REVIEW ARTICLE Implications of Cytochrome P450 Interactions When Prescribing Medication for Hypertension David A. Flockhart, MD, PhD; Jose E. Tanus-Santos, MD, PhD any of the estimated 50 million Americans with high blood pressure receive medi- cations for hypertension and for other conditions, placing them at risk for adverse drug interactions. The risk for hypertension and for adverse drug reactions is high- est in the elderly, who have the greatest need for pharmacologic therapy. The most Mimportant class of drug interactions involves the cytochrome P450 microsomal enzyme system, which handles a variety of xenobiotic substances. A potential for interactions with these enzymes exists with calcium channel blockers, ␤-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers but not with diuretic antihypertensives, which are renally elimi- nated and more vulnerable to drug interactions that occur in the kidney. This article reviews the cy- tochrome P450 enzyme system, identifies drugs and foods that have been implicated in metabolic interactions with antihypertensive agents, and suggests measures for reducing the risk of adverse events when drugs are coadministered. Arch Intern Med. 2002;162:405-412 An estimated 50 million Americans have more than 100000 deaths result from ad- hypertension.1 Although the benefits of an- verse drug reactions each year in US hos- tihypertensive therapy are well estab- pitals, representing the fourth to sixth lead- lished, it is clear that treatment with more ing cause of death. The adverse effects of than 1 drug may be necessary to achieve sat- drugs and drug interactions are of great im- isfactory blood pressure control. More- portance to patients. Being prescribed the over, many patients with hypertension wrong drug or drugs that interact is among require medication therapy for other dis- the primary concerns of patients as they en- eases or conditions. The intersection of the ter a physician’s office.6 high prevalence of hypertension, combi- nation antihypertensive therapy, and drug- INTERACTIONS RESULTING treated comorbid conditions results in the IN REMOVAL OF DRUGS possibility of many drug interactions. The FROM THE MARKET elderly are particularly vulnerable. Not only does this population take the most medi- The novel calcium channel blocker cations, but it also undergoes age-related mibefradil dihydrochloride (Posicor; changes in body and organ mass and in car- Hoffmann-LaRoche Inc, Nutley, NJ) was diac, hepatic, and renal function.2 Find- withdrawn from the market because of po- ings from one review3 indicate that ad- tentially dangerous interactions when it verse drug reactions account for 10% to 17% was coprescribed with any of more than of the medical reasons for acute hospital ad- 25 drugs, some of them resulting in rhab- mission of elderly patients. The impor- domyolysis, renal failure, and death.7,8 tance of adverse drug reactions as a cause Terfenadine (Seldane; Marion Merrell of morbidity and mortality in the United Dow Inc, Kansas City, Mo) and astemi- States has been emphasized by several re- zole (Hismanal; Janssen Pharmaceutica, cent studies4,5 that have made clear that Titusville, NJ), widely prescribed antihis- tamines, were also withdrawn. These agents From the Division of Clinical Pharmacology, Indiana University School of Medicine, serve as substrates for cytochrome P4503A, Indianapolis. Dr Flockhart is now with the Department of Medicine, Indiana University whose inhibition by ketoconazole or sev- School of Medicine, Wishard Hospital, Indianapolis. eral macrolide antibiotics may result in (REPRINTED) ARCH INTERN MED/ VOL 162, FEB 25, 2002 WWW.ARCHINTERNMED.COM 405 ©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 formation compiled by the Institute of their pharmacologic effect only CYP1A2 CYP2E1 of Medicine titled To Err Is Human14 on conversion to active metabo- CYP2C made clear that preventable drug in- lites (eg, quinapril hydrochloride to teractions contribute significantly to quinaprilat and losartan potassium the burden of iatrogenic disease and to a carboxylic acid metabolite). that the danger of this situation wors- Most important phase I reac- CYP3A ening is considerable as the number tions are catalyzed by the cyto- of medicines available to an aging chrome P450 microsomal enzymes, population increases. a set of heme-containing proteins localized primarily in hepatocytes CYP2D6 ADVERSE DRUG but also in the intestines.18,19 Collec- INTERACTIONS DUE TO tively, these enzymes catalyze oxida- Proportion of drugs metabolized by the major ANTIHYPERTENSIVE DRUGS tive and reductive reactions on a va- cytochrome P450 isozymes. The value for riety of substrates (ie, the drugs or CYP2C metabolism reflects contributions by Drug interactions with many anti- other xenobiotic substances that are CYP2C9, CYP2C10, CYP2C18, and CYP2C19. Adapted from Hardman JG, Gilman AG, Limbird hypertensive agents that are metab- acted on). Some drugs are sub- LE, eds. Goodman and Gilman’s The olized by the cytochrome P450 strates for only 1 enzyme, whereas Pharmacological Basis of Therapeutics. 