The central role of the renin-angiotensin-aldosterone system in the regulation of fluid balance and haemodynamics was not fully appreciated until the discovery and clinical application of inhibitors of the angiotensin-converting enzyme (ACE). Captopril, the first orally active compound has proved to be highly effective in mild, intermediate and severe hypertension and in congestive heart failure. This is also true for enalapril, the first of the second generation (non-sulfhydryl) of ACE inhibitors. Both compounds combine a high degree of clinical efficacy with a low rate of side effects, and both are eliminated via renal excretion. Thus, reduced doses are required in renal failure. Captopril has a shorter half-life and requires more frequent dosing than enalapril. Whether long-acting ACE inhibitors carry distinct advantages or disadvantages compared with short-acting ones is not clear, but both possibilities must be considered.
Among many new ACE inhibitors being developed, compounds eliminated via hepatic routes, such as fosfenopril and zofenopril, may prove advantageous in renal failure. Very long-acting ones, such as lisinopril, a potent ACE inhibitor already shown to be clinically effective, may add value to this group of therapeutic agents.
Drug compliance may be easily tested by measuring ACE activity in serum from patients treated with stable ACE inhibitors, such as enalapril and lisinopril, which is an obvious advantage compared with other antihypertensive compounds. The presence of ACE in sites not associated with regulation of fluid balance or blood pressure, such as macrophages and reproductive organs, and the possibility that new functions of ACE may be discovered, call for vigilance regarding possible long term side effects of ACE inhibitors.
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