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  • October 2020

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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!!

    Micro-Learning CE Associated - Click Here For Details

    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!!

    Micro-Learning CE Associated - Click Here For Details

    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!!

    Micro-Learning CE Associated - Click Here For Details

    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.
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    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

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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!!

    Micro-Learning CE Associated - Click Here For Details

    Let's just call them first generation antipsychotics! They have been around as long as I have!

    DOSAGE EQUIVALENTS AND SIDE EFFECTS OF TYPICAL ANTIPSYCHOTICS (FIRST GENERATION ANTIPSYCHOTICS)

    DRUG NAME YEAR EQUIV DOSE USUAL ADULT DOSE SIDE EFFECT SIDE EFFECT SIDE EFFECT
    EPS AC SED
    Chlorpromazine (Thorazine®) 1957 100mg 30-800mg ++ ++ +++
    Fluphenazine (Prolixin ) 1959 2mg 1-40mg ++++ + +
    Mesoridazine (Serentil®) 1970 50mg 100mg-400mg + +++ +++
    Perphenazine (Trilafon®) 1957 10mg 12-64mg ++ + +++
    Thioridazine (Mellaril®) 1962 100mg 150-800mg + +++ +++
    Trifluoperazine (Stelazine®) 1959 5mg 2-15mg +++ + +
    Thiothixine (Navane®) 1967 4mg 6-60mg +++ + +
    Molindone (Moban®) 1974 10mg 20-150mg ++ + +
    Loxapine (Loxitane®) 1975 10mg 20-250mg ++ + +
    Haloperidol (Haldol®) 1967 2mg 1-1000mg ++++ + +


    SIDE EFFECT ABBREVIATIONS:
    EPS: extrapyramidal side effects
    AC: anticholinergic side effects-note the more anticholinergic side effects, the less EPS
    SED: sedation or drowsiness.

    Prescribing notes:
    • These first-generation agents work in the central nervous system by blocking dopamine-2 (D2) receptors, which have the potential to interfere with dopamine transmission via the nigrostriatal tract and cause Parkinson like side effects.
      • perphenazine (Trilafon®) has a lower rate of extrapyramidal symptoms than the high-potency haloperidol and fluphenazine
    • In general, efficacy in treating patients with schizophrenia is similar for all of these agents. They differ by side effect profiles.
    • First generation antipsychotics are implicated with weight gain, possibly due to:
      • Increased appetite due to serotonin 5-HT2 receptor and dopamine D2 receptor blockade
      • Increased sedation and decreased physical activity due to histamine H1 receptor blockade
      • Weight gain: antipsychotic induced weight gain does not appear to be dose related
      • Pharmacodynamic profile of second-generation antipsychotics (5-HT2A antagonism, fast D2 dissociation, 5-HT1A agonism).
      • The main differences between first and second-generation antipsychotics (from a receptor binding perspective)is First-generation antipsychotics have significant potential to cause extrapyramidal side effects and tardive dyskinesia


    MAJOR SIDE EFFECTS
    Tardive dyskinesia:
    abnormal involuntary stereotyped movements of the face, mouth, trunk and limbs. May occur months or years (usually) after treatment. Affects 20-35% of treated patients. See a cumulative rate of 5% per year. They may be progressive and eventually become disfiguring. Predisposing factors: older age, years of treatment, cigarette smoking & diabetes Emphasis is on prevention.

    Prolactin Elevation:
    All typical antipsychotics elevate prolactin levels, apparently through blockade of tuberoinfundibular dopamine, allowing uninhibited secretion of pituitary prolactin. Remember dopamine puts the brakes on prolactin, therefore blocking dopamine allows prolactin to be released in higher amounts. Prolactin levels two to three times higher than normal are seen. Elevated prolactin levels cause menstrual irregularities, infertility, galactorrhea, loss of libido, and erectile and ejaculatory dysfunction.

    Extrapyramidal symptoms:
    Akathisia most common (20%). Usually occurs early and frequently mistaken for anxiety or exacerbation of psychosis. Characterized by the desire to be in constant motion, followed by the inability to sit or stand still, and consequent pacing. Increase incidence in women who smoke.

    I tell my class at St. Francis that “these are the typical antipsychotics, that we atypically use; and the atypical antipsychotics we typically use in practice today.” I prefer the new term first generation antipsychotics and the second-generation antipsychotics.

    This class of drugs as discussed last week is responsible for the emptying out of the state mental hospitals. While in high school my wife Denise volunteered at the Hollidaysburg State Mental Hospital and described the patients all had the same appearance. All of them smoked, had yellow tar stained fingers and hair from the constant cigarette smoke. Smoking was encouraged in the schizophrenic population, as it helped manage symptoms. Smoking however, also caused increased metabolism of the medications, and therefore higher doses were needed.

    Nearly 90 percent of people with schizophrenia smoke, most of them being heavy smokers, and 60 to 70 percent of people with bipolar disorder also smoke. According to recent research in China, nicotine restores dynamic intrinsic brain activity of people with schizophrenia. Maybe someday soon we’ll have the third generation of antipsychotics.

    Have a great day on the bench!!

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    Continuing our joruney through Mental Health medications...

    Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States. Thorazine (Chlorpromazine) by SK&F was the first available. This drug began the exodus of patients from our mental hospitals. Since 1955 there has been a decline by 95% of available beds to treat the mentally ill. Almost 66 years later these medications still have their place in therapy. Clozapine (Clozaril) was introduced in 1990 and opened the era of "atypical" antipsychotic drugs (second generation). These medications have taken people plagued with mental illness to become productive members of society. The role of these medications, as well as other non-anti-psychotic treatment options on our geriatric population will be discussed.

    Schizophrenia…the Basics
    • Schizophrenia affects about 1% of the world’s population
    • diagnosed primarily on the presentation of psychotic symptoms (hallucinations and delusions)
    • patients suffering from schizophrenia often present themselves with concomitant negative symptoms (e.g. apathy, anhedonia) and cognitive dysfunction.
    • Dopamine (D2) receptor is responsible for schizophrenia
    • Since 1953, a total of 19 studies of toxoplasmosis (T. gondii) antibodies in persons with schizophrenia and other severe psychiatric disorders and in controls have been reported; 18 reported a higher percentage of antibodies in the affected persons; in 11 studies the difference was statistically significant. Two other studies found that exposure to cats in childhood was a risk factor for the development of schizophrenia. Click here for article
    Researchers have been able to confirm that patients with schizophrenia show increased
    • presynaptic dopamine synthesis
    • increased dopamine release
    • increased synaptic levels of dopamine with a largely unchanged postsynaptic dopamine receptor density.
    • Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
    • Serotonin receptors with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.
    • Histamine receptors (sedation, antiemetic effect and weight gain)
    • Adrenergic receptors (lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence, weight gain as well as sexual dysfunction.
    • Muscarinic receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).
    As a group, the typical antipsychotics are dopamine receptor antagonists (D2 receptors) block certain dopamine tracts:
    • nigrostriatal: movement disorders
    • mesolimbic: relief of hallucinations & delusions
    • mesocortical: relief of psychosis & worsening of negative symptoms
    • tuberoinfundibular: prolactin release
    • In general, efficacy in treating patients with schizophrenia is similar for all of these agents. They differ by side effect profiles.
    First generation antipsychotics are implicated with weight gain, possibly due to:
    • Increased appetite due to serotonin 5-HT2 receptor and dopamine D2 receptor blockade
    • Increased sedation and decreased physical activity due to histamine H1 receptor blockade
    • Although controversial, antipsychotic induced weight gain does not appear to be dose related
    • Pharmacodynamic profile of second-generation antipsychotics (5-HT2A antagonism, fast D2 dissociation, 5-HT1A agonism).
    • The main differences between first and second-generation antipsychotics (from a receptor binding perspective).
    A excellent fact sheet is available HERE

    With a 95% decrease in available mental health beds, and with 45% of homeless patients suffering from mental illness (Mentalillnesspolicy.org), we obviously need better medications for the treatment of schizophrenia.

    140,000 mentally ill patients are homeless; 392,000 seriously mentally ill patients are incarcerated. 1.2% of Americans (3.2) million are afflicted with this disease. Individuals with schizophrenia die at a younger age than do healthy people. Males have a 5.1 greater than expected early mortality rate than the general population, and females have a 5.6 greater risk of early death.

    Suicide is the single largest contributor to this excess mortality rate, which is 10 to 13 percent higher in schizophrenia than the general population. Obviously we need a better strategy to treat this disabled group of citizens.

    Have a great day on the bench!!

    January 2020

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    Our last three antidepressants...get out your wallet!

    Vortioxetine (Trintellix®) 5, 10, 15, 20mg IR tablets
    Released October 2013 with a cost of $450.00 per month. Was initially named "Brintellix" and was changed to Trintellix in June 2016 because of confusion with antiplatelet Brilinta (ticagrelor)

    Indication: treatment of major depressive disorder.

    Mechanism: enhances of serotonergic activity in the CNS through inhibition of the reuptake of serotonin. Only compound known to inhibit serotonin reuptake and act as an agonist at serotonin type 1A receptors, a partial agonist at serotonin type 1B receptors, and an antagonist at serotonin type 1D, 3, and 7 receptors

    Use: May help improve cognitive function, especially with major depression. This drug also has anxiolytic effects

    Dosage: start with 10mg.

    Side Effects: causes minimal sexual dysfunction, low weight gain. Common side effects include nausea, constipation, vomiting. Pregnancy Category-C

    Drug-Drug Interactions: with CYPP450 3A4 and 2D6 enzyme pathways. Weak metabolizers of 2D6 pathway should not exceed 10mg

    Vilazodone HCl (Viibryd®) 10,20,40mg tablets
    Released 2011 and currently costs around $320.00 per month

    Indication: treatment of major depressive disorder (MDD)

    Mechanism: Inhibits reuptake of serotonin and partial 5HT1a receptor agonist

    Use: Stimulation of 5HT1a may account for its quicker activity which may help cover the "therapeutic lag" seen with pure SSRI. Viibryd is marketed to both augment SSRI effects and to have SSRI effects itself. Similar to using Abilify (aripiprazole) or Buspar (buspirone) to augment SSRI effects. Marketed as having less sexual side effects

    Dosage: Starting Dose: initial dose of 10 mg once daily for 7 days, followed by 20 mg once daily for an additional 7 days, and then increased to 40 mg once daily. Available as a starter pack. Take with food because administration without food can result in inadequate drug concentrations and may diminish effectiveness

    Side effects: diarrhea (28%), nausea (23%), less sexual side effects. Pregnancy Category-C Drug Interactions: avoid strong inhibitors of CYP3A4 (e.g., ketoconazole) can increase vilazodone plasma concentrations by approximately 50%, so reduce dose to 20mg.

    Esketamine (Spravato) CIII
    Ketamine first became available in 1970; Spravato was approved 2019. Cost estimated at $900/dose.

    Mechanism: non-competitive N-methyl D-aspartate (NMDA) receptor antagonist indicated, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression (TRD) in adults.

    Dose:
    • Weeks 1-4: administer twice a week (induction)
    • Weeks-5-8 administer once a week
    • Weeks-9 and beyond: administer every 2 weeks, or every week.
    Available as a 28mg nasal inhaler. Doses range from 56mg to 84mg. Because it is clinic administered it will not appear on the PDMP.
    • Most adverse effects occur in the first two hours after administration.
    • Patients self-administer in a clinic-based setting to have their blood pressure (for hypertension) monitored and mental-status monitoring (dissociation reactions~41%)
    • Be sure patients stay on their oral antidepressants.
    St. John's Wort
    See Clinician Corner 5/17/18 for a thorough discussion of this herbal product. Serotonin Syndrome
    Serotonin is responsible for:
    • Central effects: regulates attention, behavior and body temperature.
    • Peripheral effects: regulating digestive process, blood flow and breathing.
    Culprits: All SSRI, SNRI, and MAOIs have the potential to cause serotonin syndrome, especially at higher doses. Most likely to occur with addition or increase of known serotonergic agent to an established medication regimen

    Drug-Drug Interactions
    • SSRIs, TCAs, SNRIs, mirtazapine, MAOIs
    • Carbamazepine, cyclobenzaprine
    • Sibutramine (appetite suppressant)
    • Linezolid
    • Dextromethorphan, meperidine, methadone, tramadol
    Symptoms of Serotonin Syndrome include:
    • Hyperthermia (high fever) and heavy sweating
    • Muscle rigidity, myoclonus (clonic muscle twitching), loss of coordination.
    • Changes in mental status and vital signs
    • Agitation, restlessness or confusion
    • Rapid heart rate, arrhythmias and high blood pressure
    • Dilated pupils
    • Diarrhea
    • Headache
    • Shivering and piloerection (goose bumps)
    • Unconsciousness, possibly leading to death


    That wraps up a very long journey through the antidepressants. These last three drugs don't seem to get used a lot primarily due to the costs. With aripiprazole (Abilify) and buspirone (Buspar) being so cheap most insurance companies want patients to try and fail on a SSRI or SNRI plus augmenting before they approve these expensive drugs.

    I doubt I'll ever see Spravato, given its use only in certified clinics. The only clinic serving Central Pennsylvania currently is in State College (Penn State). You can go to Spravato.com and see the nearest clinic serving your area. My only experience with ketamine was after cataract surgery... I remember bright and vivid colors and a feeling of relaxation.

    I added a discussion of Serotonin Syndrome (SS), since we frequently see flags when we are filling prescriptions warning about serotonin syndrome. Although it is rare, as we see higher and higher doses of antidepressants, we need to have a great deal of respect for this condition. I have only seen one case of serotonin syndrome. She was a 40-year-old Multiple Sclerosis (MS) patient that took 40mg of fluoxetine (Prozac). She came to the pharmacy escorted by her husband hand had jerked motions as well profusely sweating. They were just to the emergency department and she got SS after taking a couple doses of dextromethorphan!

    I have great deal of respect for dextromethorphan and its drug interactions with antidepressants.

    Have a great day on the bench!!

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    Misc antidepressants....oldies but goodies!

    Older Miscellaneous Antidepressants

    Trazodone (Desyrel®)
    {FDA approved Dec-1981}

    Mechanism of Action: 5-HT2A and 5-HT2C antagonist and inhibits the reuptake of 5-HT; defined as a SARI = serotonin antagonist/reuptake inhibitor
    Starting dose (adults)
    • IR: 50mg TID (can take BID, prefer to take at bedtime)
    • May increase 50mg/ day every 3-4 days
    • Maximum Doses:
      • Outpatient: should not exceed 400mg/day (in divided doses)
      • Inpatient: should not exceed 600mg/day (in divided doses)
    Side effects: dizziness, lightheadedness, confusion, drowsiness, fatigue, headache, dry mouth, priapism (even at lower doses)
    Other Uses
    • Decrease alcohol cravings
    • Reduce depression and anxiety in patients with alcoholism
    • Panic disorder and agoraphobia with panic attacks (300mg)
    • Insomnia due to SSRI or Venlafaxine (Effexor) for its sedative effect (range 50-150mg)
    • To increase SSRI efficacy, a dose of 100mg may be needed
      • Can add on to SSRI therapy
      • Use with great caution à Prozac and Paxil can eliminate Trazodone's metabolite leading to CNS stimulation
    Drug Interactions: CYP2D6 substrates, CYP3A4 substrates
    Distinguishing Features: causes orthostatic hypotension (caution in elderly, especially when dosed at bedtime), more commonly used for insomnia than major depressive disorder
    • Doses for insomnia are subtherapeutic for depression treatment
    Bupropion (Wellbutrin, Zyban)
    {FDA approved Dec-1985}

    Mechanism of Action: norepinephrine and dopamine reuptake inhibitor (NDRI)
    Available As
    • Immediate release: 75 & 100mg
    • Sustained release (SR) 12 hours: 100mg, 150mg & 200mg
    • Sustained release (XL) 24 hours: 150mg & 300mg
    Dosage
    • Starting dose: must be started low and increased to minimize the risk of seizures
      • SR: start with 100 or 150mg QAM for 3 days
      • Then increase to 100 or 150mg BID, separating doses by 8 hours
      • Full antidepressant effect may take 4 weeks.
      • Maximum 400mg/day (200mg BID)
      • XL: start with 150mg QAM for 3 days
      • May increase to 300mg once daily in the morning
      • Separate XL doses by 24 hours
      • Maximum 450mg/day QAM
      • IR: start with 100mg BID
      • May increase to 100mg TID
      • Maximum 450mg/day (150mg TID)
    Other Uses
    • Weight loss
    • Attention deficit disorder
    • Neuropathic pain
    • Smoking cessation
    • Adjunct to SSRI
    • Bupropion plus an SSRI is the most common antidepressant combination
    Side Effects
    • Less nausea, diarrhea, and sleepiness than SSRIs
    • Seizures: be sure to titrate slowly!
      • An estimated seizure 10-fold increase occurs in patients who are dosed between 450 & 600mg
    • Blurred vision
    • Agitation
    • GI disturbances
    • Tremor
    • Excessive sweating
    • Weight loss
    • Hypertension
    • Dry mouth
    • Insomnia
    • Constipation
    • Does NOT cause sexual dysfunction + is minimally sedating
      • Often the choice antidepressant for patients complaining of sexual side effects & decreased energy levels.
    ABUSE POTENTIAL: Bupropion is called "poor man's cocaine" because users say it gives them a cocaine-like high for about $2.50/pill
    Distinguishing Features
    • May be beneficial in patients with fatigue, poor concentration, and interested in smoking cessation
    • No anxiolytic properties
    • Appetite-suppressing effects (weight neutral)
    • No sexual dysfunction
    • Caution in patients with psychotic features
    • Contraindicated in patients with bulimia, anorexia, and seizure disorder
    Mirtazapine (Remeron®)
    {FDA approved: June 1996}

    Mechanism: does NOT block reuptake of dopamine, norepinephrine or serotonin. It blocks the Histamine-1 receptor, which accounts for its drowsiness and weight gain. Mirtazapine has been said to be a functional "indirect agonist" of the 5-HT1A receptor. Increased activation of the central 5-HT1A (serotonin) receptor is a major mediator of efficacy of most antidepressant drugs
    Dose: most commonly available as 7.5mg, 15mg, 30mg and 45mg tablets. Best given at bedtime due to sedation.
    Side effects: dizziness, drowsiness and weight gain.
    Unlabeled uses: sleep apnea, weight gain, antipsychotic induced akathisia

    This column is a “catch all” of the older miscellaneous drugs. All are available generically, and the newest one is 25 years old. What I love about this column all these drugs were introduced after Denise and I graduated pharmacy school in 1981.

    I remember the Mead Johnson representative coming to talk to me about Desyrel (trazodone) a new groundbreaking antidepressant, that was nothing like those old tricyclic antidepressants. We dispensed a lot of Desyrel® until the late 1980’s when Prozac and the other SSRI’s and later Effexor® and the SNRI’s tool over the depression market. Today trazodone is dosed mostly at bedtime for insomnia.

    Wellbutrin® was another one of those drugs with a peculiar mechanism, in that it did not cause sedation, like all the others. I remember when the insurance companies refused to pay for Zyban, because it was for smoking cessation. Practitioners then wrote for “Wellbutrin-SR”, then the insurance companies required a prior auth for all bupropion!

    Those insurance companies have been saying “NO” for a very long time! Next week will cover the “newer” miscellaneous antidepressants.

    Have a great day on the bench!!

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    MAOIs potent, yes; lots of food and drug interactions keep these drugs off of our shelves.

    Monoamine Oxidase Inhibitors (MAOIs) block monoamine oxidase, an enzyme in the synaptic cleft that breaks down neurotransmitters. MAO is released from the pre-synaptic nerve terminals. Norepinephrine is not broken down, and has more dramatic effect, not only in the brain but every else in the body. MAOIs are very seldom used due to side effects and life-threatening drug interactions.

    Hypertensive crisis: extreme increases in blood pressure when MAOIs interact with OTC meds and foods containing tyramine.
    • Defined by diastolic BP >120mmHg
    • Characterized by occipital headache, palpitations, neck stiffness/soreness, Nausea/Vomiting, sweating, dilated pupils, photophobia, tachy- or bradycardia, chest pain
    • This came to be known as “Cheese Effect” because aged cheeses contain a lot of Tyramine which naturally elevates blood pressure
    • Tyramine containing foods and OTC drugs that should be avoided:
      • Aged cheeses: blue, camembert, cheddar, Roquefort, stilton and Swiss
      • Anchovies
      • Dried, aged, smoked, fermented, spoiled, or improperly-stored meat, poultry, and fish
      • Tap and non-pasteurized beers
      • Red wine, (esp. Chianti), sherry
      • Many tropical fruits à bananas and avocados (especially if overripe)
      • Also avoid drugs with vasopressors (increase BP): chocolate, cola, coffee tea, broad beans
      • Sauerkraut and soy products (tofu, soy sauce, marmite)
      • OTC cold medications containing pseudoephedrine (Sudafed®)
      • Avoid amphetamines and appetite suppressants
      • Other antidepressants
    MAOI Drugs
    • Nardil® (phenelzine) 15mg tablets (FDA approved 1961)
      • Non-selective (will increase levels of dopamine, norepinephrine, and serotonin)
      • Distinguishing Feature: may cause hepatotoxicity
    • Parnate® (tranylcypromine) 10mg tablets (FDA approved 1961)
      • Non-selective (will increase levels of dopamine, norepinephrine, and serotonin)
      • Distinguishing Feature: structurally similar to amphetamine, so stimulating; less likely to cause weight gain
    • Marplan® (isocarboxazid) 10mg tablets (FDA approved 1959)
    • Non-selective (will increase levels of dopamine, norepinephrine, and serotonin)
    • EMSAM® (selegiline transdermal system) (FDA approved 2006)
      • Selective à less “Cheese Effect” due to no tyramine inhibition at low dose
      • First + only transdermal MAOI for treatment of depression
      • Three available strengths: 6mg/ 24 hours; 9mg/ 24 hours; and 12mg/24 hour (available in boxes of 30)
      • Change patch once a day at the same time each day!
      • Avoid sympathomimetic amines such as amphetamines or cold medications containing vasoconstrictors (pseudoephedrine-Sudafed®)
      • WARNINGS/ PRECAUTIONS
        • Because of the potential for serotonin syndrome EMSAM is contraindicated with SSRI, SNRI, TCA or MAOI
          • Wait 2 weeks after stopping SSRI, SNRI, TCA or MAOI mirtazapine, bupropion, dextromethorphan, cyclobenzaprine, tramadol methadone, propoxyphene, St. John’s Wort and carbamazepine
          • Must wait 5 weeks for fluoxetine (Prozac®)
      • Other side effects: application site reaction, headache, insomnia, diarrhea, dry mouth and dyspepsia
      • Benefits: reported sexual dysfunction similar to placebo; minimal weight change
      • Distinguishing Feature: no tyramine dietary modifications at the starting or target dose of 6mg/24 hours
        • If the dose is increased to the 9mg/24hr or 12mg/24 hr, then the tyramine diet must be used
        • Drug-drug interactions still a concern

      Monoamine oxidase inhibitors

      MAO-A MAO-B
      SUBSTRATES Norepinephrine
      Serotonin
      Dopamine
      Tyramine
      LOCATION Brain, gut, liver, placenta, skin Brain, platelets, lymphocytes
      INHIBITORS Nardil, Parnate Marplan, Emsam Eldepryl (low doses) Azilect
      THERAPEUTIC USE Depression Parkinson’s disease


      Like so many drugs that were discovered in the 1950’s MAOI’s existence is due to serendipity. Researchers discovered that one of the tuberculosis drugs, iproniazid caused relief of patient’s depression. This led to the discovery of monoamine oxidase, and soon after inhibitors of this enzyme were marketed for the relief of depression.

      Due to the side effects and significant food and drug interactions these drugs are seldom used. About the only time we see this class of drugs used is in treatment resistant depression, that have failed the more common therapies.

      Although it has been a long time since I have dispensed these drugs, our local warehouse does have Nardil, Parnate and their generics in stock, along with brand name Emsam.

      The selective MAO-B inhibitors used for Parkinson’s disease are a little more commonly dispensed in the community pharmacy.

      Have a great day on the bench!!

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    Tricyclic antidepressants are as old as this author... and still going strong... (like this author)

    Tricyclic Antidepressants (TCA)
    Mechanism: inhibit the reuptake of NE and 5-HT into the presynaptic terminal. Allows more serotonin and nor-epinephrine to be available in the synapses.

    Although there are 9 different tricyclic antidepressants (TCA) approved in the United States I have only 5 on my shelf in the community pharmacy where I practice. The TCA’s can be broken down between the secondary and tertiary amines. The most common secondary amines nortriptyline and desipramine are selective inhibitors of norepinephrine reuptake. The most common tertiary amines amitriptyline, imipramine, doxepin and clomipramine are selective inhibitors of serotonin reuptake. They are also broken down by side effects.

    With 9 different TCA's when do we use them?
    • MOST sedating: Amitriptyline, doxepin and imipramine
    • MOST likely to cause weight gain: Amitriptyline, doxepin and imipramine
    • CLEANEST: Nortriptyline and desipramine are less likely to cause sedation and weight gain.
    • NOCTURNAL ENURESIS: imipramine is most used
    • OCD: Clomipramine was the first drug that was approved for Obsessive-Compulsive disorder. (When we see its highly serotonergic effects, it is no surprise)
    • INSOMNIA: Doxepin is also available as Silenor® in 3mg and 6mg tablets used for sleep maintenance.
    The most common TCA's I see in my practice are amitriptyline and nortriptyline. The following is from my lecture notes to delineate the differences between the two:
    DIFFERENCES BETWEEN Amitriptyline (Elavil®) and Nortriptyline (Pamelor®)
    • Nortriptyline is the active metabolite of amitriptyline (via CYP450-2C19)
    • Nortriptyline is generally better tolerated than amitriptyline. It has much less sedation and anticholinergic side effects.
    • The mortality from nortriptyline in overdose is similar to that from SSRIs
    • Nortriptyline is the least problematic of the tricyclic antidepressants in terms of drug interactions. It is relatively safe to combine it with certain SSRIs (sertraline and citalopram).
    • Nortriptyline is better choice for elderly.
    • Maximum dose for Nortriptyline should never exceed 150mg.
    MOST TCA's
    • Common side effects: anticholinergic side effects, sexual dysfunction, daytime drowsiness
    • Cardiac effects: may alter rate, rhythm, & contractility. May cause orthostatic hypotension.
    • CNS- seizures, respiratory depression, disorientation & coma
    • METABOLISM: most of the available tricyclic antidepressants are metabolized by the CYP-2D6 pathway. Desipramine and nortriptyline are the least problematic of the TCAs in terms of drug interactions, being only weak CYP450-2D6 inhibitors.
      • Avoid tertiary amine-TCA's in patients known to be ultra-rapid metabolizers at CYP450-2D6 (think of codeine metabolism)
      • The tertiary amines are extensive metabolized through CYP450-2C19. Avoid tertiary amines in weak metabolizers of this enzyme system.
    COMMON USES: diabetic neuropathy, phantom leg pain, cancer pain, post herpetic neuralgia
    DOSING: commonly doses begin at 25mg and are titrated to 150-300mg. (300mg-inpatient). (Except Nortriptyline)
    COST: ALL are available generically, and relatively inexpensive.
    CAUTION must be exercised with TCA in patients with suicidal thoughts due to high lethality risks with overdose. The lethal dose is only EIGHT times the therapeutic dose, so if TCA's are ingested in an overdose, they may block the sinoatrial node in the heart. TCA are more dangerous than SSRI in overdose. Therefore, a seven-day supply of a maximally dosed tricyclic antidepressant could be lethal.

    GENERIC BRAND YEAR AC H1- NET SERT
    Imipramine Tofranil® 1959 ++ + + ++
    Amitriptyline Elavil® 1961 +++ ++ + ++
    Desipramine Norpramin® 1964 + + +++ +
    Nortriptyline Pamelor® 1964 + + ++ +
    Protriptyline Vivactil® 1967 +++ + +++ +
    Doxepin Sinequan® 1969 ++ +++ + +
    Clomipramine Anafranil® 1989 + + + +++


    AC: anticholinergic side effects (dry mouth, blurry vision, constipation, urinary retention)
    H1: histamine receptor (associated with weight gain and sedation)
    NET: nor-epinephrine transporter (increases levels of nor-epinephrine by blocking reuptake)
    SERT: serotonin transporter (increases levels of serotonin by blocking reuptake)

    The tricyclic antidepressants quickly followed after the first generation antipsychotic chlorpromazine (Thorazine), in the late 1950's. Pyschopharmacotherapy was in its infancy, and 7 more TCA's followed suit after imipramine's introduction in 1959. Climipramine was the last TCA, introduced in 1989 a few months after Prozac (fluoxetine). Clomipramine (Anafranil) was the first drug indicated for treatment of OCD.

    I remember well the sale reps from Ciba-Geigy not only educating providers about the drug but also the diagnostic criteria for Obsessive-Compulsive Disorder (OCD). OCD is now very much a layman's term that is thrown around when we check our locks on our doors, or have our pantry shelves arranged!

    Wishing you and yours a Happy 2020!
    Have a great day on the bench!!

    December 2019

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    SNRI's for weight management, depression, pain, ADHS???

    Serotonin Norepinephrine Reuptake Inhibitors (SNRI)
    Mechanism: inhibits reuptake of both norepinephrine and serotonin in the presynaptic nerve terminal, allowing more serotonin and nor-epinephrine to be available in the synapses. The SNRI's are used for depression and pain management.

    SNRI Side Effects:
    • Side effects: very favorable profile: minimal sedative and cardiovascular effects.
    • Common side effects: nausea, anorexia, insomnia, nervousness, restlessness, and bruxism. All these side effects increase as dose is increased.
    Venlafaxine (Effexor®) - FDA approved 1993
    • Also approved for Generalized Anxiety Disorder and SAD
    • Unlabeled use: hot flashes, Premenstrual Dysphoric Disorder, PTSD
    • Caution: angle closure glaucoma or patients taking oral anticoagulants.
    Duloxetine (Cymbalta®) - FDA approved 2004
    • Dose: major depressive disorder: 40 mg daily (not much benefit over 60 mg/day)
    • Very low side effect profile
    • May cause decrease in body weight
    • Caution: CrCl less than 30; liver failure, alcohol abuse, closed angle glaucoma.
      • contraindicated in patients with heavy alcohol use or chronic liver disease; can lead to acute hepatitis
    • ***is approved for diabetic neuropathy and fibromyalgia***
    Desvenlafaxine (Prestiq®) - FDA approved 2008
    • Treatment of adults with major depressive disorder.
    • Is the active metabolite of Effexor. It does not require "activation" by the CYP2D6 metabolic pathway, minimizing the potential for drug interactions.
    • There was no evidence that doses greater than 50 mg/day confer any additional benefit.
    • Less sexual dysfunction.
    • Nausea most frequently during week one.
    • May increase blood pressure.
    • When discontinuing treatment, gradual dose reduction is recommended whenever possible.
    Milnacipran (Savella®) - FDA approved Jan-2009
    • Use: selective norepinephrine and serotonin reuptake inhibitor (SNRI) for management of fibromyalgia. First drug approved ONLY for fibromyalgia.
    • More potent inhibitor of norepinephrine reuptake than the other SNRIs.
    • Norepinephrine depletion is associated with pain and fatigue. 1 in 12 patients get about 50% reductions in fibro symptoms.
    • Adverse reactions: nausea, headache, constipation, dizziness, insomnia, hot flush, hyperhidrosis, vomiting, palpations, increased heart rate, dry mouth, and hypertension.
    • CAUTION: avoid in ESRD, chronic liver disease, or alcohol abuse.
    Levomilnacipran (Fetzima®) - FDA approved 2013
    • Once-daily serotonin and norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder (MDD) in adults, has received FDA approval
    • Stronger inhibitor of norepinephrine than serotonin.
    • Dosage: 40 mg to 120 mg once daily, beginning with 20 mg once daily for 2 days and then 40 mg once daily. Dosage can be increased in increments of 40 mg at intervals of 2 or more days, with 120 mg the maximum recommended dose.
    • Monitor BP and heart rate for increases.
    • CAUTION: ESRD, angle closure glaucoma, hypertension, dose dependent erectile dysfunction.


