Adverse Reactions with Angiotensin Converting Enzyme (ACE) Inhibitors

Summary

Teprotide, a nonapeptide isolated from the venom of a Brazilian pit viper, Bothrops jararaca, was the first angiotensin converting enzyme (ACE) inhibitor to be discovered and tested. It was found to be an effective, non-toxic antihypertensive agent as well as an afterload-reducing agent for patients with congestive heart failure (CHF). The primary activity of teprotide resulted from blockade of the angiotensin I converting enzyme 3-the pivotal step in the renin-angiotensin-aldosterone system (RAAS), and consequent reductions in angiotensin II levels. There was limited clinical testing for teprotide because of: (a) its scarcity; (b) the need for parenteral administration; and (c) the subsequent discovery and synthesis of captopril, the first orally active angiotensin converting enzyme inhibitor.

Captopril is the prototype oral angiotensin converting enzyme inhibitor and has been extensively studied since the initiation of formal studies in 1976. Perhaps one of the most closely researched drugs in modern times, the experience with captopril now includes more than 12,000 patients studied in formalised trials and over 4,000,000 patients treated worldwide by physicians for hypertension and congestive heart failure. Enalapril (MK421) is the first of what appears to be a growing number of analogues which are structurally and pharmacodynamically different from captopril; yet, they possess the same capacity for inhibiting the activity of angiotensin converting enzyme. The side effect profile of enalapril (and presumably future) angiotensin converting enzyme inhibitors appears to be similar to captopril, though clearly more experience is needed with newer agents.

The initial use of captopril was troubled by a relatively high incidence of side effects which will form the focus of this discussion. Partially the result of incomplete pharmacokinetic information, captopril was administered in early studies at dosages now recognised to be far in excess of those necessary for drug action. In addition, dosages were given without regard for deficiencies of renal function, now known to be the main excretory route of captopril. The population of those patients studied frequently had chronic, treatment-resistant hypertension, often associated with concomitant end-organ disease (especially renal disease); and many additional factors further complicating the clinical setting, e.g. a relatively high incidence of collagen vascular disease and immunosuppressive treatments. It is now known that each of these factors correlates with a higher incidence of side effects during the administration of captopril.

The side effects that have been observed during the administration of captopril and other angiotensin converting enzyme inhibitors may be categorised in terms of major importance as follows: haematological toxicity, e.g. neutropenia; and renal toxicities, relating to the production of either a renal functional impairment, or glomerular dysfunction, resulting in proteinuria. Side effects of lesser importance include rash and dysgeusia; and those associated with excesses of desired drug action include hypotension and hyperkalaemia. It is apparent that patients with renal impairment, collagen vascular disease or those on immunosuppressive therapy are at increased risk for certain side effects such as neutropenia. It is also clear that in uncomplicated patients, this risk is small and comparable with standard treatments. Minor side effects are present in low frequency, often transient and reversible, and those related to the inhibition of angiotensin converting enzyme are certainly preventable except in patients with underlying and clinically meaningful renovascular disease.

As extensive recent clinical experience with captopril has been accumulated over the past decade, there has not been an expansion of the spectrum of adverse reactions. In fact, as dosages and frequency of administration have been reduced without loss of drug activity, so has the incidence of many of the side effects previously described. Adverse experiences associated with enalapril and other newer angiotensin converting enzyme inhibitors presently being developed appear to be similar to those of captopril’s; however, more data on their safety profiles is anxiously awaited. In problem patients the newer angiotensin converting enzyme inhibitors may offer valuable alternatives.

Knowledge that angiotensin converting enzyme inhibition lacks the commonly accepted metabolic and autonomic side effects of other conventional antihypertensive therapies (notably diuretics, sympatholytic agents and β-adrenergic blocking agents) combined with the very favourable side effect profile hitherto described, makes this a unique and attractive therapy.