• SIGN IN
  • GET HELP
  • October 2019

    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/


    Generic Brand Sedation Anticholinergic Maximum daily dose
    FIRST GENERATION
    Chlorpheniramine Chlor-Trimeton Low-moderate Moderate 24mg
    Clemastine Tavist-1 Moderate High 2.68mg
    Diphenhydramine Benadryl High High High 200mg
    SECOND GENERATION
    Cetirizine Zyrtec Low-moderate Low to none 10mg
    Loratadine Claritin Low to none Low to none 10mg
    THIRD GENERATION
    Fexofenadine Allegra Low to none Low to none 10mg
    Desloratadine (Rx) Clarinex Low to none Low to none 5mg/day
    Levocetirizine (Rx) Xyzal Low to moderate Low to none 5mg/day


    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
    Green Chlorophyll, iron or drugs causing diarrhea (antibiotics, laxatives)
    Red or black tarry stools GI bleeding due to aspirin, NSAIDs, antiplatelet drugs, or anticoagulants
    Pale stools Liver injury from hepatoxic drugs


    Most of us seasoned practitioners have our own favorite stories about patients and their vivid descriptions of their bowel movements! Most often when they need a laxative they go to great lengths to describe their consistency of their stools.

    When I was first licensed an elderly gentleman came to the pharmacy and asked for a good "physic". He got a blank stare from this newly minted pharmacist. I asked him what he meant, and he said "Kid I need to take a good s---t" What a lesson in vocabulary building!

    I have also had patients on wax matrix potassium supplements bring in a "ghost tablet" from their stool to prove to me that the potassium I dispensed wasn't working because it did not dissolve!

    For the past 36 years I remember to tell all of my potassium patients about the ghost tablets and this is a normal sighting. My question is why don't the makers of potassium wax matrix tablets make them brown in color, rather than orange (Klotrix®) or bright yellow (K-tabs®) !

    Tomorrow morning when you flush the toilet, you will have a greater appreciation for your gastrointestinal tract! Next week we will start covering laxatives.

    Have a great day on the bench!!

    Not exactly billion dollar GI drugs... but they are still used!

    Miscellaneous GI drugs to treat GERD and Ulcers.

    We’ll wrap the last of the stomach drugs of the 1980’s three drugs with unique mechanisms of actions.
    SUCRALFATE (Carafate®) approved Oct- 1981 Indications: indicated in the short-term (up to 8 weeks) treatment of active duodenal ulcer. Because it does not suppress acid formation or release it is minimally effective for GERD.

    Mechanism: a mucosal protectant, nonabsorbable disaccharide containing sucrose and aluminum. It heals chronic ulcers without altering gastric acid or pepsin secretion or significantly buffering acid. It stimulates small-vessel formation, and granulation tissue. It binds to the injured tissue and protects it from pepsin and acid.

    Warnings/precautions/adverse effects
    • Constipation, metallic taste, hypophosphatemia (with long term)
    • Compliance problems with QID administration
    • Pregnancy Category: B
    Drug interactions – the aluminum salt is responsible for the impairment in the absorption of several drugs:
    • Bind tetracyclines & fluoroquinolones decreasing their absorption
    • Decreases warfarin absorption
    • Decreases digoxin & quinidine absorption
    • Decreases phenytoin absorption
    • Decrease levothyroxine absorption
    Counseling points:

    Sucralfate should be given on an empty stomach about half hour before meals to “coat” the lining of the stomach.

    Reglan® (metoclopramide) approved Dec-1980

    Indications: short term use (4-12 weeks) for GERD who fail to respond to conventional therapy. Also, used for diabetic gastroparesis. Metoclopramide (Reglan®) also used off label for improved lactation, by increasing serum prolactin. Generally used in patients with motility disorders, or if patients fail on high dose Proton Pump Inhibitors.

    Mechanism: is a dopamine antagonist (blocker) that stimulates motility of upper GI tract, without stimulating gastric, biliary or pancreatic secretions. Appears to sensitize tissues to acetylcholine.

    Warnings/precautions/adverse effects (Major)
    • Depression, restlessness, gynecomastia
    • Tardive dyskinesia
    • Extrapyramidal effects--Parkinson like symptoms
    • May cause drowsiness.
    • Pregnancy Category: B
    Drug interactions: increases alcohol absorption rapidly absorbed in small intestine. Decreases absorption of: cimetidine, digoxin.

    Patient counseling
    • Do not use for more than 12 weeks.
    • Dosed 5mg-10mg four times daily 30 minutes before meals and bedtime
    • Report any signs of tremor. A local neurologist tole me “Pete, before I check a suspected patient for Parkinson’s disease I always check the med list and look for metoclopramide”
    MISOPROSTOL (Cytotec® )Approved Dec-1988 Indications: prevention of NSAID gastric ulceration, in patients at high risk for complications (over 60, debilitating disease, history of ulcers) relief of GERD, reduced gastric acid secretions.
    Mechanism: has anti-secretory (inhibits gastric acid secretion) and mucosal protective properties. NSAIDs inhibit prostaglandin synthesis, a deficiency of prostaglandins within gastric mucosa may lead to diminished bicarbonate and mucus secretion, contributing to damage of gastric mucosa by NSAIDs. Misoprostol is a prostaglandin that increases bicarbonate, and mucus production, and maintains mucosal blood flow. Is also available combined with diclofenac as a single tablet (Arthrotec®)

    Warnings/precautions/adverse effects
    • Abortifacient: black box warning
    • Pregnancy Category-X
    • Diarrhea, abdominal pain up to 40% (usually dose related-take with food)
    • Use Contraceptives in female patients
    • Must have negative pregnancy test in the past 2 weeks.
    • Oral and written warnings.
    Drug interactions: none

    Back in November we talked about the fact that Tagamet was the first billion-dollar drug. The second drug to reach the billion-dollar drug rank was Zantac.

    By 1990 Zantac hit the two-billion-dollar mark. In the 1980’s there was a lot of interest in developing drugs for peptic ulcers, along with gastroesophageal reflux disease.

    A lot of us believe that the proliferation of these “stomach drugs” parallels the exponential increase in restaurants and fast food! Think about that the next time you pull the omeprazole, pantoprazole, esomeprazole, lansoprazole, rabeprazole, dexlansoprazole, ranitidine, cimetidine, famotidine and others off the shelf.

    Have a great day on the bench!!

    Flu season is in full swing... does oseltamivir make your cash register ring???

    $100.00 or more for one day of benefit... at best!

    Oseltamivir (Tamiflu) has been available for treatment of the flu since 1999. It works by inhibition of neuraminidase. By binding to neuraminidase proteins, oseltamivir prevents flu viruses from spreading from infected cells to other healthy cells. Oseltamivir is a prodrug and is pharmacologically similar to zanamivir. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite.

    So far this flu season of 2018, influenza viruses have been susceptible to the neuraminidase inhibitor antiviral medications, which also includes zanamivir (Relenza®), and peramivir (Rapivab®).

    Indications for use:
    • Patients two weeks of age and older, who have had flu symptoms for 2 days (48 hours) or less. Oseltamivir is effective against both influenza type A and B. Therapy should begin within 48 hours of the onset of symptoms. Oseltamivir may reduce symptoms by 1 day.
    • Prevention of influenza A and B in patients one year of age and older
    Warnings/Precautions/ Adverse effects:
    • Nausea, vomiting, headache and pain.
    • Drug interactions: probenecid causes a 2-fold increase due to decreased tubular secretion.
    • CDC warning: November 13, 2006: The FDA approved a labeling supplement to include a precaution about neuropsychiatric events for Oseltamivir (Tamiflu®). Self-injury and delirium has been observed in Japan primarily among pediatric patients. Monitor pediatric patients for signs of unusual behavior.
    Representative Products:

    Tamiflu® (oseltamivir) 30mg, 45mg, 75mg capsules, (generics are available)
    and powder for suspension 6mg/ml: 60 ml per bottle Adults: 75mg twice daily for 5 days. Children: based on body weight If younger than 1 year old: 3 mg/kg/dose twice daily If 1 year or older, dose varies by child’s weight:
    • 15 kg or less, the dose is 30 mg twice a day (suspension: 5ml BID)
    • >15.1 to 23 kg, the dose is 45 mg twice a day (susp: 7.5ml BID)
    • >23.1 to 40 kg, the dose is 60 mg twice a day (susp: 10ml BID)
    • >40 kg, the dose is 75 mg twice a day (susp: 12.5ml BID)
    Patients should start the 5-day regimen as soon as possible. Take two doses the first day, no matter when the prescription is received.

    The prophylaxis dose is the same as above EXCEPT all doses are given ONCE daily for 10 days. Patients need to be over 1 year of age to receive prophylaxis.

    What oseltamivir doesn’t do:
    • It does not prevent bacterial infections
    • It is NOT a substitute for the annual flu vaccine
    • Of no value if started later than 48 hours after onset of symptoms.
    APPROACH WHEN TAMIFLU (oseltamivir) liquid is not available: (from the Tamiflu® website) For patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation.
    • When TAMIFLU for oral suspension is not available from wholesaler or the manufacturer, TAMIFLU capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar (dissolved in water).
    • During emergency situations and when neither the oral suspension or the age-appropriate strengths of TAMIFLU capsules to mix with sweetened liquids are available, then a pharmacist may prepare an emergency supply of oral suspension from TAMIFLU 75 mg capsules.
    The following chart shows how to make Tamiflu in an oral suspension of 6mg/ml

    Total Volume of Prepared Oral Suspension 37.5ml 75ml 100ml 125ml 150ml
    Number of Tamiflu 75mg strength
    capsules (total strength)
    3 capsules (225mg oseltamivir) 6 capsules (450mg oseltamivir) 8 capsules (600mg oseltamivir) 10 capsules (750mg oseltamivir) 12 capsules (900mg oseltamivir)
    Amount of water 2.5ml 5ml 7ml 8ml 10ml
    Volume of vehicle (Cherry Syrup (Humco);
    OR Ora-sweet SF (Paddock Laboratories) OR simple syrup
    34.5ml 69ml 91ml 115ml 137ml


    STEPWISE DIRECTIONS:
    1. Place specific amount of water in PET or Glass bottle
    2. Separate capsules and pour powder from those capsules into bottle
    3. Gently swirl suspension to ensure adequate wetting of powder
    4. Slowly add specified amount of vehicle. Use only the vehicles listed above. Cap the bottle.
    5. Shake well for 30 seconds. Add shake well label to bottle.
    6. Stability
      1. Refrigeration: Stable for 5 weeks (35 days) when stored in a refrigerator at 2° to 8°C (36° to 46°F).
      2. Room temperature: : Stable for five days (5 days) when stored at room temperature, 25°C
    7. Counsel patient on storage, instruct to shake well, discuss dosing regimen, provide a liquid measuring device.


    Remember rimantadine (Flumadine®) and amantadine (Symmetrel®)? High levels of resistance to amantadine and rimantadine persisted among circulating influenza A viruses. Adamantanes are not effective against influenza B viruses. They have not been recommended for treatment of the flu for at least 10 years.

    All we have in the prescription department to combat influenza are the neuraminidase inhibitors. I have not dispensed Relenza® (zanamivir) in years. When I see many copays crashing the $100.00 mark, as many of elderly have not met their Medicare-D deductibles, we often put the medication back in stock.

    When we see that oseltamavir only shortens the duration by a little over one day, and has to be started within 48 hours of onset, we can see how important influenza vaccines are!

    Frequent hand washing, avoiding sick people, covering mouth and nose when sneezing are all practical tips for staying healthy this time of the year. Remember the flu virus can “live” on some surfaces for up to 24 hours. Routine cleaning of surfaces may reduce the spread of flu.

    Oseltamivir with its high cost over $100 for many, the narrow window of opportunity, and limited efficacy fo shortening flu by one day, make those flu shots in October very important indeed!

    Have a great day on the bench!!

    Hand Holding and dry crackers can only go so far in treating hyperemesis gravidarum. Prescription treatment might be warranted

    Help for Mom, when she needs it the most! Rx treatment of hyperemesis gravidarum

    Last week we discussed using two rather common over the counter medications (with physician’s approval) Vitamin B-6 and Doxylamine. As discussed, this combo could be used instead of the very expensive Diclegis®. However, Diclegis is the only FDA approved drug for treatment of nausea of pregnancy.

    The other prescription drugs listed below are being used off label for treatment of nausea and vomiting of pregnancy. This week we can discuss the prescription treatment of nausea of pregnancy, and the more intensive form: hyperemesis gravidarum.

    I’m well aware that the FDA is phasing out the traditional pregnancy categories, but they still serve as a guide for many clinicians



    DRUG THERAPY FOR NAUSEA OF
    PREGNANCY/ HYPEREMESIS GRAVIDARUM
    Pregnancy Category Comments
    Doxylamine (Unisom®) A Very safe combined with B-6
    Pyridoxine (Vitamin-B6®) A First line. Alone or in combo with Doxylamine
    Diclegis® 10mg/10mg (doxylamine succinate and
    pyridoxine hydrochloride delayed-release tablets)
    A Only FDA approved treatment for nausea of pregnancy; not for hyperemesis gravidarum
    Dramamine (Dimenhydrinate)
    Diphenhydramine (Benadryl)
    Meclizine (Antivert/Bonine/Dramamine-II)
    B Generally safe- may cause drowsiness. None are considered to be teratogenic
    Dolasetron (Anzemet®)
    Granisetron (Kytril®)
    Ondansetron (Zofran)
    B Limited human data- animal data suggests low risk. Zofran –most studied-
    Metoclopramide (Reglan®) B Watch Mom for drug induced movement disorder. Monitor baby for extrapyramidal symptoms at birth.
    Hydroxyzine (Atarax & Vistaril®) C Caused 5.8% rate major birth defects
    Chlorpromazine (Thorazine®)
    Perphenazine (Trilafon®)
    Prochlorperazine (Compazine®)
    Promethazine (Phenergan®)
    C All considered as 3rd line agents. Watch for QT prolongation and extrapyramidal effects, and movement disorders.
    Corticosteroids C
    D-1st trim
    Oral clefting first trimester exposure. Last resort.


    Ondansetron (Zofran) can be dosed at 4mg every 8 hours, up to a maximum dose of 16mg/dose. Ondansetron can cause QT prolongation, and serotonin syndrome in susceptible patients. As far as the baby goes there is a slight increase in heart defects and cleft palates, but most obstetricians feel the very small risk of these side effects are superseded by all of the well-known problems of prolonged dehydration caused by nausea and vomiting.

    According to the American College of Obstetrics and Gynecology (ACOG) prenatal vitamins in the preconception period may reduce the severity of nausea and vomiting in early pregnancy. Most clinicians do not recommend ginger supplements, due to lack of standardization, but will recommend ginger containing food such as lollipops, candy, and tea.

    Hyperemesis may lead to dehydration, vitamin deficiency, and weight loss, therefore, adequate hydration, vitamin replacement, nutrition, and antiemetic therapy is critical to avoid maternal morbidity. Most physicians feel the risk of ondansetron therapy is worth the benefit.

    So often with our pregnant population when they complain of nausea, reassuaance and dietary modifications may be all that is necessary. Basic recommendations include avoiding stimuli that trigger nausea and vomiting such as sensory stimuli to strong odors, and other sensory stimuli such. Dietary counseling about frequent small meals and avoidance of spicy or fatty foods is appropriate even though the evidence is lacking for such a recommendation.

    Most obstetricians are quite comfortable using ondansetron for nausea and vomiting of pregnancy. Now that the generics are so inexpensive obstreticians seldom hesitate to use it if needed. Remember back in 2012, when Zofran 4mg was $22.00 per tablet! We have a lot of reasonable priced medications to treat these women with very safe drugs to insure a happy and healthy pregnancy.

    Have a great day on the bench!!

    January 2018

    Help share the joy with the new mother, and make her tummy feel better too!

    Treatment and Prevention of Nausea of Pregnancy

    Often referred to as “morning sickness” 75-80% of pregnant patients complain of morning or evening nausea. The peak time for morning sickness is in the first trimester between weeks 5-12 of pregnancy. Most women experience this discomfort, and by adjusting diet or routines, have minimal difficulty as resolution occurs at the beginning of the second trimester.

    Hyperemesis gravidarum – the worst kind of morning sickness: 15% of pregnancies experience nausea and vomiting until delivery. Persistent vomiting may cause weight loss, dehydration, starvation ketosis, hypochloremic alkalosis and hypokalemia. This severe vomiting might also lead to transient elevation of liver enzymes.

    The exact cause of nausea and vomiting during pregnancy is unknown. However, it is believed to be caused by a rapidly rising blood level of human chorionic gonadotropin (HCG), which is produced in the placenta. High levels of HCG is most common with multiple gestations. High-fat diets and Helicobacter pylori infection also contributes to the incidence and severity of hyperemesis gravidarum. Helicobacter pylori, the bacteria that causes stomach ulcers in the general population, is seen in 90% of the patients with hyperemesis gravidarum.

    • Reassurance and dietary advice is all that is required in most instances.
    • Best to hospitalize patient in private room with bed rest.
    • The hospitalized patient should not eat or drink (NPO) for 48 hours, electrolyte balance and hydration should be maintained by parenteral nutrition.
    • Place patient on “dry diet” plus clear liquids 1 hour after eating.
    • Get plenty of rest.
    • Avoid smells that are bothersome.
    • Eat five or six small meals each day instead of three large meals.
    • Eat small snacks high in protein (such as a glass of milk or a cup of yogurt) throughout the day.
    • Avoid spicy foods and fatty foods.
    First line (always weigh risks versus benefits). Most over-the counter products do carry pregnancy warnings, so it is safest to use these products on a physician’s recommendation.

    • Vitamin-B-6 (pyridoxine) 10-25mg every six hours. Most often dosed at night before bed, then additional doses in the morning and in the late afternoon, IF NEEDED
    • Doxylamine (Unisom®) since 25mg is the lowest dose available in the United States, it is reasonable to use 12.5 to 25mg along with the dose of pyridoxine at bedtime, then in the morning and late afternoon if needed. Just make sure the patient is buying the “Sleep-tabs®” which contain doxylamine, and not SleepGels® which contain diphenhydramine.
    DICLEGIS: fixed dose combination drug product (Delayed-release tablets containing 10mg doxylamine succinate and 10 mg pyridoxine hydrochloride) direct cost is nearly $700 per 100 tablets 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: $600.00/ 100 tablets). BONJESTA is the same combination, but each tablet contains 20mg of pyridoxine and doxylamine.

    Writing this column takes me back 32 years ago, when my wife Denise was pregnant with our second daughter Elizabeth. She was the textbook case for hyperemesis gravidarum. She lost so much weight during her pregnancy, she weighed less after delivery than before she got pregnant!

    Of course back in 1986, we didn't have the medications we do today to help control the nausea and vomiting, on an outpatient basis. At her check-up her obstetrician was so disturbed by her weight loss, he admitted her to the hospital, for IV fluids to re-hydrate her. After spending a few days in the hospital she came home, and was able to eat small meals. She never fully got back her appetite until delivery.

    Next week we will discuss the prescription therapy for hyperemesis gravidarum. For simple cases of nausea, the pyridoxine and doxylamine may be of great benefit. Many of us seasoned pharmacists remember Bendectin® which was withdrawn by the manufacturer, as they got tired of defending this product in court.

    The ingredients in Bendectin, are the same as in Diclegis, which are rated as Pregnancy Category-A: " Controlled studies show no risk or find no evidence of harm" With the physician’s approval we can easily save our patients over $500.00 per month by substituting these over-the-counter recommendations.

    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.

    Hey, are you out of Vitamin D-2000? All I see out here is Vitamin-D 50!!

    I was dumbfounded when our OTC manager brought back a bottle of Vitamin-D and asked what this microgram stuff is about? Don't they make Vitamin D-2000 any more??

