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  • August 2021

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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!!

    Micro-Learning CE Associated - Click Here For Details

    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!!

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    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!!

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    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

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    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!!

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    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.

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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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    March 2021

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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.

    Have a great day on the bench!!

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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!

    Have a great day on the bench!!

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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.

    Have a great day on the bench!!


    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!!

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    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!!

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    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

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    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!!

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    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!!

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    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!!

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    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

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    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!!

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    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!

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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 Prandin
    Nateglinide Starlix
    Thiazolidinediones (HbA1c-.5-1) "TZD's" Increases insulin sensitivity No hypoglycemia, some weight gain (7lb) , heart failure,
    Pioglitazone Actos Bladder cancer(?)
    Rosiglitazone Avandia Heart failure (?)
    Alpha glucosidase inhibitors (HbA1c=-.5-.8) Slows intestinal carbohydrate digestion and absorption GI upset, gas, dosed with each meal. Must use glucose tablets for hypoglycemia
    Acarbose Precose
    Miglitol Glyset
    DPP4 inhibitors (HbA1c= -.5-1) Increase insulin secretion; blunts glucagon secretion Weight neutral. No hypoglycemia. Pancreatitis (?)
    Sitagliptin Januvia
    Saxagliptin Onglyza
    Linagliptin Tradjenta No renal adjustment No drug interactions
    Alogliptin Nesina
    SGLT-2 Inhibitors (HbA1c=-.5-1) Blocks reabsorption of glucose. Increases glucose in urine Slight increase in candida genital infections. Weight loss (-5 lbs)
    Canagliflozin Invokana
    Empagliflozin Jardiance (cardio protective)
    Dapagliflozin Farxiga
    Ertugliflozin Steglatro


    NON-oral MEDICATIONS
    GLP-1 agonists (HbA1c=-1-1.5) Decrease glucagon secretion, increases insulin secretion. Slows GI emptying, increases satiety Rarely causes pancreatitis and gastroparesis. Weight loss (-6lb). once weekly GLP's may cause medullary thyroid carcinoma.
    Exenatide Byetta and Bydureon Byetta dosed twice daily. Bydureon given once a week
    Liraglutide Victoza Dosed once daily cardioprotective
    Liraglutide Saxenda Dosed once daily Approved only for weight loss
    Dulaglutide Trulicity Dosed once weekly
    Semaglutide Ozempic Rybelsus-oral Dosed once weekly oral Rybelsus approved Sept 26,2019 dose 7mg or 14mg once daily in am.
    Lixisenatide Adlyxin Dosed once daily
    Insulin (HbA1c-greater than 1.5) Weight gain 7-11 lbs. Hypoglycemia
    Inhaled Afrezza Ultra-rapid acting First inhaled insulin
    Lispro Humalog Admelog Fast acting Mealtime insulin
    Humalog U-200 U-200 Kwikpen Double strength Mealtime insulin
    Aspart Novlog Fiasp Fast acting (Fiasp:2.5 minute onset) Mealtime insulin
    Glulisine Apidra Fast acting Mealtime insulin
    Regular Novolin-R Humulin-R
    NPH insulin Humulin-N Novolin-N Intermediate acting
    Detemir Levemir Long acting Basal insulin
    Glargine Lantus Basaflar Long acting Basal insulin
    Glargine Toujeo U300 Long acting First U-300 insulin. 300units/ml
    Degludec Tresiba Long acting Available as U-100 and U-200pens
    Insulin/Incretin combos
    Glargine & lixisenatide Soliqua 100/33 Long acting insulin + incretin Inject once daily, within one hour of first meal of the day. Use alternative treatments if doses below 15 Units or above 60 Units are required. Discard pen 14 days after first use.
    Degludec& liraglutide Xultophy 100/3.6 Dose 10-50 units (max) same time each day; with or without food.
    Glucagon Glucagon (Eli Lilly) (glucagon for reconstitution) Ultra-short acting treatment for hypoglycemia. Glucagon increases glucose by mobilizing conversion of glycogen stored in the liver Used to rescue insulin dependent diabetics with hypoglycemia, that can't swallow. (naturally produced in alpha cells in Islet of Langerhans)
    Auto injector Gvoke® (Xeris Pharmaceuticals) Stabilized glucagon for injection. 1mg and 0.5mg Autoinjector (Hypopen®) and prefilled syringe available
    Nasal powder Baqsimi® (Eli Lilly) Powder for nasal inhalation Available as 3mg powder


    Not much to say... here's your chart.

    My students frequently ask me for charts and I made this one a few years back, and always seem to be adding to it. Here are the past 15 newsletters rolled into one!

    If you want a PDF file of this chart, feel free to e-mail me.

    One hour before I was to launch this newsletter Novo-Nordisk announced the availability of Rybelsus(r) oral semaglutide. 7mg and 14mg. Whew... that was close.

    Have a great day on the bench!!

    Health care providers and diabetics REJOICE!!! We have glucagon that is easily administered!!

    Glucagon---now available in easy to use dosage forms!
    Paul Langerhans, a 22-year-old medical student discovered in 1869 islands of clear cells that bear his name. In 1907, another medical school student Michael Lane was able to differentiate between the alpha and beta cells. In 1922 Charles Best, a medical student working with Dr. Frederick Banting is credited with the discovery of insulin. 1923 Charles Kimball, a biochemistry student, isolated glucagon from the alpha cell, as he worked at the University of Rochester. In spite of this life-saving discovery that he named glucagon, he was never granted a PhD from that institution.

    The beta cells are associated with insulin production, while the alpha cells are associated with the production of glucagon. I find it amazing that these signifcant discoveries in diabetes were discovered by students!

    GLUCAGON: THE BASICS
    Simply put, glucagon raises blood sugars. In healthy patients, a rise in blood glucose activates both a glucose dependent and independent inhibition of glucagon secretion from alpha cells. Glucagon increases glucose by mobilizing conversion of sugar (glycogen) stored in the liver. Glucagon is further controlled by GLP-1 (glucagon like peptide) which inhibits glucagon release from the alpha cells and potentiates glucose induced insulin secretion. GLP-1 can be administered by injection with such drugs like Byetta®, Victoza®, Trulicity® and Ozempic®. Glucagon is administered for the treatment of severe hypoglycemia, especially for patients unable to swallow. Up until 2019, glucagon could only be administered as an injection that needed reconstituted. This cumbersome product required diluent placed in a vial of dry powder, swirled, withdrawn into a syringe and injected in the patient. Think about trying to utilize such a product in the event of an emergency… with your loved one. July and September 2019 brought diabetics and those of us who care for them some very good news.

    Glucagon for Injection (Eli Lilly) (cost is $300.00)

    GlucaGEN hypokit for Injection (NovoNordisk) Glucagon Emergency kit was approved in September 1998. The powder in vial needs to be reconstituted and yields a dose (adult) of 1mg SC, IM or IM. The pediatric dose for a child under 20kg= .5mg
    • Inject glucagon into the individual's buttock, arm or thigh, following the manufacturer's instructions.
    • When the individual regains consciousness (usually in 5-15 minutes), they may experience nausea and vomiting.
    • Inform provider about glucagon use to discuss hypoglycemia.
    Baqsimi ($300.00 per dose)
    is a glucagon nasal power dosed at 3mg approved by the FDA in July 2019 and marketed by Eli Lilly. Baqsimi is approved to treat severe hypoglycemia in patients with diabetes 4 and older.

    Efficacy: Baqsimi demonstrated efficacy comparable to injectable to glucagon 1mg injection. 98.9% experienced treatment success versus 100% for glucagon injection.
    Adverse effects: Aside from nausea and vomiting, nasal irritation and redness in the eyes can occur due to route of administration.
    Ease of use: Baqsimi is given on one side of the nose. It does not need to be insufflated. It is effective if a patient has nasal congestion due to cold, or if taking cold medicine. Emergency services should be called at once, and after 15 minutes another dose can be given if there is no response.

    Gvoke® ($300.00 per dose) by Xeris Pharmaceuticals
    was released this month (Sept-2019) and is the first and only premixed, pre-filled, and pre-measured liquid glucagon product, now approved for the treatment of severe hypoglycemic events among adults and pediatrics with diabetes ages two and older. Gvoke is available as a prefilled syringe as well as an autoinjector (Hypopen)

    Efficacy: Gvoke® demonstrated its ability to effectively resolve severe hypoglycemia showing 99% of adults and 100% of children achieved treatment success, which occurred in less than 14 minutes.
    Packaging: Gvoke® has two pre-measured dosing options: one for adults (1 mg/0.2 mL) and one for children (0.5 mg/0.1 mL), available in one or two-device packages.
    Ease of use: In usability studies, 99% of people were able to successfully administer a full dose of Gvoke in a simulated emergency setting

    About three years ago I attended a drug company promotional dinner for an insulin product. The chief of Endocrinology at Geisinger Dr Rick Sunderlin did an awesome presentation. After his brilliant lecture on basal insulin, I asked this question of the manufacturer “When are you going to develop an autoinjector for glucagon?”

    The manufacturer recently developed an auto injector for naloxone to complement their epinephrine auto injector. I said to the sales representatives “think about it, when a person needs to utilize an epinephrine pen, they are usually able to self-administer the dose. When a Type-1 diabetic needs a dose of glucagon they are unable to swallow and could be having seizures. The caregiver would be the one to administer glucagon and the only available devices are so cumbersome.”

    Dr Sunderlin looked at the representatives and said, “I never thought about that, your company should get working on that immediately!” So, my many years of complaining about an easy to use glucagon device has come to an end. I am thrilled with Eli Lilly and Xeris for making these life-saving drugs available to our diabetic population at a price that matches the cumbersome glucagon emergency kit.

    I don’t say it often, but “well done drug companies.”

    Have a great day on the bench!!

    Is NPH a reasonable choice to hold costs down??

    NPH --soon to be 70 years old... does it have a place in diabetes management??

    NPH “Neutral Protamine Hagedorn” as we mentioned in the history of insulin is regular insulin that is matched molecule for molecule with the protein protamine. Protamine is a protein used in the hospitals to reverse excessive bleeding caused by heparin. The first commercially available NPH was available in 1950. The human insulin formulations became available in the early 1980’s.

    Humulin-N® or Novolin -N® U-100 (isophane insulin) has an onset of action= 1.5-4 hours, with a peak between 4-12 hours. NPH insulin has a duration of action of 24 hours.

    COMPARING LONG ACTING (BASAL) insulins to NPH
    • The type of insulin (basal or prandial) does not appear to affect cardiovascular outcomes, according to the HEART2D trial. (source: https://www.ncbi.nlm.nih.gov/pubmed/19246588)
    • A large health care delivery system studied and found there was no benefit of insulin analogs compared with NPH in reducing emergency department or hospital admissions for hypoglycemia. NPH group had slightly better control (HbA1c=7.9) versus basal insulin (HbA1c 8.2) suggesting both groups were managed aggressively.
    IS NPH a reasonable choice to replace basal insulins due to cost?
    • Standard long-acting insulin analogs like glargine (Basaglar/Lantus) and detemir (Levemir) are not superior to NPH insulin in efficacy terms as determined by the number of participants reaching HbA1c targets.
    • The use of the glargine and detemir which have flatter curves, showed 50% less nighttime hypoglycemia, when compared to NPH.
    • All insulin analogs, both short- and long-acting insulin analogs, contribute to a reduced rate of overall hypoglycemia and less weight gain compared with therapies based on regular human insulin and NPH insulin.
    • SUMMARY: NPH and basal insulins show equal efficacy. Basal insulins have less night time hypoglycemia. Basal insulins have less weight gain than NPH
    COST:
    It depends… the wholesale acquisition prices are as follows:
    • Lantus 10cc vial ($300.00 per vial)
    • Humulin NPH ($160.00)
    • Novolin-N ($150.00)*** one of the big box stores has a special agreement with Novo-Nordisk for $25.00 per vial.
    Keep in mind that human insulin whether NPH, Regular or mixed 70/30 is over the counter. However, a prescription needs to be issued for a pharmacist to bill insurance.

    We know who the "big box" company is that I refer to with the $25.00 insulin. I won't mention their name because they have more lawyers than I do!.

    I commend them for being able to negotiate, with Novo-Nordisk for such a fabulous price for the treatment of diabetes. My question is why won't Novo-Nordisk make this available to all of the pharmacies? Every time a representative from Eli Lilly come to the pharmacy or the clinic I tell them this is a great opportunity to get back at Novo-Nordisk, and price their Humulin NPH, Regular and 70/30 for $25.00!

    Imagine... a world where our patients who lose their insurance coverage could go to any pharmacy and buy insulin at a reasonable price. Imagine glargine costing $32.00 per bottle... (imagine Canada!!)

    Many clinicians feel that moving from glargine to NPH is taking a 20 year step backward. The might have a point with regard to nocturnal hypoglycemia and weight gain. As far as efficacy, both products are similar; as far as costs go it isn't even close.

    Have a great day on the bench!!

    Rapid acting insulins-- for mealtimes and pumps!

    RAPID ACTING INSULINS
    Rapid acting insulins are used for mealtime management of blood sugars. The insulin is given before a meal, with some clinicians telling patients “have a fork in one hand, and your insulin pen in the other!” Ideally the patient does their carb counting and calculates the dose of mealtime insulin based on their correction factor, as well as an insulin:carb ratio. Because so many patients are unable to accurately count carbohydrates, clinicians offer a fixed dose for mealtimes along with a correction factor after the patient does a mealtime finger stick.

    INSULIN LISPRO
    Insulin lispro is a rapid acting insulin formulation, where the original human insulin amino acid sequence is changed to make it faster acting than the regular insulin our own pancreas produces. Lispro insulin substitutes lysine for proline at position B28, and proline for lysine at position (B29). Lispro has an onset of action= 0.25 hours, with a peak = .5 to 1.5 hours.
    Expect a duration of action around 2.5 hours.

    Humalog® U-100 (Lispro) by Lilly, was approved in June of 1996. It is available as a vial and Kwikpen®. The vial is available as U-100 concentration. The Kwikpen® is available as both U-100 and U-200 pens. The U-200 pen might be of value in patients that take higher doses of Humalog in that net absorption is reduced with increasing size of the subcutaneous depot. The smaller size of the depot might lead to better and more predictable absorption.
    • Admelog® U-100 (Lispro) by Sanofi-Aventis, available in vials and pens, and is considered to be a biosimilar to Humalog. Since Admelog is not FDA approved as a generic, it cannot be automatically interchanged by the pharmacy without a new prescription from the provider. As far as cost difference, currently the Humalog U-100 Kwikpens® have a wholesale acquisition cost (WAC) of $530.40, and the Admelog® Solostar has a WAC of $252.47.
    • Insulin Lispro Kwikpen® by Eli Lilly, is an” authorized generic” available with a WAC of $265.20, which was Eli Lilly’s response to Sanofi’s Admelog Solostar. Both vials and Kwikpens are now available.
    INSULIN ASPART
    Likes lispro, aspart is a rapid acting mealtime insulin that the amino acid sequence is changed to provide a more rapid response than our own regular insulin produces. Insulin aspart has a single proline to aspartic acid switch at position (B28). Aspart has an onset of action= .25 hours, with a peak in 1-2 hours, and a duration of 3-5 hours.

    Novolog® U-100 (Aspart) by Novo Nordisk, was approved in June 2000 and is available as vials and Flexpens. Novolog Flexpens have a WAC of $558.53 per box of 5 pens, for a total of 1500 units.

    Fiasp®, competitor of Novolog, also made by Novo Nordisk, approved in September 2017. Fiasp has vitamin B3, (niacinamide) which makes it more fast-acting. Both Novolog® and Fiasp® contain insulin aspart and are priced the same at $558.83 (WAC). Fiasp can be taken as much as 20 minutes after starting a meal, while other injected mealtime insulins are best taken 15-20 minutes before eating.

    INSULIN GLULISINE

    Insulin glulisine, is the third rapid acting formulation. Like the other two it has amino acid substitutions that allow for a more rapid absorption. Glulisine has an asparagine to lysine substitution at (B3) and a lysine to glutamic acid substitution at (B29). Glulisine has an onset of action= 0.25 hours, with a peak of 30-90 minutes and a duration of 2-4 hours

    Apidra® U-100 (glulisine) was approved in July 2004. Apidra is available as vials and Solostar pens. A box of 5 Solostar pens has a WAC of $548.52.



    It is nice to see Eli Lilly respond to the noise being generated about ridiculous insulin prices by offering a generic for Humalog. According to Global News Canada, caravans are travelling to Canada to buy a vial of insulin for $30.00! https://globalnews.ca/news/5249662/americans-driving-canada-insulin-prices/

    Lots of noise has been made about insulin prices including from this writer. Back when I was a new pharmacist in 1982, the independant I worked for had an “insulin club” where we offered the 13th bottle of insulin free. At that time our insulin price was $5.99 per bottle, and the 13th bottle was free!

    Yes, I know I didn’t include Afrezza® the ultra-rapid acting insulin. This column has always focused on “clinically relevant” information! Should I ever dispense Afrezza, my opinion might change. Afrezza seems headed to the same demise as did Exubera, the first inhaled insulin. I still have my original Exubera inhaler kit. Most providers refer to these mealtime insulins as "logs" .

    I teach my students that the "logs" (Novolog and Humalog) are mealtime insulin. For the other two, Fiasp I call "fast insulin aspart." For Apidra, just unscramble the letters to get "a rapid".

    Have a great day on the bench!!

    August 2019

    CLEARing up the differences in basal insulins!

    The human body spends about 12 hours in the “basal” state and 12 hours in the prandial state, and the other 12 hours in the “fed state”. In April 2000, the biggest change in diabetes therapy since the introduction of human insulin in the early 1980’s occurred. Lantus (insulin glargine) came to the market. NPH insulin was the mainstay of diabetes management since its introduction in the late 1940’s. By rearranging the amino acid sequence of human insulin, they were able to make a 24-hour insulin. No zinc acetate buffers (Ultralente), no protamine (PZI, NPH), but rearranging the sequence by changing amino acid asparagine at position A21 and replacing it with glycine. Two arginines are added to the C-terminus of the B-chain. The pH is adjusted to 4.0 to allow for complete solubility, and its clear appearance. After injection into the subcutaneous tissue, the acidic solution (pH=4) becomes neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released. The low pH is responsible for the “stinging” patients experience upon injection

    Insulin Glargine
    • Lantus ® U-100 (insulin glargine) by Sanofi-Aventis
    • Basaglar® U-100 (biosimilar insulin glargine) by Eli Lilly
    • Toujeo ® (insulin glargine) by Aventis is a U-300 insulin. May substitute unit for unit with Lantus. Some patients may need a dosage adjustment.
    Glargine has an onset of 1.1 hours, and a duration of 24 hours. It has no pronounce peak, referred to as a zero-order release. Because of the low pH, other insulins should not be mixed in the same syringe with glargine. Glargine is usually dosed in the evening; can be dosed in the morning if morning hypoglycemia is a problem (especially with the elderly). Many clinicians split the dose as well. Glargine has an expiration date of 28 days after first use of either a pen or vial.

    Insulin Detemir
    Levemir® (detemir) by Novo Nordisc became available to mount a challenge to Lantus in 2005. Like Lantus it has a one hour onset, and is peak less, but that is where the similarities end. Levemir has a duration of 16-20 hours. Very few patients get the “up to 24 hours” of coverage. Levemir is made long acting by binding the fatty acid (myristic acid) to the lysine amino acid at position B29. It is quickly absorbed after which it binds to albumin in the blood through its fatty acid at position B29. It then slowly dissociates from this complex. It’s pH is more physiologic (pH=7.4). If converting from glargine, it is NOT unit for unit and may require 1.5 to 2x increase in units. Most patients require twice daily dosing. Detemir has an expiration date of 42 days from first use of a vial or pen.

    Insulin Degludec
    Tresiba (Degludec) by Novo Nordisc, released in 2015, was another attempt to unseat glargine from its hold on the basal insulin market. Degludec has an onset and peak similar to glargine and detemir BUT has a duration of action of 42 hours which allows for more flexible dosing. Degludec is made long acting by binding hexadecanedioic acid to lysine at the B29 position which allows for the formation of multi-hexamers in subcutaneous tissues. Also, amino acid threonine in position B30 has been omitted. This allows for the formation of a subcutaneous depot that results in slow insulin release into the systemic circulation, which is active at physiologic pH. Tresiba has a pH of 7.6
    Tresiba® is available in 2 concentrations: 200 units/mL and 100 units/mL, available only in pens, and carries an expiration date of 56 days.

    Lantus came with great fanfare in 2000 and caused some confusion with patients. They were accustomed to their long acting insulin (NPH) being cloudy and their mealtime insulin (Humalog, Novolog, Regular) being clear. Sanofi did make the vial as a long skinny vial.

    Insulin glargine (Lantus and Basaglar) are the mainstays for basal insulin therapy in our area. I have maybe two patients on Levemir, and maybe three using Tresiba.

    Clinicians are most comfortable with glargine, and for the most part are reluctant to switch patients due to poor glycemic control. Now if we could get the prices under control!

    Have a great day on the bench!!

    Insulin therapy is almost 100 years old. Do we have it figured out yet?

    Basics of Insulin Therapy... first a little history
    HISTORY: Frederick Banting (who was an orthopedic surgeon), Charles Best, James Collip, and John Macleod are credited with the monumental discovery of insulin at the University of Toronto in 1922. The discovery was followed shortly after by the successful large-scale production of insulin in 1923 by the USA company Eli Lilly, resulting from a collaboration between the Toronto researchers and the company’s director of biochemical research George Clowes. Leonard Thompson, a Canadian, was the first human to receive an insulin injection, which was from the pancreas of a dog. Banting and Best used an ox pancreas as the source of insulin.

    August Krogh, who was a Danish physiologist and winner of the 1920 Nobel Prize. While touring the United States was granted permission to produce insulin in Denmark. On his return to Denmark, Krogh, together with Hans Christian Hagedorn, founded the Nordisk Insulinlaboratorium with the financial support of pharmacist August Kongsted. H.C Hagedorn: In the 1930’s this Danish chemist, prolonged the action of insulin by adding protamine (remember protamine reverses heparin) to form a precipitate. We older pharmacists remember PZI insulin (Protamine Zinc Insulin) with its 24-36 hour duration of action. In 1946 Hagedorn mixed equal portions of protamine with regular insulin, at pH of 7. This Neutral Protamine suspension of insulin was named after Dr. Hagedorn. We refer to this insulin as NPH (Neutral Protamine Hagedorn)

    Frederick Sanger in the early 1950’s determined the chemical structure of the two-chains of the mature human insulin molecule. He was awarded the Nobel Prize in 1958 for his work in elucidating the amino acid sequence for insulin, which was the first protein to have its amino acid sequence determined.

