Pharmacokinetic Drug Interactions with ACE Inhibitors

Summary

Angiotensin converting enzyme (ACE) inhibitors which have active moieties excreted mainly in urine require adjustment of either the dose or the interval between doses in patients with moderate to severe renal dysfunction or severe congestive heart failure. Those agents such as temocapril (CS 622) and fosinopril, excreted both in urine and bile, may not require such adjustment. Renal clearance of ACE inhibitors may be reduced and some accumulation may occur in elderly patients with mild renal dysfunction or congestive heart failure. The bioavailability of ACE inhibitors is reduced by concomitant food or antacids which may slow gastric emptying and raise gastric pH.

Pharmacokinetic interactions with ACE inhibitors are unlikely in patients receiving thiazide or loop diuretics. When ACE inhibitors are given hyperkalaemia may occur in patients with renal insufficiency, those taking potassium supplements or potassium-sparing diuretics, and in diabetic patients with mild renal impairment. While no pharmacokinetic interaction precludes use of this combination, the pharmacokinetics of some ACE inhibitors are subject to greater variability when patients also receive β-blockers. Calcium antagonists and ACE inhibitors have additive antihypertensive effects and pharmacokinetic interactions between these agents are unlikely. One report exists of a significant effect of coadministered hydralazine on the pharmacokinetics and urinary excretion of lisinopril. Data on interactions between ACE inhibitors and digitalis are contradictory. There is no evidence that the concomitant use of ACE inhibitors and digoxin is associated with an increased risk of digitalis toxicity.

ACE inhibitors are mainly excreted by glomerular filtration and renal tubular secretion. Possible interactions between ACE inhibitors and probenecid have been noted, with renal and total body clearance of ACE inhibitors being potentially reduced in the presence of probenecid. Probenecid pretreatment may enhance the pharmacodynamic response of ACE inhibitors.

Few but contradictory data exist on the effects of H₂-blockers on ACE inhibitor pharmacokinetics and little information is available on interactions between ACE inhibitors and hypo-glycaemic drugs. Some case reports link ACE inhibitors with the induction of lithium toxicity. Coadministration of lithium should be undertaken with caution, and frequent monitoring of lithium concentrations is recommended with all ACE inhibitors.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the haemodynamic actions of ACE inhibitors. NSAIDs reduce renal excretion of ACE inhibitors, with a corresponding increase in circulating drug concentrations. There is little information available on the pharmacokinetic interaction with ACE inhibitors and cyclosporin, but caution should be employed when they are used together. Rifampicin (rifampin) may reduce the plasma ACE inhibitor concentrations and decrease the area under their plasma concentration-time curves, by enhancing the clearance of ACE inhibitors or altering their apparent volume of distribution.