    DRUG STARTING DOSE TARGET DOSE
    Desvenlafaxine (Pristiq) 25 to 50mg 50mg to 100mg
    Duloxetine (Cymbalta) 30 to 60mg 60mg to 120mg
    Levomilnacipran (Fetzima) 20mg 40mg to 80mg
    Milnacipran (Savella) 12.5mg 100 to 200mg
    Venlafaxine (Effexor tabs) 37.5 to 75mg 75 to 375mg
    Venlafaxine XR- (Effexor-XR) 37.5 to 75mg 75 to 225


    SSRI/SNRI and Elderly November-2018:
    HYPONATREMIA:
    older patients are more likely to develop hyponatremia with an SSRI or SNRI or mirtazapine than younger counterparts. Be sure to monitor sodium especially in patients with heart failure, or those taking hydrochlorothiazide. They made the Beers List for that reason.

    The SNRI’s came into the depression treatment arena about 5 years after Prozac broke the ground for new depression therapy. These drugs also seem, because of their effect on norepinephrine, seem to be more useful for pain management than the SSRI’s.
    • Tramadol (Ultram) is a weak SNRI and a weak opioid which was approved in 1995 for treatment of pain.
    • Sibutramine (Meridia) is an SNRI and was approved in 1997, which was the first drug approved for obesity in 30 years.
    • Atomoxetine (Straterra) primarily works on norepinephrine reuptake, with minimal effect on serotonin. It was first approved in 2002 for the treatment of ADHD.
    Wishing you and yours a most Happy 2020!

    Have a great day on the bench!!

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    When I'm feeling blue, all I gotta do is...Take a pill?

    Selective Serotonin Reuptake Inhibitors (SSRI)
    Mechanism: serotonin reuptake is blocked in the pre-synaptic nerve terminal. Allows more serotonin to be available in the synapses.

    Ground Rules for Prescribing Antidepressants
    • There is a 2 to 4-week lag time to clinical efficacy, but side effects occur rapidly
    • An adequate dose and duration of treatment of at least 4-8 weeks are required to establish an adequate trial of antidepressant.
    • Antidepressant dose should be increased if patient compliance is good and no response after 3 weeks. If partial response, adjust dose in 2 weeks.
    • 25% of patients who don't respond to one SSRI will respond to another. Therefore, it's reasonable to switch from one SSRI to another if a patient is not responding. However, if a patient fails more than one SSRI, then a class switch should be considered.
    DRUG INTERACTIONS (non-MAOI):
    • highest risk of drug interactions: fluoxetine (Prozac®), fluvoxamine (Luvox®), and paroxetine (Paxil®).
    • lowest risk of drug interactions: include citalopram (Celexa®), escitalopram (Lexapro®), mirtazapine Remeron®, venlafaxine (Effexor®), and desvenlafaxine (Pristiq®).
    SSRI (Selective Serotonin Reuptake Inhibitors)
    MOST SSRI
    • Common side effects for SSRI: headache, nausea, nervousness, insomnia, agitation, sexual dysfunction, bruxism
    • Costs of SSRI: All SSRI are available generically. Are now very inexpensive.
    • Bleeding Risk: SSRIs inhibit the uptake of serotonin in platelets. This depletes serotonin in platelets and therefore inhibits their ability to initiate blood clotting. Absolute risk is small. Greater risk when combined with Aspirin or NSAIDs
    • Risk of Torsades: Sertraline, paroxetine, and fluoxetine seem less likely to cause QT prolongation.
    • HYPONATREMIA: older patients are more likely to develop hyponatremia with an SSRI or SNRI or mirtazapine than younger counterparts. Be sure to monitor sodium especially in patients with heart failure, or those taking hydrochlorothiazide.
    • FALL RISK: SSRI are on Beers list for patients with a history of falls or fractures. Watch for sedation and blurred vision to decrease fall risk
    Selective Serotonin Reuptake Inhibitors (SSRI)
    Citalopram (Celexa®)
    • Do not exceed 40 mg/day for anyone. Max= 20 mg/day for most patients over age 60.
    • Higher doses of citalopram increase the risk of QT prolongation and torsades.
    • Caution: using citalopram in patients at risk due to underlying cardiac disease or low serum potassium or magnesium.
    Escitalopram (Lexapro®)
    • S-isomer (active isomer) of Celexa
    • When citalopram is not utilized based on risk factors for TdP, use of escitalopram is not likely the safest alternative. Based on current literature, fluoxetine, fluvoxamine, and sertraline appear to have similar, low risk for QT prolongation, and paroxetine appears to have the lowest risk. https://www.ncbi.nlm.nih.gov/pubmed/24259697
    Fluoxetine (Prozac®)
    • Only SSRI that is FDA approved for major depressive disorder in children and adults.
    • LONGEST half-life of SSRI’s (1 to 3 days)
      • Active metabolite (norfluoxetine) has 4-16-day half-life.
    • Along with sertraline (Zoloft®) is the MOST activating of SSRI
    Paroxetine (Paxil®) -
  • Paroxetine (Brisdelle® 7.5mg) marketed for hot flash treatment
  • MOST sedating of SSRI
  • MOST anticholinergic side effect of SSRI
  • Pregnancy Category D
  • Considered by most to be the “dirtiest” SSRI
  • Sertraline (Zoloft®)
    • MOST Activating SSRI (along with Prozac)
    DOSING CHART

    SSRI Starting Dose Target Dose
    Citalopram 20 20 to 40
    Escitalopram 10 10 to 20
    Fluoxetine 20 20 to 60
    Paroxetine 20 20 to 40
    Sertraline 50 50 to 200


    32 years ago this month the face of America changed with the introduction of Prozac (Fluoxetine) by Eli Lilly.

    MAOIs became widely used as antidepressants in the early 1950s. Patients with tuberculosis given iproniazid, experienced relief from their depression.

    Tricyclic antidepressants, the first being imipramine (Tofranil) in 1959, followed by amitriptyline (Elavil) in 1961 and then at least a dozen more until Prozac was introduced.

    Trazodone (Desyrel®) was introduced in late 1981 and was found to be too sedating. Today we see trazodone used for sleep induction, usually for people taking SSRI’s.

    Escitalopram (Lexapro®) was approved in 2002 and was the last SSRI to be approved. We buy most of our SSRI antidepressants (except paroxetine) in bottles of 500 and turn them over quickly.

    Before we had MAOI's in the 1950's amphetamines like Benzedrine in the 1930's and 1940's were used to treat mild depression, but quickly became drugs of abuse.

    And before the advent of the amphetamines, frankincense was used to treat depression. One of the ingredients in frankincense smoke called incensole acetate has been studied in mice and has shown to relieve depression. Most of us are familiar with frankincense as it was one of the three gifts brought by the Magi that came from the East to adore the Christ Child.

    With that in mind, I wish you and your families a Merry Christmas and a Happy New Year!

    Have a great day on the bench!!

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    Lots of anti-epileptic drugs can be tried for our patients with bipolar disorder.

    Stabilizing the mood with Anti-Epileptic drugs Valproic acid and Valproate:
    • Valproic Acid, which became available as Depakene in 1978, is seldom used due to GI upset.
    • Divalproex (Depakote®) was approved in 1982, as a delayed release tablet to minimize stomach upset.
    • Divalproex extended release (Depakote-ER®) is a once daily formulation that became available in 2000. Today all forms of valproic acid/valproate are available generically.
    Oral loading dose of acute mania: 20mg/kg/day. Therapeutic levels occur in 2-3 days. Is being used more first line due to the adverse effects associated with lithium pharmacotherapy
    Mechanism: possibly increases CNS levels of GABA
    Common use: is an anti-seizure drug and can also be considered as first line treatment for mania. Divalproex is also used for panic disorder and migraine prophylaxis. Divalproex is more effective than lithium in mixed episodes.
    Adverse effects: hepatotoxicity (Black box warning) increase risk for children under
    • Teratogenicity: pregnancy category-D
      • third line drug for female patients of childbearing potential
    • Pancreatitis
    • Stomach upset featuring nausea/vomiting and diarrhea
    • Do frequent CBC, and liver enzymes
    • Thrombocytopenia appears to be dose related

    Monitoring: therapeutic serum levels: 50-100mcg/ml
    Patient Education
    • GI upset: Take with food
    • Caution driving
    • NVD may signify pancreatitis. refer if necessary.
    • If alopecia occurs, supplement with zinc and selenium
    • Weight gain: Up to 70% of patients taking valproic acid may gain weight. Almost one-half of patients may gain >10% of baseline weight

    NOTE: Treatment of ACUTE mania in patients taking Lithium or Valproate usually requires addition of an antipsychotic drug

    Carbamazepine (Tegretol®): was first approved in 1968. It is commonly available in tablets 100mg (chew) and 200mg It is also available as extended release Tegretol XR tablets 100,200 and 400mg. Carbatrol® capsules are available as 100, 200 and 300mg extended release caps
    Initial dose:( adults): 200mg twice daily. Increase every week of no more than
    • 200mg per day using a 3-4 times daily regimen.
    • Maintenance: 800-1200mg/ day maximum dose for mania is 1600mg/day
    • Therapeutic blood level: 4—12mg/liter
    Mechanism: stabilizes cell membranes. Reduces polysynaptic responses.
    Common use: indicated for treatment of epilepsy, trigeminal neuralgia
    Unlabeled use: Postherpetic neuralgia, PTSD, alcohol withdrawal,
    Bipolar disorder: used for mania or mixed episodes

    Adverse effects: contraindicated if history of bone marrow depression
    • Stevens Johnson syndrome—severe dermal reactions.
      • Genetic testing: The HLA*15:02 allele has since been associated with carbamazepine-induced Stevens Johnson Syndrome (Toxic Epidermal Necrolysis) in Taiwanese, Chinese, Indians, Malay, and Chinese- Americans, but not in Caucasians or Japanese individuals
    • Pregnancy: category D
    • Aplastic anemia—black box warning
    • Is a CYP-450 enzyme inducer-----lots of drug interactions. Also induces its own metabolism. monitor more closely during the first few months of therapy because carbamazepine induces hepatic enzymes
    Monitoring of carbamazepine
    • Baseline: complete blood tests then periodic evaluation
    • Baseline liver function, then periodic evaluation
    • Baseline and periodic eye exam
    • Urinalysis
    • BUN
    • Therapeutic blood level: 4—12mcg/liter
    Lamotrigine (Lamictal®) : was FDA approved in December 1994 Is available generically in tablet formulations chew: 5mg & 25mg. immediate release tablets: 25, 100, 150 &200mg
    Mechanism: unknown: may interfere with sodium channels and stabilize neuronal membranes, modulation presynaptic excitatory amino acid release (glutamate & aspartate)
    Lamotrigine use:
    • Lamotrigine has better evidence of efficacy than lithium for monotherapy for bipolar depression.
    • Best choice for prevention of recurrent depressive episodes.
    • The combination of lithium plus lamotrigine can be considered for patient’s refractory to monotherapy.
    • Lamotrigine should not be used for treating mania and has limited efficacy for preventing mania.
    Dosage: watch for drug interactions!
    There are different dosage regimens to follow:
    • Adding Lamictal to AED regimen containing Divalproex (a CYP-450 blocker)
      • 25mg every other day, for 2 weeks. Then 25mg every day for 2 weeks.
    • Adding Lamictal to EIAED (enzyme inducing anti-epileptic drug) . CBZ, DPH, PBARB without valproic acid.
      • 50mg daily for 2 weeks. Then 100mg daily in 2 divided doses for 2 weeks.
    • Using lamotrigine in patient taking neither an inducer or blocker:
      • 25mg daily for 2 weeks, then in crease to 50mg daily
    **Closely consult prescribing information when making Lamictal dosage adjustments. **
    Adverse effects: skin rash (discontinue if it appears)-Black box warning. Titrate slowly especially if taking Valproic acid.
    Contraindications:none.
    Drug interactions: many drug interactions between enzyme blockers and inducers.
    • Although Lamictal does not induce or inhibit other drugs, its metabolism is affected.
    • Inhibits dihydrofolate reductase. Folic acid supplementation may be necessary.
    ·Adding valproic acid to Lamictal, will increase Lamictal steady state concentration 2X!

    Drug Monitoring: optimal blood level: 4 to 20 mcg/ml. Allow 4-5 days to reach steady state
    MONITORING of MOOD STABILIZERS:
    • Trough lithium concentrations should be kept at 0.8 to 1.2 mEq/L;
    • Trough valproate levels should be kept at 50 to 125 mcg/mL
    • Trough carbamazepinelevels should be kept at 4 to 12 mcg/mL
    We dispense a fair amount do this well-known seizure medications, divalproex, carbamazepine and lamotrigine. However, most of the prescriptions filled are prescribed by psychiatrists rather than neurologists. These three drugs are most commonly used as “mood stabilizers” in the treatment of bipolar disorder.

    Of these drugs the one that takes up a lot of space in my Pharmacology notes is carbamazepine. Carbamazepine is a big-time CYP450-3A4 inducer. It is so effective at enzyme induction it induces it’s own metabolism. This can be a nightmare when a patient is taking warfarin. We don’t have a significant Asian population in Central Pennsylvania, but where you are practicing your Asian patients really need your expertise!

    Although Levetiracetam (Keppra) is a lot “cleaner” than the drugs mentioned in this newsletter, results for mood stabilization have been mixed. Although not FDA approved, we also see Topiramate (Topamax) and Gabapentin (Neurontin) used as well for bipolar disorder. But then again, we see these drugs used for a lot of non-FDA approved conditions.

    Have a great day on the bench!!

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    We Steeler fans are happy... then sad...are we bipolar? Not according to this definiton!

    Bipolar disorder... and most effective treatment is LITHIUM!
    People who live with bipolar disorder experience periods of great excitement, overactivity, delusions, and euphoria (mania) and other periods of feeling sad and hopeless (depression). Mood stabilizers (lithium, valproate, lamotrigine) are the cornerstone of the pharmacotherapy of bipolar disorder. Antipsychotics, alone or in combination with mood stabilizers, are also commonly used. There is no evidence that any one anti-psychotic is more effective than the others.

    Mood swings OR bipolar disorder? Patients with mood swings experience fluctuations in mood are caused by a situation, person, or events in their lives. While the moods of people with bipolar disorder can be affected by situational variables, people with bipolar disorder also frequently become manic or depressed for no apparent reason.

    Duration: Bipolar patients experience an elevated or irritable mood for at least four consecutive days. A patient with bipolar may have depressive episodes that last for at least two weeks at a time. Emotions tied to watching a Steeler game is not bipolar!

    BENEFITS of THERAPY:
    In addition to preventing relapse in patients with bipolar disorder, maintenance pharmacotherapy may be associated with reduced rates of violent behavior. A national registry study identified 494 convictions for violent crime (eg, assault, robbery, or threats/intimidation) in 11,918 patients with bipolar disorder and examined the time periods when patients were or were not prescribed mood stabilizers (eg, lithium, valproate, lamotrigine, or carbamazepine) or antipsychotics.

    The rate of violent behavior when mood stabilizers were prescribed was 60 percent less, compared with times when mood stabilizers were not prescribed. In addition, prescription of antipsychotics was associated with a 50 percent decrease in interpersonal violence.

    Lithium
    History: The first recorded use of lithium for the treatment of mania, based in part on the urate/lithium connection, was 1871. Use of lithium carbonate to prevent depression came in 1886. In 1948 an Australian psychiatrist started using lithium after he treated guinea pigs and noticed they became more docile. It wasn’t until 1970 the FDA approved lithium, under the trade names of Lithonate® and Eskalith® for the treatment of mania.

    Mechanism: affects synthesis, storage, and reuptake and release of central Monoamine neurotransmitters. NE, 5-HT, DA, ACH and GABA

    Dosage: acute mania- optimal response 600mg three times daily or 900mg twice daily if SR. Lithium is available in capsules and tablets as 150mg, 300mg and 600mg. Lithium is also available in sustained released tablets in 300mg and 450mg tablets. The sustained release tablets cause less stomach upset but cause more diarrhea due to more distal GI absorption.

    Common use: Lithium is effective for prevention of both manic and depressive episodes. Lithium also reduces the risk of suicide, perhaps by reducing agitation and impulsivity.
    • Considered drug of choice for maintenance treatment of bipolar disorder.
    • Considered drug of choice specially to PREVENT manic episodes
    • Using lithium reduces the risk of relapse by approximately 30 percent.
    Unlabeled uses: neutropenia, cluster headaches, premenstrual tension, bulimia, Alcoholism, Syndrome of Inappropriate Excretion of ADH, Tardive dyskinesia, psychosis. Also being used to augment the effects of antidepressants.

    Adverse effects: fine hand tremor, polyuria, mild thirst, nausea, hair loss & metallic taste.

    Monitoring: ideal blood levels: acute mania: 0.8-1.2 mEq/liter

    Maintenance is 0.6-1mEq/liter to minimize side effects.
    • Draw blood levels 12 hours after last dose.
    • Check blood levels: 5-7 days after initiation & any change in dosage.
    • Maintenance: every 1-2 months. In stable patients 6-12 months.
    • Monitor more frequently if volume depletion, or diuretic use, diarrhea or vomiting.
    • Check thyroid and renal function before starting lithium and every 6-12 months.
    • Hypothyroidism can occur and contribute to bipolar exacerbations.
    Drug Interactions:
    Increases lithium level
    • Thiazide diuretics (HCTZ, chlorthalidone)
    • Nonsteroidal anti-inflammatory drugs except aspirin
    • Angiotensin converting enzyme inhibitors (lisinopril, captopril)
    • Angiotensin receptor blockers (Irbesartan, valsartan, losartan)
    • Antibiotics tetracyclines and metronidazole (Flagyl®)
    Decreases lithium level
    • Potassium-sparing diuretics (triamterene, amiloride, spironolactone)
    • Theophylline (Theo-Dur®, Uniphyl®)

    Most providers do not feel comfortable managing Lithium, due to the toxicity and side effects. One of my former PA students that graduated around 2009 landed a job in a psychiatric hospital. Her job was unique, she managed the patient’s disease states brought on by the potent psych meds that were prescribed. Family practice providers see a lot of the metabolic abnormalities brought on by the antipsychotic drugs, so it is important to be familiar with problems brought on by these very potent medicines.

    Two years ago, I was counseling a patient who was on Lithium at the Empower-3 clinic. At our first meeting in the summer I reminded him (as I do all my lithium patients) to drink plenty of fluids. I explain to them when the “beaker”, that is your body goes low in water the concentration goes up and can cause toxicity.

    At the next meeting his caregiver said he was “chugging” 2 liters of water at a time about every 30-60 minutes. I immediately thought of the renal toxicities lithium can cause. After Vince, the Physician Assistant went in, did a complete physical and ordered blood work, it was determined he had “lithium induced nephrogenic diabetes insipidus”

    Just simple counseling a patient about their water intake lead to this rare diagnosis. That’s why we’ll take a long journey through the psych meds, because so frequently these problems fall on the lap of the family practice providers.

    Have a great day on the bench!!

    November 2019

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    More and more of our patients need our help with their psych meds!

    Behavioral Health Pharmacology
    Mental health services are challenging to get for our patients. Most psychiatrists are booked in advance, and mid-level practitioners such as CRNP’s and PA-C’s are carrying the burden. Even with their help mental health services are difficult to get for our patients. More and more mental health care is being provided by the family practice clinicians. At the request of the Physician Assistants that I work with at Empower-3, we will begin the journey through drug therapy for mental health disorders.

    Before we start the drug categories, we need to do a quick overview of the neurotransmitters.

    What makes a neurotransmitter:
    • It is synthesized in a neuron
    • Is synthesized/stored and released by the pre-synaptic terminal. When released it has a specific effect when it attaches to the receptor on the post-synaptic terminal
    • When given as a drug it exerts an identical reaction on the post synaptic terminal’s receptors
    • A specific mechanism removes the drug from the synaptic cleft,
      • either by pre-synaptic uptake (recycling) or
      • destruction by a specific enzyme
    In addition to depressed mood, abnormalities of neurotransmitter function are associated with different symptoms: Dopamine: (decrease in dopamine function)
    • Decreased ability to experience pleasure
    • Decreased motivation
    • Decreased attention
    • Cognitive slowing
    • Weight gain
    Norepinephrine (decrease in norepinephrine function)
    • Low energy & lethargy
    • Decreased alertness
    Serotonin (decrease in serotonin function)
    • Obsessive –compulsive behavior.
    NEUROTRANSMITTER SPECIFIC EFFECTS:
    SEROTONERGIC SIDE EFFECTS (excess serotonin):
    • Sexual dysfunction
    • Weight gain
    • Suppression of dopamine neurotransmission which may result in:
    • Decreased ability to experience pleasure
    • Apathy and decreased motivation
    • Decreased attention
    • Cognitive slowing
    • GI upset
    • Sleep Disturbances
    NORADRENERGIC SIDE EFFECTS (excess norepinephrine)
    • Tremor
    • Tachycardia
    • Dry mouth
    • Insomnia
    DOPAMINERGIC SIDE EFFECTS (excess dopamine)
    • Psychomotor activation
    • Aggravation of psychosis
    • Activation of motivation: rewards pathway
    • PERIPHERAL effects of dopamine:
      • At very high doses: ventricular arrhythmia, atrial fibrillation, ectopic beats, tachycardia, anginal pain, palpitation, cardiac conduction abnormalities, widened QRS complex, bradycardia, hypotension, hypertension, vasoconstriction.
      • dyspnea.
      • azotemia.
      • piloerection.
    GABA (gamma-aminobutyric acid)
    GABA is the chief inhibitory neurotransmitter of the CNS. Opposes the effect of glutamate. When released latches onto the GABA receptor which has a calming effect. Benzodiazepines work on the GABA receptor and cause a release of chloride, which is the major inhibitory ion in the CNS. Chloride ions are negatively charged causing hyperpolarization of the neuron. GABA's effects can be modulated by drugs such as benzodiazepines, barbiturates, steroids, and alcohol.
    NET EFFECT on the GABA receptor
    • Barbiturates increase the duration of chloride ion channel opening at the GABA receptor, to increase the efficacy of GABA.
    • Benzodiazepines increase the frequency of the chloride ion channel opening at the GABA receptor to increases the potency of GABA.
    GLUTAMATE
    Glutamate is the major excitatory neurotransmitter. Glutamate pathways are linked to many other neurotransmitter pathways, and glutamate receptors are found throughout the brain and spinal cord in neurons and glia. So diverse and widespread are the glutamate receptors only three prescription medications have been developed that specifically target glutamate or glutamate receptors, memantine (Namenda®), ketamine (Spravato®), and D-cylcoserine (Seromycin®). I find it incredulous that an Alzheimer's drug, an antidepressant and an anti-tuberculosis drug are all related to their effect on the glutamate receptor.

    One of the more challenging topics to teach to my Physician Assistant Sciences students is Behavioral Health. There are numerous disease states, numerous categories of drugs, and numerous generations of drug categories.

    It all began in 1954 with the introduction of Thorazine® (chlorpromazine) which began the emptying out of mental health hospitals. Today we have lots of drugs for treatment of bipolar, schizophrenia, depression and numerous other behavioral health conditions.

    The first Behavioral Medicine exam I gave at St. Francis had an average of 69%. Talk about PTSD; both the students and their professor still remember that morning back in 2005!

    Have a great day on the bench!!

    Naproxen, Ibuprofen, Meloxicam or dialysis. What would your diabetics choose??

    NSAIDS: Proceed with caution especially with Diabetics and Cardiovascular patients!!!

    NSAID use was associated with a 1.18-fold increased risk of Chronic Kidney Disease (CKD) in subjects taking NSAIDs for 1 to 89 days; and a 1.32-fold increased risk of CKD in hypertension subjects taking NSAIDs for ≥90 days, compared with subjects not taking any NSAIDs, after controlling for the confounding factors.

    https://www.ncbi.nlm.nih.gov/pubmed/26169048?dopt=Abstract

    NSAIDs reduce blood flow to the glomerulus by inhibiting production of vasodilating prostaglandins. NSAIDs can increase blood pressure, cause fluid retention, and worsen renal function in these patients. Among patients with hypertension, those who take NSAIDs for three months or longer are about 32% more likely to have chronic kidney disease than nonusers.

    TRIPLE WHAMMY: Watch combinations of NSAIDS/ ACE inhibitors and diuretics! In the normal kidney, glomerular filtration is related to glomerular blood flow.
    • NSAIDS: block prostaglandin mediated afferent arteriolar VASODILATION. (lets blood perfuse into the glomerulus)
    • ACE/ARB: block Angiotensin-2 mediated efferent arteriolar VASOCONSTRICTION (increases pressure for filtration)
    • DIURETICS: decrease plasma volume


    Above is a slide I created for FreeCE.com that I also use in my lectures, showing how NSAIDS slow down the blood flow to the kidney by blocking prostaglandin mediated vasodilatation. On the other side at the efferent arteriole vasoconstriction is blocked by ACEi/ARBS like Lisinopril or Losartan. We use ACEi and ARBs for nephroprotection because they stabilize the basement of the glomerulus. Avoiding NSAIDs is the best way to keep ACEI/ARBs on board and minimize renal problems. Above all, remember the most effective method to prevent diabetic nephropathy is tight glycemic control and control of BP and cholesterol. Weight reduction, exercise, and avoidance of smoking also help.

    Commentary:
    My wife and I frequently attend drug company sponsored dinners. It gives us pharmacists a chance to get out from behind the counter and interact with fellow health care professionals.

    Dr. Vijay Bahl, Chief of Endocrinology at UPMC Shadyside Hospital in Pittsburgh, was the presenter at the last dinner we attended. He was discussing the renal protection of canagliflozin and was talking about NSAIDs have a detrimental effect on the afferent arteriole. I asked Dr Bahl,"so you are saying NONE of our diabetic patients should EVER get an NSAID?"

    He said "correct, no diabetic patient should ever get an NSAID". Some in the room pressured him, asking if any NSAIDS are safer; some talked about acetaminophen’s lack of efficacy. Dr Bahl replied, “I tell my patients, you can either take acetaminophen for your pain, or eventually go to dialysis three times a week.” He said no one ever selects the dialysis option!

    Have a great day on the bench!!

    Do your pharmacist and patients a favor... prescribe aspirin, if indicated!

    Aspirin Dosage: for relief of mild to moderate pain is 325-1000mg every 4-6 hours., with a maximum dose = 4000 mg/day. Up to 3-4 g per day has been used for the treatment for rheumatoid arthritis, lupus, and other rheumatologic conditions. Of course watch for GI bleeding.

    Most of us pharmacists seldom see aspirin used for pain and inflammation, but rather for aspirin’s antiplatelet activity with the dose being 81-325mg/day. For acute myocardial infarction, the AHA/ACCF recommends chewing 162 to 325 mg immediately, unless patient already taking daily aspirin.

    PLATELETS before PAIN
    Aspirin’s cardiovascular benefits stem from its permanent inactivation of platelet COX-1, which blocks the production of thromboxane A2. Blocking Thromboxane A2 inhibits thromboxane A2-dependent platelet function and vasoconstriction. Aspirin irreversibly blocks platelets for their lifetime of 7 days. Complete blocking of platelet activity can be achieved with only 75 to 150 mg of aspirin.

    DOES EVERYONE GET ASPIRIN?
    The newest recommendations (ACC/AHA) : New guidelines say that daily, low-dose aspirin should be used infrequently to prevent primary cardiovascular disease. The bleed risk isn’t worth the benefit, until you have had an event. The American College of Cardiology and the American Heart Association conclude that aspirin should be reserved for people with the highest cardiovascular risk and the lowest risk for bleeding.

    Adults who are 40 to 75 years of age and are being evaluated for cardiovascular disease prevention should undergo 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimation and have a clinician–patient risk discussion before starting on pharmacological therapy, such as antihypertensive therapy, a statin, or aspirin. ASCVD calculators are found online and in many Electronic Medical Records.

    Aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit. Men seem to benefit by prevention of myocardial infection, while women get their benefit from reduction of ischemic strokes.

    RISKS vs BENEFITS
    • Avoid aspirin in patients with additional GI risks unless their CV risk is high enough to outweigh the higher bleeding risk.
    • Make sure blood pressure is controlled before starting aspirin to reduce the risk of hemorrhagic stroke.
    • Always access the risk for potential for GI bleeds when combined with other NSAIDS. Don’t forget to include over the counter ibuprofen (Advil) and naproxen (Aleve).
    • Stop Aspirin with a 7 to 10-day washout before major surgical procedures.
    • Stopping aspirin in patients with a prior heart attack leads to 4 extra heart attacks per 1000 patients per year. Aspirin is serious therapy, and I advise prescribers to write a prescription for aspirin therapy.
    PRESCRIBING ASPIRIN:
    It is best to prescribe aspirin in the following circumstances:
    • Post stenting- bare or drug-eluting: indefinitely
    • Combined with Niacin ER (Niaspan, because it blocks prostaglandin mediated vasodilatation. That is, if anyone is using Niacin for mixed hyperlipidemia.
    • Combined with clopidogrel (Plavix) or ticagrelor (Brilinta) post stent
      • Bare Metal (non-ACS) 1 month up to 12months
      • Drug-eluting: 12 months post ACS
    • Ticagrelor (Brilinta) per package insert, patient must take an 81mg aspirin with one of the two Brilinta doses daily
    • MONA (Morphine, Oxygen, Nitroglycerin, Aspirin) therapy for myocardial infarction in the Emergency Department setting..
    Aspirin has been around 120 years now, and we still have not figured it out yet!

    Vince Capone one of the Physician Assistants I work with at Empower-3, also pulls an occasional shift in the Trauma Unit at UPMC Altoona. Vince tells me that frequently people come in with aspirin on board and have bleeding due to trauma. They frequently use DDAVP (desmopressin) to reverse the action of aspirin on the platelets.

    DDAVP, can be used for Von Willebrand’s disease, for bed wetting, diabetes insipidus and to reverse the effects of aspirin. Now that is a versatile drug!

    Have a great day on the bench!!

    October 2019



    Whats up with Cox-1 and Cox-2

    MOST NSAIDS inhibit COX-1 and COX-2 : Cyclooxygenase are the enzymes that produce prostaglandins. There are two types of COX enzymes simply named, COX-1 and COX-2. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining.
    Blocking COX (Cyclooxygenase) inhibits prostaglandin and thromboxane synthesis.