    Herbert Boyer: Finally, an American! It gets even better!! Dr Boyer was born in Derry Pennsylvania in 1936 and attended St. Vincent College enrolling in their pre-med program. One of our local practitioners, Dr. William Aigner a retired family practice physician was a classmate of Dr Boyer’s. Dr Aigner relates the story that Herb was more interested in genetics, than going to med school. His classmates questioned his decision. Herb went on to found Genentech, and in 1978 produced synthetic insulin with the use of a genetically modified bacteria (E. coli). By the way in 1990, he gave $10 million to Yale, their largest gift ever received. In 2007 St. Vincent College named the School of Natural Sciences, Biology and Computing after him. I guess Herb made a good decision not attending med school!

    Source: the insulin used today is “human insulin”. In days of old sources of insulin were
    • beef: which is 3 amino acids different than human insulin
    • pork: which is 1 amino acid different (less antigenic)
      • (dogs and pigs have the SAME amino acid sequence)
    • these insulins were extracted from the pancreas of cattle and hogs.
    Human insulin: is manufactured today by 3 major drug companies:
    Eli Lilly: “Humulin®” is manufactured by recombinant gene coded to make insulin inserted into the bacterium E.coli.
    Novo Nordisk: “Novolin®” by Novo Nordisk manufactured by a recombinant gene inserted into baker’s yeast
    Sanofi Aventis: “Lantus ”and “Apidra® are produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism.

    “Regular insulin” as produced by pancreas, in healthy non-diabetic patients has the following profile:
    • onset: .5-1 hour.
    • 2-3 hour peak
    • 6-8 hour duration
    Modifications on the insulin molecule, allow for shorter durations, and much longer durations of action. Insulin can be instituted at ANY point for Type-2 diabetes and should NOT be considered as last resort for treatment of the disease. Insulin should never be perceived as a “punishment” for a Type-2 diabetic.
    Insulin resistance: Insulin resistance occurs when the body does not respond properly to its own natural insulin. Insulin is a hormone in the body that helps convert blood sugar to energy so it can be used by the body's cells. In individuals with insulin resistance, the pancreas tries to keep up with the demand for insulin by producing and releasing more. Eventually, the pancreas cannot keep up with the body's need for insulin, and excess sugar builds up in the bloodstream.

    Beta cell failure rate:
    • In a healthy adult patient, beta cells fail at about 0.3% per year. (Loss of 3% in 10 years)
    • In an adult patient with Type-2 diabetes, the beta-cell failure rate is 4-6% (loss of 40-60% in 10 years).
    • It is fair to say that if a patient develops Type-2 diabetes early enough in life, if living long enough he will need insulin therapy.
    • We are born with 91million beta cells; at diagnosis of T2DM patients have 45million
    Other points of wisdom come from Dr Vijay Bahl- endocrinologist, Pittsburgh PA.
    • We have “thrifty genes” that save energy, that have not adapted.
    • 11% of diabetics are hospitalized due to hypoglycemia
    • “insulinase” breaks down insulin in the kidney, be cautious of declining renal function
    • We are “terribly underdosing” diabetics. Most require 60-65 units of insulin, average dose in western PA is around 42 units.

    U-10 insulin. Check out the attached website for some really fun pictures from the Novo-Nordisk website.

    When Denise and I graduated Pharmacy School in 1981, ACE inhibitors were just coming to market. AIDS was part of the trademark for an adhesive dressing. Lots has changed in our 38 years of practice, but nothing more dramatically than insulin therapy. Open our refrigerators in 1981 and we had Iletin I (which was a port/beef insulin mixture) and Iletin-II (which was all beef or all pork), we had PZI, NPH, Regular, Lente, Semi-Lente, and Ultra Lente. We had insulin available in U-40, U-80 and U-100. We also hand insulin formulations from "Squibb-Novo" what was made by Novo-Nordisk.

    Most of all I remember the "Insulin club" we had at the local chain I worked at. We sold insulin for $5.99 for a bottle of "NPH-Squib" U-100 which was a beef insulin. That's right 10 cc of insulin for that ridiculous of a price, and if you bought 12 bottles you got the 13th one free!

    Today the pricing of insulin is outrageous to say the least. I remember the Lilly rep telling us in 1982 that their Humulin insulin would no longer rely on the prices of pancreases from the slaughterhouses and the prices would stabilize. In August of 2011, the cost for a 10cc vial of Lantus was $98.36 and now 8 years later the cost is $285.00! Do the math, it is a 3 fold increase!

    On January 23rd, 1923 Banting, Best, and Collip were awarded the American patents for insulin which they sold to the University of Toronto for $1.00 each. They saw so much good with their discovery. I'm sure they would be so disappointed with insulin prices today.

    Have a great day on the bench!!

    Diet and exercies are FIRST LINE treatment for Type 2 diabetes. Let's talk about weight loss with diet.

    Health benefits occur with just a 5% weight loss, however most patients need to lose a greater percentage. A 5-7% weight loss provides beneficial effects for reduction of cardiovascular disease, dyslipidemia, hypertension, and diabetes mellitus. More than a 30% weight loss goal usually requires bariatric surgery. A 15% weight loss is considered to be a success.
    The AHD study was a multi-center trial emphasizing weight loss. Patients who lost 5-7% of their body mass showed reduced use of antihypertensive medications, statins, and insulin; reduction in urinary incontinence, sleep apnea, and depression; and improvements in quality of life, physical functioning, sexual functioning, and mobility. Before we blame the fork and spoon, let’s look at some other potential causes of weight gain in the pharmacy.

    It’s my meds causing weight gain!
    • Valproic acid: Depakene/Depakote
    • Mirtazapine (Remeron)
    • Paroxetine (Paxil)
    • Amitriptyline (Elavil)
    • Prednisone
    • Insulin and sulfonylureas
    • Depo-Medroxyprogesterone
    • All first generation antipsychotics (Thorazine, Stelazine, Haldol, etc)
    Here is a breakdown of the second-generation antipsychotics:

    HIGHEST WEIGHT GAIN
    • Clozapine (Clozaril®)
    • Olanzapine (Zypexa®)
    LOWEST WEIGHT GAIN
    • Ziprasidone (Geodon®)
    • Aripiprazole (Abilify®)
    • Lurasidone (Latuda®)
    • Paliperidone (Invega®)
    It’s my thyroid causing weight gain!
    “ITS MY THYROID” if this is suspected…have the patients physician order a blood test!
    • Most of the extra weight gained in hypothyroid individuals is due to excess accumulation of salt and water.
    • In general, average about 7lb of body weight may be attributable to the thyroid, depending on severity.
    • If weight gain is the only symptom of hypothyroidism that is present, it is less likely that the weight gain is solely due to the thyroid.
    The golden rule is there are roughly 3,500 calories in a pound of fat. Think of the waist line as an individual checking account. Deposits are in the form of calories consumed and withdrawals in the form of exercise and decreased caloric intake. If less is added, and more is withdrawn, weight loss occurs.
    • Lower calorie intake by 500 kcal per day (3x 12 oz soda) lose one pound per week.
    • Deduct 500 calories per day by exercise, lose 2 pounds per week.
    • Don’t replace “fat calories” with carbs. Balance is the key to any diet plan.
    More weight loss tips for your T2DM patients
    • Adopt a healthy lifestyle
    • Follow “My-Plate” -remember it is a 9-inch plate! (go ahead—measure your dinner plate!)
    • Focus on fruits and vegetables, lean meat, low fat dairy, and whole grains
    • All foods can fit, portion control is key
    • Don’t skip meals
    • Avoiding eating-out—save calories and money too!
    • Rethink-your drink- avoid any drink that has calories. Nothing hydrates better than water.
    • Move more!!
    • Schedule an appointment with your dietician.


    Think about your T2DM learning experiences in your school’s curriculum. For all the times we recommend diet and exercise, how little exposure do we get to these concepts in our formal training? A consult from a dietician is most valuable to treat T2DM.

    We have been extolling the virtues of exercise, and my wife Denise reminded me of a quote from one of our Physician Assistant students, “you can’t exercise off a bad food choice”. Is there any wonder that our waistlines have expanded in proportion to the number of restaurants in our area?

    From 2015 to 2016, for the first time in history, Americans spent more money at bars and restaurants ($54.857 billion) than they did on groceries ($52.503 billion).

    It has been estimated that Americans eat 1/3 of their calories away from home. Huge portions of tasty, mouthwatering foods, full of calories and salt make it impossible for weight loss if patients frequent restaurants more than just on special occasions. The average restaurant meal exceeds a home cooked meal by at least 200 calories..

    Have a great day on the bench!!

    We love receptors, mechanisms of action and classes of drugs... what is first line treatment for most disease states???

    EXERCISE: FIRST LINE TREATMENT
    Since the first line treatment of Type-2 diabetes is lifestyle modification (diet and exercise) let’s discuss the benefits of exercise this week. Obesity is now killing triple the number of people who die from malnutrition as it claims more than three million lives a year worldwide, according to a landmark study.
    (http://www.telegraph.co.uk/health/healthnews/9742960/Obesity-killing-three-times-as-many-as-malnutrition.html)
    According to data by Marketdata Enterprises, Americans spend over $66 billion annually to try to lose pounds, on everything from paying for gym memberships and joining weight-loss programs to drinking diet soda. (2017 data)

    Benefits of Exercise:
    • Exercise lowers blood sugar levels, improves insulin sensitivity, and strengthens the heart.
    • Strength training, which increases muscle and reduces fat, may be particularly helpful for people with diabetes.
    • Exercise will lower HbA1c by 1-2%
    • The challenge with Diet and Exercise is that a review of the adherence literature suggests that as a group, patients with diabetes are largely nonadherent. In one early study, only 7% of the diabetic patients were judged to be “fully adherent with all aspects of their regimen”. Which put another way 93% of our patients will NOT adhere to diet and exercise in the treatment of Type-2 diabetes. Because of this, the American Diabetes Association recommends starting metformin therapy at the first visit. http://care.diabetesjournals.org/content/20/2/215.full.pdf.
    Use it or Lose it Study
    To do this, ten healthy young men decreased their daily activity level from a mean of 10,501+/-808 to 1,344+/-33 steps/day for 2 weeks. After two weeks of this inactivity the results were:
    • energy expenditure was reduced
    • body weight increased
    • decline in lean body mass in the trunk and legs
    • 6–7% reduction in cardiorespiratory fitness
    • 17% drop in peripheral insulin sensitivity. Which means, by simply increasing a patient’s activity level, they can have about a 17% decrease in the insulin they require.
    Source: J Appl Physiol. 2010 May;108(5):1023-4.

    Remind your patients of the following benefits for exercise:
    • GOALS: Patients should aim to get at least 30 minutes of aerobic exercise most days of the week. Thirty minutes can be broken up into chunks—10 minutes here and there. Build up to 30 minutes gradually.
    • PUMPING UP: Lifting weights for 20-30 minutes two or three times a week is enough to get the full benefits of strength training.
    • INCREASES HDL: A 5-10 percent weight-loss can result in a five-point increase in HDL cholesterol (good cholesterol).
    • LOWERS TRIGS: Losing 5-10 percent of body weight was shown to decrease triglycerides by an average of 40 mg/dl
    • LOWERS BP: By losing 5-10 percent of one’s weight, blood pressure, both systolic and diastolic, decrease by 5 mmHg on average
    • LOWERS HbA1c: A 5-10 percent weight-loss can decrease HbA1c by half a point on average.
    • IMPROVES SLEEP: A 5-10 percent weight-loss may improve sleep apnea and sometimes if the apnea was not very severe, one can be weaned from the CPAP breathing machine.
    EXERCISE ADHERENCE: Unfortunately, a 10-year study of 255 diabetic patients enrolled in a diabetes education program that emphasized exercise, 80 percent at six weeks were still exercising to less than 50 percent at three months to less than 20 percent at one year.

    TEST BLOOD SUGARS: If the pre-exercise blood glucose is <100 mg/dL, insulin- or sulfonylurea-treated patients should ingest extra food, in the form of 15 to 30 grams of quickly absorbed carbohydrate (such as glucose tablets, hard candies, or juice), 15 to 30 minutes before beginning exercise. Easy to remember 15-30 GM ingested 15-30 minutes before exercising if finger sticks are below 100.

    Encourage your patients to follow all aspects of their physician’s treatment plan. We pharmacists are the “adherence experts” as well as the drug experts. With only 7% of our patients adhering to drugs, diet and exercise we can make a big impact in their treatment of Type-2 diabetes.

    The first line therapy for osteoporosis, heart failure, hypertension, depression, asthma, pain management, and of course is DIET AND EXERCISE.

    Think about your training in pharmacy school, med school, PA school, and nursing school. Diet and exercise physiology are topically covered (if at all). I find it interesting that all health care disciplines miss the opportunity to teach the FIRST LINE THERAPY for the most common treated disease states!

    Have a great day on the bench!!

    Selecting combination therapy for your Type-2 diabetics is simple math...well maybe not so simple!

    We are all familiar with Metformin (Glucophage) knowing it is the first drug prescribed for our Type-2 Diabetic (T2DM) patients. As we are all aware, rarely is this monotherapy effective unless our patient makes the necessary lifestyle modifications. Most references show that only 7% of T2DM patients will make the necessary lifestyle/dietary modifications necessary to combat this disease that is now affecting 1 out of 10 Americans. For the other 93% of our patients we need to look at additional pharmacotherapy to manage their Type-2 Diabetes.

    COMBINATION THERAPY
    Even with drug treatment Type-2 diabetics, will eventually need additional therapy to treat their hyperglycemia.
    • After 3 years, 50% of patients will need a second drug
    • After 9 years, nearly 75% will need the second drug added.
    • Most common combination therapy if cost is a concern is sulfonylurea + metformin.
    • As diabetes progresses a third drug is often added—either another oral agent, GLP-1, or insulin.
    • Addition of insulin should NOT be postponed in patients with poor glycemic control that have failed on multiple drug regimens.
    • Look at the patient, consider need for weight loss, adherence, insurance coverage, cost of medications etc.
    PUTTING IT ALL TOGETHER FOR COMBINATION THERAPY

    Treatment Expected decrease in HbA1c Estimated monthly cost
    Exercise, diet weight loss 1-2%
    Metformin 1.5% $8.00
    Avandia/Actos 1-1.5% $12.00
    Sulfonylurea (glipizide, glimepiride, eglyburide) 1.5% $8.00
    Alpha glucosidase inhibitors (Precose/Glyset) 0.5-0.8% $22.00
    Glinides (Starlix/Prandin) 0.5-1% $30.00
    Incretins (Victoza, Trulicity, Ozempic) 1-1.5% $800.00
    DPP4 inhibitors (Januvia, Tradjenta) 0.5-1% $500.00
    SGLT2 inhibitors (Invokana, Jardiance, etc) 0.5-1% $550.00
    insulin -basal 1 vial 1.5-3.5% $320.00


    *Consider initial therapy with insulin if HbA1c is greater than 10%.
    Example: the goal A1C you set is 7% for example. If a patient comes in with a HbA1c =9 there is NO way he can get there by adding Januvia®!


    Xigduo, Invokamet, Glyxambi, Stegluromet, Metaglip, Glucovance, Actomet-Plus, Janumet, Jentadueto, Kombiglyze XR, Kazano…everyone wants to be second choice after metformin. These combinations, which most are not even on my shelf, show the manufacturers attempt to get their expensive drug on board with metformin.

    I tell my student pharmacists and physician assistant students that using these drugs are a simple math problem. Start with the HbA1c and see if the HbA1c lowering adds up to the lowering you need to reach a goal HbA1c of 7.

    When you look at the estimated monthly cost column, it becomes even more of a math problem! Diabetes is an expensive disease, and for the most part the better control we get of the HbA1c the higher the price tag.

    Managed care organizations don’t really know what to do. The want to keep costs down, but a stay in the hospital or a visit to the emergency room negates any costs saved by withholding these expensive medications. As always look at your patient, and do what's best for them.

    Have a great day on the bench!!

    July 2019

    The last four drug classes have 4 different mechanisms of action. The "ominous octet" of diabetes is finished.

    OTHER T2DM TREATMENTS

    ALPHA GLUCOSIDASE INHIBITORS
    Mechanism: decrease gut carbohydrate absorption and slows carbohydrate absorption, by inhibiting the enzyme alpha-glucosidase, which is needed to digest complex sugars, in the brush border of the small intestines.
    Expected reduction: HgBA1C= (.5-.8%) Expect lowering of fasting plasma glucose 35-40 mg/dl.
    Target population: elevated post prandial glucose and normal fasting glucose.

    Acarbose (Precose®)- Available strengths 25,50 & 100mg
    Miglitol (Glyset®)- Available strengths 25,50,100mg
    DOSE: Both acarbose and miglitol: Titrate gradually to decrease adverse effects. Usual dose is 50mg-100mg three times daily with meals.
    Side Effects: dose related side effects include flatulence, diarrhea, and abdominal discomfort. Pregnancy Category B - both miglitol and acarbose

    PATIENT INFORMATION- alpha glucosidase inhibitors
    • Contraindicated in inflammatory bowel disease.
    • Administer 4g chewable glucose tablets or 15g gel in patients who develop hypoglycemia. -- Patients should carry these with them
    • Recommend liver function test every 3 months the first year then periodically.
    • If a patient skips a meal, then the alpha-glucosidase inhibitor should be skipped.
    • COST: Acarbose now generic less than $30/month
    Other use: prevention of dumping syndrome in post bariatric surgery patients. Dumping syndrome is the effect of rapid gastric emptying, leading to rapid glucose absorption, and it is particularly common among post-bariatric surgery patients.

    Dumping syndrome occurs in up to 75% of patients after Roux-en-Y gastric bypass surgery. By slowing up glucose absorption after a meal, there is a significant reduction in dumping syndrome.

    NON-SULFONYLUREA SECRETAGOGUES
    Structurally different from the sulfonylureas, but also bind to ATP sensitive potassium channels in the beta cell to cause insulin release. Both are rapidly absorbed and cause peak plasma insulin levels within 30-60 minutes. Are always taken before a meal.

    Repaglinide (Prandin®) available as 0.5mg, 1mg and 2 mg tablets
    • short acting - causes quick insulin release from pancreas.
    • works well for post prandial hyperglycemia
    • starting dose: 0.5mg three times daily 15 minutes before a meal
      • may double the dose each week - up to 4mg before meals up to 4 times daily.
      • Maximum daily dose = 16mg
    • May be combined with metformin or glitazone.
    • If you skip a meal, SKIP that dose. ADD a dose if you add a meal
    • cleared by hepatic metabolism and may be useful alternative to sulfonylureas in patients with renal impairment
    Nateglinide (Starlix®) available as 60 and 120 mg tablets (available generically)
    • short acting - causes quick insulin “pulse” from pancreas
    • works well for post-prandial hyperglycemia
    • starting dose: 120mg three times daily. take 1-30 minutes before a meal.
      • 60mg TID can be given if near HbA1c goals.
    • May be used as monotherapy or combined with metformin, or glitazones.
    • Omit dose if meal is skipped.
    BROMOCRIPTINE (Cycloset®) 0.8mg
    Mechanism: dopamine receptor agonist that “normalizes aberrant hypothalamic neurotransmitter activities that , that induce, potentiate and maintain the insulin resistant and glucose intolerant state”
    Dose: 0.8mg daily, increased until therapeutic dose 1.6mg-4.8mg (2-6 tabs/day)
    Benefits: cardiovascular safety and low risk of hypoglycemia and weight gain. only lowers A1C about 0.5%. Costs up to $900/month
    CAUTION: fainting as dose increases; also nausea, dizziness and drowsiness. Avoid if nursing. Because of unique release mechanism, you may NOT prescribe generic Parlodel (bromocriptine) for Type-2 diabetes.

    COLESEVELAM (Welchol®)
    Mechanism: first lipid drug approved for glycemic control. Colesevelam is a bile acid sequestrant, like cholestyramine (Questran). Bile acids play a role in cholesterol and glucose metabolism. Reducing bile acid absorption can improve both.

    DOSE: (both available generically for around $180.00 per month)
    • 6 huge pills daily (or 3 tablets twice daily).
    • Or one packet (3.75gm) packet once daily with a meal. Mix 1 cup of water, fruit juice, or diet soft drink. Stir well and drink.
    USE: add to metformin, insulin or sulfonylureas.
    Benefit: lowers HbA1c 0.5%, but may lower LDL 20%
    CAUTION in patients with triglycerides over 300 mg/dL; Avoid if over 500 mg/dL. May increase triglycerides especially when combined with insulin or sulfonylureas. Advise taking glyburide, oral contraceptives, levothyroxine, or narrow therapeutic index drugs at least 4 hours before colesevelam.

    We’ve come a long way since the discovery of sulfonylureas in the 1950’s. There have been a lot of new drugs with unique mechanisms that we have covered the past couple of months. Today’s four classes of drugs are seldom used, with acarbose being the most popular. For the most part, acarbose is used in our Type-2 diabetics that have undergone bariatric surgery.

    We’ve discussed drugs that affects the “ominous octet” in the treatment of diabetes. We’ve discussed the drugs that affect the following pieces of the ominous octet:
    1. Beta cell- impaired insulin secretion—(SULFONYLUREAS & GLINIDES)
    2. Alpha cell- increased glucagon- (DPP4s & GLP-1’s)
    3. Intestines- decreased incretin effect - (DPP4s & GLP-1’s)
    4. Fat cells – Lipolysis (TZD’s)
    5. Kidney- increased glucose resorption (SGLT2 inhibitors)
    6. Muscles- decreased glucose reuptake (TZD’s)
    7. Brain– neurotransmitter dysfunction (Bromocriptine)
    8. Liver- Increased hepatic glucose production (Metformin)
    Have a great day on the bench!!

    Even the cheapest SGLT2 inhibitor is over $300.00 per month

    SGLT2 INHIBITORS “Glucuretics”
    Mechanism: effectively work to reduce blood glucose independently of insulin. Glucose resorption in the kidney plays an important role in glucose balance. The kidney filters about 180g of glucose each day, with virtually all glucose being “recycled” back into circulation.

    SGLT2 is a major sodium-glucose co-transporter in the kidney and is an insulin-independent pathway for the re-absorption of glucose back into the blood. The healthy kidney spills glucose into the urine, once serum glucose levels exceed 180mg/dl. Selective inhibition of SGLT2 facilitates the excretion of glucose and associated calories in the urine, thereby lowering blood glucose levels. SGLT2 inhibitors “dial back” the glucose threshold from 180mg to about 80 or 90mg/dl.

