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Antihistamines and their drug-drug interactions are reviewed in depth. The metabolism of classic or sedating antihistamines is coming to light through in vivo and in vitro studies. The polymorphic CYP 2D6 metabolic enzyme appears to be potently inhibited by many of these over-thecounter medications. The history of the discontinued second-generation antihistamines terfenadine and astemizole is reviewed to remind the reader why the understanding of the cytochrome P450 system became increasingly important when the cardiotoxicity of these drugs became apparent. The third-generation nonsedating antihistamines are also listed and compared. They have been exhaustively scrutinized for drug-drug interactions and cardiotoxicity, and they appear to have no serious drug-drug interactions at recommended doses. (Psychosomatics 2003; 44:430434)
e have previously discussed in this column the drugdrug interactions associated with antihistamines.1 Changes in the understanding of drug-drug interactions with antihistamines has occurred since that time. With antihistamines being among the most widely prescribed medications in the world,2 and many now available over the counter, we decided to review once again the drug-drug interaction issues associated with them. The classic or sedating antihistamines, with diphenhydramine (Benadryl and others) as the prototype, are
Dr. Armstrong is the Co-Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, OR, and Associate Clinical Professor of Psychiatry, Oregon Health Sciences University, Portland, OR. Dr. Cozza is the staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C., and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, MD. Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd edition (American Psychiatric Publishing, Inc., 2003). Address correspondence to Dr. Armstrong, Tuality Forest Grove Hospital, 1809 Maple St., Forest Grove, OR 97116; scott. armstrong@tuality.org (e-mail). The opinions or assertions contained herein are the private views of the authors and are not to be construed as ofcial or as reecting the views of the Department of the Army or the Department of Defense. Copyright 2003 The Academy of Psychosomatic Medicine.
greatly effective but rife with side effects, most notably sedation. In fact, they are often found in over-the-counter sleeping aids, allergy remedies, and numerous multicompound preparations for colds and u. Finkle et al.3 indicated that 47% of people with allergies take over-thecounter medications that typically contain a rstgeneration antihistamine. The drug-drug interaction proles of the classic drugs are just now being delineated. Some of the nonsedating antihistaminesthose referred to as second-generation antihistaminessuch as terfenadine (Seldane) and astemizole (Hismanal) were cardiotoxic in high concentrations. Most of these toxic antihistamines have been removed from the market. Third-generation nonsedating antihistamines, which are rapidly becoming available as over-the-counter drugs, offer better safety proles and, for the most part, less sedation at recommended doses. We will review here what is known about each generation of antihistamines as they pertain to drug interactions (Table 1).
First-Generation H1 Receptor Blockers The rst generation antihistamines are lipophilic and fall into several distinct groups according to their chemical
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dynamic effects in the subjects with genetic poor metabolism. In the normal functioning extensive metabolizers, diphenhydramine did decrease metoprolols clearance and caused more pronounced and signicant alterations of systolic blood pressure, longer duration in heart rate, and Doppler-derived aortic blood ow. On the basis of these data, diphenhydramine appears to be a potent and competitive inhibitor of CYP 2D6. The fact that it is available over the counter and hidden in multiple cold remedies suggests that patients deserve a warning about the potential for worsened side effects and toxicities and should be monitored for such. Second-Generation H1 Receptor Blockers Drug interactions involving second-generation H1 receptor antagonists (or nonsedating antihistamines) were one of the rst-studied drug-drug interactions relating to the cytochrome P450 system. These antihistamines do not cross the blood-brain barrier because they are substrates of the p-glycoprotein efux transporters.9 This property may be the reason that the drugs are less sedating, since the pglycoproteins pump out the drugs before they can enter the CNS at the blood-brain barrier.4 They are also more H1 selective than the older drugs, which also may result in less sedation as well as less weight gain and fewer other antihistaminic side effects. The rst report of life-threatening cardiac arrhythmia associated with the use of terfenadine appeared in 1989, when a patient developed an arrhythmia after an intentional overdose.10 Monahan et al.11 then fol-
Metabolism Site(s) 2D6 Unknown Unknown 3A4 3A4 3A4 None 3A4; 2D6 None None 3A4; 2D6
Enzyme(s) Inhibited 2D6 2D6 2D6 None known None known None known None known None known None known None known None known
P-Glycoprotein Substrate No No No Yes Yes Yes Yes Yes Yes Yes Yes
Diphenhydramine may be representative of the entire class of rst-generation H1 receptor antagonists, which also include tripelennamine and promethazine. b Arrhythmogenic compounds not available in U.S. market. c Active metabolite of terfenadine.