    Here are the 4 A's of Cox inhibition
    • Anti-inflammatory (reduces inflammation)
    • Antipyretic effect (reduces fever)
    • Antithrombotic effect (reduces platelet stroke risk)
    • Analgesic effects (reduces pain)
    All NSAIDs inhibit COX-1 and COX-2 to different degrees. Mechanisms of inhibition:
    • Category 1: rapid competitive reversible binding of COX-1 and COX-2 (ibuprofen, piroxicam)
    • Category 2: rapid, lower-affinity reversible binding followed by time-dependent, higher-affinity, slowly reversible binding of COX-1 and COX-2 (diclofenac, indomethacin, naproxen)
    • Category 3: rapid reversible binding followed by covalent modification of COX-1 and COX-2 (aspirin)
    PRECAUTIONS for NSAIDs:
    BAD NEWS: GASTRIC DISTRESS
    REALLY BAD NEWS: CARDIOVASCULAR RISK as well as RENAL RISK
    • KIDNEY: Caution if renal impaired, may cause nephrotoxicity by blocking afferent vasodilatation. We will devote an entire column to renal effects of NSAIDS
    • PREGNANCY: All are pregnancy Category –D in third trimester, (near delivery) due to premature closing of the ductus arteriosus. Use lowest effective dose, intermittently if possible, especially in late pregnancy (avoid during last eight weeks of pregnancy).
      • First Trimester: link to miscarriage and certain rare birth defects in the first trimester
    • NURSING MOMS: Because of its extremely low levels in breastmilk, short half-life and safe use in infants in doses much higher than those excreted in breastmilk, ibuprofen is a preferred choice as an analgesic or anti-inflammatory agent in nursing mothers. Best to avoid Naproxen (Aleve®) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
    • STOMACH: active GI disease
    • LIVER: Caution in liver impairment.
    • HEART: Exacerbation of heart failure, as well as increased risk of myocardial infarction, stroke, CV death. If an NSAID is needed Naproxen is a safer choice.
    • EVERYTHING ELSE:
      • photosensitivity
      • Avoid Aspirin & alcohol while taking NSAID
      • Watch for increased hypertension
    PREVENTION OF GASTROINTESTINAL RISKS:
    • Proton pump inhibitors
    • High dose H2RA Pepcid (famotidine) 40mg twice daily, will reduce risk of both gastric and duodenal ulcers
    • Misoprostol due to cramping, diarrhea and four times daily administration is seldom used.
    I remember as a kid growing up in the 1960's my Mom had a glass prescription bottle that had a paper note written inside. On the paper was written "DON-NO", indicating my brother was never to be taking this drug.

    The well-worn prescription label read "Butazolidin alka". Mom said it "almost knocked out his kidneys." She would ensure that there would be no repeat of that major side effect.

    I also remember my Dad at that time had a large glass bottle of "Ascriptin" which contained aspirin plus Maalox® (magnesium and aluminum hydroxide). The Maalox® was added to the aspirin to buffer the acidic effects of the aspirin.

    Until ibuprofen came over the counter in 1984, that is all we had in the NSAID family without a prescription.

    History has taught us to respect NSAIDS!

    Have a great day on the bench!!

    1898-Heroin; 1899-ASPIRIN both came from Bayer Pharmaceuticals

    NSAIDS, The Basics
    Non-steroidal anti-inflammatory drugs (NSAIDs); we use them every day in our practice. We’ve had them for many years and new information about when NOT to use them seems to come out rather frequently. With all the pressure on prescribers to avoid opioids NSAIDs are being called upon to pull the pain relief wagon. Even though a couple of these drugs (aspirin, ibuprofen, naproxen and ketoprofen) have over-the counter status, these drugs are certainly not innocuous. There are at least 16 NSAIDS with different pharmacokinetic profiles. The first and still most famous NSAID aspirin was developed by the Bayer Company in Germany in 1899, one year after Heroin® (diacetyl morphine) was introduced.

    The earliest NSAID came from white willow bark and contained salicin, similar to aspirin (acetylsalicylic acid). Our local aspen and birch trees also have salicin in their bark. Salicin was a precursor to aspirin before its development, and was used for reducing pain and inflammation. Hippocrates, the Greek physician (460 to 377 B.C.), wrote that willow leaves and bark relieved pain.

    Edward Stone, rediscovered aspirin in 1767, in effect, when he wrote that powdered willow bark seemed to benefit 50 patients with ague (malaria) and other maladies. The next big advance for non-steroidal anti-inflammatory drugs came when Felix Hoffman and Arthur Eichengrun reacted sodium salicylate with acetyl chloride to form aspirin. This compound was later marketed by Bayer under the trade name Aspirin which was registered as a trade name in January 1899.

    Mechanism: inhibit prostaglandin synthesis from arachidonic acid by inhibiting enzymes COX-1 and COX-2. Aspirin inhibits platelets by irreversible inhibition of platelet Cox-1 and inhibition of Thromboxane-A2. Today most patients use aspirin for cardiovascular protection, which will be covered later.

    AVOID: aspirin in kids under 18, due to the risk of Reye’s syndrome. Reye's syndrome is a rare but serious condition that results in fatty changes of the liver and acute encephalopathy mostly in children and teenagers recovering from a viral illness such as influenza or chickenpox. Ammonia accumulates and enters the central nervous system resulting in nausea/vomiting and altered mental status. The persistent vomiting seen with Reye's syndrome can result in dehydration and electrolyte abnormalities, especially in young children. Left untreated, patients can experience minor brain damage, seizures and possibly death. Also avoid other forms of salicylates such as Pepto-Bismol, menstrual products with magnesium salicylate and Alka-Seltzer.

    What ever happened to the other salicylates?
    • Salsalate (Disalcid): is a weak inhibitor of cyclogenase. Salsalate is a nonacetylated dimer of salicylic acid
    • Choline magnesium trisalicylate (Trilisate) is a nonacetylated dimer of salicylic acid.
    • Diflunisal (Dolobid) is a difluorophenol derivative of salicylic acid approved in 1982.
    Like Kasimir Funk, the Father of Vitamins, AlbertEichengrun is another forgotten scientist that made a huge impact on medicine.

    There are different references that describe a controversy between Dr. Albert Eichengrun and Felix Hoffman for the discovery of aspirin. In 1949, Arthur Eichengrün published a paper in which he claimed to have planned and directed the synthesis of aspirin along with the synthesis of several related compounds.

    Eichengrun claimed that Hoffmann's role was restricted to the initial lab synthesis using his (Eichengrün's) process and nothing more. Bayer denied his account of the story.

    Dr Eichengrun had another treatment that impacted the health care of its time. Dr Eichengrun developed Protargol (silver proteinate) in 1897. This drug had bactericidal properties and was the standard of care for treatment of gonorrhea for 50 years, until the availability of antibiotics.

    Have a great day on the bench!!

    Second and third generation antihistamines are valuable treatment for our allergy sufferers.

    2nd and 3rd Generation Antihistamines
    Last week we discussed the role of antihistamines in the treatment of seasonal allergies, and delineated the three generations of antihistamines. Since everything we do as practicing clinicians revolves around patient care, let’s discuss counseling points to share with each patient that utilizes our expertise.

    SECOND GENERATION ANTIHISTAMINES: do NOT cross BBB, causing minimal sedation, and NO anticholinergic side effects.
    • PREGNANCY: ACOG also recommends cetirizine and loratadine after the first trimester in patients who cannot tolerate or do not respond to maximal doses of chlorpheniramine. (All three drugs are Pregnancy Category B)
    • FYI: Cetirizine is the active metabolite of the prescription drug Hydroxyzine (Vistaril®, Atarax®)
    THIRD GENERATION are the "active enantiomers" of the second generation antihistamines
    • FEXOFENADINE: Fruit juices such as grapefruit, orange and apple juice may decrease the oral bioavailability of fexofenadine by inhibiting the activity of OATP1A2. Fexofenadine is a substrate of the intestinal uptake transporters organic anion transporting polypeptide 1A2.
    • DESLORATADINE: Desloratadine is the active metabolite of loratadine.
      • Novel use for treatment Lyme Disease: Loratadine metabolite "desloratadine" blocks BmtA (Borrelia metal transporter A). Desloratadine (which is the brand name "Clarinex") blocks manganese from entering the cell. Transition metals, including iron (Fe), zinc (Zn), and manganese (Mn), are critical to both bacterial metabolism and virulence. When these metals are blocked it starves the Borrelia burgdorferi and causing it to die in test tubes. Obviously this is way too early in the research phase for us to recommend this to our patients, so we will have to wait and see. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330029/




    REMEMBER SELDANE® ?? (removed from market in 1998) Fexofenadine is a primary metabolite of terfenadine (SeldaneRx). When terfenadine's hepatic conversion to the fexofenadine was blocked by other drugs or disease, levels of the parent drug (terfenadine) rise resulting in heart rhythm disturbances. Fexofenadine is effective in allergic disorders, and less cardiotoxic.

    REMEMBER HISMANAL®??(removed from market in 1999) Astemizole was the active ingredient in this second-generation antihistamine. This drug was also removed due to QTc interval prolongation and related arrhythmias when used with high doses, especially when taken with CYP inhibitors or grapefruit juice. This product was marketed by Janssen Pharmaceuticals.

    Both of these second generation antihistamines were pulled from the market leaving only loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra).

    Claritin became available over the counter in November 2002. Zyrtec became available in November 2007 without a prescription, and Allegra got its OTC approval in January 2011.

    Have a great day on the bench!!

    Antihistamines have been around for almost 75 years. Can you imagine life without them----Ahhhh-CHOO!!!!

    FIRST GENERATION ANTIHISTAMINES
    Last week we discussed the abundance of ragweed and its associated effects. This week we will discuss the use of antihistamines, of the first generation. Many of us “seasoned” pharmacists remember when these drugs were moved from behind the counter to OTC status. Although safe and effective, pharmacist expertise is necessary in quite a few patient groups.

    A brief HISTORY of antihistamines:
    • 1942 Bernard Halpbern introduced the first antihistamine: N-diethylaminoethyl-N-benzylalanine- Institute Pasteur in Paris
    • 1945 diphenhydramine became available, followed by chlorpheniramine, brompheniramine and promethazine later in the 1940's. Chlorpheniramine and Brompheniramine became over the counter September 9, 1976.
    • Diphenhydramine became available first as an antitussive in Aug-1981 (Benylin); as a sleep aid (50mg) in 1982 (Sominex-2), and as an antihistamine (25mg) Jan-1985 (Benadryl)

    • MECHANISM: H1-antagonists competitively inhibit the action of histamine on tissues containing H1-receptors. Some also block histamine release, but only in excessive doses. The H1-antagonists do not block antibody production or antigen-antibody interactions.
      USES: Symptomatic treatment (sneezing, rhinorrhea, and itching of eyes, nose, and throat) of allergic rhinitis, chronic idiopathic urticarial, as well as motion sickness & nausea/vomiting. Always best to start antihistamine therapy at least two hours before exposure.

      Structural Classes: Active Ingredient(s):
    • Alkylamines - brompheniramine, chlorpheniramine, triprolidine, pheniramine
    • Ethanolamines - clemastine, diphenhydramine, doxylamine
    • Ethylenediamines - pyrilamine (has some diuretic effects)
    • Piperidines - fexofenadine, loratadine
    • Piperazines: cetirizine, hydroxyzine, meclizine

    THREE GENERATIONS OF OTC ANTIHISTAMINES: First generation are the older, and more sedating antihistamines. They also cause numerous anti-cholinergic side effects. They cross the blood brain barrier.
    • Examples: Chlorpheniramine (Chlor-Trimeton), Clemastine (Tavist), Diphenhydramine (Benadryl), Brompheniramine (Dimetane)
    • First generation antihistamines are commonly used for allergy, hives, sleep induction, cough, vertigo, motion sickness, itching, adjunct for nausea and vomiting and runny nose. A lot of the benefits of these first-generation antihistamines is tied to their anti-cholinergic side effects.
    • Anticholinergic side effects: blurred vision, dry mouth, urinary retention, constipation. (“can’t see, can’t spit, can’t pee, can’t sh*t”)

    AVOID FIRST GENERATION ANTIHISTAMINES:
    • AVOID in ELDERLY: All first-generation antihistamines are listed in the Beers List. Due to their highly anticholinergic activity and reduced clearance with advanced age. Tolerance develops when used as hypnotic; may also see increased risk of confusion, dementia, cognitive impairment, dry mouth, and constipation. May also increase fall risk
    • Avoid in men with BPH (prostate hypertrophy)
    • Avoid in children under age six
    The second generation (non-sedating) do NOT cross the blood brain barrier, causing minimal sedation, and NO anticholinergic side effects.
    • Examples: Loratadine (Claritin) and Cetirizine (Zyrtec)
    • Third generation are the “active enantiomers” of the second generation antihistamines
      • Fexofenadine (Allegra) We will explore the second and third generation antihistamines next week.
    A retired allergist once told me that Central Pennsylvania was the best place on earth to practice!

    How well us seasoned pharmacists remember when antihistamines were made available over-the-counter. I remember when Benylin came over the counter, and we pharmacists were using it for everything from urticaria, insomnia to allergies.

    Antihistamines becoming over the counter started the beginning of pharmacists having a role in saving health care dollars. For every ONE dollar a patient spends in the front of our store, they save the health care system SEVEN dollars.

    The first prescription I filled as a newly licensed pharmacist in August of 1981 was for Benadyl 50mg capsules by Parke-Davis. I often wonder how many times I checked and rechecked that one!

    Next week we will cover another game changer in self care, the second and third generation antihistamines.

    Have a great day on the bench!!

    Keep the windows closed, and the air conditioner running!

    Achoooo.. That most familiar sound we hear this time of the year as the ravages of ragweed in the fields affects our patients.
    Flower pollens like those from annual plants like marigolds, petunias and impatiens rarely cause allergy, as their pollen is moved by bees. It is the windborne pollens that present the most difficulty to allergy sufferers. According to the Allergy and Asthma Foundation of America, 10-20% of us suffer from ragweed allergy.
    Here are some more teaching points to share with your ragweed patients:
    • Ragweed is most common in the Eastern states and the Midwest, mostly in rural areas. It includes several members of the daisy family.
    • A single plant produces up to 1 billion pollen grains.
    • Ragweed flowers mature and release pollen. The pollen must become airborne to fertilize other seeds.
    • Warmth, humidity and breezes after sunrise help the release. Pollen levels are highest in the morning & early afternoon (10am-3pm)
    • The pollen must then travel by air to another plant to fertilize the seed for growth the coming year.
    • Pollens can travel up to 400 miles out to sea, but most fall locally.
    Some treatment approaches can be:
    • Avoiding the peak pollen times for outdoor activity between 10am and 3pm.
    • Use central air conditioning, and HEPA filters. Maintain filters often.
    • Let the pollen outside! If you spend a lot of time outside during peak pollen time:
      • Take your shoes off outside
      • Don't wear your "outside" clothes to bed
      • Take a shower and shampoo your hair at night before going to bed.
    • Use of antihistamine therapy, which we will discuss in the next two weeks
    • Use of immunotherapy if insufficient response to antihistamines. They help desensitize the patient. Two immunotherapy options are available for severe cases of ragweed allergy:
      • Allergy shots can help build resistance to ragweed allergens.
      • Tablets that dissolve under the tongue are available by prescription. These sublingual tablets must be started 12 weeks before the beginning of ragweed season.
    Ragwitek: (Short ragweed pollen allergen extract) (cost $360.00/month)
    contains small amounts of natural short ragweed pollen that builds tolerance to decrease sensitivity to ragweed pollen.
    Use: Treatment of short ragweed-induced allergic rhinitis with or without conjunctivitis, that has been diagnosed by an allergist using skin testing.
    Dose: 1 tablet sublingual once a day (12 Amb 1-unit). Approved for ages 18-65. First dose must be dosed under medical supervision in a doctor’s office. Ragwitek® can cause severe allergic reactions that may be life-threatening.
    Medication should be laid under the tongue, and patient does not swallow for 1 minute. Patients should NOT take with food or beverages and not eat or drink for at least five minutes after administration.
    Notes: Should be started at least 12 weeks before the expected onset of ragweed pollen season and continue throughout the season. symptom score improved by approximately 18% or more.

    Next week we will explore the antihistamines.

    A retired allergist once told me that Central Pennsylvania was the best place on earth to practice!

    We have the deciduous and evergreen tree pollens in the spring, then the grass pollens in the summer. The rainy days of spring and summer produce lots of molds, leading into fall when the ragweed is in full bloom until the first killing frost. Couple that with our cool nights and everyone opens the windows (and even puts a fan in the window) to suck in all these outdoor allergens!

    We have a lot of treatment options to help our allergy suffering patients. We'll explore those treatment options in the coming weeks. We will cover first , second and third generation antihistamines.

    Wait! There are three generations of antihistamines??? Stay tuned for the next couple of weeks.

    Have a great day on the bench!!

    September 2019

    This handy chart will help you make decisions about therapy for your Type-2 patients with diabetes.

    NEWS FLASH--- oral GLP-1 available!!!

    Class / Generic name Brand name Physiologic action (Mechanism) Comments
    Biguanides (HbA1c=-1.5) Decreases hepatic glucose production Used first line. Weight neutral. GI side effects.
    Metformin Glucophage
    Sulfonylureas (2nd gen) (HbA1c= -1-1.5) Increases insulin secretion from the beta cells of pancreas Causes hypoglycemia, weight gain (5lb) , low durability
    Glyburide Micronase or Diabeta Avoid Glyburide in elderly (Beers List)
    Glipizide Glucotrol
    Glimepiride Amaryl
    Meglitinides (HbA1c=- 1-1.5) Increases insulin secretion Fast acting. Give with meal. May cause hypoglycemia
    Repaglinide 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.
    **Note: biological half-life of B12 is 1 year, therefore more than 2 years must elapse after a complete cessation of B12 intake before clinical manifestations of deficiency are apparent. 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.

    ORAL VITAMIN B12 standard dosing
    • Begin with 1000mcg per day. (because of poor absorption, about 5mcg/dose is absorbed)
    • Tablets, lozenges or sublingual gels are frequently marketed as having superior bioavailability, although evidence suggests no difference in efficacy between oral and sublingual forms
    INJECTABLE VITAMIN B12 standard dosing
    • Cyanocobalamin is commonly available as 1000mcg /ml injections
    • Start with 1000mcg IM every day for 1 week. Then 1000mcg IM weekly for 4 weeks, then 1000mcg IM monthly for prevention.
    • Recommend injectable B12 for patients with more severe deficiency or those who may not absorb it due to diarrhea, vomiting, or bowel resection.
    • Vitamin B12 injections are also recommended for patients with GI- bypass surgery (for weight loss).
    • Vitamin B12 depletion is also implicated in patients with tinnitus (ringing in the ears); supplementation might be of benefit. Poor vitamin B-12 and folate status may be associated with age-related auditory dysfunction.
    Anyone taking any acid suppressing drugs, metformin or any stomach surgery are excellent candidates for vitamin B12 therapy. When I look at the bottles of 1000 of metformin, omeprazole, ranitidine and pantoprazole, I can't help wonder how much more Vitamin B12 deficiency is undiagnosed. The challenge with Vitamin B12 is due to its storage in the liver and depletion takes a while to manifest itself.

    I have reversed at least 6 patients “neuropathy” by recommending Vitamin B12 1,000mcg per day. What they really had was a B12 deficiency, and not neuropathy. Give it that some thought especially with those Type-2 diabetics who are complaining of neuropathy, especially if their HbA1c is in the acceptable range.

    Have a great day on the bench!!

    The most important B vitamin... just ask GrandDad!

    Folic Acid---Vitamin B-9

    Dietary sources: Folate is found naturally in a wide variety of foods, such dark green leafy vegetables, fruits and fruit juices, nuts, beans, peas, dairy products, poultry and meat, eggs, seafood, and grains. Spinach, liver, yeast, asparagus, and Brussels sprouts are among the foods with the highest levels of folate. By FDA requirement, manufacturers add folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products, since 1998. This accounts for 100-180mcg per day.

    Why we need it: Folic acid is required for nucleoprotein synthesis and maintenance of normal RBC formation. Stimulates the production of red & white blood cells and platelets in certain megaloblastic anemias. Conversion to tetrahydrololate (the active form) in the gut is Vitamin B12 dependent. Oral synthetic folic acid however is completely absorbed following administration even in the presence of malabsorption syndromes.

    Indications for use: megaloblastic anemia due to deficiency of folic acid.

    Warnings: Pernicious anemia: if folic acid is given in doses over 0.lmg daily, it may obscure pernicious anemia in that hematologic remission can occur while the neurological manifestations may continue to progress. Severe nervous system damage can occur before the correct diagnosis is made.

    Pregnancy: decreased incidence of Spina bifida and anencephaly. Because of its role in the synthesis of DNA and other critical cell components, folate is especially important during phases of rapid cell growth. Supplement 400-800mcg before pregnancy occurs, since the neural tube closes between day 21 and 28 after conception. If high risk for spina bifida, may use up to 4mg (4000mcg).

    All women of child bearing capability should be taking supplemental folic acid of at least 400mcg. Since 1998, when the mandatory folic acid fortification program took effect in the United States, spinal bifida and anencephaly rates have declined by 25% to 30%. Keep in mind that half of pregnancies in the United States are unplanned, adequate folate status is especially important even before conception (planned or unplanned) occurs.

    Alcoholism: People with alcohol dependence frequently have poor-quality diets that contain insufficient amounts of folate.

    Cardiovascular: Folic acid (and vitamin B12) supplements lower homocysteine levels. However, these supplements do not actually decrease the risk of cardiovascular disease, although they appear to provide protection from stroke. Lowering homocysteine levels didn’t provide protection from myocardial infarction but did reduce risk of stroke by 25%. The dose was 2.5mg per day for a total of 5 years.

    Dementia: folic acid supplementation showed no benefit for prevention of Alzheimer’s.

    DRUGS that LOWER folic acid
    • Seizure medications: CYP450 inducers (phenytoin, phenobarbital, carbamazepine)
    • Oral contraceptives
    • Proton pump inhibitors (PPI’s) such as omeprazole (Prilosec), pantoprazole (Protonix), esomeprazole (Nexium) and others, by blocking acid formation reduce folic acid absorption.
    • Histamine-2 Receptor Antagonists (H2RA such as ranitidine (Zantac), famotidine (Pepcid), cimetidine (Tagamet) decrease acid release and lower absorption of folic acid.
    • Methotrexate (for Rheumatoid Arthritis)
    • Trimethoprim
    • Sulfasalazine (Azulfidine®) DMARD and ulcerative colitis- by inhibiting the intestinal absorption of folate
    Since we all dispense birth control pills, have many females of child bearing age, and those taken acid suppressing drugs like PPI’s and H2RA’s this is an amazing opportunity to recommend folic acid supplementation. When was your last folic acid recommendation???
    • Folic Acid is available in multivitamins, prenatal vitamins, single entity over the counter 400mcg and 800mcg, and prescription strength 1mg.
    L-methylfolate----“super folic acid”
    • L-methylfolate is the primary biologically active isomer of folate and the primary form of folate in circulation. It is also the form which is transported across membranes into peripheral tissues, particularly across the blood brain barrier, while folic acid does not.
    • USE: distinct nutritional requirements of individuals who have suboptimal L-methylfolate levels in the cerebrospinal fluid, plasma, and/or red blood cells and have major depressive disorder (MDD) especially if patient is on antidepressant therapy. Adjunctive use for treatment of depression and schizophrenia
    • One Deplin® 7.5mg tablet is bioequivalent to taking sixty-six 800 mcg folic acid pills. (53 of the 1mg tablets)
    When I look across the numerous vitamin choices, natural, synthetic, combination senior vitamins, stress vitamins, the list goes on and on. Vitamins are marketed to every age group and both sexes. We have feet upon feet of shelves of vitamins in our pharmacies.

    Lots of opportunities are available in our vitamin aisle, probably none is more important than supplementation with folic acid. That’s the pharmacist and grandfather in me talking!

    Have a great day on the bench! Merry Christmas and a Happy New Year. Be sure to slip a bottle of folic acid in her stocking this Christmas season! ??

    Have a great day on the bench!!

    With lab assay interference, be sure to chart if your patients are taking biotin!

    Let’s cover two less common vitamins, pantothenic acid (Vitamin-B5) and biotin, (Vitamin B-7). Deficiencies of these vitamins are rare, but with long term antibiotic use levels may be affected.

    Pantothenic Acid
    • Use: breakdown of fats and carbohydrates for energy, vitamin B5 (like all B- complex)
    • Deficiency is very rare, but can cause paresthesias (tingling in the feet). Pantothenic acid is synthesized by bacteria in the colon, as well as dietary intake.
    • critical to the manufacture of red blood cells, as well as sex and stress-related hormones (adrenal hormones).
    • Vitamin B5 is also important in maintaining a healthy digestive tract, and it helps the body use other vitamins, particularly B2 or riboflavin
    Drug Interactions:
    AVOID with cholinesterase inhibitors (donepezil, rivastigamine, etc). Pantothenic acid also blocks absorption of tetracyclines.

    Biotin (Also known as Vitamin-H)
    • Recommended intake is 30mcg/day. Deficiency in developed countries is rare. High levels found in liver, cauliflower, salmon, carrots, bananas, cereals, nuts, chocolate and yeast. Also synthesized by intestinal microflora. Biotin deficiency may lead to muscle pain, dermatitis, or glossitis (swelling of the tongue)
    • Excess consumption of raw egg whites lower biotin by binding to avidin, a protein found in egg whites.
    • About half of pregnant women in the United States develop a marginal biotin deficiency, especially in the early weeks of gestation. Supplementation with biotin and folic acid, reduces some teratogenic conditions, including neural tube defects.
    • Smoking may contribute to biotin deficiency
    Biotin uses:
    • functions as a cofactor for four different enzymes that catalyze carboxylation retentions. Helps metabolize carbs, fats and amino acids
    • Hair and nails: although improves the keratin infrastructure (a basic protein that makes up hair, skin, and nails) deficiency is RARE. Evidence is weak for using biotin to strengthen hair and nails. Some supplements contain 5,000mcg of Biotin, which can interfere with lab tests.
    • Deficiency state: hair loss, dry scaly skin, cheilitis, glossitis, dry eyes, loss of appetite, fatigue, insomnia, and depression
    • Excess: slower release of insulin, skin rashes, lower vitamin C and B6 levels and high blood sugar levels.
    Drug interactions: Antibiotics, by destruction of normal flora in the gut, might decrease synthesis of biotin. CYP-450 3A4 INDUCERS (such as phenytoin, carbamazepine, phenobarbital and rifampin) speed up metabolism of biotin, and decrease levels.

    Biotin Interference with Lab Assays:
    • High doses of biotin, such as those found in the Hair, Nails and Skin supplements may interfere with common laboratory immunoassays for other tests, including troponin, digoxin, and progesterone. A falsely low result for troponin, a clinically important biomarker to aid in the diagnosis of heart attacks, was reported to the FDA.
    • Biotin can also interfere with commonly used assays for thyroid-stimulating hormone (TSH) and thyroid hormone (T4), as well as detection of anti-TSH receptor antibodies.
    • If a patient’s lab values don’t match the diagnosis, verify the results with lab personnel and rule out potential biotin interference with assays. Many lab assays do not use biotin-based analyzers.
    • Always “chart” any vitamins or nutraceuticals your patient takes.
    I frequently tell my Physician Assistant Sciences students to write prescriptions for everything a patient takes, especially for the over-the counter products. I always ask in a patient interview what OTC products they take, and when we see potent former prescription products like omeprazole, fluticasone nasal spray, cetirizine and ranitidine therapeutic decisions must based on what the patient is taking.

    If it is not charted, how will a clinician know? Vitamin therapy should always be charted, we know the classic interactions between calcium supplements and tetracycline, ferrous sulfate and levothyroxine, and magnesium and fluoroquinolones. These interactions between the divalent and trivalent cations with these drugs is well documented.

    On November 28, 2017 the FDA handed out a Safety Communication #586505 that warned about the interference of lab assays with biotin based analyzers. There are many well know references that discuss all the lab interferences.

    I printed those assays out and our lab techs at Empower-3 clinic spent the morning diligently combing through all of their testing materials to see if there were any biotin-streptavidin assays. They found none. So, at that clinic we don’t need to be concerned about biotin interference, but other labs might be using that technology. Always best to chart vitamins, especially if they are taking biotin.

    Have a great day on the bench!!

    Getting nauseated from pregnancy? Getting headache from kung pao chichen? Got kidney stones? Vitamin B-6 might be the answer!

    Pyridoxine (B6)

    Sources:
    meat, fish, legume, dry yeast, potatoes and other starchy vegetables and non-citrus fruits. Function: as a coenzyme for a variety of essential reactions in the metabolism of certain amino & fatty acids. Vitamin B6 in coenzyme forms performs a wide variety of functions in the body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism

    Deficiency States:
    may lead to anemia, convulsions in infants, cheilosis (cracked lips), seborrhea like skin reactions and neuropathy. As with riboflavin, the deficiency state consists of rather diffuse symptoms, probably no wonder that Casimir Funk didn’t discover this B vitamin. Dialysis patients, and those deficient in other B-vitamins are more likely to express symptoms of Vitamin-B-6 deficiency. Health benefits conferred by ODA: may alleviate PMS symptoms, improves mood, decreases risk of heart disease, and stimulates immune system. Possibly decrease nausea of pregnancy.

    Treatment of Nausea of Pregnancy:
    Remember Bendectin? It was that combination of pyridoxine/doxylamine that was pulled from the market in the early 1980’s. Both drugs are Pregnancy Category-A, but Merrill Dow grew tired of defending claims in court. The same formulation is available as DICLEGIS: a fixed dose combination drug product (Delayed-release tablets containing 10mg doxylamine succinate and 10 mg pyridoxine hydrochloride. Diclegis dosage: Take two tablets daily at bedtime. The dose can be increased to a maximum recommended dose of four tablets daily (one in the morning, one mid-afternoon and two at bedtime) (cost: almost $600.00/ 100 tablets). The American Congress of Obstetrics and Gynecology (ACOG) recommends monotherapy with 10–25 mg of vitamin B6 three or four times a day to treat nausea and vomiting in pregnancy. If the patient’s condition does not improve, ACOG recommends adding doxylamine. Patients can find doxylamine under the brand name of Unisom SLEEPTABS 25mg, and have patients split in half. Make sure they are the SLEEPTABS, and not other Unisom formulations that contain diphenhydramine.

    Supplement B-6 with the following drugs that DEPLETE Vitamin B-6:
    • Isoniazid- to decrease peripheral neuropathy
    • Birth Control pills
    • Long Term corticosteroid use
    • Loop diuretics
    • Phenytoin, carbamazepine
    B-6 and Chinese Restaurant Syndrome:
    Proper metabolism of Monosodium Glutamate (MSG) requires sufficient vitamin B6. Supplementation may eliminate symptoms which often include headache, skin flushing, and sweating.

    Kidney stones:
    Vitamin B6 and magnesium supplementation can prevent calcium oxalate kidney stones in patients predisposed to forming these stones

    Early on in my career, we would dispense LAROBEC, which was a combination vitamin that did not contain Vitamin-B-6 due to the interaction of B-6 with oral Levodopa. It is suggested that pyridoxine accelerates systemic metabolism of levodopa, thereby decreasing availability of the amino acid to pass the blood brain barrier. Pyridoxine reduced the levels of plasma levodopa by two thirds. The combination of levodopa and carbidopa (Sinemet, Rytary) prevents the loss of levodopa effect produced by exogenous pyridoxine, so this interaction is no longer clinically significant.

    When we examine the cost savings of over $600 between Diclegis® versus Vitamin B-6 and Unisom SLEEPTABS, pharmacists and prescribers can really impact the costs of health care. We do it every day behind the counter; expertise in the vitamin aisle can also present opportunities for us as well.

    Have a great day on the bench!!

    November 2018

    Another one of Casimir Funk's vitamins... NIACIN

    Niacin (Vitamin B-3)

    Dietary sources: meat, fish, legumes, whole grains. Grains are supplemented with micronutrients such as thiamin, riboflavin, niacin, iron and folic acid.

