg RX
    • Dosage 200 every 4-6 hours prn
    • OTC maximum is 1200mg; Rx maximum is 3200mg
    Naproxen sodium (Aleve®) 220mg OTC Anaprox® 275 &550mg RX
    • OTC Dosage: 220 every 8-12 hours. OTC maximum=440-660mg
    • Rx maximum dose: Anaprox® (1100-1650)
    • Rx maximum dose: 1000-1500mg (Naproxen-Naprosyn®)
    Side effects for NSAIDS: GI toxicity, bleeding, ulceration
    Contraindications for NSAID:
    • Caution if renal impaired, may cause nephrotoxicity
    • All are pregnancy Category –D in third trimester
    • active GI disease
    • Caution in liver impairment
    • GI bleeding
    • Photosensitivity
    • Avoid Aspirin & alcohol while taking NSAID
    • Watch for increased hypertension
    • Exacerbation of heart failure
    • Increased risk of myocardial infarction, stroke, CV death
    Patient information:
    • Know signs and symptoms of GI bleeding
    • Photosensitivity
    • Avoid Aspirin & alcohol while taking NSAID
    • Take with food to avoid GI upset
    • Asthmatics –caution with aspirin
    • Do not take OTC NSAIDS with prescription NSAIDS
    Drug interactions:
    • All OTC medications should be used with caution in Warfarin patients, including acetaminophen
    • Do not take with other NSAIDS
    Numerous combinations of OTC meds with aspirin & acetaminophen:
    • Percogesic® (acetaminophen + diphenhydramine)
      • Acetaminophen 325 mg/diphenhydramine 12.5 mg: 2 tablets orally every 4 to 6 hours as needed
      • Acetaminophen 500 mg/diphenhydramine 12.5 mg: 2 tablets every 6 hours as needed
    • Excedrin® (aspirin 250mg + acetaminophen 250mg + caffeine 65mg) 2 caplets as a single dose
    • Bufferin® (aspirin 325mg + calcium carb+ mag carb + mag oxide) 2 tablets every 4 hours as needed (maximum of 12 per day)
    • Vanquish® (acetaminophen 194mg + aspirin 227mg + caffeine 33mg) max=8 caplets/day
    Other techniques to recover from headaches:
    • Lie down and relax
    • Use warm/cold compresses (your choice)
    • Warm bath or massage
    • LIMIT number of pillows!
    Dr. Robert Kaniecki: Headache Seminar offered the following about NSAID use for Migraine Headache:
    • Relatively unlikely to cause drug induced headache.
    • Safe in the presence of vascular disease
    • No Sedation
    • No Increase in Nausea
    • Efficacy for mild to moderated headache
    • High doses are to be used.
    Migraine is an inflammatory disorder.

    Can you imagine a world without over the counter ibuprofen and naproxen sodium? Up until May 18,1984, ibuprofen was prescription only. It was not until ten years later in January 1994, did naproxen come over the counter.

    I'm glad as a pharmacist we can recommend over the counter therapies to help our patients get inexpensive, quick and immediate relief for their headaches. When I spend two days a week at the Empower-3 family practice office, I see the "dark side" of NSAIDS. All of the providers are in agreement that these drugs need to be prescribed with a lot of caution. One of the physicians "detests" NSAIDs given to anyone with cardiac issues, renal issues and even hypertension that is not well controlled.

    If we see patients on long term NSAIDs at the clinic, we always check renal function to see if these prostaglandin blockers are inhibiting renal perfusion, as they are notorious for blocking afferent vasodilatation to the glomerulus.

    If ever we need a third class of drugs for pharmacist dispensing only, NSAIDs would be the first class of drugs I'd bring behind the counter... right next to the pseudoephedrine!

    Have a great day on the bench!!

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    Differentiating Between Types of Headaches: Tension, Migraine and Cluster

    TYPES OF HEADACHES

    Tension Headache definition: Also referred to as “chronic scalp muscle contraction headache”, tension headaches affect BOTH sides of the head and scalp with pain that may radiate to the jaw and shoulders. Due to blood vessel changes taking place from muscular components, causing a “band like vise” around the head. Chances are, that if an OTC recommendation can be made and is successful, it is probably a tension headache. Patients usually do not go to the physician to get treatment for tension headaches.

    Migraine headache definition: A migraine is a type of headache, usually occurring with symptoms such as nausea, vomiting, or sensitivity to light and sound. In many people, a throbbing pain is felt only on one side of the head. Migraines may last from 4-72 hours, patients will lay down for relief (turn out lights, have quiet). Migraine headaches tend to first appear between the ages of 10 and 45. Migraines may run in families. Source: Migraines start in the trigeminal nucleus caudalis.

    GENDER DIFFERENCES:
    • Women are twice as likely to get migraines than men (17.5% women experience migraines as opposed to 8.6% of men). Some women, but not all, have fewer migraines when they are pregnant.
    • Women report a longer attack duration, increased risk of headache recurrence, greater disability, and a longer period of time required to recover.
    • Women are more sensitive to triggers of smell and are more likely to become nauseous.
    • Men are 35% more likely to report overexertion as a migraine trigger. Men are more sensitive to light.
    Classic migraine (migraine with aura): recurring headache that strikes after or at the same time as sensory disturbances called aura. These disturbances can include flashes of light, blind spots and other vision changes like zigzags or loss of vision. Aura patients have more dramatic presentation of multiple clinical manifestations. Patients may feel a tingling sensation in the hand or face. Migraine with aura is associated with a 2-fold higher risk for ischemic stroke. About 1/3 of patients with migraine may experience aura although most do not experience aura with every migraine.

    Common migraine (migraine without aura): associated with nausea, vomiting, or both and are frequently accompanied by sensitivity to light, sound, and movement. If untreated, these headaches can last up to 72 hours.

    Allodynia: feel pain from stimuli that do not normally cause pain, such as combing one’s hair. Is caused by central sensitization in the brain.
    • Triptans do NOT work for allodynia
    • Treatment: start with Non-Steroidal anti-inflammatories, then follow up with a triptan in one hour.
      • (source: Dr. Gary Jay - PAINWEEK)
    Triggers: Encourage patients to identify and avoid triggers… skipping meals, disrupted sleep, stress, alcohol, wine, cheese, aspartame, etc.

    Cluster headache: a form of migraine often characterized by brief, but frequently recurrent bouts of severe headache. Frequently referred to as “suicide headaches”. Headaches may last from 45 minutes to 3 hours, maximum. May occur every other day or up to 8 times per day, even the same time each day known as circadian periodicity.
    • Patients will not lie down; they are extremely agitated and incapacitated. They walk and pace and have been known to bang their head off a wall to deflect the pain.
    • Clusters may occur in groups of up to 8 a day lasting for weeks or months.
    • Pain is intense, concentrate on 1 side of head, accompanied by “Cranial autonomic symptoms” such as tearing of the eye, runny nose, fullness of the ear and a droopy eye on the same side.
    Origin: hypothalamus, near where circadian rhythm is governed.
    Typical patient: is a middle-aged male who smokes.

    I had one of the best learning experiences in my professional career back in in 2006 when I attended “Migraine: A Day at the Office.” Where the faculty included the two top flight experts in migraine management on the East Coast, Mark W. Green Clinical professor of Neurology: Director of Headache Medicine, Columbia University and Dr Robert Kaniecki Asst. Professor of Neurology University of Pittsburgh; Director the Headache Center, Pittsburgh, PA.

    The 8-hour session I attended with my wife and daughter taught an incredible amount of information that I use to this day. For the past two Septembers, I spent a week in Las Vegas with my son-in-law Mark Garofoli and got at least 24 hours of pain management CE, including headache management.

    At the request of many fellow clinicians, I am starting a Neurology unit, since we spent five months covering Mental Health Meds. There are at least 6 new products that have been introduced in the past 2 years, and we need to learn the role of these medications. I remember well when the triptans came out in the 1990’s and changed headache management. Will the CGRP inhibitors do the same?

    Have a great day on the bench!!

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    Adolescent Sleep Deprivation: Addressing the Problem

    GETTING THE TEENS TO "UNPLUG"

    The teenage brain is not an adult brain with fewer miles on it. During adolescence, the teen brain is only 80% developed. The frontal lobe (responsible for reasoning, planning, judgement, emotional expression, problem solving, memory, language, and sexual behaviors) is not fully in gear until age 25-30.
    The adolescent brain more susceptible to alcohol induced toxicity. Adult brain cells recover faster. The teen brain is more susceptible to marijuana as well, by blocking cell signaling. What teens did last weekend still affects test taking skills on Thursday. Indulging in alcohol and marijuana over the weekend can cause a “Self-induced learning disability” Teens should not be consuming massive amounts of caffeine to keep alert due to lack of sleep

    PUT DOWN THE SCREEN and GO TO SLEEP!

    The blue light emitted by screens on cell phones, computers, tablets, and televisions restrain the production of melatonin, the hormone that controls their sleep/wake cycle or circadian rhythm.
    About 72 percent of children ages six to 17 sleep with at least one electronic device in their bedroom!
    • which leads to getting less sleep on school nights compared with other kids
    • almost an hour of sleep per night is lost
    • quality of sleep is negatively impacted
    Read a book! And here is why:
    Using any device in the hour before bed was associated with a 13 to 52 percent increase in the likelihood of needing more than 60 minutes to fall asleep. More than four daytime hours of screen time was associated with a similar increase in risk of “sleep latency,” or taking a long time to fall asleep. This technology provides excess stimuli and can trick your brain into thinking that it needs to stay awake.
    • Checking Facebook, Twitter, Instagram
    • Reading Email
    • Web surfing
    • Gaming
    GAMING: (source: Psychology Today, March 2011)
    • A growing body of evidence shows that video games and other electronics induce the fight-or-flight syndrome, putting the body in a state of stress. Think adrenalin and stimulation of the sympathetic nervous system.
    • Studies show sustained increases in blood pressure and pulse, even hours after playing a video game. It does not have to be a violent game, or even an action game-or even a game at all!
    • Over time, internet surfing and texting will similarly put the brain and body in a state of stress, just from the high level of visual and cognitive stimulation
    TAKING CONTROL of SLEEP---Sleep Tips to Promote Sleep and a Healthy Lifestyle
    Establish a regular sleep schedule
    During the day:
    • Exposure to light in the morning
    • Avoid caffeine, alcohol and nicotine
    • Exercise, but not too close to bedtime
    • Avoid lengthy or late naps
    Establish a regular bedtime routine
    About one hour before going to bed:
    • Engage in a relaxing, non-alerting activity
    • Do not drink or eat too much
    • Maintain a quiet, dark and preferably cool, but comfortable sleep environment. TV, computers, notepads, phones etc need to be turned off and powered down completely.
    Happy 5th Anniversary to Clinician’s Corner! The first Clinician’s Corner was published the first week in May 2015 for a local wholesaler to spread practical information to my fellow community pharmacists. The first column covered much needed information on Lyme Disease. In December 2015, with the help of Duquesne student Vinnie Longhi, who was doing the Rural Pharmacy Rotation and staying in our house showed me how to set up this MailChimp account. Vinnie insisted that I need to share my information with more than just customers of the warehouse.

    In the Fall of 2016 Kevin McCarthy from PharmCon “discovered” this column and made it part of his website at www.freece.com naming it “Professor Pete’s Practice Points” and made it available to over 50 thousand pharmacists nationwide. My first column for freece.com was published December 22,2016, discussing the concerns of Dextromethorphan cough syrup.

    The next big change came in December of 2019, when under the leadership of Kevin Hope and Julie Strickland from FreeCE, they began converting these columns to “micro-CE’s.” Recently an educator remarked that the average attention span today is about 22 minutes, so FreeCe.com is leading the way with my column in providing pharmacists continuing education in meaningful small bites.

    This column is #270, and I have never repeated a column that has been published by Freece.com. For the past 5 long months I have focused entirely on Mental Health (Psych) drugs. The Physician Assistants at the family practice clinic wanted me to cover psych drugs as they feel they needed brushing up on this class of meds. I am always willing to take requests and using my lecture notes I further develop topics that make for a quick 20 minute read.

    I am humbled to see how many of my fellow pharmacists, former students and physicians read this column to help provide the latest information to their patients. I am most appreciative to my colleagues at FreeCE.com.

    Have a great day on the bench!!

    May 2020

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    Adolescent Sleep Deprivation: Defining the Problem

    ADOLESCENT SLEEP DEPRIVATION: DEFINING THE PROBLEM

    The numbers and percentages are staggering. 85% of teens get less than the minimum requirement of 8 ½ hours of sleep. We all are aware that shortened sleep impairs learning, performance, health and safety. Nearly 55% of fall-asleep crashes involve drivers 25 years of age or younger. It is no surprise that almost ¼ of young adults report driving faster when drowsy.

    Why we need consistent sleep:
    • Sleep plays a vital role as adolescents develop and go through the maturation process. Adolescence is a time of increased responsibility, peer pressure and busy schedules.
    Sleep is:
    • food for the brain – produces alertness, enhances memory and the ability to learn
    • a biological requirement – helps the body perform effectively and safely
    • essential for development, particularly during growth and maturation
    • a key to good health – as important as good nutrition and regular exercise
    Sleep is a basic human drive regulated by two biological systems:
    • Sleep/Wake Homeostasis: The drive to sleep that increases the longer we are awake
    • Circadian Rhythms: The internal clock in our brain that regulates when we feel sleepy and when we are alert
    Sleep is regulated by a biological clock in the brain. The internal mechanism that regulates when we feel sleepy and when we feel alert resides in the brain and is affected by light and dark.
    • Melatonin: appears to increase the binding of GABA to its receptors by affecting membrane characteristics, not by increasing the number of receptors. GABA is an inhibitory pathway.
    • Orexin: is a neurotransmitter found in a specific part of the brain that can help keep a person awake.
    • “Non-24”: Non-24-hour sleep-wake disorder (N24) is a circadian rhythm sleep disorder in which an individual's biological clock fails to synchronize to a normal 24-hour day. Normally we fall asleep at the same time, but patients with this disorder will typically find their sleep time gradually delaying by minutes to hours every day.
    TEEN SLEEP DEPRIVATION
    • Teens need 8½ – 9½ hours of sleep, and 85% get less than the minimum requirement.
    • Teens often have poor sleep habits and irregular sleep patterns – trying to make up for sleep on weekends.
    • Teens regularly experience daytime sleepiness.
    • The biological clocks of children shift during adolescence, which drives them to a later bedtime schedule (around 11:00 pm) and a natural tendency to wake later in the morning.
    • This delayed phase syndrome can place them in conflict with their schedules – particularly early school start times.
    CONSEQUENCES of SLEEP DEPRIVATION

    PHYSICAL CONSEQUENCES
    • Cognitive, social, and behavioral performance become impaired.
    • Poor school performance and lower grades
    • Tardiness and absence from school
    • Difficulty remaining alert and paying attention
    • Reduced ability to concentrate, problem-solve, remember, and have a positive attitude
    EMOTIONAL CONSEQUENCES
    • Irritability and impaired moods
    • Problems controlling emotions and getting along with others
    • Greater risk for hyperactivity, depression and possibly violence and substance abuse
    • At risk for injuries and drowsy driving accidents
    • Overall, daytime sleepiness reduces enjoyment and quality of life.
    Even as a high school student back in the 1970’s, bedtime was no later than 9:30 on a school night. We got up every morning by 6:30am to get ready for school and catch the school bus at 7:25am. There were no negotiations; bedtime was a hard and fast rule with our family.

    Although my parents were inflexible about bedtime, there were none of the distractions that teens are “blessed” or more like cursed with. We did have a 13-inch black and white TV in the bedroom I shared with two brothers and that was it. There were no cell phones, iPads, gaming devices, Facebook, Twitter, Instagram and the countless electronic distractions that teens have today. The gray screens really do impact sleep induction so phones and tablets can mess up a good bedtime routine.

    Worse, are the gaming devices that many teens are addicted to. I hear of teens staying up until 3:00am and some as late as 5:00am playing games on their devices.

    Even in my days as a university student, I never stayed up past 11:00pm studying for any exam. My brain seemed to fry, and I was seeing less results as the night wore on. I was at the point of diminishing returns and a good night sleep gave me more benefit than cramming all night.

    Time management and sleep management are so sorely needed by today’s youth.

    Have a great day on the bench!!