    Negative effects of SGLT2 therapy:
    • Increase in genital infections and urinary tract infections
    • SGLT2 inhibitors cannot be used in stage IV nephropathy (GFR less than 30ml/min) due to mechanism of action.
    Positive effects of SGLT2 Inhibitors:
    • No hypoglycemia
    • As monotherapy or added to metformin will see reductions in blood pressure of 3-5mmHg systolic and 2mmHg diastolic.
    • No change in heart rate
    • No syncope
    • Weight loss (losing 50-85gm of glucose equates to 200-340 kcal/day
    • Mechanism of action is INDEPENDENT of insulin secretion.
    • Expect reductions in HbA1c of 0.5%-1%
    Precautions for SGLT2 Inhibitors
    • Dehydration - especially if:
      • have low blood pressure
      • take medicines to lower your blood pressure, including water pills (diuretics)
      • are on a low salt diet
      • have kidney problems
      • are 65 years of age or older.
    • Vaginal yeast infection.
    • Yeast infection of the penis. (Be sure to ask your male patients, especially if there uncircumcised) We had a patient at the clinic that was using iodine to treat his balanitis (ouch!)
    Canagliflozin (Invokana®) (Johnson & Johnson) approved April 2013
    • lowers CV risk, carries warnings of amputation
    Dapagliflozin (Farxiga®) (AstraZeneca) approved January 2014

    Empagliflozin (Jardiance®) (Boehringer/Ingelheim) approved August 2014
    • Reduces both CV risk and death
    Ertugliflozin (Steglatro®) (Merck) approved Dec 2017

    My first introduction to SGLT2 inhibitors happened in June 2012. I was updating my St. Francis lecture notes and looked up “new diabetes therapies”. I stumbled across an article about canagliflozin and how it caused the excretion of sugars from the kidney. I thought “what a crazy idea.” Since pharmacy school we were trained that glucosuria is always bad! I thought the idea would never catch on. Remember the days of Tes-Tape and Diastix measuring for sugar in the urine?

    About 3 months later I was approached by PharmCon to do a program on a new class of diabetes drugs. I asked Kevin “are these the ones that make you pee sugar?” He answered that they were, and three of them were waiting FDA approval. My mission was to introduce the world of pharmacists to SGLT2 therapy.

    After a lot of research, I learned that these “glucuretics” are a useful category of drugs. Shortly after the presentation, Invokana was approved followed by Farxiga and Jardiance. The basis for these drugs has been around for a long time. In 1835, French chemists first isolated a substance known as phlorizin from the bark of apple trees, but the doses needed to achieve lowering of blood sugars caused to many GI side effects.

    Because Invokana, Farxiga and Jardiance have a price tag of $500.00 per month, and Steglatro has a $300.00 price per month utilization in uninsured patients, and insured patients with high deductibles should be avoided.

    Have a great day on the bench!!

    $800 dollars a month will buy a lot of groceries... no wonder this class of drugs cause weight loss!

    INCRETIN MIMETICS (GLP-1 receptor agonists)
    Brand Name Generic ManufacturerYear released Year released Dose
    Byetta® exanatide Astra-Zeneca 2005 5mcg-10mcg twice daily, before meals
    Victoza® liraglutide Novo-Nordisk 2010 0.6-1.8mg /day any time
    Bydureon®BCise exenatide -er Astra-Zeneca 2012 2mg once a week
    Trulicity® dulaglutide Lilly 2014 .75- 1.5mg/week
    Ozempic® semaglutide Novo-Nordisk 2017 .25-1mg/week

    All of the incretin mimetics (GLP-1 agonists) are adjunctive therapy to improve glycemic control in Type 2 diabetics who are taking metformin, a sulfonylurea or a combination, and not having adequate control.

    2017: AACE (American Association of Clinical Endocrinologists) recommends incretins as first add on in Type-2 diabetes, after established metformin therapy. Many endocrinologists are using the GLP-1 agonists along with a basal insulin to decrease the need for mealtime “log” insulins three times daily.

    How it works: mimics natural physiology to provide self-regulating glycemic control by enhancing insulin secretion only in the presence of HYPERGLYCEMIA. GLP-1 stimulates the pancreas to INCREASE insulin and DECREASE glucagon secretion. Insulin secretion decreases as blood glucose concentrations approach normal.

    All above incretins are synthetic exendin-4 and has properties similar to naturally occurring gut hormone GLP-1 (glucagon like peptide-1), which:
    • stimulates insulin secretion in response to glucose absorption
    • suppresses glucagon production during periods of hyperglycemia.
    Incretin mimetics have been shown to suppress elevated glucagon secretions during periods of hyperglycemia and reduce food intake. It slows gastric emptying time.

    In clinical trials, most patients lost weight. Proposed weight-loss mechanisms include: Incretins bind to the GLP-1 receptor in the hypothalamus, thereby suppressing appetite. Incretins delay gastric emptying, which may cause patients to feel full faster and longer.

    Byetta dosage (exantide): ($750.00/month)
    • 5mcg/ dose given twice daily, anytime during the 60 minute period before morning and evening meal. Do NOT give AFTER a meal.
    • Dose can be increased to 10mcg twice daily after one month based on glycemic response and tolerability
    • NOT recommended in renal impairment
    • Supplied as 30 day prefilled pens.
    Victoza dosage (liraglutide): ($950.00/month)
    • 1 pen available. You dial up dose on pen for 0.6mg or 1.2mg or 1.8mg.
    • Administered once daily any time of day without regard for meals
    • Start 0.6mg daily for 1 week. After 1 week increase dose to 1.2mg. If not acceptable glycemic control may increase to 1.8mg. Use abdomen, thigh or upper arm.
    • Reduce both CV risk and death
    Bydureon dosage BCise (Exantide-extended) ($725.00/month)
    • 2mg once a week, every 7 days.
    • Comes as 4 syringe/vials per tray (one month supply)
    • NOT recommended in renal impairment
    Trulicity dosage (dolaglutide) ($785.00/month) 0.75mg and 1.5mg pens
    • Initiate at 0.75 mg subcutaneously once weekly. Dose can be increased to 1.5 mg once weekly for additional glycemic control
    • Amazing delivery device. Auto injector.
    Ozempic dosage (semaglutide) ($800/month)
    • Initiate with 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg for at least another 4 weeks. May be escalated to a max dose 1 mg.
    • Carries warning for diabetic retinopathy.
    INCRETIN MIMETICS – general prescribing rules:
    • Careful if existing stomach disease. Careful if pancreatitis risk. Caution in renal failure.
      • Do not administer incretin mimetics & DPP-4’s together – pancreatitis risk!
    • Increased risk of hypoglycemia if there is a sulfonylurea. Adjustment of sulfonylurea might be required, but do not adjust GLP-1.
    • No additional glucose monitoring is required to determine dose.
    • No additional dose planning around meal size or amount of exercise is required.
    • Risk of Thyroid C-cell tumors (black box warning- seen in rodents)
    Storage requirements: Keep under 77 degrees, do not freeze. Keep refrigerate until first use. Remember to write for pen needles for these devices.

    Insulin/Incretin combos
    Glargine & lixisenatide Soliqua® 100/33 Long acting insulin + incretin Inject once daily, within one hour of first meal of the day. Use alternative treatments if doses below 15 Units or above 60 Units are required.
    Degludec & liraglutide Xultophy® 100/3.6 Long acting insulin + incretin Dose 10-50 units (max) same time each day; with or without food.
    Although “Lizard spit” sounds like a component of witch’s brew, saliva from the Gila monster lead to one of the most important breakthroughs in Type-2 diabetes management.

    Exenatide (brand Byetta) is the synthetic version of a protein called exendin-4, which comes from the saliva of the Gila monster. The Gila monster eats only once or twice a year, and researchers were able to isolate what turned on the Gila monster’s endocrine system.

    GLP-1 agonists have vaulted into the top slot for many patients after metformin therapy is instituted. The drugs not only turn on insulin, turn off glucagon and cause weight loss, they pack quite a punch to the patient’s wallet. A month’s supply of any of the GLP-1 agonists hit the wallet between $750-$950 dollars per month. Uninsured patients can’t possibly afford any medications in this class.

    My wife Denise had a patient today that was insured but had a high deductible plan. This patient had to leave the prescription in the store, with its $800 price tag. Sounds like the manufacturers of this class of drugs are pricing themselves out of the market.

    Have a great day on the bench!!

    DPP4 INHIBITORS
    Mechanism: GLP-1 (incretin) is inactivated by the proteolytic enzyme dipeptidyl peptidase-4 (DPP-4). These drugs block DPP4 and cause increases in the concentrations of endogenous GLP-1 concentrations.

    Look at the chart above. Note that the incretins that we naturally produce blunt glucagon release and stimulate insulin release when blood sugars are elevated. Incretins, released in response to a meal, also slow digestion and promote satiety (a feeling of fullness). We have an enzyme called DPP4- (dipeptidyl peptidase) which breaks down our incretins.
    • Levels of GLP-1 decrease over time in diabetics, consequently, these DPP-4 inhibitors would be expected to be of most benefit in early Type-2 diabetes.
    • Better at reducing post prandial glucose levels than fasting levels
    • Will be mostly used as an “add-on” drug. Lowers HbA1C by only 0.6-0.8%
      • Most feel their price (Januvia cost $460. 00/month) isn’t worth the minimal HbA1c lowering
      • Only Nesina (alogliptin) is available as a generic. Is still in short supply and cost is over $200.00
    • Avoid concurrent administration with incretins (Trulicity, Victoza, Ozempic, etc) to decrease risk of pancreatitis.
    REPRESENTATIVE PRODUCTS
    • Januvia (sitagliptin) by Merck - October 2006
    • Onglyza® (saxagliptin) by Astra Zeneca - July 2009
    • Tradjenta ((linagliptin) by Eli Lilly - June 2011
    • Nesina (alogliptin) (by Takeda- Jan 2013
    Dosage of DPP4 inhibitors based on Cr Cl or drug interactions:

    Creatinine clearance Onglyza®
    saxagliptin
    Nesina®
    alogliptin
    Januvia®
    sitigliptin
    Tradjenta®
    linagliptin
    50ml/min 5mg/day 25mg/day 100mg/d 5mg/day
    30- 50ml /min 2.5mg/day 12.5mg/day 50mg/d 5mg/day
    < 30ml/min 2.5mg/day 6.25mg/day 25mg/d 5mg/day
    CYP450 3A4/5 2.5mg/day none none 5mg/day

    As we pharmacists and providers are aware treating diabetes is an expensive proposition. The DPP-4 inhibitors truly frustrate me, seeing that we are lucky to lower HbA1c by even 1%. These meds are expensive for the lightweights they are with respect to Type-2 Diabetes therapy.

    Only Tradjenta® (linagliptin) doesn’t require renal dosing, but with a price tag of $450.00 it is hardly a bargain. We have drugs with better efficacy than the DPP-4 inhibitors, now only if we can get prices down to a reasonable level. The DPP-4’s are considered “weight neutral”, which is about their only redeeming value.

    Have a great day on the bench!!

    June 2019

    I found us another cheaper treatment--TZD's for T2DM !! I just can't spell THIAZOLIDINEDIONES (or say it either!!)

    THIAZOLIDINEDIONES (“glitazones”) (“TZD’s”)
    • Troglitazone (Rezulin) - removed from market in late 90’s due to drug induced hepatitis..
    • Pioglitazone (Actos)-Available strengths= 15, 30 and 45mg (available generically rather inexpensive)
    • Rosiglitazone (Avandia)= available strengths= 2,4,8mg
    Mechanism of TZD’s:
    • work on the peroxisome proliferator-activated receptors (PPARs) gamma receptors, increasing insulin sensitivity in adipose and muscle tissue.
    • main action occurs in muscle tissue (~80%), where they increase insulin stimulated glucose disposal.
    • also affect the liver (~20%) where they decrease excessive hepatic glucose production.
    • can take 6 to 14 weeks to achieve maximum effects.
    • Caution using TZD’s with patients with CHF. Liver function tests at baseline, then periodically, thereafter for both TZD’s.
    • TZD’s might also increase fracture risk especially in women.
    • Weight gain is possible—over a period of 6 months-1 year a 2-3 KG increase can occur and can be much higher. Combination therapy with insulin can produce an even more dramatic weight gain.
    • Expected reduction: HgBA1c = (0.5- 1.4%) Fasting plasma glucose: 25-50mg/dl
    • Target population: insulin resistant
    • Monotherapy, but usually add-on to Metformin
    Actos ® (pioglitazone) available generically. Very inexpensive. (released July 1999)
    initial= 15-30mg (usual=15-45mg) ( max=30mg if combined with other agents)
    • Actos ® pioglitazone LOWERS triglycerides about 9% to 12% while Avandia® rosiglitazone can INCREASE triglycerides up to 15%. Like fibrates, Pioglitazone works on the PPAR-alpha receptors, which might account for its lipid lowering effect.
    • Actos® pioglitazone also raises HDL about 12% to 19% as compared to 8% to 19% for Avandia® rosiglitazone
    • Potential to cause bladder cancer. Avoid if potential for bladder cancer.
    Avandia ® (rosiglitazone) (released May 1999)
    initial= 4mg QD or divided BID max= 8mg. (max= 4mg if using sulfonylureas)
    COST= very expensive- no generics due to no demand, cost is$180/month.
    November 2007 required GlaxoSmithKline to include a black box warning about heart risks on the drug’s label. In 2010 a REMS program was instituted. In 2013 restrictions were lifted by FDA.

    COMMENTS:
    • Caution using TZD’s with patients with heart failure. Liver function tests at baseline, then periodically, thereafter for both TZD’s.
    • TZD’s might also increase fracture risk especially in women.
    • Weight gain is possible—over a period of 6 months-1 year a 2-3 KG increase can occur, and can be much higher. Combination therapy with insulin can produce an even more dramatic weight gain.
    • TZD’s are effective for Polycystic Ovary Disease, however, are not commonly used because they are Pregnancy Category C. Frequently when poly cystic ovary disease is treated, ovulation returns and pregnancy can occur.
    • D/C if ALT levels > 2.5 times Upper Normal Limit (UNL) or jaundice is observed.
    Educate your patients about the signs of liver toxicity: nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice (skin and eyes), dark urine.

    At the Empower-3 clinic I staff on Mondays and Tuesdays, we frequently have patients that have no insurance and need treated for Type-2 Diabetes. As far as affordable medications we have only metformin, sulfonylureas and now pioglitazone.

    We don’t use much pioglitazone, due to the bad press that Avandia got 10 years ago.

    I attended a drug company sponsored dinner and an endocrinologist from Pittsburgh stated he uses a lot of pioglitazone. Most in the audience looked skeptically and some slightly cringed. His rationale was that pioglitazone doesn’t have the problems that rosiglitazone caused.

    Pioglitazone costs around $15.00 per month. Pioglitazone is significantly cheaper than the DPP-4 inhibitors (Januvia, Tradjenta) and has a greater lowering of HbA1c.

    If your patient has no cardiac contraindications or bladder cancer concerns, this might be a reasonably priced treatment option especially if uninsured.

    Have a great day on the bench!!

    Hard to believe we once were skeptical about prescribing metformin? Now we wonder if they should put it in the water!!

    Remember life before metformin?
    Metformin (Glucophage)

    Mechanism of action:
    • Decreases hepatic glucose production & improves insulin sensitivity in hepatic and peripheral tissues.
    • Major effects occur in the liver to decrease hepatic glucose output, and to a lesser extent, by increasing peripheral glucose utilization. Figure this drug works about 80% in the liver and 20% in the periphery.
    EXPECTED REDUCTIONS:
    • Reduction in HgBAc1: (1.5%)
    • Reduction in Fasting plasma glucose: 50-70 mg/dl
    Target population: overweight, insulin resistant and children (approved for patients over age -10)
    DOSE: Start low and go slow to avoid gastrointestinal upset.
    • initial: 500 BID or 850 QD (XR=500mg at supper)
    • usual: 1000mg BID or 850 TID maximum dose=2550mg/day (XR=1500-2000 at supper)
    • COST: both immediate release and extended release are available generically are inexpensive. Wide formulary coverage.
    CAUTION: Metformin XR 1000mg is ridiculously expensive. The cheapest generic formula for Metformin ER 1000mg is nearly $900.00 for 60 tablets. Valeant Pharmaceuticals makes a generic that the wholesale acquisition is $6,000 for 60 tablets.

    We can fill 120 generic Metformin XR-500mg for less than $20.00!!

    Metformin should be prescribed at the first office visit when the diagnosis of Type-2 diabetes is made. Metformin can be used as monotherapy or:
    • Combined with Sulfonylurea (Glucovance®= metformin + glyburide)
    • Combined with Thiazolidinediones (ActoPlus Met ®=metformin + pioglitazone)
    • Combined with DPP-4 inhibitors (Janumet® = (metformin + sitagliptin)
    • Combined with SGLT2 Inhibitors (Invokamet= metformin + canagliflozin)
    • Can be combined with insulin or GLP-1 agonists.
    Patient Information
    • Watch for Lactic Acidosis (rare - 3/100,000 patient years). Here are signs and symptoms:
      • feeling very weak, tired or uncomfortable
      • unusual muscle pain or cramps
      • trouble breathing
      • unusual or unexpected stomachache, decreased appetite or diarrhea
      • feeling cold, dizzy or light-headed
      • developing an irregular heartbeat
    • Contraindicated if serum creatinine over 1.5 in males or over 1.4 in females.
    • Caution if ethanol abuse & hepatic insufficiency.
    • 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
    • Take with food to minimize GI upset.
    • Titrate slowly to decrease adverse GI side effects (metallic taste, diarrhea, nausea, abdominal pain)
    • HEART FAILURE: Metformin is no longer contraindicated. It was thought that decreased kidney perfusion in patients with worsening heart failure could cause lactic acid accumulation. Metformin is beneficial in STABLE heart failure patients and does NOT increase lactate levels. Collectively, metformin has consistently been associated with an approximately 20% lower mortality rate compared with other antihyperglycemic agents
    WATCH for Metformin induced Vitamin B12 deficiency
    • Up to 30% of patients on metformin have reduced B12 absorption which could eventually lead to B12 deficiency. Besides ANEMIA, Vit-B12 deficiency can cause peripheral nerve damage, which can be mistaken for Diabetic Peripheral Neuropathy (DPN). I have treated four men who were taking metformin who had tingling in their hands, and Vitamin B-12 stopped the tingling.
    • Check B12 levels if new DPN or neuropathy gets worse. The lower B12 levels may cause an increased risk of peripheral neuropathy.
    • Treatment: Injectable B-12 usually not necessary, oral B12 (1000mcg PO daily) is enough. Don’t stop metformin, just treat the B12 deficiency.
    Polycystic Ovary Disease:
    Also used for Polycystic ovary disease. Also lowers serum androgen concentrations and leads to increased rates of ovulation in patients with Polycystic Ovary Disease. Pregnancy Category=B


    Another plant is the source of a very common diabetes drug. The biguanides were first discovered in the French lilac or goat's rue. The medicinal value of this plant in lowering blood sugars was elucidated in the 1700’s but it wasn’t until 1995 that this drug became available in the United States as “Glucophage®”.

    I remember when metformin was introduced, most of us were skeptic since it was a close cousin to phenformin (D.B.I.) which was pulled from the market in 1978 due to significant lactic acidosis.

    It wasn’t until the endocrinologists started prescribing this drug for a few years before the family practice doctors were comfortable.

    Have a great day on the bench!!

    Chevy Belairs, Elvis and sulfonylureas... all got their start in the 1950's

    Sulfonylurea history: 1950’s medicine!

    In the late 1930’s Dr. Marcel Janbon while working on a sulfa compound for typhoid fever, noticed that it caused hypoglycemia. Some patients experienced prolonged and profound hypoglycemia. This was about 15 years after the discovery of insulin by Dr. Frederic Banting and his student Charles Best at the University of Toronto. In 1946 it was confirmed that indeed sulfonylurea products caused insulin release as long at the pancreas was producing insulin.
    Mechanism of action: interact with ATP sensitive potassium channels in the beta cell membrane to increase the secretion of insulin, at all levels of glucose concentration. Second-generation drugs penetrate cell membranes more easily than first-generation sulfonylureas.

    Most believe that at time of diagnosis of T2DM, about 50 of beta-cell function is already lost. With long term use, the patient’s total number of beta cells decreases, beta cell function declines and these drugs become less effective. Failure rates are about 5-10% per year. When they fail, a different type of drug should be added. (Don’t replace with another sulfonylurea if the patient fails on a sulfonylurea.)

    Common adverse events: include weight gain, hypoglycemia, and water retention. First-generation sulfonylureas tend to produce an increase in adverse events, ionically bind to plasma proteins, and lead to more drug–drug interactions.

    FIRST GENERATION SULFONYLUREAS (still available as of 2019-seldom used)

    GENERIC NAME Available in USA DAILY DOSE RANGE DURATION of ACTION EQUIV. DOSE
    Tolbutamide (Orinase®) May 1957 500-2000mg/day in divided doses 6-12 hours 1000mg
    Tolazamide (Tolinase®) July 1966 100-1000mg/day in divided doses Up to 24 hours 250mg
    Chlorpropamide (Diabinese®) Oct 1958 100-500mg single dose 24-72 hours 250mg
    Acetazolamide Dymelor® 1964 Not available


    SECOND GENERATION SULFONYLUREAS

    GENERIC NAME Available in USA DAILY DOSE RANGE DURATION of ACTION EQUIV. DOSE
    Glyburide (Micronase) (Diabeta) May 1984 1.25- 20mg/ day in single or divided doses Up to 24 hours 5mg
    Micronized Glyburide (Glynase®) March 1992 1.5-18mg/day in single or divided doses Up to 24 hours 3mg
    Glipizide (Glucotrol®)) May 1984 2.5-40mg/day in single or divided doses 6-12 hours 10mg
    Glipizide-XL Glucotrol-XL® April 1994 Up to 20-30mg daily Up to 24 hours 10mg
    Glimepiride Amaryl® Nov 1995 1-4mg as a single dose Up to 24 hours 2mg


    REVERSAL of SULFONYLUREAS: (Overdose)
    Treatment of sulfonylurea induced hypoglycemia: Octreotide is used in extreme emergency only. Octreotide is a somatostatin analog that is known to suppress numerous hormones including insulin. It inhibits release of insulin from the beta cells. Frequently referred to as “Endocrinologist’s bleach” Typical doses administered in emergency room setting:
    • In adults, the dose of octreotide is 50 to 150 mcg administered by intramuscular, or subcutaneous, injection every six hours.
    • In children, the dose of octreotide is 1 to 1.5 mcg/kg (up to 150 mcg) every six hours
    Dextrose itself induces insulin secretion, thus theoretically contributing to rebound hypoglycemia when used to treat hypoglycemia.

    Who’s at risk for sulfonylurea induced hypoglycemia?
    (Duration of hypoglycemia in overdose of some sulfonylurea agents can be up to 72 hours.)
    • A single tablet of glipizide or glyburide can cause symptomatic hypoglycemia in infants or toddlers.
    • Risk factors for sulfonylurea-induced hypoglycemia include young age, malnutrition, alcohol use, and kidney or liver disease.
    SULFONYLUREAS? Yeah, they are cheap, but should we be practicing 1950’s medicine?
    • Metformin is always first line for type 2 diabetes. Start at first visit when first diagnosed
    • Don’t trash Sulfonylureas completely as they lower A1C about 1% and cost about $10/month instead of up to $800/month for the newer meds like the GLP-1’s (Ozempic, Trulicity and Victoza).
    • Consider sulfonylureas when cost is a concern, such as with uninsured patients.
    • Since they're likely cranking out insulin sulfonylureas may be a good choice for patients within about 5 years of diagnosis.
    • Caution about use in elderly patients or those with renal impairment. Avoid glimepiride and glyburide. Glipizide is least likely to cause hypoglycemia in these patients.