    In May 2016, the U.S. Food and Drug Administration (FDA) announced regulations that require amendments to the existing supplement facts label, which uses units and conversions based on the Recommended Daily Allowances that were established back in 1968. The new regulations will be mandatory in 2019-2020. On Sept. 29, 2017, the FDA released its proposed rule to extend the compliance dates for Supplement and Nutrition Facts Labeling. The agency said it wanted to give manufacturers more time to comply, citing concerns from stakeholders that the current deadlines would not give them enough time to do so. Some of the vitamin companies have made the labeling change, which I’m sure will cause a lot of confusion, both for patients and prescribers. Let’s hope EPIC and other electronic medical records convert soon, as the new nomenclature is appearing on our shelves!

    To convert Vitamin A as retinol:
    From IU to mcg: IU/3.33 = mcg


    INTERNATIONAL UNITS
    (old labeling)
    MICROGRAMS
    (new labeling)
    5000iu 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)


    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 1250mcg= 1.25mg


    To convert Vitamin E if the product label has dl-Alpha-tocopherol (blended) 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) 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


    I called our primary vitamin vendor, and asked why they made these label changes. She assured me those changes are being made by the FDA's insistence. I asked her if they are providing conversion charts for the pharmacies, and prescribers. She answered, "not that I know of !"

    Some of the labels are not "cross referenced" so we might not see both strengths on the label. According to the FDA both micrograms and international units may be on the label. I looked all over for charts for the conversions for the new labeling changes for the fat soluble vitamins.

    So in my frustration I created this chart, so you wouldn't have to. Feel free to copy this chart, make shelf talkers out of it, anything to take care of your patients.

    The next vitamin representative that comes to my store, will face a very long discussion. I'm all for FDA compliance, but I'm also for excellent patient care! The vitamin companies need to "step up" and assist the health care practitioners in this conversion.

    Have a great day on the bench!!

    Treatment of diarrhea... should we or shouldn't we??

    What goes along with nausea and vomiting?

    Why of course it is diarrhea!! Diarrhea, like vomiting is frequently due to a response of the gastrointestinal tract to remove bacteria and toxins. The most frequent problem that diarrhea causes is dehydration. As with vomiting, our goal for patients with gastroenteritis is to prevent dehydration.

    This is the time of year we see patients standing in the gastrointestinal section, holding a box of Imodium, and looking our way for some help. Before you pull that box of loperamide off the shelf, I have a few (actually quite a few) questions?
    • How long and how often do you have these episodes?
    • Any other symptoms?
    • Which anti-diarrhea medications have you tried?
    • Characteristics of your stool?
    • Have you changed your diet? Drinking non-chlorinated water?
    • Have you recently traveled to a foreign country?
    • Anyone in your household have diarrhea or can you contribute it to a particular food?
    • What medications are you currently taking?
    • Any medical conditions or chronic illnesses?
    Refer to physician immediately if any of the following (source: cdc.gov)
    • Elderly age
    • History of chronic medical conditions or concurrent illness
    • Fever over 102.2 °F
    • Visible blood in stool
    • High output of diarrhea, including frequent and substantial volumes of stool
    • Persistent vomiting
    • Signs consistent with dehydration (e.g., sunken eyes or decreased tears, dry mucous membranes, orthostatic hypotension or decreased urine output)
    • Change in mental status (irritability, apathy, or lethargy)
    • Suboptimal response to oral rehydration therapy already administered or inability to administer oral rehydration therapy
    May I check your med list?
    Here are some drugs that have the potential to cause diarrhea:
    • Laxatives
    • Antibiotics (broad spectrum)
    • Magnesium salts
    • Propranolol
    • Parasympathomimetics (pilocarpine, cevimeline bethanechol)
    • Metoclopramide
    • Digitalis
    • Colchicine
    • Seldom used drugs: indomethacin, methyldopa, theophylline, misoprostol
    What if it is the “Stomach flu”- gastroenteritis:
    • Follow rehydration protocol as for nausea and vomiting. Oral rehydration solutions (Pedialyte®)
    • Antimotility agents such as (diphenoxylate/atropine) Lomotil® or (loperamide) Imodium® should be considered only in adult patients who are NOT febrile or having bloody/mucoid diarrhea. Antimotility agents may reduce diarrheal output and cramps, but do not accelerate cure.
    • Antimotility agents are generally contraindicated for children.
    'Tis the season for the big three... nausea, vomiting and diarrhea. I had three different patients today, presenting with flu symptoms. I have yet to dispense Tamiflu® (oseltamivir) which is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset. Most patients seem to be well past that 48 hour window where oseltamivir is effective, when they seek medical advice.

    With Tamiflu's wholesale acquisition cost being over $150.00, and the generic being over $100.00 is it a good investment to treat most of our patients? I'm a believer in re-hydration, management of fever with acetaminophen and of course frequent hand washing!

    Refer patients to the physician when appropriate. Be sure to share the information in the past three Clinician Corner Columns with your patients, especially with regard to hydration and introduction of solid foods.

    Have a great day on the bench!!

    OTC treatment for Nausea and Vomiting--- a lot cheaper than a visit to the Emergency Department!

    OTC treatment options for treatment of vomiting...

    Now that we have had the big “germ exchange” also known as the holiday season, a lot of patients are coming to ask our advice for treatment of nausea and vomiting. I know of one physician office where they tell the patients to stay home, keep hydrated and stay off work! The nurses won’t even give the adult patients an appointment! We talked in previous columns about the viruses that cause nausea and vomiting.
    Last week we discussed the prescription treatment of nausea, so this week we can address the needs of those patients who come to us first for treatment of this quickly spreading viral gastroenteritis. The first concern we will always have is that our patient doesn’t get dehydrated. That must be the first, and only concern we should have. As we discussed before vomiting is our body’s way of getting rid of bacteria, viruses and toxins that shouldn’t be there. Our goal need not so much be stopping of the vomiting, rather the prevention of dehydration.

    Signs and symptoms of DEHYDRATION
    • Dry or sticky mouth
    • Lethargy or coma (severe dehydration)
    • Low blood pressure
    • Low or no urine output, concentrated urine that looks dark yellow. (Consult MD if more than 8 hours)
    • Sunken soft spots (fontanelles) on the top of an infant's head. (Consult MD)
    • No tears
    • Sunken eyes
    We have a couple of products over-the counter that are traditionally used for nausea. Their efficacy is doubtful.
    • Emetrol®: mixture of dextrose, fructose and phosphoric acid. Is hyperosmolar and works on GI wall to decrease smooth muscle contraction and delay gastric emptying time. Best for food and drink nausea.
    • Cola syrup (Coke®) contains the same sugars and phosphoric acid. Don’t use regular soda, even de-fizzed.
      • 2-12 years old: 5-10 ml every 15 minutes until vomiting stops; not to exceed 5 doses per hour. Not recommended if under 2 years
      • 12 years old: 15-30 mL every 15 minutes until vomiting stops; not to exceed 5 doses per hour
    WHO (World Health Organization) ELECTROLYTE FORMULATION:
    Available on-line, recipe and dosing. Contains: sodium chloride, potassium chloride, sodium bicarbonate, sugar and water.

    Commercially Available Electrolyte Replacements
    • Oral fluids should be replaced quickly, but in a controlled fashion, to prevent the dehydration from becoming more severe. Recommend a teaspoon (5 mL) every five minutes until the patient can tolerate more.
    • Oral replacement should start at 50 to 100 mL/kg with an extra 2 mL/kg for each emesis or 10 mL/kg for each loose stool.
    • Pedialyte®: is an oral electrolyte replacement solution, sold in liters and a variety of flavors: bubble gum, mixed fruit, plain, blue raspberry, cherry punch, grape. Generic formulations are available.
    Dosing of Electrolyte Solutions
    • For infants under 1 year of age: Consult your doctor.
    • For children 1 year and older and adults: Begin with small frequent sips every 15 minutes, increasing serving size as tolerated. Continue for as long as diarrhea is present.
    • To maintain proper hydration, 1-2 liters (32 to 64 fl oz) of Pedialyte may be needed per day. Consult your doctor if vomiting, fever, or diarrhea continues beyond 24 hours or if consumption needs are greater than 2 liters (64 fl oz) per day
    WHAT TO AVOID: Fluids to be avoided include:
    • hypertonic fruit juices and drinks
    • carbonated beverages and caffeine containing beverages,
    • powered gelatin mixes which can make diarrhea worse, and lack the necessary electrolytes.
    • Even our beloved Gatorade diluted with water, still contains too much sugar for treatment of diarrhea. If anything, recommend sugar free Gatorade (G2®)
    The return to solid foods: BRAT diet:
    The BRAT diet is a bland-food diet that is often recommended for adults and children. BRAT stands for Bananas, Rice, Applesauce and Toast. The BRAT diet helps recovery upset stomach or diarrhea for the following reasons:
    • It includes “binding” foods. These are low-fiber foods that make stools firmer. It includes bananas, which are high in potassium and help replace nutrients the body has lost because of vomiting or diarrhea.
    • Some clinicians feel this diet lacks adequate protein for long term use.

    I remember as a student pharmacist that one of my jobs was pouring "Coca-Cola®" syrup into four ounce bottles. We would buy our Coke syrup in gallon jugs, package them up, slap on a label from the Coca-Cola company onto the amber bottle giving directions for use. Most of the time we would tell patients to dump the Coke syrup over crushed ice and sip slowly.

    This activity of bottling up Coke syrup came to a screeching halt after the Tylenol Tragedy of 1982, when tamper resistant packaging was required for Over-the Counter sales. Today we buy it nicely packaged in four ounce bottles from a variety of distributors under the name "Cola Syrup"

    With the every sky-rocketing prices of an Emergency Department visit, we pharmacists can save the health system a pile of money by treating vomiting over-the counter. I have a flyer I created on the BRAT diet that I share with my patients. Often when the nausea subsides they start eating a regular diet which seems to aggravate the gastrointestinal tract.

    The BRAT diet for a day or so seems to be an easy way to ease back into a normal diet. Keep reminding your patients that effective hand washing is the most beneficial way to prevent viral gastroenteritis.

    Wishing you and your family a Health and Happy 2018!

    Have a great day on the bench!!

    December 2017

    Treatment of nausea and vomiting... lots of receptors we can block!

    Prescription treatment of nausea and vomiting

    Antihistamine-anticholinergic agents (histamine-1 blockers)
    Examples: doxylamine (Unisom), diphenhydramine (Benadryl), hyoscyamine (Levsin)


    Indication: for mild nausea and vomiting. Are of greater benefit in prevention of nausea arising from motion sickness.

    Mechanism: appear to interrupt various visceral afferent pathways, that stimulate nausea and vomiting. Most antihistamines do have anticholinergic activity, and can be useful for nausea and motion sickness.

    Adverse effects: Drowsiness, confusion, blurred vision, dry mouth, urinary retention, possible tachycardia in elderly. Increased sedation with alcohol—careful on cruise ships!


    Phenothiazines (dopamine blockers)
    Examples: promethazine, prochlorperazine, haloperidol

    Promotility agents (dopamine blockers)
    Example: metoclopramide (Reglan)


    Indication: more severe nausea and vomiting. Are inexpensive and are used for long term nausea. Most useful in patients with viral gastroenteritis or those receiving mildly emetogenic doses of chemotherapy.

    Mechanism: act on the CTZ (Chemoreceptor trigger zone) by inhibiting dopaminergic transmission. Also decrease vomiting caused by gastric irritants suggesting they inhibit stimulation of peripheral vagal and sympathetic afferents. Metoclopramide (Reglan) has a unique mechanism of action that is to stimulate motility in the upper GI tract. Metoclopramide has a similar side effect profile to the phenothiazines.

    Adverse effects: Extrapyramidal reactions, Parkinson-like side effects, hypersensitivity with possible liver dysfunction, marrow aplasia, excessive sedation

    5-HT-3 Receptor Antagonist (serotonin blockers)
    Examples: ondansetron (Zofran) granesitron (Kytril)


    Indication: effective in prevention of chemotherapy induced vomiting. Also, effective for post-op nausea, and radiation induced nausea. Frequently combined with corticosteroids (dexamethasone or methylprednisolone) for maximal emesis control.

    Mechanism: mucosal entero chromaffin cells in the GI tract release serotonin which stimulates 5HT3 receptors. This causes vagal afferent discharge, inducing vomiting. With the binding of the 5HT3 receptors serotonin stimulation is blocked and hence vomiting is blocked.

    Adverse effects: headache, constipation, Can prolong the QT interval. May cause torsades, ventricular arrhythmias, or sudden death. If given to a high-risk drug to a high-risk patient such as the elderly, women, or those with heart failure, bradyarrhythmias, or low serum potassium or magnesium.

    NK-1 receptor antagonist
    Example: aprepitant (Emend)


    Indication: antiemetic in combination with other antiemetics for nausea with highly emetogenic cancer chemotherapies
    Mechanism: selective high affinity antagonist or human substance –P/ neurokinin-1 receptor. Little or no affinity for 5-HT3, dopamine, and corticosteroid receptors. Antagonizes the NK-1 receptor
    Adverse effects: Many GI, cardiovascular and CNS effects, diaphoresis and alopecia, drug interactions

    Cannabinoids
    Examples: dronabinol (Marinol) , marijuana


    Indication: used as an appetite stimulant and antiemetic. Effective in treating nausea caused by chemotherapy, but associated with CNS side effects in most patients.
    Mechanism: THC (tetrahydrocannabinol) appears to affect the central cerebral cortex axis. Available as dronabinol. Antiemetic effect associated with a “high” and appears better tolerated in the young.
    Adverse effects: Orthostatic hypotension, drowsiness, sedation, dry mouth, euphoria

    Keep in mind that the reason we have vomiting is a protective mechanism to keep our body from retaining harmful bacteria, viruses and toxins. Suppression of vomiting should be necessary only after a few days, and dehydration can occur. Next week we will discuss the over-the counter treatments, as well as patient care information for vomiting


    I remember when Reglan (metoclopramide) came out in the early 1980's to much fanfare as another treatment option for GERD. It was the first treatment option since the phenothiazines in the 1950's!! It quickly became the "go to" for nausea and vomiting for the oncology doctors. We quickly found out that the 10mg four times daily dose caused a lot of Parkinson like side effects.

    I had a neurologist tell me "Pete, before I even check a patient for cogwheel rigidity to diagnose Parkinson's disease, I check the med list and look for Reglan first!" Usually drug induced Parkinsonism presents as a bilateral tremor. Parkinson's disease usually first presents as a tremor on one side, before progressing to the other side.

    In the 1990's ondansetron (Zofran) became available. I remember when Zofran was nearly one thousand dollars for a bottle of 30. We only used Zofran for nausea induced by cancer chemotherapy. Today the generics cost the pharmacy less than ten dollars for a bottle of 30 tablets, and I see ondansetron being used for any kind of nausea and vomiting from chemo, nausea of pregnancy to simple GI upset!

    Have a great day on the bench!!

    Be sure to avoid these "uninvited guests" at your next Holiday Party!!

    Vomiting... don't let it ruin your holidays.

    Vomiting is a protective reflex that allows us to rid ourselves of ingested toxins or poisons. There are five principle neurotransmitter receptors responsible for vomiting. Gastroenteritis is most commonly associated with the dopamine and serotonin receptors. I have listed examples of drugs that react with those receptors:

    Name of Receptor Drug working on that receptor
    muscarinic (M1) anticholinergics: dicyclomine (Bentyl), hyoscyamine (Levsin))
    dopamine (D2) metoclopramide (Reglan), prochlorperazine (Compazine)
    histamine (H1) diphenhydramine (Benadryl) doxylamine (Unisom)
    serotonin (5HT3) ondansetron (Zofran), granisetron (Kytril)
    neurokinin 1 (NK1) Aprepitant (Emend)


    Who invited these guys to my Christmas Party…? Listed below are the three most common viruses implicated in nausea and vomiting.
    • Norovirus (Norwalk-like virus) is common among school-age children. It may also cause outbreaks in hospitals and on cruise ships. It is the most common GI virus.
    • Rotavirus is the leading cause in children. It can also infect adults who are exposed to children with the virus, and people living in nursing homes. Vaccination has greatly reduced this virus
    • Enteric adenovirus: can cause systemic infection
    The Christmas Germ Exchange- We exchange presents, cards, food, handshakes, hugs and kisses at Christmas time. We also exchange a lot of bacteria and viruses!
    • Most viruses and bacteria are passed from person to person by unwashed hands. Other potential causes can be:
      • Improper handling of food
      • Improper cooking of shellfish
      • Improper hand washing after toileting
      • Surfaces not properly sanitized after food preparation.
    • A vaccine to prevent rotavirus infection is recommended for infants starting at age 2 months. (Rotavirus is the leading cause of viral gastroenteritis in kids up to 2 years of age)
    .
    I have this vomiting …was it something I ate at the party??

    Raw seafood Norwalk-like virus, Vibrio, hepatitis A
    Raw eggs Salmonella
    Undercooked meat or poultry Salmonella, Campylobacter, E. coli (STEC), Clostridium perfringens
    Unpasteurized milk or juice Salmonella spp, Campylobacter, E. coli, Yersinia enterocolitica
    Unpasteurized soft cheeses Salmonella, Campylobacter, E.coli (STEC) Yersinia enterocolitica, Listeria monocytogenes
    Homemade canned goods Clostridium botulinum
    Raw hot dogs, deli meat Listeria monocytogenes


    GETS YOU SICK (less serious) GETS YOU TO THE HOSPITAL (serious)
    Novovirus Clostridium botulinum
    Salmonella Listeria
    Clostridium perfringens Shiga-Toxin producing Escherichia coli (STEC)
    Campylobacter Vibrio
    Staphylococcus aureus


    Now What Happens??
    • The CTZ (chemoreceptor trigger zone) is located in the 4th ventricle of the brain. It is the major chemosensory organ for emesis, usually associated with chemically induced vomiting. Because of its location, blood-born and cerebrospinal fluid toxins have easy access to the CTZ. It is our defense against ingesting poisons; our brain works to eliminate these toxins form our GI tract. This mechanism frequently “kicks in” during cancer chemotherapy. This mechanism also “kicks in” to eliminate those toxins and viruses that we are exposed to these holidays.
    Next week we will discuss treatment of nausea and vomiting.

    Hand-washing should be our first line of defense against the bacteria and viruses that can cause vomiting.

    Here is what the CDC says about hand washing on their website:

    "Hand-washing is like a "do-it-yourself" vaccine—it involves five simple and effective steps (Wet, Lather, Scrub, Rinse, Dry) you can take to reduce the spread of diarrheal and respiratory illness so you can stay healthy. Regular hand-washing, particularly before and after certain activities, is one of the best ways to remove germs, avoid getting sick, and prevent the spread of germs to others. It's quick, it's simple, and it can keep us all from getting sick. Hand-washing is a win for everyone, except the germs."

    Source: CDC

    Have a great day on the bench!!

    Antacid therapy --- not as harmless as we might believe??

    Antacids: Warnings, Precautions and Drug Interactions

    After last week’s inorganic chemistry lesson, lets get down to the information that impacts our patients! All the reactions had one thing in common, generation of a chloride salt: aluminum chloride, magnesium chloride, calcium chloride or sodium chloride. Many of our patients can experience adverse effects from these mono and polyvalent cations..

    Warnings/precautions/adverse effects of antacid therapy.
    • Use calcium carbonate, and magnesium antacids cautiously in renal impaired patients
    • Sodium bicarbonate is contraindicated in hypertension, heart failure, renal disease & edema. Do not use for ulcers. Zegerid OTC contains both omeprazole and sodium bicarbonate.The manufacturer states sodium bicarbonate “protects the omeprazole from stomach acid”, but still it is sodium bicarbonate!
    • Use antacids cautiously in elderly where there is decreased GI motility
    • Aluminum containing antacids cause constipation.Use with caution with patients suffering with dehydration or intestinal obstruction.Caution in dialysis patients.
    • Chronic administration of calcium carbonate should be avoided because of hypercalcemia, and because calcium ions cause further stimulation of acid secretion.Calcium carbonate causes constipation.
    • Magnesium containing antacids may cause diarrhea.
    • Hypophosphatemia and osteomalacia can occur with long term use of aluminum hydroxides, but can occur with short term use in malnourished patients like alcoholics.
    Drug interactions with antacid therapy:
    • Tetracyclines & fluoroquinolones are BOTH bound by antacids. Separate tetracyclines by 2 hours, and fluoroquinolones by 4 hours.
    • Enteric coated drugs: coating is destroyed by antacid exposure.
    • Antacids interfere with absorption of: digoxin, cimetidine, ranitidine, anticholinergics, phenothiazines, phenytoin, quinidine and ketoconazole (they require acid for absorption). Separate these drugs from antacids by 2 hours.
    • Separate from Levothyroxine (Synthroid) by 4 hours
    .
    After reviewing all of the potential drug: antacid interactions we pharmacists have another opportunity to interact with our patient population in providing expertise. Antacid therapy is not as innocuous as we might believe.

