Favism

Favism.  G6PD deficiency.  Name derived from the hemolytic anemia a patient with G6PD deficiency will suffer after consuming fava beans.  My preceptor at my most recent rotation recently emailed me, asking if I would fill a prescription for the second generation antihistimine, meclizine, for a patient with G6PD deficiency.  Before I could answer, I had to take a few steps back and look at what exactly G6PD deficiency is.

G6PD, or glucose-6-phosphate dehydrogenase, is the rate limiting enzyme for a process that produces NADPH as a byproduct.  NADPH is a reducing agent used in the synthesis of fatty acids and cholesterol and is also utilized to protect cells from oxidative damage.

NADPH is essential to erythrocytes, which having no nucleus, during their 120 day lifecycle are unable to synthesize new proteins to repair cellular damages.  Erythrocytes rely heavily on reducing agents, like NADPH, to protect against oxidative damage.

Patients with G6PD deficiency have genetic mutations in the glucose-6-phosphate dehydrogenase enzyme.  The mutation in the enzyme determines the severity of the NADPH deficiency, and therefore the ability of erythrocytes to react to oxidative damage.  

Under conditions of oxidative stress when NADPH supplies are not sufficient to reduce the damage done to the cell, oxidized hemoglobin clumps together within the erythrocyte creating Heinz bodies, which are characteristic of G6PD deficiency.  This leads to hemolytic anemia, as the red cells burst and die.  

Symptoms of G6PD deficiency are brought on by oxidative stress; a variety of stressors can bring about hemolytic anemia.  Infections, diabetic ketoacidosis, fava beans, and some medications can bring on hemolytic anemia within days of exposure.  

Hemolytic anemia is often brought on by medications in patients with G6PD deficiency when glutathione reduces the medication in the liver during the metabolism process.  In order for the body to return glutathione to its usable state, the oxidized glutathione is reduced by NADPH.  When the mutant enzyme cannot keep up with replacing the NADPH stores, erythrocytes begin to suffer oxidative damage and anemia results, with the tell-tale Heinz bodies, dark urine, and often patients experience back-ache.

Unfortunately the medications that cause hemolytic anemia in this patient population are not structurally similar.  Additionally, many medications that are metabolized by glutathione reductase are safe, in therapeutic doses, for patients with G6PD deficiency to take, for example acetaminophen.

G6PD deficiency is genetic; prevalence varies among populations.  Persons of mediterranean, African, and middle eastern decent are more likely to have this deficiency.  A number of researchers have hypothesized that this enzyme mutation may have evolutionary survival benefits.  For example, like patients with an allele for sickle cell disease, recent studies have shown that patients with G6PD deficiency are less susceptible to malaria caused by Plasmodium falciparum.  

so...  Would I fill meclizine 25 mg for a patient with a salicylate allergy and G6PD deficiency?

Although metabolized in the liver, meclizine does not place patients with G6PD deficiency at risk of hemolytic anemia and is therefore safe to take.  Diphenhydramine, however, poses a low risk of hemolytic anemia.

Medications that put G6PD deficient patients at high risk of hemolytic anemia include: trimethoprim, dapsone, sulfa drugs like sulfamethoxazole, chloroquine, quinine, quinidine, ciprofloxacin, nitrofurantoin, primiquine, and probenecid.  This list is not all inclusive and other medications, like acetaminophen, diphenhydramine, and phenytoin pose a low risk of causing hemolytic anemia.

Patients with a G6PD deficiency can be referred to the G6PD Deficiency Favism Association’s website, available at http://www.g6pd.org for more information on their condition and for an extended list of medications to avoid.  

References:

Meisenberg G, Simmons WH, ed.  Principles of Medicinal Biochemistry.  2nd ed. Mosby-Elsevier, Philidelphia.  copyright 2006.

Beutler E.  G6PD deficiency.  Blood Journal 1994; 84: 3613-3636.

Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics.  11th ed.  New York: The McGraw-Hil Companies, Inc.; 2006.

DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com (cited 11/27/2010).

G6PD Deficiency Favism Association.  Available at http://www.g6pd.org (cited 11/27/2010).

Kastrup EK, Spenard PL, Tra PN, Williams AL, Wickersham RM, Schwalm AJ, et al., editors.  Drug Facts and Comparisons.  2010 ed. St. Louis: Wolters Kluwer Health; 2009.

Dabigatran

I have never liked the sight of blood, which is why the thought of anti-coagulants at first made me uneasy.  However, blood clots can pose a significant health risk.

Symptoms of blood clots depend on where the clot is.  In hospitals or airplanes, where the patient is less able to move around to keep blood flowing through their veins, there is a serious risk of blood clotting in the legs due to venous stasis, which could result in a DVT, or deep venous thromboembolism.  A blood clot that travels to the lungs is a pulmonary embolism, a blood clot that gets lodged in a coronary artery causes a myocardial infarction, and a blood clot that blocks a cerebral artery results in a stroke.  

Clots are a serious health risk.  A person with no baseline risk of clotting has no need for daily anti-coagulant therapy.  However, there are a number of disease states and conditions that increase a patient’s risk of a blood clot.  

Anti-platelet medications such as aspirin and clopidogrel reduce risk in patients with low baseline risks of blood clots.  However, certain conditions mandate stronger anti-coagulant therapy.

