Clinical Relevance of Cimetidine Drug Interactions

Abstract

The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

Effects of cimetidine on pharmacokinetics and pharmacodynamics of losartan, an AT1-selective non-peptide angiotensin II receptor antagonist

“…Since losartan has been shown to be extensively metabolized in human liver slice incubations [22], the most likely explanation for the decrease in losartan AUC is inhibition of one or more cytochrome P450 pathways for metabolism of losartan, (presumably CYPs 3A4 and 2C9 [6]). Cimetidine has been shown to alter the metabolism of other drugs which are metabolized by CYP 3A4, including dihydropyridine calcium channel blockers [7,8,9], dapsone [10], and midazolam [7]. Other mechanisms may apply including inhibition of renal tubular secretion of losartan, although the minor role of the renal route in the elimination of losartan (only 3% of an oral dose of losartan is excreted unchanged in the urine in patients with normal renal function [23]) suggests that this is unlikely.…”

“…While losartan is not a prodrug, formation of the metabolite is important to the activity of losartan as a once-daily treatment of hypertension [5]. Available in vitro data suggest that this reaction can be catalysed by CYPs 3A4 and 2C9 [6].Numerous studies have shown that cimetidine, a commonly prescribed H2-antagonist, nonspecifically inhibits the oxidative metabolism of many drugs, including those metabolized by CYP 3A4 such as nifedipine, nisoldipine and dapsone [7][8][9][10]. Since the duration of action of losartan is dependent on the formation of E-3174, it was of interest to determine whether cimetidine alters concentrations in plasma of losartan and/or E-3174.…”

H2-Antagonists and Alcohol

“…Cimetidine significantly impairs the metabolism of a large number of other drugs by interfering with the hepatic microsomal cytochrome P450 system (Shinn 1992;Somogyi & Gugler 1982). Feely and Wood (1982) have shown an increase in the peak serum alcohol concentration following cimetidine medication, but the mechanism of this interaction was unclear.…”

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“…Cimetidine increases the plasma levels of theophylline, warfarin, metronidazole, imipramine, triazolam, diazepam, phenytoin, lidocaine, quinidine, nifedipine and propranolol [36-42]. Cimetidine must therefore be used with caution in patients treated concomitantly with other medications [43,44].…”