    Have a great day on the bench!!

    Did you eat too much at your holiday party??

    Antacid Therapy

    Indications for antacid therapy: Antacids today should be only used short term. Antacids work quickly to treat ulcer pain and heal ulcer. They neutralize gastric acid, which in turn increases Lower Esophageal Sphincter (LES) tone. The LES tone is important to keep the gastric contents from “splashing up” into the esophagus. Antacids inhibit the conversion of pepsinogen to pepsin thus raising the pH of the gastric contents.

    Antacids have a rapid onset (5-15min) short duration (30-60minutes). They are ideal for immediate relief of gastrointestinal distress.

    Mechanism: reduces concentration and total load of acid in gastric contents. The hydroxide ions or the carbonate ions neutralize the hydrogen ions (H+).

    Active ingredients of antacid therapy: the chemistry behind antacid therapy:

    Aluminum hydroxide: Al(OH)3 + 3HCl à AlCl3 + 3 H2O. Aluminum hydroxide plus hydrochloric acid produces aluminum chloride and water.

    Magnesium hydroxide: Mg(OH)2+2HCl à MgCl2+2H2O. Magnesium hydroxide plus hydrochloric acid produces magnesium chloride and water.

    Calcium carbonate: CaCO3 + 2HClà CaCl2 + H2O +CO2. Calcium carbonate plus hydrochloric acid produces calcium chloride, water and carbon dioxide

    Sodium bicarbonate: NaHCO3 + HClà NaCl + H2O + CO2. Sodium bicarbonate plus hydrochloric acid produces sodium chloride, water and carbon dioxide

    Simethicone is frequently included in antacid formulations as an “anti-gas” agent: Mechanism: silicon polymers that reduces surface tension of gas bubbles embedded in the intestinal mucosa. Simethicone is often added to antacids to reduce gas pain. The gas bubbles then coalesce and then are more easily eliminated through belching (upper GI) of flatulence (lower GI). Simethicone dosages: Children: less than 24 months: 20mg 4 times daily Age 2-12: 40mg 4 times daily Adults: 40-360mg after meals and at bedtime as needed.

    I hope you enjoyed this "throwback" to Freshman Inorganic Chemistry!! Next week we can discuss the warnings, precautions and side effects of antacid therapy.


    Since Tagamet came out in 1977, what were out patients with peptic and duodenal ulcer disease? I remember my Dad using Pro-Banthine® (propantheline), an anticholinergic which was approved in 1953. Robinul® (glycopyrrolate), another anticholinergic was approved in 1961 and also used to inhibit stomach acid secretion. Pushing doses of these anti-cholinergic drugs did indeed inhibit gastric secretions, but at what a price given all the side effects of dry mouth, blurry vision, constipation, urinary retention, etc.

    Antacid therapy was the mainstay for these patients. Most patients always had a bottle of Maalox (mag/alum hydroxide) or Mylanta in their medicine cabinets, work lockers and even in their car.

    The standard regimen included one ounce (30ml) one hour before each meal, one ounce after each meal and at bedtime. Patients could go through 7 ounces of antacid per day, and many bought a couple of bottles at a time. Talk about inconvenient dosing regimens.

    We can now see how back in 1977 Tagamet (cimetidine) was met with such enthusiasm!

    Have a great day on the bench!!

    November 2017

    Happy 40th Birthday Histamine-2 Receptor Antagonists!!! Hoooray for H2RA's!!!

    Tagamet has been around for 40 years...we still love this class of drugs!

    Mechanism: competitively inhibits the histamine at parietal cell receptor sites, thus reducing the volume and hydrogen ion concentration of gastric acid secretions.

    Indications: Histamine-2 receptor antagonists (H2RA) are preferred to antacids because of compliance, and lack of effect on GI motility. Reasonably effective to treat mild/moderate gastroesophageal reflux disease (GERD). Less reliable for healing erosive esophagitis. May be useful for PUD or hypersecretory states (Zollinger-Ellison syndrome). H2RA work faster than proton pump inhibitors (which may take up to 3 days). The onset of action for the H2RA’s is within one hour and lasts between 6-12 hours.



    Drug Year of Rx INTRO-USA Approved OTC Healing Dose Prevention Dose OTC Brand/Strength
    Cimetidine (Tagamet®) 1977 June 1995 800mg HS 400mg HS Tagamet HB 200mg
    Ranitidine (Zantac®) 1983 December 1995 300mg HS 150mg HS Zantac 75mg, 150mg tabs
    Famotidine (Pepcid®) 1986 April 1995 40mg HS 20mg HS Pepcid AC-10
    Pepcid AC-20
    Nizatidine (Axid®) 1988 May 1996 300mg HS 150 HS Axid-AR-75mg


    Counseling Points:
    • All H2RA are listed a Pregnancy Category-B (no proven risk in humans). However, all packages do carry the warning to consult physician if pregnant.
    • Cimetidine (Tagamet): weak anti-androgenic effects; male gynecomastia & impotence at high doses. May cause feminization of male fetus. Even though cimetidine is Pregnancy Category-B, I would never advise a pregnant patient to use this drug.
    • Pepcid Complete contains: Famotidine 10 mg, Calcium carbonate 800 mg, Magnesium hydroxide 165 mg. I don’t recommend calcium containing antacids, because the calcium will stimulate gastric acid release.
    • Axid-R-75mg is not current available.
    Drug interactions
    Cimetidine reduces hepatic metabolism of drugs metabolized by cytochrome P450 pathway.
    • CYP450*3A4 -simvastatin, Protease Inhibitors (HIV)
    • CYP450*2D6- codeine, fluoxetine etc.
    • CYP450*1A2 – fluoxetine, EtOH, amitriptyline, clopidogrel
    • CYP450*2C9 –ibuprofen, naproxen, glipizide
    • Ranitidine (Zantac) has about 10% affinity for CYP450 3A4 than that of cimetidine, so we expect insignificant drug interactions.
    • Nizatidine (Axid) and famotidine (Pepcid) have no affinity for CYP450 3A4.

    Cimetidine (Tagamet®) was the first billion-dollar drug released back in the 1970’s for treatment of stomach ulcers. In 1964, it was well known that histamine stimulated gastric acid release. However the traditional anti-histamines (Benadryl, ChlorTrimeton) had no effect on gastric acid release. I remember in Medicinal Chemistry class back in 1980 the professor discussing how this class of drugs will change the way drugs are developed, since this was one of the first classes of drugs designed based on the discovery of the receptor site, and developing drugs to fit that receptor.

    Ranitidine (Zantac®) was introduced in US market in 1983 and was the world's biggest-selling prescription drug by 1987. It has since largely been superseded by the even more effective proton-pump inhibitors, with Prilosec (omeprazole) taking over the acid suppression market for many years.

    Have a great day on the bench!!

    Lots of information about PPI's... should they even be over the counter??

    Sending out this newsletter one day early... Tis the season for overeating... Happy Thanksgiving!

    As we discussed last week, there have always been safety concerns with these medications. Denise and I were to a drug company sponsored dinner last week, and I specifically asked one of the local GI docs about “deprescribing PPI’s”. He acknowledged this as a hot topic in the GI arena, but he said that neither he or his colleagues were in any rush to stop this therapy, given the amazing benefits that appropriate PPI therapy brings to our sickest patients. He reminded us about GI bleeds, Zollinger Ellison, NSAID induced gastropathy and Barrett’s esophagitis. Of course, this astute GI doctor sees only the sickest of patients.

    I also reminded him that “deprescribing” PPI’s will be a huge challenge, given the fact that they are available over the counter. With the life-saving potential of PPI therapy let’s discuss the adverse effects, and how we can best help our patients.

    • Fracture risk: at higher doses, new research shows increase risk of hip fractures possibly due to impaired calcium absorption. Fracture risk is a greater concern with high dose, and long term (over 1 year) of PPI therapy. Remind patients to take calcium (citrate), vitamin-D, and to exercise. Elderly patients on PPI therapy will benefit by using calcium citrate, because its absorption is less dependent on stomach acid.
    • B-12 deficiency: May also cause a cobalamin deficiency due to protein-bound dietary Vit-B12 malabsorption. Long term PPI use will decrease serum B-12 levels. Keep in mind that our liver has about two years of Vitamin-B12 on board so deficiency may take a while. Folate levels appear to be unaffected.
    • Decreased Magnesium levels: becomes more apparent with long term PPI use. Low magnesium levels can occur three months into PPI therapy, but risk is higher after one year. Patients should watch for muscle cramps, heart palpitations, dizziness, tremors, or seizures.
    • Pneumonia: PPIs increase gastric pH, which may allow more bacterial growth. The resulting change in gastrointestinal (GI) and respiratory flora may increase the risk for infection. The incidence of hospital-acquired and community-acquired pneumonias appears to be increased with PPI therapy.
    • Clostridium difficile: increase in Clostridium difficile infections and diarrhea occur as a direct result of PPI usage. About 42% of patients being treated for C. difficile while taking a PPI will have a recurrent infection within 90 days. Infections may be decreased by limiting PPI use to patients who truly need them
    • Alzheimers : (?) The results of one study showed that of the 2950 patients who were regularly using a PPI had a significantly higher risk for dementia compared with those not taking this drug. Later refuted by a study was published in the Journal of the American Geriatrics Society (2017) which addressed previous studies that suggested that PPI use was linked to increased risk of cognitive impairment in adults aged 75 years or older. For now, Alzheimer's seems to be unlikely caused by PPI use.
    • Renal Failure: Compared with patients who took an H2 blocker (Zantac, Tagamet, etc), PPI users had a 19% increased risk of estimated glomerular filtration rate (eGFR) falling below 60 mL/min/1.73m2 and a 26% increased risk of CKD (eGFR below 60 on 2 separate occasions at least 90 days apart, based on the Chronic Kidney Disease Epidemiology Collaboration equation). Source: www.renalandurologynews.com. The Taiwanese National Health Insurance data did a rather large study of two groups of over 16,000 patients taking and not taking PPI’s. Here is what their observations were:
      • PPI users were 42% more likely to have Chronic Kidney Disease (CKD) than non-users
      • CKD risk rose by 23% with each milligram increase in PPI dose
      • CKD risk rose by 2% per month of PPI use

    If you thought about starting Prilosec OTC or any other proton pump inhibitor (PPI) because of holiday over indulgence, after reading this newsletter you might want to reconsider!

    In 1982 when Helicobacter pylori was first reported, the world of GI disease was forever changed. Now Americans spend nearly 11 Billion dollars on PPI use, and up to 1/3 is believed to be inappropriate. The numbers are staggering when one sees that only Dexilant (Dexlansoprazole) is the only brand name; the rest are quite inexpensive. The 1200 square foot neighborhood drug store I work in buys its Omeprazole-20 and Pantoprazole -40 in bottles of 1000!

    Counseling points:
    • Inform patients that PPI’s take about three to five days to see benefit. It takes that long to “shut down” acid production.
    • If they are buying these PPI’s over the counter, the package specifically says they are to be used only for two weeks at a time, and then no more than three “cycles” per year.
    • Always scan the patient profile looking for Clopidogrel (Plavix). Some of the PPI’s do block the activation of clopidogrel. Pantoprazole (Protonix) is our “go to” PPI for patients taking clopidogrel.
    Have a great day on the bench!

    We are a little too comfortable with Proton Pump Inhibitors...

    Proton Pump Inhibitors and Acid Suppression

    As my student pharmacists will tell you that half of my conversations start out with “Back in the old days, when I was your age...” Back then the histamine-2 receptor antagonists (H2RA) were just in their infancy. Physicians and patients rejoiced when we no longer had to use high dose anticholinergics such as Pro-Banthine (propantheline) and Robinul (glycopyrrolate) to suppress stomach acid. General surgeons whose bread and butter were gastrectomy procedures due to stomach ulcers were maybe not quite so excited. Guys like my Dad and Grandfather were delighted, as they both had two previous gastrectomies due to recurrent stomach ulcers. Tagamet (cimetidine) released in August of 1977and became the blockbuster drug of the 1970's, being the first drug to reach one billion dollars in sales. I remember going to the drug store for my Grandpa and spending $27 for one hundred tablets!

    A question on my state board licensure exam was “Which of the following drugs is free of side effects, and drug interactions?” The answer was Tagamet! It was sold by one of my all-time favorite drug reps, a gentleman named “Ray”. In June of 1983 Ray met some very stiff competition when Zantac (ranitidine) was approved.

    Tagamet was initially approved as four times a day dosing, then changed to 400mg twice daily dosing to compete with Zantac. The battle was on, and Zantac wrestled a good bit of this lucrative business away from the original H2RA. It became apparent that Tagamet after being used by millions of patients, indeed had side effects such as blocking CYP-450-3A4, as well as causing gynecomastia in men by blocking testosterone formation. I hope they changed that state board question!

    The very lucrative H2RA market joined by Pepcid (famotidine) and Axid (nizatadine) came to a screeching halt in the 1990's. Omeprazole was first marketed in the United States in 1989 by Astra, now (AstraZeneca), under the brand name Losec. In 1990, at the request of the FDA, the brand name Losec was changed to Prilosec to avoid confusion with the Lasix 20mg (furosemide). As when the FDA intervenes, things often go amiss, and the new name led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac)!!

    I remember discussing this new class of stomach acid suppressants with none other than “Ray” the Tagamet salesman. Ray said “no doubt this Losec shuts down stomach acid production better than Tagamet, but the question becomes... how much is too much” Ray said certainly stomach acid does more than causes stomach ulcers, and aids digestion; but what about its protective effect. Possibly could stomach cancers become more common with this drug. No one seemed concerned about this excess acid suppression, obviously Ray had to try to protect his turf. Prilosec buried the competition.

    In 2002 the generics were approved by the FDA, and prices dropped like a rock. Insurance companies no longer required prior authorizations, because they were so cheap. Today most pharmacies are lucky to get reimbursed $10 a month! People get prescribed these drugs and are left on them indefinitely. Much to my amazement this powerhouse acid blocker went over the counter in 2003, and was welcomed by all consumers as a cheaper alternative to the prescription variety. Other proton pump inhibitors like Zegerid and Prevacid followed suit., and had their own OTC formulations. Patients didn't even need to consult a physician or a pharmacist. Sure, the FDA required a 14 day limit on the box, and a warning of no more than 3 cycles of 14 tablets per year; as the companies sold these drugs in “warehouse packs”!

    Today the focus is “deprescribing” proton pump inhibitors. How do we even begin, when the patients can buy these potentially harmful drugs without a prescription? Next week we will discuss the numerous potential side effects of these commonly (over)prescribed drugs. My salesman friend “Ray” might have been on to something!


    How well I remember how the dreaded "stomach ulcers" ravaged my family. My Dad and Grandpa were always plagued by GI ulcers. Both had stomach resections due to "bleeding ulcers". Both took H2RA therapy and did very well on them.

    Next week we will discuss the ramifications of long term PPI therapy. If there is EVER a reason for a "behind the counter" class of drugs, the Histamine-2 blockers and Proton Pump Inhibitors should be the first to be regulated.

    Have a great day on the bench!

    Instead of $800 to treat EACH person, let's use an effective over-the -counter treatment for pinworms!

    PYRANTEL PAMOATE

    Mechanism: It is poorly absorbed from the GI tract in humans and acts by paralyzing worms. Pyrantel causes the release of acetylcholine, inhibits cholinesterase, and stimulates ganglionic neurons, acting as a depolarizing neuromuscular blocking agent in pinworms. These actions cause extensive depolarization of the pinworm’s muscle membrane, producing tension of the pinworm's muscles, which causes paralysis and release of their hold to the intestinal wall. They are unable to latch onto the intestinal mucosa, and are passed out in the stool.
    • Pyrantel pamoate is available over the counter as a 50 mg/mL suspension.
    • The dose of pyrantel pamoate for pinworms is 11 mg/kg of base, up to 1 g, given orally as a single dose. The dose should be repeated after two weeks. Package has detailed instructions by weight.The over-the counter products have detailed weight based dosing instructions. Approved for 2 years of age and older. Maximum dose is 1gram.
    • May administer with food, milk or fruit juice, at any time of day. Fasting, purgation, or special diets are not necessary for effective treatment
    • Does not reliably kill pinworm eggs. Give second dose is to prevent re-infection by adult worms that hatch from any eggs not killed by the first treatment.
    • There are numerous brand names, such as: Pin-X , Pin-Rid, Antiminth, Reese’s Pinworm Medicine. Cost is around $15.00 per ounce. Became OTC in 1986
    PREVENTION of REINFESTATION
    • Repeated infections should be treated by the same method as the first infection.
    • Treat all household members if more than one is infected. In institutions, mass and simultaneous treatment, repeated in 2 weeks.
    • Good hand washing hygiene! Soap and water after toilet.
    • Best to not allow children to share the same bathwater, reuse or share washcloths. Showering may be preferred to avoid possible contamination of bath water.
    • Clip fingernails regularly, and avoid biting the nails and scratching around the anus.
    • Frequent changing of underclothes and bed linens first thing in the morning is a great way to prevent possible transmission of eggs in the environment and risk of reinfection. Do not shake out bed linens, the eggs can become airborne. These items should be \ carefully placed into a washer and laundered in hot water followed by a hot dryer to kill any eggs that may be there.
    • Clean shared surfaces like doorknobs, toilet seats, and furniture with a disinfectant, such as bleach
    • Pinworm eggs are spread easily and even the cleanest and most careful people can get them. Be sure to re-assure parents and caregivers.

    Last week we discussed prescription treatment options for pinworm infestation. We explored treatment options such as Emverm® (mebendazole) and Albenza (albendazole).

    Both products were extremely expensive costing as much as $400.00 for initial treatment, followed by a second dose in two weeks. Today we pharmacists can step in and use a very affordable self-care treatment option for our patients.

    Just as important as the treatment, is the second follow-up dose as well as the prevention of re-infestation. Treatment failures are rare, and re-infestation is common. Be sure to share these "practice points" wih all of your patients.

    Have a great day on the bench!

    "Quit scratching down there".... better have a look. It might be pinworms!

    PINWORMS - The basics and prescription Treatment.

    Pinworm infections are caused by a small, thin, white roundworm called Enterobius vermicularis. This infection affects all people, especially children, institutionalized persons, and household members of persons with pinworm infection. Pinworms are spread by humans, and not by pets!

    Epidemiology
    Mode of transmission: Pinworms are transmitted from fecal to hand to mouth. Eggs may also be ingested by inhalation. The incubation period for pinworms is 1 to 2 months or longer for the adult gravid female to mature in the small intestine.

    These eggs are deposited around the anus by the worm and can be carried to common surfaces such as hands, toys, bedding, clothing, and toilet seats. By putting anyone’s contaminated hands (including one’s own) around the mouth area or putting one’s mouth on common contaminated surfaces, a person can ingest pinworm eggs and become infected with the pinworm parasite. Since pinworm eggs are so small, it is possible to ingest them while breathing.

    Symptoms: often asymptomatic, but itching around the anus (pruritis ani) is common.