    Function: oxidation reduction reactions it is an essential co-enzyme for many dehydrogenases in Krebs cycle. Lipid & protein metabolism.

    Deficiency states are rare, due to the presence in most of the foods we ear. Niacin deficiency causes Pellagra “translation: rough skin”. Primary symptoms involve the 3 D’s of Pellagra: Dermatitis, Diarrhea, Dementia.

    Health benefits conferred by Optimal Daily Allowance (ODA) : decreases cholesterol & triglycerides. Decreases risk of heart disease (?)

    Adverse effects: flushing, GI upset, and may increase blood sugar levels. The “flushing” is similar to a hot flash, and is driven by prostaglandins. This flushing can be blocked by taking an Aspirin 325mg tablet one hour before the dose of niacin. Acetaminophen (Tylenol) does NOT work.

    Supplemental doses: 50mg, 100mg, 250mg & 500 mg (immediate release release)
    • No Flush niacin (inositol hexaniacinate) not as effective for hyperlipidemia
    • At doses over 1 gram per day, Niacin will increase the chances of rhabdomyolisis, if a patient is currently taking a statin. Use only if benefits outweigh the risks
    • OTC-Niacin: The immediate-release niacin formulations are more likely to cause flushing, especially first dose. Long-acting niacin Slo-Niacin (long acting niacin) is more likely to cause liver problems. Don’t recommend it for hyperlipidemia.
    Let’s discuss prescription Niacin extended release:
    • Niaspan® (Rx only) is an extended release prescription product that is used for hyperlipidemia, with minimal risk for liver dysfunction. Has fallen out of favor since September 2014. AIM-HIGH study: was stopped 18 months early because interim analysis showed lack of benefit of simvastatin/niacin vs simvastatin alone.
    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 does not improve outcomes.

    Patient Education for niacin therapy:
    • Cutaneous flushing- may be managed with Aspirin 325mg 1 hour before dose.
    • Take with food or light snack to decrease GI upset.
    • 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.
    SAFETY: For every 1000 patients treated for about 4 years with a statin plus niacin ( + aspirin), about 18 more will develop diabetes and 37 more diabetics will have worse glycemic control, compared to patients on a statin alone. Knowing that hyperlipidemia and diabetes go hand-in hand, this hardly seems a good trade-off.

    RECOMMENDATION: Niacin is associated with stomach upset, diarrhea, rash, muscle pain, and flushing with possibly more infections and GI bleeding. If they have low LDL and stable cardiovascular disease recommend stopping the Niacin

    The latest on Niacin: Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) study showed a form of vitamin B3 (niacinamide) showed a reduction in the risk of skin cancer of 23%. The though is that niacinamide may help repair sun-damaged skin and prevent immune suppression in the skin after sun exposure.
    • Dose is 500mg BID if they have non-melanoma skin cancer. Reduces risk by 1 lesion per year. No proof of efficacy if patient does NOT have skin cancer.
    • Keep recommending proper application of sunscreen and protective clothing.
    “Urban Legend”:
    No scientific evidence indicates that taking niacin can alter a urine drug test result. However, readily accessible information on the Internet lists ingestion of niacin as a way to prevent detection of tetrahydracannabinol (THC), the main psychoactive ingredient of marijuana. High dose niacin, may cause liver toxicity.

    As we journey through the water-soluble vitamins, lets focus on Niacin (Vitamin B-3) which is available both as an extended release prescription product, as well as over the counter in our vitamin aisles. Niacin (B-3) is one of the vitamins discovered by Casimir Funk. In the early 1900’s this condition was common in the southern United States due to diets being heavy in corn-based products. United States Surgeon General Joseph Goldberger observed the link in pellagra and orphanages and mental hospitals. In 1926 he established a diet that supplemented Brewers yeast to correct this deficiency. Pellagra can also occur in populations that are homeless, alcoholic or psychiatric patients who refuse food.

    Here's a word that we don't use in our daily conversation: NIXTAMALIZATION: which is a process the ancient Aztecs and Mayans used when processing corn (maize). By cooking the corn in a lime solution, it would free up the bound niacin in the corn kernel, and allow it to be absorbed. This is how the Central America Indian populations ate a corn based diet, but didn't suffer from pellagra. Over 90% of the niacin in corn is bound up, and is not absorbed unless the corn is nixtamalized.

    Have a great day on the bench!!

    Riboflavin does more than turn your pee neon yellow!

    Vitamin B-2 (Riboflavin)

    Function of riboflavin:
    Function: central component in a number of enzyme systems. Acts as a cofactor for various respiratory flavoproteins.

    Dietary sources: milk and eggs, meats, fish, green vegetables, yeast, and enriched foods such as fortified cereals and breads. Grains have been fortified with B vitamins since the 1950’s. Folic acid was added to the grain fortification program in 1998 to prevent neural tube defects. Because riboflavin is light sensitive, milk is usually commercially sold in an opaque container.

    Deficiency States: Riboflavin deficiency is extremely rare in the United States. In addition to inadequate intake, causes of riboflavin deficiency can include endocrine abnormalities (such as thyroid hormone insufficiency) and some diseases.
    • Cheilosis: (inflamed lips) cracks and sores at corners of the mouth
    • Stomatitis (inflammation of oral mucosa)
    • Ophthalmologic: Corneal Vascularization, amblyopia, dimness of vision without detectable lesions of eye
    • Sebaceous dermatosis
    Potential riboflavin deficiency states:
    • Patients with anorexia nervosa
    • Very rarely, inborn errors in metabolism of riboflavin dependent enzymes
    • Maladaptive syndromes including celiac disease
    • Long term phenobarbital use may speed up oxidation of riboflavin
    • Lactose intolerant patients who avoid dairy products.
    Migraine Prophylaxis:
    Many neurologists will try first line for migraine prophylaxis. A few small studies found evidence of a beneficial effect of riboflavin supplements on migraine headaches in adults and children. In a randomized trial in 55 adults with migraine, 400 mg/day riboflavin reduced the frequency of migraine attacks by two per month compared to placebo. Riboflavin is available over the counter in 100mg tablets.

    Drug interactions/Adverse effects: minimal. Not toxic due to limited GI absorption. This is the vitamin that turns your urine a bright yellow a couple hours after ingestion.

    Riboflavin (Vitamin-B-2) was not one of Casimir Funk's discoveries, probably because of it's non-specific symptoms in a state of deficiency. Although most of our patients get adequate riboflavin intake from their diet, we dispense a fair amount or riboflavin.

    Most of our neurologists will start a patient on riboflavin (200mg-400mg/day) along with magnesium oxide 400mg twice a day. In high doses the magnesium can cause diarrhea. Due to limited gastrointestinal absorption of riboflavin excessive doses rarely cause harm.

    Have a great day on the bench!!

    Thiamine: necessary for select groups of patients.

    Vitamin B-1 (Thiamine) (also spelled “thiamin”)

    Function of Thiamine:
    Function: precursor for thiamine pyrophosphate, which is a coenzyme required for carbohydrate oxidation. Thiamine plays a role in nerve conduction.

    Deficiency States:
    Also associated with malabsorption, dialysis, and protein-calorie under nutrition. In addition to insufficient intakes of thiamine from the diet, the causes of thiamine deficiency include lower absorption or higher excretion rates than normal due, for example, to certain conditions (such as alcohol dependence or HIV/AIDS) or use of some medications
    • Dry beriberi: nervous system deficiency resulting in a degenerating neuropathy characterized by neuritis, paralysis, and atrophy of muscle. Some patients develop “Wrist drop” and marked wasting of lower extremities. Accompanied by low calorie intake and inactivity. Heavy alcohol intake may cause Wernicke’ encephalopathy & Korsakoff’s psychosis.
    • Wet beriberi: involves cardiovascular system, resulting in edema, partly due to myocardial insufficiency, palpitations, tachycardia, and abnormal EKG. Accompanied by severe physical exertion, and high carbohydrate intake. Has marked peripheral vasodilation.
    Alcoholics:
    Most thiamine deficiencies in the US are due to alcoholism. Chronic alcohol use disorders appear to be the most common cause of thiamine deficiency. Up to 80% of people with chronic alcoholism develop thiamine deficiency because ethanol reduces gastrointestinal absorption of thiamine, thiamine stores in the liver, and thiamine phosphorylation.

    People with alcoholism tend to have poor nutritional intake and therefore inadequate intakes of essential nutrients, including thiamine. Wernicke-Korsakoff syndrome is one of the most severe neuropsychiatric sequelae of alcohol abuse. The “triad of Wernicke” symptoms are: encephalopathy, oculomotor dysfunction and gait ataxia. All patients with alcohol abuse should be supplemented with thiamine.

    Other patient groups prone to thiamine deficiency:
    • Patients with HIV/AIDS
    • People with Type-1 and Type-2 diabetes have 75% less thiamine levels (increase renal clearance)
    • People with gastric bypass surgery
    • Furosemide (Lasix®) increases the clearance of thiamine from the kidneys leading to deficiency.
    • Other intake deficiencies: dieting, starvation hyperemesis of pregnancy
    How much Thiamine should I recommend?
    Dosing of Thiamine (Vitamin B-1):
    • Dietary requirements for thiamine are only 1 to 2 mg daily, absorption and utilization of thiamine are incomplete, and some patients have genetically determined requirements for much larger dose. Most over the counter once daily vitamins contain 1.5 mg of thiamine.
    • Most patients are started on IV thiamine in the hospital.
    • After discharge daily oral administration of 100 mg of thiamine (Vitamin B-1), is recommended until the patient is no longer at risk.


    Thiamine is the first vitamin we will study that Casimir Funk discovered. Funk experimented with extracts made from the dark outer coating of rice that was removed during polishing. He found that there was a substance within that coating that cured beriberi.

    He experimented with pigeons by feeding them polished rice (rice without the hulls). The pigeons got sick and showed signs of beri-beri. When Funk fed them an extract from the rice hulls, he reversed the beri-beri. Knowing that the pigeons were given adequate protein he knew it was not a protein deficiency. In 1936 Dr Funk was able to elucidate the structure of thiamine.

    Three more of Funk's vitamins left to study!

    Have a great day on the bench!!

    Out in the vitamin aisle are a LOT of questions, and our patients are counting on our expertise!

    Last week we covered the regulation of vitamins, this week as we continue “Vitamin Boot camp” we will do an overview of these amazing compounds that sit out front on the shelves of our stores. The first question we will answer is “what does a vitamin do?” Vitamins in general work in the body by 3 different mechanisms:

    Who takes them:
    1. Coenzymes: Most water soluble vitamins are co¬enzymes. Remember in biology we learned that an enzyme is a catalyst for biochemical reactions. Co-enzymes are non-protein compounds that are necessary for the functioning of an enzyme.
    2. Antioxidants (Vitamin A, C & E)- are enzymes or other organic substances, that are capable of counteracting the damaging effects of oxidation in animal tissue. They protect tissues from damage by “free radicals”
    3. Hormones (Vitamin A, D, K are hormones) A hormone by definition is internally secreted compound, that affect the functions of specifically receptive organs or tissues when transported to them by the body fluids.
    The next question becomes; how much should I recommend for a patient?
    1. RDA: (Recommended Daily Allowance) is the level of intake of essential nutrients that are considered adequate to meet the known nutritional needs of practically all healthy patients.
    2. The DRI (Dietary Reference Intake) also include other reference values such as the Estimated Average Requirement (EAR) , and Adequate Intake (AI). The RDA, EAR, and AI all define nutritional intake adequacy. These are all for healthy individuals.
    3. The Dietary Reference Intakes (DRI) also includes the tolerable upper intake level of vitamins (UL). The UL is defined as the highest level of intake of a nutrient that will not pose risk of adverse health effects to most individuals in the general population.
    Vitamin deficiencies… not so much in America, in the USA will see syndromes of vitamin excess rather than deficiency, especially with vitamins A, D, B-6. Vitamin deficiency is usually insidious in nature, with rather non-specific symptoms. Therefore, a physical exam is rarely helpful in diagnosis. Most characteristic physical findings are seen late in the course of the syndrome. For example, swelling of the tongue (glossitis) and dry scaling and cracking of the lips (cheilosis) are seen with deficiencies in many of the “B” vitamins. These abnormalities suggest a nutritional deficiency, but NOT for a specific nutrient.

    The following chart is the MDR and dietary sources for the vitamins.

    VITAMIN MDR-adults Dietary Sources
    Thiamine (vitamin B1) 1.2mg/day Peas, pork, legumes, whole grains
    Riboflavin (vitamin B2) 1.1-1.3mg/day Liver, eggs, dark greens, whole grains
    Niacin (vitamin B3) 14-16mg/day Liver, fish, poultry, meat, whole grains
    Pantothenic acid (vitamin B5) 5mg/day liver, kidney, meats, egg yolk, whole grains, and legumes.
    Pyridoxine (vitamin B6) 1.3mg/day Pork, meats, whole grains, greens.
    Biotin (vitamin B7) 30mg/day liver, kidney, egg yolk, milk, most fresh vegetables, grains
    Folic acid (vitamin B9) 400mcg/day Liver, meats, fish, whole grains, legumes citrus
    Cobalamin (vitamin B12) 2.4mcg/day meats, liver, kidney, fish, eggs, milk and milk products, oysters, shellfish
    Ascorbic acid (vitamin C) 75-90mg/day Plant foods; citrus is highest
    Vitamin-A 3000iu (men)
    2300iu (women)
    fish liver oils, egg yolks, green leafy & yellow vegetables
    Vitamin-D 600iu fish liver oils, egg yolk, fortified milk, synthesized in skin exposed to UV light
    Vitamin-E 22.5iu Vegetable oils, wheat germ, leafy vegetables, egg yolk, margarine, legumes
    Vitamin K 120mcg leafy vegetables, vegetable oils, liver, & synthesis by intestinal flora


    Casimir Funk (1884-1967), a Polish biochemist who is credited with formulating the concept of vital amines, which today we call “vitamins”, and matching them to their deficiency disorders. In 1912 Dr. Funk wrote a book postulating that the diseases of beriberi, scurvy, pellagra, and rickets could be prevented with “vitamines”. He realized that poor nutrition, specifically white rice, lead to disease states which could be manage with appropriate nutrition, such as brown rice.

    He is considered the Godfather of the vitamin movement. We have sections in our drug stores that are there due to the efforts of this little recognized researcher, who never received the Nobel prize. Dr Funk elucidated the causes, and therefore the management of four disease states, and was never appropriately honored for his efforts.

    Have a great day on the bench!!

    Hey doc? Which one of these vitamins should I take??

    Vitamins--does everyone need them?

    Who takes them:
    • More than one-half of Americans take multiple vitamins either single entity or multivitamins
    • 70% of adults over the age of 65 report taking a vitamin or mineral supplement.
    • Total spent is $12 billion per year.
    • About one in four young children takes an MVM.
    • Adolescents are least likely to take them.
    Who regulates them:
    The FDA loosely regulates dietary supplements, under the Dietary Supplement Health and Education Act of 1994 (DSHEA ’94).
    In June 2007, FDA established dietary supplement "current Good Manufacturing Practice" (cGMP) regulations requiring that manufacturers evaluate their products through testing identity, purity, strength, and composition. Dietary supplementary are: vitamins, minerals, other botanicals, amino acids, enzymes, organ tissues, glandular, and metabolites. These dietary supplements fall under the category of "foods" and not "drugs".

    They do NOT need FDA approval before marketing nor do they need to be registered with the FDA before being produced or sold. The manufacturer does not have to prove that the supplement is effective, unlike for drugs. The manufacturer can say that the product addresses a nutrient deficiency, supports health, or reduces the risk of developing a health problem, if that is true. If the manufacturer does make a claim, it must be followed by the statement “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.”

    FDA regulates the label content and health claims. Claims that can be used on food and dietary supplement labels fall into three categories: health claims, nutrient content claims, and structure/function claims. Here are some examples of permissible supplement claims:
    • “Supports a healthy immune system”
    • “Builds strong bones”
    • “Maintains bowel regularity”
    • “Decreases blood platelet stickiness”
    • “A good source of Vitamin-C”
    Notice no disease state is mentioned, such as “prevents osteoporosis”, or “prevents stroke”. Burden of proof is on the FDA to prove that a supplement is Unsafe, before that product can be removed from the market. It is the responsibility of the manufacturer to ensure product safety and product efficacy.

    Reporting by patients and manufacturers:
    Starting December 22, 2007, any serious adverse events reported to a dietary supplement manufacturer must be reported to FDA within 15 days of the manufacturer receiving the adverse event report. Adverse drug events can also be reported directly to the FDA via the MedWatch program. https://www.fda.gov/Safety/MedWatch/default.htm

    For the next couple of months, we will journey through our vitamin aisle. We are expected to have a high level of expertise with vitamins. Unfortunately, our level of training with respect to over the counter therapies taught in pharmacy school is minimal. I’ll be providing you with the therapeutic uses of each vitamins, as well as uses for vitamins as therapeutic agents. We will also focus on vitamin depletion caused by the prescription products we commonly dispense. I’m not a “vitamin nut” I believe appropriately recommended vitamins are of great value to our patients. Next week we can discuss “at risk” populations and therapeutic dosing of vitamins and supplements.

    Good resource to read:
    https://www.hopkinsmedicine.org/health/healthy_aging/healthy_body/is-there-really-any-benefit-to-multivitamins

    Have a great day on the bench!!

    October 2018

    SERMS- very specific targets in the woman's body.

    As we move through the month of October, we are discussing women’s health issues. The first three units we discussed breast cancer. Last week we discussed raloxifene and tamoxifen, which are SERMS (selective estrogen receptor modifiers). Estrogen receptors are present throughout the body. SERMs act as agonists or antagonists on various estrogen tissue receptors, including breast, bone, endometrium, hypothalamus and coagulation system. We will discuss in detail the three other SERMS, not associated with breast cancer prevention.
    • Nolvadex® (tamoxifen): (BREAST CANCER PREVENTION)is considered first line therapy of estrogen receptor positive breast cancer. Both for pre-menopausal and post-menopausal women. (No effect on vaginal tissue)
    • Evista® (raloxifene): (BREAST CANCER PREVENTION/OSTEOPOROSIS) is for reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis OR if at high risk for invasive breast cancer. (No effect on vaginal tissue)
    Osphena (ospemifene) (DYSPAREUNIA) 60mg tablets
    Dose: take (1) tablet daily
    Mechanism: estrogen agonist on vaginal tissue. Minimal effect in uterine tissue and serves as an estrogen antagonist in breast tissue. Ospemifene may have a positive effect on bone tissue. Up to 45% of postmenopausal women can experience vulvovaginal atrophy due to estrogen loss.
    Indications: approved by the FDA to treat moderate to severe dyspareunia (painful intercourse), due to estrogen deficiency of menopause.
    Watch for: May make hot flashes worse. Scan for CYP4503A4 interactions
    NOTES: expect about 45% of postmenopausal women to experience vulvovaginal atrophy (VVA) due to declining estrogen levels. Symptoms of VVA may include dryness, itching, irritation, and dyspareunia. Diagnosis of VVA is based on symptoms as well as various laboratory findings. Vaginal lubrication decreases and vaginal pH increases. One of the best indicators of VVA is a pH of 5 or higher. On a cellular level, increases in the number of parabasal cells are seen as well as a decrease in the superficial cell layer.
    USE: being promoted for its estrogenic effect on vaginal symptoms.

    Duavee®: (conjugated estrogens/ bazedoxifene) (MENOPAUSAL SYMPTOMS)
    Use: moderate to severe hot flashes and preventing osteoporosis. Estrogen is used for menopausal symptoms & osteoporosis. Bazedoxifene (SERM) is added to inhibit estrogen's endometrial effects (instead a progestin). Must have intact uterus, because SERM reduces risk of endometrial hyperplasia.
    BEST USE: women who want to use estrogen for menopausal symptoms but need an alternative to a progestin.

    Clomifene (Clomid):
    (FERTILITY) is a nonsteroidal estrogen receptor modulator (SERM). It inhibits the negative feedback response on the hypothalamus by bonding to estrogen receptors. This causes an increase in release of FSH (follicle stimulating hormone) and LH (luteinizing hormone). This promotes follicular growth and maturation. Enhancement of the natural hypothalmic-pituitary-ovarian axis is the primary mechanism of action.
    Dosage: 50mg daily beginning day 5 of the cycle.

    The first SERM available was (Clomid (Clomifene) which was first approved in 1967. Clomid was the first ever drug to "enhance" fertility. It increases the odds of pregnancy from 1.3% to 5.5% per cycle.

    Nolvadex (tamoxifen) was released in 1977 for prevention of breast cancer. It wasn't until 1997 when another SERM became available, Evista (Raloxifene) for osteoporosis. Both Duavee (bazedoxifene) and Osphena (ospemifene) were released in 2013.

    Have a great day on the bench!!

    Breast Cancer Prevention medications available in the community pharmacy

    For the month of October our focus is on breast cancer its diagnosis and prevention. This week we discuss our role as community pharmacists in the treatment with drug therapy. Here is a brief review of the two main classes of drug therapy, along with counseling points for those therapies.

    Role of Anti-Estrogens: (SELECTIVE ESTROGEN RECEPTOR MODULATORS)

    For breast cancer that is estrogen receptor positive, ANTI-Estrogens are the mainstay of treatment. Antiestrogens bind to estrogen receptors and prevent receptor mediated gene transcription, and are therefore used to block the effect of estrogen on the end target. 70-75% of Breast cancer tumors are estrogen receptor positive.

    Nolvadex® (tamoxifen): available as tablets 10 & 20mg is an estrogen antagonist, structurally related to the synthetic estrogen diethylstilbestrol (DES) and is considered first line therapy of estrogen receptor positive breast cancer. Tamoxifen is the only “anti-estrogen” that can be used for BOTH pre-menopausal and post-menopausal women.

    Side effects include: hot flashes, nausea, skin rash, vaginal bleeding, hypercalcemia, increased bone pain if tumor has metastasized to the bone. Thrombotic events (PE and DVT) cataract formation, uterine cancer.

    Dosage: Breast cancer patients: 20-40mg daily (divide dose if more than 20mg) High risk women: use 20mg daily for 5 years.

    Evista® (raloxifene) Available as tablets: 60mg
    Dosage: 60mg once daily
    Indications: Reduction in risk of invasive breast cancer in postmenopausal women with Osteoporosis OR if at high risk for invasive breast cancer.

    Adverse effects: Venous thromboembolic potential. (PE, DVT, stroke). May cause hot flashes, muscle aches & pains.

    Mechanism: binds to estrogen receptors. Binding results in activating some and blocking other pathways. Effects on bone similar to estrogen therapy. However, it acts as an antagonist on receptors in the breast and endometrium.

    Efficacy: seems to be less effective than Tamoxifen for breast cancer treatment.

    ROLE of Aromatase Inhibitors for prevention of Breast Cancer
    In postmenopausal women and women whose ovaries have been removed, the main source of estrogen is derived from the peripheral conversion of androstenedione produced by the adrenal gland into the female hormones estrone and estradiol. This conversion requires the aromatase enzyme, which also catalyzes the conversion of androgens to estrogens in the ovary of pre-menopausal women and in extra-glandular tissue, including the breast itself, in post-menopausal women. Aromatase inhibitors effectively reduce the levels of circulating estrogens. Indicated only for post-menopausal women.

    Side effects: hot flashes, infrequent vaginal bleeding, do not predispose to endometrial cancer. All these drugs are available generically and are rather inexpensive therapies.
    • Arimidex® (anastrozole) available as 1mg tablets dosed once daily.
    • Femara® (letrozole) available as 2.5mg tables dosed once daily.
    • Aromasin® (exemestane) available as 25mg tablets dosed once daily after a meal
    Counseling points for breast cancer during drug treament:
    • Drug therapy is used following “adjuvant therapy” which consists of surgery & radiation to “clean up” cancer cells that may have spread beyond breast
    • Goal of hormonal therapy is block estrogen’s growth promoting effect. Continue anti-estrogen therapy for 5 years—patient adherence is paramount!
    • Tamoxifen and aromatase inhibitors are first line. Remember that only tamoxifen can be used in pre-menopausal women.
    • Hot flashes are most common side effect.
    Aromatase inhibitors cause less hot flashes that Tamoxifen. SSRI/SNRI’s may be of benefit: Effexor® (venlafaxine) & Celexa® (citalopram) are best choices.

    Avoid Prozac® (fluoxetine), Cymbalta® (duloxetine), Wellbutrin® (bupropion) & especially Paxil® (paroxetine) because they decrease formation of active metabolite of tamoxifen, decreasing efficacy of tamoxifen.
    • Teach patients symptoms of venous thromboembolism (tamoxifen side effect):
      • Shortness of breath
      • Chest pains worsen with breathing or coughing.
      • Coughing up blood
      • Pain, tenderness, swelling, warmth, redness in one leg
    • Aromatase inhibitors may cause significant bone loss. Osteoporosis and fractures have been reported. Treat accordingly- drugs like Alendronate (Fosamax®) are a good choice.
    We pharmacists should always be preaching adherence for all medications, be it for an antibiotic for a urinary tract infection, or for Type-2 diabetes medications.Adherence for these drugs for the prevention of breast cancer are critical indeed. According to a study women on tamoxifen with an adherence rate of less than 80% (determined by prescription records) had an increased risk of mortality at a median duration of 2.4 years. Adherence makes a huge difference for the breast cancer prevention with tamoxifen or the aromatase inhibitors.

    Missing just 6 doses a month can be cause a significant rise in mortality. Recommend any of the adherence apps on a patients phone, set an alarm, and recommend using a plastic pill box to improve adherence. I also recommend enrolling any of these breast cancer patients in your pharmacy's medication synchronization program.

    Have a great day on the bench!!

    More than wearing a pink ribbon... share this information with your patients (guys too!)

    Prevention--Mammograms save lives The newest recommendations from the American Cancer Society recommends all women should begin having yearly mammograms at age 45 and can change to having mammograms every other year beginning at age 55. Women should talk to their health professional if they have any symptoms or changes in their breasts, or if breast cancer runs in their family. Some patients as young as 40 years of age can begin annual mammograms.

    Breast Self-Exams- a smaller role in decection
    Breast self-exam (BSE) is an option for women starting in their 20s. Women should be told about the benefits and limitations of BSE. Women should report any breast changes to their health professional right away. Benefits of breast exam is minimal whether performed by a health care provider or the patient. Research has shown that BSE plays a small role in finding breast cancer compared with finding a breast lump by chance or simply being aware of what is normal for each woman. Some women feel very comfortable doing BSE regularly (usually monthly after their period) which involves a systematic step-by-step approach to examining the look and feel of one’s breasts. Other women are more comfortable simply feeling their breasts in a less systematic approach, such as while showering or getting dressed or doing an occasional thorough exam. Sometimes, women are so concerned about “doing it right” that they become stressed over the technique. Doing BSE regularly is one way for women to know how their breasts normally look and feel and to notice any changes. The goal, with or without BSE, is to report any breast changes to a doctor or nurse right away. Bottom line: The American Cancer Society does not recommend clinical breast examination (CBE) for breast cancer screening among average-risk women at any age. (source JAMA)

    Common Types of Breast Cancer
    Ductal carcinoma. The most common kind of breast cancer. It begins in the cells that line the milk ducts in the breast, also called the lining of the breast ducts. Ductal carcinoma in situ (DCIS). The abnormal cancer cells are only in the lining of the milk ducts and have not spread to other tissues in the breast. Has a higher risk of subsequent invasive cancer. Invasive ductal carcinoma. The abnormal cancer cells break through the ducts and spread into other parts of the breast tissue. Invasive cancer cells can also spread to other parts of the body. Lobular carcinoma. In this kind of breast cancer, the cancer cells begin in the lobes, or lobules, of the breast. Lobules are the glands that make milk. Lobular carcinoma in situ (LCIS). The cancer cells are found only in the breast lobules. Lobular carcinoma in situ, or LCIS, does not spread to other tissues. Invasive lobular carcinoma. Cancer cells spread from the lobules to the breast tissues that are close by. These invasive cancer cells can also spread to other parts of the body

    Reducing Risk of Breast Cancer
    • Keep a healthy weight and exercise regularly (at least four hours a week).
    • Get enough sleep.
    • Don’t drink alcohol, or limit alcoholic drinks to no more than one per day.
    • Avoid exposure to chemicals that are carcinogenic
    • Reduce exposure to radiation during medical tests like mammograms, X-rays, CT scans, and PET scans.
    • Discuss with prescriber about hormone replacement therapy or oral contraceptives and the risks associated with therapy. Remember for estrogen replacement… lowest possible dose for shortest period of time.
    • Breastfeeding may be protective
    What about the guys? (source: American Cancer Society)
    • About 2,550 new cases of invasive breast cancer will be diagnosed in men in 2018
    • Treatment: mastectomy is indicated but follow-up with radiation or chemotherapy is not as definitive as it is for women. Most breast cancer in men is treated the same as in women.
    • About 480 men will die from breast cancer in 2018
    • Overall odds of a male getting breast cancer is 1:833
    • Overall odds of a woman getting breast cancer are 1:8
    • White males are 1/100th as likely to die of breast cancer compared to white women, while black men are 1/70th as likely as black women to die from breast cancer.
    Breast cancer treatment including surgery, radiation and chemotherapy have indeed become more specialized in the 37 years I've been practicing. At one time it was the realm of the general surgeon, while today there are surgeons who specialize in breast cancer surgery and reconstruction.

    Even the rural hospital in the small town of Tyrone where I live has its own breast cancer treatment center, with outstanding surgeons and radiologists. There are plenty of resources for our female (and male!) population in detection, prevention and treatment of breast cancers. It is our job as health care professionals to see that our patients are encouraged to use these available resources.

    Have a great day on the bench!!

    We need to do more for our female patients than just wear a pink ribbon!

    Breast Cancer Basics

    After skin cancer, breast cancer is most common cancer in women, causing more deaths than any malignancy other than lung cancer. The lifetime risk of developing breast cancer in women is 1 in 8 (13%). There was a 7% drop in breast cancer incidence in 2003, probably due to drop in Hormone Replacement Therapy due to publication of the Women’s Health Initiative (WHI) study in 2002. This study established that HRT increases risk of breast cancer.

    Breast cancer warning signs and symptoms
    • Breast lumps: Single painless mass that feels solid. Breast pain is not usually a symptom of malignancy, but it can occur.
    • Skin changes: areas of thickening, swelling, depression, dimpling, redness, irritation or unusual appearance on the breast or underarm.
    • Veins on surface of one breast have become more prominent.
    • Nipple discharge: bloody or watery from one nipple only is cause for most concern
    • Nipple changes: turning inward, rash, changes in nipple skin texture.
    • Breast cancer develops in the breast tissue, usually in the milk ducts (ductal carcinoma) or glands (lobular carcinoma)
    Factors that increase risk for breast cancer Risk factors for a 2-5 fold increase:
    • Age: 78% of women with invasive breast cancer are 50 or older
    • Inherited genetic mutations: Genes BRCA-1, BRCA-2 have a 60-85% chance of developing breast cancer.
    • Personal history: previous breast biopsy result of atypical hyperplasia increases risk 4 to 5 times
    • Women with breast cancer in one breast have a 3-4 times greater risk of developing a new cancer in the other breast, or the same breast..
    • High dose radiation the chest (Hodgkin’s disease treatment)
    • Family history: 1 first degree relative (mom, sister, and daughter) doubles risk. First degree relatives is 5 times the risk
    Risk Factors for a 1.1 to 2 fold increase
    • Race (white women are more susceptible)
    • Use of estrogen
    Current or recent use of HRT- risk returns to normal in 5 years after stopping hormone replacement.