    We all know what Type-2 diabetes mellitus looks like. We all know this is a rapidly growing disease. I won’t spend a lot of your precious time discussing the incidence of this very common disease. One factor stands out. The incidence of T2DM was about 1% of our nation when the sulfonylureas came to market in the mid 1950’s. Just in that short span the incidence of diabetes mellitus Type-2 is now almost ten times that.

    A Center for Disease Control and Prevention (CDC) report finds that as of 2015, 30.3 million Americans – 9.4 percent of the U.S. population –have diabetes. Another 84.1 million have prediabetes, a condition that if not treated often leads to type 2 diabetes within five years. The patient profile is typically adults over 40, with a higher frequency in overweight teens.

    Cause: poor insulin metabolism in the body, or reduced insulin production by pancreas, or both. After several years of insulin resistance, insulin production decreases. The result is the same as Type-1, glucose builds up in blood and body cannot make efficient use of its source of fuel.

    So, do sulfonylureas have a place in T2DM therapy. As always it depends... on the patient (or more specifically their insurance or lack thereof)

    Have a great day on the bench!!

    Helping our cirrhosis patients lower ammonia levels... Might cost $40, could be $2,500.00 per month!

    TREATMENT OF EXCESSIVE AMMONIA LEVELS IN HEPATIC INSUFFICIENCY

    Mechanism:
    Alcohol’s harmful effects on liver cells not only interfere with the normal functioning of the liver but also impact distant organs, including the brain. Prolonged liver dysfunction resulting from excessive alcohol consumption can lead to the development of a serious and potentially fatal brain disorder known as hepatic encephalopathy, which is believed to be due to excess circulating ammonia levels.

    Hepatic encephalopathy is a complication of hepatic cirrhosis and is characterized by a spectrum of neuropsychiatric abnormalities such as personality changes, deterioration of mental status with psychomotor dysfunction, impaired memory, sensory abnormalities, etc. Clinical manifestation can range from subtle cognitive abnormalities to coma. Overt hepatic encephalopathy occurs in about 30%-45% of patients with cirrhosis.

    PHARMACOLOGICAL MECHANISMS OF TREATMENT:
    • sugar molecules to decrease systemic absorption of ammonia OR
    • antibiotics to reduce the bacteria which produce ammonia in the gastrointestinal tract
    • correct hypokalemia, since low potassium levels increases renal ammonia production.
    Lactulose (cost for 64 oz= $40.00/month)
    • Lactulose (Chronulac, Constulose®) alters the acidity in the colon, which prevents absorption of ammonia, one of the toxins. Remember biochemistry, where the charged ions are less likely to be absorbed. By acidifying the colonic contents to a pH of approximately 5, the ammonia ion becomes protonated, thus positively charged, and less likely to be absorbed.
    • This partially dissociates, acidifying the colonic contents (increasing the H+ concentration in the gut). This favors the formation of the nonabsorbable NH4+ from NH3, trapping NH3 in the colon and effectively reducing plasma NH3 concentrations.
    • The laxative action of lactulose moves the ammonia ions out of the colon, by stimulating bowel movements.
    DOSE: oral dose of 15–30 ml twice daily
    EXPECT 3-4 loose bowel movements per day
    PRECAUTIONS: Overdosage can result in ileus, severe diarrhea, electrolyte disturbances, and hypovolemia. Hypovolemia may be sufficiently severe as to actually induce a flare of encephalopathy symptoms

    Rifaximin (Xifaxan 550) ($2500.00/month) oral antibiotic agent with minimal gut absorption that concentrates in the GI tract. It has a broad-spectrum in vitro activity against gram-positive and gram-negative aerobic and anaerobic enteric bacteria, and has a low risk for bacterial resistance since it's not systemically absorbed. This drug is usually added to lactulose, not instead of lactulose. DOSE: Rifaximin, oral dose of 550 mg twice daily Rifaximin (Xifaxan) was approved in May 2015 FDA for treatment of IBS with diarrhea (IBS-D) in adults.

    Less commonly used antibiotics:
    • Neomycin ($150.00/month)
      • Is a non-absorbable aminoglycoside antibiotic that decreases the ammonia forming bacteria in the gut.
      • DOSE: oral dose of 500 mg four times daily (use high doses with caution). High doses may cause ototoxicity and nephrotoxicity.
    • Metronidazole (Flagyl) oral dose of 250 mg four times daily—short term use only.
    • Vancomycin (Vancocin) oral dose of 250 mg four times daily
    AVOID: Avoid medications that depress central nervous system function, especially benzodiazepines. Patients with severe agitation and hepatic encephalopathy may receive haloperidol as a sedative.

    Alcoholism can contribute to declining health in a lot of ways. We've reviewed the needs of vitamin supplementation (March 21,2019) for our alcoholic patients. Alcoholism can also damage kidney function.

    The liver seems to take most of "the beating" from excess alcohol consumption. Lots of meds need to be adjusted with liver dysfunction, most notably acetaminophen. It is fascinating to me the connection between our gut, which produces ammonia, and our liver which breaks down ammonia, and our brain that is affected by these elevated ammonia levels.

    My "go to" website for liver toxicity is operated by the National Institutes of Health and can be found at: https://livertox.nih.gov/

    Have a great day on the bench!!

    May 2019

    We have 3 major treatment options to help our patients abstain from alcohol.

    Last week we discussed the role of common drugs such as the benzos- Librium, Valium, Ativan, Gabapentin and Tegretol for the treatment of alcohol detoxification. Let's now take a look of keeping our patients with alcohol use disorder from relapsing.

    Alcohol Relapse Prevention Agents
    Naltrexone (ReVia®)     (approved 1984)
    Mechanism: Blocks opioid receptors to reduce the pleasurable effects from alcohol. Increases abstinence days, reduces heavy drinking days and improves overall outcome.
    DOSAGE: 25-50mg per day by mouth, up to 100mg per day.
    • BEST CHOICE (Pros): Abstinence from alcohol is NOT required for therapy. Helps for patients with high levels of cravings, especially in risky drinking situations. Helps prevent relapses into heavy drinking in patients who are not completely abstinent
    • CONTRAINDICATIONS: opiate abusers. Patients with severe liver pathology. Can't be given to patients currently receiving opioid therapy. Don't use for kidney disease.
    • Patients should carry identification noting that they are on naltrexone in case of an injury requiring opioid therapy
    Naltrexone Injectable extended release (Vivitrol® 380mg)-     (approved 2006)
    once a month current cost : over $1,300.00
    • To avoid sudden opiate withdrawal, must be taken 7-14 days after last consumption of opioids; must not be actively drinking at time of injection. Good choice if patient compliance is an issue
    • Patient should stop drinking before Vivitrol injection.
    • May cause injection site reactions such as necrosis.
    • If pain management is needed, Vivitrol blocks opioid receptors for 28 days.
    Disulfiram (Antabuse®)      (approved 1951)
    Mechanism: blocks acetaldehyde dehydrogenase. Acetaldehyde increases 5-10 times higher. Acetaldehyde causes: flushing, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pains, palpitations, hypotension, tachycardia, syncope
    • Initial dose: 500mg daily for 1-2 weeks. May take HS if drowsiness.
    • Maintenance: 250mg/day (average) range: 125-500mg
    Patient counseling points
    • Avoid alcohol in all forms
    • Clinically it reduces drinking days, but does not enhance abstinence.
    • Compliance is THE major factor determining efficacy of disulfiram.
    • Pros: for a person who needs emergency help to stop drinking NOW.
    • Does not reduce cravings.
    • CONTRAINDICATIONS: use of alcohol, coronary artery disease, liver disease, severe myocardial disease.
    Acamprosate (Campral®) 333mg enteric coated tablets     (approved 2004)
    Mechanism: reduces the anxiety & other unpleasant effects of alcohol withdrawal. It works by balancing the GABA and glutamate neurotransmitters in the brain. It is for patients who are abstinent and decrease relapse to heavy drinking. (Better effect with Campral and Naltrexone together) Dosage: two tablets (666mg) three times daily. (333 TID if moderate renal impairment; CrCl=30-50ml/minute)
    • Do not give if severely renal impaired.
    • Adverse Effects: Diarrhea, itching, depression, insomnia, cardiomyopathy (rare)
    Patient counseling points:
    • BEST CHOICE: for patients with significant liver pathology, because it is excreted unchanged in the kidneys. Patients with SEVERE alcohol withdrawal symptoms. Patients able to initiate abstinence but have difficulty in maintaining newly regained abstinence. Most successful outcomes in studies when patients were abstinent of alcohol. Better evidence for achieving abstinence than naltrexone.
    • ADHERENCE: adherence is the biggest challenge with acamprosate with three times a day dosing.
    • CONTRAINDICATIONS: severe renal impairment. Creatinine Clearance less than 30ml/min
    • MAJOR SIDE EFFECT: diarrhea
    Thiamine & Multivitamin
    • Chronic alcoholism interferes with the absorption of Thiamin and Folic acid
    • Thiamine (Vitamin B 1) 100mg daily to prevent Wernicke-Korsakoff syndrome, an often fatal encephalopathy.
    Treatment should begin at the beginning of alcohol withdrawal and continue at least through the alcohol withdrawal period. Ensure folic acid is in multivitamin and prevent such complication as megaloblastic anemia

    How long should treatment last?
    • Patients who maintain abstinence or adequately reduce heavy drinking, should continue psychosocial treatments for at least six months
    • Medication treatment should last one year, longer if tolerated.
    • Stability time increases as treatment time increases.
    One of the parameters we monitor at the Empower-3 clinic is adherence. Adherence can be verified by a simple interview question. I usually say "I see you are on a lot of medications, let's say in the course of a month how many times do you miss a dose of your medications?" Most people are honest, and I always follow up by asking "What do you attribute your success to? Do you use an app on your phone, or a plastic pill reminder?" Fortunately if they have insurance that is billed our system can look up refill history, which occasionally points out a discrepancy.

    Adherence to statins and ACE-inhibitors can be part of our Star Ratings calculations, so it is important for our patients to be adherent to these medications. However, adherence is of critical importance in the treatment of alcohol use disorder. All these medications are effective, but only if patients take them.

    Unfortunately, on all therapies, half the patients relapse after 3 months. Looks like many opportunities for patient counseling by your community pharmacist.

    Have a great day on the bench!!

    Benzos are still the mainstay of treatment of alcohol withdrawal

    Prevalence of Drinking:
    https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics
    Who's drinking? According to the 2015 National Survey on Drug Use and Health (NSDUH),
    • 86.4 percent of people ages 18 or older reported that they drank alcohol at some point in their lifetime
    • 70.1 percent reported that they drank in the past year
    • 56.0 percent reported that they drank in the past month.
    Prevalence of Binge Drinking and Heavy Alcohol Use: defined as NIAAA defines binge drinking as a pattern of drinking that brings blood alcohol concentration (BAC) levels to 0.08 g/dL. This typically occurs after 4 drinks for women and 5 drinks for men—in about 2 hours
    • in 2015, 26.9 percent of people ages 18 or older reported that they engaged in binge drinking in the past month;
    • 7.0 percent reported that they engaged in heavy alcohol use in the past month
    Alcohol Use Disorder (AUD): defined a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences
    • Adults (ages 18+): According to the 2015 NSDUH, 15.1 million adults ages 18 and older (6.2 percent of this age group) had AUD.
    • This includes 9.8 million men (8.4 percent of men in this age group) and 5.3 million women (4.2 percent of women in this age group).
    • About 6.7 percent of adults who had AUD in the past year received treatment. This includes 7.4 percent of males and 5.4 percent of females with AUD in this age group.5
    Alcohol Use Disorder in the Youth:
    • Youth (ages 12-17): According to the 2015 NSDUH, an estimated 623,000 adolescents ages 12-17 (2.5 percent of this age group) had AUD.
    • This number includes 298,000 males (2.3 percent of males in this age group) and 325,000 females (2.7 percent of females in this age group).
    • About 5.2 percent of youth who had AUD in the past year received treatment. This includes 5.1 percent of males and 5.3 percent of females with AUD in this age group.
    TREATMENT OF ALCOHOL DETOXIFICATION
    Benzodiazepines are the mainstays of treatment for alcohol withdrawal, particularly inpatient, however anticonvulsants are becoming increasingly popular for outpatient detox due to good efficacy and a lower potential for abuse
    • The doses of benzodiazepines used for alcohol detox are much higher than those used to treat anxiety.
    • IV therapy required for ALL patients with seizures or DT (delirium tremors). Convert to oral dosing as soon as possible. Avoid IM due to erratic absorption.
    • Adverse effects: Sedation, dizziness, delirium, hypotension, respiratory depression

    Drug Dose Pros Cons
    Chlordiazepoxide (Librium) 50-100mg Q 6 hours initially, then taper down Long acting, fewer breakthrough symptoms Very sedating
    Diazepam (Valium) 10-20mg Q 6 hours initially, then taper down Fast onset of action, long acting Higher abuse potential
    Lorazepam (Ativan) 2-4mg Q 6h, then taper down Less sedation. Treatment of patients with advanced cirrhosis or acute alcoholic hepatitis. Shorter acting, more breakthrough symptoms, unlabeled use
    Oxazepam (Serax) 15-30mg QID, then taper down Less sedation, lower abuse potential, better for elderly patients. Treatment of patients with advanced cirrhosis or acute alcoholic hepatitis. Patients may experience more breakthrough or rebound symptoms

    Anticonvulsants
    • Becoming increasingly popular for outpatient detox due to good efficacy and a lower potential for abuse
    • Use of anticonvulsants for alcohol detox should be considered in patients where there is a high potential for abuse, or for whom sedation poses a serious concern
    • Detox using anticonvulsants may be used in outpatient settings where withdrawal symptoms are less severe, and patients are at a lower risk for serious complications
    • Phenobarbital: works synergistically with benzodiazepines, which increase the frequency of GABA chloride channel opening, and barbiturates, which increase the duration of channel opening. Used for refractory DT's
    Carbamazepine (Tegretol)
    Dosed: 200mg QID x 1 day, then 200mg TID x 1 day, then 200mg BID x 1 day, then 200mg QD x 2 days. May be OK for outpatient alcohol withdrawal, little effect for DT's
    • Less sedating, and less abuse potential than benzos
    • Many drug interactions (enzyme inducer)-speeds up metabolism of other drugs
    • Watch for blood dyscrasias, liver failure, Stevens Johnson syndrome
    Gabapentin (Neurontin)
    Dosed 400mg TID x 3 days, then BID x 1 day. Three 100mg rescue doses may be used daily
    • Less sedating, and less abuse potential
    • Fewer drug interactions than carbamazepine
    Next week we will discuss Alcohol Relapse Prevention Agents

    I am always impressed with the doses of benzodiazepines for alcohol withdrawal. They seem outrageously high, but certainly needed to treat the withdrawal as well as the delirium tremors (TD's)

    Just this past week two of my former physician assistant students texted me about using a benzo in a patient with liver dysfunction. I remember the three drugs by the acronym ""LOT" lorazepam (Ativan), oxazepam (Serax) and temazepam (Restoril).

    These three drugs are metabolized by glucuronide conjugation, and NOT by CYP metabolism. They are also the best choice benzos for elderly patients, who have declining CYP function, as glucuronide conjugation doesn't drop as significantly as people age.

    (Remember of course we should always avoid benzos in the elderly if possible due to increase fall risk).

    Have a great day on the bench!!

    With the cost of cigarettes... Chantix looks like a bargain!

    Last week we discussed the role of nicotine replacement products. This week we will focus on the role of prescription drugs indicated for smoking cessation.

    The effect of smoking on drug metabolism:
    Hydrocarbons found in tobacco smoke induce CYP450 microsomal enzymes (primarily CYP1A2). Smoking cessation or the use of nicotine products may alter the clearance of many drugs that are metabolized by this enzyme system. When a patient quits smoking, levels of these drugs have the potential to increase: Theophylline (Theo-24) , clozapine (Clozaril), olanzapine (Zyprexa), and tizanidine (Zanaflex), caffeine and acetaminophen.

    Bupropion-SR 150mg -------cost $20.00/month
    Mechanism: Blocks re-uptake of dopamine and norepinephrine. Weak nicotinic receptor antagonist.
    Usual dose: 150mg daily for 3 days. Then increase to 150mg twice daily. Separate doses by 8 hours.
    Initiate treatment when patient is still smoking. Takes 1 week to achieve steady state blood levels.
    Set a target quit date within the first 2 weeks of treatment. Continue treatment for 7 to 12 weeks. After 7 weeks of treatment failure, unlikely patient will succeed. Consider stopping therapy.

    May be combined with nicotine patches. Consider for smokers with history of depression. This drug is safe for patients with cardiovascular disease. BEST OPTION: This drug may be useful in delaying weight gain from smoking cessation. AVOID: if bipolar, pregnant or history of seizures and patients with significant anxiety

    Varenicline (Chantix®) cost----$450.00/month Mechanism: nicotinic receptor partial agonist. Having the drug on board blocks some of the pleasurable effects that patients get if they smoke. Have patients set quit day around day 8, after full titration. STARTER PACK: Dose: day 1-3: 0.5mg daily
    • Day 4-7: 0.5mg BID
    • Day 8-through end of treatment- 1mg BID
    • Assess after 12 weeks. If successful start a second 12-week drug course.
    Common Adverse effects: Nausea, dream changes, constipation, gas and vomiting. Prescribe with caution:
    • Avoid: Chantix should NOT be used by pilots, air traffic controllers, truckers, and bus drivers. This recommendation was first made in 2008. Chantix is still on the “Do not issue- Do not fly” list as of February 21, 2019. (source faa.gov)
    • Mental Health effects: Patients should stop taking Chantix and call their health care professionals right away if they notice any side effects on mood, behavior, or thinking. Suggested link to heart attacks, seizures, diabetes, dizziness, and confusion. The black box warning for adverse psychiatric events was removed on December 16,2016
    • Cardiovascular risk: A comprehensive evaluation of cardiovascular (CV) risk with CHANTIX suggests that patients with underlying CV disease may be at increased risk; however, these concerns must be balanced with the health benefits of smoking cessation. (Chantix package insert). Most sources agree Chantix is save for CV patients, as smoking is a greater risk factor.
    • Renal dosing: Severe Renal Impairment (estimated creatinine clearance less than 30 mL/min): Begin with 0.5 mg once daily and titrate to 0.5 mg twice daily. For patients with end-stage renal disease undergoing hemodialysis, a maximum of 0.5 mg daily may be given if tolerated. (Chantix package insert)
    Patient education:
    • Set a quit date. Start Chantix® one week before that. Prescribe the “starter pack.”
    • Take after a meal with a full glass of water to minimize GI upset.
    • Caution driving until patient sees how the drug affects them.
    • Caution if kidney problems, pregnant (Category-C) or nursing.
    Second Line Drugs for Smoking Cessation:
    • Nortriptyline (Pamelor): Blocks reuptake of norepinephrine with a lesser effect on serotonin. Similar efficacy to bupropion or nicotine replacement, but safety profile limits its usage.
    • Clonidine (Catapres): Stimulates alpha-2-adrenoceptors in the brainstem and reduces sympathetic outflow
    Money, Money. When I first started practicing in 1981, there was a sign in the window Cigarettes $.69 per pack. Patients commented “when those cigarettes cost one dollar per pack, I’ll QUIT!

    38 years later the average cost of a pack of cigarettes in Pennsylvania cost $8.27 which includes $3.07 in taxes. Our neighbors to the north in New York state lead the nation with an average pack price of $10.45 including $4.75 in taxes. The state of Missouri has the lowest average price per pack at $4.38 with only 36 cents worth of tax. You can look up your states information at: https://www.salestaxhandbook.com/cigarette-tax-map

    I’ve never had a patient pay cash for Chantix, but the truth is a two-pack per day smoker would break even buying Chantix. If a patient quits smoking all together after 12 weeks, they would save $480 per month or $5760 per year!! Just the financial incentive should help patients see the light and quit smoking.

    Clinicians Role: Dr. Boris Lushniak (former Acting Surgeon General) at a Salus University commencement address stated that ALL health care professionals should discuss at EVERY encounter diet, exercise and smoking cessation. No matter if you are a physical therapist, optometrist or pharmacist we need to offer our skills to these patients!



    Have a great day on the bench!!

    How many times should we encourage our patients to quit smoking.......... as long as it takes!

    "Quitting smoking is easy. I've done it a thousand times" -Mark Twain
    • In 2017, an estimated 14% (34.3 million) U.S. adults were current cigarette smokers. More than 16 million Americans live with a smoking-related disease. While this number is down from rates in the mid 90's, it still presents a huge public health concern. Smoking is responsible for about 90% of deaths due to lung cancer and COPD.
    Estimates show smoking increases the risk:           source cdc.gov/tobacco
    • For coronary heart disease by 2 to 4 times
    • For stroke by 2 to 4 times
    • Of men developing lung cancer by 25 times
    • Of women developing lung cancer by 25.7 times
    • Smoking causes diminished overall health, increased absenteeism from work, and increased health care utilization and cost.
    Nicotine's effect on the body:
    • Nicotine stimulates the CNS meso-limbic dopamine system, which is believed to be the neuronal mechanism underlying the reinforcement and reward experienced with smoking.
    • Smoking cessation is associated with a flu-like syndrome, cravings, irritability, insomnia, headache, and fatigue.
    • Nicotine withdrawal can lead to insomnia, anxiety, and depression, and exacerbate underlying psychiatric disorders.
    • Blood pressure: it is recommended not to measure a patient's blood pressure within 30 minutes after nicotine exposure (vaping, cigarettes or smokeless tobacco)

    TREATMENT OPTIONS ADVANTAGES DISADVANTAGES
    Bupropion
    Zyban®
    May be used in combination with other therapies, Insurance coverage for cost Risk of seizures, Other side effects, Prescription only
    Varenicline
    Chantix®
    More effective than Zyban or Nicotine Replacement Expensive. Risk of suicidality Nightmares, Psychiatric disturbances
    Counseling Highly successful, Cost effective with peer support, Availability Depression, Withdrawal side effects.
    Combined Therapy Many options, adaptive to each patient, lower cost if not using medications Withdrawal side effects. Costs if using drugs.
    Cold Turkey Minimal Costs, can be managed alone, One-step process Tolerating withdrawal symptoms, usually not successful if not fully committed
    Nicotine Fading Inexpensive, Easy to follow Patient must be highly committed to quitting
    Nicotine Patch (OTC) Able to purchase OTC, Easy to apply, can be managed alone Patient must be highly committed. Must not smoke while using the patch, Side effects, having to apply every 24hrs, Costs
    Nicotine Gum(OTC) Inhaler(Rx) Nasal(Rx) Can be managed alone, Able to purchase OTC, Easy to use. Patient must be highly committed. Must completely stop smoking while using, Side effects, Can’t use with dentures, Highly addictive, Costs


    Nicotine Replacement Prescribing Information
    • Nicotine replacement products (gum, patches, lozenges) are all equally effective in helping patients kick the habit.
    • Use a patch for continuous relief from cravings and the gum, spray, or inhaler for breakthrough urges if needed, depending on the patients choice of dosage form
    • Don't prescribe nicotine replacements with Varenicline (Chantix). The combo causes more nausea and probably won't work any better.
    Next week we can focus on the prescription drug therapy for smoking cessation

    Commentary:
    "Why should I quit now, the damage is done?" asked a patient I saw today at the clinic. He was age 56 years old, took Ranexa, Metoprolol, Spiriva, Cozaar, Plavix, aspirin and a few others. He survived a massive heart attack a few years ago, and never stopped his pack and a half habit.