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    Alternatives to amphetamines and methylphenidate to treat ADHD…

    TREATMENT OF ADHD FOR THE OTHER 20% WHO DO NOT RESPOND TO, OR CANNOT TOLERATE STIMULANTS:
    • Some antidepressants
      • Bupropion (Wellbutrin®) has the most efficacy for adult ADHD
    • Modafinil (Provigil®) functions as a stimulant for excess daytime sleepiness without the apparent severe side effects and withdrawal issues associated with the CII (amphetamines, methylphenidate) medications.
      • Mechanism: is a wake promoting agent but is not a direct- or indirect-acting dopamine receptor agonist. In lab studies modafinil binds to the dopamine transporter and inhibits dopamine reuptake.
      • Warnings: watch for dermatologic and psychiatric reactions.
      • Contraindication: not for use in children of any age
    Best options for “tics” induced by amphetamine use
    Background
    About 20% of ADHD patients have a tic disorder. Stimulants may worsen tics, at least in some patients. Labeling of some stimulant medications contraindicates their use in patients with tics or Tourette’s syndrome. However, recent studies suggest that stimulants can be used safely in patients with tics, and do not always significantly worsen tic

    Atomoxetine (Strattera®): ideal for patients with substance abuse history, tics, or failure on stimulants.
    Mechanism: selectively inhibits presynaptic norepinephrine reuptake in the prefrontal cortex.
    Dose: Given once daily or divided BID without regard to meals. Start with 0.5mg/kg; titrate to a maximum of 1.4mg/kg.
    Warnings:
    • Atomoxetine increased the risk of suicidal ideation in short-term studies in children or adolescents with ADHD
    • Adjust doses down in patients receiving strong CYP2D6 inhibitors such as paroxetine (Paxil®) and fluoxetine (Prozac®) or patients known to be CYP2D6 poor metabolizers. CYP2D6 is enzyme responsible for activating codeine to morphine.
    • May increase heart rate and blood pressure.
    • Frequently causes headache, insomnia and increased anxiety
    Efficacy:
    • stimulants are usually better than atomoxetine (Strattera)
    • You have to treat 5 children with atomoxetine (Strattera) to see a positive outcome
    • You have to treat 3 with methylphenidate to see a positive outcome.
    • Use a stimulant first for most patients
    • Half of patients who don't respond to methylphenidate will respond to atomoxetine (Strattera). (Possibly genetics?)
    • No need to taper the old med when switching to atomoxetine (Strattera)
    Central Alpha Agonists: decrease sympathetic outflow. May be a good choice for patients with tics or insomnia. Clonidine and Guanfacine may be useful in over aroused, easily frustrated, highly active, or aggressive individuals
    • Guanfacine extended release (Intuniv®): Causes sedation, fatigue and hypotension. Start with 1mg, may increase by 1mg per week. Max-4mg/day. Longer half life and fewer side effects than clonidine.
    • Clonidine extended Release (Kapvay®) 0.1mg
      • Dose: 0.1mg at bedtime; titrate to a maximum of 0.4mg at bedtime
    Theories for causing ADHD

    Psychiatry Today Advisor (dated April 14, 2020) listed the following as potential causes for ADHD:
    • Journal of the American Academy of Child & Adolescent Psychiatry suggests low maternal levels of Vitamin-D can cause ADHD (odds adjusted ratio-1.53)
    • Journal of Pediatrics- maternal obesity could contribute to ADHD. Depending on maternal BMI odds adjusted ratio could be as high as 1.96
    • JAMA Network Open: nonionizing radiation, a common exposure given its source in electric appliances, power lines, and wireless network infrastructure, could be another key risk factor in ADHD development
    August Birthdays?
    New England Journal of Medicine:
    Children with August birthdays who are sent to school with a September 1st cut off are more likely to be diagnosed and medicated for ADHD, due to immature behavior. There might be an age difference of one year in the same classroom between kids born in August versus September. The researchers analyzed data from a large insurance company to make this determination. Prescription data was also utilized.

    From the available data, it looks like stimulants have the upper hand in the treatment of ADHD. The downside of those drugs is the fact they are in Schedule-2 and have significant abuse potential. Clinicians always must consider not only the pediatric patient, but the potential of drug abuse from family members.

    About 15 years ago I got a call from the elementary school nurse in the town I practiced in. She asked me to verify what Adderall-XR 15mg caps looked like. My heart sunk, as most pharmacists would question as to whether a dispensing error was made. I described a blue and white capsule with “Adderall-XR 15mg” emblazoned on. She confirmed that is what the capsule looked like, so I wondered about her question.

    She asked what the contents looks like… I described that they were small round pellets kind of like Contact® cold capsules (only us old timers understand that analogy). She went on and said, “so it is not a plain white powder”, and I told her no, it looks like pellets. Just as she suspected a family member was dumping out the medicine and replacing it with a white powder substance (probably powdered sugar) and sending them to school!

    Always consider the family circumstances when prescribing any Schedule-2 substance.

    Have a great day on the bench!!

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    ADHD Treatment with Stimulants: Let’s Not Get Too Comfortable!

    TREATMENT OF ADHD: STIMULANTS

    A little taste of history…

    Amphetamines: blocks or reverse the direction of the neurotransmitter transporters that mediate presynaptic uptake of dopamine, norepinephrine and serotonin. Treatment of ADHD began in 1936 with the approval of Benzedrine®, the racemic mixture of amphetamine (both levo and dextro). Benzedrine® was first approved as an inhaler in 1933. It took until 1959 to require a prescription. According to the AAP (American Academy of Pediatrics), at least 80% of ADHD patients will respond positively to stimulants if used in a systematic fashion. 69.3% of kids with diagnosed ADHD take medication.

    Obetrol®: was a weight loss drug that contained mixed amphetamine salts. At one time Obetrol® had two methamphetamine salts and was withdrawn in the early 1970’s.
    It was reformulated by dropping the methamphetamine but kept the same name Obetrol® for weight loss. In 1996, it was renamed “Adderall” and was approved for treatment of ADHD.

    February 9, 2005: Health Canada has suspended market authorization of ADDERALL XR™ (amphetamine salts), a drug approved for Attention Deficit Hyperactivity Disorder (ADHD) in children. This was later reversed.

    Methylphenidate: Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It was synthesized in 1944 and identified as a stimulant and approved for use in 1955. The drug was named after the researcher’s wife “Rita” who used it for low blood pressure.
    Historical note: Ritonic®: tonic of methylphenidate, hormones and vitamins, marketed as Ritonic® in 1960, intended to improve mood and maintain vitality in women.

    Psychostimulants are considered first line agents for ADHD, unless the patient has a history of:
    • substance abuse
    • bipolar disorder
    • active psychotic disorder
    The use of ADHD drugs is on the rise as more adults are being diagnosed with ADHD.

    ADULTS: 4.4% of adult population is diagnosed with ADHD, although this number is believed to be higher. There is an 85% risk of adult ADHD if diagnosed as a child.

    FDA-approved psychostimulants for the treatment of ADHD:

    Considerations before prescribing amphetamines/ methylphenidate:
    • Stimulants increase blood pressure by 3 to 4 mmHg and heart rate by 1 to 2 beats per minute, on average, in children and adolescents.
    • In adults, they can increase systolic blood pressure by about 5 mmHg. These effects raise concern that stimulants may increase the risk of cardiovascular events
    • A weekend drug holiday might be effective for managing insomnia or appetite suppression; may also be tried to reduce effect on growth, especially in patients with a family history of short stature.
    • Stimulants and atomoxetine are unlikely to increase stroke, heart attacks, or sudden death. Still, avoid them in patients with serious heart problems, or if blood pressure or heart rate increase would be a problem. Adderall was temporarily removed from the Canadian market due to these adverse effects
    • Regardless of chosen medication, monitor heart rate, blood pressure, height, and weight.
    • Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products
    • Tolerance to stimulants is unlikely. Plateau effect after first week is not tolerance.
    • Stimulant dose based on weight, disease severity, and target symptoms (hyperactivity may require higher doses than inattentiveness).
    • Long-acting medications just as effective as shorter-acting agents. Long-acting agents usually preferred for convenience and to minimize breakthrough symptoms, irritability, and headache.
    • Common side effects include anorexia, abdominal pain, insomnia, and headache.
    • Rarely, stimulants may cause psychotic symptoms such as hallucinations. Final adult height might be decreased by less than an inch
    Typical maximum dosages:
    • Methylphenidate: 30mg up to 60 mg for adults
    • Methylphenidate XR (Concerta®); 54mg children; 72mg adults
    • Daytrana® patches maximum: 30mg
    • Quillivant® maximum dose: 60mg/day
    • Dexmethylphenidate tablets: 20 mg/day. XR capsules= 30mg children; 40mg adults
    • Dextroamphetamine 40mg (rarely 60mg)
    • Lisdexamphetamine 70mg maximum
    • Mixed amphetamine: 30mg child maximum for adults 60mg
    BENEFITS of TREATMENT:
    Treatment of ADHD with stimulants and psychotherapy has been shown to decrease disruptive behaviors and improve academic performance, self-esteem, cognition, and personal relationships. In addition, it has been reported that ADHD children treated with stimulant therapy during childhood are at lower risk for drug and alcohol abuse when they are older than those who are not treated.

    REASONS TO STOP TREATMENT
    • Hallucinations
    • Delusions
    • Paranoia
    • Aggression
    • Cardiovascular adverse event
    COMMONLY PRESCRIBED METHYLPHENIDATE & AMPHETAMINE PRODUCTS:
    • Ritalin® (methylphenidate) 5mg, 10mg 20m IR. SR20 and SR-30mg caps
      • Dose: Twice daily to three times daily (morning, noon, 4 PM if needed), preferably 30 to 45 minutes before meals
    • Concerta® (methylphenidate extended release tablets) 18, 27, 36, 54 mg ER tabs
      • Dose: given once daily in the morning (without regard to meals)
    • Metadate CD® (methylphenidate extended release caps) 10, 20, 30, 40, 50, 60 mg
      • Dose: Given once daily in the morning before breakfast. May be taken whole or sprinkled over applesauce. If sprinkled over applesauce, should be used immediately
    • Daytrana® (methylphenidate transdermal patch) 1.1 mg/hr (10 mg/9 hr)--1.6 mg/hr (15 mg/9 hr) 2.2 mg/hr (20 mg/9 hr)--3.3 mg/hr (30 mg/9 hr)
      • Dose: apply (1) patch daily in the morning. Worn daily for 9 hours (apply 2 hours before desired effect). Can be worn up to 16 hours if longer effect needed. Remove at least 3 hours before bedtime.
    • Quillivant® XR oral suspension 5mg/5ml oral suspension -extended release
      • Extended release methylphenidate. Give once daily in the morning with or without food. Reconstitute with water. Shake bottle vigorously for at least 10 seconds prior to administration. Use oral dosing dispenser for administration. Store reconstituted suspension at room temp for up to 4 months
    • Quillichew® XR chewable tablets 10, 15, 20, 30 and 40mg extended release tablets
    • Focalin®: dexmethylphenidate 2.5, 5, 10mg immediate release (generic)
      • Dose: Given BID at least 4 hours apart without regard to meals
    • Focalin XR®: 5, 10, 15, 20, 25, 30, 35, 40 mg caps (generic)
      • Dose: Given once daily in the morning. May be taken whole/ sprinkled over applesauce. (may dose every 8-12 hours)
    • Aptensio XR®: methylphenidate ER capsules 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 60mg
    • Journay PM®: 20,40, 60, 80 and 100mg ER capsules
      • Extended release methylphenidate dosed before bedtime. Dose is released for morning symptoms.
    --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
    • Dexedrine®: dextroamphetamine 5 and 10mg tablets
      • Dose: Given 2 to 3 times daily. First dose upon awakening; additional doses at 4 to 6-hour intervals.
    • Adderall® mixed amphetamine salts: 5, 7.5, 10, 12.5, 15, 20, 30 mg tablets
      • Dose: Usually given once or twice daily. May give second dose 6 to 7 hours after morning dose. Consider giving larger dose in the morning. Can split max dose 3 times daily
      • Prescriber note: all strengths are same price; all tablets are scored.
    • Adderall-XR®: mixed amphetamine salts. 5, 10, 15, 20, 25, 30 mg ER caps
      • Dose: Given once daily in the morning without regard to meals. May be taken whole or sprinkled on applesauce. Consume immediately
    • Vyvanse® (lisdexamfetamine) 20, 30, 40, 50, 60, 70 mg caps
      • is a pro-drug broken down when taken orally to the active form (dextroamphetamine). This limits its abuse potential when used IV or intranasally.
      • Dose: Given once daily in the morning without regard to meals. May be taken whole or contents dissolved in glass of water. Consume immediately.
      • VYVANSE for B.E.D.: Vyvanse is the first and only medication approved to treat moderate to severe Binge Eating Disorder in adults. It is NOT a weight loss drug, but rather for adults who have been diagnosed with moderate to severe B.E.D.
    • Mydayis®: Extended-release capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg
      • long-acting Mixed Amphetamine salts lasts 16 hours after dosing. For ADHD in patients 13 years and older. Not to be used in children 12 years and younger.
    I find it fascinating that stimulants were used for a number of years before they even required a prescription. After the Controlled Substance Act of 1970, it became one of the highest regulated prescription drugs, landing in Schedule-2! Amphetamines have a most interesting history from their discovery in the mid 1930’s to the homemade meth labs in the 2000’s.

    My students, both pharmacy and Physician Assistant, are amazed to realize that this methamphetamine is not some home-made clandestine drug, but rather is still available as a prescription product. I remember dispensing Desoxyn® and Desoxyn® Gradumets by Abbott Labs for weight loss.

    In the early 1990’s, the prescribing and dispensing of amphetamines as weight loss drugs fell out of favor. In the mid and late 1990’s a resurgence of amphetamine prescribing occurred as a treatment for ADHD. My daughter Elizabeth, an elementary school teacher, tells me she can tell the morning the kids miss a dose of their ADHD meds as they become completely unglued.

    Personally, these drugs scare me. In 2002, a local Boy Scout died at Summer Camp while taking his prescribed amphetamines for ADHD. The pharmacy where he got the prescription from was turned upside down, the summer camp was investigated, and the physician was scrutinized. The camp was ultimately sued (and found liable) for not having a defibrillator on site.

    Seeing a 12-year-old boy in a casket wearing his Boy Scout uniform has given me a great deal of respect and fear for this class of drugs. I believe that it is important, then, for pharmacists to understand both the history and current landscape surrounding the use of these drugs:

    Have a great day on the bench!!

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    Diagnosis of Attention Deficit/Hyperactivity Disorder

    DIAGNOSIS OF ATTENTION DEFICIT/HYPERACTIVITY DISORDER

    Since many of our patients and a few of us are “quarantined”, and I have a daughter who teaches in the elementary and middle schools, I thought It would be timely to cover under our Mental Health unit the diagnosis and treatment of ADHD.

    BACKGROUND: What’s in a name??

    Up until 1987, this condition was called attention deficit disorder (ADD), but this is an outdated term. The term was once used to refer to someone who had trouble focusing but was not hyperactive. Since 1987, ADHD is the term used by the American Psychiatric Association.

    ADHD affects between 5% of all children (American Psychiatric Association) and 11% (CDC’s number) possibly as many as 6.4 million American children. Boys are more likely to be diagnosed with ADHD than girls (12.9% compared to 5.6%)

    DIAGNOSIS
    There are three types of ADHD:
    • inattentive (trouble focusing, following instructions, and finishing tasks)
    • hyperactive-impulsive (constantly on the go, talking excessively, and interrupting others)
    • combined (symptoms of both inattention and hyperactivity-impulsivity)
    To meet the diagnostic criteria according to the DSM-5 (Diagnostic and statistical Manual of psychiatric disorders) a few aspects must be considered to meet a diagnosis of ADHD:

    Inattention: Six or more symptoms of inattention for children up to age 16 years, or five or more for adolescents age 17 years and older and adults; symptoms of inattention have been present for at least 6 months, and they are inappropriate for developmental level:
    1. Has lack of detail or makes careless mistakes.
    2. Has difficulty paying attention.
    3. Doesn't pay attention when spoken to directly.
    4. Doesn't follow instructions or fails to complete homework or other tasks.
    5. Often seems disorganized.
    6. Avoids tasks requiring sustained mental effort or concentration.
    7. Often loses things needed for tasks (toys, pencils, homework).
    8. Becomes easily distracted.
    9. Is forgetful.
    Hyperactivity/Impulsivity: Six or more symptoms of hyperactivity-impulsivity for children up to age 16 years, or five or more for adolescents age 17 years and older and adults; symptoms of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for the person’s developmental level:
    1. Often fidgets, taps hands, squirms in seat.
    2. Gets up and moves around during activities in situations when remaining seated is expected.
    3. Often runs or climbs in inappropriate situations.
    4. Is unable to play quietly.
    5. Seems "driven by a motor."
    6. Talks excessively.
    7. Blurts out answers before complete question is given.
    8. Can't seem to wait for his or her turn.
    9. Interrupts or intrudes others often.
    In addition, the following conditions must be met:
    • Several symptoms were present before age 12 years.
    • Several symptoms are present in two or more setting (such as home/school/work).
    • Symptoms interfere with, or reduce the quality of, social, school, or work functioning.
    • Ruled out other mental health disorders, situational or physical conditions.
    More severe cases of ADHD in children, as described by parents, were diagnosed earlier.
    • The median age of diagnosis for severe ADHD was 4 years.
    • The median age of diagnosis for moderate ADHD was 6 years.
    • The median age of diagnosis for mild ADHD was 7 years.
    When I begin this unit with my didactic class at St. Francis, I playfully ask the women in class “After a rough day in kindergarten, how many of you came home and lined up all of your doll babies, and siblings and played school.” Invariably almost every one of the women’s hands go up. When I ask the exact same question of the men, never in 15 years did a hand go up indicating that they went home and played school! I often say that classroom learning was never designed for boys and the numbers associated with ADHD seem to bear that out.

    I detested school as a kid. I would cry every morning before kindergarten and not want to go. When I see what my granddaughter learns in kindergarten, I wouldn’t have a chance today. Back in 1963 kindergarten consisted of a workbook, where you would circle the biggest house; nap time, cookies and milk, play in the sawdust box and go home. Today, Regina is learning sight words and how to add! When I graduated from Pitt in 1981 my mother hugged me and said of all her kids, she figured I would be the last one to stay in school this long! I often wonder what Mom thinks when she looks down from above and sees me going to school on Thursday mornings at St. Francis!

    Have a great day on the bench!!

    April 2020

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    Covering the Hypnotics that Work on the Benzodiazepine Receptor... Let the Chloride Rush In!

    COVERING THE HYPNOTICS THAT WORK ON THE BENZODIAZEPINE RECEPTOR

    Hypnotics working on the benzodiazepine (BZ) receptor:

    Mechanism: The GABA(A)-(gamma-aminobutyric acid type A) receptors are the major inhibitory neuronal receptors in the mammalian brain. Their activation by GABA opens the intrinsic ion channel, enabling chloride to rush into the cell causing hyperpolarization. Chloride is the major inhibitory ion in the CNS. The major isoform of the GABA-A subunit contains alpha, beta, and gamma subunits. The alpha1-containing BzR (benzo receptor) have been proposed to be responsible for the sedative action; the alpha2 and/or the alpha3 subtypes are responsible for the anxiolytic properties.