    Use of oral contraceptives: no increase risk if stopped greater than 10 years ago Prolonged estrogen stimulation
    • Early menstruation (less than age 12)
    • Late menopause (over age 55)
    • Pregnancy: no children, or first pregnancy after age 30.
    • Lifestyle: alcohol consumption: greater than 3 drinks per day.
    • Obesity
    Breast cancer receptors:
    1. Estrogen: About 80% of breast cancers are estrogen receptor positive. Cancers grow in response to estrogen. Known as ER positive.
    2. Progesterone: About 65% of the estrogen receptor positive receptor positive breast cancers are progesterone receptor positive. Cancer grows in response to progesterone. Known as PR positive.
    3. Human epidermal growth factor receptor-2: (HER2) – is a protein which promotes the growth of cancer cells. Is not inherited from a parent. It accounts for about 20% of all breast cancers,and are the most rapid growing and aggressive cancers.
    Any of these three cancers are treatable, with specific therapy directed at the receptor to help destroy the rapid growing cells.

    And now for the really bad news:
    Triple-Negative Breast Cancer
    Between 10% and 20% of breast cancers are known as “triple negative” because they don’t have estrogen and progesterone receptors and don’t express the HER2 protein. Many breast cancers associated with the gene BRCA1 are triple negative.
    • There are currently no “targeted therapies”, so treatment includes surgery either lumpectomy or mastectomy, followed by chemotherapy or radiation. Chemotherapy is considered to be the “backbone” for TNBC therapy.
    • TNBC is more commonly diagnosed in women younger than 40 years compared with hormone-positive breast cancer. (twice the incidence in some studies versus hormone receptor positive)
    • African American women have a higher incidence than non-African American women.
    • Pre-menopausal women have a higher incidence than that of post-menopausal women
    • One study demonstrated that breast feeding women were at a lower risk for TNBC, however this study has not been duplicated.
    • Prognosis is poorer than women with other receptor positive cancers.
    With October being breast cancer awareness month, let's focus on our female patients, and provide them with sound, clinical information concerning breast cancer. Breast cancer awareness should be more than just using those "Breast Cancer Awareness" prescription bags, or wearing a pink ribbon.

    Let's pledge to provide our female patients with good information about breast cancer, and encourage them to get their mammograms. As pharmacists we can also do our part to encourage adherence to the medications prescribed for the treatment of the hormone positive breast cancers.

    Have a great day on the bench!!

    September 2018

    Is it time to get out the DDT? What to do when exposed to bedbug infestation!

    Bedbugs---what to do when they show up!

    Treatment of a bitten patient:
    • Treatment might not be necessary, as the bites usually resolve without any intervention.
    • Oral antihistamines to relieve itching
    • Prednisone, at doses of 40-60mg per day seem to be of little value.
    • Topical corticosteroids seem to be effective Use mild potency such as triamcinolone 0.1% cream on the bites.
    • May have to treat secondary infections.
    Prevention:
    • using a hair dryer on end seams of mattress will “chase” the bed bugs out of hiding for detection.
    • Check out hotel/motel rooms and look for bedbugs or their feces before climbing into bed. Be sure to check out the mattress cords and crevices in box springs.
    • Placement of luggage on a luggage rack or away from the bed or upholstered furniture while traveling. Some sources recommend placing luggage in the bathtub, as bedbugs can’t crawl up that slippery surface.
    • Placement of worn garments in a sealed plastic bag to minimize bedbug attraction to worn clothing.
    • It’s no bargain mattress even if the bedbugs are free! Examine carefully garage sales or resale shops (especially bedding items), for bedbugs or bedbug feces prior to bringing them inside the home
    • Rid Home Lice, Bedbug and Dust mite Spray: contains Permethrin 0.5% - might be of benefit to spray areas that are not directly slept on.
    Eradication of Bedbugs:
    Insecticides and heat treatment are the best options. Combinations of insecticides are generally used to avoid failure due to resistance. Long-lasting residual insecticides may be necessary for heavy infestations. Heat treatment involves use of equipment to heat rooms to a lethal temperature. All stages of bedbugs can be killed at 50°C (122°F) Cold treatment can be successful in the home environment if the freezer is set to 0- degrees F. You must leave the items in the freezer at that temperature for four days

    Your Friendly Exterminator says:
    (January 2011) We are using Pyrethrins; Also using heat—over 120 degrees will kill bedbugs. Bedbugs are attracted to carbon dioxide (CO2). We have CO2 machines that attract bedbugs, and then get trapped in plastic traps. Note: The EPA says Some bed bug populations have become resistant to pyrethrins and pyrethroids

    (August 2018):
    use Alpine WSG (Dinotefuran) to treat. This is a broad spectrum insecticide. The exterminator described a huge problem in Altoona Housing projects. He spends more time in the housing projects combating infestation than in hotels. Hotels deal immediately with the problem, and keep things cleaned up afterward. Such is not the case with the residents in the housing projects. Alpine WSG (dinotefuran) is a neonicotinoids are synthetic forms of nicotine and act on the nicotinic receptors of the nervous system by causing nerves to fire continually until they fail. Because neonicotinoids use this different mechanism of action, bed bugs that are resistant to other pesticides will remain susceptible to the neonicotinoid. (source: EPA)

    Permethrin spray that we use as a mosquito and tick repellent is designed for clothing and gear and lasts up to 6 weeks. We spray our hiking and gardening clothes every 6 weeks to keep the deer ticks off. Repellent should be applied outdoors and before clothing is worn; hang clothing, spray and let dry two hours (four hours in humid conditions).

    We also spray our suit cases with permethrin 0.5% before packing for a trip. Make sure they are closed. Package reads “for clothing and gear” , so it is appropriate to use on our suitcases. Seems like a good idea to keep these critters from hi-jacking a ride back to Tyrone, PA ! That hotel room you just checked into is only as clean as the last guests who left!

    Have a great day on the bench!!

    Wanna sleep tight? Make sure these little guys don't hitch a ride from the hotel to your bedroom! View this email in your browser

    BEDBUG BUG BASICS

    BEDBUGS (Cimex lectularius) are wingless insects about the size of an apple seed that feed on warm blooded animals. Bedbugs are nocturnal and hide during the day. Bedbugs are associated with unsanitary conditions but may be found in the cleanest of homes, hotels, or other buildings and have occurred in all social and economic classes. Infestations most often occur where there is a high turnover of occupants, such as hotels, motels, cruise ships, dormitories, apartment complexes, and shelters.

    The Care and feeding of bedbugs:
    • Bedbugs feed on a blood meal for about 10 minutes, injecting an anticoagulant. Females need a blood meal at least every 14 days to produce eggs. Females lay one to three eggs per day, and up to 500 eggs in a lifetime. Males also need a blood meal every 14 days to mate.
    • Unlike fleas or ticks, they do not live on their food source. They hide near their host, and bite during the night.
    • Adult bedbugs can live without feeding for 2 or 3 months which makes getting rid of them such a challenge. (Not like lice that are dead in 10 days without a human host)
    • Presentation: The bite reaction usually presents as a red bump (wheal) ranging in size from a few millimeters to 1 centimeter and does not usually have a red puncture mark in the middle. The bites can occur in lines or clusters of three or four.
    Where to look:
    Around the bed, they can be found near the piping, seams and tags of the mattress and box spring, and in cracks on the bed frame and headboard. If the room is heavily infested, you may find bed bugs:
    • In the seams of chairs and couches, between cushions, in the folds of curtains.
    • In drawer joints.
    • In electrical receptacles and appliances.
    • Under loose wall paper and wall hangings.
    • At the junction where the wall and the ceiling meet.
    • Even in the head of a screw.
    The role of DDT

    DDT’s history parallels closely the presence of bedbugs. DDT (dichloro-diphenyl-trichloroethane) was developed as the first of the modern synthetic insecticides in the 1940s. Initially used effectively to combat malaria, typhus, and the other insect-borne human diseases among both military and civilian populations. DDT was also effective for insect control in crop and livestock production, institutions, homes, and gardens. DDT was banned in 1972, was considered to be the first victory for the environmentalist movement.

    DDT is still present in the environment
    • will accumulate in fatty tissues, and
    • can travel long distances in the upper atmosphere
    • DDT is one of 12 pesticides recommended by the World Health Organization for indoor residual spray programs.
    Because of DDT use in the 1940’s, bedbugs were virtually eliminated. After the year 2001, they have made a resurgence, as the DDT has “worked out” of the environment.

    Next week we will discuss Treatment and Prevention of Bedbugs.



    I, Peter Kreckel of sound mind and body, bequeath this box of DDT to...

    When my father-in-law passed away back in 2012, I helped my wife Denise and her sisters clean out his garage. The garage was full of "treasures" like jars of nails, nuts, bolts, tools and even a bumper off of a Corvair! I left with the grand prize that I have pictured here, a box of unopened DDT, that back in the day retailed for $1.99 for a one pound box!

    I keep it in my garage, and my wife insists if a bedbug ever finds its way from a hotel into our house, she will be more than prepared to bring it to it's demise! I'm sure it will remain unopened, and when the day comes that Gretchen and her siblings clean out my garage, this family heirloom will move to the next generation!

    Good night, sleep tight and thanks to the DDT in my garage, the bedbugs won't bite!!

    Have a great day on the bench!!

    This should be the last column that leaves you scratching!

    SCABIES

    Caused by the mite: Sarcoptes scabei . Mostly affects the interdigital & popliteal folds, axillary folds, umbilicus & scrotum. Spread by direct, prolonged, skin-to-skin contact with a person who has scabies. Transmitted through direct contact, and frequently sexual contact. Can survive off a human host 24-36 hours under normal conditions of heat and humidity. Increased humidity prolongs survival off the host.

    Clinical presentation:
    • Severe itching and an inability to sleep.
    • Excoriations in the interdigital web spaces, wrists, buttocks, elbows groin & scalp.
    Diagnosis:
    • Look for burrows made by the mite, and skin scrapings. Short irregular mark, 2-3 cm long and the width of a hair.
    • The diagnosis of scabies is confirmed by detecting scabies mites, eggs, or feces with microscopic examination.
    Permethrin 5% (Elimite) DRUG of CHOICE available in 60 gm tubes

    Warnings/Precautions / Adverse Effects
    • Pregnancy category-B
    • Not recommended if nursing.
    • Can be used in children over age 2 months.
    • Caution with asthmatics.
    Patient Education
    • Thoroughly massage cream from the head to the soles of the feet. Rarely do scabies affect the heads of adults. They may infest the infants or geriatrics around the hairline.
    • Remove cream by washing off in bathtub or shower after 8 to 14 hours.
    • One application is generally curative. (30gm is sufficient for 1 adult)
    • Patients may experience itching after treatment, rarely a sign of treatment failure. Living mites after 14 days would indicate that re-treatment is necessary
    Crotamiton lotion 10% and Crotamiton cream 10%
    10% (Eurax®); Crotan® approved by the FDA for treatment of scabies, but due to frequent treatment failures is seldom used.

    Ivermectin (Stromectol®) may be a safe and effective treatment for scabies, although not FDA-approved for scabies. Consider for patients who have failed treatment with or who cannot tolerate FDA-approved topical medications for the treatment of scabies. If used for classic scabies, two doses of oral ivermectin (200µg/kg/dose) should be taken with food, each approximately one to two weeks apart.

    A patient weighing 75kg (165lbs) would take 15,000mcg or 15 mg. Dose would be five tablets as a single dose.
    (SHORTCUT: weight in pounds divided by 33 equals the number of 3mg tablets of ivermectin)

    Might be a good option for nursing homes, where head to toe treatment of each patient is impractical. After successful treatment, patients may continue to itch for several weeks.
    • A steroidal cream like Triamcinolone 0,1% cream will help resolve the dermatitis.
    • Short course of corticosteroids, like prednisone will also decrease itching.
    • Oral antihistamines like diphenhydramine (Benadryl) or hydroxyzine (Atarax) might be of some benefit to relieve itching.
    • If no relief of itching, recheck for reinfestation.
    Worst of the worst: Crusted scabies or “Norwegian scabies” — occurs only in people with a weakened immune system (such as HIV infection, lymphoma, or other conditions). This condition may also affect older adults or those with Down syndrome. Ivermectin or permethrin 5% are used to treat this condition. Lesions appear as large, crusty red patches or bumps on the skin.

    Scabies is another one of those dreaded skin conditions, that after reading this article will leave you scratching. A patient with ordinary scabies may have an average of 12 mites; however, those with crusted scabies (Norwegian scabies) may have thousands of mites. The infestation occurs at all ages, but particularly in children. It is a common public health problem in poor communities and is widespread in many underdeveloped countries.

    It can spend a maximum of only 2 weeks without a human host to live upon and when doing so hides out in clothing, bed linens and sleeping bags. Called the “seven year itch” because it used to wax and wane in about seven year epidemic cycles, the little critters are no longer sticking to that schedule and have become more difficult and resistant to former treatments.

    I love the shortcut for dosing the ivermectin. I can see that being very helpful if you had a large population to dose such as in a nursing home or large family.

    Vince, one of the excellent Physician Assistants I work with at Dr. Gates office, tells me he is a scabies expert because of his time serving in the U.S Army. When we see that scabies thrive in close quarters and can live in sleeping bags without a human host for 14 days, our servicemen are definitely at risk.

    Have a great day on the bench!!

    Those sneaky little head lice are becoming resistant to over-the- counter products!

    Prescription Products for Pediculosis

    OVIDE® (malathion)
    Mechanism: is an organophosphate cholinesterase inhibitor. Widely used as a lawn and garden insecticide. Has been on, and off the market for the past several years. Has “high” Ovicidal activity. This seems to be the “go to” product when concern of resistance to permethrins. Malathion was first registered as an insecticide in 1956. Became prescription product (Ovide®) in 1982.

    Warnings/Precautions /Adverse Effects
    • Flammable!! 78% alcohol. Do not expose to flame or hairdryers or electric curlers.
    • Don’t use if under age 6. May use down to 24 months if resistance is a problem. (AAP) The safety and effectiveness of malathion lotion has not been established by well controlled trials in children less than 6 years old. Malathion is contraindicated in children younger than 2 years of age.
    • Unpleasant odor, due to sulfhydryl groups
    Application Information:
    1. Avoid any open flames.
    2. Apply to dry hair, especially back of head and behind ears.
    3. Wash hands after application.
    4. Allow hair to air dry (no hairdryers!)
    5. After 8-12 hours wash hair with non-medicated shampoo
    6. Reapply in 7-9 days only if required.
    ULESFIA® (benzyl alcohol lotion)

    Mechanism: does not have ovicidal activity. It inhibits lice from closing their respiratory spiracles which allows the product to penetrate lice, causing them to asphyxiate. Can be used on age 6 months and older.

    Application Information: As with the other topical agents, two applications of Ulesfia, separated by at least seven days are necessary to eradicate lice. May be a good choice for parents concerned with “pediculicides” NOTE: because it suffocates the lice (a physical action), less likely to develop resistance to this product. I tell my students it is like an ant becoming resistant to a sledge hammer!

    NATROBA® (spinosad)

    One treatment is usually needed with Natroba ® Repeat in 7 days only if live lice are seen again.

    Mechanism: Spinosad causes neuronal excitation and involuntary muscle contractions in lice. After periods of excitation, the lice become paralyzed and die. Use in patients at least 6 months of age.

    Dosage: Apply to dry hair. Leave on 10 minutes. Rinse thoroughly. Combing not required.

    STROMECTOL (ivermectin) 3mg tablets (usual dose 200mcg/kg)

    Mechanism:
    Ivermectin binds to glutamate chloride channels in nerve and muscle cells of lice. This leads to an increased permeability to chloride ions resulting in paralysis and death. Based on this mechanism, it would appear that ivermectin is not ovicidal.

    Dosage: used for certain parasitic infections (off-label for scabies or lice) use 400mcg/kg. a 15kg child would take about 2 tablets. Repeat dose in 7 days to eradicate any newly hatched lice.

    SKLICE (Ivermectin topical)
    Can be used in patients 6 months of age and older.
    Completely coat hair. Leave on 10 minutes, then rinse well. No combing needed

    Lindane
    old brand name was Kwell®, now only as a generic. Second-line treatment.

    Mechanism: neurotoxic to head lice and their eggs.
    Indications: has fallen into disfavor because of potential toxicities, and its efficacy is LESS than other agents available. 45-70% ovicidal

    Warnings/Precautions /Adverse Effects/Drug Interactions
    • Patient MUST weigh at least 110 pounds.
    • Do not prescribe more than 2 oz. of product
    • Do not retreat.
    • Black box warning: neurological toxicity. Has caused seizures and deaths.
    • Avoid using in infants, children, and elderly. Must weigh over 110lbs.
    • Pregnancy category-C
    • Caution if using with drugs that lower seizure threshold (theophylline, Wellbutrin, quinolones, antidepressants, meperidine, methocarbamol)
    Trimethoprim-sulfamethoxazole —
    Combination therapy with topical permethrin (Nix) and oral trimethoprim-sulfamethoxazole (Bactrim) may be more effective than treatment with permethrin alone. The mechanism of action of trimethoprim-sulfamethoxazole may involve the death of symbiotic bacteria in the louse gut that produce B vitamins necessary for louse survival. This combo is 92% effective compared with only 72% efficacy with permethrin alone. By itself Trimeth/sulfa was shown to be 78% effective. With risks of Stevens-John Syndrome, and allergic reactions it is best to reserve this combo for resistant cases.

    Head Lice Chart

    Brand name Generic Name Minimum treatment age Ovicidal? (kills nits?) Major warnings/precautions
    Nix crème rinse Permethrin 1% 2 months of age and older Good activity resistance is becoming a problem
    RID/ A-200 Pyrethrins/pipronyl butoxide Over 2 years of age NO Retreat in 7-9 days. Avoid if allergic to chrysanthemums or ragweed.
    Ovide Malathion 0.5% Over 6 years of age.
    Contraindicated if under age-2 yrs
    Partially ovicidal Flammable. No hair dryers
    Ulesfia Benzyl alcohol 5% Over 6 months of age NO, it suffocates live lice Retreat in 7 days
    Sklice Ivermectin lotion 0.5% Over 6 months of age Prevents newly hatched nymphs from surviving. Single treatment only. No combing needed.
    Natroba Spinosad 0.9% Over 6 months of age Kills live lice and unhatched eggs Nit combing not required
    Lindane (Kwell) Lindane Must weigh over 110 lbs About 50% ovicidal Second line. Potent neurotoxin. (AVOID!)


    Last week we covered the OTC options for Head Lice Control. Although safe and effective, resistance is becoming a problem and sometimes the need to bring out the “big guns” to take care of those pesky bugs.

    Keep in mind though, a lot of treatment failures are due to inadequate environmental controls and are not so much as resistance as re-infestation. Other causes might be improper use of the products dispensed be it not completely covering the hair or not leaving the product on long enough.


    I was also amazed to learn about using trimethoprim/sulfamethoxazole (Bactrim) for head lice. I have not seen it used as a treatment for head lice, but after reading the literature, it might be an option as resistance keeps popping up. When DDT was banned in the 70's there was a scramble for insecticides to replace that very potent bug killer. My favorite extreme example of drug pricing going crazy is malathion. Malathion is frequently used as an insecticide around the home and garden, in a 50% strength, while the prescription strength is 1/100% as whet we can buy in a hardware store! Of course we cant recommend the lawn/garden product for human use, but this yet another example of how ridiculous the drug prices can be!!

    Have a great day on the bench!!


    Same ingredient, but when dispensed as a prescription the price goes up exponentially.
    ORTHO MALATHION IS NOT FOR HUMAN USE!!!

    August 2018

    We can treat those pesky head lice without a prescription!

    The first line therapy for head lice is over-the-counter...

    Permethrin 1% Crème rinse (NIX®):
    Made from a natural chrysanthemum extract, pyrethrins are neurotoxic to lice. Permethrin is a synthetic pyrethroid. Was first approved in 1986 by prescription and in 1990 was moved to over the counter. Is available as a 1% crème rinse, which is considered to be first line treatment for head lice. Mechanism: acts on the parasites nerve cell membrane. Resulting in paralysis of the pest. Remains on hair shaft for 14 days, despite normal shampooing. Can be used prophylactically, in “epidemics” where over 25% of the population (family, daycare, or classroom) is affected. Is 70-80% ovicidal. We are seeing an increase of resistance to permethrin. May be used for a child as young as 2 months.

    Directions for Permethrin creme rinse:
    1. Wash hair first, with regular shampoo.
    2. Towel dry briskly
    3. Apply a sufficient amount of permethrin crème rinse to saturate hair and scalp (especially problem areas)
    4. Let on hair for NO longer than 10 minutes.
    5. Rinse with water
    6. May reapply in 7 days if necessary. One application is generally curative. However, Permethrin’s adherence to the hair shaft can be affected by conditioners and silicone-based additives present in almost all currently available shampoos. This may impair efficacy of the crème rinse. Many experts routinely advise re-treatment on day-9.
    Piperonyl Butoxide (4%), Pyrethrum Extract (Equivalent to 0.33% Pyrethrins) (Rid®

    Brand: RID® and other generics are available over the counter
    Pyrethrins are naturally occurring pyrethroid extracts from the chrysanthemum flower. Pyrethrins are safe and effective when used as directed. Pyrethrins can only kill live lice, not unhatched eggs (nits). Piperonyl Butoxide/pyrethrin Lice Killing Shampoo is designed to be used on DAY ONE and then again 7 to 10 days later, but not before. To apply the shampoo, follow the directions on the package, including:
    1. Protect child's eyes—Use towels to protect child's eyes from treatment and prevent clothes from getting wet.
    2. Apply Piperonyl Butoxide/pyrethrin Lice Killing Shampoo—Apply thoroughly to DRY HAIR or other affected area. Wetting the hair dilutes the treatment making it less effective.
    3. Let set for 10 minutes—first apply behind the ears and to the back of the neck. Lice can crawl up and down the shaft of the hair very quickly, so it is important to apply the treatment from the roots to the ends of the hair. Allow product to remain on the hair (or other affected area) for 10 minutes, but no longer.
    4. PRECAUTION: A second treatment is recommended 9 to 10 days after the first treatment to kill any newly hatched lice before they can produce new eggs. Pyrethrins generally should not be used by persons who are allergic to chrysanthemums or ragweed. Piperonyl Butoxide/pyrethrin is approved for use on children 2 years of age and older.
    For all lice killing shampoos: All topical pediculicides should be rinsed from the hair over a sink rather than in the shower or bath to limit skin exposure and with warm rather than hot water to minimize absorption attributable to vasodilation. Removal of nits immediately after treatment with a pediculicide is not necessary to prevent spread, because only live lice cause an infestation. Individuals may want to remove nits for aesthetic reasons or to decrease diagnostic confusion. Because none of the pediculicides are 100% ovicidal, manual removal of nits (especially the ones within ½ inch of the scalp) after treatment with any product is recommended by some.

    RID LICE CONTROL SPRAY (permethrin 0.5%)
    Contains permethrin 0.5% (just like the tick repellant for clothing). Spray only those garments and parts of bedding, including mattresses and furniture that cannot be either laundered or dry cleaned. Most agree that this treatment is no more effective than a thorough vacuuming with a Shop-vac. Some sources recommend against using these insecticides at all. Viable nits are unlikely to incubate and hatch at room temperatures which are cooler than a human host; if they did, the nymphs would need to find a source of blood for feeding within hours of hatching. Next week we will discuss the prescription treatment of head lice infestations, and I’ll provide a summary treatment chart.

    Last week we covered the topic of head lice, and patient consultation points. This week's discussion focuses on the OTC recommendations we can use for the treatment of head lice. In this week's column are the directions, and counseling points to share with those “slightly” upset caregivers.

    Probably our first step is to always reassure the very upset parent, then provide all of the counseling points to insure a successful treatment. Be sure to share last week's column with those parents who seem to be full of misinformation.

    Help educate parents and schools that there's no medical reason to keep kids out of school after treatment. Explain that remaining nits or itching doesn't indicate treatment failure, only live lice do.

    Have a great day on the bench!!

    School opens soon--- time to "brush up" on our lice treatments!

    SEPTEMBER IS NATIONAL HEADLICE PREVENTION MONTH!!

    With school around the corner, one of the biggest concerns parents have is if their child brings home some unwanted friends, those being of the six-legged variety… head lice! This week we will cover the basics of head lice and next week we can cover the pharmacological treatment.

    PEDICULOSIS (LICE): Pediculosis is a skin infection caused by blood sucking lice. They are small flat wingless insects with stubby antennae and 3 pairs of legs that end in sharp curved claws.

    There are 3 major types of lice:
    • Head Lice : Pediculus humanus capitis
    • Body Lice : Pediculus humanus corporis
    • Pubic Lice: Pthirus pubis (note: different species than above)
    Life cycles of the human louse:
    • All lice need human warmth to survive.
    • Head and pubic lice spend their entire life cycle on the skin of human host.
    • Head & pubic lice deposit their eggs (known as nits) on hair strands, about 1/4th of an inch from the skin. Each louse develops from eggs (nits) that incubate 1 week. When the eggs hatch the nymphs appear the eggs are small and gray white.
    • Each louse survives about 1 month as a mature adult.
    • The female head louse can produce 3-6 eggs per day. Head lice nits can survive 10 days off a body.
    • Nits are easier to find than the live adults. Check around the back of the ears, and the nape of the neck (warmest parts of the body). Nits are cemented to hair shaft, unlike dandruff that can be brushed away.
    Non-Pharmacological treatment of lice:
    • Change clothing daily
    • All household contacts should be inspected and treat if necessary
    • Bed linens and clothes should be washed in hottest water (130degrees or hotter), and dried on heated air cycle for at least 20 minutes to kill both the lice and nits. Dry cleaning also kills head lice and nits. Only items that have been in contact with the head of the infested person in the 48 hours before treatment should be considered for cleaning.
    • Wash hairbrushes, combs, toys in hot water (130degrees) for at least 10 minutes.
    • Stuffed animals, pillows and articles that can’t be laundered. Stuff into large trash bag, seal the bag, and hold for 2 weeks.
    • All household items, carpets, chairs & couches should be thoroughly vacuumed. OTC sprays such as A-200 or R&C spray are no more effective than vacuuming
    HEAD LICE MYTHS are numerous! The following FACTS should reassure and inform patients and parents!
    • No significant difference in incidence between various socioeconomic classes or races.
    • Hygiene & hair length are NOT contributing factors.
    • Head lice do not fly or jump. They can crawl about 3 feet.
    • Head lice do NOT carry other disease. (Body lice can)
    • Head lice cannot be contracted from pets.
    • Head does NOT have to be shaved to get rid of the lice.
    • Washing head with brown soap is not effective.
    • Head lice are not related to ticks
    • Hair does NOT fall out because of infestation
    • Head lice can occur at any time of the year.
    HEAD LICE TRUTHS:
    • Females are more susceptible to head lice infestations.
    • White children are more susceptible that black children in the United States
    • Pruritus occurs as an allergic reaction to lice saliva injected during feeding
    No Nit Policy…. NO WAY!!!
    From the CDC website---Here’s why “no-nit” policies should be discontinued” Both the American Academy of Pediatrics (AAP) and the National Association of School Nurses (NASN) are in favor of stopping the common practice of “no-nit” policies for the following reasons:
    • Many nits are more than ¼ inch from the scalp. Such nits are usually not viable and very unlikely to hatch to become crawling lice, or may in fact be empty shells, also known as ‘casings’.
    • Nits are cemented to hair shafts and are very unlikely to be transferred successfully to other people.
    • The burden of unnecessary absenteeism to the students, families and communities far outweighs the risks associated with head lice.
    • Misdiagnosis of nits is very common during nit checks conducted by nonmedical personnel.
    As we approach the end of August the school buildings that have been quiet for nearly three months are coming back to life. In Central Pennsylvania where we live, the sports page, full of football stories is the harbinger to the first day of school. Kids are getting their backpacks ready, and the first day of school of outfits are hanging in the closet.

    The kids are excited, and the parents are looking forward to the first day as well. However one facet of the beginning of school is the return of the six legged critters, head lice.

    Nothing upsets and frustrates parents more than when their kids bring home these unwanted inhabitants of the kids hair! I made sure that the generic permethrin creme rinse is stacked up in the front shelves of the store. I sure it wont be there for long!

    In the next two weeks we will cover the over the counter lice treatments, followed by the prescription treatments for pediculosis capitis.

    Have a great day on the bench!! (you can stop scratching now!)

    You'll never flush your toilet again without thinking about this newsletter!

    Steatorrhea and Pancreatic Enzymes

    Why is fat content of the stool most important:
    Healthy people, excrete less than 6 grams of fat per day even if intake is increased to 100 to 125 g of fat/day. Most patients experiencing steatorrhea excrete more than 20 gram of fat per day in their stool. The pancreas normally responds with between 700,000 and 1,000,000 lipase units (USP) per meal.

    The activity of the lipase in patients with EPI (exocrine pancreatic insufficiency) is generally 10% of that of healthy individuals. Since all three enzymes (amylase, protease and lipase) are excreted parallel, lipase is used to determine the appropriate dose of pancreatic enzyme supplements.

    Absorption: Of all the macronutrients (fat, carbohydrates, and protein), the absorption process of fat is the most complex and tends to be the most sensitive to interference from disease processes.

    Calories: Fat is the most calorically dense macronutrient and, therefore, its malabsorption is a critical factor in the weight loss that often accompanies malabsorptive disorders. Protein and carbohydrates contain 4 kcal per gram, while fat contains 9 kcal per gram.

    Patients should be followed up in two weeks to assess and titrate PERT (pancreatic enzyme replacement therapy) dose if needed. The dosage should be individualized and adjusted based on:
    • Clinical symptoms
    • Degree of steatorrhea present
    • Fat content of the diet
    As unpleasant as this may sound patients need to report the frequency and consistency of their stools, along with the following symptoms:

    Clinical Symptom tracker
    • Frequency of diarrhea or loose stoolst
    • Bloating
    • Excessive gas
    • Abdominal pain
    • Rush to bathroom during the night
    Stool appearance indicating steatorrhea:
    • Stool color- pale yellow
    • Foul smelling stool
    • Stool floats on top of water, rather than sinking
    • Hard to flush stool
    • Greasy appearance
    • Droplets of oil in your toilet
    Degree of steatorrhea present
    • Foul smelling stools (we are aware than no one’s stools smell good, but have your patients report on foul smelling stools)
    • Do their stools float on the top of the water in the toilet bowl?
    Fat content of the diet:
    Restriction of the fat content to 20gm per day is recommended. If this is unsuccessful, pancreatic enzymes need to be taken. Remember though that fat is an important macronutrient. Medium chain triglycerides (MCTs) can be supplemented to provide extra calories in patients with weight loss and a poor response to diet and pancreatic enzyme therapy

    Adherence Of course, before we make any adjustments to therapy, we need to ask the patient about adherence and measure their understanding about the pancreatic enzymes.
    • Remind the patient that PERT should be taken with meals and snacks to aid in digestion
    • Confirm that the total daily dose of PERT is divided among approximately 3 meals and 2 to 3 snacks a day
    • Ensure the patient understands that half of the prescribed enzyme dose for an individualized full meal should be taken with each snack
    Self-Care Strategies:
    • Vitamin supplementation, including fat-soluble vitamins A, D, E, and K
    • A nutritionally well-balanced diety
    • Abstaining from alcohol
    • Smoking cessation
    Follow up care:
    • After 12 months, 61% of PERT patients are still on their starting dose
    • 67% of patients are under dosed on their PERT
    Most of us did it today, and if not, will be doing it tomorrow. Yet most of us feel very uncomfortable discussing our bowel movements let alone listening to someone else’s vivid description of theirs.