9th ed. system have been reported. For ex- others are substrates for more than New York, NY: McGraw-Hill Health Professions ample, cimetidine hydrochloride can 1. Certain drugs act on enzymes that Division; 1996.19 decrease metabolism and increase metabolize other substrates in a way steady-state plasma concentrations of that has lasting effects; these are prolongation of the electrocardio- several concomitantly administered the agents most likely to be in- graphic QT interval and lethal car- drugs, including calcium channel volved in clinically important drug diotoxicity.9,10 The combination of blockers.15 Azole antifungal agents interactions. cisapride, the oral gastrointestinal such as ketoconazole and flucona- The nomenclature for cyto- tract prokinetic agent used for the zole can also affect the metabolism chrome P450 enzymes is based on treatment of gastroesophageal re- of calcium channel blockers and how homologous their amino acid flux disease, with several drugs that some angiotensin II receptor block- sequences are.19,20 A hierarchy of cy- elevate its plasma concentrations has ers.16 Even grapefruit juice can in- tochrome P450 classification (des- resulted in serious and sometimes fa- crease drug bioavailability via the cy- ignated with the prefix CYP) pro- tal ventricular arrhythmias, includ- tochrome P450 system.17 This article ceeds from the family (designated by ing torsade de pointes. Therefore, reviews the mechanisms of the mi- Arabic numerals) to the subfamily concomitant use of cisapride with the crosomal enzyme system that con- (designated by capital letters) to in- antibiotics clarithromycin, erythro- tribute to normal metabolism and dividual isoforms (designated by mycin, and troleandomycin; the an- drug interactions, identifies a vari- Arabic numerals), eg, CYP3A4. Al- tidepressant nefazodone hydrochlo- ety of drugs implicated in interac- though hundreds of cytochromes ride; the antifungals fluconazole, tions with antihypertensive agents, P450 have been identified, only 6 ketoconazole, and itraconazole; and and suggests measures for reducing isoforms catalyze the oxidative me- the protease inhibitors indinavir the risk of adverse events when other tabolism of most drugs in common sulfate and ritonavir is contraindi- drugs are coadministered with anti- use: CYP1A2, CYP2C9, CYP2C19, cated.11 There is a longer list of other hypertensive agents. CYP2D6, CYP2E1, and CYP3A4.21 drugs that must be prescribed with For pharmacokinetic reasons, The Figure depicts the proportion great caution to patients receiving most orally administered drugs are of drugs metabolized by the major cisapride. Numerous warnings to lipid soluble and nonpolar rather cytochrome P450 isoforms. Exten- physicians and health care providers than hydrophilic and polar. Once sive metabolism by CYP3A4 in the about potentially lethal drug interac- absorbed, lipophilic drugs undergo intestinal mucosa and the liver con- tions with cisapride did not improve a 2-stage biotransformation in the tributes to the low oral bioavailabil- appropriate prescribing of the drug. liver. In phase I, they are converted ity of many drugs.19 It became clear that more than 30% to active or inactive metabolites. Two major mechanisms are of the prescriptions were inappro- However, because excretion ulti- responsible for cytochrome P450– priate,12 and sale of the drug in the mately depends on aqueous solubil- mediated drug interactions: induction United States was restricted by the ity in urine or feces, many drugs and and potent inhibition. Induction re- manufacturer and the Food and Drug their active metabolites undergo a ferstoincreasedsynthesisordecreased Administration in July 2000.13 The re- second biotransformation (phase II) degradation of cytochrome P450 en- cent series of drug withdrawals ow- to render them polar and hydro- zymes, actions that expedite conver- ing to drug interactions seems to em- philic. Highly hydrophilic drugs sion to inactive metabolites. Thus, in- phasize the importance of educating (eg, atenolol and nadolol), on the duction results in decreased plasma physicians, nurses, pharmacists, and other hand, generally escape he- levels of the substrate and a decrease their patients about drug interac- patic metabolism and are excreted in its pharmacodynamic effect. Ex- tions, but it also makes abundantly