    Selected benzodiazepine hypnotics:

    Temazepam (Restoril®) capsules 7.5mg, 15mg, 22.5mg and 30mg
    • Most commonly used BZ hypnotic
    • Half-life is 3.5-18 hours
    • NOTE: one of the safer choices in its class for the elderly, as it is less like to accumulate. Metabolized by conjugation. Less dependent on global liver function.
    Estazolam (Prosom®) tablets 1mg and 2mg
    • Half-life is 8-28 hours
    Triazolam (Halcion®) tablets 0.125mg and 0.25mg
    • Very short acting. Peak 1-2 hours, with a half-life is 1.5 to 5.5 hours
    • Side effects: anterograde amnesia, sleep rebound
    THE “Z” Hypnotics= Zolpidem (Ambien®), Zaleplon (Sonata®), Eszopiclone (Lunesta®)
    [04-30-2019] The Food and Drug Administration (FDA) is advising that rare but serious injuries have happened with certain common prescription insomnia medicines because of sleep behaviors, including sleepwalking, sleep driving, and engaging in other activities while not fully awake (making phone calls, having "sleep sex", or preparing and eating food). These complex sleep behaviors have also resulted in deaths. These behaviors appear to be more common with eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien) than other prescription medicines used for sleep. All received a black box warning.
    • Mechanism: Basically, they all selectively attach to the GABA-BZ receptors found in close proximity to the benzodiazepine receptors. Specifically, they bind to GABA receptor complex located on the alpha subunit (BZ receptor). They are not benzodiazepines.
    Zolpidem (Ambien®) Schedule-IV
    Is an imidazopyridine, available as 5mg and 10 mg tablets, as well as extended release formulations:
    Ambien CR® 6.25 and 12.5mg. All formulations are generically available.
    • Usual adult dose: 10mg (12.5mg-CR) at bedtime. If elderly or debilitated or female start with 5mg. Don’t exceed the maximum dose of 10mg (12.5mg CR)
    • Peak after administration is 1.6hr. Half-life = 2.6hr (average)
    • Very little rebound insomnia upon discontinuation. Very little withdrawal syndrome.
    • Very little effect on sleep stages. Preserves deep sleep stages (3 & 4)
    • Pregnancy: Category- B
    Feb2018: FDA release: FDA has informed the manufacturers that the recommended dose of zolpidem for women should be lowered from 10 mg to 5 mg for immediate-release products. FDA recommends that the bedtime dose be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving.

    Zaleplon (Sonata®) Schedule-IV
    Is a pyrazolopyridine, available as 5mg and 10mg capsules. Generic formulations are available.
    • Usual adult dose: 10mg at bedtime. If elderly or low weight start with 5mg. Take right at bedtime OR may take if having trouble falling asleep.
    • Maximum dose: 20mg if patient does not benefit from a trial of lower dose.
    • High fat meal does decrease absorption, and therefore reduce effect of Sonata on sleep latency.
    • Peaks within 1 hour of oral administration. Mean half-life= 1 hour
    • Little rebound insomnia. Has been reported in patients taking the 20mg dose. Was resolved by the second night.
    • Amnesia: may be caused by Sonata, which can be avoided if patient is able to get over 4 hours of sleep. Pregnancy: Category-C
    • Most common use: Zaleplon is the drug of choice for sleep lab studies.
    Eszopiclone (Lunesta®) tablets 1mg, 2mg 3mg Schedule IV (available 12/15/04)
    Is a cyclopyrrolone, available as 1mg, 2mg, and 3mg tablets. Generic formulations are available.
    • Usual adult dose: starting- 2mg immediately before bedtime. May increase to 3mg if indicated, which is more effective for sleep maintenance.
    • Elderly: starting: 1mg immediately before bedtime. May increase to 2mg. If can’t stay asleep, recommended dose is 2mg.
    • High fat meals decrease absorption & reduce effect upon sleep latency
    • Drug interactions: Cytochrome CP3A4 inhibitors start with 1mg. May increase to 2mg only if needed.
    • Onset of action= 60minutes, with a half-life = 6 hours
    • Precautions: drug will cause withdrawal symptoms if discontinued rapidly.
    • Pregnancy Category-C
    • Eszopiclone works quickly and should be taken right before bed because of risk of falling.
    • Avoid alcohol. Will increase side effects.
    • Do not take unless you are able to get 8 or more hours of sleep, before you must be active again.
    • Eszopiclone does not lose effectiveness over 6 month and was the first prescription sleep aid approved for long term use.

    We pharmacists love our mechanisms of action. What subunit do the Z-hypnotics bind to? They are not benzodiazepines …to me they work on the benzo receptor, they cause patients to sleep, patients must avoid alcohol, and they allow chloride to influx into the GABA channel.

    If it looks like a duck, and walks like a duck… well, you get the message!

    I’m not terribly comfortable with the amounts of the hypnotics we dispense. My sister who is an amazing nurse told me at one time they would dispense Chloral Hydrate (Noctec®) along with a shot of bourbon at the hospital in the early 1980’s. She said her floor was as quiet as the catacombs! This is referred to in the movies as “slipping a Mickey Finn.”

    I had a female patient who, during the night, fell down her basement steps and went back to bed, with a fractured wrist.

    My wife had a patient who got up in the morning with brownie batter all over her pajamas. She woke up during the night and started mixing a batch of brownies in the kitchen and went back to bed. Thank heavens she didn’t turn on the stove!

    I’m a believer in good sleep hygiene and adjusting one’s lifestyle to sleep patterns. We need to knock off the computers and gray screens a couple of hours before bed, one of the biggest reasons teenagers do not sleep as much. We must also control our diet and exercise; we are often mentally tired but seldom physically tired. I won’t lay in bed more than 15 minutes if I can’t fall back to sleep.

    On those mornings when I’m unable to sleep, I say “insomnia is God’s gift to busy people.” Next week we will cover the sleep aids that do not work on the benzo receptors.

    Have a great day on the bench!!

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    Still not sleeping... these drugs don't work on the GABA receptor.

    HYPNOTICS NOT WORKING AT THE GABA RECEPTOR

    Melatonin receptor agonists:
    Melatonin is a hormone synthesized in the pineal gland, collected by the venous capillary system, then secreted into the cerebrospinal fluid and the venous systemic circulation. It is produced from tryptophan. In the brain, melatonin appears to increase the binding GABA to its receptors by affecting membrane characteristics, not by increasing the number of receptors. No surprise that the pineal gland starts to function after 6 months, when babies start sleeping during the night. Pineal gland function declines as we age… no surprise their either!
    • MT1 receptor: activation of the MT1 receptor causes sleepiness
    • MT2 receptor: activation is related to light-dark synchronization, causing our natural circadian rhythms.
    Ramelteon (Rozerem®)
    available as 8mg tablets ($466.00/month) (generic= $120.00/month)
    Mechanism: selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus, inhibiting the neuronal firing that maintains wakefulness. Is NOT a CNS depressant. It is not a scheduled drug. Ramelteon shows no evidence of abuse, dependence or withdrawal, or rebound insomnia.
    Indications: for insomnia characterized with difficulty of sleep onset. Can be prescribed long term.
    Avoid in patients with severe hepatic impairment or taking fluvoxamine (Luvox®). Avoid with alcohol. May cause increased prolactin levels, and decreased testosterone levels. Patient information:
    • Take 30 minutes before bed and activities confined to preparing for bed.
    • Avoid hazardous activity (driving etc.) after taking
    • Do not take with, or immediately after a high fat meal.
    • Report cessation of menses, galactorrhea, decreased libido, and fertility problems.

    Melatonin (available OTC)
    cost about $10/month
    Available as 1mg, 3mg 5mg and 10mg capsules/tablets Melatonin is non-scheduled, non-habit forming Dose 1 to 10mg at bedtime. Don’t exceed 10mg.
    There is a slight increase for bleeding risk with melatonin. Monitor in suspect patients, frail, elderly, or patients that are anticoagulated.
    Jet lag: Melatonin can improve some symptoms of jet lag, such as alertness and psychomotor performance, may also be useful for daytime sleepiness and fatigue. Think of interaction with MT2 receptor.
    Might not be effective for decreasing sleep latency.

    Hetlioz® (tasimelteon)
    (cost about $10,000/month)
    Is another melatonin agonist that is only approved for non-24 sleep-wake disorder, where patients can't synchronize their internal clock to the 24-hour light-dark cycle. It occurs in over half of blind people, rarely in sighted people.
    Hetlioz increases nighttime sleep in blind patients about same as melatonin (28 minutes) at a cost of $10,000/MONTH.
    Do not prescribe Hetlioz for sighted or blind patients who don't have non-24.

    Antihistamines
    Diphenhydramine (Benadryl®), Tylenol PM®, Nytol®, Sominex®, Simply Sleep®
    Contain 25mg of diphenhydramine as an OTC sleep aid.
    Dose 50mg mg at bedtime. (generally, 25mg is adequate)
    Side effects: drowsiness, anticholinergic side effects, avoid in older males.
    Evidence: There is little evidence that diphenhydramine improves insomnia. Will also cause daytime sedation the next day. Use of diphenhydramine to treat insomnia is not recommended, especially for long term use.

    DRUGS FOR SLEEP MAINTENENCE

    Tricyclic Antidepressant
    Doxepin (Silenor)
    3mg and 6mg tablets (cost: $500.00/30tab) (30 Doxepin 10mg=$14.00/30)
    USE: Very low dose anti-depressant that is used for insomnia. It increases sleep time by 30 minutes and is most useful for patients having trouble staying asleep. Doesn’t help with sleep INDUCTION, just maintenance. Prescribing low dose doxepin (10mg) is a cheaper alternative than using Silenor or it’s expensive generic. The generic Silenor currently costs $400 for 30 tablets.

    Orexin receptor antagonist
    BELSOMRA (suvorexant)
    FDA approved Aug 14, 2014 Schedule- IV
    Dose: 5mg, 10mg,15mg, 20mg available (approx. $440/month)
    Start with 10mg, may increase to a max of 20mg if tolerated. Start with 5mg if CYP450-3A4 blocking drug.
    Indication: for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance
    Mechanism: is a highly selective antagonist for orexin receptors. Orexin is a neurotransmitter found in a specific part of the brain that can help keep a person awake. The mechanism by which BELSOMRA exerts its therapeutic effect is presumed to be through antagonism of orexin receptors.
    Precautions: A variety of cognitive, behavioral changes and other neuro-psychiatric symptoms, such as halucinations and amnesia have been reported to occur in association with the use of hypnotics. “Sleep driving” and other complex behaviors (preparing and eating food, making phone calls, or having sex), with amnesia for the event have been reported with the use of hypnotics.

    This class of drugs does not have any action at the GABA receptor, so it seems they could be safer. They seem to be a lot less habit forming and have a niche for patients that might have some abuse potential. Their high prices frequently require prior authorizations when prescribed.

    For the most part melatonin over the counter and doxepin low dose are the cheapest alternatives in this class. Don’t forget to remind your patients to practice good sleep hygiene:
    • Regular waking time (set alarm!) including weekends.
    • Go to bed only when sleepy. Avoid trying to “force sleep.”
    • Avoid daytime naps.
    • Exercise, but not within 1 hour of bedtime.
    • Sleep in a cool room (avoid temperature extremes).
    • Avoid alcohol and stimulants before bedtim (including chocolate, coffee, soda, etc).
    • Avoid stressful arguments.
    • Bedroom is for sleeping and sex.
    • NO TV, computers, or reading. AVOID GRAY SCREENS!
    • Schedule “worry time” during the day. Do not take your troubles to bed.
    • Avoid excess fluids in the evening, to avoid restroom trips.
    • Do something relaxing and enjoyable before bed.

    Have a great day on the bench!!

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    IF WE ARE TO HOLD BENZODIAZEPINES, WHAT IS LEFT TO TREAT ANXIETY?

    Non-habit forming anxiolytics:

    Buspirone (Buspar®) (FDA approved:1986)
    Mechanism: Is an azapirone, with no GABA receptor interaction. Buspirone interacts primarily with serotonin (5-HT31a) and dopamine and blocks alpha adrenergic receptors.

    Dosage: Initial dose: 15mg /day, may increase 5mg every 2 or 3 days. Don’t exceed 60mg.
    COMMON USES of Buspirone
    • Augment the effects of SSRI
    • Improves SSRI induced sexual dysfunction.
    • Long term anxiety control
    Worth knowing about buspirone
    • Not a Benzodiazepine, no anticonvulsant effect, no muscle relaxant effect.
    • Food does affect absorption, so take it at consistent times. May take with food to avoid GI upset.
    • No sedation. Slight chance of drowsiness.
    Link with href-->

    March 2020

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    SELECTION OF SECOND-GENERATION ANTIPSYCHOTICS

    April 2005: Black box warning on all atypical antipsychotics concerning “sudden death” due to use of these drugs in elderly patients, when used for “behavior” problems. Use with caution in debilitated or elderly patients. Black box warning below applies to ALL atypical antipsychotics. (Below is the black box warning for Zyprexa ®):

    Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks) in these patients revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. ZYPREXA (olanzapine) is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS).

    Time of effective results: Although many drugs may reach “steady state” in a matter of a few days, allow 4 to 6 weeks for drug to take effect.

    NON-ADHERENCE: Long acting salts: ideal for noncompliant patients.
    • Haloperidol (Haldol®) decanoate 50mg and100mg/mL (every 4 weeks)
    • Fluphenazine (Prolixin®) decanoate 25mg/mL (every 3 weeks)
    • Risperidone (Risperdal®) consta: 25, 37.5 or 50mg (every 2 weeks)
    • Aripiprazole (Abilify Maintena®) 400mg IM/month
    • Olanzapine pamoate (Zyprexa Relprevv®) 100-300mg every 2 weeks or 300mg-405mg every month.
    • Paliperidone (Invega Sustenna®) 117-234mg per month
    • Paliperidone (Invega Trinza®) 410-819mg every 3 months
    FDA-Approved Adult Indications for Atypical Antipsychotics (cms.gov)

    INDICATION ATYPICAL ANTIPSYCHOTICS
    Bipolar-1 disorderaripiprazole, asenapine, olanzapine, quetiapine, quetiapine extended-release (XR), risperidone, ziprasidone
    Bipolar depressionlurasidone, olanzapine, quetiapine, quetiapine XR
    Schizophreniaaripiprazole, asenapine, brexpiprazole, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, quetiapine XR, risperidone, ziprasidone
    Schizoaffective disorderclozapine, paliperidone
    Adjunct to Major Depressive Disorderaripiprazole, brexpiprazole, olanzapine, quetiapine XR
    Tapering doses: must be done gradually, watching for signs of re-occurrence. Reduce dose after acute episode, slowly and gradually reduce to lowest effective dose. Abrupt withdrawal may precipitate relapse.

    Monitoring of metabolic parameters:
    Many psych clinics are aware of the metabolic effects of the second-generation antipsychotics. Clinicians MUST be cognizant of the diabetes, obesity and dyslipidemias that these drugs can cause.
    • Clozapine and Olanzapine are the biggest offenders
    • Risperidone, Iloperidone and Quetiapine cause moderate weight gain
    • Aripiprazole, Ziprasidone, Asenapine, Paliperidone, Lurasidone are considered to be “weight neutral”
    Monitoring recommendations:
    • Weight: check at baseline and then 1, 2, and 3 months after starting or changing therapy and then every 3 months.
    • Fasting glucose and blood pressure: check at baseline, 3 months, and then at least annually.
    • Lipids: check at baseline, 3 months, then every 5 years if normal. Because of risk factors, however it is wise to check lipid parameters annually. NOTE: diabetes and hyperlipidemia been noted in patients who have not had significant weight gain.
    • Waist measurement: check at baseline, then annually
    Consider switch to different antipsychotic if glucose or lipids worsen or if patients have more than a 5% weight gain.

    SEXUAL SIDE EFFECTS:
    • 60 to 70 percent of patients taking paliperidone and risperidone experienced sexual side effects. (no surprise-think prolactin)
    • 50 to 60 percent of those on olanzapine, quetiapine, and ziprasidone
    • Less than 50 percent on clozapine
    • 16 to 27 percent on aripiprazole
    OTHER STUFF: There is little clinical evidence to support the use of combination therapy of antipsychotic drugs within the same class. The atypical antipsychotics may range in cost from $10 to $1200 per month. Some studies have shown evidence that prescribing 2 or more atypical antipsychotics increases the occurrence of extrapyramidal symptoms.

    PREGNANCY
    • Limited data available for 1st and 2nd generation antipsychotics in pregnancy
    • Chlorpromazine (Thorazine®) was at one time used for morning sickness, without causing reported teratogenesis
    • Only clozapine (Clozaril®) and lurasidone (Latuda®) have received a Category-B rating from FDA
    • Risk of weight gain which may be problematic in pregnancy are greater with second generation anti-psychotics

    CONDITION BEST CHOICE WORST CHOICE (AVOID)
    Minimize weight gainAripiprazole, Lurasidone, Asenapine, ZiprasidoneClozapine (worst), Olanzapine (worst), Quetiapine
    Minimize Extrapyramidal SymptomsQuetiapine, IloperidoneRisperidone, Paliperidone
    Minimize QT prolongationAripiprazole, Lurasidone, OlanzapineZiprasidone, Iloperidone, Paliperidone
    Minimize HyperprolactinemiaRisperdone, Paliperidone
    Minimize SedationAripiprazole, Risperidone, Paliperidone, Ziprasidone
    Treatment of Agitation or Treat insomniaOlanzapine, Quetiapine
    COST (for brevity brand names are listed)Risperidone, Clozapine, Olanzapine, Quetiapine, Aripiprazole, Paliperidone, & Ziprasidone are available genericallyAsenapine, Iloperidone, Lurasidone, Brexpiprazole, Cariprazine are still brand

    One of my students from St. Francis University took a job at Western Psychiatric Clinic in Pittsburgh after graduation. In her years there she never wrote for an anti-psychotic medication; that was the job of the psychiatrists!