    Diagnosis:
    • Seeing worms in the perianal region 2 to 3 hours after the infected person is asleep.
    • Touch the perianal skin with transparent tape to collect possible pinworm eggs around the anus at first rising. Use tongue blade with double side tape
    • Microscopically test for eggs under the fingernails (since anal itching is a common symptom)
    RX Treatment Options
    • Mebendazole (Emverm®-100mg)
      WAC=$369.00 per tablet AWP=$442.80
      • Dose= 100mg as a single dose. A second dose in 2 weeks may be appropriate if needed; both CDC and Sanford Guide recommend a second dose 2 weeks later. Tablets may be chewed, swallowed whole, or crushed and mixed with food.
      • Do not take concurrently with Metronidazole (Flagyl®) due to an increase incidence of Stevens-Johnson’s Syndrome
      • Approved for children 2 years of age and older
      • Emverm.com is a patient friendly website with good information. Also has a $60 coupon available.
    • Albendazole (Albenza®-200mg) currently
      $365.64 for 2 tablets AWP=$438.77/2
      • THIS IS AN OFF LABEL USE: Dose= 400mg (2 tablets) as a single dose. Repeat dose in 2 weeks. It is listed in the Sanford guide as a secondary treatment option.
        • Can be dosed down to 1 year old (200mg/dose)



    Pinworm and eggs, from the CDC website. Lots of good patient information for pinworms on the CDC website.


    So, as we can see there is only one prescription option that has FDA approval for treatment of pinworms. Next week the pharmacists can “take over” and we will cover a reasonable treatment option, along with patient counseling points for pinworm infections.

    Have a great day on the bench!

    October 2017

    My grandkids Luke and Anna made a big contribution to this column. Antibiotic associated diarrhea happens this time of year.

    Cefdinir and Amox/Clav- useful for ear infections - but be sure to "cover their butts"

    Now that winter is approaching and respiratory and ear infection season is closely approaching, we pharmacists can be instrumental in prevention of diaper rash. 18-35 percent of all children exposed to antibiotic therapy will develop antibiotic associated diarrhea. The more broad-spectrum antibiotics will cause a higher incidence of diarrhea. Amoxicillin/clavulanate and cefdinir are the pediatrician’s favorites.

    Amoxicillin/Clavulanate (Augmentin®) is notorious for causing stomach upset and diarrhea. Most of the gastrointestinal distress can be traced back to the clavulanate component which increase efficacy of amoxicillin by destroying the beta-lactamase that the bacteria produce. By blocking the effect of the beta-lactamase, the amoxicillin can do its job of destroying the bacteria. The problem is there are numerous strengths of amoxicillin/clavulanate, and for pediatric patients we need to dose based on the amoxicillin component at 80-90mg/kg/day (referred to Amox/Clav HD). For illustration let’s assume we have a 37 lb child (16.5kg). The calculated dose would be 1500mg per day.

    Drug To get 1500mg amox You get this much clavulanate daily
    Augmentin 125/31.25 12 teaspoons 375mg
    Augmentin 250/62.5 6 teaspoons 375mg
    Augmentin 400/57 3.75 teaspoons 213.75
    Augmentin-ES 600/42.9 2.5 teasp 107.25
    Augmentin 250/125 6 tablets 750mg
    Augmentin 500/125 3 tablets 375mg
    Augmentin 875/125 2 tablets 250mg


    As you can see from the above chart for a child getting Amoxicillin 1500mg per day (37lb child) would get 107.25mg of clavulanate should the prescriber use Augmentin ES 600, versus 375mg of clavulanate should the prescriber use Augmentin 250/5.

    Whenever you are prescribing Augmentin therapy HD (high dose) as is recommended for otitis media, it is critical to use Augmentin ES 600mg/42.9 to minimize clavulanate exposure and decrease incidence of severe GI upset and diarrhea. Always call the prescriber if a child has otitis media, and the prescriber writes for anything other than Amox/clav -ES 600/5ml to minimize the clavulanate exposure and therefore the gastrointestinal side effects. Remind patients to keep the suspension refrigerated at all times, and to use a protective diaper rash paste BEFORE administering the first dose.

    Cefdinir (Omnicef®) is a third-generation cephalosporin that causes a lot less gastrointestinal upset. It is dosed at 14mg/kg/day in 1 or 2 doses. Because it is broad spectrum, it can kill off more gut bacteria and cause diarrhea. In infants, especially if they are formula fed, the cefdinir binds to the iron in the milk and can cause a red stool, resembling blood which can greatly upset the parents. Be sure to warn them of this harmless side effect.

    Also with Cefdinir, dispense in the box to keep the glass bottle from breaking, give with food, and do not refrigerate. And like amox/clav it carries a 10-day expiration date. Be sure to always give an appropriate measuring device.




    Yes, a picture is worth a thousand words!


    Imagine a new Mom changing her infants diaper, and seeing these red streaks in the diaper, which could be easily confused for rectal bleeding. Fortunately the Mom was my daughter Gretchen, who is a doctor of Pharmacy, and teaches Clinical Pharmacy Practice at West Virginia University. Her son Luke, was being treated for a case of recurrent otitis media. So dramatic is this specimen, she snapped a picture for me to share with my students and colleagues. The color would even be brighter for a formula fed baby. For comparison, we snapped a picture of my son Phil's daughter Anna's diaper a normal breast fed diaper.

    Keep this image in mind when you are either prescribing, or dispensing Cefdinir (Omnicef®)

    Special thanks to Luke and Anna for your input (well, I guess output) for this column.

    "We interrupt our discussion about diaper rash" ---- Hand, Foot, Mouth Disease is spreading. Be ready to help your patients NOW!

    Hand, Foot, Mouth Disease affects...hand, foot and mouth! (of course).

    I will delay discussing diaper rash induced by antibiotics because of an “epidemic” that is spreading in our area. Recently, hand, foot, and mouth disease is on the rise with cases affecting local school districts. One of the local school districts ordered cases of hand sanitizers from a local pharmacy. I can’t think of a disease that has a more descriptive name than “Hand, Foot and Mouth Disease” abbreviated HFMD.

    Etiology:
    Hand, foot, and mouth disease is caused by viruses that belong to the Enterovirus genus, which includes the polioviruses, coxsackieviruses, echoviruses, and enteroviruses.

    Coxsackievirus A16:
    is the most common cause of hand, foot, and mouth disease in the United States, but other coxsackieviruses can also cause the illness.

    Enterovirus 71:
    has also been associated with cases and outbreaks of hand, foot, and mouth disease. Less often, enterovirus 71 has been associated with severe disease, such as encephalitis. Patients can be affected with a couple of different enteroviruses.

    Epidemiology:
    Patients with HFMD is most contagious during the first week of illness and be contagious for days or weeks after symptoms go away. Adults, may not develop any symptoms, but they can still spread the virus to others. Everyone especially those with direct contact with children and infants must maintain good hand hygiene so they can minimize their chance of spreading or getting infections. Daycares because of their multiple diapering “events” can see this virus spread quickly through a classroom.

    Patient Information:
    Here’s some useful information about this condition that Karen Quach one of my student pharmacists would like to share.

    Hand, foot, and mouth disease is a common childhood infection most often occurring in confined spaces, such as daycares and schools, in the summer and fall months. It is characterized by small sores that can form in the mouth, and on the hands, feet, buttocks, and genitals. This is the main symptom to look out for, and the sores can appear as small red spots, bumps, or blisters. In addition, some children may present with a mild fever. Although this infection is generally mild, it is highly contagious and may cause pain, including painful swallowing.

    Hand,Foot,Mouth disease on 15 month old

    The infection itself is not treated and should resolve without medicine within one week. Until then, children should maintain adequate fluid intake to prevent dehydration. If needed, over the counter medications such as acetaminophen (Tylenol) or ibuprofen (Advil, Motrin) can be used to relieve pain. Cool liquids and foods such as popsicles and ice cream may help to numb the pain.

    The virus travels in body fluids, including mucus from the nose, saliva, bowel movements, and fluid from the sores. Therefore, the most important method to prevent spread of infection is proper hygiene. Tips include washing hands frequently with soap and water, using alcohol-based hand sanitizers, covering the mouth and nose when sneezing and coughing, properly disposing infected tissues, and disinfecting contaminated surfaces and objects. Additionally, infected children should be kept home when they have symptoms to prevent spread to other children.



    We got a request to put together a newsletter about hand, foot and mouth disease because of a local outbreak. Like any good preceptor, I turned the project over to my student pharmacist.

    We have two students living with us right now and last week for Pharmacy Month, Gabrielle Dziuba published a newsletter on Poison Prevention. I turned this project over to Karen Quach. She did a stellar job, and we also published her newsletter in the local paper. Her research is the information that contains the patient information.

    Karen Quach, PharmD Candidate
    University of Pittsburgh School of Pharmacy Class of 2018

    Treating Diaper Rash, and saving the money for the college fund!

    Treating Diaper Rash--simple as A-B-C-D-E!!!

    Diaper rash is almost always caused by Candida albicans, and like any yeast thrives where it is warm, dark and moist. Here are some treatment strategies to help manage diaper rash in our pediatric population. It’s as easy as A, B,C, D & E.

    A = air out the skin by allowing the child to go diaper-free, best to do on a hard surface floor for easy clean up. Don’t expose to sun for longer periods of time to prevent possible sunburn.

    B = barrier; use a paste or ointment to protect the skin. Protectants: are first line therapy and can be used for protection (anticipated during antibiotic therapy) or treatment. Provides physical barrier to protect skin against irritants and moisture. Also provides lubrication to reduce skin-to diaper friction.

    C = clean; Clean area with water—avoid rubbing area. Use a squirt bottle, pat and air dry. If using Baby wipes, they should be free of soaps, dyes, perfume and alcohol.

    D = disposable diapers; are best option during an episode of diaper rash, rather than cloth diapers. If using cloth diapers, avoid plastic panties.

    E = educate; educate your patients about how to prevent a recurrence of diaper rash

    Pharmacologic Measures:
    Antifungal agents
    • Don’t use routinely, only when C. albicans is suspected.
    • Characterized by beefy red plaques, with scales and satellite papules & pustules. Pustules are superficial.
    • May use Miconazole and Clotrimazole which are OTC, or Nystatin (Rx-only)

    Vusion® (miconazole 0.25%) – is a product for diaper rash. Contains also white petrolatum & Zn oxide. Lower concentration causes less systemic absorption, however higher strength Miconazole has not been shown to cause problems. The cost of a 50gm tube of Vusion diaper rash ointment is $560.00!

    “GrandDad Kreckel” has calculated that 90gram of Zinc Oxide + 15g Miconazole 2% will yield a concentration of miconazole .28%. The leftover $550.00 can be applied to the grandkids college fund!

    Cholestyramine/Aquaphor -compounded medication for Diaper Rash Cholestyramine is a bile acid sequestrant, and Aquaphor is a greasy vehicle to protect the bottom. Usually made as a 20% paste. INGREDIENTS:
    • Cholestyramine light powder (80% anhydrous) ---------------25gm
    • Petrolatum ointment base (Aquaphor) --------------------------75gm
    • Dispense as 100gm. Good for 180 days.
    What not to use: Talc and cornstarch- not recommended due to potential inhalation by the infant. OTC Antibiotic ointments: Over-the-counter antibiotic creams or ointments (such as Neosporin or Bacitracin) are not recommended because neomycin and bacitracin cause allergic reactions.
    • Bacitracin is the 2003 Allergen of the Year (American Contact Dermatitis Society)
    • Neomycin is the 2010 Allergen of the Year (American Contact Dermatitis Society)
    Corticosteroids: Hydrocortisone 1% (otc): can be used for moderate to severe diaper rash, or allergic dermatitis. Can be used for up to 2 weeks maximum. Do NOT use stronger corticosteroids (avoid all RX!!)
    Peruvian balsam: Butt Paste (Boudreaux Butt Paste) – contains Zn oxide, Peruvian balsam, boric acid, castor oil and petrolatum. (FDA cautions that Peruvian balsam may cause skin sensitivities.)

    Treating diaper dermatitis can be challenging and even frustrating for parents. There are a lot of old time remedies that shouldn't be used today, especially being the powders. When you think about the ingredients in the common powders, they can do more harm than good. Talc is actually a mineral, or stone that is pulverized to dust. Corn starch is a "starch" which we remember from biochem class is a string of sugar molecules linked together, which is just like "feeding" the Candida albicans. The talc being a mineral can be inhaled into the child's lungs, and long term exposure can cause damage. Although both do reduce friction between skin folds, they are not recommended for treatment.

    I am a huge fan of plain and simple. When Regina, Luke or Anna get diaper rash the miconazole and zinc oxide combination works very well. It is only used when Candida is suspected, and not for prophylaxis.

    Next week we will discuss diaper rash, and provide counseling points to parents when giving their children antibiotics.

    Have a great day on the bench!!

    When the grandkids get diaper rash... GrandDad comes to the rescue!

    When Candida albicans affects the grandkids... treatment of diaper dermatitis

    This week we continue our discussion of yeast and fungi focusing on Candida albicans, in a different patient population, that is in our infants and diaper wearing toddlers. When we think of the ideal environment for yeast and fungi to grow, we think of warm, dark and moist. What better place to grow than a baby’s diaper! Candida albicans is the most common cause of diaper rash in infants. The fungi take advantage of the warm, moist conditions inside the diaper.

    Causes of diaper dermatitis:
    • Too much moisture
    • Rubbing and friction
    • Skin contact with urine and feces
    • Allergic reaction to the diaper material or to creams, powders or wipes

    Role of Candida albicans:
    • Infection often occurs after 48-72 hours of active eruption.
    • It is isolated from the perineal area in as many as 92% of children with diaper dermatitis.
    • Other microbial agents have been isolated less frequently, perhaps more because of secondary infections.
    • Peak incidence occurring when the individual is aged 9-12 months
    • Diaper dermatitis is prevalent in 7-35% of the infant population.

    Pathophysiology
    • Wet skin increases the penetration of irritant substances.
    • Superhydration urease enzyme found in the stratum corneum liberates ammonia from cutaneous bacteria.
    • Irritation occurs because:
      • Urease has a mild irritant effect on nonintact skin.
      • Lipases and proteases in feces mix with urine on nonintact skin and cause an alkaline surface pH, adding to the irritation. The bile salts in the stools enhance the activity of fecal enzymes, adding to the effect

    Prevention
    • Change your baby's diaper often.
    • Keep the diaper loose enough to let air reach the skin inside the diaper.
    • Gently clean the affected skin with warm water. Pat gently with a clean, soft towel.
    • Don't use wipes that contain alcohol or perfume.
    • If you use cloth diapers and wash them yourself, use very hot water. Rinse carefully
    • Note: Feces in breastfed infants have a lower pH, and breastfed infants are less susceptible to diaper dermatitis.
    • Broad spectrum antibiotics can cause Candida albicans to overgrow by destruction of “good” bacteria.
      • Amoxicillin/clavulanate (Augmentin®)
      • Third generation cephalosporins
        • Cefdinir (Omnicef®)
          • Recommend topical protection before the first dose of broad spectrum antibiotics

    This area of study is of particular interest to me not only as a young pharmacist when we had three kids in four and one-half years, but now we are blessed with three grandchildren!

    Our three year old Regina is potty trained but our 15 month old grandson Luke, and 9 month old granddaughter Anna are in diapers, and GrandDad comes to the rescue to treat diaper dermatitis.

    This week we covered the basics, and next week we will discuss treatment of diaper rash, and of course what NOT to use! The money we can save in the treatment of diaper rash will go a long ways for their college funds.

    Have a great day on the bench!!

    September 2017

    Our female patients can benefit from these treatment options

    Treatment of Vaginal Candidiasis..

    The most mentioned vaginal yeast infection that our patients experience is actually the second most common vaginal infection. Candidiasis is the second most common cause of vaginitis symptoms and accounts for approximately one-third of vaginitis cases. Bacterial vaginosis is the most common, but no over-the counter treatment exists. Ten to twenty percent of healthy women of reproductive age have Candida albicans present in the vaginal tract.

    Risk Factors for vulvovaginal candidiasis are as follows
    • Patients with Type-2 diabetes, are more prone to candida albicans infections especially if they are not well controlled
    • Patients exposed to antibiotic therapy-25-33 % of females exposed to antibiotic therapy. This is due to the destruction of the normal healthy flora, allowing the overgrowth of candida species. Lactobacillus is of no value in treatment or prevention.
    • Immunosuppressed patients- patients with a less than robust immune system, either due to corticosteroid therapy, or HIV are more susceptible to candida infections.
    • Elevated estrogen levels: patients taken oral contraceptives, or estrogen supplements have a higher incidence.
    • Sexual activity: vaginal candidiasis is not considered a sexual transmitted infection, because it is part of the normal flora. Patients report an increased incidence of yeast infections when they begin sexual activity.

    Symptoms: itching of the vulva is the most common sign, remembering that yeast isn’t the only organism that causes itching. Patients may experience vulvar burning, soreness, and irritation. Some patients may experience burning on urination, with the source of the burning being the vulva and not the urethra. Patients may experience dyspareunia as well. Symptoms are often worse during the week prior to menses.

    Treatment:

    Diflucan® (Fluconazole) (Rx only)
    150mg tablet given as a single dose. Fluconazole remains in the vaginal secretions up to 72 hours. Avoid if pregnant.

    Miconazole (Monistat®) (OTC) Is available as a cream, or vaginal suppository, or insert
    • Monistat-3: (200mg supp.) 1 supp vaginally at bedtime for 3 nights
    • Monistat-3 (4% prefilled cream 200mg each) vaginally at bedtime for 3 nights
    • Monistat-7: (100mg supp) 1 supp vaginally at bedtime for 7 nights
    • Monistat-7 (2% cream, 100mg each dose): 1 applicatorful vaginally at bedtime for 7 nights. Best treatment option for treatment of patients who are pregnant, or patients with diabetes.
    • Monistat-1 Combo pack: miconazole 1200mg insert plus miconazole cream for application to vulva
    CAUTION: potential CYP 4503A4 interactions due to topical absorption of miconazole

    Clotrimazole (Gyne Lotrimin®) Available as a cream
    • Gyne-Lotrimin 1% cream: 1 applicatorful vaginally at bedtime for 7nights
    • Gyne-Lotrimin 2% cream: 1 applicatorful vaginally at bedtime for 3 nights
    Terconazole (Terazole®) (Rx only) Available as cream or suppository.
    • Terazol 0.4% cream: 1 applicatorful vaginally at bedtime for 7 nights
    • Terazol 0.8% cream: 1 applicatorful vaginally at bedtime for 3 nights
    • Terazol 80mg supp: 1 suppository vaginally at bedtime for 3 nights
    Butoconazole (Gynazole®) Rx Only 2% cream 5gm
    • Insert one applicator at bedtime as a single dose. May weaken diaphragms or condoms, due to mineral oil in the formulation.

    Women indeed are very proactive in their healthcare,and we pharmacists have the opportunity to guide them through the feminine hygiene aisle.

    When Monistat (miconazole) first became available in 1991, there was great concern from gynecologists that these products might be misused. Labeling on these vaginal candidiasis products specifically say " Do not use if you have never had a vaginal yeast infection diagnosed by a doctor."

    Patients should really have had a previous diagnosed yeast infection, and be aware of the symptoms before purchase of such a product. Remember that yeast isn't the only condition that itches.

    Have a great day on the bench!!

    They're in a rush to treat their thrush!

    Candida albicans-- a pathogen in our crosshairs...this week!

    Now that we have learned how to wipe out the Trichophyton species, especially T. rubrum, we switch to another pathogen that we frequently see on our mucus membranes, Candida albicans, which is more specifically a yeast. Our first mucus membrane we will cover is the oral-pharyngeal cavity.

    Candida albicans infection of the mouth is commonly referred to as “thrush”. Candida albicans is a yeast of our normal flora, that is kept “in check” by a variety of bacteria especially Lactobacillus . When the immune system is weakened, or the bacteria are wiped out by antibiotics, Candida albicans can overgrow.

    Symptoms: Candidiasis in the mouth and throat is most often seen as white patches on the inner cheeks, tongue, roof of the mouth, and throat. Other symptoms might include: redness or soreness, feeling like cotton in the mouth and loss of taste. Patients may also experience pain while eating or swallowing or angular cheilitis (cracking and redness at corners of the mouth).