    As unpleasant as these discussions are, stool consistency is about the only gauge our patients have to assist with appropriate dosing of pancreatic enzymes.

    Most of us cringe when we head out to our laxative section, where we often get excruciating descriptions of patient’s bowel movements. When we are monitoring the efficacy of pancreatic enzyme replacement therapy, such descriptions are necessary for clinicians to gauge the success of the therapy.

    I'd recommend discussing the contents of this column with all of your patients within the two weeks suggested after a new start. For pharmacists, at the first refill it would be worth discussing specifically adherence, as well as stool appearance. Hey, we're accustomed to hearing such descriptions anyway!

    I remember one of my first lower GI consults, after I was recently licensed in 1981. A rough old gent walked into the store and asked me for a “physic” after asking him what he meant, as I’ve never heard that term before. He said “listen buddy I can’t s----” , using the four letter work my Mom would wash our mouths out with soap if she caught us saying that!

    The available pancreatic enzymes: Creon® (Abbvie), Zenpep® (Allergan), Pancreaze® (Janssen), Viokace® (Allergan), and Pertzye® (Digestive Care) are currently the only FDA-approved PEPs that are marketed in the United States. They have excellent websites, that have savings programs for our patients. The sales representatives are a wealth of information as well.

    Have a great day on the bench!!

    Patient information to help our patients get the most benefit from their pancreatic enzymes

    When Our Patients Pancreas Fails--

    Your six-inch pancreas is quite a busy organ, producing close to 2000ml (2 quarts) of pancreatic juices that aid in digestion. As discussed last week when the pancreas fails to produce adequate enzymes we see several symptoms of inappropriate digestion such as diarrhea, gas, unexplained weight loss and steatorrhea.

    SOURCE: The digestive enzymes lipase, protease and amylase are extracted from the pancreas of pigs. Both Muslim and Jewish leaders approve these pork derived enzymes if there are no other alternatives for treatment of the patient’s condition.

    HISTORY: In July 1991, FDA announced that all pancreas enzyme products (PEPs) must be approved, and the companies were required to submit a New Drug Application, even though these drugs have been around a long time. This was done to assure the safety, effectiveness, and product quality, due to variations between the actual enzyme content in the product and the amount indicated on the label. Some companies began the application process soon after that announcement. The FDA required approval of all marketed PEPs by April 28, 2008. Because the manufacturers struggled with this time frame the FDA extended the approval deadline to April 28,2010 The FDA provided technical assistance to all manufacturers of PEPs and extension of the approval deadline, however some of the products failed to get FDA approval for marketing prior to the April 28, 2010 deadline.

    DOSING: The initial dose of pancreatic enzyme replacement therapy (PERT) can be calculated, based on the weight of the patient. Dosage adjustments thereafter are based on the following 3 parameters:
    • degree of steatorrhea present
    • content of dietary fat in the ingested meal
    • clinical symptoms of the disease
    The recommended dosage of all pancreatic enzyme replacement products is 500 lipase units/kg/meal. These patients based on symptoms can be titrated to a maximum of 2,500 lipase units per kg/meal.

    Starting dose: Looking at the math a 180-pound patient (80kg) patient should be taking around 40,000 units per meal as a starting dose. Think Creon® 36,000 one capsule at each meal.

    Maximum dose: The above patient would be able to take a maximum dose of 200,000 lipase units per meal. (after titration of course). Think a maximum of Creon® 36,000 at a dose 5 capsules per meal. Most patients should be on 2 capsules per meal (72,000 units)

    Observing these calculations, most patients (estimated 2/3) are under dosed. Unfortunately, after 12 months at least 60% of the patients are on their initial starting dose and have not been upwardly titrated. Tell patients it may take 1-2 weeks for a patient to adjust their dose of the new PEP. Patients usually take half of a mealtime dose for each substantial snack.

    Approved Products include: Creon® (Abbvie), Zenpep® (Allergan), Pancreaze® (Janssen), Viokace® (Allergan), and Pertzye® (Digestive Care) are currently the only FDA-approved PEPs that are marketed in the United States Viokace is the only pancreas enzyme product (PEP) without an enteric coating. Viokace must be taken with a proton pump inhibitor (PPI). The PPI decreases stomach acid to help prevent the drug from breaking down in the stomach and delays the release of the drug until it reaches the lower digestive tract.

    PATIENT INFORMATION
    • Take with every meal or snack or the symptoms of malabsorption may return if doses are missed.
    • Heat labile: Capsules must be swallowed with a cold drink, as a hot drink might weaken the enzymatic activity. Also, enzymes should not be carried in trouser pockets, due to body radiating heat.
    • The capsules should be swallowed whole and must not be crushed or chewed. If opened and sprinkled it should be on an acidic food (such as applesauce). Do not retain in the mouth, due to potential irritation of oral mucosa.
    • If you are having a large extended meal more than 2 courses, divide dose during the meal.
    Since use of PEPs preceded the Federal Food, Drug and Cosmetic Act of 1938, they had been marketed without formal FDA approval, and major differences were reported between the actual enzyme content in the product and the amount indicated on the label.

    After reading this letter it is obvious that we pharmacists at each refill should be questioning our patients as to the level of improvement of their gastrointestinal symptoms, especially steatorrhea. Although these enzymes are expensive, the biggest waste of money comes if the patients are not deriving benefit due to improper dosing or adherence.

    Next week we will discuss follow up care.

    Have a great day on the bench!!

    We think a lot about insulin and the pancreas... let's explore the other function of our pancreas.

    Digestive enzymes and your "tired" pancreas...

    Digestive enzymes are available in the front of our stores, but most often are prescribed and dispensed from the pharmacy. With all the Type-2 diabetics we care for, we realize the function of the pancreas is to produce insulin from the beta cells, and glucagon from the alpha cells in the islet of Langerhans. Another extremely important, and often forgotten function of the pancreas is to produce the digestive enzymes to process the foods we eat.

    Just as the endocrine function (insulin and glucagon production) may fail, the effectiveness of the exocrine function (production of digestive enzymes) may fail as well. When the exocrine function becomes impaired, this condition is referred to as EPI (Exocrine Pancreatic Insufficiency)

    In people with EPI, it is the exocrine function of the pancreas that is affected. EPI occurs when prandial enzyme output is ≤10% of normal. The undigested food moving through the intestines that causes the unpleasant symptoms of EPI.

    EPI is a condition that can be managed with prescription medication called PERT (pancreatic enzyme replacement therapy). PERTs replace the enzymes the pancreas is no longer making. The capsules/tablets are taken with every meal to help break down food into nutrients that can be absorbed. They contain the enzymes lipase which breaks down fats, protease which breaks down proteins, and amylase which breaks down carbohydrates.

    SYMPTOMS OF EPI
    • Frequent diarrhea (usually characterized by frequent, soft bowel movements that appear pale)
    • Unexplained weight loss
    • Steatorrhea (due to excess fat content, stools are loose, floating, oily, foul smelling, and hard to flush)
    • Flatulence and bloating
    • Abdominal pain
    • Conditions associated with EPI:
      • Chronic pancreatitis (CP)
      • Cystic fibrosis (CF
      • Pancreatic cancer
      • Partial resection or total pancreatectomy
      • Diabetes mellitus
    DIAGNOSIS OF EPI
    • Fecal Elastase-1 Concentration (done with a single stool sample)
    • Fecal Fat Collection (done over a 72-hour time period)
    • Secretin and/or cholecystokinin (CCK) stimulation tests (available in specialized pancreatic centers- not done routinely)
    TREATMENT of EPI
    Along with the pancreatic enzyme replacement therapy (which we will “digest” next week) the following should be recommended:
    • A nutritionally well-balanced diet
    • Vitamin and mineral supplements, including fat-soluble vitamins A, D, E, and K
    • Lifestyle modifications such as abstaining from alcohol and smoking cessation
    • Check the med list: Most drugs report diarrhea as a side effect, but especially watch out for:
      • Selective Serotonin Reuptake Inhibitors (Citalopram, fluoxetine, sertraline and others)
      • Other antidepressants such as bupropion and trazodone
      • Lithium
      • Metformin- frequently prescribed for our Type-2 diabetics, who are also at risk for EPI
      • Proton pump inhibitors (omeprazole, esomeprazole) along with H2RA’s like ranitidine and famotidine (very rare)
      • Bisphosphonates (alendronate, ibandronate, risedronate)
      • Colchicine
      • NSAIDS- (ibuprofen, naproxen and others)
      • ACE inhibitors
      • Chemotherapeutic drugs
    Our pancreas is an important organ to keep us going metabolically. We quickly think of insulin from the beta cells, maybe glucagon from the alpha cells, but equally important is the digestion of our foods from the exocrine function of the pancreas. After the next couple weeks of discussion with relationship of digestive enzymes we will come to appreciate this six inch organ, that weighs only 2 to 3 ounces even more!

    Have a great day on the bench!!

    JULY 2018

    I take a statin and my legs hurt... will Co-Q -10 help??

    Statin Induced Myopathy Treatment and Prevention:

    Coenzyme Q-10 has been touted for everything from eye disease, heart disease to HIV. Most of the time we are using it for people who complain about muscle pain while on a statin for cholesterol management. Many of our patients complain about muscle aches, some of them are not even on statins. Here are the terms used to describe muscle pain. First recommendation is to have a creatine kinase (CK) level done.

    • Myopathy - a general term related to any muscle complaint. Muscle weakness (not due to pain), with or without an elevation in Creatine Kinase (CK) level.
    • Myalgia - muscle complaints (i.e., ache, weakness) without elevations in CK. This is the most common myopathy reported with statins
    • Myositis – inflammation of the muscles
    • Myonecrosis – Elevation in muscle enzymes compared with either baseline CK levels (while not on statin therapy) or the upper limit of normal that has been adjusted for age, race, and sex:
      • Mild – Threefold to 10-fold elevation in CK.
      • Moderate – 10-fold to 50-fold elevation in CK.
      • Severe – 50-fold or greater elevation in CK.
    • Rhabdomyolysis - markedly elevated levels of CK, usually greater than ten times the upper limit of normal; usually accompanied by creatinine elevation, acute renal failure including brown urine, and urinary myoglobin. Defined as myonecrosis with myoglobinuria or acute renal failure (an increase in serum creatinine of least 0.5 mg/dL).
    Many of the elevations in CK are due to statin therapy but is not usually a concern until it is over 10 times the upper limits of normal. This is very rare, and occurs in less than 0.5% of patients. Unfortunately, many patient’s statin therapy is discontinued due to perceived side effects of muscle pain. Hypothyroidism, acute or chronic renal failure, and obstructive liver disease can also enhance to statin induced muscle pain.
    • If the patient has muscle pain my first approach would be to recommend switching to a hydrophilic statin. Pravastatin (Pravachol®) -a lightweight- and rosuvastatin (Crestor®) -a powerhouse- are both available generically and are hydrophilic. Those two are least likely to cause muscle pain.
    • A lot of the elevations of CK might be due to statin drug interactions with CYP450-3A4, and rosuvastatin and pravastatin are not metabolized by this enzyme system, and are safer.
    • I am not a huge fan of Zetia (ezetimibe), which blocks the absorption of cholesterol. Most clinicians feel the liver “up-regulates” cholesterol production in response to decreased absorption. Most want a statin on board with ezetimibe therapy, which now is rather cheap to use.
    • Always avoid gemfibrozil (Lopid®) with statin therapy.
    • Never prescribe Simvastatin (Zocor®) 80mg due to increased risk of rhabdomyolysis.
    CoQ10 for myopathy prevention: The link to statin therapy-
    Statins inhibit CoQ10 formation 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.

    Adverse effects: Most studies have not reported serious side effects related to CoQ10 use. The most common side effects of CoQ10 include insomnia, increased liver enzymes, rashes, nausea, upper abdominal pain, dizziness, sensitivity to light, irritability, headaches, heartburn, and fatigue.
    • CoQ10 should not be used by women who are pregnant or breastfeeding.
    • Statins may lower the levels of CoQ10 in the blood. However, it is unclear what type of health effect this may have on an individual.
    • CoQ10 may make warfarin, an anticoagulant (blood thinner), less effective.
    The only way I recommend Co-Q10 if that is the only thing that will keep a patient on their statin. I think of it as an expensive placebo! We struggle to find cheaper prescription prices for our statins, and it is counter-intuitive to recommend a very expensive supplement. A few case reports have noted benefit with doses of 30 to 250 mg daily. There is currently inadequate evidence to recommend CoQ10 supplementation for prevention of statin-induced muscle toxicity.

    Have a great day on the bench!!

    Another benefit of this drug...you don't have to check the PDMP!!!

    Melatonin-- a good night sleep might be in our supplement section!

    Melatonin is classified as a “dietary supplement by the FDA.
    Endogenous melatonin, secreted by the pineal gland is a neurohormone used to regulate sleep-wake cycles or circadian rhythms. Melatonin is synthesized from the amino acid tryptophan. Melatonin secretion begins around the third or fourth month of life, peaks in pediatric years, and lessens as we age. This decline in melatonin secretion seems to be due to calcification of the pineal gland. A 70-year-old has about ¼ of the melatonin secretion as young adults do. Supplementation of melatonin seems to be a reasonable option for sleep induction.

    • USE: May be useful may help to regulate sleep disturbances that occur with insomnia, jet lag, rotating shift-work, depression, chronic kidney disease.
    • 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.
    Might not be effective for decreasing sleep latency.
    • DOSE: 0.3—1 mg produce physiological melatonin levels in the circulation; Suggest higher doses of (2—6 mg) which are needed to obtain beneficial effects. Maximum: 10 mg/day. Doses over 10mg may produce supraphysiologic concentrations of melatonin which can produce numerous biological effects. Daytime sleepiness, impaired mental and physical performance, hypothermia , and hyperprolactinemia can be caused by excessive melatonin doses. These effects are not observed with physiologic concentrations of melatonin.
    Novel uses for melatonin:
    • is an orphan drug for blind people who have no light dark cycle, and cant synchronize sleep.
    • is being studied for relief of perioperative anxiety (3-5mg) – causes less respiratory depression, sedation and delirium than the benzos.
    Ramelteon (Rozerem®) available as 8mg tablets ($490.00/month) Mechanism: selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus , inhibiting the neuronal firing that maintains wakefulness. Rozerem® shows no evidence of abuse, dependence or withdrawal, or rebound insomnia and can be prescribed long term.

    Tasimelteon (Hetlioz®) is 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 recommend Hetlioz for sighted or blind patients who don't have non-24.

    Melatonin warnings:
    • Asthma: melatonin may play role in the expression of asthma symptoms- patients should seek advice before starting this therapy.
    • Drowsiness precautions, driving, dangerous tasks that require alertness.
    • Avoid during pregnancy and breast feeding.

    We all see a lot of issues using the traditional sleep aids in our patients, especially the elderly. We often hear of reports of “sleep driving” on zolpidem (Ambien), not to mention the risk of falls. Many of our patients seeing that their benzodiazepines, like temazepam (Restoril), and the “Z” hypnotics like zolpidem are not covered for sleep and look in the over the counter aisle for relief. Keep in mind that due to their anticholinergic effects the antihistamines are not recommended for the elderly due to exacerbation of prostate symptoms and increase fall risk. That rules out all the “PM” products that contain diphenhydramine. Melatonin seems to be an option worth exploration.

    Sleep hygiene is also worthy of discussion. Use of laptops, tablets, smartphones before bedtime can have a negative impact on melatonin secretion, circadian rhythms, and sleep. Any device with a “gray screen” all which are low light emitting, and dilates the pupils can cause this effect. One study compared the effects of reading an “e-book” versus a printed book for four hours prior to bedtime for five consecutive nights. The e-book readers had suppressed melatonin concentrations in the early part of the night, a delayed endogenous circadian melatonin phase, felt less sleepy before bed, took longer to fall asleep, and reported feeling sleepier the following morning, than the “paper book” readers. Looks like this gray haired pharmacist needs to create these columns in the morning, and NOT before bedtime.

    Have a great day on the bench!!

    Milk thistle-- should we get out the "weedeater" or the mortar and pestle?

    Milk Thistle—this invasive weed might have health benefits for your liver.

    Latin Name: Silybum marianum also called “Mary thistle” or “holy thistle”

    Milk thistle grows in North and South America, and throughout most of the world, as it is native to the Mediterranean region. This plant is considered by most to be an invasive species. Silymarin is the main component of milk thistle seeds.

    People have used milk thistle for liver disorders, such as hepatitis and cirrhosis, and gallbladder problems. Silymarin is the most commonly used herbal supplement in the United States for liver problems. Silymarin has chemo preventive effects on hepato-cellular carcinoma, according to in vivo and in vitro studies. The silymarin exerts antioxidant activity, stabilizes liver cell membranes, promotes regeneration of the hepatocytes, and inhibits fibrogenesis in the liver, which drives the progression of chronic liver disease. Silymarin also increases survival time in patients with alcoholic cirrhosis.

    Milk thistle products are available as capsules, powders, and extracts. Capsules are available in 175mg, 250mg and 1000mg strengths.

    EVIDENCE:
    The 2008 Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) study, sponsored by the National Institutes of Health (NIH), found that hepatitis C patients who used silymarin had fewer and milder symptoms of liver disease and somewhat better quality of life but no change in virus activity or liver inflammation. A 2012 clinical trial, higher-than-usual doses of silymarin were no better than placebo for chronic hepatitis C in people who had not responded to standard antiviral treatment.

    DIABETES:
    Milk thistle might lower blood sugar in people who have type 2 diabetes

    NASH:
    NonAlcoholic SteatoHepatitis (NASH) is a more severe form of liver disease with inflammation and sometimes fibrosis, which is becoming one of the most frequent causes for liver transplants. Weight loss, statins and pioglitazone (Actos) may reduce liver fat, fibrosis and inflammation. Use pioglitazone (Actos) whether patient has diabetes or not. Milk thistle seems to be of minimal value.

    SAFETY:
    In clinical trials, milk thistle appears to be well tolerated in recommended doses. Occasionally, people report various gastrointestinal side effects.

    CYP2C9 interactions:
    milk thistle is an inhibitor of CYP450-2C9 and might potentially produce clinically significant increases in warfarin (Coumadin and diazepam (Valium). Other references discount any CYP family interactions with milk thistle.

    ALLERGIC REACTIONS:
    Milk thistle may produce allergic reactions, which tend to be more common among people who are allergic to plants in the daisy family (for example, ragweed, chrysanthemum, marigold, and daisy).

    DIABETES:
    Compounds in milk thistle may lower blood sugar levels in people with type 2 diabetes. Some of the compounds in milk thistle have peroxisome proliferator-activated receptor (p-par) agonist properties similar to the TZD’s like Actos (pioglitazone) People with diabetes should use caution, and monitor for hypoglycemia.


    Next I'm walking around the fields and forests of Central Pennsylvania, and my shoelaces get untied by this noxious week, I will have a greater respect for milk thistle! Milk thistle, although originally from the Mediterranean area can easily be spotted along hedgerows and in the farmers fields of most areas of our country.
    This herbal might have a place in therapy, although not useful for NASH, it might benefit certain populations suffering from liver disease. With its low incidence of drug interactions, and minimal adverse reactions I'm OK with my patients trying this herbal product. Although it doesn't lower viral load in our hepatitis patients, the HALT-C study showed a better "quality of life." Isn't that after all what healthcare is all about?

    Have a great day on the bench!!

    Is ginger effective for treatment of nausea and vomiting?

    Ginger snaps and ginger ale... good for snacks, not so for vomiting!

    Latin Name: Zingiber officinale

    Ginger can be found in our kitchens as spice for “ginger snaps” and in “ginger ale”. Ginger which is found in the tropics has green-purple flowers and a rhizome (a bulky underground stem) that is the basis for its use in the kitchen. Ginger has been used since antiquity, especially in Asian medicine, dried ginger has been used for thousands of years to treat stomach ache, diarrhea, and nausea.

    Dramamine offers as a brand extension an all-natural product with ginger root (2 capsules=1000mg), along with its dimenhydrinate 50mg and meclizine 25mg versions! Foods containing ginger as a flavoring agent, like ginger ale or ginger snaps are not effective in treatment of nausea.

    Ginger has been studied for nausea for a variety of situations, such as motion sickness, post op nausea, and chemotherapy. It is more effective than placebo, however prescription medications are more effective for treatment of vomiting. Ginger provided little benefit in treatment of nausea and vomiting due to chemotherapy. Ginger’s most common strengths are 250mg and 550mg per capsule.

    Nausea of Pregnancy: the usual dose of ginger is 250mg four times daily. This supplement might bring adequate relief, but for hyperemesis gravidarum using metoclopramide (Reglan) or ondansetron (Zofran) would provide greater benefit. According to a meta-analysis by the American Board of Family Medicine, ginger (Z. officinale) was better than placebo in improving nausea of early pregnancy when given at doses of 1 gram/day for a duration of at least 4 days. The ACOG (American College of Obstetricians and Gynecologists) list ginger as a treatment option for nausea of pregnancy. Safety in pregnancy has not been adequately proven.

    Side Effects

    Heartburn: For non-pregnant patients, GI reflux has been commonly reported with ginger. In a study of the prevention of postoperative nausea and vomiting, 8% of subjects had heartburn after taking 1 gram of ginger.

    Bleeding risk: advise caution if the patient is currently taking any anti-platelet drugs (aspirin, clopidogrel) or anticoagulants as ginger could possibly increase bleeding risk.
    As with all herbal supplements in the United States there is variation between products due to lack of standardization.


    Back when Zofran® (ondansetron) came to market in 1992 it was extremely expensive costing around $40.00 per tablet. Its unique mechanism of action is that it blocks serotonin, a natural substance that causes nausea and vomiting. This was a godsend to oncologists who struggled with the vomiting caused by chemotherapy regimens, especially cisplatin.

    Family practice physicians were using other alternatives such as prochlorperazine (Compazine) promethazine (Phenergan) and metoclopramide (Reglan). The extrapyramidal side effects of these "dopamine blockers" could make treatment of nausea and vomiting a challenge.

    Ginger was frequently recommended for the simple nausea of "the flu", or due to motion sickness. Ginger is better than placebo, but is not as effective as the serotonin or dopamine blockers.

    Today ondansetron tablets are very inexpensive, and are frequently prescribed for treatment of all forms of nausea and vomiting. However in September 2011, the FDA warned "Ondansetron may increase the risk of developing abnormal changes in the electrical activity of the heart, which can result in a potentially fatal abnormal heart rhythm"

    Have a great day on the bench!!

    JUNE 2018

    Urinary Tract infections: prevention with cranberry juice or tablets are of no value. Save your cranberries for your next turkey dinner!

    When the first urinary tract infection is caused by Escherichia coli, women appear to be more likely to develop a second UTI within six months than those with a first UTI due to another organism. A study done in Finland showed 44 percent of women with an E.coli urinary tract infection had a recurrence within one year. This is indeed a very common complaint with our female patients and the go to our supplement aisle looking for a “natural” product to prevent these bothersome infections.

    Cranberry (Vaccinium macrocarpon) is an evergreen bush that grows in North America. For years it has been touted for its use in prevention of urinary tract infections. Here is what you need to share with your patients.


    Cranberry therapy is not worth trying: Any of the oral cranberry products to date have no data to support its use, and causes significant GI upset and heartburn. Withdrawal rates have been quite high (up to 55%), suggesting that these products may not be acceptable over long periods. Adverse events include gastrointestinal intolerance, weight gain (due to the excessive calorie load) and drug-cranberry interactions (due to the inhibitory effect of flavonoids on cytochrome P450-mediated drug metabolism).
    • Drinking cranberry juice appears to be safe, although large amounts can cause stomach upset and may over time increase the risk of kidney stones.
    • Large doses of cranberry may alter levels of warfarin (Coumadin).
    Approaches to Urinary Tract infection prophylaxis that are worth trying:
    • Post coital antibiotic treatment: antibiotic treatment after each act of sex using: trimeth/sulfa SS; Nitrofurantoin 50mg or 100mg capsules (not MacroBID), cephalexin 250mg or ciprofloxacin 125mg
    • Continuous antibiotic prophylaxis: daily antibiotic treatment with trimethoprim 100mg (watch for resistance), trimeth/sulfa SS, nitrofurantoin 50mg or 100mg (not MacroBID), cephalexin 250 or ciprofloxacin 125mg
    • Self-treatment: women who can self-diagnose and who are compliant can be given a course of therapy with Trimeth/Sulfa DS or Ciprofloxacin or Levofloxacin. Women should call provider if symptoms are not resolved in 48 hours
    Patient counseling tips that work to prevent recurrent urinary tract infections:
    • Urinate immediately after having sexual intercourse. Urinating flushes out bacteria that may have entered the urethra during intercourse.
    • Use proper hygiene. Wipe front to back.
    • Rinse the vulva after sex.
    • Keep well hydrated with water and avoid “holding it” throughout the day
    • Wear regular cotton underwear. Thong underwear can lead to UTI’s by tracking bacteria from the rectal area into the urethra via the vagina.
    • Don’t smoke, it lowers your immunity.
    • Avoid condoms coated with nonoxynol-9

    We see a lot of patients coming to our pharmacies getting Trimeth/Sulfa DS, Nitrofurantoin, Levofloxacin and Ciprofloxacin for urinary tract infections. Of course, some of us gray haired pharmacists remember Mandelamine®(Methenamine mandelate) and Hiprex® (methanamine hippurate), which became available in 1967, are seldom used today.

    Females, due to their own special structural anatomy have a shorter urethra and the E.coli more easily “climb” through this shorter urethra and colonize in the bladder.

    Another challenge becomes finding appropriate therapy for treatment of urinary tract infections. The Sanford Antibiotic Guide recommends avoiding Trimeth/Sulfs DS (Bactrim-DS) if local E. coli resistance rates are over 20%. The same reference recommends avoiding fluoroquinolone (levofloxacin/ciprofloxacin) therapy if local resistance rates are over 10%. The latest antibiogram from our local hospital calculates a 27% resistance rate for Trimeth Sulfa and a whopping 35% resistant rate for the fluoroquinolones against E. coli.

    Fortunately our nitrofurantoin resistance rate is just 6% for E. coli. Bacterial resistance is becoming a bigger challenge for our female patients suffering from urinary tract infections.

    Have a great day on the bench!!

    What about all natural Red Yeast Rice for management of cholesterol?

    Red yeast rice (RYR) (Monascus purpureus) is a nutraceutical that lowers LDL-C levels by 20 to 30 percent. Red yeast rice is a fermented rice product that has been used in Chinese cuisine (like Peking duck) and medicinally to promote "blood circulation”. Because it is a “natural product “patients assume it is a safer alternative to the prescription statins.

    Red yeast rice may also induce muscle complaints because of its statin-like content. The product contains varying amounts of a family of naturally occurring substances called monacolins that have HMG CoA reductase inhibitor activity. The LDL-C lowering effect of red yeast rice is due to the presence of monacolin K, a compound like lovastatin (Mevacor®).

    According to a meta-analysis it will:
    • lower LDL-C by 19-62 mg/dL
    • increase HDL by 3mg/dL
    • lowers triglycerides by 23mg/dL
    When we directly compare it to lovastatin, the daily lovastatin content of red yeast rice was 0.2 percent of the total product, which at the recommended dose of red yeast rice of 2.4 g/day translates into a daily lovastatin dose of 4.8 mg, compared to lovastatin (Mevacor®) that we have available in the pharmacy. The capsules are available as 600mg and can be dosed as two capsules twice daily.

    My concerns:
    • Wide variability exists in the amount of lovastatin-like compounds in commercially available RYR products. In a study that evaluated the content of twelve preparations of commercially available red yeast rice, the total monacolin content ranged from 0.31 to 11.15 mg/capsule and monacolin K (similar to lovastatin) ranged from .1mg to 10 mg per capsule. This study also showed that four of the preparations had elevated levels (1.6mcg/day) of citrinin, a potentially kidney damaging mycotoxin.
    • Although red yeast rice lowers LDL-C like a mild potency statin, and may be tolerated by some patients who have discontinued statin therapy for muscle side effects, this therapy is not recommended due to lack of clinical outcomes data, variable drug bioavailability, and possible toxic effects from contaminants.
    • In 1998, the FDA determined that a red yeast rice product that contained a substantial amount of monacolin K was an unapproved new drug, not a dietary supplement. On several occasions since then, the FDA has acted against companies selling red yeast rice products that contain more than trace amounts of monacolin K, warning them that it is against the law to market these products as dietary supplements. Truth be known our patients and we pharmacists have no idea what is in these products, as the labels state only the amount of red yeast rice that they contain, not the amounts of monacolin K or other monacolins.
    • Lack of standardization, nephrotoxicity, as well as the costs of these products do not allow me to recommend this product. Most products are well over $18.00/month.

    Before recommending Red yeast rice, think about the active compound in this natural product, that being lovastatin or Mevacor®. Lovastatin is considered a sensitive CYP3A4 substrate, since its levels may be increased five-fold or higher by CYP3A4 inhibitors. Lovastatin was a game changer in the world of hyperlipidemia management. Up until Mevacor® became available in 1987 clinicians managed cholesterol levels with diet, exercise and bile acid sequestrants, such as cholestyramine (Questran) and colestipol (Colestid).

    Simvastatin (Zocor®) and Pravastatin (Pravachol®) became available in 1991. Fluvastatin (Lescol®) followed in 1993, to be joined by the blockbuster atorvastatin (Lipitor) in 1996.

    Cerivastatin (Baycol®) came to the market in 1997, only to be withdrawn after four years in 2001, because of 52 deaths attributed to drug-related rhabdomyolysis that lead to kidney failure.

    Rosuvastatin (Crestor®) came to the market in 2003, and the last one to join the HmgCo-A reductase family was pitavastatin (Livalo®) in 2009. Except for pitavastatin, all of the statins are now available generically.

    When we recommend statins, we think of drug interactions, cost and potency and of course insurance coverage. Most clinicians when selecting a statin today gravitate toward rosuvastatin because it meets the parameters of minimal drug interactions and potency.

    Most would agree that the active ingredient in red yeast rice (lovastatin) would be our last choice. Red yeast rice with the potential for contamination with citrinin, along with the lack of standardization between products, should be our last choice in the management of hyperlipidemia.

    Have a great day on the bench!!

    Ceiling fans and dry tee shirts might be your patients best treatment option for hot flashes!

    Black Cohosh:
    • Cimicifuga racemose- rhizomes and roots are used. It is a member of the buttercup family.
    • USE: extracts seem to modestly reduce symptoms of menopause, such as hot flashes. However, there is considerable variability in the preparations used in clinical trials, and in the results obtained. Historically was one of the ingredients in Lydia Pinkham’s Vegetable Compound
    • Remifemin® contains only black cohosh, and has been one of Germany's top proprietary herbs since the 1960's. It is not recommended to be used over 6 months.
    • Germany's Commission E has found this extract of black cohosh effective for the treatment of dysmenorrhea, PMS, and climacteric ailments since 1989. Remifemin is the only formulation approved by Commission E.
    What the US studies show: With a daily dose of 40 mg, for a mean duration of 23 weeks, compared to placebo, hormone therapy, red clover and fluoxetine. Reported outcomes included vasomotor symptoms, vulvovaginal symptoms, menopausal symptom scores and adverse effects. There was no significant difference between black cohosh and placebo. Source:http://www.ncbi.nlm.nih.gov/pubmed/22972105 Results for evening primrose oil and flaxseed have also been disappointing.