    According to the CDC.gov/tobacco website there are plenty of good reasons for him to quit to quit:
    • Quitting smoking cuts cardiovascular risks. Just 1 year after quitting smoking, your risk for a heart attack drops sharply.
    • Within 2 to 5 years after quitting smoking, your risk for stroke may reduce to about that of a nonsmoker’s.
    • If you quit smoking, your risks for cancers of the mouth, throat, esophagus, and bladder drop by half within 5 years.
    • Ten years after you quit smoking, your risk for dying from lung cancer drops by half.
    Dr. Boris Lushniak, the acting Surgeon General under President Obama said at a graduation I attended “At every encounter with every patient we need to discuss weight control, exercise and smoking cessation.” At the Empower-3 clinic where I staff, I take his advice. Every patient, every time.

    Mark Twain's quote gives them permission to fail...I just want them to try!

    Have a great day on the bench!!

    Lowering uric acid levels can cost from $20.00 per year up to $572,000 per year!!!

    Lets stop those gout flares, tophi and kidney stones by lowering uric acid levels.

    Ground Rules for Prophylactic Drug Therapy for GOUT:
    • Neither uricosurics or xanthine oxidase inhibitors should be initiated aggressively in patients with active acute gouty arthritis.
    • Patients after an acute gouty arthritis attack are candidates for long term prophylaxis aimed at reducing the serum uric acid levels.
    • Goal of chronic therapy is to decrease future attacks, and reduce body stores of urate, and reversing the effects of urate deposits.
    • The most widely recommended goal range of urate-lowering therapy the magic number for serum urate is less than 6 mg/dL, which is substantially below the urate solubility limit. Urate levels over 11mg/dl is a significant risk for kidney stones.
    XANTHINE OXIDASE INHIBITORS:
    How they work: Xanthine oxidase is an enzyme that drives the conversion of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. Hypoxanthine and xanthine are more water soluble than uric acid. By blocking this conversion step of purines, the water-soluble precursors are excreted, and uric acid’s formation is blocked. There are currently two xanthine oxidase inhibitors available.

    ALLOPURINOL (Zyloprim®)
    is available in tablets of 100mg & 300mg strengths. This drug was first approved 1966. MECHANISM OF ACTION: Allopurinol is a xanthine oxidase inhibitor which is metabolized to oxypurinol, which is also active in inhibiting xanthine oxidase. This facilitates the clearance of oxypurines which are the more water-soluble precursors of uric acid. INDICATIONS FOR USE: Control of gout and hyperuricemia. Management of patients with primary and secondary sign/symptoms of gout (frequent gout attacks, tophi, joint destruction, uric acid lithiasis & nephropathy). Allopurinol is not an innocuous drug. Not recommended for treatment of asymptomatic hyperuricemia.

    RECOMMENDED DOSE: start low to prevent acute gouty flare-ups. Start with 100mg daily. If CrCl <30, start at 50mg. Increase by 100mg each week until uric acid level is 6mg/dl or less. Average dose is 200-300mg for mild gout. For patients with severe tophaceous may need 400-600mg/day. May be dosed once daily, however if over 300mg/day is required, divided doses. Maximum=800mg/day to get uric acid level under 6mg/dL. Take with food or mild to minimize GI upset. Must have good renal function for this dose of 800mg.

    Patients need to take NSAID or colchicine when starting to prevent acute flare.

    WARNINGS/PRECAUTIONS/ADVERSE EFFECTS
    • A rash might occur during therapy, which should be reported to practitioner at once. This rash may be simple rash or serious Stevens-Johnson syndrome (which is exfoliative and erythematous)
    • Rarely: alopecia, neutropenia, hepatitis
    • Diarrhea & nausea
    • Pregnancy Category: C
    • Bone marrow depression is rare
    • Test for human leukocyte antigen (HLA-B*5801 in Asian patients (Chinese, Thai and Korean). Do not administer allopurinol in patients that test positive for this antigen.
    DRUG INTERACTIONS:
    Increase in skin rash with Amoxicillin and Ampicillin. Increases levels of 6-mercaptopurine (Purinethol) and azathioprine (Imuran) by reducing their metabolism. Reduce dose of these drugs by 75% if they are used with allopurinol. This should be considered a life-threatening interaction

    DRUG MONITORING:
    • Titrate to dosage to lower uric acid to 6mg/dl
    • Decrease dose if renal impaired for maintenance.
    • If Creatinine clearance:
      • 20ml/min= 200mg daily.
      • 10ml/min = 100mg daily
    PATIENT EDUCATION--allopurinol
    • Report sign of rash, painful urination, blood in urine immediately to practitioner
    • Continue acute therapy. Optimal allopurinol may take 2-6 weeks.
    • Increase fluid intake to decrease renal stones
    • Take with food to minimize GI irritation.
    Febuxostat (Uloric) 40mg and 80 mg (approved 2009) cost: over $380/month
    Mechanism: xanthine oxidase inhibitor. Will lower uric acid more effectively, than allopurinol, but does NOT prevent gout flares any more effectively then allopurinol.
    BLACK BOX WARNING: Febuxostat has a higher risk of death than allopurinol Allopurinol should be used first line for most patients. If using Uloric, titrate the dose up to 80mg/day if needed to get serum uric acid below 6 mg/dL in patients with good renal function. No dosage for mild to moderate renal impairment, but if CrCl <30 mL/min, there is no evidence – not recommended. Check LFT at 2months and 4 months, then periodically.
    For both xanthine oxidase inhibitors: Azathioprine (Imuran) & 6-mercaptopurine (Purinethol) both are chemo drugs & immunosuppressants are metabolized by xanthine oxidase pathway. Allopurinol & febuxostat will increase the levels of these drugs to dangerous levels

    URICOSURIC:
    PROBENECID (Benemid®)
    (ColBenemid® has colchicine added) 500mg tablets
    MECHANISM OF ACTION: uricosuric: promotes excretion of uric acid by blocking its reuptake in the proximal convoluted tubule.
    Dosage: 250mg BID for 1 week. Then increase to 500mg BID thereafter. Do NOT start until acute attack has subsided. Take with food.

    WARNINGS/PRECAUTIONS/ADVERSE EFFECTS
    • 10% patients may develop uric acid stones. Advise drinking 2 liters of water per day
    • Pregnancy Category: B
    • Patients with urolithiasis or a creatinine clearance of less than 60ml/min should avoid probenecid.
    DRUG INTERACTIONS: prevents tubular secretion of weak organic acids and has potential drug interactions: penicillin, cephalosporin, nitrofurantoin, and Rifampin. AVOID ASPIRIN: interferes with uric acid secretion.
    Diuretics such as Lasix® (furosemide) and Hydrochlorothiazide (HCTZ) are magnified. Patients taking sulfonylureas should be monitored closely. May precipitate acute gouty arthritis attack

    PATIENT EDUCATION
    • Drink at least 2 liters of water per day to decrease uric acid stone formation.
    • Take with food if GI upset occurs.
    • Avoid Aspirin may antagonize uricosuric effect
    LOSARTAN (Cozaar) Losartan has a mild uricosuric effect, that maxes out at 50mg dose. Figure about 0.5mg/dl reduction. Other ARBs like irbesartan do NOT have a similar uricosuric effect. Good drug to consider for hypertensive patients with hyperuricemia.

    URATE TRANSPORTER INHIBITORS LESINURAD: Zurampic®200mg was removed from the market February 2019 due to economic reasons. and not related to any efficacy, safety or clinical concerns with lesinurad.
    Mechanism: Lesinurad inhibits the urate transporter, URAT1, which is responsible for most of the renal reabsorption of uric acid which increases uric acid excretion and thereby lowers UA.
    Combination drug: Duzallo® (approved August 17,2017) (removed from market 2/1/2019)

    VITAMIN-C (ascorbic Acid)
    Might help increase renal excretion of uric acid and reduce gout flares. Suggested dose 500 to 1000 mg/day from food or supplements. Expect a maximum of 0.5mg/dl lowering

    Urate-Oxidase (Recombinant)Enzyme PEGLOTICASE (Krystexxa®) by Savient Approved 9/14/2010
    Mechanism: Krystexxa is a uric acid specific enzyme that reduces uric acid by metabolizing uric acid to harmless chemicals that are excreted in the urine. Pegloticase is a recombinant porcine-like uricase. Similarly to rasburicase, both enzymes metabolize uric acid to allantoin. This reduces the risk of precipitates, since allantoin is five to ten times more soluble than uric acid.
    Dosage: given every 2 weeks as an infusion
    Adverse reactions: 25% experience severe allergic reactions.
    • May also see gout flares, injection site bruising, irritation of nasal passages, constipation, chest pain and vomiting.
      • Pretreat with antihistamine and corticosteroid to prevent anaphylaxis.
      • Pretreat with NSAIDS or colchicine 1 week before to prevent gout flares.
      • Cost= about $22,000 per vial. he recommended dose and regimen of KRYSTEXXA for adult patients is 8 mg (uricase protein) given as an intravenous infusion every two weeks. The optimal treatment duration with KRYSTEXXA has not been established. (Over half million dollars per year)
    What if our patient has no symptoms (ASYMPTOMATIC HYPERURICEMIA)?

    Most agree that a persistent urate level of >8 mg/dL as the threshold for initiating evaluation and, where warranted, lifestyle and/or pharmacologic intervention with xanthine oxidase inhibitors for management of asymptomatic hyperuricemia


    I remember 14 years ago back in 2005 preparing my gout lecture for St. Francis. I told the students that this was my favorite unit since not one thing changed from when I graduated in Pharmacy School in 1981 until that point.

    We learned about allopurinol, probenecid, colchicine, indomethacin, naproxen and ibuprofen in pharmacy school.

    For the next 4 years I used the same introduction. In 2009 my gout lecture changed with the addition of febuxostat, and then in following years I added peglitocase, and then lesinurad followed by Vitamin-C and losartan!

    Like every category of drugs new information is always coming out, and we are challenged to keep up with it.

    Have a great day on the bench!!

    April 2019

    We'll have lots of educating to do with our patients. FDA labeling changes on fat soluble vitamins are sure to cause lots of confusion.

    TREATMENT OF ACUTE GOUT ATTACKS

    Ground Rules for Drug Therapy
    • Neither uricosurics or xanthine oxidase inhibitors should be initiated aggressively in patients with active acute gouty arthritis.
    • Patients after an acute gouty arthritis attack are candidates for long term prophylaxis aimed at reducing the serum uric acid levels.
    • Goal of acute treatment is to relieve pain and inflammation. The “villain” is monosodium urate crystals.
    • Goal of chronic therapy is to decrease future attacks, and reduce body stores of urate, and reversing the effects of urate deposits.
    BENEFITS AND RISKS OF PHARMACOLOGICAL THERAPY
    • Even without treatment attacks of gout will end in 3 to 10days.
    • The goal of therapy is to relieve pain.
    • Use uric acid lowering drugs if patient has 2 or more attacks per year.
    • Long term goal of therapy is to prevent acute attacks.
    • Risks will be discussed with each pharmacological agent.
    NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
    NSAIDS are a reasonable option in patients without contraindications such as decreased kidney function or stomach ulcers. Indomethacin (Indocin) was approved in June 1965, and due to adverse GI effects, is only used for treatment of acute gout flares. There is no convincing evidence that it is any more effective than other NSAIDS, such as Ibuprofen (Motrin, Advil), Naproxen (Naprosyn, Aleve) or celecoxib (Celebrex). For cardiac patients naproxen is the safest choice of the NSAIDS.

    NSAIDS should be dosed as soon as onset of symptoms and taken on a consistent basis, not as needed until resolution of the acute gout flare.

    CORTICOSTEROIDS
    Instead of NSAIDs for acute gout- just as effective for pain relief and are sometimes better tolerated.

    Recommended dose: Prednisone 30 to 60 mg/day for acute gout until symptoms resolve. May take 5 to 7 days. Tapering is not necessary at this dose and duration

    Adverse effects: have patients with diabetes monitor blood sugars more frequently. May also cause fluid retention, hypertension and CNS adverse effects.

    COLCHICINE (Colcrys®)
    MECHANISM OF ACTION: Inhibits phagocytosis of urate crystals by leukocytes. Reduces inflammatory response to the deposited crystals. Although it is anti-inflammatory, it is not analgesic. Will not prevent the progression of gout to chronic gouty arthritis.

    INDICATIONS FOR USE
    • Specifically indicated for treatment and relief of pain in acute attack
    • Recommended for prophylactic use between attacks
    • Effective in aborting an attack at the first sign of articular discomfort.
    • If used for acute flare, must be started within 36 hours of symptom onset.
    Acute attack: COLCRYS instructions: 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1-hour period. (3 tablets maximum).

    Prophylactic dosing: 1-2 tablets per day for the first six months of urate lowering therapy. Remember, the initiation and titration of urate lowering therapy can cause a gout flare. Colchicine as prophylaxis, for the first 6 months of urate lowering therapy, is optional.

    WARNINGS/PRECAUTIONS/ADVERSE EFFECTS
    • Nausea, vomiting and diarrhea and bloating occur in up to 80% of patients.
    • Do not give to patients with active peptic ulcer disease
    DRUG INTERACTIONS:
    Life threatening interactions can occur with colchicine. Colchicine is a known substrate for p-glycoprotein (PGP) a transmembrane protein that acts to eliminate drugs by expelling them into the bile, urine and intestine and acting as blood brain barrier.

    CAUTION: using colchicine with clarithromycin, Erythromycin, Cyclosporine, Amiodarone, azole antifungals, Simvastatin and Verapamil. Symptoms of colchicine toxicity include diarrhea, myalgia and abdominal pain, may see dehydration, pancytopenia and acidosis. Of the 117 deaths from normal doses of colchicine reviewed by FDA, over half were taking clarithromycin (Biaxin®) New dose recommendation: if taking any of these CYP450 inhibitors: Two tablets only. Don’t repeat for 3 days.


    For pharmacists our typical gout patient comes hobbling into the store, usually an overweight guy, with the toe cut out of a pair of slippers.

    Of all the drugs that we dispense for an acute gout flare, colchicine is the most fun to talk about with student pharmacists and student PA's. "Back in the old days" we would dispense: Colchicine 0.6mg #12 tablets with the SIG: Take 2 tablets stat, then 1 tablet every 2 hours until bloody vomit or bloody diarrhea occurs. We were not so kind and gentle back in the day with acute gout flares!

    Colchicine comes from the Autumn crocus (Colchicum autumnale), and first mentioned for joint swelling in the Ebers papyrus. Initially, colchicine was used as a purgative, because it caused so much gastrointestinal distress. It wasn't used for gout because of the horrible gastrointestinal effects. Once the dose o 0.6mg became commonly used colchine fell in favor for gout flare treatment.

    In 1962 Kefauver Harris Amendment or "Drug Efficacy Amendment" required drugs to prove efficacy before they could appear on the U.S. market, however previously available drugs like colchicine were grandfathered in. Colchicine was cheap and readily available, until....

    In 2006, the FDA launched the “Unapproved Drugs Initiative,” which targeted old drugs, like colchicine that had never been approved by the FDA. The rationale was that older unapproved drugs, like colchicine despite obvious efficacy, deserve as much scrutiny for efficacy and safety as do newer drugs. The price went from $6.00 per 100 tablets to $6.00 per tablet.

    Have a great day on the bench!!

    We'll have lots of educating to do with our patients. FDA labeling changes on fat soluble vitamins are sure to cause lots of confusion.

    TREATMENT OF ACUTE GOUT ATTACKS

    Ground Rules for Drug Therapy
    • Neither uricosurics or xanthine oxidase inhibitors should be initiated aggressively in patients with active acute gouty arthritis.
    • Patients after an acute gouty arthritis attack are candidates for long term prophylaxis aimed at reducing the serum uric acid levels.
    • Goal of acute treatment is to relieve pain and inflammation. The “villain” is monosodium urate crystals.
    • Goal of chronic therapy is to decrease future attacks, and reduce body stores of urate, and reversing the effects of urate deposits.
    BENEFITS AND RISKS OF PHARMACOLOGICAL THERAPY
    • Even without treatment attacks of gout will end in 3 to 10days.
    • The goal of therapy is to relieve pain.
    • Use uric acid lowering drugs if patient has 2 or more attacks per year.
    • Long term goal of therapy is to prevent acute attacks.
    • Risks will be discussed with each pharmacological agent.
    NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)
    NSAIDS are a reasonable option in patients without contraindications such as decreased kidney function or stomach ulcers. Indomethacin (Indocin) was approved in June 1965, and due to adverse GI effects, is only used for treatment of acute gout flares. There is no convincing evidence that it is any more effective than other NSAIDS, such as Ibuprofen (Motrin, Advil), Naproxen (Naprosyn, Aleve) or celecoxib (Celebrex). For cardiac patients naproxen is the safest choice of the NSAIDS.

    NSAIDS should be dosed as soon as onset of symptoms and taken on a consistent basis, not as needed until resolution of the acute gout flare.

    CORTICOSTEROIDS
    Instead of NSAIDs for acute gout- just as effective for pain relief and are sometimes better tolerated.

    Recommended dose: Prednisone 30 to 60 mg/day for acute gout until symptoms resolve. May take 5 to 7 days. Tapering is not necessary at this dose and duration

    Adverse effects: have patients with diabetes monitor blood sugars more frequently. May also cause fluid retention, hypertension and CNS adverse effects.

    COLCHICINE (Colcrys®)
    MECHANISM OF ACTION: Inhibits phagocytosis of urate crystals by leukocytes. Reduces inflammatory response to the deposited crystals. Although it is anti-inflammatory, it is not analgesic. Will not prevent the progression of gout to chronic gouty arthritis.

    INDICATIONS FOR USE
    • Specifically indicated for treatment and relief of pain in acute attack
    • Recommended for prophylactic use between attacks
    • Effective in aborting an attack at the first sign of articular discomfort.
    • If used for acute flare, must be started within 36 hours of symptom onset.
    Acute attack: COLCRYS instructions: 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1-hour period. (3 tablets maximum).

    Prophylactic dosing: 1-2 tablets per day for the first six months of urate lowering therapy. Remember, the initiation and titration of urate lowering therapy can cause a gout flare. Colchicine as prophylaxis, for the first 6 months of urate lowering therapy, is optional.

    WARNINGS/PRECAUTIONS/ADVERSE EFFECTS
    • Nausea, vomiting and diarrhea and bloating occur in up to 80% of patients.
    • Do not give to patients with active peptic ulcer disease
    DRUG INTERACTIONS:
    Life threatening interactions can occur with colchicine. Colchicine is a known substrate for p-glycoprotein (PGP) a transmembrane protein that acts to eliminate drugs by expelling them into the bile, urine and intestine and acting as blood brain barrier.

    CAUTION: using colchicine with clarithromycin, Erythromycin, Cyclosporine, Amiodarone, azole antifungals, Simvastatin and Verapamil. Symptoms of colchicine toxicity include diarrhea, myalgia and abdominal pain, may see dehydration, pancytopenia and acidosis. Of the 117 deaths from normal doses of colchicine reviewed by FDA, over half were taking clarithromycin (Biaxin®) New dose recommendation: if taking any of these CYP450 inhibitors: Two tablets only. Don’t repeat for 3 days.


    For pharmacists our typical gout patient comes hobbling into the store, usually an overweight guy, with the toe cut out of a pair of slippers.

    Of all the drugs that we dispense for an acute gout flare, colchicine is the most fun to talk about with student pharmacists and student PA's. "Back in the old days" we would dispense: Colchicine 0.6mg #12 tablets with the SIG: Take 2 tablets stat, then 1 tablet every 2 hours until bloody vomit or bloody diarrhea occurs. We were not so kind and gentle back in the day with acute gout flares!

    Colchicine comes from the Autumn crocus (Colchicum autumnale), and first mentioned for joint swelling in the Ebers papyrus. Initially, colchicine was used as a purgative, because it caused so much gastrointestinal distress. It wasn't used for gout because of the horrible gastrointestinal effects. Once the dose o 0.6mg became commonly used colchine fell in favor for gout flare treatment.

    In 1962 Kefauver Harris Amendment or "Drug Efficacy Amendment" required drugs to prove efficacy before they could appear on the U.S. market, however previously available drugs like colchicine were grandfathered in. Colchicine was cheap and readily available, until....

    In 2006, the FDA launched the “Unapproved Drugs Initiative,” which targeted old drugs, like colchicine that had never been approved by the FDA. The rationale was that older unapproved drugs, like colchicine despite obvious efficacy, deserve as much scrutiny for efficacy and safety as do newer drugs. The price went from $6.00 per 100 tablets to $6.00 per tablet.

    Have a great day on the bench!!

    We no longer eat liver, kidneys, thymus glands and pancreases but our diet today can elevate our uric acid levels.

    PHARMACOLOGICAL AGENTS THAT MAY CAUSE OR WORSEN HYPERURICEMIA:
    • Alcohol
    • Chemotherapeutic drugs
    • Levodopa
    • Salicylates greater than 2g/day. BUT greater than 5gm/day decrease uric acid.
    • Low dose (81mg) aspirin does not affect uric acid levels.
    • Nicotinic acid (niacin)
    • Cyclosporine (Neoral), tacrolimus (Prograf)
    • Diuretics: all diuretics (especially loop and thiazide diuretics) except spironolactone cause hyperuricemia, by the following mechanisms:
      • A direct effect of diuretics on promoting urate reabsorption by the proximal tubule, increasing serum uric acid.
      • Indirect effect of diuretic-induced volume depletion on increasing urate reabsorption by the proximal tubule
    Conditions that can increase uric acid levels:

    Hypothyroidism- may predispose patients to hyperuricemia
    Psoriasis- quick turnover of cells and systemic inflammation may contribute to hyperuricemia
    Obesity- can be a contributory factor
    Primary Hyperuricemia: Can be caused by increased production of purines OR decreased renal clearance of uric acid.
    MEN account for 80% of hyperuricosuric kidney stones (uric acid or calcium) . Peak onset is age-45 The serum uric acid is elevated (over 7.5mg/dl) in 95% of patients who have measurements during the attack. During attack ESR (erythrocyte sedimentation rate) and white cell count are frequently elevated.