    Who is at risk: Candidiasis in the mouth, throat, or esophagus is uncommon in healthy adults. People who are at higher risk for getting candidiasis in the mouth and throat include babies, especially those younger than one-month old, and people who:
    • Wear dentures
    • Have diabetes
    • Have cancer
    • Have HIV/AIDS: thrush is one of the most common infections seen in the AIDS population.
    • Take antibiotics or corticosteroids, including inhaled corticosteroids for conditions like asthma
    • Take medications that cause dry mouth or have medical conditions that cause dry mouth
    • Smoke
    Treatment of Adults:
    The treatment of oropharyngeal candidiasis in patients without AIDS is usually accomplished with local therapy for 7 to 14 days. For topical agents, successful therapy depends on adequate contact time between the agent and the oral mucosa. Options include:
    • Clotrimazole troches or lozenges are dosed at 10mg 5 times a day slowly dissolved in the mouth for about 15-30 minutes. They are effective, however adherence to a five time per day regimen is difficult. Often patients with radiation to salivary glands, or patients with Sjogrens syndrome lack adequate saliva, and might have difficulty getting these lozenges to dissolve. Don’t eat or drink while using.
    • Nystatin suspension 100,000 units/ml swish and swallow 4-6 ml four times daily is effective but has a bitter taste. It also contains sucrose, which can cause dental caries when used over prolonged time periods.
    • Fluconazole tablets: 200mg first dose then follow with 100mg-200mg daily. Best option for topical treatment failures. Has 90% success rate.
    Children Doses for Candida albicans eradication:

    Nystatin Oral suspension 100,000 units/ml:
    • For older infants: 2 mL four times a day.
    • For premature and low-birth-weight infants: 1 mL four times a day.
    • Because treatment is topical, and maximal contact time improves efficacy, the suspension should be retained in the mouth for as long as possible before swallowing.
    • Infants should avoid feeding for 5 to 10 minutes after administration to keep nystatin from washing out of the mouth.
    Fluconazole: available as 10mg/ml and 40mg/ml in 35ml bottles for reconstitution
    • Dose: 6 orally once on the first day (maximum dose 200 mg followed by 3 once per day (maximum dose 100 mg) for a total of 7 to 14 days. Doses are higher for HIV infection.
    Prevention of reinfection in babies
    • Sterilize items that are placed in the infant's mouth. Bottle nipples and pacifiers that are to be reused should be boiled after each use.
    • Breast feeding: Topical miconazole or clotrimazole is applied to the nipples to treat the lactating woman. Azoles are preferred over nystatin since there is less resistance of Candida species. Wipe off prior to feeding and reapply after each feeding.

    Thrush is treated first line with topical therapy either nystatin or clotrimazole. Reinforce to the patient that is the contact with the inside of the mouth is what will lead to resolution of the yeast infection. Nystatin ahs been round since the early 1950's and still has a place in therapy for Candida albicans only. It has no effect on any other fungi other than C. albicans. Nystatin was discovered in 1950 by Rachel Fuller Brown and Elizabeth Lee Hazen named nystatin after the New York State Health Department in 1954.

    These patients do require a lot of patient counseling, and if appropriate an accurate measuring device.

    Have a great day on the bench!!

    Do your toenails look unsightly? Some of the treatments lack efficacy!

    Toenail fungus--persistence is the key to efficacious treatment

    Your fingernails and toenails are composed of keratin and adherent connective tissue, the same stuff that your hair is made of. Nails grow at an average rate of 0.1 mm/day (1 cm every 100 days).

    Finger nails require 3 to 6 months to re-grow completely while toe nails require 12 to 18 months. Onychomycosis is a fungal infection of the nails, sometimes caused by Candida species, however 80% of the toenail infections are caused by dermatophytes (Trichophyton rubrum), whose name sounds very familiar to us!

    Diagnosis is based on clinical exam and history, microscopy, and culture. Back when both oral prescription drugs were expensive and cost over $600 for a course of therapy, the insurance companies required a positive culture for approval. Now that the oral treatments are available generically, that requirement has been lifted.
    • OTC nail lacquers (Fungi-Nail®) treat fungus around the nail, they don't penetrate the nail plate. Don't recommend them due to minimal efficacy. Contains undecylenic acid, and despite its trade name is only for athlete’s feet.
    • Rx products provide best treatment option.
    • Advise patients about possible recurrence.
    Treat fingernails for 6 weeks and treat toenails for 12 weeks. (reference: Sanford guide 2017)
    • Terbinafine (Lamisil®)- fewest drug interactions; check liver function; most efficacy: Cure rate: (46%). Side effects include headache, gastrointestinal disturbance (diarrhea and/or dyspepsia), rash and elevated liver enzymes.
      • Dose: 250mg every 24 hours
    • Itraconazole (Sporanox®)– CYP4503A4 interactions; need liver function tests. Cure rate (23%pulse). Side effects include, skin rash, high triglycerides, cardiac side effects and gastrointestinal effects (nausea, bloating, and diarrhea)
      • Pulse Dose: 200mg BID for 1 week/month x 2-3 months
      • or 200mg/ day for 3 months
    • Fluconazole (Diflucan®) Cure rate:(28%), less drug interactions than itraconazole. Frequent relapse, due to poor retention in the nail.
      • Dose: 150-300mg every week for 3-6 months.
    • Ciclopirox (Penlac®) nail lacquer -Complete cure rate (7%)
    • Efinaconazole (Jublia®) nail lacquer- Complete cure rate (17%)
    • Tavaborole (Kerydin®) nail lacquer- Cure rate (<10%)
    Vicks Vap-o-rub?
    • A small study of 18 participants, where fifteen of the 18 participants (83%) showed a positive treatment effect. Source: J Am Board Fam Med. 2011 Jan-Feb;24(1):69-74. doi: 10.3122/jabfm.2011.01.100124
    • 5 of 18 (27.8%) had a mycological and clinical cure at 48 weeks;
    • 10 of 18(55.6%) had partial clearance
    • 3 of 18 (16.7%) showed no change.
    Since our enemy Trychophyton rubrum is everywhere, re-infection is a possibility if measures are not taken to make the feet an inhospitable environment for this fungus. Fungus breed where it is warm, dark and moist. Here are some points to share with our patients:
    • 1 in 5 “cures” will relapse (20%) within 2 years
    • Keep feet clean and dry
    • Change socks often
    • Antifungal product for feet and shoes.
    • Sports shoes that fit well will reduce microtrauma to the nail plate. Wear sandals when possible.
    • Using communal showers leads to fungal infection, so these should be avoided
    • Care with hygiene is needed to reduce cross-infection between family members
    • Throw out old “creek shoes”.
    • Emollients can be used to avoid cracks in the skin that allow fungus to enter.
    Certain-Dri®—Prevention of onychmycosis
    • Contains aluminum chloride-12%.This product stops the feet from sweating, creating the moist environment for the fungus to grow.
    • Water-based and unscented which makes it gentler on skin
    • Should not wash off after bathing or showering, if application instructions are followed. Use only a few times a week.

    Onychomycosis treatment varies from practitioner to practitioner. I've seen podiatrists use the Terbinifine 250mg daily for 84 days, with great results. I've seen podiatrists remove the entire nail, and treat with Terbinifine 250mg for 84 days.

    I once had a patient tell me that her dermatologist said "I'm not knocking out your liver so you can have pretty toenails." He went on to say "It is a cosmetic condition, and if treated it will come back... just get over it." She went to her podiatrist, he did the necessary blood work, like liver function testing, was treated for 84 days and she has been "fungus free" for over 15 years. She is meticulous about her foot care.

    One of the points we want to share with our patients is that re-infection is indeed a possibility, and we should counsel our patients to follow the steps necessary to prevent re-infection.

    Have a great day on the bench!!

    Another fungus among us...look what the cat (or puppy) brought in!!

    What is this rash that looks like a worm??

    Trichophyton rubrum is the most common cause (about 47%) of tinea corporis commonly known as “ringworm”. This is the same organism that can also cause jock itch, athlete’s foot, and nail fungus. Tinea corporis usually begins as a circular or oval, scaling patch that is itchy and spreads centrifugally on the smooth skin, (other than the scalp, groin, palms, and soles). The center of the lesion clears while an active, advancing, raised border remains. The result is a ring-shaped plaque from which the disease derives its common name of ringworm. How do I get it? Epidemiology:
    • May result from contact with infected humans, animals, or inanimate objects. Commonly transmitted by kittens and puppies.
    • Occupational risk: farm worker, zookeeper, laboratory worker, veterinarian
    • Environmental exposure: gardening, contact with animals, towels and shared grooming appliances.
    • Recreational exposure: contact sports especially wrestling, contact with sports facilities (gym mats, locker room floors). Interestingly enough the ringworm spread by wrestling has its own specific name: “Tinea corporis gladiatorum” named after the gladiators of Rome.
    How do I get rid of it? Treatment of Tinea corporis (ringworm):

    TOPICAL THERAPY
    • Terbinifine (Lamisil®): apply once daily for 7 days
    • Clotrimazole (Lotrimin®): apply twice daily for up to 14 days
    • Miconazole (Micatin): apply twice daily for up to 28 days
    SYSTEMIC THERAPY
    May be indicated if tinea corporis includes extensive skin infection, immunosuppression, resistance to topical antifungal therapy (azoles and allylamines) , or the comorbid presence of tinea of the scalp or of the nails.
    • Terbinafine (Lamasil®) 250 mg per day for one to two weeks.
    • Itraconazole(Sporanox®) 200 mg per day for one week
    • Fluconazole (Diflucan®) 150 to 200 mg once weekly for two to four weeks
    • Griseofulvin (remember that drug?) seldom used because 4 weeks of treatment are needed.
    • Itraconazole and Griseofulvin are the most expensive treatment options. Fluconazole and Griseofulvin are the longest treatment options.

    When I was discussing this column with a fellow pharmacist they asked me the differences between "tinea versicolor" and "tinea corporis". Although they share the name "tinea", both affect the smooth skin, and are caused by a fungus which thrives in hot and humid conditions, there is a huge difference between the two.

    Ringworm as we can read from this column ringworm is caused by the Trychophyton genus, where Tinea versicolor is caused by Malassezia furfur. The Malassezia furfur fungus is part of our normal flora, while ringworm is not. We don't get tinea versicolor by spreading from other sources as it is part of our normal skin flora. Versicolor is much harder to control because we harbor it on our skin.

    However, once ringworm is eradicated, a patient needs to be re-exposed to get another ringworm infection.

    Have a great day on the bench!!

    August 2017

    Hey doc---I got “gaulded”--- what do you got for that??

    Tinea Cruris "jock itch"

    Tinea cruris (jock itch) is a dermatophyte infection involving the fold between the upper thigh and groin area. Most common cause is Trichophyton rubrum, other species of tinea may cause jock itch as well. Tinea cruris is far more common in men than women. Often, infection results from the spread of the dermatophyte infection from concomitant tinea pedis, moving up the leg. Tinea on the groin looks like scaly, itchy, red spots, usually on the inner sides of the skin folds of the thigh. Predisposing factors include copious sweating, obesity, diabetes, and immunodeficiency. Infection may spread to the perineum and perianal areas, into the gluteal cleft, or onto the buttocks. Usually the scrotum in males is not involved.

    Treatment: first line therapy is topical antifungals, azoles or squalene epoxidase inhibitors. If unsuccessful consider oral treatment.

    • Terbinafine (Lamisil cream):
      • Mechanism- inhibits squalene epoxidase, thus weakening the fungal cell wall
      • For tinea cruris apply once a day for 7 days
    • Clotrimazole (Lotrimin) or Miconazole (Micatin):
      • Mechanism- inhibits ergosterol synthesis.
      • Apply twice daily for 2 weeks.
      • Any of the OTC or Rx azole antifungals are equally effective
    “Tightie whities” or boxers?? Cotton briefs hold moisture and keep it against the skin, allowing dark, warm moist conditions that the dermatophytes thrive in. If you choose briefs, say at the gym or running, choose moisture-wicking synthetic materials and be sure to shower and put on a fresh pair after working out. Going “commando” (or naked) would be the best.

    Here is a tip… put on your socks before underwear to minimize the chance of the athlete's foot fungus from moving to the groin area.


    I remember my first week working in a rural area of Central Pennsylvania. An old woodsman came in and asked me if I could help him. Being that energetic (and inexperienced) pharmacist I said sure. He told me he got "gaulded" , which I thought he said "scalded", and he pointed "down there". Needless to say I've learned a lot about being "gaulded" (tinea cruris) over the past number of years. Back then we didn't have much to help our patients until the antifungals became OTC.

    One year at Boy Scout Camp, when I was the Scoutmaster, one of my 6th graders came to me. He said he was "hurting" down there...I asked him to describe what was going on. He said "Mr K it feels like my crotch is on fire" I asked him if he was showering, and he said "every day, but because the showers are not private we are all showering with our swimming suits on, so no one can see our equipment". I left camp, bought a can of clotrimazole spray (in case the other guys got it) and gave it to him, with instructions to not shower in a swimming suit! He was better the next day, and many years after at his Eagle Scout Banquet I presented him with the left over spray.

    Have a great day on the bench!!

    ATHLETE'S FOOT - Tinea pedis

    Athlete’s foot is usually treated topically due to decreased side effects of this route of administration. It is the most common dermatophyte infection, affecting up to 70% of adults. Causative organisms: Trichophyton, Epidermophyton or Microsporum. Infection is usually acquired by means of direct contact with the causative organism in “surface reservoirs”, as may occur by walking barefoot in locker rooms or swimming pool facilities. If unchecked, osteomyelitis can result from mycotic infections of the feet, including tinea pedis. These complications are seen more frequently in patients with diabetes. Diabetics should check their feet every day with a mirror, and look between the toes for signs of athlete’s foot. The fissures between the toes can serve as a major port of entry for Staph aureus, the major cause of osteomyelitis in patients with diabetes, which may lead to amputation.

    TREATMENT
    • Terbinafine (Lamisil cream):
      • Mechanism- inhibits squalene epoxidase, thus weakening the fungal cell wall
      • For tinea pedis apply twice a day x 7 day. Apply for 2 weeks if bottom/sides of feet are affected.
    • Miconazole (Micatin) or Clotrimazole (Lotrimin):
      • Mechanism- inhibits ergosterol synthesis.
      • Apply twice daily for 4 weeks.
      • Any of the OTC or Rx azole antifungals are equally effective
    Unfortunately, athlete’s foot symptoms may linger for up to 4 weeks. Recurrence might be due to previous treatment failure. Because patients experience recurrence 70% of the time, prevention is warranted. Share these prevention tips with your patients:
    • Patients should be advised to wear non-occlusive footwear such as sandals as frequently as possible, but especially in the summer.
    • Wash socks after each wearing in the hot cycle of the washer and dried in the hot cycle of the dryer before wearing again. Athletic shoes also may be sprayed with disinfectants and/or treated with bleach to destroy fungi.
    • During the bath or shower, patients must wash the feet and toes carefully each day. Patients should be taught to dry the feet thoroughly after each bath or shower, paying closer attention to the interdigital spaces.
    • Wait for 10 to 15 minutes after bathing to don socks and shoes to help the feet dry. The goal is to have the feet completely dry other than when bathing.

    What about us??? Most of us as business professionals, should wear socks and leather shoes that “breathe” and reduce sweating. We should also change to sandals as soon as we can and wear them until bedtime or go barefoot around the house as much as possible (except for diabetic patients with peripheral neuropathy)

    Socks? Wool socks: If your feet are often cold, or you live a in a cold climate (like Central Pennsylvania), wool socks may be a better fit. Wool fibers are both hydrophobic (repels water) and hygroscopic (absorbs water), which is a fancy way of saying that it can absorb or give off moisture. In fact, they - wool fibers - can absorb up to 1/3 of their own weight in moisture before feeling "wet". Merino wool is less like to be itchy. Merino wool socks are more expensive, it is best not to machine wash wool socks. I wear wool socks for extra padding on my feet. The outer layer of wool fibers have a high concentration of fatty acids, which have anti-bacterial properties, and reduce foot odor.

    Cotton socks: less itchy, are cheaper and absorb moisture but they saturate quickly and dry slowly. Are cooler on the feet and are machine washable. When cotton socks get damp/wet they will continue to feel cold and damp, which wetness and increased friction may enhance blister formation.

    Have a great day on the bench!!

    Mechanisms of action are the best clue as to what to recommend for the "fungus among us"!

    We pharmacists love our mechanism of actions, and knowledge of where the multitude of antifungals fit in drives our product selection. Below is a chart, that describes the mechanism of actions for efficacious treatment of dermatophytic and candida infections. Although there are other agents available, I am highlighting the most common and most effective agents we use in community pharmacy practice.

    Agents used in the treatment of dermatophyte infections.

    Oral Azole Antifungals
    Impairs the synthesis of ergosterol, the main sterol of fungi membranes, allowing increased permeability and leakage of cellular components. Inhibits fungal CYP-450 14-alpha-desmethylase thereby decreasing ergosterol.
    Ketoconazole (Nizoral) (Rx)
    Most potent azole blocker of CYP-450. Most drug interactions and side effects of oral azoles. As of 2013 NOT recommended as oral therapy for treatment of dermatophytes.
    Fluconazole (Diflucan) (Rx)
    Widest therapeutic window. For treatment of thrush and vaginal candidiasis. Not effective for filamentous fungi (aspergillosis).
    Itraconazole (Sporanox) (Rx)
    May induce heart failure. Caution in cardiac patients.
    Oral Antifungal
    First antifungal; isolated in 1939, produced from Penicillium griseofulvin. Disrupts spindle formation. Skin infections only. It is deposited in newly forming skin where it binds to keratin precursor cells, protecting the skin from new infection. Therapy must continue until new tissue replaces old diseased tissue.
    Griseofulvin (Gris-Peg) (Rx)
    Absorption improves with a high fat meal. Takes 2-6 weeks for treatment. (6 months for onychomycosis).
    Oral Squalene Epoxidase Inhibitor
    These antifungal agents are reversible, noncompetitive inhibitors of the squalene epoxidase. The buildup of squalene is toxic to the cell wall. This causes pH imbalances and malfunction of membrane bound proteins.
    Terbinifine (Lamisil) (Rx)
    Most often used for onychomycosis (nail fungus). Doesn’t reach effective levels for treatment of skin infections.
    Topical Azole Antifungals
    Impairs the synthesis of ergosterol, the main sterol of fungi membranes, allowing increased permeability and leakage of cellular components. Inhibits fungal CYP-450 14-alpha-desmethylase thereby decreasing ergosterol. For topical treatment of dermatophytes, no azole antifungal Rx or OTC is superior to another.
    Miconazole (Micatin, Monistat)
    Topical use for dermatophytes or vaginal yeast infections. Caution with warfarin may ↑ INR, by blocking CYP-450 metabolism and cause bleeding.
    Clotrimazole (Lotrimin), Butoconazole(Gynazole)
    OTC available for treatment of vaginal yeast infections. Clotrimazole cream for topical dermatophytes.
    Ketoconazole (Nizoral), Econazole (Spectazole) (Rx)
    Prescription only for treatment of topical dermatophytes.
    Terconazole (Terazol) (Rx)
    Terconazole contains a triazole ring, a structure developed specifically to improve antifungal activity. Rx only for vaginal candida infections.
    Topical Squalene Epoxidase Inhibitors
    These antifungal agents are reversible, noncompetitive inhibitors of the squalene epoxidase. The buildup of squalene is toxic to the cell wall. This causes pH imbalances and malfunction of membrane bound proteins.
    Terbinifine (Lamisil)
    Most effective OTC treatment for dermatophytes.
    Topical antifungal inhibiting cell membrane staility.
    Binds to trivalent cations (iron and aluminum), which inhibit essential co-factors in enzymes. Can be fungicidal or fungistatic.
    Ciclopirox (Loprox, Penlac) (Rx)
    Available as cream, gel, suspension, shampoo and nail lacquer.
    Topical Anticandidal Agents
     
    Nystatin (Mycostatin) (Rx)
    Polyene antifungal binds to ergosterol in fungal membrane causing membrane to become leaky. Only effective for candida (yeast). Too toxic for parenteral use. Used only topically, usually for diaper rash.
    Miscellaneous
     
    Zinc Pyrithione-ZPT (Head & Shoulders)
    Shown to significantly reduce the numbers of yeast organisms. Helps prevent the dandruff-causing microbe, Malassezia globosa, from forming scalp irritants, and normalizing keratinization.
    Selenium Sulfide (Selsun) 2.5% (Rx)
    For treatment of dandruff and tinea versicolor via its anti-Malassezia effect and significantly reduces the rate of cell turnover.