    What she was responsible for was the management of the side effects that were caused by the medications that were written for. She was kept very busy monitoring the metabolic parameters for the second-generation antipsychotics. She would start patients on metformin, glipizide, and statin therapy as they developed Type-2 diabetes.

    She was a great asset to the treatment team, as most psychiatrists are not comfortable with the monitoring and management of the metabolic problems caused by the therapies that the prescribe. It gives me great appreciation of the side effect profiles of this whole class of drugs.

    Now that we are comfortable with the second-generation antipsychotics regarding their efficacy, let’s look at what separates them. Most feel it is the side effect profiles that separate these drugs. We’ll discuss the major parameters that separate this class of drugs. For the sake of brevity, I’ll use generic names on the charts.

    Have a great day on the bench!!


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    Switching antidepressants require knowing their mechanism of action. AntiDepressants and weight gain and pregnancy.

    SWITCHING METHODS for ANTIDEPRESSANT THERAPY

    Direct switch
    From one SSRI to another SSRI, venlafaxine (Effexor), or duloxetine (Cymbalta).
    • Can switch from paroxetine (Paxil) to sertraline (Zoloft), the next day.
    • Switching from fluoxetine (Prozac) should wait 4 to 7 days because of its long half-life. Then start another SSRI with low dose. Monitor for signs of exacerbation of depression.

    Cross-tapering
    Gradually reduce the dose of the old drug while simultaneously increase the dose of the new drug. Use when switching to meds with a different mechanism. Usually takes 1-2 weeks.
    • Such as switching from an SSRI to bupropion (Wellbutrin) or mirtazapine (Remeron).
    • Cross-tapering is also a good idea when switching from paroxetine (Paxil) or venlafaxine (Effexor). Because of short half-life may cause discontinuation symptoms.
    • When cross-tapering, new symptoms can be due to THREE different causes.
      • Discontinuation symptoms from stopping the first drug.
      • Side effects from the new drug.
      • Depression or anxiety symptoms because neither drug is working.
    Wash out
    A wash-out period is necessary when switching to or from an MAO inhibitor. Only after a 4 to 8-week trial of an antidepressant, switching is recommended. For partial responders you can choose between switching OR addition of a second agent.
    • MAOI to tricyclic: wait 2 to 3 weeks between stopping one drug and starting another.
    • SSRI to MAOI: wait 4 to 5 weeks
    • Elderly patients will tolerate a switch to venlafaxine (Effexor) rather than addition of Lithium, bupropion (Wellbutrin) or liothyronine (Cytomel)
    • Within the 3 groups anti-depressant response may be augmented by: Under psychiatric consult use Lithium or liothyronine (Cytomel 25mcg) (liothyronine-T3).
    WEIGHT GAIN on Antidepressants:
    Weight gain is problematic antidepressant therapy. As far as side effects sexual dysfunction (17%) and drowsiness (17%) with weight gain being third most common problem at 12%. Weight gain can be attributed to carbohydrate craving and improved appetite as patients experience remission of depression.
    Patients gain an average of 6 pounds on mirtazapine (Remeron) or paroxetine (Paxil)
    Weight-neutral SSRIs: suggest fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), or escitalopram (Lexapro).
    Weight loss antidepressant: Bupropion (Wellbutrin) is associated with about a 6 lb. weight LOSS

    MAINTENANCE:
    If first episode is after age 50 or before age 20, or 3 episodes at any age. Keep on indefinitely. If tapering is decided, reduce over several months, monitoring for relapse.

    TREATMENT OF DEPRESSION IN PREGNANT PATIENTS
    Depression occurs in 14-23% of pregnant women.
    Key points:
    • ALL SSRI are Pregnancy Category-C except Paxil (paroxetine) Cat-D
    • ALL SNRI are Pregnancy Category-C
    • TCA anticholinergic effects and toxicity in overdose limit usefulness


    Are seeing a 2-fold increase in cardiac congenital malformations. 2% (paroxetine exposed) vs 1% Persistent pulmonary hypertension: increase risk if SSRI used after 20th week. Poor neonatal adaptation: rapid breathing, hypoglycemia, Irritability, weak/absent cry, and seizures are seen in 15-30% of babies born to Moms taking SSRI in 3rd trimester.
    • Tapering SSRI in 3rd trimester leads to antepartum and/or postpartum depression.
    TREATMENT:
    Cognitive therapy is a must, before conception and during pregnancy.
    • Fluoxetine (Prozac) well studied, long half-life may cause accumulation. Increased risk of withdrawal symptoms after birth.
    • Stopping pharmacotherapy should be only attempted in women who do not have a history of severe recurrent depression. Do not consider stopping antidepressants if woman is suicidal, other concurrent psychiatric conditions or functional incapacitation.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560196

    No topic in the clinic seems to be discussed more than the switching of antidepressants. Some meta-analysis showed antidepressants no more effective than placebo. However, in a 2018 article in the Lancet showed that antidepressants are indeed more efficacious versus placebo, but that was during the first 8 weeks of study.

    The data supporting long term effectiveness of antidepressants doesn’t seem so robust. Because of these efficacy issues, we frequently switch antidepressants looking for one that will benefit our patients.

    Knowing how to switch antidepressants is a necessary skill in the family practice clinic.

    Have a great day on the bench!!

    March 2020

    Micro-Learning CE Associated - Click Here For Details

    Switching antidepressants require knowing their mechanism of action. AntiDepressants and weight gain and pregnancy.

    SWITCHING METHODS for ANTIDEPRESSANT THERAPY

    Direct switch
    From one SSRI to another SSRI, venlafaxine (Effexor), or duloxetine (Cymbalta).
    • Can switch from paroxetine (Paxil) to sertraline (Zoloft), the next day.
    • Switching from fluoxetine (Prozac) should wait 4 to 7 days because of its long half-life. Then start another SSRI with low dose. Monitor for signs of exacerbation of depression.

    Cross-tapering
    Gradually reduce the dose of the old drug while simultaneously increase the dose of the new drug. Use when switching to meds with a different mechanism. Usually takes 1-2 weeks.
    • Such as switching from an SSRI to bupropion (Wellbutrin) or mirtazapine (Remeron).
    • Cross-tapering is also a good idea when switching from paroxetine (Paxil) or venlafaxine (Effexor). Because of short half-life may cause discontinuation symptoms.
    • When cross-tapering, new symptoms can be due to THREE different causes.
      • Discontinuation symptoms from stopping the first drug.
      • Side effects from the new drug.
      • Depression or anxiety symptoms because neither drug is working.
    Wash out
    A wash-out period is necessary when switching to or from an MAO inhibitor. Only after a 4 to 8-week trial of an antidepressant, switching is recommended. For partial responders you can choose between switching OR addition of a second agent.
    • MAOI to tricyclic: wait 2 to 3 weeks between stopping one drug and starting another.
    • SSRI to MAOI: wait 4 to 5 weeks
    • Elderly patients will tolerate a switch to venlafaxine (Effexor) rather than addition of Lithium, bupropion (Wellbutrin) or liothyronine (Cytomel)
    • Within the 3 groups anti-depressant response may be augmented by: Under psychiatric consult use Lithium or liothyronine (Cytomel 25mcg) (liothyronine-T3).
    WEIGHT GAIN on Antidepressants:
    Weight gain is problematic antidepressant therapy. As far as side effects sexual dysfunction (17%) and drowsiness (17%) with weight gain being third most common problem at 12%. Weight gain can be attributed to carbohydrate craving and improved appetite as patients experience remission of depression.
    Patients gain an average of 6 pounds on mirtazapine (Remeron) or paroxetine (Paxil)
    Weight-neutral SSRIs: suggest fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), or escitalopram (Lexapro).
    Weight loss antidepressant: Bupropion (Wellbutrin) is associated with about a 6 lb. weight LOSS

    MAINTENANCE:
    If first episode is after age 50 or before age 20, or 3 episodes at any age. Keep on indefinitely. If tapering is decided, reduce over several months, monitoring for relapse.

    TREATMENT OF DEPRESSION IN PREGNANT PATIENTS
    Depression occurs in 14-23% of pregnant women.
    Key points:
    • ALL SSRI are Pregnancy Category-C except Paxil (paroxetine) Cat-D
    • ALL SNRI are Pregnancy Category-C
    • TCA anticholinergic effects and toxicity in overdose limit usefulness


    Are seeing a 2-fold increase in cardiac congenital malformations. 2% (paroxetine exposed) vs 1% Persistent pulmonary hypertension: increase risk if SSRI used after 20th week. Poor neonatal adaptation: rapid breathing, hypoglycemia, Irritability, weak/absent cry, and seizures are seen in 15-30% of babies born to Moms taking SSRI in 3rd trimester.
    • Tapering SSRI in 3rd trimester leads to antepartum and/or postpartum depression.
    TREATMENT:
    Cognitive therapy is a must, before conception and during pregnancy.
    • Fluoxetine (Prozac) well studied, long half-life may cause accumulation. Increased risk of withdrawal symptoms after birth.
    • Stopping pharmacotherapy should be only attempted in women who do not have a history of severe recurrent depression. Do not consider stopping antidepressants if woman is suicidal, other concurrent psychiatric conditions or functional incapacitation.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560196

    No topic in the clinic seems to be discussed more than the switching of antidepressants. Some meta-analysis showed antidepressants no more effective than placebo. However, in a 2018 article in the Lancet showed that antidepressants are indeed more efficacious versus placebo, but that was during the first 8 weeks of study.

    The data supporting long term effectiveness of antidepressants doesn’t seem so robust. Because of these efficacy issues, we frequently switch antidepressants looking for one that will benefit our patients.

    Knowing how to switch antidepressants is a necessary skill in the family practice clinic.

    Have a great day on the bench!!

    Micro-Learning CE Associated - Click Here For Details

    Let's just call them first generation antipsychotics! They have been around as long as I have!

    DOSAGE EQUIVALENTS AND SIDE EFFECTS OF TYPICAL ANTIPSYCHOTICS (FIRST GENERATION ANTIPSYCHOTICS)

    DRUG NAME YEAR EQUIV DOSE USUAL ADULT DOSE SIDE EFFECT SIDE EFFECT SIDE EFFECT
    EPS AC SED
    Chlorpromazine (Thorazine®) 1957 100mg 30-800mg ++ ++ +++
    Fluphenazine (Prolixin ) 1959 2mg 1-40mg ++++ + +
    Mesoridazine (Serentil®) 1970 50mg 100mg-400mg + +++ +++
    Perphenazine (Trilafon®) 1957 10mg 12-64mg ++ + +++
    Thioridazine (Mellaril®) 1962 100mg 150-800mg + +++ +++
    Trifluoperazine (Stelazine®) 1959 5mg 2-15mg +++ + +
    Thiothixine (Navane®) 1967 4mg 6-60mg +++ + +
    Molindone (Moban®) 1974 10mg 20-150mg ++ + +
    Loxapine (Loxitane®) 1975 10mg 20-250mg ++ + +
    Haloperidol (Haldol®) 1967 2mg 1-1000mg ++++ + +


    SIDE EFFECT ABBREVIATIONS:
    EPS: extrapyramidal side effects
    AC: anticholinergic side effects-note the more anticholinergic side effects, the less EPS
    SED: sedation or drowsiness.

    Prescribing notes:
    • These first-generation agents work in the central nervous system by blocking dopamine-2 (D2) receptors, which have the potential to interfere with dopamine transmission via the nigrostriatal tract and cause Parkinson like side effects.
      • perphenazine (Trilafon®) has a lower rate of extrapyramidal symptoms than the high-potency haloperidol and fluphenazine
    • In general, efficacy in treating patients with schizophrenia is similar for all of these agents. They differ by side effect profiles.
    • First generation antipsychotics are implicated with weight gain, possibly due to:
      • Increased appetite due to serotonin 5-HT2 receptor and dopamine D2 receptor blockade
      • Increased sedation and decreased physical activity due to histamine H1 receptor blockade
      • Weight gain: antipsychotic induced weight gain does not appear to be dose related
      • Pharmacodynamic profile of second-generation antipsychotics (5-HT2A antagonism, fast D2 dissociation, 5-HT1A agonism).
      • The main differences between first and second-generation antipsychotics (from a receptor binding perspective)is First-generation antipsychotics have significant potential to cause extrapyramidal side effects and tardive dyskinesia


    MAJOR SIDE EFFECTS
    Tardive dyskinesia:
    abnormal involuntary stereotyped movements of the face, mouth, trunk and limbs. May occur months or years (usually) after treatment. Affects 20-35% of treated patients. See a cumulative rate of 5% per year. They may be progressive and eventually become disfiguring. Predisposing factors: older age, years of treatment, cigarette smoking & diabetes Emphasis is on prevention.

    Prolactin Elevation:
    All typical antipsychotics elevate prolactin levels, apparently through blockade of tuberoinfundibular dopamine, allowing uninhibited secretion of pituitary prolactin. Remember dopamine puts the brakes on prolactin, therefore blocking dopamine allows prolactin to be released in higher amounts. Prolactin levels two to three times higher than normal are seen. Elevated prolactin levels cause menstrual irregularities, infertility, galactorrhea, loss of libido, and erectile and ejaculatory dysfunction.

    Extrapyramidal symptoms:
    Akathisia most common (20%). Usually occurs early and frequently mistaken for anxiety or exacerbation of psychosis. Characterized by the desire to be in constant motion, followed by the inability to sit or stand still, and consequent pacing. Increase incidence in women who smoke.

    I tell my class at St. Francis that “these are the typical antipsychotics, that we atypically use; and the atypical antipsychotics we typically use in practice today.” I prefer the new term first generation antipsychotics and the second-generation antipsychotics.

    This class of drugs as discussed last week is responsible for the emptying out of the state mental hospitals. While in high school my wife Denise volunteered at the Hollidaysburg State Mental Hospital and described the patients all had the same appearance. All of them smoked, had yellow tar stained fingers and hair from the constant cigarette smoke. Smoking was encouraged in the schizophrenic population, as it helped manage symptoms. Smoking however, also caused increased metabolism of the medications, and therefore higher doses were needed.

    Nearly 90 percent of people with schizophrenia smoke, most of them being heavy smokers, and 60 to 70 percent of people with bipolar disorder also smoke. According to recent research in China, nicotine restores dynamic intrinsic brain activity of people with schizophrenia. Maybe someday soon we’ll have the third generation of antipsychotics.

    Have a great day on the bench!!

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    Continuing our joruney through Mental Health medications...

    Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States. Thorazine (Chlorpromazine) by SK&F was the first available. This drug began the exodus of patients from our mental hospitals. Since 1955 there has been a decline by 95% of available beds to treat the mentally ill. Almost 66 years later these medications still have their place in therapy. Clozapine (Clozaril) was introduced in 1990 and opened the era of "atypical" antipsychotic drugs (second generation). These medications have taken people plagued with mental illness to become productive members of society. The role of these medications, as well as other non-anti-psychotic treatment options on our geriatric population will be discussed.

    Schizophrenia…the Basics
    • Schizophrenia affects about 1% of the world’s population
    • diagnosed primarily on the presentation of psychotic symptoms (hallucinations and delusions)
    • patients suffering from schizophrenia often present themselves with concomitant negative symptoms (e.g. apathy, anhedonia) and cognitive dysfunction.
    • Dopamine (D2) receptor is responsible for schizophrenia
    • Since 1953, a total of 19 studies of toxoplasmosis (T. gondii) antibodies in persons with schizophrenia and other severe psychiatric disorders and in controls have been reported; 18 reported a higher percentage of antibodies in the affected persons; in 11 studies the difference was statistically significant. Two other studies found that exposure to cats in childhood was a risk factor for the development of schizophrenia. Click here for article
    Researchers have been able to confirm that patients with schizophrenia show increased
    • presynaptic dopamine synthesis
    • increased dopamine release
    • increased synaptic levels of dopamine with a largely unchanged postsynaptic dopamine receptor density.
    • Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
    • Serotonin receptors with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.
    • Histamine receptors (sedation, antiemetic effect and weight gain)
    • Adrenergic receptors (lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence, weight gain as well as sexual dysfunction.
    • Muscarinic receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).
    As a group, the typical antipsychotics are dopamine receptor antagonists (D2 receptors) block certain dopamine tracts:
    • nigrostriatal: movement disorders
    • mesolimbic: relief of hallucinations & delusions
    • mesocortical: relief of psychosis & worsening of negative symptoms
    • tuberoinfundibular: prolactin release
    • In general, efficacy in treating patients with schizophrenia is similar for all of these agents. They differ by side effect profiles.
    First generation antipsychotics are implicated with weight gain, possibly due to:
    • Increased appetite due to serotonin 5-HT2 receptor and dopamine D2 receptor blockade
    • Increased sedation and decreased physical activity due to histamine H1 receptor blockade
    • Although controversial, antipsychotic induced weight gain does not appear to be dose related
    • Pharmacodynamic profile of second-generation antipsychotics (5-HT2A antagonism, fast D2 dissociation, 5-HT1A agonism).
    • The main differences between first and second-generation antipsychotics (from a receptor binding perspective).
    A excellent fact sheet is available HERE

    With a 95% decrease in available mental health beds, and with 45% of homeless patients suffering from mental illness (Mentalillnesspolicy.org), we obviously need better medications for the treatment of schizophrenia.

    140,000 mentally ill patients are homeless; 392,000 seriously mentally ill patients are incarcerated. 1.2% of Americans (3.2) million are afflicted with this disease. Individuals with schizophrenia die at a younger age than do healthy people. Males have a 5.1 greater than expected early mortality rate than the general population, and females have a 5.6 greater risk of early death.

    Suicide is the single largest contributor to this excess mortality rate, which is 10 to 13 percent higher in schizophrenia than the general population. Obviously we need a better strategy to treat this disabled group of citizens.

    Have a great day on the bench!!

    January 2020

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    Our last three antidepressants...get out your wallet!