    Adverse effects: Stomach upset, headache are common side effects. There have been reports of liver damage in patients, one patient needing a liver transplant.

    Drug interactions: because of the potential (not yet proven) estrogenic effects of black cohosh, do not recommend in patients taking tamoxifen (Nolvadex). No other drug interactions have been reported.

    Non-Hormonal alternatives for hot flashes:
    • most references recommend venlafaxine (Effexor), desvenlafaxine (Pristiq), paroxetine (Paxil, Brisdelle), citalopram (Celexa), and escitalopram (Lexapro) have a similar modest benefit for hot flashes. Most sources seem to favor citalopram as the favorite at a 20mg dose for hot flashes.
    • Gabapentin (Neurontin) is a good option for women who have their hot flashes at night. It is effective when the hot flashes occur in the first four hours of sleep, especially if the hot flashes wake up the woman.
    So, as with so many of the herbal preparations there just isn’t a lot of evidence for use of black cohosh. This drug seems to be safer than most herbal supplements for most of our middle aged women, and for some it might be worth a try. Share this information that there isn’t a lot of evidence for use of black cohosh. Might be best to save the money and turn on the ceiling fan in the bedroom!

    I remember back in the day in the 1980’s when we bought our Premarin 0.625 and Premarin 1.25mg in bottles of 1000! We would sell 100 Premarin for around $15.00. Then the HERS trial came out at the turn of the millennium, and we have all but stopped dispensing this drug. Back in the 1980’s we were using it for everything from osteoporosis, hot flashes, prevention of colon cancer and even cardiac protection. After the results of the HERS trial, estrogen was to be used for relief of vasomotor symptoms, at the lowest possible dose for the shortest period of time. Estrogen is no longer recommended for prevention of chronic heart disease, osteoporosis, or prevention of dementia. That same bottle of 100 Premarin® costs the pharmacy almost $550.00 !!

    “Hot flashes” are the most common complaint during the menopausal transition, occurring in up to 80 percent of women. However, only about 20 to 30 percent of women seek medical attention for treatment. Indeed, estrogen has fallen out of favor, and our female patients (including our wives!) are looking for relief of hot flashes and turn to the over the counter supplements such as black cohosh, the active ingredient in Remifemin®.

    Have a great day on the bench!!

    Valerian root might be an option for our anxious patients... and you don't have to check the PDMP!!

    Valerian... seems good for insomnia--- and unlike Zolpidem, you can "tweet" !!

    Valerian (Valeriana officinalis) is a perennial plant native to North America, Europe and Asia. For hundreds of years it has been used in Europe as a sedative and an antispasmolytic to relieve insomnia, anxiety, muscle spasms and stress induced palpitations. Native Americans boiled the roots into a tea for calming the nerves. The roots contain essential oil with monoterpenes and sesquiterpenes (valerenic acids).

    Various compounds have been detected in valerian, including alkaloids, flavonoids, and GABA, which seem to have some affinity for the GABA receptor. Remember from our basic pharmacology when the GABA receptor is activated by benzodiazepines we will see sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant effects. Could we then expect the same from valerian?

    Source: Valerian products are made from its roots, rhizomes (underground stems), and horizontal stems. Dried roots are prepared as teas or tinctures, and dried plant materials and extracts are put into capsules.

    Efficacy: Some studies suggest that valerian may be useful for insomnia and other sleep disorders; results of other studies do not. Some of these studies had small sample sizes, used different amounts and sources of valerian, measured different outcomes, or did not consider potential bias resulting from high participant withdrawal rates. Overall, the evidence from these trials for the sleep-promoting effects of valerian is inconclusive.

    Numerous trials have not shown it to be better than placebo, while some other trials showed it had less side effects than placebo! One study showed a decrease in slow-wave sleep onset (13.5 minutes) compared with placebo (21.3 minutes). Another study enlisting 75 patients comparing Valerian 600mg to oxazepam (Serax®) 10mg. Both groups had the same improvement in sleep quality but the valerian group reported fewer side effects than did the oxazepam group. Those patients experienced less morning drowsiness. NCBI

    Adverse effects: Few adverse events have been reported because of valerian. As we would expect from its sedative properties, valerian can cause drowsiness or dizziness. The risk of respiratory depression should be considered if valerian is used with multiple sedating drugs (like benzos) and/or significant alcohol consumption. Valerian can cause abdominal pain in large doses.

    Worth recommending? Valerian is a seems to be a safe herbal choice for the treatment of mild insomnia and has good tolerability. Valerian seems to be more effective when used continuously rather than as an acute sleep aid. Most references recommend using 400mg-900mg one hour before bedtime. Best results occur when a person takes it for at least 28 days. A potential advantage of valerian over benzodiazepines is the lack of sleepiness on awakening when used at the recommended dosages. Valerian also may be helpful in weaning patients with insomnia from benzodiazepines.

    In 1960 the first benzodiazepine, chlordiazepoxide (Librium) hit the market, introduced by Roche Labs. In 1963 diazepam (Valium) was released and the market really took off. All the benzodiazepines work on the GABA receptor to allow chloride to rush into the neuron. Chloride is the major suppressing ion in the CNS. The Z-hypnotics zolpidem (Ambien®), zaleplon (Sonata®) and eszopiclone (Lunesta®) work at the same receptor, causing influx of chloride and causing the same net effect.

    When combined with opioids, benzodiazepines can cause an increase in opioid deaths. More than 30 percent of overdoses involving opioids also involve benzodiazepines. According to Psychiatry-Online (18March2016) between 1996 and 2013, the number of adults filling a benzodiazepine prescription increased 67 percent, from 8.1 million to 13.5 million. Among those filling benzodiazepine prescriptions, the median cumulative quantity filled over the year increased by 140 percent, from 86.8 mg to 208.0 mg lorazepam equivalents. Meanwhile in this time frame deaths involving benzodiazepine increased fivefold.

    Pharmacists and prescribers are feeling the heat when it comes to prescribing benzodiazepines and opioids, especially in combination. Valerian root might be an option, rather than another new start on a benzo!

    In recent news actor Roseann Barr blamed her controversial tweet on "Ambien tweeting". Sanofi quickly responded: "People of all races, religions and nationalities work at Sanofi every day to improve the lives of people around the world. While all pharmaceutical treatments have side effects, racism is not a known side effect of any Sanofi medication."

    My take on valerian: If it works for a particular patient, that is one less benzo we have to check the PDMP for!

    Have a great day on the bench!!

    May 2018

    Since I turned 60 last weekend, these men's health issues have become more important!

    Saw Palmetto, how effective is it for BPH?

    Common Names: saw palmetto, American dwarf palm tree, cabbage palm, is a tree native to South Eastern United States.

    Latin Name: Serenoa repens, Sabal serrulata
    • USE: urinary symptoms associated with benign prostatic hyperplasia (BPH), as well as for chronic pelvic pain, bladder disorders, decreased sex drive, hair loss, hormone imbalances, and prostate cancer.
    • Medicinal part: The ripe fruit of saw palmetto is used in several forms, including ground and dried fruit or whole berries. It is available as liquid extracts, tablets, capsules, and as an infusion or a tea. The saw palmetto berry contains over 100 different compounds, mostly fatty acids, long chain alcohols and sterols.
    EVIDENCE: (or lack thereof) Some studies compare saw palmetto’s efficacy to that of finasteride (Proscar), which “shrinks” the prostate gland allowing for better emptying of the bladder.
    • Placebo-controlled, double-blind studies of its use in benign prostatic hyperplasia (BPH) have been carried out in > 2000 patients in Germany. A 1998 meta-analysis of published trials concluded that compared to finasteride, saw palmetto appears to produce similar improvements (28%) in urinary tract symptoms and flow measures. Some studies suggest that it's comparable to finasteride, less effective than alpha-blockers.
    • 2011 NCCIH-cofunded study in 369 older men demonstrated that saw palmetto extract administered at up to three times the standard daily dose (320 mg) was no more effective than placebo. The supplement should be a fat soluble saw palmetto extract that contains 85 to 95% fatty acids and sterols.
    • A 2012 study in JAMA concluded that increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. This study reached the same conclusion as the New England Journal of Medicine in 2006, of the lack of efficacy of saw palmetto.
    • UP-To-Date® does not recommend any herbals for BPH until herbals are further studied. Given the body of evidence against herbal products, efficacy is likely tied to the placebo effect.
    DRUG INTERACTIONS:
    • Saw Palmetto does have anti-coagulant properties, do not recommend if patient takes any blood thinning drugs such as warfarin, aspirin, Plavix, Xarelto, or NSAIDS.
    • Because of saw palmetto’s mechanism of action being anti-estrogenic and anti-androgenic, it may decrease the efficacy of oral estrogen and oral contraceptives. It is recommended that a condom be used to prevent pregnancy if partner is using birth control pills.
    • Speaking of drug interactions, certain medications need to be avoided in men of my age group, especially if they have BPH:
    MEDICATIONS to Avoid with BPH:
    • Testosterone: causes prostate enlargement and growth
    • Sympathomimetic agents: may cause or worsen urinary difficulty in patients with prostate enlargement due to smooth muscle contraction in the bladder neck via stimulation of alpha-1 adrenergic receptors. Therapy with sympathomimetic agents should be administered cautiously in patients with hypertrophy or neoplasm of the prostate. Avoid amphetamines, pseudoephedrine and phenylephrine.
    • Drugs with significant anticholinergic (antimuscarinic) adverse effects: decrease urinary bladder detrusor muscle contractility, resulting in urinary retention (antihistamines, TCA, phenothiazines). However, drugs like Detrol® (tolterodine) poses little risk of urinary retention, IF there is good flow. Antimuscarinics work during storage, rather than voiding.
    • Anticholinergics: same as above (benztropine, hyoscyamine)
    • Diuretics: polyuria secondary to high dose therapy may present as urinary frequency.
    CAUTION: Be sure that prostate cancer has been ruled out before recommending saw palmetto.

    According to the May 2016 fact sheet from the Department of Professional Employees, more than 26.2 percent of pharmacists were 55 years or over in age. As this gray haired 60-year-old pharmacist approaches senior citizen status let’s talk about saw palmetto and its use in treatment for BPH.

    Benign Prostatic Hypertrophy (BPH) is characterized by too frequent urination, having trouble starting or maintaining urination, and needing to urinate during the night. The urethra, the tube that “drains” urine from the body, runs through the prostate gland in men. When the prostate gland is enlarged, obstruction of the urethra occurs and men may have trouble urinating.

    At the Empower-3 clinic where I practice two days a week, we have changed three men from Flomax (tamsulosin) to alfuzosin (Uroxatrol) which both drugs have generic formulations that are inexpensive. According to Up-To-Date®, tamsulosin decreased the volume of ejaculate in more than 90 percent of patients, with 35% had no ejaculate.

    Silodosin (Rapaflo) produces retrograde ejaculation (semen gets rerouted into the bladder) in 28 percent of patients. There are no reports of Alfuzosin (Uroxatrol) causing these ejaculatory difficulties. Have that conversation with your sexually active males on alpha-1 blockers!

    Have a great day on the bench!!

    Ginkgo biloba for memory, circulation, tinnitus?? Depends what side of the ocean you are on. Germans consider it first line.

    When is the last time you wrote or filled a prescription for Ginkgo biloba?

    GINKGO BILOBA
    Ginkgo biloba “maiden hair tree” said to be the world's oldest living tree species. The leaves are used with the highest concentrations occurring in the autumn when the leaves begin to change color. Even so, the compounds need to be extracted. Dried leaves, and teas are probably ineffective. Dose 120-240mg daily in 2-3 doses. USE: dementia, including Alzheimer's, vascular, and mixed dementia. Also used for cerebral vascular insufficiency. Ginkgo has also been used for peripheral occlusive vascular disease (intermittent claudication). It has also been tried for sexual dysfunction, multiple sclerosis and tinnitus.

    CAUTION:
    if taking oral anticoagulant therapy. Ginkgo inhibits the binding of platelet-activation factor (PAF) to platelets; this action may increase bleeding time and can augment effects of anti-coagulant therapy. Stop 2-3 weeks before elective procedure. Also use caution if given with other NSAIDS and herbals like turmeric.

    SIDE EFFECTS:
    headache, nausea, gastrointestinal upset, diarrhea, dizziness, or allergic skin reactions. More severe allergic reactions have occasionally been reported.

    CANCER:
    According to a study done on rats and mice by the National Toxicology Program, Ginkgo biloba extract caused cancers of the thyroid gland in male and female rats and male mice and cancers of the liver in male and female mice.

    German Commission E:
    monograph states that Ginkgo Biloba Extract formulation (which is the dry leaf extract and is standardized) is effective for symptomatic treatment of organic brain syndrome caused by cerebral insufficiency or dementia syndromes. This is dated 1994, and whether these results can be extrapolated to other ginkgo products is uncertain. German physicians still consider Ginkgo extract to be the first choice for their dementia patients; it is also used for depression, Raynaud’s disease and tinnitus.

    Here is what the studies say: (and it is all bad news for gingko)
    GEM Study (Gingko Evaluation of Memory study) which enrolled 3,000 volunteers over the age of 75, were taking 240mg of standardized gingko daily. They were followed for an average of 6 years. Analysis of the data was disappointing, showing that ginkgo was ineffective in slowing cognitive decline, lowering blood pressure, or reducing the incidence of hypertension. This study was funded by NCCIH (National Center for Complementary and Integrative Health)
    National Institute on Aging did a trial of more than 200 healthy adults over age 60 found similar results in that ginkgo taken for 6 weeks showed no improvement in memory.

    Alzheimer’s disease, which is the most common cause of dementia and affects as many as 5.1 million Americans age 65 and older in the U.S., may triple in the next 40 years. (With my 60th birthday coming this Friday, I now pay attention to these statistics!!)

    We all dispense a lot of Donepezil, Rivastigmine and Galantamine. Only 1 in 12 patients on these cholinesterase inhibitors show any improvement. Not to mention that 1 in 12 patients have significant side effects, usually GI upset (due to increased GI secretions), as well as bradycardia and fainting.

    These cholinesterase inhibitors are first line for mild to moderate Alzheimer's if the patient or family wants to try drug therapy. Cholinesterase inhibitors increase the levels of acetylcholine, which may cause increase in increase in urinary incontinence, which is usually treated with an anti-cholinergic. The two opposing drugs may lead to a pharmacological stalemate.

    Many of our caregivers, sometimes out of desperation will turn to herbals or over the counter supplements to help their loved ones. Gingko biloba and DHA, a component of fish oil are touted as being beneficial for “memory support”.

    Have a great day on the bench!!

    We dispense a lot of generic antidepressants to our patients. Are there any over-the counter treatment options??

    St. John's Wort and treatment of depression

    Common Names: St. John’s wort, hypericum, Klamath weed, goatweed.
    Latin Name: Hypericum perforatum: flowering tops of St. John's wort are used to prepare teas, tablets, and capsules containing concentrated extracts. St. John's wort consists of the dried, above ground parts of H. perforatum gathered during flowering season near the end of June around the Feast of St. John the Baptist (June 24th). Antidepressant activity of SJW is attribute to its hyperforin content, which is highest in the plant during its flowering season. Hyperforin has strong reuptake inhibitor effects on all four of the mood neurochemicals (serotonin, norepinephrine, dopamine and GABA)

    USE: depression, dysthymia, and sleep disturbances.
    DOSE: most common regimen is 300mg up to 3 times daily up to 6 weeks Before we even discuss all the ramifications of using this drug, consider the following:
    • Should we even be considering the treatment of depression as “treatable” condition for our patients? Do we have the clinical skills necessary to manage treatment of depression? This pharmacist certainly does not.
    • Before recommending this herbal, remember that inadequately treated depression may become severe and, in some cases, may be associated with suicide.
    EVIDENCE
    • The German Commission E has recognized St. John's wort as a "modestly effective" antidepressant. Some sources say it is comparable to low dose SSRI’s (like Prozac) or Tri Cyclic Antidepressants (like Elavil)
    • Doubtful efficacy for the treatment of moderate to severe major depressive disorder
    • Remember: Some studies highlight the ongoing concerns with placebo response rates in antidepressant studies which have recently been estimated to be as high as 35—45%. Almost ½ of your patients will get a positive effect from taking a placebo.
    • Usual dose: The usual dose for mild depression and mood disorders is 300 mg (standardized to 0.3% hypericin extract), 3 times per day, with meals. As with all antidepressants expect about three weeks for benefit.
    • Topical use: some value for treating Herpes labialis. Dynamiclear is a single application product for cold sore treatment. He topical oil may have some value in treatment of psoriasis lesions.
    PRECAUTIONS
    • potent photosensitizer- make sure patients are using sunscreen. Risk increases when patients take 2-4 grams of St. John’s Wort extract (contains 5-10mg hypericin)
    • may precipitate manic attack if a patient is bipolar
    • Combining St. John’s wort with certain antidepressants can lead to a potentially life-threatening increase of serotonin, thus precipitating “serotonin syndrome”. Serotonin syndrome symptoms range from tremor and diarrhea, confusion, muscle stiffness, tachycardia (rapid heartbeat), seizures, hyperthermia (high fever), and even death. Dextromethorphan may also precipitate serotonin syndrome when given with antidepressants.
    • Avoid if pregnant or nursing
    DRUG: DRUG INTERACTIONS: CYP450-3A4 inducer (expect to decrease levels of interacting drugs), avoid using St. John’s Wort with any drug metabolized by the CYP450-3A4 pathway especially:
    • Warfarin and anticoagulants
    • Phenobarbital and phenytoin
    • Digoxin
    • Other antidepressants
    • Birth control pills
    • Some HIV drugs (NNRTI and Protease inhibitors)
    • Monamine oxidase inhibitors (MAOI)
    • Alprazolam (Xanax) will speed up its metabolism and decrease efficacy by half.
    We can tell that by our purchases of generic Zoloft, Prozac, Celexa and Lexapro in bottles of 500 or 1000 that depression is one of the most common conditions we treat in our pharmacies. Although this herb is in the “Top 10” of herbs used in the United States it also made the “Top 4 Herbal Supplements Your Doctor Hates” list by US News and World Report (2/22/12).

    If our patient's would insist on counseling or the appropriateness of St. John's Wort the minimum "screening questions" we could ask are: (source: aafp.org)
    • "During the past month, have you often been bothered by feeling down, depressed, or hopeless?"
    • "During the past month, have you often been bothered by having little interest or pleasure in doing things?"
    Given the facts of the drug interactions, the placebo effect of treating depression, the potential for serotonin syndrome and even suicide, self-management of depression for our patients is not recommended. Let’s leave the treatment of this condition to clinicians with some level of experience. I'm not recommending that we become amateur psychiatrists!

    Have a great day on the bench!!

    Most of our migraine patients will do anything to alleviate the severity or frequency of their headaches. This herbal product might be of benefit.

    Feverfew... neurologist recommended!

    Petasites is a genus of flowering plants in the sunflower family, that are commonly referred to as butterburs and coltsfoots. Tanacetum parthenium, Chrysanthemum parthenium (feverfew, bachelor’s buttons, featherfew) is ranked #19 as the most often used herb in the US. The leaves or flowers, which can be fresh or dried, as well as a tincture are available. The active ingredient parthenolide, has been studied to prevent menstrual cramps, cancer, as well as treat rheumatoid arthritis and migraine headaches. Petasin appears to be a major active compound of petasites hybridus extract. It has inhibitory activities on leukotriene generation in eosinophils and neutrophils. This indicates that it may have anti-inflammatory and anti-allergy properties.

    EVIDENCE FOR USE:
    • MIGRAINE HEADACHES: Some research suggests that feverfew may be helpful in preventing migraine headaches; however, results have been mixed and more evidence is needed from well-designed studies. Five trials (total 343 patients) were unable to establish that feverfew is efficacious for preventing migraine. There is insufficient evidence from some controlled clinical trials that feverfew was better than placebo for migraine treatment. Side effects were minimal with only mild and transient adverse events were reported in the included trials. Some of the trials used an alcoholic extract, while trials that used the dried leaves seemed to show more efficacy for migraine treatment.
    • Some studies showed patients reported a decrease in severity and frequents of headaches, as well as a decrease in nausea. American Academy of Neurology and the American Headache Society suggest that a feverfew extract may be effective and should be considered for migraine prevention. Petadolex® is the brand most studied.
    • RHEUMATOID ARTHRITIS: One study found that feverfew did not reduce rheumatoid arthritis symptoms in women whose symptoms did not respond to conventional medicines. It has been suggested that feverfew could help those with milder symptoms. It was found to no more effective than placebo for the treatment of rheumatoid arthritis.
    • CANCER: Did show some anti-cancer effects in lab studies. Human studies are needed.
    FEVERFEW PRECAUTIONS:
    • If allergic to other members of the daisy family (which includes ragweed and chrysanthemums) are more likely to be allergic to feverfew.
    • Pregnancy and nursing: NOT recommended during pregnancy, because of its abortifacient properties in early pregnancy.
    • People taking anticoagulants should use feverfew with caution because feverfew may potentiate the activity of anticoagulants such as warfarin
    • Side effects: Common: Minor gastrointestinal distress; oral ulcerations from chewing fresh feverfew leaves; airborne contact dermatitis; exacerbated dermatitis following use of a moisturizer containing feverfew.
    Feverfew got its name from the Greeks, who thought it reduced fever, but is of minimal value. In the 1980’s it was frequently recommended along with magnesium and Riboflavin (B2) for the prevention of migraine headaches. Many of our local neurologists start patients with Magnexium Oxide and Riboflavin (B-2) as initial prophylactic therapy.

    As we journey through the many herbals that are available to our patients, we wont seen many that are endorsed by traditional medical societies. Feverfew is one exception to that notion. After reading that the American Academy of Neurology and the American Headache Society recommend it's use, I'd feel comfortable recommending it to my patients.

    The challenge, as always in the United States, is the lack of standardization of these herbal products. Petadolex® seems to be the product with the most support for efficacy. It is available through our pharmacy warehouses, and retails around $45.00 per month. Most references, particular in Canada require feverfew supplements should be standardized to contain at least 0.2% parthenolide.

    Have a great day on the bench!!

    Echinacea... might be better for our patients than a Z-pak!

    Our next herbal product...Echinacea

    Echinacea is one of the top five herbs that our patients have questions about. Many have their own notions on this herbs efficacy. Like all products we sell it does come with a few warnings that might not make it appropriate therapy for a select group of patients. Efficacy seems to be another issue.

    Ecinacea comes from the Echinacea angustifolia, or E.purpurea, or E.pallida (American cone flower, Kansas snake root). It is found widely throughout North America and was used by the Native Americans both topically and orally for the treatment of burns, snakebites, pain, cough, and sore throat. All nine species are native to North America. The fresh or dried roots or above-ground parts that are collected at the time of flowering of the Echinacea angustifolia, is what is used in medicinal preparations.

    USE:
    Echinacea is used today in the prevention and treatment of the common cold to decrease both the duration and severity. According to most current literature, prevention and treatment of common cold is modest at best. Well-designed clinical trials have not proven its benefit in treatment/prevention of upper respiratory infections, including the common cold.

    PRECAUTIONS:
    • Allergy to related plants in the daisy family: ragweed, chrysanthemums, marigolds, and daisies.
    • The immune stimulating effects of Echinacea have led to concerns regarding the use of Echinacea in patients with autoimmune disorders. It isn’t known whether Echinacea may exacerbate autoimmune disorders, such as Lupus, Sjogrens syndrome or rheumatoid arthritis. I wouldn’t recommend Echinacea in any of these patients. Patients that have atopic dermatitis have increase likelihood of allergic reactions and should also avoid echinacea.
    • According to one study the authors noted that there were small trends in the direction of a benefit from echinacea—an average half-day reduction in duration, or an approximate 10 percent decrease in severity—the researchers concluded that echinacea, at this dose formulation, does not significantly change the course of the common cold.
    • A 2001 study of 80 adult male and female subjects showed a reduction of duration of cold symptoms from 9 days for the placebo group versus 6 days for the echinacea group. https://www.ncbi.nlm.nih.gov
    • Dose most frequently studied: (The echinacea tablets contained the equivalent of 675 mg of E. purpurea root and 600 mg of E. angustifolia root.) Most common strength available OTC is 400mg capsules.
    • Commission E monographs from Germany: Only two preparations have been approved by the German Commission E. These include the root extract of Echinacea pallida used to support and promote natural powers of resistance of the body, especially infectious conditions (influenza and colds), and the expressed juice of Echinacea purpurea, as a supplemental treatment for upper respiratory and urinary tract infection.
    So it seems like Echinacea doesn’t have the evidence that supports our recommendation for treatment or prevention of the common cold. As we with Vitamin C, patients need to be on it chronically to reduce the duration or intensity of the common cold. Antibiotic prescriptions that many prescribers send our way, actually do more harm.

    The latest antibiograms from Central Pennsylvania hospitals are showing resistance to Azithromycin (Z-pak) of 50%. Thanks to the indiscriminate use of antibiotics, Azithromycin is ineffective against the most common bacterial pathogen half of the time! All of a sudden now using echinacea for the common cold doesn’t seem like such a bad idea!

    Just make sure it is for the right patient. With the lack of standardization of herbal products in the United States, and the fact there are 9 different species of coneflower makes consistency of Echinacea very challenging.

    Remember if you treat the common cold it lasts 7 days; if untreated it lasts one week!

    Have a great day on the bench!!

    April 2018

    We have insulin, sulfonylureas, SGLT2 inhibitors, gliptins, alpha glucosidase inhibitors, DPP4 inhibitors and biguanides... how about a sprinkle of cinnamon?

    Instead of all those pills, can I take a natural product for my Type-2 diabetes?

    Cinnamon fits into both the food and medicinal herb categories. We have our “Cinnamon Toast Crunch” (my kids favorite) cereal for breakfast, and we sell cinnamon in our herbal section to improve glycemic control for our diabetics. Because of the lack of standardization in the United States, and the very conflicting data, I am hesitant to recommend this herbal product. Cinnamon contains coumarins, which in high doses can lead to liver toxicity, when doses exceed 7grams. Here is some background information:

    From Cinnamomum aromaticum, a small evergreen tree native to Southern India and Sri Lanka, Malaysia and Madagascar. Cinnamon bark (Cinnamomum verum) is the most common type used in the Western world, as a cooking spice. Bark most commonly used and occasionally, leaves and buds.

    Use: Treatment of Type-2 Diabetes. Cassia cinnamon (“Chinese cinnamon”) is believed to be most effective. This type of cinnamon is commonly found in herbal products in pharmacies and health food stores. As of now most believe it is to be used as “adjunctive” therapy, when added to sulfonylurea therapy (8.22% to 7.86% after 12 weeks) in a well-designed study. Seemed to be of some benefit in those with poor glycemic control, by increasing sensitivity at the insulin receptor.

    ADA journal article: 60 DM Type-2 patients studied for 60 days: After 40 days, all three levels of cinnamon reduced the mean fasting serum glucose (18–29%), triglyceride (23–30%), LDL cholesterol (7–27%), and total cholesterol (12–26%) levels; no significant changes were noted in the placebo groups. Dose used was 1g, 3g, 6g of cinnamon. (2004 article). Patients took 1, 3 and 6 grams of cinnamon in the study arm. This study was done in Pakistan.

    National Institutes of Health: “High-quality clinical evidence (i.e., studies in people) to support the use of cinnamon for any medical condition is generally lacking”

    University of Connecticut School of Pharmacy: Diabetes Care. 2008;31(1):41. PRECAUTIONS/CONTRAINDICATIONS:
    • RESULTS: Five prospective randomized controlled trials were identified. Upon meta-analysis, the use of cinnamon did not significantly alter A1C, Fasting Blood Glucose, or lipid parameters. Subgroup and sensitivity analyses did not significantly change the results.
    • CONCLUSIONS: Cinnamon does not appear to improve A1C, FBG, or lipid parameters in patients with type 1 or type 2 diabetes.
    CAUTION: Cassia cinnamon contains coumarin, consuming large amounts my lead to liver toxicity.
    DRUG/FOOD INTERACTIONS: Cinnamon may reduce the effectiveness of tetracycline antibiotics. PREGNANCY: Use of cinnamon in amounts greatly exceeding those found in foods is not recommended during pregnancy

    In 1958 the rate of Type-2 diabetes in the United States was 1%, sixty years later we are approaching the 10% mark. Many of our patients want to take "natural" products to manage their Type-2 diabetes. Most often they inquire about cinnamon, and the results are variable indeed.

    Depending on what the patients want to believe they can find evidence supporting claims that cinnamon is useful for Type-2 diabetes management.

    There is a plant called goats rue (Latin: Galega officinalis) that is endemic to the temperate climates of Europe and the United States. By studying some of the compounds in this plant the biguanide class was discovered which includes phenformin (D.B.I) which was removed from the market in the 1970's due to lactic acidosis, as well a metformin (Glucophage). Goat's rue was considered an agricultural pest and placed on the "Federal Noxious Weed List" in the United States. Think of that next time you prescribe or dispense metformin!

    The newest class of diabetes drugs, the "flozins" or SGLT-2 inhibitors like canaglaflozin (Invokana) also came from a natural product. Phlorizin, a naturally occurring compound extracted from the root bark of an apple tree in 1835 and later identified as a SGLT1 and SGLT2 dual inhibitor, was the precursor to this category of drugs.

    Maybe there is an active compound in cassia cinnamon that will be elucidated as a treatment for Type-2 diabetes, but for now tell your patients that it is best to sprinkle their cinnamon on a fresh apple!

    Have a great day on the bench!!

    Bright yellow and in our spice cabinet, this Indian herb may be beneficial to our arthritis patients.

    Turmeric---not just for cooking!

    Latin name: Curcuma longa

    Common Name: Indian saffron or curcuma which is related to ginger, is grown throughout India, other parts of Asia, and Central America. Turmeric is a major ingredient in curry powder. The medicinal part of the plant used is the dried rhizome.

    Primary active ingredients: curcuminoids, which are bright yellow and used to color foods and cosmetics. Turmeric is what gives curry it’s bright yellow color in cooking. The German Drug Codex monograph requires turmeric to contain not less than 3.0% curcuminoids, calculated as curcumin, and not less than 3.0% volatile oil.

    Possible uses: osteoarthritis, digestive disorders, and potentially stroke prevention by quelling inflammation in blood vessels,

    Possibly effective: Osteoarthritis-- Some turmeric extracts can improve symptoms of osteoarthritis. Taking a specific turmeric extract (Meriva by Indena) 500 mg twice daily seems to reduce pain and improve functionality in patients with osteoarthritis of the knee after 2-3 months of treatment. Patients using this product saw decreased use of NSAIDS.

    The University of Arizona Health Sciences secured an NIH grant to conduct studies of turmeric (CLaRA study), where they found turmeric to be effective as an anti-inflammatory, in rheumatoid arthritis patients. Researchers also found that turmeric blocks a protein that causes bone breakdown in these patients.

    The rhizome contains an anti-inflammatory and choleretic volatile oil. Anti-inflammatory actions may be due to leukotriene inhibition, as well as COX-2 inhibition. Turmeric has been used as a “digestive aid”; as a choleretic it increases release of bile, therefore it is contraindicated if the patient has gallstones.