    Where is the Undecylenic Acid, Tolnaftate, Absorbine Junior, Gold Bond, etc.? Although I also did leave out some prescription products as well (sertaconazole, oxiconazole, naftifine), this comprehensive guide will treat the topical fungal infections the community pharmacist sees. Our treatment decisions must be dictated by efficacy, cost and of course patient safety. In the upcoming weeks we will be covering specific topical disease states such as tinea pedis, cruris, corporis, thrush, vulvovaginal candidiasis, onychomycosis, and diaper rash. After this "series" we will feel much better treating "the fungus among us"!!

    Have a great day on the bench!!

    Are you left scratching your head on how to treat dandruff patients?

    Treatment options and patient care points for dandruff

    Etiology: Dandruff is the most common form of scalp seborrheic dermatitis. We are familiar with the appearance of dandruff, which the scalp shows fine, white, diffuse scaliness without underlying erythema. The rate of turnover of the epithelial cells is about twice the normal rate in patients affected with dandruff. Malassezia (formerly called Pityrosporum) is a “lipid dependent” fungus (yeast) that lives on the scalps of most healthy patients. Sometimes it grows out of control, feeding on the oils secreted by hair follicles and causing irritation that leads to increased cell turnover. The result is many dead skin cells, which fall off, clump together with oil from hair and scalp, and become visible. Unfortunately, they end up on our black tuxedos or cocktail dresses!

    Factors influencing overgrowth: increased oil production; hormonal fluctuations; stress; illness; neurological disorders, such as Parkinson's disease; a suppressed immune system; infrequent shampooing and extra sensitivity to the malassezia fungus may contribute to the development of dandruff.

    Treatment : The 2017 Sanford Guide recommends two first line treatments for dandruff: ketoconazole 2% or selenium sulfide 2.5%

    Nizoral® Ketoconazole 2% Shampoo(Rx) only:
    • Acts by blocking the biosynthesis of ergosterol, the primary sterol derivative of the fungal cell membrane. Ketoconazole weakens the fungal cell membrane.
    • Apply twice a week. Leave on for 5 minutes and thoroughly rinse.
    • Patient Care points: immediate lather hair when starting shower, to let ketoconazole saturate the hair and scalp for 5 minutes to get full benefit. Nizoral® A/D shampoo 1% is the over the counter version
    Selenium Sulfide 2.5% (lotion/shampoo)
    • Controls dandruff via its anti-Malassezia effect and significantly reduces the rate of cell turnover.
    • Usually applied twice a week. Thoroughly rinse.
    • Patient care points: Remove jewelry to prevent staining from sulfide. Although this is the most effective treatment for dandruff, the sulfide (“rotten egg”) smell steers patients away from this drug. Selsun Blue 1% is the over the counter version.
    Head and Shoulders® Zinc pyrithione (ZPT)
    • Heals the scalp by normalizing epithelial keratinization, sebum production, or both. Also shown to significantly reduce the numbers of yeast organisms. Helps prevent the dandruff-causing microbe, Malassezia globosa, from forming scalp irritants
    • Dosage: Is effective if used three times a week.
    • Patient care points: Don’t alternate between ZPT and non-medicated shampoos.Use only ZPT containing product if using every day.
    Neutrogena T/gel: Coal tar based .5%
    • Mechanism: Keratolytic agent which reduces rate of skin cell formation, and also softens keratin; also elicits antiseptic & antibacterial properties
    • Dosage: best if used twice a week.
    • Patient care points: Use caution in exposing scalp to sunlight after applying this product. It may increase your tendency to sunburn for up to 24 hours after application. Does smell like a freshly paved road.

    Lots of marketing goes into shampoos for a good reason. Most people need them, and use them every day. Most patients have their favorite, and that is what they stick with.

    My "oily skin" and very abundant growth of Malassezia, make me a primary candidate for using a dandruff control. What is my favorite? I don't like the smell (neither does Mrs. Kreckel!) of the selenium sulfide. I have had the best success with ZPT, since I want to use it every day.

    Have a great day on the bench!!

    Only our fungi get motivated in this hot and steamy weather!

    TINEA VERSICOLOR -- Pathology and Treatment

    With the very warm weather we have been experiencing, the heat may make us humans feel lethargic. However, the yeast that causes Tinea versicolor gets “supercharged” and grows more rapidly in this heat and humidity. Tinea versicolor is a superficial skin infection -often referred to as “sweat rash” caused by Malassezia furfur (aka: Pityrosporum ovale or Pityrosporum orbiculare) M. furfur can be found in normal skin flora. Under the right conditions yeast converts to the hyphal phase and causes disease. Most often seen in hot/ humid climates, oily skin, hyperhidrosis, hereditary factors, corticosteroid treatment, and immunosuppression. Look around shirt collar lines, under bra’s, folds of skin, armpits etc. and you will see these flat discolored lesions. These lesions don’t change colors with sun exposure; they are lighter in the summer than surrounding skin, and darker in the winter. The lesions will glow yellow/green when lit up with a Wood’s lamp (“black light”).

    TREATMENT OF TINEA VERSICOLOR

    • (selenium sulfide 2.5% shampoo (Rx).
    Apply a thin layer covering the body surface from the face to the knees once daily for seven days. Leave on skin for five to ten minutes before rinsing. Remind patients to remove jewelry before application, as it may damage jewelry. Apply once a month for 3 applications to help prevent recurrences. Disadvantages: odor of the product which smells like rotten eggs. Some patients a stinging sensation after application
    • Head and Shoulders shampoo (OTC): Zinc pyrithione shampoo(ZPT) applied once daily, leave on for 5 minutes. Apply daily for 2 consecutive weeks.
    • Nizoral® ketoconazole 2% shampoo (Rx) single application for five to ten minutes is effective (80% mycotic cure rate). May be applied up to 3 days.
    • Topical azoles: usually applied daily for 14 days. Examples: Clotrimazole (Lotrimin-OTC) Miconazole (Micatin-OTC), Ketoconazole (Nizoral-Rx), Econazole (Spectazole-Rx)
    • Oral Treatment of tinea versicolor:
      • Fluconazole 400mg as a single dose.Exercise to a sweat, and do not shower for 12 hours.
        • Alternative: 300mg once a week for 2 consecutive weeks (75% cure rate)
      • Itraconazole 400mg every 24 hours for 3-7 days
      • Ketoconazole (??) Oral ketoconazole is no longer approved by FDA as of 2013 for any topical infections due to hepatotoxicity and other safety concerns, such as adrenal insufficiency and multiple drug interactions.
      • Terbinifine (Lamisil) oral tablets are of little value in the treatment.It does not achieve fungicidal levels in the skin.A 1% topical solution applied to the skin was effective in clinical trials.

    Relapse rates: Tinea versicolor’s causative agent is “normal flora.” 60% of cases relapse one year after treatment, and 80% relapse after two years. Prophylaxis (especially in warm weather) use selenium sulfide 2.5% or ketoconazole 2% shampoo applied to the entire body for ten minutes once per month is an effective prophylactic therapy.

    Tinea versicolor is commonly seen this time of the year. As the heat and humidity increase, so does the activity of our oil and sweat glands! This provides a perfect breeding ground for overgrowth of our normal flora M. furfur.

    Because more of our patient's skin is exposed due to our summer clothing and bathing suits, this common dermatological condition is more readily seen, and frequently patients come seeking our advice.

    Up until a few years ago, most dermatologists were using Ketoconazole 200mg tablets, taken as 2 tablets after a high fat meal. Patients were told to exercise until a heavy sweat, and then don't shower for 12 hours so the ketoconazole could be exposed to the M. furfur. After the FDA sternly warned practitioners in 2013 not to use ketocnazole for tinea infections, this is no longer used and a whole host of other treatments have been used. Although ketoconazole is still in the 2017 Sanford Guide, it is NOT recommended.

    I feel that prevention of recurrence is as important as appropriate treatment of the initial infection.

    Have a great day on the bench!

    July 2017

    The kidney and parathyroid are the big players in calcium and potassium levels.

    Potassium and Calcium

    POTASSIUM
    The kidney is the major player in potassium homeostasis, regulating about 90% of excretion. K+ balance is maintained by adjusting secretion into the urine in response to dietary intake. Low levels of potassium can result in muscle weakness, adverse effects on the kidneys and cardiac arrhythmias.

    Drugs that Lower Potassium Levels

    THIAZIDE DIURETICS
    Work in the distal tubule of the kidney. Keep dose under 25mg/day to decrease likelihood of hypokalemia.
    Loop Diuretics
    Furosemide, Torsemide, Bumetanide
    20 mEq potassium per day is sufficient to prevent hypokalemia with diuretics. Use 40-100mEq to correct deficiency
    Antipsychotic drugs
    (Risperidone and quetiapine)
    Can be a concern in the elderly
    Carbonic Anhydrase Inhibitors Acetazolamide (Diamox) Mild diuretic that works in the proximal convoluted tubule. A weak diuretic most commonly used for glaucoma and altitude sickness.
    Amphotericin B Half of patients will get hypokalemia
    Excessive sweating, vomiting and diarrhea. Colon cleansing. Contribute to hypokalemia by K+ loss


    CALCIUM
    Serum calcium is regulated by parathyroid hormone (PTH) and vitamin D. These hormones effect the bone, kidney, and the gastrointestinal tract. Parathyroid hormone decreases calcium excretion in the kidney, increases absorption of calcium in the gut, and increases bone resorption.

    Drugs that lower calcium levels

    Bisphosphonates
    (Alendronate (Fosamax®), Risedronate (Actonel®), Ibandronate (Boniva®) etc)
    Block osteoclast re-absorption of bone
    Calcitonin (Miacalcin®) Block osteoclast re-absorption of bone
    Cinacalcet (Sensipar®) Lowers serum calcium (binds to receptors on parathyroid gland)
    Phenytoin (Dilantin®) (and other inducers of Vitamin-D) Phenytoin, being an inducer speeds up conversion of vitamin D to inactive metabolites
    Vitamin-D deficiency Blocks absorption of calcium from gut
    Corticosteroids Increase renal calcium excretion and decrease gastrointestinal calcium absorption, resulting in reduced serum calcium
    Excess phosphate levels (seen in chronic kidney disease) May lead to decrease calcium absorption from the gut.
    Low magnesium levels (most commonly due to
    alcoholism, malabsorption, and diuretic therapy)
    Magnesium depletion can cause hypocalcemia by producing parathyroid hormone (PTH) resistance,


    Last week, in response to a request from a Physician Assistant, we covered drugs that caused excessive levels of potassium and calcium. This week we will explore the common causes of deficiency of these two ions. Potassium and calcium are frequently checked in the physicians office, and sometimes drug therapy can be responsible for their low levels.

    Have a great day on the bench!!

    Remember learning about parathyroid hormone and aldosterone?

    Drugs causing Hypercalcemia and Hyperkalemia
    One of my former Physician Assistant Students asked me to write my next column about drugs that affect calcium and potassium. Lots of physiological events can cause increases in these two very important cations, as well as drug therapy. Here are the highlights of drugs causing elevated levels of calcium and potassium.

    Drugs causing HYPERCALCEMIA

    THIAZIDE DIURETICS
    Hydrochlorothiazide, chlorthalidone
    Cause calcium retention by increased resorption of calcium in renal tubules.
    Calcipotriol (Dovonex ®) Caution with high doses or in patients with severe, extensive psoriasis
    Lithium (Eskalith) Usually mild, likely due to increased secretion of parathyroid hormone (PTH). May take 4 weeks post lithium to resolve
    Excessive Calcium Supplementation Obviously!
    Theophylline toxicity Results in mild hypercalcemia
    Vitamin-A intoxication May cause stimulation of bone resorption
    Vitamin-D intoxication In the gut increases the absorption of calcium
    HYPERPARATHYROIDISM Hypercalcemia from hyperparathyroidism is usually mild, asymptomatic, and sustained for years
    MALIGNANCIES Rapidly progressive; a RAPID rise in calcium levels should increase suspicion of malignancy.
    RENAL FAILURE Especially if given calcium carbonate or calcium acetate as phosphate binder


    DRUGS CAUSING HYPERKALEMIA

    Potassium-sparing diuretics
    (triamterene, amiloride)
    Block directly the K+-Na+ exchange in the collecting tubules.
    Aldosterone antagonist (spironolactone/epleronone) Compete with aldosterone for receptor sites
    NSAIDs By inhibiting renal function (block afferent vasodilatation of arterioles). May also inhibit renin secretion.
    ACE inhibitors
    (lisinopril,enalapril,quinapril, benazepril etc.)
    By blocking Angiotensin-II, aldosterone is decreased. Aldosterone is responsible for increasing the excretion of potassium.
    Angiotensin-receptor blockers
    (ARBs) (Losartan, Irbesartan, olmesartan, etc)
    By blocking Angiotensin-II, aldosterone is decreased. Aldosterone is responsible for increasing the excretion of potassium.
    Non Selective beta-blockers
    (propranolol, labetalol)
    Interfere with the beta-2-adrenergic facilitation of potassium uptake by the cells. Selective BB like atenolol (mostly ß-1) have minimal effect. All ß-blockers at high dose lose beta selectivity.
    Cyclosporine or tacrolimus Due to reduced efficiency of urinary potassium excretion
    Trimethoprim-sulfamethoxazole Trimeth blocks apical membrane sodium channels in the mammalian distal nephron, blocking the excretion of K+
    Heparin Reversible aldosterone suppression
    Ketoconazole Inhibits aldosterone synthesis
    Herbs Alfalfa, Dandelion Horsetail, Nettle are high in potassium
    Miscellaneous: Pentamidine & Metyrapone Inhibits distal nephron reabsorption of Na+ by blocking apical Na+ channels in a manner similar to "potassium-sparing" diuretic
    Potassium supplements in excessive doses Obviously!


    So, as we can see many of our commonly used drug therapies can have a significant impact on these two very important ions. The concern becomes even greater in our patients that are elderly or frail.


    "The Request line is open"

    Do you remember those days of listening to the local AM radio station? How excited we would be when the announcer would say "the request line is open", and we would jam the phone lines with our requests to hear the Beatles, Beach Boys, or Sonny and Cher!!

    I have tons of material to share with my column readers, but I also am delighted when I get an e-mail requesting a specific topic that my readers find of clinical interest. Today's column's request came from a practicing physician assistant who wanted a quick column on the drugs that cause changes in calcium and potassium. Next week we can discuss drug therapy that can cause lowering of potassium and calcium.

    Have a great day on the bench!!

    We always are promoting "covering up" and sunscreen....what happens when our patients don't listen???

    TREATMENT OF SUNBURN
    • Most sunburn is self-treatable. Most are usually first or second degree burns. First degree burns are simple redness of the skin. Second degree burns are when blisters appear. Apply cool compresses; frequent cool baths or showers. Pat skin dry with towel. Do not rub.
    • Minor burns can be treated with protectants which reduce dryness of skin, and prevent friction damage.
    • No topical spray will stop the underlying burn process, or stop the formation of blisters.

    Let’s talk about the two most common “remedies” for sunburn treatment:
    Dermoplast® spray: (Benzocaine 20%) is the most effective topical anesthetic. Using a strength less than 20% is not effective. Benzocaine may cause hypersensitivity reactions (1%)
    Solarcaine® gel: (Lidocaine) Caution with broken skin (might precipitate cardiac arrhythmia)
    • Best not to recommend topical anesthetics, due to short duration of effectiveness: max= 45 minutes, and potential for side effects. Do not recommend for small children.

    Ibuprofen: Did you notice after a major sun exposure, a day later the redness gets worse? Erythema becomes clinically apparent 3 to 6 hours after exposure, peaks at 12 to 24 hours, and usually subsides at 72 hours. Three hours after UVB exposure, neutrophilic infiltration begins and peaks at 24 hours, and continues up to 48 hours later.
    • Prostaglandins and nitric oxide are most commonly implicated in the delayed erythema reactions that follow within 14-20 hours after exposure and persists for 1 to 3 days. So, by using an oral medication that blocks prostaglandins, like NSAIDS we can arrest the delayed onset erythema (redness).
    • Best option for treatment of sunburn to manage the pain, and slow down the delayed erythema is IBUPROFEN. Start use immediately after a “major” exposure.

    Refer to a physician when:
    • If more than 10% of body surface of a child is sunburned, a physician should be consulted.
    • If a patient presents with: fever, headache, confusion, nausea, vomiting chills
    • Secondary infection may develop, leading to scarring.Infection is hard to treat because dead skin is an excellent medium for microbial growth.Signs of infection include increased pain, swelling, redness drainage or pus from blisters.

    Does Sunscreen cause Vitamin-D Deficiency? The short answer is “yes”
    • Effective use of a sunscreen blocks the synthesis of Vitamin-D in the dermis. Middle aged and elderly persons who use sunscreens daily have significantly lower concentrations of 25-Hydroxyvitamin D3.
    • 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 skin cancer”

    We see a lot of requests for recommendations for sunburn treatment this time of year. Lots of people are looking for aloe gel and other sunburn remedies. The truth is, just cooling down the skin makes our patients feel better, so a spray bottle filled with water is as effective as any topical cooling gel. Topical anesthetics are of short term value, and has risks if the skin is broken or the patient is very young or very old.

    Incidence: the estimated sunburn prevalence among all adults in the US was approximately 34 percent. Sunburn occurs more frequently among adolescents and young adults. In nation-wide surveys in the United States, approximately 70 percent of adolescents aged 11 to 18 years and 50 percent of adults aged 18 to 29 years reported at least one sunburn in the previous year.

    A lot of patients need our expertise!

    Have a great day on the bench!!

    Let's look at PREVENTION of Sunburn!

    Last week, we discussed the mechanics of sunscreens and product selection. Here are some tips to share with your patients about sunscreens.

    UVA Light: is continuous throughout the day and may exceed the intensity of UVB by up to 1,000 fold. UVA light penetrates to the dermis and is responsible for producing tanning, but may also damage blood vessels. UVA causes photo aging which is the dry, scaling, yellow and deeply wrinkled, thinner & more fragile skin. Photo aging is NOT simply an accelerated aging process. UVA exposure is associated with photo-sensitivity, drug reactions, and basal cell carcinoma.

    UVB Light: penetrates the epidermis and is responsible for erythema (burn). Most intense between 10am and 4pm. More intense in summer months and higher elevation. A positive effect of UVB exposure is that it induces the production of Vitamin-D in the skin.

    Tips for sunburn prevention
    • Avoid long term exposure during peak hours (10am - 4pm)
    • Sunglasses: Make sure they are UV protected. With cheap dark glasses, pupil dilates allowing more harmful UV rays to damage the retina. Better not to wear sunglasses than cheap sunglasses that are not UV protected!!! UV blocking sunglasses also prevent cataracts.
    • Clothing: Hats, long sleeve shirts, and long lightweight pants. A typical summer tee shirt has an SPF of only about 7. Down to 3 if wet. Yes, I was amazed too when I read how little protection a tee shirt offered. It is better than going "unprotected" and re-application isn't necessary! Check out the fabrics "UPF" (Ultraviolet Protection Factor), which indicates what fraction of the sun's unltraviolet rays can penetrate the fabric. A shirt with a UPF of 50, for example, allows just 1/50th of the sun's UV radiation to reach the skin.
    • Hats: Baseball caps leave the ears, neck and lower face unprotected. Wear wide brimmed hats to ensure that the tips of the ears are covered. Take it from a guy who has had two actinic keratosis lesions removed from his left ear!
    • Automobiles: UVB does not penetrate window glass. Windshields have UVA filters, but side windows do not. Consider sunscreen in the car if photosensitive, even if windows are up.