    Vortioxetine (Trintellix®) 5, 10, 15, 20mg IR tablets
    Released October 2013 with a cost of $450.00 per month. Was initially named "Brintellix" and was changed to Trintellix in June 2016 because of confusion with antiplatelet Brilinta (ticagrelor)

    Indication: treatment of major depressive disorder.

    Mechanism: enhances of serotonergic activity in the CNS through inhibition of the reuptake of serotonin. Only compound known to inhibit serotonin reuptake and act as an agonist at serotonin type 1A receptors, a partial agonist at serotonin type 1B receptors, and an antagonist at serotonin type 1D, 3, and 7 receptors

    Use: May help improve cognitive function, especially with major depression. This drug also has anxiolytic effects

    Dosage: start with 10mg.

    Side Effects: causes minimal sexual dysfunction, low weight gain. Common side effects include nausea, constipation, vomiting. Pregnancy Category-C

    Drug-Drug Interactions: with CYPP450 3A4 and 2D6 enzyme pathways. Weak metabolizers of 2D6 pathway should not exceed 10mg

    Vilazodone HCl (Viibryd®) 10,20,40mg tablets
    Released 2011 and currently costs around $320.00 per month

    Indication: treatment of major depressive disorder (MDD)

    Mechanism: Inhibits reuptake of serotonin and partial 5HT1a receptor agonist

    Use: Stimulation of 5HT1a may account for its quicker activity which may help cover the "therapeutic lag" seen with pure SSRI. Viibryd is marketed to both augment SSRI effects and to have SSRI effects itself. Similar to using Abilify (aripiprazole) or Buspar (buspirone) to augment SSRI effects. Marketed as having less sexual side effects

    Dosage: Starting Dose: initial dose of 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then increased to 40 mg once daily. Available as a starter pack. Take with food because administration without food can result in inadequate drug concentrations and may diminish effectiveness

    Side effects: diarrhea (28%), nausea (23%), less sexual side effects. Pregnancy Category-C Drug Interactions: avoid strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase vilazodone plasma concentrations by approximately 50%, so reduce dose to 20mg.

    Esketamine (Spravato) CIII
    Ketamine first became available in 1970; Spravato was approved 2019. Cost estimated at $900/dose.

    Mechanism: non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults.

    Dose:
    • Weeks 1-4: administer twice a week (induction)
    • Weeks-5-8 administer once a week
    • Weeks-9 and beyond: administer every 2 weeks, or every week.
    Available as a 28mg nasal inhaler. Doses range from 56mg to 84mg. Because it is clinic administered it will not appear on the PDMP.
    • Most adverse effects occur in the first two hours after administration.
    • Patients self-administer in a clinic-based setting to have their blood pressure (for hypertension) monitored and mental-status monitoring (dissociation reactions~41%)
    • Be sure patients stay on their oral antidepressants.
    St. John's Wort
    See Clinician Corner 5/17/18 for a thorough discussion of this herbal product. Serotonin Syndrome
    Serotonin is responsible for:
    • Central effects: regulates attention, behavior and body temperature.
    • Peripheral effects: regulating digestive process, blood flow and breathing.
    Culprits: All SSRI, SNRI, and MAOIs have the potential to cause serotonin syndrome, especially at higher doses. Most likely to occur with addition or increase of known serotonergic agent to an established medication regimen

    Drug-Drug Interactions
    • SSRIs, TCAs, SNRIs, mirtazapine, MAOIs
    • Carbamazepine, cyclobenzaprine
    • Sibutramine (appetite suppressant)
    • Linezolid
    • Dextromethorphan, meperidine, methadone, tramadol
    Symptoms of Serotonin Syndrome include:
    • Hyperthermia (high fever) and heavy sweating
    • Muscle rigidity, myoclonus (clonic muscle twitching), loss of coordination.
    • Changes in mental status and vital signs
    • Agitation, restlessness or confusion
    • Rapid heart rate, arrhythmias and high blood pressure
    • Dilated pupils
    • Diarrhea
    • Headache
    • Shivering and piloerection (goose bumps)
    • Unconsciousness, possibly leading to death


    That wraps up a very long journey through the antidepressants. These last three drugs don't seem to get used a lot primarily due to the costs. With aripiprazole (Abilify) and buspirone (Buspar) being so cheap most insurance companies want patients to try and fail on a SSRI or SNRI plus augmenting before they approve these expensive drugs.

    I doubt I'll ever see Spravato, given its use only in certified clinics. The only clinic serving Central Pennsylvania currently is in State College (Penn State). You can go to Spravato.com and see the nearest clinic serving your area. My only experience with ketamine was after cataract surgery... I remember bright and vivid colors and a feeling of relaxation.

    I added a discussion of Serotonin Syndrome (SS), since we frequently see flags when we are filling prescriptions warning about serotonin syndrome. Although it is rare, as we see higher and higher doses of antidepressants, we need to have a great deal of respect for this condition. I have only seen one case of serotonin syndrome. She was a 40-year-old Multiple Sclerosis (MS) patient that took 40mg of fluoxetine (Prozac). She came to the pharmacy escorted by her husband hand had jerked motions as well profusely sweating. They were just to the emergency department and she got SS after taking a couple doses of dextromethorphan!

    I have great deal of respect for dextromethorphan and its drug interactions with antidepressants.

    Have a great day on the bench!!

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    Misc antidepressants....oldies but goodies!

    Older Miscellaneous Antidepressants

    Trazodone (Desyrel®)
    {FDA approved Dec-1981}

    Mechanism of Action: 5-HT2A and 5-HT2C antagonist and inhibits the reuptake of 5-HT; defined as a SARI = serotonin antagonist/reuptake inhibitor
    Starting dose (adults)
    • IR: 50mg TID (can take BID, prefer to take at bedtime)
    • May increase 50mg/ day every 3-4 days
    • Maximum Doses:
      • Outpatient: should not exceed 400mg/day (in divided doses)
      • Inpatient: should not exceed 600mg/day (in divided doses)
    Side effects: dizziness, lightheadedness, confusion, drowsiness, fatigue, headache, dry mouth, priapism (even at lower doses)
    Other Uses
    • Decrease alcohol cravings
    • Reduce depression and anxiety in patients with alcoholism
    • Panic disorder and agoraphobia with panic attacks (300mg)
    • Insomnia due to SSRI or Venlafaxine (Effexor) for its sedative effect (range 50-150mg)
    • To increase SSRI efficacy, a dose of 100mg may be needed
      • Can add on to SSRI therapy
      • Use with great caution à Prozac and Paxil can eliminate Trazodone's metabolite leading to CNS stimulation
    Drug Interactions: CYP2D6 substrates, CYP3A4 substrates
    Distinguishing Features: causes orthostatic hypotension (caution in elderly, especially when dosed at bedtime), more commonly used for insomnia than major depressive disorder
    • Doses for insomnia are subtherapeutic for depression treatment
    Bupropion (Wellbutrin, Zyban)
    {FDA approved Dec-1985}

    Mechanism of Action: norepinephrine and dopamine reuptake inhibitor (NDRI)
    Available As
    • Immediate release: 75 & 100mg
    • Sustained release (SR) 12 hours: 100mg, 150mg & 200mg
    • Sustained release (XL) 24 hours: 150mg & 300mg
    Dosage
    • Starting dose: must be started low and increased to minimize the risk of seizures
      • SR: start with 100 or 150mg QAM for 3 days
      • Then increase to 100 or 150mg BID, separating doses by 8 hours
      • Full antidepressant effect may take 4 weeks.
      • Maximum 400mg/day (200mg BID)
      • XL: start with 150mg QAM for 3 days
      • May increase to 300mg once daily in the morning
      • Separate XL doses by 24 hours
      • Maximum 450mg/day QAM
      • IR: start with 100mg BID
      • May increase to 100mg TID
      • Maximum 450mg/day (150mg TID)
    Other Uses
    • Weight loss
    • Attention deficit disorder
    • Neuropathic pain
    • Smoking cessation
    • Adjunct to SSRI
    • Bupropion plus an SSRI is the most common antidepressant combination
    Side Effects
    • Less nausea, diarrhea, and sleepiness than SSRIs
    • Seizures: be sure to titrate slowly!
      • An estimated seizure 10-fold increase occurs in patients who are dosed between 450 & 600mg
    • Blurred vision
    • Agitation
    • GI disturbances
    • Tremor
    • Excessive sweating
    • Weight loss
    • Hypertension
    • Dry mouth
    • Insomnia
    • Constipation
    • Does NOT cause sexual dysfunction + is minimally sedating
      • Often the choice antidepressant for patients complaining of sexual side effects & decreased energy levels.
    ABUSE POTENTIAL: Bupropion is called "poor man's cocaine" because users say it gives them a cocaine-like high for about $2.50/pill
    Distinguishing Features
    • May be beneficial in patients with fatigue, poor concentration, and interested in smoking cessation
    • No anxiolytic properties
    • Appetite-suppressing effects (weight neutral)
    • No sexual dysfunction
    • Caution in patients with psychotic features
    • Contraindicated in patients with bulimia, anorexia, and seizure disorder
    Mirtazapine (Remeron®)
    {FDA approved: June 1996}

    Mechanism: does NOT block reuptake of dopamine, norepinephrine or serotonin. It blocks the Histamine-1 receptor, which accounts for its drowsiness and weight gain. Mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor. Increased activation of the central 5-HT1A (serotonin) receptor is a major mediator of efficacy of most antidepressant drugs
    Dose: most commonly available as 7.5mg, 15mg, 30mg and 45mg tablets. Best given at bedtime due to sedation.
    Side effects: dizziness, drowsiness and weight gain.
    Unlabeled uses: sleep apnea, weight gain, antipsychotic induced akathisia

    This column is a “catch all” of the older miscellaneous drugs. All are available generically, and the newest one is 25 years old. What I love about this column all these drugs were introduced after Denise and I graduated pharmacy school in 1981.

    I remember the Mead Johnson representative coming to talk to me about Desyrel (trazodone) a new groundbreaking antidepressant, that was nothing like those old tricyclic antidepressants. We dispensed a lot of Desyrel® until the late 1980’s when Prozac and the other SSRI’s and later Effexor® and the SNRI’s tool over the depression market. Today trazodone is dosed mostly at bedtime for insomnia.

    Wellbutrin® was another one of those drugs with a peculiar mechanism, in that it did not cause sedation, like all the others. I remember when the insurance companies refused to pay for Zyban, because it was for smoking cessation. Practitioners then wrote for “Wellbutrin-SR”, then the insurance companies required a prior auth for all bupropion!

    Those insurance companies have been saying “NO” for a very long time! Next week will cover the “newer” miscellaneous antidepressants.

    Have a great day on the bench!!

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    MAOIs potent, yes; lots of food and drug interactions keep these drugs off of our shelves.

    Monoamine Oxidase Inhibitors (MAOIs) block monoamine oxidase, an enzyme in the synaptic cleft that breaks down neurotransmitters. MAO is released from the pre-synaptic nerve terminals. Norepinephrine is not broken down, and has more dramatic effect, not only in the brain but every else in the body. MAOIs are very seldom used due to side effects and life-threatening drug interactions.

    Hypertensive crisis: extreme increases in blood pressure when MAOIs interact with OTC meds and foods containing tyramine.
    • Defined by diastolic BP >120mmHg
    • Characterized by occipital headache, palpitations, neck stiffness/soreness, Nausea/Vomiting, sweating, dilated pupils, photophobia, tachy- or bradycardia, chest pain
    • This came to be known as “Cheese Effect” because aged cheeses contain a lot of Tyramine which naturally elevates blood pressure
    • Tyramine containing foods and OTC drugs that should be avoided:
      • Aged cheeses: blue, camembert, cheddar, Roquefort, stilton and Swiss
      • Anchovies
      • Dried, aged, smoked, fermented, spoiled, or improperly-stored meat, poultry, and fish
      • Tap and non-pasteurized beers
      • Red wine, (esp. Chianti), sherry
      • Many tropical fruits à bananas and avocados (especially if overripe)
      • Also avoid drugs with vasopressors (increase BP): chocolate, cola, coffee tea, broad beans
      • Sauerkraut and soy products (tofu, soy sauce, marmite)
      • OTC cold medications containing pseudoephedrine (Sudafed®)
      • Avoid amphetamines and appetite suppressants
      • Other antidepressants
    MAOI Drugs
    • Nardil® (phenelzine) 15mg tablets (FDA approved 1961)
      • Non-selective (will increase levels of dopamine, norepinephrine, and serotonin)
      • Distinguishing Feature: may cause hepatotoxicity
    • Parnate® (tranylcypromine) 10mg tablets (FDA approved 1961)
      • Non-selective (will increase levels of dopamine, norepinephrine, and serotonin)
      • Distinguishing Feature: structurally similar to amphetamine, so stimulating; less likely to cause weight gain
    • Marplan® (isocarboxazid) 10mg tablets (FDA approved 1959)
    • Non-selective (will increase levels of dopamine, norepinephrine, and serotonin)
    • EMSAM® (selegiline transdermal system) (FDA approved 2006)
      • Selective à less “Cheese Effect” due to no tyramine inhibition at low dose
      • First + only transdermal MAOI for treatment of depression
      • Three available strengths: 6mg/ 24 hours; 9mg/ 24 hours; and 12mg/24 hour (available in boxes of 30)
      • Change patch once a day at the same time each day!
      • Avoid sympathomimetic amines such as amphetamines or cold medications containing vasoconstrictors (pseudoephedrine-Sudafed®)
      • WARNINGS/ PRECAUTIONS
        • Because of the potential for serotonin syndrome EMSAM is contraindicated with SSRI, SNRI, TCA or MAOI
          • Wait 2 weeks after stopping SSRI, SNRI, TCA or MAOI mirtazapine, bupropion, dextromethorphan, cyclobenzaprine, tramadol methadone, propoxyphene, St. John’s Wort and carbamazepine
          • Must wait 5 weeks for fluoxetine (Prozac®)
      • Other side effects: application site reaction, headache, insomnia, diarrhea, dry mouth and dyspepsia
      • Benefits: reported sexual dysfunction similar to placebo; minimal weight change
      • Distinguishing Feature: no tyramine dietary modifications at the starting or target dose of 6mg/24 hours
        • If the dose is increased to the 9mg/24hr or 12mg/24 hr, then the tyramine diet must be used
        • Drug-drug interactions still a concern

      Monoamine oxidase inhibitors

      MAO-A MAO-B
      SUBSTRATES Norepinephrine
      Serotonin
      Dopamine
      Tyramine
      LOCATION Brain, gut, liver, placenta, skin Brain, platelets, lymphocytes
      INHIBITORS Nardil, Parnate Marplan, Emsam Eldepryl (low doses) Azilect
      THERAPEUTIC USE Depression Parkinson’s disease


      Like so many drugs that were discovered in the 1950’s MAOI’s existence is due to serendipity. Researchers discovered that one of the tuberculosis drugs, iproniazid caused relief of patient’s depression. This led to the discovery of monoamine oxidase, and soon after inhibitors of this enzyme were marketed for the relief of depression.

      Due to the side effects and significant food and drug interactions these drugs are seldom used. About the only time we see this class of drugs used is in treatment resistant depression, that have failed the more common therapies.

      Although it has been a long time since I have dispensed these drugs, our local warehouse does have Nardil, Parnate and their generics in stock, along with brand name Emsam.

      The selective MAO-B inhibitors used for Parkinson’s disease are a little more commonly dispensed in the community pharmacy.

      Have a great day on the bench!!

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    Tricyclic antidepressants are as old as this author... and still going strong... (like this author)

    Tricyclic Antidepressants (TCA)
    Mechanism: inhibit the reuptake of NE and 5-HT into the presynaptic terminal. Allows more serotonin and nor-epinephrine to be available in the synapses.

    Although there are 9 different tricyclic antidepressants (TCA) approved in the United States I have only 5 on my shelf in the community pharmacy where I practice. The TCA’s can be broken down between the secondary and tertiary amines. The most common secondary amines nortriptyline and desipramine are selective inhibitors of norepinephrine reuptake. The most common tertiary amines amitriptyline, imipramine, doxepin and clomipramine are selective inhibitors of serotonin reuptake. They are also broken down by side effects.

    With 9 different TCA's when do we use them?
    • MOST sedating: Amitriptyline, doxepin and imipramine
    • MOST likely to cause weight gain: Amitriptyline, doxepin and imipramine
    • CLEANEST: Nortriptyline and desipramine are less likely to cause sedation and weight gain.
    • NOCTURNAL ENURESIS: imipramine is most used
    • OCD: Clomipramine was the first drug that was approved for Obsessive-Compulsive disorder. (When we see its highly serotonergic effects, it is no surprise)
    • INSOMNIA: Doxepin is also available as Silenor® in 3mg and 6mg tablets used for sleep maintenance.
    The most common TCA's I see in my practice are amitriptyline and nortriptyline. The following is from my lecture notes to delineate the differences between the two:
    DIFFERENCES BETWEEN Amitriptyline (Elavil®) and Nortriptyline (Pamelor®)
    • Nortriptyline is the active metabolite of amitriptyline (via CYP450-2C19)
    • Nortriptyline is generally better tolerated than amitriptyline. It has much less sedation and anticholinergic side effects.
    • The mortality from nortriptyline in overdose is similar to that from SSRIs
    • Nortriptyline is the least problematic of the tricyclic antidepressants in terms of drug interactions. It is relatively safe to combine it with certain SSRIs (sertraline and citalopram).
    • Nortriptyline is better choice for elderly.
    • Maximum dose for Nortriptyline should never exceed 150mg.
    MOST TCA's
    • Common side effects: anticholinergic side effects, sexual dysfunction, daytime drowsiness
    • Cardiac effects: may alter rate, rhythm, & contractility. May cause orthostatic hypotension.
    • CNS- seizures, respiratory depression, disorientation & coma
    • METABOLISM: most of the available tricyclic antidepressants are metabolized by the CYP-2D6 pathway. Desipramine and nortriptyline are the least problematic of the TCAs in terms of drug interactions, being only weak CYP450-2D6 inhibitors.
      • Avoid tertiary amine-TCA's in patients known to be ultra-rapid metabolizers at CYP450-2D6 (think of codeine metabolism)
      • The tertiary amines are extensive metabolized through CYP450-2C19. Avoid tertiary amines in weak metabolizers of this enzyme system.
    COMMON USES: diabetic neuropathy, phantom leg pain, cancer pain, post herpetic neuralgia
    DOSING: commonly doses begin at 25mg and are titrated to 150-300mg. (300mg-inpatient). (Except Nortriptyline)
    COST: ALL are available generically, and relatively inexpensive.
    CAUTION must be exercised with TCA in patients with suicidal thoughts due to high lethality risks with overdose. The lethal dose is only EIGHT times the therapeutic dose, so if TCA's are ingested in an overdose, they may block the sinoatrial node in the heart. TCA are more dangerous than SSRI in overdose. Therefore, a seven-day supply of a maximally dosed tricyclic antidepressant could be lethal.

