A compilation of drug interactions between H 2 antagonists and cardiovascular drugs is found in Table I. Cimetidine's potency, lipophilicity, and affinity for binding to the P-450 cytochrome system can probably be attributed to the drug interactions that have been identified with the H 2 antagonists. The mechanism for most cimetidine drug interactions is inhibition of hepatic metabolism. There is conflicting evidence regarding significance of altered liver blood flow for both cimetidine and ranitidine and their influence on other agents. Cimetidine may increase propranolol's blood concentrations and potentiate beta blocking effects through inhibition of hepatic microsomal enzymes and possibly through reduction of hepatic blood flow. Ranitidine has no effect on propranolol. Cimetidine, when administered concurrently with metoprolol, could possibly cause an increase in plasma metoprolol concentrations or bioavailability through inhibition of hepatic P-450 metabolizing enzymes. No effect of cimetidine on metoprolol pharmacodynamics was evident. Ranitidine has no effect on metoprolol pharmacokinetics or pharmacodynamics. Neither H 2 antagonist altered the kinetics or physiologic effects of atenolol. Atenolol is the drug of choice in patients receiving H 2 antagonists, since no interaction has been observed. Metoprolol could probably be used safely in most patients, as no change in pharmacodynamics has been evident. Concurrent administration of cimetidine and nifedipine may result in alterations in heart rate and blood pressure. The mechanism is inhibition of oxidative liver metabolism. Ranitidine has no effect on nifedipine. Studies are needed to investigate the interaction between the H 2 antagonists and diltiazem or verapamil. Cimetidine, given concomitantly with lidocaine, may increase lidocaine concentrations and clinical symptoms of lidocaine toxicity. The mechanism involved is probably a reduction in oxidative drug metabolism or liver blood flow. Ranitidine has no significant effects on lidocaine pharmacokinetics. Cimetidine may increase quinidine levels and symptoms of quinidine toxicity. Additionally, enhanced arrhythmic effects may be observed. The interaction probably caused by an inhibition of hepatic drug metabolism of quinidine by cimetidine would be most significant in patients with liver disease and in the elderly. Ranitidine may enhance quinidine's arrhtthmic effect. Cimetidine can possibly increase procainamide and NAPA serum concentrations, especially in the elderly and in patients with renal dysfunction, predisposing them to adverse side effects. The interaction is mediated by a reduction of tubular secretion of procainamide and NAPA. Conflicting results have been found for ranitidine's influence on procainamide and NAPA. Ranitidine, particularly at higher doses, may alter procainamide and NAPA kinetics. Cimetidine did not alter digoxin pharmacokinetics. Concurrent cimetidine and digoxin administration may possibly increase digoxin serum levels due to altered bioavailability of digoxin tablets. Dosage increases or decreases of cardiovascular drugs usually will not be necessary when H 2 antagonists are administered simultaneously. Patients should be assessed for signs and/or symptoms of adverse or toxic side effects of their cardiac drugs. Monitoring of lidocaine, quinidine, procainamide, NAPA, and digoxin concentrations is recommended to complement clinical judgment and avoid toxicity. Based on the literature, no significant pharmacokinetic clinical effects on cardiac drugs have been noted with ranitidine, while cimetidine may have significant kinetic effects on propranolol, nifedipine, lidocaine, quinidine, procainamide, and NAPA. Since pharmacokinetics, dosing regimens, and cost of cimetidine and ranitidine are comparable, ranitidine is probably the H 2 receptor antagonist of choice to use when concurrent cardiovascular agents are administered. Future investigations will identify other H 2 antagonist-cardiovascular interactions.
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