    Application and general information for sunscreens
    • Apply 30 minutes before sun exposure and cover all exposed areas evenly and liberally. Figure 1 0z. per adult application in a swimsuit.
    • Water Resistant: The formula retains SPF after 40 minutes of activity in water, sweating or perspiring.
    • VERY Water Resistant: The formula retains SPF after 80 minutes of activity in water, sweating or perspiring.
    • Water resistance claims on the product's front label must tell how much time a user can expect to get the declared SPF level of protection while swimming or sweating, based on standard testing. Two times are permitted on labels: 40 minutes or 80 minutes. Apply frequently!

    FDA CLASSIFICATION of Sunscreens
    (June 18, 2012 - FDA.gov)
    • "Broad Spectrum" and "SPF 15" (or higher) not only protect against sunburn, but, if used as directed with other sun protection measures, can reduce the risk of skin cancer and early skin aging. For these broad spectrum products, higher SPF (Sun Protection Factor) values also indicate higher levels of overall protection.
    • Any sunscreen not labled as "Broad Spectrum" or that has an SPF value between 2 and 14, has only been shown to help prevent sunburn. "Skin Cancer/Skin Aging Alert: Spending time in the sun increases your risk of skin cancer and early skin againg. This product has been shown only to help prevent sunburn, not skin cancer or early skin aging."

    "What should I wear to the beach??? Well, certainly my readers or patients wouldn't be asking me for fashion advice!! Here is some practical advice to protecting you and your patients from the damaging effects of the sun's rays. Although, we pharmacists are the experts in selecting medications both oral and topical, we can offer advice to our patients with respect to clothing, as well as automobile glass when it comes to sun protection!

    I learned a lot putting this column together! Be sure to share these safety tups with your patients.

    There is an excellent website I used as a reference: www.skincancer.org

    Have a great day on the bench!!"

    June 2017

    When choosing an SPF, more isn't always better!

    Sunscreens - The basics

    Skin Protection Factor (SPF) : how the efficacy of a sunscreen is expressed. It is a ratio of the time required to produce minimal redness with a sunscreen, to the time to produce minimal redness without a sunscreen. An SPF of 15 will allow a person to remain in the sun without burning 15 times longer, than if the skin was unprotected.
    Minimal Erythema Dose (MED): is the amount of solar radiation to produce minimal skin redness. MED times SPF =Safe Duration of Exposure. The MED is not a standard amount of exposure. It varies from person to person. Dark skinned individuals demonstrate higher MED. Fair skinned individuals (like redheads) have lower MED. Let’s consider two patients:
    1. Fair skin, redhead: Without sunscreen gets red in the sun within 10 minutes.
    2. Dark skinned brunette: Without sunscreen she gets red in the sun in about 30 minutes.
    • If both use a sunscreen with an SPF of 30, the redhead will turn red in 300 minutes (5 hours) while the brunette would turn red in 900 minutes (15 hours). This IS assuming they are applying the sunscreen frequently according to package instructions.
    • Your patients will have varying responses to sunscreens based on their individual skin type.
    Chemically: absorb a specific portion of the spectrum thus preventing harmful rays from hitting the skins surface. Examples: PABA, Cinnamates, Ethylhexylsalicylates, Benzopheones. Most sunscreens contain combinations of 2 or 3 of the classes.
    Physically: provide a physical barrier to UV radiation and scatter or reflect the harmful rays. Most commonly referred to as “sunblock” Examples: Zinc oxide, red petrolatum, Titanium dioxide. An SPF of at least 15 is recommended for most people by the Skin Cancer Foundation. HOWEVER...
    • Products with SPF over 30 only block UVB slightly more than those of SPF=30. The higher concentration of chemicals increases potential for adverse effects, such as skin rashes. SPF over 30 are labeled as “SPF 30 plus”. An SPF of 30 blocks 97% of the UVB rays.An SPF of 15 blocks 93% of UVB rays. Higher SPF products do increase the likelihood of allergic reactions.
    • By bumping the SPF from 15 to 30, it may offer an extra margin of safety to consumers who do not apply a sunscreen as frequently as indicated.


    “An ounce of prevention is worth a pound of cure”, is a well-worn adage we pharmacists use when discussing blood pressure, Type-2 diabetes, and osteoporosis. This adage is even more applicable with summer officially here as of June 21st at 12:24am. With the appearance of much desired sunshine and hence the need to protect our patients from the sun's damaging rays, our expertise is needed. Let's make the summer vacation of 2017 a safe and fun time whether enjoying the mountains of Pennsylvania, the beautiful sands of Myrtle Beach, or wherever your favorite summer destination is! This week let’s describe the basics of sunscreens. We will cover in the upcoming weeks the proper application of sunscreen and the treatment of sunburn.

    Oral corticosteroids are great--just make sure they are prescribed long enough!

    Treatment of Poison Ivy- the RIGHT way!
    Last week we discussed avoiding the Toxicodendron family of plants. I can easily identify the plant, when it appears growing on the side of a tree or along a hedgerow. The challenge becomes when the leaves are chopped up by a weed eater, or a lawnmower! So let’s discuss the treatment of poison ivy when a patient comes into your pharmacy or clinic.

    Refer to a prescriber when:
    • Over 25% of body surface area is contaminated, or if any sign of infection.
    • Limited but disabling involvement (hands, face, area around mouth/eyes, or genitals)
    • If patient has history of severe reactions
    Treatment of poison ivy-needs at least 14 days!
    Have you noticed when a patient gets a methylprednisolone dosepak that after the pack is completed a few days later they come back, and think they got “another batch” of poison ivy? Truth is, it is the original case but the treatment was not long enough in duration, and the patient is experiencing “rebound symptoms”. A six day treatment pack is not adequate.
    • Oral prednisone: 0.5 to 2mg/ kg / day tapered over 14 to 21 day period. Usually start with 60mg per day, and taper down over a 14-21 day period. Using a 21 day regimen will decrease the likelihood of rebound dermatitis.
    • Medrol dosepak (6 day therapy) is not long enough of duration.
    Topical treatment of poison ivy
    • Oatmeal baths might be soothing but are not of much value. They might make the tub slippery, and clog the drain!
    • Calamine actually hinders treatment and is of minimal value for poison ivy. It will help with the itching. Hydrocortisone 1% OTC is of limited value—use only in mild cases.
    • Avoid: topical antihistamines, topical anesthetics, topical antibiotics, as well as poison ivy extracts. Jewelweed (Impatiens biflora) extract is promoted for relief of poison ivy, but is of no value.
    • Burows solution is available over the counter: (aluminum acetate): dissolve 1 packet (Domeboro®) in 1 pint of water, and apply as a wet dressing for 15-30 minutes 3 to 6 times daily. This self care product greatly relieves itching.
    • Topical prescription corticosteroids are most effective in early stages BEFORE the blisters form. They will help with itching, and promote drying of the lesions. They are of little value once the blisters form.


    We see a lot of poison ivy in our area, and frequently it is treated with a Methylprednisolone six day dosepak. The patients will come back a couple of days after completion of the pack, and think they got into another "batch" of poison ivy. The truth is they were not treated adequately the first time.

    I saw such a patient today, her arms slathered with Calamine lotion Her arms were blistered, and she had a prescription for a Methylpred 4mg dose pack, and an 80gram tube of triamcinolone 0.1% cream. After reading this newsletter, it is obvious that all three treatments were wrong. Calamine is worthless, and needs to be scrubbed out; the triamcinolone cream is not recommended since the blisters were present AND the corticosteroid should be given 14-21 days! (Feel free to share this newsletter with your colleagues!)

    Poison Ivy--it's all about the oil. Identification is key to prevention!

    Poison Ivy: Leaflets three let them be! Hairy vine no friend of mine!
    The Toxicodendron (“means poisonous tree”) genus of plants causes more contact dermatitis than all other causes combined. Ten to fifty million Americans develop allergic contact dermatitis to a Toxicodendron annually. In one study 10% of all occupational injuries among seasonal farm, workers in PA and NY were due to poison ivy contact. The genus/species names are as follows:
    • common or northern poison ivy (Toxicodendron radicans)
    • western poison ivy (Toxicodendron rydbergii)
    • eastern poison oak (Toxicodendron toxicarium)
    • western poison oak (Toxicodendron diversilobum)
    • poison sumac (Toxicodendron vernix)
    Regardless of the species name all the treatment protocols are the same. Allergic Contact Dermatitis (ACD) has 2 distinct phases.
    • A sensitization phase where a specific hypersensitivity to the allergen is acquired.
    • An elicitation phase during which dermatological response is visible.
    Identification of Poison Ivy:
    • Poison ivy is typically a hairy, ropelike vine with three shiny green (or red in the fall) leaves budding from one small stem. “Leaves of three let them be!” and “Hairy vine, no friend of mine”.
    • May have yellow or green flowers and white to green-yellow or amber berries
    • Poison sumac, may be harder to identify because it more often forms leaflets of five, seven, or more that angle upward toward the top of the stem.Poison sumac presents as a woody shrub that has stems that contain 7-13 leaves arranged in pairs
    Here’s what happens
    • Urushiol, which is an oleoresin (lacquer) oozes from the broken leaf and stems, causing the characteristic black dots which is oxidized urushiol (due to the enzyme laccase found in the oleoresin) and can be found on plant leaves within 10 minutes of its exposure to oxygen. Urishiol can be transmitted to the patient by contact with the plant, or pets, tools, gloves, shoes and clothing for months. Washing clothes in regular laundry detergent will decontaminate fabrics. Poison Ivy should NEVER be burned, as it vaporizes the oil, causing lung damage.
    • The characteristic wheals and blisters of poison ivy contain serum, and NOT the urushiol. Poison ivy and other poison plant rashes can't be spread from person to person. But it is possible to pick up the rash from plant oil that may have stuck to clothing, pets, garden tools, and other items that have come in contact with these plants.
    In summary, make sure your patients are educated about Lyme disease, and are using insect repellents, wearing long sleeve shirts and pants treated with permethrin, and know appropriate tick removal procedures. Have them seek care in case of a tick bite. As you see from this column, untreated Lyme can have some devastating effects on our patients.

    When contacted:
    When a patient is exposed to a poisonous plant, like poison ivy, oak or sumac:
    • Immediately rinse skin with rubbing alcohol, poison plant wash, or degreasing soap (such as dishwashing soap) or detergent, and lots of water. Professor Pete takes a half bar of Fels Naphtha soap (old fashioned washboard soap) in a nylon stocking, and carries it backpacking or ties it to his canoe seat. The soap is always handy, and never gets soggy.
    • Rinse frequently so that wash solutions do not dry on the skin and further spread the urushiol.
    • Scrub under nails with a brush.
    • Wash exposed clothing separately in hot water with detergent.
    • After use, clean tools with rubbing alcohol or soap and lots of water. Urushiol can remain active on the surface of objects for up to 5 years. Wear disposable gloves during this process.



    Leaflets three--let them be!
    (Notice the "hairy vine")

    I've spent almost 20 years in leadership positions with Cub Scouts and Boy Scouts, and teaching about poison ivy seems to be the one condition that the general public is most misinformed about! First concern people have is about spreading poison ivy, when the rash starts to blister and seep. These lesions contain serum and can't be spread. The only way the rash can occur is direct contact with the urushiol to a sensitized patient. Identification of poison ivy is another teaching moment. Last week in our landscaping in the front of our home, I found a beautiful specimen of poison ivy. I gently removed it with a rake, and put it on the front curb and took a picture, which appears in this edition. I have gotten poison ivy several times while planting flowers at our cemetery. I guess I'm not good at identifying poison ivy when it is chopped up with a weed-eater or lawn mower! People love to dump stuff on their poison ivy lesions that often does more harm than good-- next week we will talk about appropriate treatment of poison ivy, both from the patients standpoint, as well as the prescriber's standpoint.

    What happens when the tick bite goes undiscovered or untreated?

    Progression of Lyme Disease

    As we discussed last week, Lyme disease, caused by the spirochetal bacterium Borrelia burgdorferi, remains the most common vector-borne disease in the United States. Lyme disease was first described in 1977 as "Lyme arthritis" in studies of a cluster in Connecticut of children who were thought to have juvenile rheumatoid arthritis. When some of these kids got ear infections, and were treated with amoxicillin the “arthritis” went away. The multisystem nature of the infection became clear as involvement of other systems was soon identified.

    The problem with Lyme disease isn’t so much with the tick we remove, but the one that is never discovered, and inoculates our patient with the Borrelia burgdorferi spirochete. Only about 25 percent of patients with erythema migrans recall the tick bite that transmitted Lyme disease. The characteristic rash erythema migrans (the “bullseye” rash) occurs in 70 to 80% of the cases. We can also say that 20-30% of the time patients do not get the rash. Here is what happens if Lyme disease remains undiagnosed and progresses.

    Early Disseminated Lyme disease
    Occurs days to weeks after tick bite and left untreated, the infection may spread and see:
    • Additional erythema migrans lesions appear in other areas of the body
    • Neurological consequences:
      • Facial or Bell's palsy (loss of muscle tone on one or both sides of the face)
      • Severe headaches and neck stiffness due to meningitis (15% of patients)
    • Pain and swelling in muscles and the large joints (such as knees) (60% of patients)
    • Shooting pains that may interfere with sleep
    • Heart palpitations and dizziness due to changes in heartbeat (1% of patients)

    Late Disseminated Lyme disease
    • Occurs a few months to years post-tick bite
    • Approximately 60% of patients with untreated infection may begin to have intermittent bouts of arthritis, with severe joint pain and swelling. (60% of untreated patients)
    • Affects Large joints (knees) see pain and significant swelling.
    In summary, make sure your patients are educated about Lyme disease, and are using insect repellents, wearing long sleeve shirts and pants treated with permethrin, and know appropriate tick removal procedures. Have them seek care in case of a tick bite. As you see from this column, untreated Lyme can have some devastating effects on our patients.

    Here is the latest on treatment of Lyme disease with of all things loratadine (Claritin) and desloratadine (Clarinex). Here is what happens:

    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…..Source: http://www.pnas.org/content/106/9/3449.full

    There is lots of information on the CDC website with patient friendly downloads on Lyme disease: https://www.cdc.gov/lyme/toolkit/index.html
    (Hey, we pay our taxes, might as well reap some benefits)

    Appropriate prophylaxis and treatment of Lyme disease

    Lyme Disease - Treatment Options

    Let’s assume our patients didn’t adequately follow last week’s prevention tips. We can cover two scenarios. The first we will discuss when a patient finds a tick on their skin, and then remove it. Then we can discuss treatment when the characteristic rash appears.

    Pharmacological Prophylaxis of Lyme disease: The Infectious Disease Society of America recommends prophylaxis of a tick bite only when:
    • Attached tick identified as an adult or nymphal deer tick (Ixodes scapularis)
    • Tick is estimated to have been attached for 36 + hours
    • The antibiotic can be given within 72 hours of tick removal
    • The local rate of tick infection with B. burgdorferi is ≥20 percent.
    • Doxycycline is not contraindicated. Don’t give if the patient is pregnant, nursing or a pediatric patient.
    Recommended dose: Doxycycline 100mg (2) tablets as a single dose with food. Dispense #2 tablets.

    Pharmacological Treatment of Lyme Disease
    The first sign of infection is usually a circular rash called erythema migrans or EM. This rash occurs in approximately 70-80% of infected persons and begins at the site of a tick bite after a delay of 3 to 30 days. A distinctive feature of the rash is that it gradually expands over a period of several days, reaching up to 12 inches (30 cm) across. The center of the rash may clear as it enlarges, resulting in a bull’s-eye appearance. It may be warm but is not usually painful. Some patients develop additional EM lesions in other areas of the body Treatment of early erythema migrans: (appearance of red “bulls-eye” rash)
    • Doxycycline (Vibra-tab) 100mg twice daily for 14-21 days. Avoid doxycycline if pregnant or under age 8.
    • Amoxicillin (Amoxil) 500mg three times daily for 14-21 days
    • Cefuroxime (Ceftin) 500mg twice daily for 14-21 days
    • Erythromycin (Ery-tab) 250mg four times daily for 14-21 days (extremely expensive)
    Note: 10 days may be as effective as 20 days. (Source: Sanford Guide)

    Since pharmacists are indeed the “drug experts” as well as the “cost experts” consider the following:
    • I personally do not dispense the doxycycline capsules, and use only tablets due to the choking hazard of the capsules. Some European countries ban the capsules for this reason. I have had two students in my class say they had esophageal burns due to capsules getting stuck in the throat. Remember to avoid doxycycline in children whose teeth are not fully erupted.
    • Amoxicillin is equally effective as doxycycline, but it needs to be dosed three times a day. Best option for pediatrics and pregnant women. Amoxicillin is still the least expensive treatment for Lyme erythema migrans. Amoxicillin should NOT be used for prophylaxis (as doxycycline is). Amoxicillin might also be a better choice for patients who experience photosensitivity on previous doxycycline therapy.

    "As we discussed last week, prevention is indeed key for our patients who are headed to the outdoors. Although we commonly think of Boy Scouts, hikers, campers, and fishermen keep in mind that other outdoor activities such as gardening and even golf may expose patients to deer ticks.

    This morning I decided to take my 5K hike through the neighboring farm, and through the woods. My wife reminded to put on my hiking pants, that I previously sprayed with permethrin. The grass was up to my waist in the fields. I saw a big doe (probably hiding her fawn) in the first field. After I got on the road, my pants were soaked with the morning dew, but there wasn't a tick anywhere on my light polyester pants.

    One of the first patients I saw this morning was at the minute clinic, and brought a prescription for Doxycycline for 2 of the 100mg tablets. I gave her the flyer from last week, and she said she did have the permethrin, but neglected to treat her clothes this year! She promised me she would spray them when she got home. The lady behind her was listening in and quickly picked a can of permethrin of the shelf and bought it. My wife Denise called and told me she treated a patient with doxycycline for erythema migrans, who never heard of permethrin clothing spray! He was curious when the doxycycline would be "washed out" so he could canoe again, since he had such a photosensitivity rash last time. Amoxicillin might have been a better choice for this patient. So you see we have a lot of educating to do. Even though the IDSA guidelines came out in 2006, and have not changed many clinicians might not be choosing the optimal therapy for their patients."

    May 2017

    Lyme Disease is in Full Swing in the United States

    Lyme Disease

    CAUSED: by the bacterium Borrelia burgdorferi and is transmitted to humans by the bite of infected blacklegged ticks (Ixodes scapularis).
    SYMPTOMS: include fever, headache, fatigue, and a characteristic skin rash called erythema migrans, which occurs 3-30 days after the tick bite.

    THE RASH "Erythema migrans"
    • May occur anywhere on the body, and appears in approximately 70 to 80 percent of infected persons. (Keep in mind that 20-30% of the time there is NO rash.)
    • Begins at the site of a tick bite after a delay of 3 to 30 days (average is about 7 days)
    • Expands gradually over a period of days reaching up to 12 inches or more (30 cm) across
    • May feel warm to the touch but is rarely itchy or painful
    • Sometimes clears as it enlarges, resulting in a target or “bull’s-eye” appearance

    PREVENTION: “An ounce of prevention is worth a pound of cure”- Benjamin Franklin
    • Wear high socks, long pants and long sleeve lightweight shirts. Best if color is white or very light to spot ticks easier. Walk in the center of a trail, and avoid tall grasses in fields and meadows
    • Checking for ticks: Check legs and feet frequently. Know how to spot and identify ticks. Nymphal ticks are as small as a poppyseed. Use bright light and magnifying glass. Check each other in hard to see areas, especially folds of skin.
    • Pets: use a scheduled tick killing shampoo. Brush pet daily outside the house.

