PHARMACOKINETIC DRUG-INTERACTIONS WITH ACE-INHIBITORS

Angiotensin converting enzyme (ACE) inhibitors which have active moiet ies excreted mainly in urine require adjustment of either the dose or the interval between doses in patients with moderate to severe renal d ysfunction or severe congestive heart failure. Those agents such as te mocapril (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 s low gastric emptying and raise gastric pH. Pharmacokinetic interaction s with ACE inhibitors are unlikely in patients receiving thiazide or l oop diuretics. When ACE inhibitors are given hyperkalaemia may occur i n patients with renal insufficiency, those taking potassium supplement s or potassium-sparing diuretics, and in diabetic patients with mild r enal impairment. While no pharmacokinetic interaction precludes use of this combination, the pharmacokinetics of some ACE inhibitors are sub ject to greater variability when patients also receive beta-blockers. Calcium antagonists and ACE inhibitors have additive antihypertensive effects and pharmacokinetic interactions between these agents are unli kely. One report exists of a significant effect of coadministered hydr alazine on the pharmacokinetics and urinary excretion of lisinopril. D ata on interactions between ACE inhibitors and digitalis are contradic tory. 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 rena l 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. P robenecid pretreatment may enhance the pharmacodynamic response of ACE inhibitors. Few but contradictory data exist on the effects of H-2-bl ockers on ACE inhibitor pharmacokinetics and little information is ava ilable on interactions between ACE inhibitors and hypoglycaemic drugs. Some case reports link ACE inhibitors with the induction of lithium t oxicity. Coadministration of lithium should be undertaken with caution , and frequent monitoring of lithium concentrations is recommended wit h all ACE inhibitors. Nonsteroidal anti-inflammatory drugs (NSAIDs) ma y attenuate the haemodynamic actions of ACE inhibitors. NSAIDs reduce renal excretion of ACE inhibitors, with a corresponding increase in ci rculating drug concentrations. There is little information available o n the pharmacokinetic interaction with ACE inhibitors and cyclosporin, but caution should be employed when they are used together. Rifampici n (rifampin) may reduce the plasma ACE inhibitor concentrations and de crease the area under their plasma concentration-time curves, by enhan cing the clearance of ACE inhibitors or altering their apparent volume of distribution.