    GENERIC BRAND YEAR AC H1- NET SERT
    Imipramine Tofranil® 1959 ++ + + ++
    Amitriptyline Elavil® 1961 +++ ++ + ++
    Desipramine Norpramin® 1964 + + +++ +
    Nortriptyline Pamelor® 1964 + + ++ +
    Protriptyline Vivactil® 1967 +++ + +++ +
    Doxepin Sinequan® 1969 ++ +++ + +
    Clomipramine Anafranil® 1989 + + + +++


    AC: anticholinergic side effects (dry mouth, blurry vision, constipation, urinary retention)
    H1: histamine receptor (associated with weight gain and sedation)
    NET: nor-epinephrine transporter (increases levels of nor-epinephrine by blocking reuptake)
    SERT: serotonin transporter (increases levels of serotonin by blocking reuptake)

    The tricyclic antidepressants quickly followed after the first generation antipsychotic chlorpromazine (Thorazine), in the late 1950's. Pyschopharmacotherapy was in its infancy, and 7 more TCA's followed suit after imipramine's introduction in 1959. Climipramine was the last TCA, introduced in 1989 a few months after Prozac (fluoxetine). Clomipramine (Anafranil) was the first drug indicated for treatment of OCD.

    I remember well the sale reps from Ciba-Geigy not only educating providers about the drug but also the diagnostic criteria for Obsessive-Compulsive Disorder (OCD). OCD is now very much a layman's term that is thrown around when we check our locks on our doors, or have our pantry shelves arranged!

    Wishing you and yours a Happy 2020!
    Have a great day on the bench!!

    December 2019

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    SNRI's for weight management, depression, pain, ADHS???

    Serotonin Norepinephrine Reuptake Inhibitors (SNRI)
    Mechanism: inhibits reuptake of both norepinephrine and serotonin in the presynaptic nerve terminal, allowing more serotonin and nor-epinephrine to be available in the synapses. The SNRI's are used for depression and pain management.

    SNRI Side Effects:
    • Side effects: very favorable profile: minimal sedative and cardiovascular effects.
    • Common side effects: nausea, anorexia, insomnia, nervousness, restlessness, and bruxism. All these side effects increase as dose is increased.
    Venlafaxine (Effexor®) - FDA approved 1993
    • Also approved for Generalized Anxiety Disorder and SAD
    • Unlabeled use: hot flashes, Premenstrual Dysphoric Disorder, PTSD
    • Caution: angle closure glaucoma or patients taking oral anticoagulants.
    Duloxetine (Cymbalta®) - FDA approved 2004
    • Dose: major depressive disorder: 40 mg daily (not much benefit over 60 mg/day)
    • Very low side effect profile
    • May cause decrease in body weight
    • Caution: CrCl less than 30; liver failure, alcohol abuse, closed angle glaucoma.
      • contraindicated in patients with heavy alcohol use or chronic liver disease; can lead to acute hepatitis
    • ***is approved for diabetic neuropathy and fibromyalgia***
    Desvenlafaxine (Prestiq®) - FDA approved 2008
    • Treatment of adults with major depressive disorder.
    • Is the active metabolite of Effexor. It does not require "activation" by the CYP2D6 metabolic pathway, minimizing the potential for drug interactions.
    • There was no evidence that doses greater than 50 mg/day confer any additional benefit.
    • Less sexual dysfunction.
    • Nausea most frequently during week one.
    • May increase blood pressure.
    • When discontinuing treatment, gradual dose reduction is recommended whenever possible.
    Milnacipran (Savella®) - FDA approved Jan-2009
    • Use: selective norepinephrine and serotonin reuptake inhibitor (SNRI) for management of fibromyalgia. First drug approved ONLY for fibromyalgia.
    • More potent inhibitor of norepinephrine reuptake than the other SNRIs.
    • Norepinephrine depletion is associated with pain and fatigue. 1 in 12 patients get about 50% reductions in fibro symptoms.
    • Adverse reactions: nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpations, increased heart rate, dry mouth, and hypertension.
    • CAUTION: avoid in ESRD, chronic liver disease, or alcohol abuse.
    Levomilnacipran (Fetzima®) - FDA approved 2013
    • Once-daily serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder (MDD) in adults, has received FDA approval
    • Stronger inhibitor of norepinephrine than serotonin.
    • Dosage: 40 mg to 120 mg once daily, beginning with 20 mg once daily for 2 days and then 40 mg once daily. Dosage can be increased in increments of 40 mg at intervals of 2 or more days, with 120 mg the maximum recommended dose.
    • Monitor BP and heart rate for increases.
    • CAUTION: ESRD, angle closure glaucoma, hypertension, dose dependent erectile dysfunction.


    DRUG STARTING DOSE TARGET DOSE
    Desvenlafaxine (Pristiq) 25 to 50mg 50mg to 100mg
    Duloxetine (Cymbalta) 30 to 60mg 60mg to 120mg
    Levomilnacipran (Fetzima) 20mg 40mg to 80mg
    Milnacipran (Savella) 12.5mg 100 to 200mg
    Venlafaxine (Effexor tabs) 37.5 to 75mg 75 to 375mg
    Venlafaxine XR- (Effexor-XR) 37.5 to 75mg 75 to 225


    SSRI/SNRI and Elderly November-2018:
    HYPONATREMIA:
    older patients are more likely to develop hyponatremia with an SSRI or SNRI or mirtazapine than younger counterparts. Be sure to monitor sodium especially in patients with heart failure, or those taking hydrochlorothiazide. They made the Beers List for that reason.

    The SNRI’s came into the depression treatment arena about 5 years after Prozac broke the ground for new depression therapy. These drugs also seem, because of their effect on norepinephrine, seem to be more useful for pain management than the SSRI’s.
    • Tramadol (Ultram) is a weak SNRI and a weak opioid which was approved in 1995 for treatment of pain.
    • Sibutramine (Meridia) is an SNRI and was approved in 1997, which was the first drug approved for obesity in 30 years.
    • Atomoxetine (Straterra) primarily works on norepinephrine reuptake, with minimal effect on serotonin. It was first approved in 2002 for the treatment of ADHD.
    Wishing you and yours a most Happy 2020!

    Have a great day on the bench!!

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    When I'm feeling blue, all I gotta do is...Take a pill?

    Selective Serotonin Reuptake Inhibitors (SSRI)
    Mechanism: serotonin reuptake is blocked in the pre-synaptic nerve terminal. Allows more serotonin to be available in the synapses.

    Ground Rules for Prescribing Antidepressants
    • There is a 2 to 4-week lag time to clinical efficacy, but side effects occur rapidly
    • An adequate dose and duration of treatment of at least 4-8 weeks are required to establish an adequate trial of antidepressant.
    • Antidepressant dose should be increased if patient compliance is good and no response after 3 weeks. If partial response, adjust dose in 2 weeks.
    • 25% of patients who don't respond to one SSRI will respond to another. Therefore, it's reasonable to switch from one SSRI to another if a patient is not responding. However, if a patient fails more than one SSRI, then a class switch should be considered.
    DRUG INTERACTIONS (non-MAOI):
    • highest risk of drug interactions: fluoxetine (Prozac®), fluvoxamine (Luvox®), and paroxetine (Paxil®).
    • lowest risk of drug interactions: include citalopram (Celexa®), escitalopram (Lexapro®), mirtazapine Remeron®, venlafaxine (Effexor®), and desvenlafaxine (Pristiq®).
    SSRI (Selective Serotonin Reuptake Inhibitors)
    MOST SSRI
    • Common side effects for SSRI: headache, nausea, nervousness, insomnia, agitation, sexual dysfunction, bruxism
    • Costs of SSRI: All SSRI are available generically. Are now very inexpensive.
    • Bleeding Risk: SSRIs inhibit the uptake of serotonin in platelets. This depletes serotonin in platelets and therefore inhibits their ability to initiate blood clotting. Absolute risk is small. Greater risk when combined with Aspirin or NSAIDs
    • Risk of Torsades: Sertraline, paroxetine, and fluoxetine seem less likely to cause QT prolongation.
    • HYPONATREMIA: older patients are more likely to develop hyponatremia with an SSRI or SNRI or mirtazapine than younger counterparts. Be sure to monitor sodium especially in patients with heart failure, or those taking hydrochlorothiazide.
    • FALL RISK: SSRI are on Beers list for patients with a history of falls or fractures. Watch for sedation and blurred vision to decrease fall risk
    Selective Serotonin Reuptake Inhibitors (SSRI)
    Citalopram (Celexa®)
    • Do not exceed 40 mg/day for anyone. Max= 20 mg/day for most patients over age 60.
    • Higher doses of citalopram increase the risk of QT prolongation and torsades.
    • Caution: using citalopram in patients at risk due to underlying cardiac disease or low serum potassium or magnesium.
    Escitalopram (Lexapro®)
    • S-isomer (active isomer) of Celexa
    • When citalopram is not utilized based on risk factors for TdP, use of escitalopram is not likely the safest alternative. Based on current literature, fluoxetine, fluvoxamine, and sertraline appear to have similar, low risk for QT prolongation, and paroxetine appears to have the lowest risk. https://www.ncbi.nlm.nih.gov/pubmed/24259697
    Fluoxetine (Prozac®)
    • Only SSRI that is FDA approved for major depressive disorder in children and adults.
    • LONGEST half-life of SSRI’s (1 to 3 days)
      • Active metabolite (norfluoxetine) has 4-16-day half-life.
    • Along with sertraline (Zoloft®) is the MOST activating of SSRI
    Paroxetine (Paxil®) -
  • Paroxetine (Brisdelle® 7.5mg) marketed for hot flash treatment
  • MOST sedating of SSRI
  • MOST anticholinergic side effect of SSRI
  • Pregnancy Category D
  • Considered by most to be the “dirtiest” SSRI
  • Sertraline (Zoloft®)
    • MOST Activating SSRI (along with Prozac)
    DOSING CHART

    SSRI Starting Dose Target Dose
    Citalopram 20 20 to 40
    Escitalopram 10 10 to 20
    Fluoxetine 20 20 to 60
    Paroxetine 20 20 to 40
    Sertraline 50 50 to 200


    32 years ago this month the face of America changed with the introduction of Prozac (Fluoxetine) by Eli Lilly.

    MAOIs became widely used as antidepressants in the early 1950s. Patients with tuberculosis given iproniazid, experienced relief from their depression.

    Tricyclic antidepressants, the first being imipramine (Tofranil) in 1959, followed by amitriptyline (Elavil) in 1961 and then at least a dozen more until Prozac was introduced.

    Trazodone (Desyrel®) was introduced in late 1981 and was found to be too sedating. Today we see trazodone used for sleep induction, usually for people taking SSRI’s.

    Escitalopram (Lexapro®) was approved in 2002 and was the last SSRI to be approved. We buy most of our SSRI antidepressants (except paroxetine) in bottles of 500 and turn them over quickly.

    Before we had MAOI's in the 1950's amphetamines like Benzedrine in the 1930's and 1940's were used to treat mild depression, but quickly became drugs of abuse.

    And before the advent of the amphetamines, frankincense was used to treat depression. One of the ingredients in frankincense smoke called incensole acetate has been studied in mice and has shown to relieve depression. Most of us are familiar with frankincense as it was one of the three gifts brought by the Magi that came from the East to adore the Christ Child.

    With that in mind, I wish you and your families a Merry Christmas and a Happy New Year!

    Have a great day on the bench!!

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    Lots of anti-epileptic drugs can be tried for our patients with bipolar disorder.

    Stabilizing the mood with Anti-Epileptic drugs Valproic acid and Valproate:
    • Valproic Acid, which became available as Depakene in 1978, is seldom used due to GI upset.
    • Divalproex (Depakote®) was approved in 1982, as a delayed release tablet to minimize stomach upset.
    • Divalproex extended release (Depakote-ER®) is a once daily formulation that became available in 2000. Today all forms of valproic acid/valproate are available generically.
    Oral loading dose of acute mania: 20mg/kg/day. Therapeutic levels occur in 2-3 days. Is being used more first line due to the adverse effects associated with lithium pharmacotherapy
    Mechanism: possibly increases CNS levels of GABA
    Common use: is an anti-seizure drug and can also be considered as first line treatment for mania. Divalproex is also used for panic disorder and migraine prophylaxis. Divalproex is more effective than lithium in mixed episodes.
    Adverse effects: hepatotoxicity (Black box warning) increase risk for children under
    • Teratogenicity: pregnancy category-D
      • third line drug for female patients of childbearing potential
    • Pancreatitis
    • Stomach upset featuring nausea/vomiting and diarrhea
    • Do frequent CBC, and liver enzymes
    • Thrombocytopenia appears to be dose related

    Monitoring: therapeutic serum levels: 50-100mcg/ml
    Patient Education
    • GI upset: Take with food
    • Caution driving
    • NVD may signify pancreatitis. refer if necessary.
    • If alopecia occurs, supplement with zinc and selenium
    • Weight gain: Up to 70% of patients taking valproic acid may gain weight. Almost one-half of patients may gain >10% of baseline weight

    NOTE: Treatment of ACUTE mania in patients taking Lithium or Valproate usually requires addition of an antipsychotic drug

    Carbamazepine (Tegretol®): was first approved in 1968. It is commonly available in tablets 100mg (chew) and 200mg It is also available as extended release Tegretol XR tablets 100,200 and 400mg. Carbatrol® capsules are available as 100, 200 and 300mg extended release caps
    Initial dose:( adults): 200mg twice daily. Increase every week of no more than
    • 200mg per day using a 3-4 times daily regimen.
    • Maintenance: 800-1200mg/ day maximum dose for mania is 1600mg/day
    • Therapeutic blood level: 4—12mg/liter
    Mechanism: stabilizes cell membranes. Reduces polysynaptic responses.
    Common use: indicated for treatment of epilepsy, trigeminal neuralgia
    Unlabeled use: Postherpetic neuralgia, PTSD, alcohol withdrawal,
    Bipolar disorder: used for mania or mixed episodes

    Adverse effects: contraindicated if history of bone marrow depression
    • Stevens Johnson syndrome—severe dermal reactions.
      • Genetic testing: The HLA*15:02 allele has since been associated with carbamazepine-induced Stevens Johnson Syndrome (Toxic Epidermal Necrolysis) in Taiwanese, Chinese, Indians, Malay, and Chinese- Americans, but not in Caucasians or Japanese individuals
    • Pregnancy: category D
    • Aplastic anemia—black box warning
    • Is a CYP-450 enzyme inducer-----lots of drug interactions. Also induces its own metabolism. monitor more closely during the first few months of therapy because carbamazepine induces hepatic enzymes
    Monitoring of carbamazepine
    • Baseline: complete blood tests then periodic evaluation
    • Baseline liver function, then periodic evaluation
    • Baseline and periodic eye exam
    • Urinalysis
    • BUN
    • Therapeutic blood level: 4—12mcg/liter
    Lamotrigine (Lamictal®) : was FDA approved in December 1994 Is available generically in tablet formulations chew: 5mg & 25mg. immediate release tablets: 25, 100, 150 &200mg
    Mechanism: unknown: may interfere with sodium channels and stabilize neuronal membranes, modulation presynaptic excitatory amino acid release (glutamate & aspartate)
    Lamotrigine use:
    • Lamotrigine has better evidence of efficacy than lithium for monotherapy for bipolar depression.
    • Best choice for prevention of recurrent depressive episodes.
    • The combination of lithium plus lamotrigine can be considered for patient’s refractory to monotherapy.
    • Lamotrigine should not be used for treating mania and has limited efficacy for preventing mania.
    Dosage: watch for drug interactions!
    There are different dosage regimens to follow:
    • Adding Lamictal to AED regimen containing Divalproex (a CYP-450 blocker)
      • 25mg every other day, for 2 weeks. Then 25mg every day for 2 weeks.
    • Adding Lamictal to EIAED (enzyme inducing anti-epileptic drug) . CBZ, DPH, PBARB without valproic acid.
      • 50mg daily for 2 weeks. Then 100mg daily in 2 divided doses for 2 weeks.
    • Using lamotrigine in patient taking neither an inducer or blocker:
      • 25mg daily for 2 weeks, then in crease to 50mg daily
    **Closely consult prescribing information when making Lamictal dosage adjustments. **
    Adverse effects: skin rash (discontinue if it appears)-Black box warning. Titrate slowly especially if taking Valproic acid.
    Contraindications:none.
    Drug interactions: many drug interactions between enzyme blockers and inducers.
    • Although Lamictal does not induce or inhibit other drugs, its metabolism is affected.
    • Inhibits dihydrofolate reductase. Folic acid supplementation may be necessary.
    ·Adding valproic acid to Lamictal, will increase Lamictal steady state concentration 2X!