    Uric Acid Stones
    • Up to 20% of patients with gout develop uric acid stones.
    • Uric acid stones are found in 5-10% of urinary stones. Additionally, 15-20% of patients with calcium stones have hyperuricosuria.
    • The urinary solubility of uric acid depends on its concentration in urine and the urinary pH. At a pH below 5.5, nearly 100% of uric acid exists in an undissociated form.
    • Expect one or more of these factors may be found in patients with uric acid-related calculi. The 3 mechanisms responsible for uric acid related stone formation include:
      • an acidic urinary environment (pH < 5.5) is the most important factor observed in patients with uric acid stones
      • dehydration
      • hyperuricosuria. Urine uric acid levels in these patients may be elevated or within the reference range
    High purine foods to avoid if following "gout diet"
    Most of us are acutely aware that gout was called the "King’s disease" since excessive consumption of purine-rich foods and alcoholic drinks are independent risk factors for gout. Since most of us do not consume organ meats such as liver, kidneys and “sweatbreads” research has recently shown that fructose (think high fructose corn syrup) and sugar-sweetened soft-drinks increase the risk of developing gout. Here is a quick list of foods to be avoided:
    • Organ meats and seafood
    • Meat extracts and gravies
    • Yeast and yeast extracts, which includes beer and other alcoholic beverages
    • Beans, peas and lentils
    • Oatmeal
    • Spinach, asparagus, cauliflower, mushrooms
    SAFE FOODS: Low-fat dairy products, coffee, and vitamin C appear to have a protective effect. As you can see from the list above, following this low purine diet can be challenging, since so many nutritional foods need to be avoided.

    Definitive diagnosis: Definitive: birefringent monosodium urate crystals in affected joint appear as needle like shape

    Suggestive:
    • More than 1 attack of arthritis
    • Development of maximum inflammation within 1 day
    • Redness over joint
    • Painful or swollen first metatarsophalangeal joint (great toe)
    • Unilateral attack on first metatarsophalangeal joint
    • Unilateral attack on tarsal joint
    • Tophus
    • Hyperuricemia
    • Asymptomatic swelling within a joint.
    NON-PHARMACOLOGICAL TREATMENT MEASURES
    • Modification of diet (at best lowers UA by 1mg%)
    • Rest of the joint
    • Application of ice
    • Physiotherapy
    • Losing weight decreases stress on affected joint. Big toe gets most "shock" and most likely to be affected by uric acid crystals. Because the great toe is the coldest joint, due to distance from core of the body, the insoluble uric acid crystals are more likely to settle there.
    Gout is the most common inflammatory arthritis, affecting approximately 8.3 million Americans (6.1 million men and 2.2 million women).

    Gout prevalence has been increasing over the last half century, due to the aging of the population, increased use of medications that can trigger gout, and the obesity epidemic. It is no longer a disease of the rich and well fed.

    Gout occurs when the rather insoluble uric acid forms crystals that precipitate in the joints, most commonly the big toe. Gout attacks usually occur suddenly at night, may cause a patient to wake up. Gout attacks are often triggered by stressful events, alcohol, drugs, or another illness.

    These nasty uric acid crystals can also precipitate in the kidneys causing stones, and under the skin. Tophi (singular: tophus) are a nodular mass of uric acid crystals. Tophi are characteristically deposited in different soft tissue areas of the body in chronic (tophaceous) gout. Tophi are definitive lesions for gout diagnosis.

    Have a great day on the bench!!

    Can we recommend vaping for smoking cessation...for now, probably NOT.

    VAPING VS NICOTINE REPLACEMENT FOR SMOKING CESSATION

    A British study enrolled 900 people who wanted to quit smoking. The United Kingdom National Health Service stop-smoking services did a study where half of the participants randomly got e-cigarettes. The other half got traditional treatment: nicotine patches plus gum, lozenges, nicotine inhalers or whatever kind of oral nicotine they preferred. "The e-cigarettes were significantly more effective than nicotine replacement treatment," the researchers reported.

    As reported in the New England Journal of Medicine online, about 10 percent of people with standard treatment quit smoking for at least a year, while 18 percent of the people given e-cigarettes had quit. Almost two times as many quit smoking with vaping.

    HOWEVER of the 18% who vaped 90% of them continued to vape after one year and of the 10% who quit who used standard treatment, 80% were completely done with nicotine replacement at one year. The vapers were addicted to the nicotine. Incidentally, the e-cigarettes used in this study contained much lower levels of nicotine (18mg/ml) than found in some common brands used in the US (such as Juul at 23mg and 40mg per 0.7ml pod)

    Vaping Cigarettes
    NO tar Tar
    NO carbon monoxide Carbon Monoxide
    4 ingredients Thousands of chemicals (7,000)
    No second-hand smoke Second hand smoke
    No stink Stinks


    Bronchiolitis obliterans: also known as “popcorn lung” is a type of lung disease, which is not cancer. Inflammation causes scarring which leads to lung damage. A link between breathing in a chemical called diacetyl, a flavor enhancer, was made when a cluster of popcorn factory workers were all found to have the rare lung condition. It was not related to use of e-cigarettes, because e-cigarettes were not developed yet. Cherry, custard, and pastry flavors are most likely to contain diacetyl as a flavor enhancer.

    The chemicals found in e-cigarette liquid, known as "e-juice," may be a potential cause of popcorn lung. According to the American Lung Association, using electronic cigarettes or vaping, particularly the flavored varieties, can cause popcorn lung. However, e-cigarette vapor has been proven to contain diacetyl.

    JUUL LABS EFFORT TO COMBAT UNDERAGE USE:
    (see juul.com for complete list)
    • Pledged $30 million over the next three years to independent research, youth and parent education and community engagement.
    • Will use ID matching and age verification for online purchase.
    • Restricting the sales of flavored JUUL pods (Mango, Fruit, Cucumber, and Creme)
    • Funding secret-shopper program, which will now check compliance with bulk-purchasing restrictions.
    • Stopping social media like Facebook and Twitter to promote Juul products
    The best studied smoking cessation strategies include:
    • behavioral therapy, such as individual counseling or smoking cessation classes.
    • nicotine replacement therapy, such as a long-acting nicotine patch and short-acting nicotine gum
    • medications to reduce the urge to smoke, such as varenicline (Chantix) or bupropion (Zyban).
    • at every patient encounter smoking cessation should be discussed
    Recommending electronic cigarettes is still unproven and more head-to head controlled studies need to occur before we should be comfortable recommending e-cigarettes for smoking cessation.

    Prevention through Education
    For now, we, as health care professionals should focus on prevention of smoking, by educating teenagers and their parents. E-cigarettes are highly addictive and could cause lifelong problems. Every effort should be made to keep our youth away from electronic cigarettes.

    Hardly a day goes by at the Empower-3 clinic where when we discuss smoking cessation one of our patients, they will state that "I quit smoking; I’m just vaping now."

    Yes, they quit using the combustible tobacco, but they are still satisfying their nicotine addiction with electronic cigarettes. The truth is according to a 2015 Harvard study, "dual use" of tobacco products — vaping and smoking cigarettes — is not rare, nearly 60% of e-cigarette users also smoked cigarettes.

    Many people are still using combustible tobacco and vaping when it is not convenient for them to smoke.

    Have a great day on the bench!!

    We'll have lots of educating to do with our patients. FDA labeling changes on fat soluble vitamins are sure to cause lots of confusion.

    Use of E-cigarettes or Juuling

    JUULING—Today’s Health Concern

    Juul® pods are becoming a health concern for all of us clinicians and parents. The individual sucks on a small device that looks like a USB flash drive and it delivers unusually heavy doses of nicotine. Juuling is the act of vaping from a device known under the brand name Juul®. It looks like a flash drive and can be plugged into a laptop's USB slot to recharge. The Juul® was developed by two men who found it inconvenient go outside to smoke. These devices were originally developed to be used adults using combustible tobacco and “marketed” to those that are committed to stop smoking. However, these devices are becoming increasingly popular to many teenagers.

    According to the CDC, during 2016-2017, JUUL Labs’ sales increased 641 percent — from 2.2 million devices sold in 2016 to 16.2 million devices sold in 2017. By December of 2017, JUUL Labs’ sales comprised nearly 1 in 3 e-cigarette sales nationally, giving it the largest market share in the United States. Both combustible tobacco and vape liquids contain nicotine, which is highly addictive. The first e-cigarette “Vuse” was introduced in 2013 therefore there is less than seven years of experience to observe the outcomes. No deaths have been reported yet, due to lack of long-term exposure data.

    National Institute on Drug Abuse points out that the one-year increases in the prevalence of nicotine vaping translate into approximately 1.3 million additional adolescents who vaped in 2018, as compared with 2017. In September 2018, FDA announced the issuance of more than 1,300 warning letters and civil money penalty complaints to retailers who illegally sold JUUL and other e-cigarette products to minors. With vaping occurring for less than 6 years the FDA has acted (466 less years than combustible tobacco!) These warning letters are important because it found that 74 percent of youth who used JUUL reported obtaining the device from a physical retail store, and about half reported obtaining the device from a social source such as a friend or family member.

    America’s teens report a dramatic increase in their use of vaping devices in just a single year, with 37.3 percent of 12th graders reporting “any vaping” in the past 12 months, compared to just 27.8 percent in 2017. These findings come from the 2018 Monitoring the Future (MTF)

    HOW DO THEY WORK? “Smoking with a battery” The Juul is battery operated and works by heating a pod of e-liquid or “juice”. This juice contains nicotine, flavorings and other chemicals. Once heated the liquid creates an aerosol or vapor that the user inhales, and the user gets a very quick and powerful burst of nicotine.

    DOES JUULING CAUSE ADDICTION? Each pod contains the same amount of nicotine that is in one pack of cigarettes. The nicotine cycle is one that is most difficult to break because nicotine is vaporized, travels through the body in only 5-10 seconds, crosses the blood brain barrier, and causes dopamine release. (Dopamine is released and makes you feel good). This “feel-good” neurotransmitter causes one to crave more nicotine. When the nicotine level drops the smoker craves another puff on the Juul. The more addicted one becomes the more one must use to get the same effects. Nicotine suppresses insulin production, which staves off hunger, and provides appetite control. Hence, when a patient fears smoking cessation because of potential weight gain, that concern should be addressed.

    People currently report an uptick in nicotine use when starting to vape because that initial buzz that is seen with cigarettes is not achieved, there for a higher milligram or increased frequency can be seen. Vaping solutions are available in different concentrations: 0, 3, 6, 12, 18, 24 and 36 mg/mL. Depending on the flavor, JUUL pods are available in 3% or 5% strength. Each 5% JUUL pod contains about 40 mg per pod. Each 3% JUUL pod contains about 23 mg per pod. Each pod contains about .7ml of nicotine.

    Sources:

    Denise and I had the privilege of attending a program sponsored by our local Chamber of Commerce, featuring Dr. George Zlupko.

    Dr. Zlupko is our areas leading pulmonologist, who founded the Lung Disease Center of Central Pennsylvania and has provided services to the Altoona area for 3 decades.

    He spent an hour discussing the latest health concern, that being of e-cigarettes. I decided that we can spend the next two columns focusing on this heath threat. In the next two “Clinician Corners” we will use the term “Juuling” as this is the most popular vaping device. Certainly, all electronic cigarettes are part of this epidemic, especially with our concerns to our youth.


    According to the Boston University Medical Center, it all started on October 15,1492, when the Native Americans offered Christopher Columbus a gift of tobacco leaves. It took until 1964, when the Surgeon General's report on "Smoking and Health" was published elucidating the dangers of tobacco use.

    It took 472 years for the government to publish information that tobacco consumption was a health risk! In 1966 warning labels started appearing on packs of cigarettes (190 years after signing the Declaration of Independence). In 1971 the last ads for cigarettes appeared on America’s television sets.

    Have a great day on the bench!!

    March 2019

    Bariatric patients- have great need for our vitamin expertise, from vitamins to appropriate dosage forms.

    The special needs of bariatric surgery patients:

    We've finished our journey through the vitamin aisle, and many of our patients are need of our acquired vitamin expertise. This column will address the need of patients who have undergone gastric bypass surgery.

    • Obesity-related conditions include heart disease, stroke, type 2 diabetes and certain types of cancer, some of the leading causes of preventable death.
    • The medical costs for people who are obese are at least $1,500 higher than those of normal weight.
    Bariatric surgery is becoming increasingly popular to treat America's "expanding" epidemic. Pharmacists are needed to insure that the nutritional requirements are being met for this population. We are the experts in dosage form selection, as well as cost management. Here are some of the most common deficiencies that may occur in our bariatric surgery patients.

    CALCIUM: Calcium carbonate requires an acidic environment for dissolution and subsequent absorption in duodenum and proximal jejunum. Bypass may produce relative decrease in stomach acid production. Calcium citrate might be best option. Chewable calcium citrate, or gummies are the best option.

    VITAMIN-D: Decrease in fat absorption can lead to deficiency in fat-soluble vitamins. Roux-en-Y gastric bypass and biliopancreatic diversion are more likely to produce vitamin D deficiency than other surgeries. Have the physician check 25-hydroxy-vitaminD levels. Also: 10,000 IU of vitamin A, 2000 IU of vitamin D, and 300 mcg of vitamin K per day.

    IRON: avoid sustained release iron and enteric coated products. Might see decreased iron absorption due to decreased stomach acid production.

    VITAMIN B-1 (thiamine): is absorbed primarily in the duodenum and proximal jejunum. Bariatric surgery bypasses the duodenum and proximal jejunum and thiamine deficiency may occur within three weeks post-op. If the patient has persistent vomiting or severely diminished oral intake, they are at a higher risk of deficiency. Thiamine deficiency may be exacerbated by changes in the gut flora.

    VITAMIN- B-12 (cyanocobalamin): most common deficiency after Roux-en-Y surgery. At least 33% of patients will become vitamin deficient. Noticeable symptoms of a vitamin B12 deficiency can take years to develop, since we carry about 2 years of Vitamin B-12 in our livers. Irritability, weakness, numbness, anemia, loss of appetite, headache, personality changes, and confusion are some of the signs and symptoms associated with very low levels of vitamin B12. Supplement with 500-1000mcg/day orally per day. Consider Vitamin B-12 injections if patients are deficient after using the oral forms.

    FOLIC ACID: supplement with 0.4-2mg/day. Especially important in women that are still menstruating.

    TABLET SIZE: two months postoperatively, all medications should be given in a liquid dosage form, a crushed tablet, or an opened capsule. If a tablet must be used, start with the smallest tablet available. Solid dosage forms: recommend smaller than M&M’s candy.

    EXCIPIENTS: avoid sucrose, corn syrup, maltose, fructose, lactose, honey, mannitol, sorbitol to minimize dumping syndrome. Dumping syndrome can occur in up to 50 percent of post gastric bypass patients when high levels of simple carbohydrates are ingested. Dumping may contribute to weight loss in part by causing the patient to modify his/her eating habits. Early dumping syndrome has a rapid onset, usually within 15 minutes, due to rapid emptying of food into the small bowel. Due to the hyperosmolality of the food, rapid fluid shifts from the plasma into the bowel occur, resulting in low blood pressure and a sympathetic nervous system response. Patients often present with colicky abdominal pain, diarrhea, nausea, and racing heartbeat. Acarbose (Precose®) lowers both postprandial glucose hyperglycemia and reactive hypoglycemia, which subsequently lead to a significant reduction in dumping symptoms.

    Here are the chilling statistics about our nations obesity rates:
    • 93.3 million of U.S. adults are obese.
    • Seven states (Alabama, Arkansas, Iowa, Louisiana, Mississippi, Oklahoma and West Virginia) had adult obesity rates of 35 percent or higher, led by West Virginia at 38.1 percent. West Virginia had the highest adult diabetes rate at 15.2% and the highest hypertension rate at 43.5 percent
    • 18.5% of our youth are obese.
    • The lowest adult obesity rates were in Colorado (22.6 percent), the District of Columbia (23.0 percent) and Hawaii (23.8 percent).
    • Data for 2016 showed that 22.2 percent of adult college graduates had obesity, compared with 35.5 percent of adults with less than a high school education.
    Best advice might be, stay youthful, go to college and live in Colorado!

    Have a great day on the bench!!

    Alcoholics need our expertise in selecting vitamins:

    ALCOHOLICS NEED VITAMINS:

    Alcoholics often eat poorly, limiting their supply of essential nutrients and affecting both energy supply as well as cell and organ system structure maintenance. In general, moderate drinkers (two drinks or less per day) seem to be at little risk for nutritional deficiencies. Furthermore, alcohol affects all the pharmacokinetic parameters:

    Digestion: decreasing secretion of digestive enzymes from the pancreas, as well as damaging the absorptive surface of the stomach.

    Storage: a damaged liver doesn’t store the Vitamins A and Vitamin E

    Renal Damage: alcohol consumption, especially binge drinking can lead to dehydration, affecting kidney function. Liquor selectively increases renal perfusion and basal metabolic rates of renal tubes hence causing an increase in diuresis, leading to massive dehydration. Elevations in blood pressure from alcohol can cause renal damage.

    Excretion of nutrients: improper digestion of fats might cause a decrease in the fat soluble vitamins A, D ,E, & K.

    Vitamin Supplementation in the Alcoholic Patient:
    • Vitamins A, D, E, and K — Vitamin A, D, E, and K levels are often deficient in patients with chronic pancreatitis or alcoholic liver disease.
    • Thiamine (B-1) deficiency is found in up to 80 percent of adults with chronic alcohol use.
    • Pyridoxine (B-6) deficiency occurs in over 50 percent of alcoholic patients and is caused by reduced intake and increased breakdown of pyridoxine during ethanol metabolism.
    • Folic Acid (B-9) Two-thirds of binge drinkers will have folate deficiency caused by malabsorption, reduced intake, and increased urinary excretion. This can cause macrocytic anemia and intestinal malabsorption.
    • Zinc: Alcoholics up to half of that population need zinc supplementation due to poor diet.
    • Vitamin B-12: The presence of alcoholic liver disease elevated the serum concentration of vitamin B12 but not the level of folic acid. The vitamin B12 concentration reflects the degree of hepatocytes injury by alcohol. Alcoholics may have normal to high normal levels of Vitamin B-12.
    Our alcoholic patients have a variety of nutritional needs. Poor eating habits, combined with the depletion that alcohol can cause in the body make this population in need of our expertise.

    Here is a handy checklist of the vitamins that alcoholics need

    Rx:
    Thiamine 100mg: once daily
    Pyridoxine 50mg: once daily
    Folic acid 1mg: once daily
    Zinc 50mg: once daily

    Have a great day on the bench!!

    It's been a long walk through the supplement section of the pharmacy. We are finally at the end: ZINC!

    ZINC

    Zinc is considered to be an essential “trace element” that has to come from the diet. Zinc is an enzyme cofactor and protects and stabilizes cell membranes from lysis caused by complement activation and toxin release. Involved in over 100 enzymes, zinc deficiency presents as growth failure, primary hypogonadism, skin disease, impaired taste and smell, impaired immunity and resistance to infection. Zinc deficiency is rare in the United States, but very common worldwide, especially in developing countries.

    SOURCES FOR ZINC: Daily Value (DV) for zinc is 15 mg for adults and kids age 4 and older.
    • red meat, poultry and eggs
    • beans, nuts
    • Oysters are the highest (34mg/serving 340% of DV) seafood (such as crab and lobster),
    • whole grains, fortified breakfast cereals, and dairy products
    • Phytates, which are present in whole-grain breads, cereals, legumes, and other foods—bind zinc and inhibit its absorption. Zinc from plants and grains is lower- but still is adequate. Iron and coffee contain phytates, which can inhibit zinc absorption.
    • IRON (over 25mg) may decrease zinc absorption. Take iron between meals
    ZINC DEFICIENCY signs and symptoms:
    • loss of appetite and impaired immune function.
    • Severe zinc deficiency causes hair loss, diarrhea, weight loss and increase in pneumonias, mostly seen in developing countries.
    • Zinc deficiency in poor countries causes an increase in pediatric infections. Has been evaluated as an effective therapeutic and preventative measure for infections.
    • Eye and skin lesions
    • Delayed sexual maturation, impotence, hypogonadism in males
    • •Delayed wound healing, taste abnormalities, and mental lethargy can also occur
    PATIENTS NEEDING ZINC SUPPLEMENTATION:
    • GROUPS at greatest risk: GI surgery- especially gastric bypass surgery, ulcerative colitis and Chron’s disease.
    • Alcoholics up to half of that population need zinc supplementation due to poor diet.
    • Vegetarians require 50% more of RDA, due to lack of intake of meat products.
    • Sickle cell anemia and alcoholics. Zinc deficiency also affects approximately 60%–70% of adults with sickle cell disease. Zinc supplementation has been shown to improve growth in children with sickle cell disease
    • ZINC FOR COLD: a 2004 review showed zinc lozenges may reduce the duration and severity of cold symptoms, when taken within 24 hours of onset of symptoms. The safety of intranasal zinc has been called into question due to numerous reports of anosmia (loss of smell), which may be long-lasting or permanent, from the use of zinc-containing nasal gels or sprays.
    • ZINC FOR THE EYES (AMD): zinc is not effective for the primary prevention of early adult macular degeneration (AMD), although zinc might reduce the risk of progression to advanced AMD.
    DRUG INTERACTIONS INVOLVING ZINC
    • May bind tetracyclines as well as fluoroquinolones (Cipro, Levaquin)
    • Diuretics may lower zinc levels by 60%
    • Iron blocks zinc absorption
    • Zinc may increase bleeding risk when taken with
      • Anticoagulants (warfarin, Xa inhibitors-Xareolto®, Eliquis®, Savaysa®)
      • Antiplatelet drugs (Clopidogrel-Plavix®)
      • NSAIDS (Naproxen,etc))
    • Zinc may lower blood sugar levels
    EXCESS ZINC : may cause nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches. Over 150mg of zinc per day may cause
    • low copper status
    • altered iron function
    • reduced immune function
    • reduced levels of high-density lipoproteins
    • Affect urinary physiology
    • Look for zinc-free denture adhesives, especially if using in large quantities
    We started this journey through the vitamin aisle on November 1,2018 with Clinician’s Corner. Now 4 and ½ months later we wrap up this journey through the vitamins and supplements with Zinc.

    We’ve covered everything from “A” to “Zinc”, with one notable exception. Fluoride was not covered in this unit, because oral fluoride requires a prescription. I covered this very important ion in the dental section, back on April 20, 2017.

    Next Clinician’s Corner we’ll talk about specific patients, and who should be talking these vitamins and supplements. I’ll provide you with information that applies to specific patients, because if what we read doesn’t apply to patient care, it is simply pharmacy trivia!