    PRECAUTIONS/CONTRAINDICATIONS:
    • High doses of turmeric can act as a blood thinner, and also cause stomach upset. Avoid turmeric/curcumin in patients that take blood thinners such as warfarin (Coumadin).
    • Are about to have surgery
    • Pregnant
    • Have gallstones or any gallbladder disease
    Dose:
    • Osteoarthritis: In capsule form use 400 mg to 600 mg, three times per day.
    • Rheumatoid Arthritis: 500 mg twice daily.
    In last week’s column, I invited all my readers to feel free to e-mail me their request for whatever herb they would like covered. My first response was from one of my pharmacist colleagues who is 87 years old, and still practicing part time. He is a voracious reader, and is a self-proclaimed “nerd” as I am. To respond to this very seasoned pharmacist’s request the first herb we will cover is Turmeric or Tumeric.

    Our warehouse has at least 12 different brands of turmeric capsules available, and most cost less than $10.00 per month. This is one herb I will feel comfortable recommending to our arthritis patients, as long as they do not have any contraindications as listed in this newsletter. There seems to be a fair amount of efficacy for this herb, and our questions about its use will be answered when the CLaRA study is completed.

    Have a great day on the bench!!

    Herbal Therapy-- pharmacists are expected to have some degree of proficiency!

    Herbal Pharmacy --- what a challenge!

    So often it is difficult to substantiate any benefit from Herbal therapy, while side effects seem to appear rapidly. I find these products to be particularly challenging, given the fact we seem to have better pharmacotherapeutic choices in the prescription department.

    Herbals: Challenges for pharmacists
    • our training is very limited- including mine
    • the prescribing community knows even less!
    • consistency of products between distributors and manufacturers
    • At best supporting literature is weak. Frequently we see conflicting studies and results.
    Best website I’ve found: National Center for Complementary and Integrative Health.
    https://nccih.nih.gov/health
    • For this project I’ve joined the American Botanical Council (ABC) for access to the Commission-E monographs. The cost is $50 per year, which allows you access to this herbal website. You can read about each herb individually, or can look up therapeutic categories, and the herbs that are associated with treatment of that disease state.
    Herbal Regulations
    • The FDA loosely regulates dietary supplements, under the Dietary Supplement Health and Education Act of 1994 (DSHEA ’94)
    • Dietary supplementary are considered to be: vitamins, minerals, other botanicals, amino acids, enzymes, organ tissues, glandular, and metabolites. These dietary supplements fall under the category of "foods" and not "drugs".
    • Consequently, scientific data supporting claimed benefit are not always available as for traditional pharmaceuticals. The burden of proof for safety and adulteration of products lays on the Food and Drug Administration (FDA)
    • Consumers should also note that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products.
    • Given the regulatory structure for herbal medicines, there is substantial variation in the quality of commercially available products in the United States and elsewhere. Variability in product quality can impact the product's efficacy, safety, and therefore clinical usefulness.
    What Germany does so well:
    • Commission-E is Germany’s equivalent to the FDA in the United States.
    • There are 380 monographs evaluating the safety and efficacy of herbs for licensed medical prescribing in Germany. Published in 1998.
    • Official monographs that give the approved uses, contraindications, side effects, dosage, drug interactions and other therapeutic information essential for the responsible use of herbs and phyto-medicines.
    • Up to 70% of German doctors prescribe "phytomedicines"
    SAFETY of Herbals: Despite ephedra products comprising only 0.8 percent of all dietary supplement sales in 2001, they were responsible for 64 percent of all herb-related adverse events reported to United States Poison Control Centers during the same year. Fortunately, the FDA banned all products containing ephedra in April 2004. Then the manufacturers substituted bitter orange (citrus aurantium) which contains “synephrine” for ephedra in weight loss products. Synephrine has been associated with serious cardiovascular and neurological side effects.

    I think most of us pharmacists would feel better about recommending these herbal products if we had the guidance of the FDA, as do our pharmacists in Germany have with the Commission-E monographs. Until that happens, I will continue to proceed with caution. Patients seem to equate safety with natural products. I always remind my patients that one of our favorite botanicals is “digoxin” from the foxglove plant, knowing that 1mg can stop a person’s heart. Natural does not equate to safety!

    Feel free to send me an email, so we can explore in depth herbals you might have questions about.

    Have a great day on the bench!!

    Fresh fruits and vegetables might be adequate to prevent constipation, but when it comes to opioid induced constipation, a pharmacist recommendation is critical.

    Management of Opioid Induced Constipation

    Numerous side effects are commonly seen with opioid use such as euphoria, respiratory depression, sedation, GI upset and constipation. Of all the common side effects associated with opioid use, the patient never develops a tolerance to constipation. Opioid induced constipation (OIC) occurs in approximately 40% of patients treated with opioids.
    • Use Rome III criteria (less than 3 BM per week)
    • OIC is dose related. As doses escalate, OIC becomes more prevalent
    • Mechanism: opioids bind to mu receptors in the GI tract inhibiting peristalsis.
    Over The Counter:
    • Stool softeners can result in "all mush, no push" simply because there's not enough GI motility. Stool softeners are of little value for OIC.
    • For patients on opioids (hydrocodone, oxycodone, codeine etc.) recommend a stimulant laxative (senna or bisacodyl) to increase GI motility plus docusate if the stool is too hard to pass.
    • OTC Polyethylene Glycol 3350 (MiraLAX) is another excellent choice.
    Peripherally Acting Mu-Opioid Receptor Antagonists (PAMORAs)
    How they work: preferentially block mu-opioid receptors in the GI tract and do not interfere with the pain-relieving effects of opiates on the mu receptor in the central nervous system.

    Methylnaltrexone: (Relistor®)
    • Mechanism: Methylnaltrexone is a PAMORA with a quaternary amine structure, blocking the ability of methylnaltrexone to cross the blood-brain barrier.
    • Indication: Treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.
    • Warnings/Precautions/Adverse Effects:
      • Contraindicated if known or suspected mechanical gastrointestinal obstruction
      • Discontinue therapy if severe or persistent diarrhea occurs
      • Use with caution in patients with known or suspected lesions of the GI tract
      • May cause gastrointestinal perforation (serious adverse effect)
      • Pregnancy category: B
      • May cause diaphoresis, abdominal pain, flatulence, nausea, dizziness (common adverse effects)
    • Effects can be seen within 4 hours of administration
    Relistor® (methylnaltrexone) injection dosage:
    cost around $125 for 12mg vial


    Injection is based on body weight. Typical dose is 12mg SC once a day for chronic non-cancer pain.
    Relistor 150mg (ORAL) tablets cost: $1635.00/month
    Dose: 3 x150mg tablets (450mg) daily in the morning half hour before first meal of day

    Naloxegol (Movantik®) cost: $314/month
    opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.
    Dose: 25mg once daily; if not tolerated reduce to 12.5mg daily. If renal impairment less than 60ml/min, use 12.5mg daily. Take on empty stomach, one hour before a meal or 2-3 hours after a meal.
    Drug interactions: Avoid CYP450-3A4 inhibitors (diltiazem, verapamil, erythromycin), or reduce to 12.5mg daily. Avoid grapefruit juice.
    STOP all maintenance laxatives before starting Naloxegol, may restart in 3 days if not effective.
    • effective in people who have taken opioid pain medicines for at least 4 weeks
    • if opioid is stopped, stop Movantik®
    Naldemedine (Symproic®) cost: $314/month
    opioid antagonist indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain. Is a derivative of opioid antagonist naltrexone. It has a large polar side chain to prevent penetration into the CNS. Works by blocking opioid receptors in the GI tract.
    Dose: 0.2mg tablet once daily, any time of day, with or without food.
    Drug interactions: is a substrate of CYP 450 3A4 watch for drug interactions with rifampin (induce). CYP-450 3A4 blockers can cause excessive levels of naldemedine.
    Prescription medications for treatment of OIC
    • Methylnaltrexone (Relistor) 12mg SC daily (chronic non-cancer pain)
      • Relistor 150mg tablets 3 tablets in the morning
    • Naloxegol (Movantik) 25mg orally in the morning
    • Naldemedine (Symproic) 0.2mg tablet orally daily in the morning
    • Lubiprostone (Amitiza) 24mcg orally twice daily (see last week’s newsletter)
    Opioid induced constipation can be a challenge to treat. So often a clinician will recommend docusate for prevention which for most cases is not adequate to treat OIC. Addition of fiber like Metamucil or Citrucel is a worse choice as lack of peristaltic activity can lead to impaction.

    Fresh fruits and vegetables might be adequate for a teenager who has their wisdom teeth extracted to prevent constipation for their acute hydrocodone prescription. However for our patients taking chronic opioids, this newsletter will be of great benefit helping clinicians select appropriate treatment. Stimulant laxatives over the counter are the most economical ways to handle OIC, however for patients receiving higher doses of opioids, prescription treatment might be indicated.

    Have a great day on the bench!!

    March 2018

    We'll explore some of the most expensive treatment options for constipation...of course they are prescription!!

    PRESCRIPTION TREATMENT of CIC and IBS-C!

    Let’s look at the prescription options for treatment of chronic idiopathic constipation (CIC) and Irritable bowel syndrome constipation predominant (IBS-C)

    NEWER TREATMENTS OF CHRONIC CONSTIPATION

    AMITIZA® (Lubiprostone) : 8mcg and
    24mcg(AWP=445.32)
    First approved 2006


    Mechanism: Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby increasing the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. Indication

    • Treatment of chronic idiopathic constipation (CIC) in adults.
    • Treatment of irritable bowel syndrome with constipation (IBS-C) in women over 18 years old
    • Also indicated for opioid induced constipation.
    Warnings/precautions/adverse effects
    Potential to cause miscarriage (have negative pregnancy test, use contraceptive measures) Pregnancy category: C
    May cause nausea, diarrhea, abdominal distention, loose stools, flatulence and vomiting
    May also cause headache, dizziness and peripheral edema

    Amitiza® (lubiprostone) 24mcg and 8mcg CIC: Dosage: 1 capsule (24mcg) BID with food IBS-C: 8mcg BID for women age 18 and over.

    LINZESS® (linaclotide) 72mcg, 145cg and 290mcg caps
    (AWP=$464.47)-
    First approved:2012


    Indication: irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC).

    Dose: one capsule each day on an empty stomach, at least 30 minutes before your first meal of the day. Swallow LINZESS capsules whole. Do not break or chew the capsules
    Mechanism: guanylate cyclase-C agonist. By increasing the concentration of cyclic guanosine monophosphate (cGMP), linaclotide leads to secretion of chloride and bicarbonate into the intestinal lumen which causes an increase in fluid and GI transit time.
    • For IBS-C, linaclotide should be dosed as 290 mcg once daily on an empty stomach. For IBS-C, Linzess decreases PAIN from IBS-C
    • For CIC, the approved dose is 145 mcg or 72mcg once daily on an empty stomach
    • Do not use in patients less than 18 years of age
    TRULANCE® (plecanatide) 3mg tablets ($466.16)
    First approved-2017

    Trulance (plecanatide) 3 mg tablets is indicated in adults for the treatment of
    • Chronic Idiopathic Constipation (CIC) and
    • Irritable Bowel Syndrome with Constipation (IBS-C).
    Mechanism: Except for a single amino acid substitution, Trulance is structurally identical to human uroguanylin. Uroguanylin activity modulates within the changing pH environment of the intestines, coinciding with areas of fluid secretion, and decreases pain sensation.
    Dose: 3mg once a day, taken with or without food.

    Next week we will discuss the prescription treatment options for opioid induced constipation.

    TFiber supplements and stimulant laxatives have been around for a very long time. Many of us “seasoned” pharmacists remember “if not nature---Metamucil” and “Doxidan in the PM for a BM and the AM.” We cant forget to mention "Natural and Gentle Fletcher's Castoria".

    And of course every Saturday night Lawrence Welk would be promoting "Serutan--that is Natures spelled backward." There have always been a lot of advertising for laxatives in the media, but our patients always asked for our recommendations.

    Since 2006, we have had three new laxatives on the prescription shelves that are indeed effective and very expensive. We've seen ads on TV for Amitiza "move to your own beat" as well as Linzess "ease the pain"-- just ask your doctor!! Just be sure to have enough in your health savings accounts!

    Have a great day on the bench!!

    When fiber and softeners are not quite enough, we have to "get things moving" with a stimulant laxative.

    Sometimes our patient's boels need a little "push"

    Laxatives that Result in Soft or Loose stool in 6-12 hours

    Bisacodyl (oral) Dulcolax® 5mg 5-15mg daily HS
    Senna Senokot® 8.6mg 2HS, max=4 daily
    Magnesium hydroxide Milk of Magnesia (400/5) 30-60ml HS


    Stimulant agents

    Indication: Are effective as initial therapy to treat constipation but should not be used for more than 1 week. Chronic use was believed to lead to cathartic colon, which results in poorly functioning colon, resembling ulcerative colitis. However, most of these cases are reported before 1960 when toxic cathartics were used (podophyllin). Still a subject of controversy whether mild laxatives can be used long term.

    Mechanism: Increases propulsive contractions by local irritation or action on the intramural nerve plexus of the intestinal smooth muscle, stimulate secretion of water and electrolytes.

    Patient information:
    • Causes discoloration of urine
    • Temporary measure, do not use for longer than one week, without consultation.
    • These agents are often abused.
    • Are excreted in breast milk.
    • May cause harmless melanotic pigmentation of colon
    • May color the urine from pink to brown.
    Senokot® (senna) 8.6mg/ tablet.
    Dosage: start 2 tablets at bedtime; do not exceed 2 tablets twice a day. Senna is often combined with docusate.

    Dulcolax® (bisacodyl) 5mg tablets Dosage: start with 1 tablet at bedtime. Usual adult dose is 2 tablets at bedtime. NOTE: this product is enteric coated do not crush or chew. Do not take within 1 hour of antacids, milk or any product that raises gastric pH.

    Magnesium hydroxide

    Indication: can be used as an antacid for temporary relief of heartburn, or occasionally as a laxative.

    Mechanism: Highly osmotic ions draw water into the intestine and cause an increase in the intraluminal pressure, thereby exerting a mechanical stimulus that increases intestinal motility. Increase cholecystokinin – pancreozymin which is an enzyme that increases the secretion of fluids into the GI tract.

    Drug interactions: Oral anticoagulants, Digoxin, Tetracyclines, Quinolones

    Patient information:
    • May lead to hypermagnesemia (as much as 20% Mg may be absorbed)—problem if renal impaired. Patients with a CrCl <30 mL/minute should be monitored by serum magnesium levels.
    • Sodium: hypertensive or CHF patients should not receive these on a long term basis due to fluid retention from sodium absorption.
    • May see abdominal cramping, excessive diuresis, Nausea, vomiting, dehydration electrolyte disturbances, incontinence.
    • Milk of Magnesia 400mg/5ml
    Is an 8% suspension of magnesium hydroxide Antacid: For the temporary relief of heartburn, upset stomach, sour stomach, or acid indigestion. Laxative: For relief of occasional constipation. Expect results within 30 minutes to 6 hours. Dose: 1 to 2 ounces at bedtime. Shake well before using and follow dose with 8 oz of water.

    Thanks to the frequent practice of "cross-branding" we pharmacists should always be consulted before our patients make a laxative purchase. Some companies use their Proprietary name to enhance a whole line of products. I feel Dulcolax is the worst offender as they have the "Dulcolax" name blasted across their softener which actually contains docusate sodium.

    Among us older practitioners Dulcolax has always meant bisacodyl. Clinicians should encourage patients to consult the pharmacist before purchasing laxative products. Better yet it is prudent for clinicians to write a prescription for the patient to decrease confusion.

    However, I once received a prescription from a physicians office that was computer generated. It said "Dulcolax" (docusate) - take 4 capsules at bedtime the night before the test. I called the physician's office and told them this was the same as "Colace" . The nurse told me, that was the first thing that came up under "Dulcolax". She authorized me to switch it to the bisacodyl product.

    You can only imagine how confused our patients can get with this very foolish practice. As I tell my students---"when I become head of the FDA...this is the first thing I will change!"

    Have a great day on the bench!!

    Sometimes we need more than prunes and psyllium!

    Laxatives that cause softening of feces in 1-3 days

    Generic Representative Brand Dosage
    STOOL SOFTENER
    Docusate sodium Colace® 50, 100 50-360mg/day
    Docusate calcium Surfak 240mg 50-360mg/day
    MINERAL OIL Kondremul® 15-30ml
    LACTULOSE Chronulac®, Constulose® 15-30ml
    SORBITOL 30-50gm
    PEG 3350 soln Miralax® 1 cap 17gm in 8oz water


    Stool softeners

    Indication: Beneficial in anorectal conditions in which passage of a firm stool is painful. Generally used for prevention of constipation.

    Mechanism: Anionic surfactants increase the wetting efficiency of intestinal fluid, thereby softening fecal mass. Facilitates admixture of fat and water to soften stool.
    FYI: Docusate is a “soap” and bridges the barrier between the lipid stool, and water. Cut open a capsule, add to a small prescription vial, add water and shake. Looks like dish-washing soap.

    Patient information:
    • Take with fill glass of water.
    • Do not take with any mineral oil containing laxatives, as this will lead to the oil’s absorption and cause hepatotoxicity.
    Available as:
    • Colace® (docusate sodium) 50mg (rarely used) 100mg (common) 50- 300mg daily in divided doses.AKA : “DOSS”or “DSS””: dioctyl sodium sulfosuccinate
    • Surfak® (Docusate calcium) 240mg dose: one capsule daily.
    Emollients (lubricants)
    Indication: prophylactically in patients who should not strain (anorectal surgery, MI)

    Mechanism: Softens fecal contents by coating them, thereby preventing the colonic absorption of water.

    Patient Information:
    • Do NOT give with stool softeners (Colace, Surfak)
    • Avoid in any patient with the potential to aspirate such as GI reflux, as this could cause lipid pneumonia
    • May cause anal leakage leading to anal pruritis. May stain clothes/furniture.
    • If used long term, supplement with fat soluble vitamins (ADEK) as this will impair their absorption.
    • Take on an empty stomach.
    Available as:
    • Mineral oil: dose 15-45ml HS
    • Kondremul® (mineral oil emulsion) dose: 30-75 ml at bedtime. This product is a pleasantly flavored marshmallow liquid, and is much more palatable than straight mineral oil.
    Lactulose
    Chronulac® (Rx only) Indication: useful particularly in elderly patients. Not usually first line. Takes at least 24-48 hours for action.
    • Also used for hepatic encephalopathy to decrease blood ammonia levels.Because colon contents are now more acidic than blood, ammonia migrates from blood to colon, acid colon contents convert NH3 to the ammonium ion (NH4+) trapping it and preventing its reabsorption.Also because of the laxative effect of lactulose, the ammonia spends less time in the colon, decreasing time for absorption to occur.
    Mechanism: disaccharide used orally or rectally. Metabolized by colonic bacteria to form lactic acid, formic acid, acetic acid and carbon dioxide. Increase osmotic pressure and acidify the colonic contents, thus increasing stool water content and softening.

    Patient information:
    • Give with fruit juice, water or milk to increase palatability.
    • Will cause significant gas, leading to -flatulence, abdominal pain and cramping.
    • May also cause diarrhea and electrolyte imbalances.
    • Because it contains galactose & lactose, use with caution in diabetics.
    • If used over 6 months in elderly measure: electrolytes (K & Cl) & carbon dioxide periodically.
    Available as: Chronulac® (lactulose) 10gm / 15ml available in pints and quarts Dosage 15-30ml daily. Increase to 60ml if necessary.

    Sorbitol
    Not available as a laxative but is available as a sweetening agent for prescription compounding. Along with mannitol, these are alcohol sugars that are used as sweeteners. If your patients are ingesting excessive sugar free candy or gum diarrhea can occur.
    Mechanism: similar to lactulose.

    Polyethylene glycol laxatives
    Indication: Used for colon cleansing before diagnostic procedures or colorectal operations. Can also be used in lower doses for chronic constipation.

    Mechanism: is an osmotic laxative that large molecules draw water into the gut, and increased volume results in distention of the intestines, increasing peristalsis and bowel motility, and softening stools.
    FYI: the number 3350 is the molecular weight of this particular polyethylene glycol.

    Patient information
    • May cause abdominal cramping, flatulence, rectal irritation and incontinence.
    Miralax® contains PEG 3350 (this product for long term management of constipation)

    Dosage: 1 capful (17gm) in 8 oz of water once daily.
    • Available prescription sizes: 255gm (2 weeks supply) and 527gm as (1 month supply).
    • Caution: some generic caps are “oversized” and have a fill line inside. May cause over dosage—more than 17 grams.17gm= 1 heaping tablespoonful
    • Also available over the counter in 7-day, 14-day and 28-day packaging.
    GoLytely, CoLyte, Nu-Lytely: contains PEG 3350, in a 4 liter jug, (approximately 230-240Gm)

    The 4L jug should be reconstituted to the fill line early in the morning, then refrigerated. Do not add flavors (unless provided by manufacturer) or colors to the solution. Follow prescribers protocol.
    • Some prescribers give Metoclopramide (Reglan®) to decrease nausea
    There is always a lot of opportunities for us to discuss laxative use with our patients. Often the intake of water, fiber supplements, fresh fruits and vegetables on't produce the desired results.

    Of all the products we discuss today, docusate (Colace®) and PEG3350 (Miralax®) are the most common we use in the pharmacy. PEG3350 falls nicely into the "softener" category when taken as a 17gm dose once a day. I remember as a much younger pharmacist we had a patient who had multiple sclerosis. She battled constipation for many years.

    Her very astute neurologist would have me break down a bottle of the bowel preparation, and she would mix a portion with water and drink it over a 2 day period. In 1999, Miralax was finally released as a single daily dose of 17 grams. In 2006 the Bayer company got FDA approval to sell this product over-the-counter. In 2012 the product became available as a generic.

    This laxative is the "go to" for pediatric patients (with a doctors recommendation).

    Have a great day on the bench!!

    Less than 10% of our patients ingest enough fiber for bowel regularity. What can we do to help them...

    An apple a day is a good start!!

    The traditional classification of laxatives by mechanism of action is not very useful. Many mechanisms have not been elucidated. Most work by promotion of mechanisms associated with diarrhea, such as electrolyte secretion, decreased water & electrolyte secretion, increased intraluminal osmolarity, and increased hydrostatic pressure in the gut.

    Classification is best accomplished by dividing the drugs into categories based on their time to onset of action. for the next couple newsletters we will focus on laxatives that cause soften of feces in 1-3 days

    Generic Representative Brand Dosage
    BULK FORMING AGENT
    Methylcellulose Citrucel® 4-6 gm per day
    Wheat Dextrin Benefiber® 2 teaspoon up to 3 times daily
    Psyllium Metamucil®, Konsyl® Varies
    Polycarbophil FiberLax®, Fibercon® 4-6gm per day


    Bulk Forming Agents:

    Fiber are natural or synthetic polysaccharide derivatives that absorb water to soften stool and increase bulk, which stimulates peristalsis. Because dietary fiber works in both small and large intestines the onset of action is slow (12-24 hours—up to 72 hours.). Fiber supplements are used to prevent rather than treat constipation. Insoluble fiber does not absorb water; while soluble fiber does. Both help material move through your digestive tract, but soluble fiber can help give stool a softer, bulkier consistency that’s easier to pass.

    Metamucil®: is made from ground psyllium husks, from the plantago ovata plant. Adult dose is 1-2 rounded teaspoonful in 8oz of water 1 to 3 times daily. If using the “Orange Smooth-Real Sugar” product the dose is 1 tablespoonful.

    Fun Fact: Metamucil website has dosages for
    • For helping feel less hungry between meals
    • For promoting and maintaining digestive health
    • For helping lower cholesterol to promote heart health- (psyllium traps bile acids)
    • For helping maintain healthy blood sugar levels as part of your diet
    Patient counseling points:
    • There are Metamucil capsules available, if patients complain of grittiness especially if they wear dentures
    • Make sure patients mix with adequate water
    • Because of fermentation it may cause abdominal cramping, bloating, flatulence, distention, esophageal obstruction, intestinal obstruction, allergic reactions
    • Drug interactions: oral anticoagulants, digitalis, salicylates, tetracycliness
    Citrucel®
    is a synthetic bulk laxative containing methylcellulose. Methylcellulose is derived from cellulose which comes from the cell walls of green plants. It is less likely to cause fermentation leading to bloating and flatulence.
    Dose: 1 tablespoonful 1 to 3 times daily.

    Patient counseling points:
    • Available as orange flavor, sugar free and caplets.
    • Be sure to mix with adequate fluids to prevent esophageal obstruction.
    • Mix with cold fluids, avoiding carbonated beverages and milk.
    Benefiber®
    ingredient: wheat dextrin, which is extracted from wheat starch. Wheat dextrin is a soluble fiber which absorbs water in the intestine to form a viscous liquid which promotes peristalsis and reduces transit time. Helps lower cholesterol (LDL and total cholesterol), reduces risks of coronary heart disease and type 2 diabetes. May be beneficial lowering blood sugar and reducing risk for heart disease.
    Dose 2 teaspoonfuls daily, up to 3 times daily. Benefiber® promotes wheat dextrin as a "prebiotic" which are carbohydrates that act as food for beneficial bacteria in the gut. These carbs (or starches) travel undigested to the colon, where they ferment and produce small chain fatty acids that feed the gut flora. Prebiotics encourage growth of good flora and crowd out the "bad flora"

    Patient counseling points:
    • Will not thicken in liquid, no taste, no gritty texture.
    • Will not alter taste of food or beverages.
    • May mix with water, juice, coffee, baked goods
    • Patients should avoid if they are gluten sensitive
    Calcium polycarbophil (FiberLax®, FiberCon & Equilactin): can be used for both diarrhea and constipation. Is a “stool normalizer”. Polycarbophil absorbs about ten times its own weight of water under acidic conditions, but the swells to 70 times its weight in the neutral pH of the small and large intestines.
    Each caplet contains 625mg calcium polycarbophil=500mg polycarbophil
    Dose: 2 caplet 1 to 4 times daily.

    We discuss another common problem that presents in our clinics, that in many cases can be ameliorated by adequate diet, exercise and hydration. The recommended levels for dietary fiber is 25 grams/day for adult women, 38 grams/day for adult men (consisting of fruits, vegetables, legumes, whole grains)

    About 90% of the US population does not consume this level of dietary fiber, averaging only 15 grams/day.

    "An apple a day keeps the doctor away" with its 4.4 gm of fiber. You will do better with a pear (5.5gm), or half of an avocado (6.75gm) or best of all 1 cup of navy beans at 19.1 grams! Adequate dietary intake as well as exercise and hydration might be all our patients need.

    Have a great day on the bench!!

    We do this every morning! You'll see things in a different way next time you flush!

    There are different types of constipation!!

    We clinicians have a real opportunity to bring comfort to our patients that present to us with constipation. We’ve been all trained to ask about stool frequency, consistency, remitting factors, diet, and exercise but we also need to inquire about the presence of pain. Pain in the belly seems to be the determining factor between Chronic Idiopathic Constipation(CIC) and Irritable Bowel Syndrome Constipation Predominant (IBS-C).

    But as always before we act on any such symptom we need to check the medication list for DRUGS frequently causing constipation:
    Medications that can affect the color of our stools (feces)

    Opioids Calcium channel blockers
    Anticholinergics Calcium carbonate
    Aluminum antacids Iron supplements
    Antidepressants Clonidine
    Antipsychotics Sucralfate
    Diuretics Cholestyramine


    CHRONIC IDIOPATHIC CONSTIPATION (CIC)

    Chronic idiopathic constipation is frequently referred to as “functional constipation”. It is estimated that 14% (as many as 35 million) patients may suffer from this condition.
    • Chronic constipation was more common in females, in older subjects, and those of lower socioeconomic status. 58% of patients suffering from CIC are female
    • Chronic constipation has also been linked to impaired quality of life, especially among the elderly.
    • 72% of CIC patients self-treat with OTC medications, while 13% receive prescription therapy.
    IRRITABLE BOWEL SYNDROME-Constipation predominant (IBS-C)
    Irritable bowel syndrome is defined as abdominal pain or discomfort associated with constipation. This condition is long-lasting and keeps recurring. Patients will have hard or lumpy stools at least 25% of the time, and loose or watery stools less than 25% of the time. It is estimated that 5% (as many as 13 million) patients may suffer from IBS-C. 64% of IBS-C patients are female, and 66% are under the age of 50, therefore this seems to be a “younger woman” problem.
    • Pain is what separates IBS-C from CIC, patients will complain “it feels like a knot in my guts”. 62% will experience abdominal pain.
    • 72% of the patients are constipated, and 59% will have incomplete evacuation on bowel movements
    • 57% of IBS- C patients will self-treat with OTC medications, while 15% will receive prescription medications.
    • OTC meds most often recommended by physicians
      • 52% fiber supplements: psyllium, methylcellulose, wheat dextrin etc.
      • 32% OTC laxatives: senna, docusate, bisacodyl etc.
    Next week we will begin discussions of the pharmacological treatment of constipation.

    We pharmacists are frequently asked what to recommend for constipation. We all have shelves full of laxatives. For the next couple of weeks we will discuss all of the treatment options for constipation, but first we need to know if we should even recommend a self-care product.

    Simply getting the bowels to move might not be adequate treatment for our IBS-C patients. Referral to a gastroenterologist is prudent when there is any type of belly pain or any appearance of blood in the stool.

    Have a great day on the bench!!

    February 2018

    We do this every morning! You'll see things in a different way next time you flush!

    The consistency of our patients stools depend on a lot of factors!!

    Getting to know your innards:
    How long does it take my food to digest? That depends on a lot of factors, depending on the food types we eat, and medications we might be taking to decrease our stomach acid. The pH of your stomach is 1.5 to 3.5, because your stomach excretes about 1.5 liters of gastric acid daily. Fat takes longer to leave the stomach than other foods, sometimes remaining in the stomach for up to six hours. Remember a big meal of a double burger and fries? You feel full for a very long time. Liquids take around 20-30 minutes to exit the stomach. Water and liquids do fill you up, but that effect doesn’t last very long. Complex carbohydrates break down at a slower rate than simple carbohydrates. Proteins take about 1.5 hours to leave the stomach.

    Usually, most of a regular-sized meal empties from the stomach within two hours. After that it takes about 6 hours to pass through the small intestine, where bicarbonate is added to the mix to bring the pH to a more neutral 7. Your small intestine as around 22.5 feet long and about 1.5 inches wide. Food enters the large intestine, which is around 5 feet long, for more digestion and absorption of water and essential vitamins. Undigested material gets pushed toward the anus for elimination. It takes an average of 33 hours (almost 1.5 days) for foods to reach from the mouth to the anus.
    Once it gets to the end, for elimination our stools can be graded for texture and even color depending on medications being taken: Bristol Stool Scale: is a scale that gastroenterologists use to “classify” our feces. Feel free to see the Bristol Stool Scale charts on-line!
    • Type 1: Separate hard lumps, nut-like in appearance
    • Type 2: Sausage-shaped, but lumpy
    • Type 3: Like a sausage but with cracks on its surface
    • Type 4: Like a sausage or snake, smooth and soft. (most normal stool)e
    • Type 5: Soft blobs with clear cut edge
    • Type 6: Fluffy pieces with ragged edges, a mushy stool
    • Type 7: Watery, no solid pieces, entirely liquid
    Medications that can affect the color of our stools (feces)

    Color Agents
    black Iron, charcoal, bismuth (PeptoBismol)
    Red or orange phenazopyridine, rifabutin, rifampin, or antacids with aluminum. Cefdinir interacts with iron in baby formulas, and breast milk
    White speckled Antacids with aluminum
    Yellow Alli (orlistat) or anything that inhibits fat absorption