    INSPECTION:
    • Bathe or shower as soon as possible after coming indoors (preferably within 2 hours) to wash off and more easily find ticks that are crawling on you.
    • Conduct a full-body tick check using a hand-held or full-length mirror to view all parts of your body upon return from tick-infested areas. Parents should check their children for ticks under the arms, in and around the ears, inside the belly button, behind the knees, between the legs, around the waist, and especially in their hair.
    • Examine gear and pets. Ticks can ride into the home on clothing and pets, then attach to a person later, so carefully examine pets, coats, and day packs.
    • Tumble clothes in a dryer on high heat for an hour to kill remaining ticks

    TICK REMOVAL: Removal with tweezers and magnifying glass. Wear gloves place tweezers on head of tick as near skin as possible. Pull slowly, steadily and upward. Don’t twist, squeeze, jerk or crush tick. Save tick in jar or vial. Wash site of removal with soap and water. Do not use matches, petroleum jelly, gasoline, kerosene, nail polish remover.

    INSECT REPELLANTS:

    Deet (N,N-diethyl-3-methylbenzamide) can be used directly to the skin. Use repellents that contain 20 to 30% DEET (N, N-diethyl-m-toluamide) on exposed skin and clothing for protection that lasts up to several hours. Always follow product instructions. Parents should apply this product to their children, avoiding hands, eyes, and mouth.
    Permethrin: Use products that contain permethrin on clothing. Treat clothing and gear, such as boots, pants, socks and tents with products containing 0.5% permethrin. It remains protective through several washings. Permethrin is available OTC as a solution for application to clothing. Available Sawyer Clothing Insect Repellant, or Repel Clothing and Gear. Once applied to clothing it remains effective for up to 6 weeks, even after several launderings. Good for clothes that are exposed to tick infested areas. Effective against ticks that carry Lyme disease and Rocky Mountain Spotted Fever. Repellant should be applied outdoors and before clothing is worn; hang clothing, spray and let dry two hours (four in humid conditions).

    "In Pennsylvania we love our sports teams, the Eastern Side of the state has the Phillies, Eagles and Flyers; the western side has the Pirates, Steelers and Penguins. These teams over the years have been “#1” in their respective sports. The whole state has its “#1” in statistics too, that being for the third straight year, leading the nation in number cases of Lyme disease.

    Now that winter has released its clutches on our country, everyone is headed to the great outdoors either for picnics, hiking, camping and even less enjoyable, gardening and mowing the lawn! Many of our patients are presenting to our pharmacies/offices with questions about Lyme disease. I just sprayed my hiking pants with Permethrin spray!

    Lots of good information on the CDC website. Below is a picture of the rash and other Lyme symptoms."

    Hey doc.. I have a lot of pain with this tooth. What can I take?

    If it's mechanical-- only the dentist can help

    Dental pain: Basically, if a mechanical problem exists (broken tooth, ill-fitting dentures, missing fillings, chipped or broken tooth), our patient should always be referred to the dentist. In the meantime, dental pain from a toothache is best treated orally with NSAIDS (ibuprofen, naproxen). Topical treatment is short lived and is not of much use and should be discouraged. Make sure that NSAIDS are appropriate for that patient. One of the more common OTC treatments many patients use is Anbesol which contains phenol and is of no use in treating dental pain. It will however, in high enough dose, cause caustic chemical burns in the mouth. Advise against its use.

    Teething pain in babies: recommend acetaminophen or ibuprofen if old enough (over 6 months). Do not recommend benzocaine topical products, homeopathic remedies or heaven forbid rubbing whiskey on the gums (sorry Grandma!). Have patient consult pediatrician for appropriate doses if under two years of age.

    Missing fillings, cracked caps, broken off teeth? Don't apply any sort of medication, such as aspirin, or topical anesthetics, directly to the tooth. Bite down on tea bag to stop bleeding. It is best to avoid eating, but if necessary eat only soft foods until patient can be seen by a dentist. To manage pain, apply ice to the face outside the lips or cheek at the location of the injured tooth. Do not apply ice directly to the tooth. Over-the-counter pain meds (Ibuprofen or Naproxen) if appropriate, are effective to minimize pain.

    First Aid for Tooth Avulsion- "Knocked out teeth"

    Best Choice: For professions around activities where teeth can be knocked out, such as athletic trainers, coaches, school nurses and emergency responders, Save-a-Tooth® is a proprietary product that should be carried to all events. This product keeps the tooth alive and nourishes cells until implantation occurs. About 90% success rate (versus 10%). If no one has this product available, (which is most likely) pick up tooth by crown, not the root. Rinse the affected tooth with water if dirty. Reposition into socket at once (if possible). Do NOT let the avulsed tooth dry-out! It is important to remember that time is extremely important here. After 30 minutes the success rate of tooth reimplantation drops sharply.
    • may hold in mouth next to cheek (Not recommended in cases where there is a fear of the patient swallowing their tooth)
    • drop into glass of milk (Best option if you don’t have Save-a-tooth)
    • see the dentist/endodontist within 30 minutes
    "Meth Mouth" is most commonly attributed to the abuse of methamphetamine (crystal meth, crank). This drug is made in meth labs, through the conversion of pseudoephedrine to methamphetamine. According to the American Dental Association, “meth mouth” is probably caused by a combination of drug-induced psychological and physiological changes including, xerostomia (dry mouth), extended periods of poor oral hygiene, frequent consumption of high-calorie carbonated beverages, teeth clenching and grinding (bruxism). The Pennsylvania Dental Association also contends the acidic nature of methamphetamine destroys enamel. (Due to highly corrosive nature of manufacturing process) “Meth mouth” is a misnomer. Not all patients with these blown away teeth are methamphetamine addicts. Meth mouth also describes any chronically using any amphetamine, or any opioid. This condition can also be seen in anorexia/bulimic patients.

    What the dentist sees: of the 28 teeth, most adults have (32 minus 4) most patients come in with at least 20 teeth blown away. The challenge is once these patients are in detox with the opioids withdrawn, the exposed nerves become very painful, and patients seek dental help. Generally speaking, dentures are the only viable treatment option.

    "We have spent the past thirteen columns meticulously going through all the products in our dental section, gaining a level of expertise that we didn’t have, thanks to the input of Dr. Rodney Messner. We have a lot of products to choose from to help our dental patients, but there are some complaints that we just can’t fix! This column is dedicated to what we can’t fix, and should be immediately referred to a dentist. Unfortunately many of our states do not reimburse dentists adequately and they will lose money seeing these patients that frequently come to our pharmacy with dental issues. A day doesn't go by when we get a prescription for Clindamycin and Ibuprofen from the Emergency Department from our local hospital. These patients are in pain and this is only a temporary fix. Only the expert care of a dentist will be able to remedy their dental problems. We as pharmacists like to help our patients, and sometimes the best advice we can give is to recommend our patients for appropriate dental care. Remember--"Dentistry isn't expensive...neglect is!" "

    Dr. Rodney Messner of CherryTree Dental Associates has been most helpful in providing expertise for these columns. His expertise in the treatment of tooth avulsion is most appreciated for this column. We wish him continued success in his practice.

    Dr. Rodney A. Messner, DMD

    Dry mouth complaints??... before heading to the dental section... check the med list!!!

    Treatment and Prevention of Xerostomia

    A healthy patient produces saliva at the rate of 0.5ml per minute, approximately 30 ml of (1 ounce) per hour. In a person with xerostomia, the rate is reduced to 0.1ml per minute, approximately 6ml (1 teaspoonful) per hour. Besides adding in chewing and digestion, saliva maintains the pH balance in the mouth by secreting bicarbonate ions, produced in the salivary ducts, which combine with and neutralize the H+ ions produced in the fermentation process. Inadequate production of saliva is a risk factor for dental caries.

    The Most Common Causes of Xerostomia:

    • Lesions in the salivary glands or duct obstruction
    • Radiation injury to the salivary glands
    • Sjogrens syndrome: 9:1 female: male ratio. Most common disease affecting salivary gland. These patients also experience dry eyes, dry skin, difficulty in swallowing and swollen inflamed joints
    • Hypertension, alcohol, tobacco, caffeine use
    • Cystic fibrosis
    • Lupus, Crohn's disease, Biliary cirrhosis, HIV

    Many Drugs are Commonly Implicated in Causing Xrostomia:

    • Numerous psychotherapeutic agents: benzodiazepines, buspirone, TriCyclic Antidepressants (Elavil), Selective Serotonin Reuptake Inhibitors (Prozac, Zoloft), MAOI (Emsam), Effexor, Wellbutrin. Lithium, Valproic acid, numerous antipsychotics.
    • Antihypertensive agents: clonidine, enalapril, methyldopa, prazosin
    • Diuretics: HCTZ, Furosemide, Spironolactone
    • Anticholinergics: Benztropine, Trihexyphenidyl, Atropine, Dicyclomine, Hyoscyamine.
    • First generation antihistamines: Diphenhydramine, promethazine, hydroxyzine. This is primarily to their anticholinergic side effects.

    OTC treatment of Xerostomia: topical treatment of xerostomia is available as "Saliva substitutes".

    Saliva substitutes may be most useful before sleep, because viscosity of saliva changes at night; after waking at night with dry mouth symptoms, during telephone conversations, during social and workplace interactions, and in patients with dentures.

    • Contain carboxymethylcellulose and or mucins for lubrication and viscosity.
    • Contain xylitol or sorbitol as sweeteners. Remember sugar alcohols can cause diarrhea.
    • Trade names: MouthKote, Biotene Oralbalance gel, Biotene mouth spray, Salivart, Xero-lube

    Patient tips:

    • Sip water and sugar free drinks.Avoid sugary drinks and caffeine
    • Chew Sugarless gum or suck on sugarless hard candies
    • Use a humidifier
    • Breathe through the nose, not the mouth
    • Practice good oral hygiene: brush, floss, see dentist regularly.
    • Treat cracked lips with petroleum jelly or lip balm
    • Eat high moisture foods (Mashed potatoes instead of French fries). Avoid spicy foods

    RX Treatment:

    Includes the parasympathomimetics or the "cholinergic agonists": pilocarpine (Salagen), cevimeline (Evoxac). Patients may complain of excess sweating and gastrointestinal upset. Patients should be monitored for development of oral candidiasis (thrush).

    Special thanks to Dr. Rodney Messner from CherryTree Dental Associates for his review of this column:


    Dr. Rodney A. Messner, DMD

    Dr. Rod adds:

    • Biotene products seem to be the most popular with my patients.
    • Xerostomia is a very common problem among our older patients. I do see it a good bit in my dental practice
    • Don't forget to advise patients to avoid highly acidic foods/drinks as well due to their erosive effect on teeth. With limited saliva production, these drinks can quickly damage the protective enamel layer.


    Clenching teeth---our dentists can help!

    Bruxism--again we have to check the med list!!

    Bruxism refers to repetitive jaw-muscle activity characterized by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible. stress and anxiety but by sleep disorders, an abnormal bite or teeth that are missing or crooked. The symptoms of teeth grinding include:
    • Clicking or popping jaw joints
    • Eating disorders
    • Enlarged jaw muscles
    • Earache because of proximity of ear canal to TMJ
    • Dull headaches
    • Jaw pain and stiffness on waking
    • Teeth that are painful or loose, due to wearing down of enamel and increasing sensitivity
    • Fractured teeth and excessive tooth wear
    Treatment may include mouth guards, and skeletal muscle relaxants.

    German researchers did a small study of 69 patients, and concluded that participants with high sleep bruxing activity tend to feel more stressed at work and in their daily life, and, according to the questionnaire, seem to deal with stress in a negative way. Bruxism is a dangerous dental problem that can not only wear down teeth, but also make them sensitive or loose or even fracture them. Besides worn tooth surfaces, which can lead to sensitivity, symptoms can include headaches and a sore jaw.

    Causes of Bruxism:

    Bruxism presents with multifactorial etiologies many of which remain unclear, but several factors may be involved which include, the use of psychoactive substances (tobacco, alcohol, caffeine, or medications for sleep and depression) increases arousal and leads to problems falling asleep, staying asleep and daytime sleepiness. Mental disorders, anxiety, stress and adverse psychosocial factors are significantly related to tooth grinding during sleep and it has been found that nearly 70% of bruxism occurs because of stress or anxiety.

    Pharmacotherapy may contribute to bruxism, believed to be due to lowering dopamine levels. Selective Serotonin Reuptake Inhibitors (SSRI) are most commonly implicated with Citalopram (Celexa), Fluoxetine (Prozac) and Paroxetine (Paxil) being the biggest culprits. Mirtazapine (Remeron) might be a better choice.


    TREATMENT (Pharmacotherapy) of BRUXISM
    • STOP the offending medication!
    • Buspirone (anxiolytic) may help with anxiety, without contributing to bruxism
    • Propranolol, Gabapentin, Botulism toxin have all been used.
    • Clonazepam has most evidence, and has the additional benefit of decreasing nighttime leg movements.
    Mechanical treatment of Bruxism: Mouth Guards
    • Premade Plastic Mouth Guards-flexible plastic- don’t always fit adequately over the teeth. May be an obstructive hazard
    • "Boil and Bite" Mouth Guards OTC fit better than the pre-made but are more uncomfortable to wear. May interfere with tongue movement.
    • CUSTOM FIT Mouth Guards: made by dental professionals, from soft rubber up to acrylic, for heavy grinding.
    • Occlusal splints (bite guards) have become first line therapy as they protect the teeth from premature wear, reduce jaw muscle activity and the noise of teeth grinding.


    Special thanks (once again) to Dr. Rod Messner for his expertise in reviewing this column for content.


    Dr. Rodney A. Messner, DMD

    April 2017

    Might want to grab a bottle of water after reading this column! (it is cheaper however if you drink it out of the faucet!)

    Have a soda...and a smile??

    Dr. Rod Messner has this to say about soda consumption: "When I was in Dental School at Temple University, one of the professors gave us first year dental students a most discouraging prediction: with every city fluoridating their water the upcoming generation will have teeth that will never dec... most of you will probably starve, as drilling and filling is our bread and butter" . "Since I first heard that statement 32 years ago, one thing has been made very clear to me: Human behavior always trumps good science! The science related to the deleterious effect of regular consumption of soft drinks is good science as well as the voluminous data related to systemic fluoride."

    "However, when our patients regularly ingest 6 liters of Mountain Dew per day, (yes 6 liters) no amount of flossing, tooth brushing, or fluoridated mouthrinse is going to help this patient! What we do know about the dental effects of soft drink consumption is that when compared with caries, dental erosion seems to have a much stronger relationship with soft drinks. In order to advise your patients on ways they can reduce dental caries risk, low-calorie and sugar-free foods should be recommended. However, sugar-free soft drinks often have as high an erosive potential as sugar-containing soft drinks."

    Dr. Messner provides these great insights, and 32 years since he heard that prediction we Americans are doing very little to decrease soda consumption. Consider the following: According to the New York Times 5% of the federal "food stamp" budget (SNAP) is spent on these soft drinks, while the category of "sweetened beverages" (energy drinks, fruit juices and teas) accounts for 10% of the grocery bill. The Department of Agriculture is coming under fire for "subsidizing the soda industry"

    https://www.nytimes.com/2017/01/13/well/eat/food-stamp-snap-soda.html?_r=1
    Here is the history of how much soda Americans consume:
    • 1970- Americans consumed 20 gallons soda per year (7-oz/day)
    • 1981- Americans consumed 32 gallons soda per year (11oz/day)
    • 2002- Americans consumed 54 gallons soda per year (20oz/day)
    • 2015- Americans consumed 41 gallons soda per year (14oz/day)
    It's called "pop" in the Midwest and most of Canada. It's "soda" in the Northeast. And it goes by a well-known brand name in much of the South. Where I live in Blair County, Pennsylvania is on the edge of the "pop versus soda" line. Folks to our west in Pittsburgh call it "pop" and the folks to our east call it "soda". Horry County, South Carolina, home of PharmCon it is called by a well-known "brand name". Yes there is a website: popvssoda.com !!

    • Larger serving sizes make the problem worse. From 6.5 ounces in the 1950s, the typical soft drink had grown to up to 20 ounces by the 1990s.

    Three ingredients in this delicious, fizzy drink cause the problems with our teeth:

    • Sugar: obvious contributor to dental caries. Note that this also includes corn syrup! This we see regularly as one of the top food additives to avoid in our diet for better health!!
    • Phosphoric acid: gives the "bite" to soft drinks. The pH of soda, and our mouths have a lot to do with the destruction of the enamel of our teeth.
    • pH of a soft drink ranges from 2.47-3.35
    • pH in our mouth is normally about 6.2 to 7.0
    • At a pH of 5.2 to 5.5 or below the acid begins to dissolve enamel on our teeth
    • Citric acid: Non-cola drinks contain citric acid which is also harmful to teeth
    As far as interprofessional interactions with dentists and pharmacists, Dr. Messner offers the flowing closing comments: "It is necessary to educate out patients about the harmful effects of excessive soft drink consumption and to advise them with the following tips to prevent dental erosion and caries: limiting soft drink intake, choosing low erosive soft drinks, improving their drinking habits, toothbrushing at least twice per day, and avoiding brushing teeth within 1 hour after consuming acidic food, and using a fluoride or a remineralizing toothpaste."
    I remember as a kid growing up, seldom was there soda in our house. We had to go to our Grandpa's house for a visit if we wanted such a treat. I remember well the 7 ounce soda bottles, and how there were judiciously passed out to us youngsters. As we discussed last week, about 2/3 of the municipal water supplies are fluoridated and with the large increases in consumption of sugared beverages and soda-pop, we are confident that our fellow health care clinicians in the dental profession will be plenty busy… for a long time! Once again, I want to express my sincere appreciation to Dr. Rodney Messner for his input on this column. With over 30 years of clinical experience, and an extremely busy schedule I'm delighted to have him contribute his expertise to this column. Have a great day on the bench!!

    "Keeping teeth strong with fluoride!
    Dr. Rod Messner is a huge fan too! "


    Fluoride---friend or foe??

    How fluoride works: The risk of dental caries is reduced due to the uptake of fluoride by enamel cystallites and formation of fluorhydroxyapatite which is resistant to acid solubilization. Fluoride is anticariogenic because it replaces the hydroxyl ion in hydroxyapatite with the fluoride ion to form fluorapatite on the outer surface of the enamel. Fluorapatite hardens the enamel and makes it more acid resistant. Fluoride also has demonstrated antibacterial activity. Fluoride is most beneficial from birth to age 12 because unerupted permanent teeth are mineralizing at that time. Whether a person receives fluoride supplementation depends on the concentration of the drinking water. Adding fluoride to the water reduces dental caries by 25%. Because of this contribution to public health, the CDC named community water fluoridation one of 10 great public health achievements of the 20th century. The American Dental Association, the American Academy of Pediatrics, the US Public Health Service and the World Health Organization all support fluoridation of water.

    Sources of fluoride:
    • Drinking water: About 66% of the US population lives in a municipality with a fluoridated water system. The United States Public Health Service recommends an optimal fluoride concentration of 0.7 milligrams/liter (mg/L). This concentration of fluoride in drinking water is the concentration that provides the best balance of protection from dental caries while limiting the risk of excess fluoride (dental fluorosis).
    • Dentist applied: fluoride based varnishes and gels can be applied directly to the teeth during a dental visit.
    • OTC mouthwashes: Children under the age of 6 years should not use mouthwash, unless directed by a dentist, because they may swallow large amounts of the liquid inadvertently.
    • Rx Gels and toothpastes such as Prevident 5000 and others. Rx products deliver about four times as much fluoride as do the OTC products.

    Does it work?

    The prevalence of dental caries in at least one permanent tooth (excluding wisdom teeth) decreased from 90% among those aged 12-17 years in the 1960s to 60% among those aged 12-19 years in 1999-2004. Obviously, people should drink municipal water to get the benefits of fluoride! And that includes the astronomical rise in soda consumption… which we can talk about next week... You can check your water supply, or the water supply where you practice at this website: https://nccd.cdc.gov/DOH_MWF/Default/Default.aspx

    How to supplement patients whose water supply is not fluoridated:

    Water concentration of Fluoride Age of patient Supplementation mg/day
    >0.6 ppm of fluoride 6 months - 3 years 0mg
    3 years - 16 years 0mg
    0.3 - 0.6ppm of fluoride 6 months - 3 years 0mg
    3 years - 6 years 0.25mg/day
    6 years - 16 years 0.5mg/day