    Remember... the "Request line" is always open. If there is a topic relevant to patient care that applies to pharmacy and general practice patients, feel free to e-mail me with any requests. With my lecture notes from St. Francis University, I can cover most any topic of interest to the primary care providers, CRNP's, Physician Assistants and pharmacists.

    Have a great day on the bench!!

    Calcium: lots of choices in our supplement aisle. Make sure our patients get the best one, for them!

    Let's discuss one of the most common supplements in our vitamin section, calcium. Calcium is most abundant mineral in our body. Calcium is found in some foods, added to others, available as a dietary supplement in out vitamin section, and present in some medicines, we recommend as an antacid (Tums).

    Our bodies use calcium for vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling and hormonal secretion., however less than 1% of total body calcium is needed to support these critical metabolic functions. The other 99% is stored in bones and teeth.

    Frank calcium deficiency is rare especially with our diet. Over the long term, inadequate calcium intake may cause osteopenia which if untreated can lead to osteoporosis. Older individuals may suffer from bone fractures due to osteopenia and osteoporosis. Rickets can be seen, but this is usually attributed to Vitamin-D deficiency.

    About 43% of the U.S. population (including almost 70% of older women) uses dietary supplements containing calcium, increasing calcium intakes by about 330 mg/day among supplement users. Our job as pharmacists is to make sure they are taking the RIGHT calcium supplement.

    AGE of PATIENT MALE FEMALE
    14-18 years 1,300mg 1,300mg
    19-50 years 1,000mg 1,000mg
    51-70 years 1,000mg 1,200mg
    71+ years 1,200mg 1,200mg


    Calcium carbonate: (Os-Cal-500 and generics)
    • Contains 40% Calcium (1250mg Calcium carbonate yields Calcium++ 500mg)
    • Should be taken with a meal. Optimal absorption occurs in the presence of gastric acid. May cause constipation, divided dosing and adequate fluids should alleviate its occurrence
    • Must divide doses. Approximately 500mg can be absorbed at a single time
    Calcium Citrate (Citracal® and generics)
    • Contains 21% calcium by weight. May be taken with or without meals. Does not require stomach acid for absorption. Best choice for elderly with reduced gastric acid.
    • Best choice for patients on proton pump inhibitors or H2 receptor antagonists.
    • Digoxin
    • Works best for patient’s complaining of GI upset.
    • Must divide doses, is a higher pill burden.
    Calcium Consultation Points
    • Tetracyclines, fluoroquinolones--decreased efficacy of the antibiotic. Separate doses by at least 2-3 hours.
    • L-thyroxine & Bisphosphonates--decreased efficacy by decreasing absorption. Separate dose from calcium by 4 hours.
    • Corticosteroids decrease absorption of calcium, and over time can lead to osteoporosis.
    • Thiazide diuretics increase urinary calcium reabsorption. Studies have shown fewer fractures on patients on thiazide diuretics. If diuresis is needed, a thiazide would be a good choice. Loop diuretics increase the excretion of calcium.
    • Most agree the optimal daily dose for adults is 1200mg Calcium along with Vitamin-D 800iu (20mcg)
    Who should supplement:
    • Post-menopausal women
    • Pregnant women
    • Vegetarian, because they eat more plant based diet, the consume more oxalic and phytic acids which block absorption of calcium.
    • Prednisone can cause calcium depletion and eventually osteoporosis if used chronically
    • Patients using acid suppressing therapy- proton pump inhibitors (Omeprazole etc.) and histamine-2 receptor blockers (Ranitidine, etc.)
    • Bariatric surgery weight loss patients should use calcium citrate, preferably a chewable dosage form.
    As we live longer, the bones might need a little help from calcium supplementation. The aging process does cause wear and tear on our bones. Every time I check a prescription for Omeprazole (Prilosec), Pantoprazole (Protonix), Ranitidine (Zantac) and Famotidine (Pepcid) I should wonder about the impact these drugs have.

    The adverse effects of proton pump inhibition (PPI's) and Histamine-2 receptor blockade (H2RA) are well know such as B-12 deficiency, calcium deficiency, magnesium deficiency, Clostridium difficile and pneumonia. Like B-12 deficiency, calcium malabsorption caused by PPI's and H2RA's is an easy fix in the community pharmacy.

    When we buy our Omeprazole and Pantoprazole in bottles of 1000 in the small corner drugstore where I work, I cant help but wonder how much untreated calcium deficiency is slipping out the front door. Calcium citrate should be flying off the shelf in the front of the store as briskly as the omeprazole and ranitidine fly out of the pharmacy!

    Have a great day on the bench!!

    February 2019

    Iron keeps the blood happy, but not necessarily the GI tract!

    IRON SUPPLEMENTATION

    Let's discuss another very common cation, which approximately 14% to 18% of Americans supplement their diets with. Iron is a mineral that is naturally present in many foods, used to fortify some food products, and available as a dietary supplement. Iron is an essential component of hemoglobin, a red blood cell protein that transfers oxygen from the lungs to the tissues. Iron is also in myoglobin, a protein that provides oxygen to muscles, iron also supports metabolism. Iron is also needed for growth, development, normal cellular functioning, and synthesis of some hormones and connective tissue.

    Sources: The richest sources of heme iron in the diet include lean meat and seafood (about 15% of Western diet). Dietary sources of nonheme iron include nuts, beans, vegetables, and grain products that are fortified (about 85%). Heme iron has higher bioavailability.

    Correction of iron deficiency:
    • Bone marrow response to iron is limited to 20mg/d of elemental iron
    • An increase in hemoglobin level of 1g/dL should occur every 2-4 weeks
    • Oral: only 10% of an oral iron dose is absorbed in patients with normal iron stores.
    • 20% to 30% of oral iron dose is absorbed in persons with inadequate iron stores
    • May take up to 4 months for iron stores to return to normal after hemoglobin is corrected.
    • Goal dose: Ferrous sulfate 325mg by mouth three times daily. May increase compliance by starting slowly. One tablet at bedtime on empty stomach, may increase 1 tablet every week. Take 1 or 2 hours before a meal because food can decrease absorption by 50%. If GI upset occurs, may take with small snack such as crackers. NO milk or tea.
    • Extended-release or enteric-coated formulations have been found to transport iron past the duodenum and proximal jejunum, thereby reducing the absorption of iron. Vitamin C is added to some products to enhance iron absorption
    • Orange juice (Vitamin-C) can double the absorption. About 200 mg is needed to increase absorption of 30 mg of elemental iron.
    • Take 1 hour before or 3 hours after antacids. Food decreases absorption. Proton Pump inhibitors (Prilosec), Histamine-2 Receptor blockers (Zantac) will impair iron absorption.
    • If constipation occurs initiate stool softener with docusate (Colace®) 100mg one daily


    Iron salt Yields elemental iron Percentage
    Ferrous sulfate 325mg 65mg 20%
    Ferrous gluconate 35mg 12%
    Ferrous fumarate 99mg 33%


    What about Nu-Iron or Ferrex? (iron polysaccharide) Iron polysaccharide causes somewhat less GI upset than ferrous sulfate. Despite the adverse GI side effects, the ferrous sulfate shows a better hematological response versus the iron polysaccharide. Iron polysaccharide, because of its delayed release is not as well absorbed as ferrous sulfate.

    Iron-Drug Interactions be sure to AVOID:
    • Fluoroquinolones
    • Tetracycline
    • Digoxin
    • Carbidopa/levodopa (Sinemet, Stalevo)
    • Levothyroxine (AVOID iron by 4 hours!)
    Most common side effects:
    Metallic taste, constipation, nausea, diarrhea, dark stools, and abdominal pain

    REMEMBER: Insist on child resistant packaging if there is ANY chance small children may be in the home. Iron is still the #1 cause of pediatric fatalities due to toxicity. Before the mandatory child resistant packaging, iron overdose accounted for 1/3 of pediatric poisonings.

    Patient groups most likely to need iron supplementation
    • Pregnant women
    • Infants and young children
    • Women with heavy menstrual bleeding
    • Frequent blood donors
    • Patients with cancer
    • Patients with gastric disorders (gastrectomy, weight loss surgery, ulcerative colitis, celiac disease)
    • Proton pump inhibitors
    • reduce absorption of non-heme iron.
    • ACE cough: iron might inhibit the dry cough associated with ACE inhibitors.
    When to consider IV iron:
    allergic reactions to the older formulation of iron dextran made clinicians reluctant to consider IV. With the newer formulations of iron salts, allergic reactions to IV iron are much rarer.
    • ongoing blood loss
    • physiologic or anatomic abnormality that interferes with oral absorption
    • intolerable gastrointestinal side effects of oral iron.
    Iron is another nutritional supplemented along with thiamine, niacin, riboflavin, folic acid, to enriched flour. In the United States, about half of dietary iron comes from bread, cereal, and other grain products. We have a lot of patients who in spite of the ubiquitous presence of iron in our grains still require iron supplementation.

    Iron supplementation is an opportunity for the pharmacist to do some beneficial counseling to our patients. Gradually introducing the ferrous sulfate is key to decreasing GI upset. If a patient gets GI upset negotiate with them to get this important supplement on board. An empty stomach is best for absorption, but if GI upset occurs consider a light snack of water and crackers.

    Encourage them to take about 250mg of Vitamin-C along with the iron to get the most absorption. Even dosing the iron every other day is of great benefit, and better than the patient giving up on iron therapy.

    Be sure to use this information to work with patients to decrease chance of drug interactions. Levothyroxine and iron is the most common interaction. Separation of doses are critical. If a patient is taking their iron three times a day, and we need to separate the levothyroxine by 4 hours I frequently have patients take their Levothyroxine at bedtime when they brush their teeth.

    Have a great day on the bench!!

    Too much of a good thing, and a lot harder to treat: HYPERkalemia

    TREATMENT of HYPERkalemia

    Last week we discussed potassium supplementation and the treatment of hypokalemia. Even more challenging is when the potassium levels rise excessively, due to chronic kidney disease, heart failure, excessive tissue trauma (burns, etc.) or medications.

    Hyperkalemia: serum potassium level greater than 5.5 mEq (mmol)/L. Hyperkalemia is a serious and potentially life-threatening disorder. It can cause: muscle fatigue, weakness, paralysis, nausea and life threatening cardiac arrhythmias.

    Drugs noted for causing HYPERkalemia:
    • NSAIDS (Ibuprofen, Naproxen, etc)
    • Potassium Sparing Diuretics (triamterene, amiloride, spironolactone)
    • Angiotensin Converting Enzyme inhibitors (Lisinopril, Enalapril Captopril etc)
    • Angiotensin Receptor Blockers (Valsartan, Irbesartan, Losartan etc)
    • Heparin
    • Trimethoprim (Bactrim-DS)
    • Excess doses of potassium supplements
    Treatment for hyperkalemia involves three goals, namely restoring normal potassium balance, preventing serious complications, and treating the cause Treatment for severe hyperkalemia can be broken down into three steps:
    1. Antagonizing the effects of potassium on excitable cell membranes
      • Calcium gluconate is used to antagonize the effects of potassium on the heart muscle in patients with severe hyperkalemia. NO effect on blood levels of K+

    2. Redistributing extracellular potassium into cells Beta agonists (high-dose nebulized albuterol) help shift potassium from the extracellular fluid to intracellular fluid in patients with severe hyperkalemia. Insulin can be used to help shift potassium from the extracellular fluid to intracellular fluid in patients with severe hyperkalemia. Give with glucose to prevent hypoglycemia.

    3. Enhancing elimination of potassium from the body. Beta agonists (high-dose nebulized albuterol) help shift potassium from the extracellular fluid to intracellular fluid in patients with severe hyperkalemia. Insulin can be used to help shift potassium from the extracellular fluid to intracellular fluid in patients with severe hyperkalemia. Give with glucose to prevent hypoglycemia.
      • Dialysis
      • Diuretics (loop diuretics)
      • thiazide diuretics can be used only down to CrCl=40
    ORAL DRUG THERAPY (Potassium Binders)

    Sodium polystyrene sulfonate
    (Kayexalate, Kionex, SPS) -available 1958


    Mechanism: ion exchange resin absorbs potassium in the intestinal lumen.

    Dose: The average daily adult dose of the resin is 15 g to 60 g. Each gram of resin may bind as much as 1 mEq of potassium and release 1 to 2 mEq of sodium

    Side effects: GI disturbance, Constipation, Hypokalemia, Hypocalcemia Hypomagnesemia, Sodium retention, Nausea, Vomiting GI tract ulceration or necrosis, which could lead to perforation.

    Avoid in patients on opioid therapy, post op patients, C. dif patients, and patients prone to small or large bowel obstruction.

    Use SPS only the following criteria are met:
    • Potentially life-threatening hyperkalemia
    • Dialysis is not readily available
    • Other therapies to like diuretics, or rapid restoration of kidney function have failed or are not possible
    Veltassa (patiromer) released October 2015, is the first new treatment for hyperkalemia in 50 years. Mechanism: is powder form that spherical beads bind to potassium in exchange for calcium, primarily in the colon. The potassium is then excreted from the body fecally.

    Limitation of Use: Veltassa® should not be used as an emergency treatment for life threatening hyperkalemia because of its delayed onset of action.

    Dosage: Administer Veltassa at least 6 hours before or 6 hours after other oral medications. Administer with food. Starting dose of Veltassa is 8.4 grams patiromer once daily. Available in individual packets. Monitor serum potassium and adjust the dose of Veltassa based on the serum potassium level and the desired target range.
    All of the drugs for treatment of hyperkalemia require a hands on approach for mixing and measuring the resins. This is a great opportunity for the independent pharmacist to provide the “hands on” care these complicated patients require.

    Lokelma (sodium zirconium cyclosilicate) “ZS-9” released November 2018

    Limitation of Use: do not use as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.

    Mechanism: potassium binder. Sodium zirconium cyclosilicate is a non-absorbed zirconium silicate that preferentially exchanges potassium for hydrogen and sodium. This complex is passed out fecally with bound potassium.

    Dosage/Administration: Recommended starting dose is 10 g administered three times a day for up to 48 hours.
    • For maintenance treatment, recommended dose is 10 g once daily. (2.1)
    • Adjust dose at one-week intervals as needed (by 5 g daily) to obtain desired serum potassium target range
    Avoid: patients with severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders

    Good things come to those who wait! It took almost 60 years to get a potassium binder than wouldn’t cause bowel necrosis and do more harm than good.

    Kayexalate (SPS) was first introduced the year I was born in 1958. The two new potassium binders came out the past two years.

    Veltassa is available as a specialty pharmacy drug. The starting dose for Veltassa, is 8.4grams per day, GoodRx prices it around $900.00 per month.

    Lokelma is stocked in our warehouse with average wholesale price of $786.00 per month, and is readily available in the community pharmacy practice setting. Loretto, PA 15940

    Have a great day on the bench!!

    Beef, chicken, tomato, orange or cherry---having trouble picking a potassium supplement??

    POTASSIUM

    Another important cation we frequently dispense in the pharmacy is potassium. Potassium is the most abundant cation in intracellular fluid, where it is responsible for maintaining intracellular fluid volume. Intracellular fluid, which is found inside the cells accounts for 55% of our body’s total water volume. Potassium is important for establishing resting membrane potential in neurons and muscle fibers. Potassium also regulates the pH of body fluids when exchanged for H+. Normal range for potassium is 3.7 to 5.2 mEq/L.

    Potassium is lost through the kidneys when patients take diuretic therapy for high blood pressure, heart failure, kidney failure to help remove excess fluid. Diarrhea, vomiting and corticosteroid use can also deplete potassium. Thiazide diuretics “lightweight diuretics” – HCTZ, chlorthalidone can cause potassium depletion, but the more potent “loop diuretics” -Lasix (furosemide); Demadex (torsemide), Bumex (bumetanide)can cause significant potassium loss.

    Hey doc, do I have to swallow those horse pills? Can’t I just eat a banana? I never recommend potassium rich foods to replace potassium chloride supplements when they are prescribed. Consider the following:

    • Bananas: contain 1mEq of potassium per inch, and a 10 inch banana contains about 140 calories. Bananas cost about 59-79 cents per pound. Could you imagine eating 4 large bananas a day, at almost 600 calories!
    • Orange juice to get 10mEq of potassium you need to drink 7 ounces which is 90 calories. To replace 40mEq would be nearly 400 calories.
    • Potassium rich foods contain potassium phosphate, not potassium chloride, which is important with diuretic loss as well as vomiting and diarrhea.
    Guidelines for potassium repletion:
    • Loop or thiazide diuretics: 20 mEq potassium per day is sufficient to prevent hypokalemia with diuretics
    • 40 – 100 mEq potassium required to correct mild potassium deficits
    • Up to 120 mEq required for severe deficiencies
    • Total daily doses should be divided in 3 – 4 doses to prevent GI side effects
    Alternative therapies for Potassium Repletion K-sparing diuretics- work in the distal tubule and exchange sodium for potassium, and help retain potassium.
    • Spironolactone (Aldactone) and Eplerenone (Inspra) inhibit the effects of aldosterone to decrease potassium elimination, and are more effective in lowering blood pressure than are amiloride (Midamor) & triamterene (Dyrenium), which work independently of aldosterone. Eplerenone is a “go to” drug for patients complaining of gynecomastia due to spironolactone therapy.
      • *Excessive urinary potassium wasting may require potassium-sparing diuretics + potassium supplementation (CHF, cirrhosis or nephrotic syndrome)
    Patient counseling points
    • All potassium tablets should be taken with food to minimize GI upset.
    • To reduce esophagitis with oral potassium, counsel patients to drink at least 100 mL of water and stay upright for five to ten minutes after administration.
    • Watch salt substitutes. Contain 15-20 mEq per ¼ teaspoon serving
    • Advise patients about the potential for seeing “ghost tablets: in their stool, the left over wax remnants (especially the bright yellow ones!)

    Remember Kaon®, Kato® and Potage®? Kaon was a potassium gluconate supplement, that fell out of favor, knowing that chloride needed to be supplemented too. Kato was a tomato juice flavored potassium supplement, the drug company’s rationale was if you have to drink something salty, might as well be something that goes well with salt.

    Even more ridiculous was the potassium supplement Potage®, which is the French word for soup. Potage, playing off the fact that soups contain salt offered two different flavors the patient could choose from both chicken and beef! We also had effervescent tablets called K-lyte® and K-lyte Cl, which had a salty orange or salty cherry flavor.

    Today we have only a couple of options, like sustained released capsules (Micro-K-10®), sustained released wax based tablets (Klotrix® and K-tabs®) and microencapsulated tablets (K-Dur® and Klor-Con-M). Most patients have their preferences for their potassium tablet—I’m just glad we no longer must deal with what flavor to select. “I’m sorry ma’am but your insurance plan only covers beef flavor, and not chicken; chicken flavor requires a prior auth!!”

    Next week, we’ll discuss too much of a good thing. “Hyperkalemia”.

    Have a great day on the bench!!

    Diuretic therapy makes us think of potassium---but don't forget magnesium!

    MAGNESIUM

    Magnesium is important for:
    • managing bone metabolism
    • nerve transmission, cardiac excitability, neuromuscular conduction, muscular contraction, vasomotor tone, and blood pressure
    • managing bone metabolism
    • Insulin and glucose metabolism
    Sources of magnesium:
    • Food sources of magnesium include green leafy vegetables, nuts, legumes, and whole grains
    • 50% stored in bone, the other half in soft tissues, less than 1% in blood.
    • Low magnesium leads to decreased levels of calcium and potassium- mag homeostasis is related to K+ and Ca++
    • Magnesium level: 1.7-2.2mg/dL (1.8-3.6mg/dl, depending on labs)
    Uses for magnesium:
    • Intravenous magnesium is used for treatment of torsade de pointes
    • Treatment of eclampsia and preeclampsia
    • Headache: cluster and migraine sufferers generally have low magnesium levels. Low magnesium levels relate to factors that promote headaches, including neurotransmitter release and vasoconstriction.
    • Severe asthma exacerbations
    • Constipation
    Magnesium loss can cause: cardiac arrhythmias, tremors and neuromuscular hyperexcitability, lowered potassium and calcium levels.

    Patients most susceptible to magnesium deficiency:
    • Patients with diabetes: will have lower magnesium levels due to the diuresis caused by high urine glucose levels. Low magnesium levels might worsen insulin resistance, a condition that often precedes diabetes, or it might be a consequence of insulin resistance. There is insufficient evidence to promote magnesium supplementation to prevent diabetes.
    • Patients with alcoholism (30%) substitute alcohol for food as well as malabsorption syndrome
    • diuretic therapy, especially loop diuretics like Lasix, Bumex, Demadex: magnesium gets washed out. Addition of amiloride (Midamor), a potassium sparing diuretic may help with magnesium loss by increasing reabsorption in the distal tubule.
    • Chronic diarrhea and chronic steatorrhea
    • Proton pump inhibitors (omeprazole, pantoprazole etc.) if used over a year, especially if on diuretic therapy. Patients on PPI therapy should have their magnesium levels checked periodically.

    Salt Brand name % Mag Points to consider
    Mag Chloride Slow-Mag; Mag-64 12% 20% absorbed
    Mag citrate Citroma 16% Limited absorption
    Mag hydroxide Milk of Magnesia 42% Minimal absorption
    Mag Oxide Mag-Ox-400 60% 4% absorbed


    Rx to OTC Connection:

    Rx Treatment: If magnesium loss due to diuretic use, consider the addition of a potassium-sparing diuretic (amiloride/ spironolactone), to help retain magnesium (as well as potassium)

    Drug Interactions: Magnesium can greatly reduce the absorption of tetracyclines, fluoroquinolones (Cipro, Levaquin), and most important Levothyroxine (Synthroid). Be sure to separate by 4 hours. Sustained-release preparations (Slow-Mag) have the advantage that they are slowly absorbed and thereby minimize renal excretion of the administered magnesium

    As we have wrapped up all the vital-amines (vitamins) lets discuss some other critical supplements. First let’s start with magnesium. We all know that potassium gets most of the attention when we think of diuretic use, but magnesium is becoming equally important. Magnesium is the 2nd most abundant intracellular divalent cation. Involved in more than 300 metabolic reactions in the body, Including protein synthesis, cellular energy production and storage, cell growth and reproduction, DNA and RNA synthesis, and stabilization of mitochondrial membranes.

    Have a great day on the bench!!

    January 2019

    Our pharmacists that work in a grocery store see more of this fat soluble vitamin than the rest of us do!

    Got broccoli? Got Kale? That's where most of us can buy our Vitamin-K!
    Let’s wrap the last fat soluble vitamin. This one we never get to recommend over the counter. We get plenty from our diet, as well as make our own in our gut. We learned in school that fat soluble vitamins are accumulated, and water soluble vitamins are quickly removed. Not the case for Vitamin-K, which hangs around in our bodies for less than one week.