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umn.17 They are located on the luminal surface of epithelial cells in the gut, liver, kidney, testes, and the blood-brain barrier. P-glycoproteins may limit absorption and hence distribution of drugs that are substrates of p-glycoprotein. If a p-glycoprotein inhibiting substance is coadministered with a drug that is usually a substrate of (or stopped by) p-glycoprotein, the substrate drug will gain admittance to the gut, brain, testes, etc. Fexofenadine is considered a probe drug for p-glycoprotein because it is not metabolized and its bioavailability and clearance are dependent on pglycoprotein gene expression. Wang et al.18 demonstrated that a single dose of St. Johns wort (SJW) increased the concentration and decreased the clearance of fexofenadine, indicating inhibition of intestinal p-glycoprotein by SJW. Of interest is that chronic use of St. Johns wort decreased plasma concentration of fexofenadine, meaning that St. Johns wort may become a p-glycoprotein inducer or stimulator with chronic use. Rifampin is an inducer of intestinal p-glycoprotein, upregulating p-glycoprotein expression on the apical surface of intestinal cells. It has been found to increase the clearance of fexofenadine and reduce its bioavailability in healthy volunteers.15 The clinical implication of this effect on p-glycoprotein is that fexofenadine may lose effectiveness. Cetirizine (Zyrtec) is the carboxylic acid metabolite of hydroxyzine. With regard to cetirizine, there are no reports in the literature of QTc prolongation or hepatic metabolism. In studies in which healthy volunteers were administered cetirizine at three times the recommended dose, no effect on QTc was found. Cetirizine is a racemic mix of R and S enantiomers. Levocetirizine, the S enantiomer of racemic cetirizine, seems to have a smaller volume of distribution than cetirizine, providing for better safety and efcacy. There are no reports of cardiotoxicity or drug interactions to date.19 Loratadine (Claritin or Alavert) is hepatically metabolized at CYP 3A4 and CYP 2D6. Its safety prole has been the subject of much professional debate. Initially, loratadine was believed to not be associated with QTc prolongation at high doses, even in in vivo drug interaction studies involving potent 3A4 inhibitors such as erythromycin.2,12,13 The package insert does state that 3A4 inhibitors can increase levels of loratadine, but that CYP 2D6 takes over when this occurs. The package insert does not mention that the drug may affect the QTc.20 Abernethy et al.21 studied healthy volunteers who received nefazodone (a potent 3A4 inhibitor) 300 mg every 12 hours (a high dose, but it is the recommended maximum dose by the manufacturer) with terfenadine (60 mg b.i.d.), loratadine
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1. Armstrong SC, Cozza KL: Med-psych drug-drug interactions update. Psychosomatics 2002; 43:16917 2. Woosley RL: Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol 1996; 36:233252 3. Finkle W, Adams J, Greenland S, Melmon KL: Increased risk of serious injury following an initial prescription for diphenhydramine. Ann Allergy Asthma Immunol 2002; 89:244248 4. Chen C, Hanson E, Watson JW, Lee JS: P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists. Drug Metab Dispos 2003; 31:312318 5. Sharma A, Hamelin BA: Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a birds eye view. Curr Drug Metab 2003; 4:105129 6. Hamelin BA, Bouayad A, Drolet B, Gravel A, Turgeon J: In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispos 