Pharmacokinetic Drug Interactions with ACE Inhibitors

Abstract

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 beta-blockers. Calcium antagonists and ACE inhibitors have additive anti-hypertensive 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 hypoglycaemic 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.(ABSTRACT TRUNCATED AT 400 WORDS)

In Vitro Evaluation of Inhibitory Effects of Antidiabetic and Antihyperlipidemic Drugs on Human Carboxylesterase Activities

“…Thus, it was considered that the concomitant use of simvastatin and lovastatin possibly attenuates the drug efficacy of ACE inhibitors via CES1A inhibition. However, in contrast to that in vitro study, the lack of interaction in vivo in human between enalapril and simvastatin (Shionoiri, 1993) and between ramipril and simvastatin was reported (Meyer et al, 1994). In vivo drug-drug interactions can be quantitatively predicted by comparing the maximum value of the unbound concentration at the inlet to the liver (I inlet, u, max ) estimated using pharmacokinetic data and the value of K i obtained in vitro (Ito et al, 1998).…”

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

“…We also found that diltiazem and verapamil (K i 9.0 6 0.5 mM and 16.0 6 1.1 mM, respectively) were weaker than simvastatin at inhibiting CES1 hydrolysis of TPL. Little or no clinical interactions have been demonstrated between EPL/RPL and simvastatin (Shionoiri, 1993;Meyer et al, 1994); therefore, these drugs might also possess a low potential for affecting the pharmacokinetics of ACE inhibitors. However, with the lengthening list of CES1 substrates and inhibitors, the possibility of clinically significant interactions has increased for scenarios in which several of these drugs are administered concomitantly.…”

Interaction Studies of ACE Inhibitors with Statins

“…Granulocytopaenia occurs after combined therapy of ACE inhibitors and interferones [37]. ACE inhibitors interact with different drugs, like NSAIDs [38]. Cytokines antagonize the hypotensive effect of ACE inhibitors [39]; severe hypokalaemia occurs with potassium-depleting diuretics [40] and potassium-sparing diuretics produce hyperkalaemia [41,42].…”

“…ACE inhibitors interact with different drugs, like NSAIDs [38]. Cytokines antagonize the hypotensive effect of ACE inhibitors [39]; severe hypokalaemia occurs with potassium-depleting diuretics [40] and potassium-sparing diuretics produce hyperkalaemia [41,42]. ACE inhibitors were shown to increase potassium levels in the body [43].…”