    Sources for Vitamin K: leafy vegetables, vegetable oils, liver, & synthesis by intestinal flora. Phylloquinone (Vitamin K-1) is present primarily in green leafy vegetables and is the main dietary form of vitamin K. Menaquinones (Vitamin K-2), especially long-chain menaquinones, are produced by bacteria in the human gut.
    • Function: essential for formation of clotting Factors VII, IX, X, prothrombin, proteins C and S
    Deficiency States: When we ingest Vitamin-K the body retains only about 30% to 40% of an oral physiological dose, while about 20% is excreted in the urine and 40% to 50% in the feces via bile. This rapid metabolism accounts for vitamin K's relatively low blood levels and tissue stores compared to those of the other fat-soluble vitamins.
    • May be due to excessive antibiotic use. Newborns & preemies at increased risk. Deficiency cause hemorrhage due to prothrombin deficiency.
    • Cystic fibrosis patients because of fat malabsorption and broad-spectrum antibiotic use (that kills off bacteria that produces Vitamin-K) should be supplemented with Vitamin-K
    • Vitamin-K stores are small- deficiency may develop in a week.
    Interactions: warfarin antagonizes the Vitamin K in the clotting cascade We are familiar with using Vitamin-K to reverse the effects of Warfarin. However, this approach is not too frequently used. Vitamin-K (Mephyton®) is now over $60 per tablet! Since this product is only available in 100 count bottles, most pharmacies will not have $6,000 worth of inventory sitting on the shelf for a patient needing two tablets.
    • If the INR is over goal, and less than 4.5—just hold the next dose of warfarin
    • If the INR is between 4.5-10, Vitamin K is usually not administered, unless there is a pressing need like surgery, or there is an active bleed. Just simply hold 1 or 2 doses.
    • If the INR is over 10, give 2.5 to 5 mg whether bleeding or not.
    • If there is a major bleed, use PCC (Prothrombin complex concentrate-Kcentra®) is preferred over FFP (Fresh Frozen Plasma). Of course, the cost of K-Centra® being over $10,000 per dose maybe it is not so preferred!
    Counseling points: Lots of the foods we are told to eat to maintain a healthy and balanced diet are loaded with Vitamin-K. It is best we don’t discourage our patients from eating healthy. Here are some rough guidelines for Vitamin-K consumption if our patients are being managed on warfarin (Coumadin®).
    • High in vitamin K foods: limit to (1) serving per day
      • (kale, spinach, collard greens, Swiss chard, parsley)
    • Moderately high: limit (3) servings per day
      • (broccoli, Brussels sprouts, endive, green lettuce)
    Best advice: eat a consistent diet!

    In the mid 1980’s as a young pharmacist I had a discussion with one of my patients about her Coumadin®. Generic warfarin was not available at the time, but her cardiologist was frustrated with her because her INR was always “out of whack.”

    The cardiologist even went so far as to “accuse” me of dispensing a generic for Coumadin. I asked her about her diet, and she stated, “my heart doctor is always yelling about my weight, so I’ve been eating mostly salads and I lost a few pounds.” I told her that was probably the reason there was so much of a struggle with her INR. Her doctor doubted that that could cause such fluctuations! Now the anticoagulant clinics always discuss diet, because we know that Vitamin K content in food has a significant effect on patients taking warfarin and trying to manage their INR.

    Coumadin® (warfarin) hit the US market in 1954, and the generic version was only approved in 1997. President Dwight Eisenhower was the first celebrity to be managed with Coumadin® after his heart attack in 1955. Even though this molecular entity has been available for over 65 years, we still have not figured it out!

    Genetic variations in metabolism, Vitamin-K sensitivity and the food interactions with Vitamin-K in our diet are making the newer Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) much more desirable to manage our patients in need of anticoagulation.

    Have a great day on the bench!!

    Recommending Vitamin-E for everything-- those were the good old days!

    Vitamin E (tocopherol)
    is a fat-soluble vitamin with antioxidant properties; it protects cell membranes from oxidation and destruction. A few decades ago it was widely touted for everything, however lately its use has fallen out of favor. As an antioxidant, it protects cells from the damage caused by free radicals. Free radicals are produced from the conversion of food to energy. People are also exposed to free radicals in the environment from cigarette smoke, air pollution, and ultraviolet light from the sun.
    • Source: there are 8 naturally tocopherols. The most active is d-alpha-tocopherol.
    • Dietary sources: Vegetable oils, wheat germ, leafy vegetables, egg yolk, margarine, legumes.
    Cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was published in October 16, 2011 edition of The Journal of the American Medical Association.
    • 400 IUs /day & over significantly increased the risk of prostate cancer among healthy men when compared with healthy men taking placebo.
    • The researchers found that the increased risk means that there will be 1 to 2 more prostate cancers per 1000 patients who took the high dose vitamin E for one year. Interestingly, in men who received both vitamin E and selenium, there was no increased rate of prostate cancer.
    Heart disease: Most clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality. However, participants in these studies have been largely middle-aged or elderly individuals with demonstrated heart disease or risk factors for heart disease.

    Cognition: most research results do not support the use of vitamin E supplements by healthy or mildly impaired individuals to maintain cognitive performance or slow its decline with normal aging. Weak evidence suggests a possible role in slowing the progression of Alzheimer disease, tardive dyskinesia, and macular degeneration. Not much current evidence is available to support supplementation of Vitamin-E for prevention or treatment of cancer, cardiovascular or cerebrovascular disease.

    Dosage: Most sources do not recommend supplementing with more than 400iu of Vitamin E- d-alpha tocopherol.

    CAUTION: increased bleed risk with anticoagulants (warfarin). High doses of Vitamin-E inhibit platelet aggregation, and significantly increase risk of bleeding.

    Under the FDA’s new labeling regulations for foods and dietary supplements that take effect by January 1, 2020 (for companies with annual sales of $10 million or more) or January 1, 2021 (for smaller companies), vitamin E will be listed only in mcg and not IUs. New labeling requirements for FAT SOLUBLE vitamins are to take effect, to label fat soluble vitamins by their weight (in mcg) as opposed to measure activity (in IU). It gets even more confusing for Vitamin-E.

    To convert Vitamin E if the product label has dl-Alpha-tocopherol (blended)[synthetic] as the ingredient:
    From IU to mg: IU * 0.9 = mg

    INTERNATIONAL UNITS (old labeling) MICROGRAMS (new labeling)
    30iu 27mg
    100iu 90mg
    200iu 180mg
    400iu 360mg
    800iu 720mg
    1000iu 900mg


    To convert Vitamin E if the product label has d-Alpha-tocopherol (pure d-alpha) [natural] as the ingredient:
    From IU to mg: IU * 0.67 = mg.

    INTERNATIONAL UNITS (old labeling) MICROGRAMS (new labeling)
    30iu 20.1mg
    100iu 67mg
    200iu 134mg
    400iu 268mg
    800iu 536mg
    1000iu 670mg


    Walking out to my vitamin section and recommending Vitamin E, for me is a very rare occurrence… if at all!

    A possible use for Vitamin-E: Treatment of fibrocystic breast disease: There is a possible beneficial effect of vitamin E on breast pain in premenstrual women who experience breast pain that fluctuates during the menstrual cycle. One study showed a dose of Vitamin-E 200 IU twice daily for two months improved symptoms in women with cyclic breast pain. Minimal benefit was observed after 4 months.

    Decades ago we were recommending Vitamin E for everything from memory improvement, Parkinson's disease to cancer prevention. We seldom recommend it today, as excess Vitamin-E is likely to cause harm. I'd avoid recommending it in our older male patients as well as anyone taking any blood thinning medications. Our diet seems to provide us with adequate Vitamin-E

    Have a great day on the bench!!

    Got Sun??? Not in Central Pennsylvania for sure. Let's go to the vitamin aisle and buy some Vitamin-D

    Vitamin-D

    Sources: very few foods contain natural Vitamin-D: fish liver oils, egg yolk, fortified milk, synthesized in skin exposed to UV light. Vitamin-D3 (cholecalciferol) comes from animal source. Vitamin-D2 (ergocalciferol) comes from plant sources.

    Function: acts as a hormone, and plays a role in calcium homeostasis. Vitamin D regulates calcium and phosphorus metabolism. Following conversion to active metabolites (eg, calcifediol, calcitriol), maintenance of normal calcium and phosphate concentrations is achieved by promoting intestinal calcium and phosphate absorption in the gut, mobilization of calcium from bone, and reduction of renal calcium/phosphate excretion. Calcitriol is the most active metabolite.

    Deficiency: More adults are deficient in vitamin D for the following reasons:
    • increased use of sunscreens
    • spending more time indoors
    • and less efficient vitamin D absorption as people age
    • Darker skin and living at higher latitudes also increase risk.
    • renal failure, hypoparathyroidism, estrogens, phenytoin, phenobarbital, fat malabsorption, high alcohol consumption
    • Consider testing for patients who are likely to be deficient such as house bound elderly, especially in a nursing home.
    Rickets: still common in tropical countries even though adequate skin exposure. Soft bones in children become easily deformed. Low blood calcium & phosphate occur because of Vitamin-D deficiency. Lack of Vitamin -D stimulates parathyroid hormone to restore calcium levels.

    DOSE: adults recommend 800-2000iu per day. Feel comfortable recommending up to 2000iu of Vitamin-D without doing the 25-hydroyx-vitamin-D level. Most evidence from studies suggests that to prevent falls, a dose of at least 800 IU per day is required for our elderly patients.

    Do I have to swallow a capsule, what about drinking milk, or exposure to sunshine? Dairy Products: It takes about 5 quarts of milk, to equal 2000iu in a capsule…. not to mention over 2750 calories!

    Sun Exposure: Sun Exposure (Ultraviolet-B) 2 to 3 times a week during mid-day. Bare arms & legs for10-15 minutes per session is usually adequate. The effect of sunlight exposure and vitamin D synthesis is reduced in individuals with darker skin pigment. Effective use of a sunscreen does block the synthesis of Vitamin-D in the dermis. Middle aged and elderly persons who use sunscreens daily have significantly lower serum concentrations of 25-Hydroxyvitamin D3. However, the benefits of using a sunscreen, far outweigh the disadvantages of a decrease in Vitamin-D. A local dermatologist told me “it is easier to treat Vitamin-D deficiency than it is to treat skin cancer...so use a sunscreen.”

    What is the difference between ergocalciferol (Vit-D2) and cholecalciferol (Vit-D3): Vitamin D2 (ergocalciferol) available as Drisdol® comes from ergosterol, a plant sterol, and yeast. Vitamin D3 (cholecalciferol) is synthesized in the skin via 7-dehydrocholesterol, a cholesterol precursor. The vitamin D2 in supplements is made by irradiating ergosterol from yeast, and vitamin D3 in supplements is made by irradiating 7-dehydrocholesterol from lanolin. Both D2 and D3 are efficient at raising serum vitamin D levels. But at high doses vitamin D3 seems be almost twice as potent. In patients with renal disease (especially stage 5 or dialysis patients), production of active vitamin D (calcitriol) is impaired, and use of calcitriol (Rocaltrol) or other active vitamin D sterol may be indicated.

    What about Infants & children?
    • Recommended daily intake of vitamin D is 400 IU per day in all infants (beginning in the first few days of life), children, and adolescents.
    • Breastfed and partially breastfed infants should begin vitamin D supplementation beginning in the first few days of life.
    Excessive dose: Side effects with excessive use may include nausea, anorexia, weight loss, constipation, polyuria, polydipsia, hypertension, weakness, and muscle aches or stiffness.

    Under the FDA’s new labeling regulations for foods and dietary supplements that take effect by January 1, 2020 (for companies with annual sales of $10 million or more) or January 1, 2021 (for smaller companies), vitamin D will be listed only in mcg and not IUs. New labeling requirements for FAT SOLUBLE vitamins are to take effect, to label fat soluble vitamins by their weight (in mcg) as opposed to measure activity (in IU)

    To convert Vitamin D: From IU to mcg: IU/40 = mcg

    INTERNATIONAL UNITS (old labeling) MICROGRAMS (new labeling)
    400iu 10mcg
    800iu 20mcg
    1000iu 25mcg
    2000iu 50mcg
    5000iu 125mcg
    50,000iu Rx only 1250mcg= 1.25mg


    As we continue our review of the fat soluble vitamins, lets discuss Vitamin-D, the one fat soluble vitamin we should be recommending. In a study done in 2011, the overall prevalence rate of vitamin D deficiency was 41.6%, with the highest rate seen in blacks (82.1%), followed by Hispanics (69.2%).

    With 41% of the population being vitamin D deficient, especially in these latitudes, we need to be recommending this Vitamin a whole lot more. Drinking milk and sun exposure is not the answer to correcting this wide scale deficiency. People low in vitamin D who take a supplement may be less likely to fall. That makes sense, given that vitamin D plays a key role in keeping bones and muscles strong.

    Have a great day on the bench!!

    Next time you are in the butcher shop... avoid the polar bear liver!

    Now we start our journey through the fat-soluble vitamins of A, D, E, K. These vitamins can accumulate and cause adverse effects. Rarely does someone get excess fat-soluble vitamins from the diet, but excess supplementation may cause accumulation and potential serious side effects. Vitamin-A

    What it does: Vitamin A is the name of a group of fat-soluble retinoids, which are involved in immune function, vision, reproduction, and cellular communication. Vitamin A is critical for vision as an essential component of rhodopsin, a protein that absorbs light in the retinal receptors, and because it supports the normal differentiation and functioning of the conjunctival membranes and cornea. Vitamin A also supports cell growth and differentiation, playing a critical role in the normal formation and maintenance of the heart, lungs, kidneys, and other organs
    • Dietary sources: fish liver oils, egg yolks, green leafy, orange & yellow vegetables.
    • Random useless fact: Toxic doses of Vitamin-A if polar bear liver is consumed.
    Deficiency States:
    • Night blindness: early sign of Vitamin-A deficiency. May progress to xerophthalmia which is dryness & ulceration of the cornea. May progress to blindness.
    • See decrease in heath and integrity of skin
    • Patients that need Vitamin supplementation include those taking Orlistat (Alli/Xenical), cystic fibrosis patients; however, deficiency is rare in the United States.
    Adverse effects: dry mucus membranes, cheilitis, yellowing of skin, fatigue, nausea, hair loss, headache, vertigo, blurred vision, birth defects, loss of muscular coordination, dry scaly skin. To help remember the side effects of Vitamin A therapy think of the topical side effects of Accutane (isotretinoin), which is a Vitamin-A analog.
    • Multivitamin supplements typically contain 2,500–10,000 IU vitamin A, often in the form of both retinol and beta-carotene
    • RDAs for vitamin A are given as mcg of retinol activity equivalents (RAE) to account for the different bioactivities of retinol and provitamin A carotenoids.
    • Excess Vitamin-A supplementation: leads to increased intracranial pressure (pseudotumor cerebri), dizziness, nausea, headaches, skin irritation, pain in joints and bones, coma, and even death.
    Under the FDA’s new labeling regulations for foods and dietary supplements that take effect by January 1, 2020 (for companies with annual sales of $10 million or more) or January 1, 2021 (for smaller companies), vitamin A will be listed only in mcg RAE and not IUs. New labeling requirements for FAT SOLUBLE vitamins are to take effect, to label fat soluble vitamins by their weight (in mcg) as opposed to measure activity (in IU)
    • To convert Vitamin A as retinol: From IU to mcg: IU/3.33 = mcg
    INTERNATIONAL UNITS (old labeling) MICROGRAMS (new labeling)
    a5000iu 1500mcg (1.5mg)
    8000iu 2400mcg (2.4mg)
    10,000iu 3000mcg (3mg)
    • To convert Vitamin A as beta-carotene: From IU to mcg: IU/1.66 = mcg
    INTERNATIONAL UNITS (old labeling) MICROGRAMS (new labeling)
    25,000iu 15,000mcg (15mg)


    Smokers should avoid Vitamin-A supplements. Taking beta-carotene seems to increase the risk of lung cancer in people who smoke (especially those smoking more than 1 pack per day), former smokers, asbestos exposure, and those who use alcohol (one or more drinks per day) in addition to smoking. Beta-carotene from the diet does not seem to have this adverse effect. (CARET and ATBC studies)

    As the writer of these practice points, I always try to write things that are clinically relevant, that is applicable to a patient you might see in your pharmacy or clinic. I frequently use the example of polar bear liver as a fun fact, but of no clinical applicability. I have yet to have ever seen a case of hypervitaminosis-A due to eating polar bear liver. We have lots of grocery stores in our area, but I’ve never seen polar bear liver for sale!

    Research has shown that a healthy adult person can tolerate a maximum of around 10,000 units of vitamin A. Adverse effects occur comes 25,000 and 33,000 units of ingestion. One pound of polar bear liver — a fist-sized chunk and barely a meal — can contain 9 million units of vitamin A!

    Knowing to avoid Vitamin-A supplementation in smokers is far more critical to our patient’s safety, than the knowledge of the adverse effects of polar bear liver consumption!

    Have a great day on the bench!!

    We expect a LOT from our vitamin-C ! From prevention of colds to cancer!

    Let’s wrap up all of the water-soluble vitamins this week. We are familiar the B-complex, they are short lived in the body, but remember that Vitamin-B-12 is stored in the liver and we have 2 years on board! So…. What happened to the other Vitamin-B numbers??
    • Vitamin B4: adenine: is synthesized by the human body.
    • Vitamin B8: adenosine monophosphate, is synthesized by the human body.
    • Vitamin B10: para-aminobenzoic acid (PABA)
    • Vitamin B11: pteryl-hepta-glutamic acid, one of five folates necessary for humans
    So here is our last water soluble vitamin…
    Vitamin-C (ascorbic acid)

    Source:
    citrus fruits, tomatoes, potatoes, cabbage, green peppers, kiwifruit, broccoli, strawberries, Brussels sprouts, and cantaloupe.
    Uses in the body: Vitamin-C is seen as a necessary co-factor for fatty acid transport, collagen synthesis, neurotransmitter synthesis, and nitric oxide synthesis. Is necessary for wound healing.

    Deficiency States
    • Scurvy: due to increased requirements or low intake. Became common during long voyages at sea. The timeline for the development of scurvy varies, depending on vitamin C body stores, but signs can appear within 1 month of little or no vitamin C intake (below 10 mg/day)
    • Will see capillary fragility (especially in gingival), loose teeth and hemorrhages. In children abnormal bone and tooth development. May see swollen joints.
    • Adverse effects: renal calculi, GI irritation & diarrhea at high doses
    • Beneficial drug interaction: increases iron absorption. I recommend patients take orange juice (or Vitamin-C) with their ferrous sulfate to help double the absorption of the iron.
    May help decrease gout flares, if taken chronically. Ascorbic acid is an antioxidant which binds up free radicals. Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role.
    Adequate intake levels for Vitamin-C:
    • Men age 19 and older: 90 mg/day
    • Women age 19 year and older: 75 mg/day
    • Smokers (or if exposed to second hand smoke): add 35mg
    Vitamin-C and the common cold: In the general population, use of prophylactic vitamin C modestly reduced cold duration by 8% in adults and 14% in children. When taken after the onset of cold symptoms, vitamin C did not affect cold duration or symptom severity. Best to take Vitamin-C long term, as its benefits at onset of cold are minimal. (source nih.gov)

    Excess supplementation of Vitamin-C: Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1 g/day, absorption is less than 50%. Absorbed, unmetabolized Vitamin-C is excreted in the urine. Taking excessive doses isn’t more beneficial and may cause adverse effects. The most common complaints are diarrhea, nausea, abdominal cramps, and other gastrointestinal disturbances due to the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract. Excess supplementation is not recommended in any patients with a predisposition to form oxalate stones in the kidney, especially men.

    Linus Pauling, winner of two Nobel Prizes one for Chemistry and for Peace was the biggest advocate for excess Vitamin C supplementation. In 1970 he published a book "Vitamin-C and the Common Cold", where advocated taking 3 grams of ascorbic acid per day. He also wrote a book "How to Live Longer and Feel Better." which also advocated mega doses of Vitamin-C. He indeed generated a lot of controversy within the medical community as advocating Vitamin C to prevent the cold and flu.

    As we are gearing up for cold and flu season my advice to my patients is to wash hands frequently, get your flu shot, get plenty of rest and of course ...avoid those humans!

    Have a Happy and Healthy 2019!!!

    Have a great day on the bench!!

    December 2018

    I see myself recommending this more than any other supplement--Vitamin B-12 (cyanocobalamin)

    Vitamin-B12 (cyanocobalamin)

    Source of B12:
    muscle meats, liver & dairy products. Not found in vegetables. Vegetarians are at risk.
    • Function: involved in cell division, and recycling of folate. Folate deficiency is observed as a feature of B12 deficiency. Symptoms of deficiency are reflected in organ systems with rapidly duplicating cells. Vital for cell growth and mitosis. This includes the hematopoietic system, gastrointestinal tract and neurological systems. Vitamin B12 is required for proper red blood cell formation, neurological function, and DNA synthesis
    • Deficiency:
      • Pernicious anemia which is a megaloblastic anemia.
      • Untreated Vitamin B12 deficiency may cause neuropathy.
      • Like folic acid Vitamin B-12 is involved in homocysteine metabolism, which high levels are implicated in myocardial infarctions. The American Heart Association has concluded that the available evidence is inadequate to support a role for B12 and other B vitamins in reducing cardiovascular risk
    • Remember –large doses of folic acid will correct the hematological symptoms but will allow neurological damage to progress.
    • Vitamin B12 is bound to protein in meats and dairy products and is released by the activity of hydrochloric acid and gastric protease (an enzyme that breaks down protein) in the stomach. When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is already in free form and, thus, does not require this separation step. Free vitamin B12 then combines with intrinsic factor, a glycoprotein secreted by the stomach’s parietal cells, and the resulting complex undergoes absorption within the distal ileum. If there is insufficient intrinsic factor, a small amount is absorbed through passive diffusion.
    • Decreased production of intrinsic factor: due to pernicious anemia, gastrectomy or bariatric surgery.
    Causes of Vitamin B12 deficiency
    • Dietary deficiency of Vitamin B-12 is rare. Noticeable symptoms of a vitamin B12 deficiency can take years to develop. Irritability, weakness, numbness, anemia, loss of appetite, headache, personality changes, and confusion are some of the signs and symptoms associated with very low levels of vitamin B12. True vegans need to supplement B12 however fortified breakfast cereals are a readily available source of vitamin B12 with high bioavailability.
    • Many patients have trouble absorbing B12 from food due to reduced gastric acidity from Proton Pump Inhibitors (PPIs) (Prilosec, Nexium and others) or H2RA’s (Zantac, Pepcid, and others) or lack of intrinsic factor. Remember the Vitamin B-12 injection shortage? Oral supplements can be used since about 1% of oral supplements will be passively absorbed, without gastric acid or intrinsic factor.
    • Metformin long term will deplete vitamin B12 levels. The challenge becomes that Vitamin B12 deficiency may look like diabetic peripheral neuropathy, with numbness and tingling in the feet and hands.