    Drug Monitoring: optimal blood level: 4 to 20 mcg/ml. Allow 4-5 days to reach steady state
    MONITORING of MOOD STABILIZERS:
    • Trough lithium concentrations should be kept at 0.8 to 1.2 mEq/L;
    • Trough valproate levels should be kept at 50 to 125 mcg/mL
    • Trough carbamazepinelevels should be kept at 4 to 12 mcg/mL
    We dispense a fair amount do this well-known seizure medications, divalproex, carbamazepine and lamotrigine. However, most of the prescriptions filled are prescribed by psychiatrists rather than neurologists. These three drugs are most commonly used as “mood stabilizers” in the treatment of bipolar disorder.

    Of these drugs the one that takes up a lot of space in my Pharmacology notes is carbamazepine. Carbamazepine is a big-time CYP450-3A4 inducer. It is so effective at enzyme induction it induces it’s own metabolism. This can be a nightmare when a patient is taking warfarin. We don’t have a significant Asian population in Central Pennsylvania, but where you are practicing your Asian patients really need your expertise!

    Although Levetiracetam (Keppra) is a lot “cleaner” than the drugs mentioned in this newsletter, results for mood stabilization have been mixed. Although not FDA approved, we also see Topiramate (Topamax) and Gabapentin (Neurontin) used as well for bipolar disorder. But then again, we see these drugs used for a lot of non-FDA approved conditions.

    Have a great day on the bench!!

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    We Steeler fans are happy... then sad...are we bipolar? Not according to this definiton!

    Bipolar disorder... and most effective treatment is LITHIUM!
    People who live with bipolar disorder experience periods of great excitement, overactivity, delusions, and euphoria (mania) and other periods of feeling sad and hopeless (depression). Mood stabilizers (lithium, valproate, lamotrigine) are the cornerstone of the pharmacotherapy of bipolar disorder. Antipsychotics, alone or in combination with mood stabilizers, are also commonly used. There is no evidence that any one anti-psychotic is more effective than the others.

    Mood swings OR bipolar disorder? Patients with mood swings experience fluctuations in mood are caused by a situation, person, or events in their lives. While the moods of people with bipolar disorder can be affected by situational variables, people with bipolar disorder also frequently become manic or depressed for no apparent reason.

    Duration: Bipolar patients experience an elevated or irritable mood for at least four consecutive days. A patient with bipolar may have depressive episodes that last for at least two weeks at a time. Emotions tied to watching a Steeler game is not bipolar!

    BENEFITS of THERAPY:
    In addition to preventing relapse in patients with bipolar disorder, maintenance pharmacotherapy may be associated with reduced rates of violent behavior. A national registry study identified 494 convictions for violent crime (eg, assault, robbery, or threats/intimidation) in 11,918 patients with bipolar disorder and examined the time periods when patients were or were not prescribed mood stabilizers (eg, lithium, valproate, lamotrigine, or carbamazepine) or antipsychotics.

    The rate of violent behavior when mood stabilizers were prescribed was 60 percent less, compared with times when mood stabilizers were not prescribed. In addition, prescription of antipsychotics was associated with a 50 percent decrease in interpersonal violence.

    Lithium
    History: The first recorded use of lithium for the treatment of mania, based in part on the urate/lithium connection, was 1871. Use of lithium carbonate to prevent depression came in 1886. In 1948 an Australian psychiatrist started using lithium after he treated guinea pigs and noticed they became more docile. It wasn’t until 1970 the FDA approved lithium, under the trade names of Lithonate® and Eskalith® for the treatment of mania.

    Mechanism: affects synthesis, storage, and reuptake and release of central Monoamine neurotransmitters. NE, 5-HT, DA, ACH and GABA

    Dosage: acute mania- optimal response 600mg three times daily or 900mg twice daily if SR. Lithium is available in capsules and tablets as 150mg, 300mg and 600mg. Lithium is also available in sustained released tablets in 300mg and 450mg tablets. The sustained release tablets cause less stomach upset but cause more diarrhea due to more distal GI absorption.

    Common use: Lithium is effective for prevention of both manic and depressive episodes. Lithium also reduces the risk of suicide, perhaps by reducing agitation and impulsivity.
    • Considered drug of choice for maintenance treatment of bipolar disorder.
    • Considered drug of choice specially to PREVENT manic episodes
    • Using lithium reduces the risk of relapse by approximately 30 percent.
    Unlabeled uses: neutropenia, cluster headaches, premenstrual tension, bulimia, Alcoholism, Syndrome of Inappropriate Excretion of ADH, Tardive dyskinesia, psychosis. Also being used to augment the effects of antidepressants.

    Adverse effects: fine hand tremor, polyuria, mild thirst, nausea, hair loss & metallic taste.

    Monitoring: ideal blood levels: acute mania: 0.8-1.2 mEq/liter

    Maintenance is 0.6-1mEq/liter to minimize side effects.
    • Draw blood levels 12 hours after last dose.
    • Check blood levels: 5-7 days after initiation & any change in dosage.
    • Maintenance: every 1-2 months. In stable patients 6-12 months.
    • Monitor more frequently if volume depletion, or diuretic use, diarrhea or vomiting.
    • Check thyroid and renal function before starting lithium and every 6-12 months.
    • Hypothyroidism can occur and contribute to bipolar exacerbations.
    Drug Interactions:
    Increases lithium level
    • Thiazide diuretics (HCTZ, chlorthalidone)
    • Nonsteroidal anti-inflammatory drugs except aspirin
    • Angiotensin converting enzyme inhibitors (lisinopril, captopril)
    • Angiotensin receptor blockers (Irbesartan, valsartan, losartan)
    • Antibiotics tetracyclines and metronidazole (Flagyl®)
    Decreases lithium level
    • Potassium-sparing diuretics (triamterene, amiloride, spironolactone)
    • Theophylline (Theo-Dur®, Uniphyl®)

    Most providers do not feel comfortable managing Lithium, due to the toxicity and side effects. One of my former PA students that graduated around 2009 landed a job in a psychiatric hospital. Her job was unique, she managed the patient’s disease states brought on by the potent psych meds that were prescribed. Family practice providers see a lot of the metabolic abnormalities brought on by the antipsychotic drugs, so it is important to be familiar with problems brought on by these very potent medicines.

    Two years ago, I was counseling a patient who was on Lithium at the Empower-3 clinic. At our first meeting in the summer I reminded him (as I do all my lithium patients) to drink plenty of fluids. I explain to them when the “beaker”, that is your body goes low in water the concentration goes up and can cause toxicity.

    At the next meeting his caregiver said he was “chugging” 2 liters of water at a time about every 30-60 minutes. I immediately thought of the renal toxicities lithium can cause. After Vince, the Physician Assistant went in, did a complete physical and ordered blood work, it was determined he had “lithium induced nephrogenic diabetes insipidus”

    Just simple counseling a patient about their water intake lead to this rare diagnosis. That’s why we’ll take a long journey through the psych meds, because so frequently these problems fall on the lap of the family practice providers.

    Have a great day on the bench!!

    November 2019

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    More and more of our patients need our help with their psych meds!

    Behavioral Health Pharmacology
    Mental health services are challenging to get for our patients. Most psychiatrists are booked in advance, and mid-level practitioners such as CRNP’s and PA-C’s are carrying the burden. Even with their help mental health services are difficult to get for our patients. More and more mental health care is being provided by the family practice clinicians. At the request of the Physician Assistants that I work with at Empower-3, we will begin the journey through drug therapy for mental health disorders.

    Before we start the drug categories, we need to do a quick overview of the neurotransmitters.

    What makes a neurotransmitter:
    • It is synthesized in a neuron
    • Is synthesized/stored and released by the pre-synaptic terminal. When released it has a specific effect when it attaches to the receptor on the post-synaptic terminal
    • When given as a drug it exerts an identical reaction on the post synaptic terminal’s receptors
    • A specific mechanism removes the drug from the synaptic cleft,
      • either by pre-synaptic uptake (recycling) or
      • destruction by a specific enzyme
    In addition to depressed mood, abnormalities of neurotransmitter function are associated with different symptoms: Dopamine: (decrease in dopamine function)
    • Decreased ability to experience pleasure
    • Decreased motivation
    • Decreased attention
    • Cognitive slowing
    • Weight gain
    Norepinephrine (decrease in norepinephrine function)
    • Low energy & lethargy
    • Decreased alertness
    Serotonin (decrease in serotonin function)
    • Obsessive –compulsive behavior.
    NEUROTRANSMITTER SPECIFIC EFFECTS:
    SEROTONERGIC SIDE EFFECTS (excess serotonin):
    • Sexual dysfunction
    • Weight gain
    • Suppression of dopamine neurotransmission which may result in:
    • Decreased ability to experience pleasure
    • Apathy and decreased motivation
    • Decreased attention
    • Cognitive slowing
    • GI upset
    • Sleep Disturbances
    NORADRENERGIC SIDE EFFECTS (excess norepinephrine)
    • Tremor
    • Tachycardia
    • Dry mouth
    • Insomnia
    DOPAMINERGIC SIDE EFFECTS (excess dopamine)
    • Psychomotor activation
    • Aggravation of psychosis
    • Activation of motivation: rewards pathway
    • PERIPHERAL effects of dopamine:
      • At very high doses: ventricular arrhythmia, atrial fibrillation, ectopic beats, tachycardia, anginal pain, palpitation, cardiac conduction abnormalities, widened QRS complex, bradycardia, hypotension, hypertension, vasoconstriction.
      • dyspnea.
      • azotemia.
      • piloerection.
    GABA (gamma-aminobutyric acid)
    GABA is the chief inhibitory neurotransmitter of the CNS. Opposes the effect of glutamate. When released latches onto the GABA receptor which has a calming effect. Benzodiazepines work on the GABA receptor and cause a release of chloride, which is the major inhibitory ion in the CNS. Chloride ions are negatively charged causing hyperpolarization of the neuron. GABA's effects can be modulated by drugs such as benzodiazepines, barbiturates, steroids, and alcohol.
    NET EFFECT on the GABA receptor
    • Barbiturates increase the duration of chloride ion channel opening at the GABA receptor, to increase the efficacy of GABA.
    • Benzodiazepines increase the frequency of the chloride ion channel opening at the GABA receptor to increases the potency of GABA.
    GLUTAMATE
    Glutamate is the major excitatory neurotransmitter. Glutamate pathways are linked to many other neurotransmitter pathways, and glutamate receptors are found throughout the brain and spinal cord in neurons and glia. So diverse and widespread are the glutamate receptors only three prescription medications have been developed that specifically target glutamate or glutamate receptors, memantine (Namenda®), ketamine (Spravato®), and D-cylcoserine (Seromycin®). I find it incredulous that an Alzheimer's drug, an antidepressant and an anti-tuberculosis drug are all related to their effect on the glutamate receptor.

    One of the more challenging topics to teach to my Physician Assistant Sciences students is Behavioral Health. There are numerous disease states, numerous categories of drugs, and numerous generations of drug categories.

    It all began in 1954 with the introduction of Thorazine® (chlorpromazine) which began the emptying out of mental health hospitals. Today we have lots of drugs for treatment of bipolar, schizophrenia, depression and numerous other behavioral health conditions.

    The first Behavioral Medicine exam I gave at St. Francis had an average of 69%. Talk about PTSD; both the students and their professor still remember that morning back in 2005!

    Have a great day on the bench!!

    Naproxen, Ibuprofen, Meloxicam or dialysis. What would your diabetics choose??

    NSAIDS: Proceed with caution especially with Diabetics and Cardiovascular patients!!!

    NSAID use was associated with a 1.18-fold increased risk of Chronic Kidney Disease (CKD) in subjects taking NSAIDs for 1 to 89 days; and a 1.32-fold increased risk of CKD in hypertension subjects taking NSAIDs for ≥90 days, compared with subjects not taking any NSAIDs, after controlling for the confounding factors.

    https://www.ncbi.nlm.nih.gov/pubmed/26169048?dopt=Abstract

    NSAIDs reduce blood flow to the glomerulus by inhibiting production of vasodilating prostaglandins. NSAIDs can increase blood pressure, cause fluid retention, and worsen renal function in these patients. Among patients with hypertension, those who take NSAIDs for three months or longer are about 32% more likely to have chronic kidney disease than nonusers.

    TRIPLE WHAMMY: Watch combinations of NSAIDS/ ACE inhibitors and diuretics! In the normal kidney, glomerular filtration is related to glomerular blood flow.
    • NSAIDS: block prostaglandin mediated afferent arteriolar VASODILATION. (lets blood perfuse into the glomerulus)
    • ACE/ARB: block Angiotensin-2 mediated efferent arteriolar VASOCONSTRICTION (increases pressure for filtration)
    • DIURETICS: decrease plasma volume


    Above is a slide I created for FreeCE.com that I also use in my lectures, showing how NSAIDS slow down the blood flow to the kidney by blocking prostaglandin mediated vasodilatation. On the other side at the efferent arteriole vasoconstriction is blocked by ACEi/ARBS like Lisinopril or Losartan. We use ACEi and ARBs for nephroprotection because they stabilize the basement of the glomerulus. Avoiding NSAIDs is the best way to keep ACEI/ARBs on board and minimize renal problems. Above all, remember the most effective method to prevent diabetic nephropathy is tight glycemic control and control of BP and cholesterol. Weight reduction, exercise, and avoidance of smoking also help.

    Commentary:
    My wife and I frequently attend drug company sponsored dinners. It gives us pharmacists a chance to get out from behind the counter and interact with fellow health care professionals.

    Dr. Vijay Bahl, Chief of Endocrinology at UPMC Shadyside Hospital in Pittsburgh, was the presenter at the last dinner we attended. He was discussing the renal protection of canagliflozin and was talking about NSAIDs have a detrimental effect on the afferent arteriole. I asked Dr Bahl,"so you are saying NONE of our diabetic patients should EVER get an NSAID?"

    He said "correct, no diabetic patient should ever get an NSAID". Some in the room pressured him, asking if any NSAIDS are safer; some talked about acetaminophen’s lack of efficacy. Dr Bahl replied, “I tell my patients, you can either take acetaminophen for your pain, or eventually go to dialysis three times a week.” He said no one ever selects the dialysis option!

    Have a great day on the bench!!

    Do your pharmacist and patients a favor... prescribe aspirin, if indicated!

    Aspirin Dosage: for relief of mild to moderate pain is 325-1000mg every 4-6 hours., with a maximum dose = 4000 mg/day. Up to 3-4 g per day has been used for the treatment for rheumatoid arthritis, lupus, and other rheumatologic conditions. Of course watch for GI bleeding.

    Most of us pharmacists seldom see aspirin used for pain and inflammation, but rather for aspirin’s antiplatelet activity with the dose being 81-325mg/day. For acute myocardial infarction, the AHA/ACCF recommends chewing 162 to 325 mg immediately, unless patient already taking daily aspirin.

    PLATELETS before PAIN
    Aspirin’s cardiovascular benefits stem from its permanent inactivation of platelet COX-1, which blocks the production of thromboxane A2. Blocking Thromboxane A2 inhibits thromboxane A2-dependent platelet function and vasoconstriction. Aspirin irreversibly blocks platelets for their lifetime of 7 days. Complete blocking of platelet activity can be achieved with only 75 to 150 mg of aspirin.

    DOES EVERYONE GET ASPIRIN?
    The newest recommendations (ACC/AHA) : New guidelines say that daily, low-dose aspirin should be used infrequently to prevent primary cardiovascular disease. The bleed risk isn’t worth the benefit, until you have had an event. The American College of Cardiology and the American Heart Association conclude that aspirin should be reserved for people with the highest cardiovascular risk and the lowest risk for bleeding.

    Adults who are 40 to 75 years of age and are being evaluated for cardiovascular disease prevention should undergo 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimation and have a clinician–patient risk discussion before starting on pharmacological therapy, such as antihypertensive therapy, a statin, or aspirin. ASCVD calculators are found online and in many Electronic Medical Records.

    Aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit. Men seem to benefit by prevention of myocardial infection, while women get their benefit from reduction of ischemic strokes.

    RISKS vs BENEFITS
    • Avoid aspirin in patients with additional GI risks unless their CV risk is high enough to outweigh the higher bleeding risk.
    • Make sure blood pressure is controlled before starting aspirin to reduce the risk of hemorrhagic stroke.
    • Always access the risk for potential for GI bleeds when combined with other NSAIDS. Don’t forget to include over the counter ibuprofen (Advil) and naproxen (Aleve).
    • Stop Aspirin with a 7 to 10-day washout before major surgical procedures.
    • Stopping aspirin in patients with a prior heart attack leads to 4 extra heart attacks per 1000 patients per year. Aspirin is serious therapy, and I advise prescribers to write a prescription for aspirin therapy.
    PRESCRIBING ASPIRIN:
    It is best to prescribe aspirin in the following circumstances:
    • Post stenting- bare or drug-eluting: indefinitely
    • Combined with Niacin ER (Niaspan, because it blocks prostaglandin mediated vasodilatation. That is, if anyone is using Niacin for mixed hyperlipidemia.
    • Combined with clopidogrel (Plavix) or ticagrelor (Brilinta) post stent
      • Bare Metal (non-ACS) 1 month up to 12months
      • Drug-eluting: 12 months post ACS
    • Ticagrelor (Brilinta) per package insert, patient must take an 81mg aspirin with one of the two Brilinta doses daily
    • MONA (Morphine, Oxygen, Nitroglycerin, Aspirin) therapy for myocardial infarction in the Emergency Department setting..
    Aspirin has been around 120 years now, and we still have not figured it out yet!

    Vince Capone one of the Physician Assistants I work with at Empower-3, also pulls an occasional shift in the Trauma Unit at UPMC Altoona. Vince tells me that frequently people come in with aspirin on board and have bleeding due to trauma. They frequently use DDAVP (desmopressin) to reverse the action of aspirin on the platelets.

    DDAVP, can be used for Von Willebrand’s disease, for bed wetting, diabetes insipidus and to reverse the effects of aspirin. Now that is a versatile drug!

    Have a great day on the bench!!

    October 2019



    Whats up with Cox-1 and Cox-2

    MOST NSAIDS inhibit COX-1 and COX-2 : Cyclooxygenase are the enzymes that produce prostaglandins. There are two types of COX enzymes simply named, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining.
    Blocking COX (Cyclooxygenase) inhibits prostaglandin and thromboxane synthesis.