Atrial fibrillation is an arrhythmia that results in blood stasis in the heart when the electrical signaling in the heart prevent the heart from beating at a normal rhythm.  Patients with atrial fibrillation are at higher risks of clots, their risk is calculated from five of risk factors (the CHADS2 score).  For years, the only available oral anti-coagulant has been warfarin (brand Coumadin) which requires patients to be closely monitored by a physician for their INR, international normalized ratio or bleeding time.  The INR is kept within a specific range, usually 2-3 but it depends on the condition, lower INRs are associated with increased risk of clot whereas a high INR could result in a life threatening bleed.

Warfarin inhibits the production of vitamin K dependent clotting factors; it inhibits numerous clotting factors in the clotting cascade but its effects can be reversed by administration of vitamin K.  It is the only medication of its class and was first developed as a rat poison. 

Warfarin tablets are very inexpensive.  However, use of this medication requires a lot of monitoring and constant dosage adjustments.  Furthermore, if the patient changes the amount of vitamin K consumed within a week, the patient’s INR will change.  Additionally, the time to reach optimal clotting time is dependent on the half life of the clotting factors, and not on the medication.  Even after steady state has been reached, clotting factors that were produced before administration of warfarin will keep the INR low.  Approximately 5 days are needed before warfarin is showing its full effects, although the INR will start to increase after a few days of therapy.

A second class of anti-coagulants are the direct thrombin inhibitors (DTIs).  This class has been restricted to injection drugs until only recently.  The first of the class, lepirudin, is derived from hirudin, an anti-coagulant released by leeches to allow the continuous sucking of blood without clotting.   While there is no antidote for DTIs, they only inhibit one clotting factor making them a “cleaner” class of drugs. 

Dabigatran etexilate is the first oral direct thrombin inhibitor to be available on the market in the United States.  There are currently only two available doses on market: one for patients will normal renal function (150 mg twice daily) and a second for patients whose creatine clearance is below 30 mL/min (75 mg twice daily).  Monitoring of INR is not necessary.

Two major ground breaking trials were published comparing warfarin and dabigatran in venous thromboembolism treatment and as clot prophylaxis in patients with atrial fibrillation at the end of 2009 in the New England Journal of Medicine.

In a non-inferiority study by the RE-LY study group, over 18,000 patients with atrial fibrillation and a CHADS score of at least 1 were randomized to three treatment arms: 110 mg dabigatran twice daily, 150 mg dabigatran twice daily, or a warfarin dose titrated to a goal INR.  The warfarin arm was not blinded.  The patients were studied for 2 years until stroke or systemic embolism and the primary secondary outcome was major hemorrhage.  

Both doses of dabigatran were shown to be non-inferior to warfarin and the higher dose of dabigatran was shown to superior to warfarin.  There was a statistically significant reduced risk of hemorrhagic stroke with both doses of dabigatran compared to warfarin and less bleeding with the 110 mg twice daily dose of dabigatran than warfarin.  The risk of a major bleed with warfarin found within the RE-LY trial was found to be higher than the risk determined in prior studies.  The risk of major bleeding with warfarin determined in this study may have biased the results in favor of dabigatran.

The RE-COVER trial published in NEJM in 2009 compared the treatment of venous thromboembolism (VTE) by dabigatran compared with warfarin.  1274 patients were randomized to receive 150 mg dabigatran twice daily or warfarin titrated to an INR of 2-3.  Dabigatran was determined to be non-inferior to warfarin for treatment of a VTE with no statistically significant difference in bleeding.  However, more patients on dabigatran therapy experienced dyspepsia and were more likely to discontinue the study drug.

Dabigatran has been shown to be a safe alternative to warfarin in the treatment of VTE and in prevention of clots in atrial fibrillation.  There is less monitoring involved, making it ideal to health care professionals but patients should be monitored for compliance due to the high incidence of dyspepsia.  Although it is more expensive, it would be interesting to see in a pharmacoeconomic analysis if the cost of the drug is offset by reduced cost of monitoring.

References:

Baetz BE et al.  Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases.  Pharmacotherapy 2008; 28(11): 1254- 1373.  Accessed at http://www.medscape.com/viewarticle/583856 on 11/10/2010.

Medi C et al.  Stroke risk and antithrombotic strategies in atrial fibrillation.  Stroke 2010; 41: 2705-2713.

Ezekowitz MD et al.  The evolving field of stroke prevention in patients with atrial fibrillation.  Stroke 2010; 41(suppl 1): S17-S20.

Connolly SJ et al.  Dabigatran versus warfarin in patients with atrial fibrillation.  The New England Journal of Medicine 2009; 361(12): 1139- 1151.

Camm AJ.  The RE-LY study: randomized evaluation of long-term anticoagulant therapy: dabigatran vs. warfarin.  European Heart Journal 2009; 30: 2554- 2555.

Gericke CA.  RE-LY study (dabigatran vs. warfarin in atrial fibrillation)- a call for caution.   European Heart Journal E-letter; published November 26, 2009.  Available at http://eurheartj.oxfordjournals.org/content/30/21/2554.extract/reply#ehj_el_95

Schulman S et al.  Dabigatran versus warfarin the the treatment of acute venous thromboembolism.  The New England Journal of Medicine 2009; 361(124): 2342- 2352.