1998; 26:536539 7. Lessard E, Yessine M, Hamelin BA, Gauvin C, Labbe L, OHara G, LeBlanc J, Turgeon J: Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol 2001; 21:175184 8. Hamelin BA, Bouayad A, Methot J, Jobin J, Desgagnes P, Poirier P, Allaire J, Dumesnil J, Turgeon J: Signicant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP 2D6 activity. Clin Pharmacol Ther 2000; 67:466477 9. Hait WN, Gesmonde JF, Murren JR, Yang JM, Chen HX, Reiss M: Terfenadine (Seldane): a new drug for restoring sensitivity to multidrug resistant cancer cells. Biochem Pharmacol 1993; 45:401406 10. Davies AJ, Harindra V, McEwan A, Ghose RR: Cardiotoxic effect with convulsions in terfenadine overdose. BMJ 1989; 298:325 11. Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR Jr: Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264:27882790 12. Yap TG, Camm AJ: The current cardiac safety situation with antihistamines. Clin Exp Allergy 1999; 29(suppl 1):1524 13. Renwick AG: The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes. Clin Exp Allergy 1999; 29(suppl 3):116124 14. Slater JW, Zechnich AD, Haxby DG: Second generation antihistamines: a comparative review. Drugs 1999; 57:3147 15. Hamman MA, Bruce MA, Haehner-Daniels BD, Hall SD: The
effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther 2001; 69:114121 16. Craig-McFeely PM, Acharya NV, Shakir SA: Evaluation of the safety of fexofenadine from experience gained in general practice use in England in 1997. Eur J Clin Pharmacol 2001; 57:313320 17. Armstrong SC, Cozza KL: Consultation-liaison psychiatry drugdrug interactions update. Psychosomatics 2001; 42:269272 18. Wang Z, Hamman MA, Huang SM, Lesko LJ, Hall SD: Effect of St Johns wort on the pharmacokinetics of fexofenadine. Clin Pharmacol Ther 2002; 71:414420 19. Baltes E, Coupez R, Giezek H, Voss G, Meyerhoff C, Strolin Benedetti M: Absorption and disposition of levocetirizine, the eutomer of cetirizine, administered alone or as cetirizine to healthy volunteers. Fundam Clin Pharmacol 2001; 15:269277 20. Claritin package insert. Kenilworth, NJ, Schering Corporation, Sept 2000 21. Abernethy DR, Barbey JT, Franc J, Brown KS, Feirrera I, Ford N, Salazar DE: Loratadine and terfenadine interaction with nefazodone: both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001; 69:96103 22. Geodon package insert. New York, Pzer Roerig, July 2002 23. Barbey J: Loratadine/nefazodone interaction. Clin Pharmacol Ther 2002; 71:403 24. Kosoglou T, Sal M, Lim JM, Batra VK, Cayen MN, Affrime MB: Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratidine with concomitant administration of ketoconazole or cimetidine. Br J Clin Pharmacol 2000; 50:581589 25. Wang E, Casciano CN, Clement RP, Johnson WW: Evaluation of the interaction of loratadine and desloratadine with P-glycoprotein. Drug Metab Dispos 2001; 29:10801083 26. McClellan K, Jarvis B: Desloratadine. Drugs 2001; 61:789796 27. Desloratadine (Clarinex). Med Lett Drugs Ther 2002; 44:2728 28. Baneld C, Hunt T, Reyderman L, Statkevich P, Padhi D, Affrime M: Lack of clinically relevant interaction between desloratadine and erythromycin. Clin Pharmacokinet 2002; 41(suppl 1):2935 29. Baneld C, Herron J, Keung A, Padhi D, Affrime M: Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole. Clin Pharmacokinet 2002; 41(suppl 1):3744 30. Henz BM: The pharmacologic prole of desloratadine: a review. Allergy 2001; 56:713 31. Geha RS, Meltzer EO: Desloratadine: a new, nonsedating, oral antihistamine. J Allergy Clin Immunol 2001; 107:751762
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