    Here are the 4 A's of Cox inhibition
    • Anti-inflammatory (reduces inflammation)
    • Antipyretic effect (reduces fever)
    • Antithrombotic effect (reduces platelet stroke risk)
    • Analgesic effects (reduces pain)
    All NSAIDs inhibit COX-1 and COX-2 to different degrees. Mechanisms of inhibition:
    • Category 1: rapid competitive reversible binding of COX-1 and COX-2 (ibuprofen, piroxicam)
    • Category 2: rapid, lower-affinity reversible binding followed by time-dependent, higher-affinity, slowly reversible binding of COX-1 and COX-2 (diclofenac, indomethacin, naproxen)
    • Category 3: rapid reversible binding followed by covalent modification of COX-1 and COX-2 (aspirin)
    PRECAUTIONS for NSAIDs:
    BAD NEWS: GASTRIC DISTRESS
    REALLY BAD NEWS: CARDIOVASCULAR RISK as well as RENAL RISK
    • KIDNEY: Caution if renal impaired, may cause nephrotoxicity by blocking afferent vasodilatation. We will devote an entire column to renal effects of NSAIDS
    • PREGNANCY: All are pregnancy Category –D in third trimester, (near delivery) due to premature closing of the ductus arteriosus. Use lowest effective dose, intermittently if possible, especially in late pregnancy (avoid during last eight weeks of pregnancy).
      • First Trimester: link to miscarriage and certain rare birth defects in the first trimester
    • NURSING MOMS: Because of its extremely low levels in breastmilk, short half-life and safe use in infants in doses much higher than those excreted in breastmilk, ibuprofen is a preferred choice as an analgesic or anti-inflammatory agent in nursing mothers. Best to avoid Naproxen (Aleve®) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
    • STOMACH: active GI disease
    • LIVER: Caution in liver impairment.
    • HEART: Exacerbation of heart failure, as well as increased risk of myocardial infarction, stroke, CV death. If an NSAID is needed Naproxen is a safer choice.
    • EVERYTHING ELSE:
      • photosensitivity
      • Avoid Aspirin & alcohol while taking NSAID
      • Watch for increased hypertension
    PREVENTION OF GASTROINTESTINAL RISKS:
    • Proton pump inhibitors
    • High dose H2RA Pepcid (famotidine) 40mg twice daily, will reduce risk of both gastric and duodenal ulcers
    • Misoprostol due to cramping, diarrhea and four times daily administration is seldom used.
    I remember as a kid growing up in the 1960's my Mom had a glass prescription bottle that had a paper note written inside. On the paper was written "DON-NO", indicating my brother was never to be taking this drug.

    The well-worn prescription label read "Butazolidin alka". Mom said it "almost knocked out his kidneys." She would ensure that there would be no repeat of that major side effect.

    I also remember my Dad at that time had a large glass bottle of "Ascriptin" which contained aspirin plus Maalox® (magnesium and aluminum hydroxide). The Maalox® was added to the aspirin to buffer the acidic effects of the aspirin.

    Until ibuprofen came over the counter in 1984, that is all we had in the NSAID family without a prescription.

    History has taught us to respect NSAIDS!

    Have a great day on the bench!!

    1898-Heroin; 1899-ASPIRIN both came from Bayer Pharmaceuticals

    NSAIDS, The Basics
    Non-steroidal anti-inflammatory drugs (NSAIDs); we use them every day in our practice. We’ve had them for many years and new information about when NOT to use them seems to come out rather frequently. With all the pressure on prescribers to avoid opioids NSAIDs are being called upon to pull the pain relief wagon. Even though a couple of these drugs (aspirin, ibuprofen, naproxen and ketoprofen) have over-the counter status, these drugs are certainly not innocuous. There are at least 16 NSAIDS with different pharmacokinetic profiles. The first and still most famous NSAID aspirin was developed by the Bayer Company in Germany in 1899, one year after Heroin® (diacetyl morphine) was introduced.

    The earliest NSAID came from white willow bark and contained salicin, similar to aspirin (acetylsalicylic acid). Our local aspen and birch trees also have salicin in their bark. Salicin was a precursor to aspirin before its development, and was used for reducing pain and inflammation. Hippocrates, the Greek physician (460 to 377 B.C.), wrote that willow leaves and bark relieved pain.

    Edward Stone, rediscovered aspirin in 1767, in effect, when he wrote that powdered willow bark seemed to benefit 50 patients with ague (malaria) and other maladies. The next big advance for non-steroidal anti-inflammatory drugs came when Felix Hoffman and Arthur Eichengrun reacted sodium salicylate with acetyl chloride to form aspirin. This compound was later marketed by Bayer under the trade name Aspirin which was registered as a trade name in January 1899.

    Mechanism: inhibit prostaglandin synthesis from arachidonic acid by inhibiting enzymes COX-1 and COX-2. Aspirin inhibits platelets by irreversible inhibition of platelet Cox-1 and inhibition of Thromboxane-A2. Today most patients use aspirin for cardiovascular protection, which will be covered later.

    AVOID: aspirin in kids under 18, due to the risk of Reye’s syndrome. Reye's syndrome is a rare but serious condition that results in fatty changes of the liver and acute encephalopathy mostly in children and teenagers recovering from a viral illness such as influenza or chickenpox. Ammonia accumulates and enters the central nervous system resulting in nausea/vomiting and altered mental status. The persistent vomiting seen with Reye's syndrome can result in dehydration and electrolyte abnormalities, especially in young children. Left untreated, patients can experience minor brain damage, seizures and possibly death. Also avoid other forms of salicylates such as Pepto-Bismol, menstrual products with magnesium salicylate and Alka-Seltzer.

    What ever happened to the other salicylates?
    • Salsalate (Disalcid): is a weak inhibitor of cyclogenase. Salsalate is a nonacetylated dimer of salicylic acid
    • Choline magnesium trisalicylate (Trilisate) is a nonacetylated dimer of salicylic acid.
    • Diflunisal (Dolobid) is a difluorophenol derivative of salicylic acid approved in 1982.
    Like Kasimir Funk, the Father of Vitamins, AlbertEichengrun is another forgotten scientist that made a huge impact on medicine.

    There are different references that describe a controversy between Dr. Albert Eichengrun and Felix Hoffman for the discovery of aspirin. In 1949, Arthur Eichengrün published a paper in which he claimed to have planned and directed the synthesis of aspirin along with the synthesis of several related compounds.

    Eichengrun claimed that Hoffmann's role was restricted to the initial lab synthesis using his (Eichengrün's) process and nothing more. Bayer denied his account of the story.

    Dr Eichengrun had another treatment that impacted the health care of its time. Dr Eichengrun developed Protargol (silver proteinate) in 1897. This drug had bactericidal properties and was the standard of care for treatment of gonorrhea for 50 years, until the availability of antibiotics.

    Have a great day on the bench!!

    Second and third generation antihistamines are valuable treatment for our allergy sufferers.

    2nd and 3rd Generation Antihistamines
    Last week we discussed the role of antihistamines in the treatment of seasonal allergies, and delineated the three generations of antihistamines. Since everything we do as practicing clinicians revolves around patient care, let’s discuss counseling points to share with each patient that utilizes our expertise.

    SECOND GENERATION ANTIHISTAMINES: do NOT cross BBB, causing minimal sedation, and NO anticholinergic side effects.
    • PREGNANCY: ACOG also recommends cetirizine and loratadine after the first trimester in patients who cannot tolerate or do not respond to maximal doses of chlorpheniramine. (All three drugs are Pregnancy Category B)
    • FYI: Cetirizine is the active metabolite of the prescription drug Hydroxyzine (Vistaril®, Atarax®)
    THIRD GENERATION are the "active enantiomers" of the second generation antihistamines
    • FEXOFENADINE: Fruit juices such as grapefruit, orange and apple juice may decrease the oral bioavailability of fexofenadine by inhibiting the activity of OATP1A2. Fexofenadine is a substrate of the intestinal uptake transporters organic anion transporting polypeptide 1A2.
    • DESLORATADINE: Desloratadine is the active metabolite of loratadine.
      • Novel use for treatment Lyme Disease: Loratadine metabolite "desloratadine" blocks BmtA (Borrelia metal transporter A). Desloratadine (which is the brand name "Clarinex") blocks manganese from entering the cell. Transition metals, including iron (Fe), zinc (Zn), and manganese (Mn), are critical to both bacterial metabolism and virulence. When these metals are blocked it starves the Borrelia burgdorferi and causing it to die in test tubes. Obviously this is way too early in the research phase for us to recommend this to our patients, so we will have to wait and see. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330029/




    REMEMBER SELDANE® ?? (removed from market in 1998) Fexofenadine is a primary metabolite of terfenadine (SeldaneRx). When terfenadine's hepatic conversion to the fexofenadine was blocked by other drugs or disease, levels of the parent drug (terfenadine) rise resulting in heart rhythm disturbances. Fexofenadine is effective in allergic disorders, and less cardiotoxic.

    REMEMBER HISMANAL®??(removed from market in 1999) Astemizole was the active ingredient in this second-generation antihistamine. This drug was also removed due to QTc interval prolongation and related arrhythmias when used with high doses, especially when taken with CYP inhibitors or grapefruit juice. This product was marketed by Janssen Pharmaceuticals.

    Both of these second generation antihistamines were pulled from the market leaving only loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra).

    Claritin became available over the counter in November 2002. Zyrtec became available in November 2007 without a prescription, and Allegra got its OTC approval in January 2011.

    Have a great day on the bench!!

    Antihistamines have been around for almost 75 years. Can you imagine life without them----Ahhhh-CHOO!!!!

    FIRST GENERATION ANTIHISTAMINES
    Last week we discussed the abundance of ragweed and its associated effects. This week we will discuss the use of antihistamines, of the first generation. Many of us “seasoned” pharmacists remember when these drugs were moved from behind the counter to OTC status. Although safe and effective, pharmacist expertise is necessary in quite a few patient groups.

    A brief HISTORY of antihistamines:
    • 1942 Bernard Halpbern introduced the first antihistamine: N-diethylaminoethyl-N-benzylalanine- Institute Pasteur in Paris
    • 1945 diphenhydramine became available, followed by chlorpheniramine, brompheniramine and promethazine later in the 1940's. Chlorpheniramine and Brompheniramine became over the counter September 9, 1976.
    • Diphenhydramine became available first as an antitussive in Aug-1981 (Benylin); as a sleep aid (50mg) in 1982 (Sominex-2), and as an antihistamine (25mg) Jan-1985 (Benadryl)

    • MECHANISM: H1-antagonists competitively inhibit the action of histamine on tissues containing H1-receptors. Some also block histamine release, but only in excessive doses. The H1-antagonists do not block antibody production or antigen-antibody interactions.
      USES: Symptomatic treatment (sneezing, rhinorrhea, and itching of eyes, nose, and throat) of allergic rhinitis, chronic idiopathic urticarial, as well as motion sickness & nausea/vomiting. Always best to start antihistamine therapy at least two hours before exposure.

      Structural Classes: Active Ingredient(s):
    • Alkylamines - brompheniramine, chlorpheniramine, triprolidine, pheniramine
    • Ethanolamines - clemastine, diphenhydramine, doxylamine
    • Ethylenediamines - pyrilamine (has some diuretic effects)
    • Piperidines - fexofenadine, loratadine
    • Piperazines: cetirizine, hydroxyzine, meclizine

    THREE GENERATIONS OF OTC ANTIHISTAMINES: First generation are the older, and more sedating antihistamines. They also cause numerous anti-cholinergic side effects. They cross the blood brain barrier.
    • Examples: Chlorpheniramine (Chlor-Trimeton), Clemastine (Tavist), Diphenhydramine (Benadryl), Brompheniramine (Dimetane)
    • First generation antihistamines are commonly used for allergy, hives, sleep induction, cough, vertigo, motion sickness, itching, adjunct for nausea and vomiting and runny nose. A lot of the benefits of these first-generation antihistamines is tied to their anti-cholinergic side effects.
    • Anticholinergic side effects: blurred vision, dry mouth, urinary retention, constipation. (“can’t see, can’t spit, can’t pee, can’t sh*t”)

    AVOID FIRST GENERATION ANTIHISTAMINES:
    • AVOID in ELDERLY: All first-generation antihistamines are listed in the Beers List. Due to their highly anticholinergic activity and reduced clearance with advanced age. Tolerance develops when used as hypnotic; may also see increased risk of confusion, dementia, cognitive impairment, dry mouth, and constipation. May also increase fall risk
    • Avoid in men with BPH (prostate hypertrophy)
    • Avoid in children under age six
    The second generation (non-sedating) do NOT cross the blood brain barrier, causing minimal sedation, and NO anticholinergic side effects.
    • Examples: Loratadine (Claritin) and Cetirizine (Zyrtec)
    • Third generation are the “active enantiomers” of the second generation antihistamines
      • Fexofenadine (Allegra) We will explore the second and third generation antihistamines next week.
    A retired allergist once told me that Central Pennsylvania was the best place on earth to practice!

    How well us seasoned pharmacists remember when antihistamines were made available over-the-counter. I remember when Benylin came over the counter, and we pharmacists were using it for everything from urticaria, insomnia to allergies.

    Antihistamines becoming over the counter started the beginning of pharmacists having a role in saving health care dollars. For every ONE dollar a patient spends in the front of our store, they save the health care system SEVEN dollars.

    The first prescription I filled as a newly licensed pharmacist in August of 1981 was for Benadyl 50mg capsules by Parke-Davis. I often wonder how many times I checked and rechecked that one!

    Next week we will cover another game changer in self care, the second and third generation antihistamines.

    Have a great day on the bench!!

    Keep the windows closed, and the air conditioner running!

    Achoooo.. That most familiar sound we hear this time of the year as the ravages of ragweed in the fields affects our patients.
    Flower pollens like those from annual plants like marigolds, petunias and impatiens rarely cause allergy, as their pollen is moved by bees. It is the windborne pollens that present the most difficulty to allergy sufferers. According to the Allergy and Asthma Foundation of America, 10-20% of us suffer from ragweed allergy.
    Here are some more teaching points to share with your ragweed patients:
    • Ragweed is most common in the Eastern states and the Midwest, mostly in rural areas. It includes several members of the daisy family.
    • A single plant produces up to 1 billion pollen grains.
    • Ragweed flowers mature and release pollen. The pollen must become airborne to fertilize other seeds.
    • Warmth, humidity and breezes after sunrise help the release. Pollen levels are highest in the morning & early afternoon (10am-3pm)
    • The pollen must then travel by air to another plant to fertilize the seed for growth the coming year.
    • Pollens can travel up to 400 miles out to sea, but most fall locally.
    Some treatment approaches can be:
    • Avoiding the peak pollen times for outdoor activity between 10am and 3pm.
    • Use central air conditioning, and HEPA filters. Maintain filters often.
    • Let the pollen outside! If you spend a lot of time outside during peak pollen time:
      • Take your shoes off outside
      • Don't wear your "outside" clothes to bed
      • Take a shower and shampoo your hair at night before going to bed.
    • Use of antihistamine therapy, which we will discuss in the next two weeks
    • Use of immunotherapy if insufficient response to antihistamines. They help desensitize the patient. Two immunotherapy options are available for severe cases of ragweed allergy:
      • Allergy shots can help build resistance to ragweed allergens.
      • Tablets that dissolve under the tongue are available by prescription. These sublingual tablets must be started 12 weeks before the beginning of ragweed season.
    Ragwitek: (Short ragweed pollen allergen extract) (cost $360.00/month)
    contains small amounts of natural short ragweed pollen that builds tolerance to decrease sensitivity to ragweed pollen.
    Use: Treatment of short ragweed-induced allergic rhinitis with or without conjunctivitis, that has been diagnosed by an allergist using skin testing.
    Dose: 1 tablet sublingual once a day (12 Amb 1-unit). Approved for ages 18-65. First dose must be dosed under medical supervision in a doctor’s office. Ragwitek® can cause severe allergic reactions that may be life-threatening.
    Medication should be laid under the tongue, and patient does not swallow for 1 minute. Patients should NOT take with food or beverages and not eat or drink for at least five minutes after administration.
    Notes: Should be started at least 12 weeks before the expected onset of ragweed pollen season and continue throughout the season. symptom score improved by approximately 18% or more.

    Next week we will explore the antihistamines.

    A retired allergist once told me that Central Pennsylvania was the best place on earth to practice!

    We have the deciduous and evergreen tree pollens in the spring, then the grass pollens in the summer. The rainy days of spring and summer produce lots of molds, leading into fall when the ragweed is in full bloom until the first killing frost. Couple that with our cool nights and everyone opens the windows (and even puts a fan in the window) to suck in all these outdoor allergens!

    We have a lot of treatment options to help our allergy suffering patients. We'll explore those treatment options in the coming weeks. We will cover first , second and third generation antihistamines.

    Wait! There are three generations of antihistamines??? Stay tuned for the next couple of weeks.

    Have a great day on the bench!!

    September 2019

    This handy chart will help you make decisions about therapy for your Type-2 patients with diabetes.

    NEWS FLASH--- oral GLP-1 available!!!

    Class / Generic name Brand name Physiologic action (Mechanism) Comments
    Biguanides (HbA1c=-1.5) Decreases hepatic glucose production Used first line. Weight neutral. GI side effects.
    Metformin Glucophage
    Sulfonylureas (2nd gen) (HbA1c= -1-1.5) Increases insulin secretion from the beta cells of pancreas Causes hypoglycemia, weight gain (5lb) , low durability
    Glyburide Micronase or Diabeta Avoid Glyburide in elderly (Beers List)
    Glipizide Glucotrol
    Glimepiride Amaryl
    Meglitinides (HbA1c=- 1-1.5) Increases insulin secretion Fast acting. Give with meal. May cause hypoglycemia
    Repaglinide