The pharmacokinetics of angiotension converting enzyme (ACE) inhibitors enalapril (10 mg orally) and its active metabolite, enalaprilat (10 mg intravenously) were studied in nine young healthy volunteers aged 22‐30 years and nine sex matched elderly subjects aged 65‐73 years. After both drugs, a biexponential curve was fitted to the decline in plasma enalaprilat concentration. Area under the plasma concentration‐time curve (AUC) was greater in the elderly for both drugs. Clearance (CL) and clearance/bioavailability (CL/F) were less in the elderly for enalaprilat and enalapril, respectively. There was no difference in F between young (0.62 +/‐ 0.16) and elderly subjects (0.61 +/‐ 0.15). Enalaprilat CL and enalapril CL/F were significantly and positively correlated to endogenous creatinine clearance. There was a significant difference in the weight corrected volume of distribution at steady state after enalaprilat between the young and elderly (P less than 0.02). The relationship between plasma enalaprilat concentrations and percentage ACE inhibition, using the Hill equation, showed no difference in the sensitivity to ACE inhibition between the young and the elderly group. The pharmacokinetic differences observed are likely to be related to an age dependent decline in renal function as well as changes in body composition. Kinetic differences partly explain the greater pharmacodynamic response in the elderly.

1 Angiotensin converting enzyme inhibitors reduce blood pressure without reflex tachycardia, possibly as a result of enhanced hypothesis that this results from the removal of the parasympathetic activity. We examined the vagolytic action of angiotensin II or alternatively by acetylcholinesterase inhibition.2 Both captopril and [Sar1ala8] angiotensin II, (saralasin), caused modest falls in blood pressure, without increasing heart rate in normotensive subjects. 3 Captopril and saralasin significantly attenuated the vagally mediated heart rate slowing after facial immersion in water. There was a close correlation between the effects produced by captopril and saralasin on the diving reflex. 4 Infusion of subpressor doses of angiotensin II, reversed the hypotensive effect of captopril and returned the bradycardia after facial immersion to placebo level. 5 In vitro neither captopril nor enalapril or lisinopril affected bovine erythrocyte acetycholinesterase activity. 6 The parasympathetic effect of angiotensin converting enzyme inhibitors appear to reflect a direct consequence of the removal of angiotensin II.Keywords angiotensin converting enzyme inhibitors heart rate angiotensin II acetylcholinesterase parasympathetic effect

In a double‐blind, placebo controlled, crossover study 12 patients with essential hypertension received single doses of 5, 10 and 20 mg of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor. All doses similarly and significantly (P less than 0.05) reduced supine and erect blood pressure without increasing heart rate. The hypotensive effect was evident within 1 h, maintained for up to 8 h, with a maximal effect at 6 h. There was no discernible effect on blood pressure at 24 h after dosing. Plasma ACE activity was markedly inhibited to the same extent after all doses, with a peak inhibition of 94‐96% at 2‐3 h. At 24 h residual inhibition of ACE was 49‐54%. Plasma renin activity increased in a dose‐dependent manner with a peak at 6 h, and returned to baseline at 24 h. No correlation was found between the reduction in blood pressure and plasma renin activity, either at baseline or following cilazapril. There were no significant changes in plasma noradrenaline and the responses to upright posture and to dynamic exercise were preserved. There was no evidence of impaired exercise performance. Cilazapril is a potent ACE inhibitor with a rapid onset and a prolonged duration of action. These results suggest that peak ACE inhibition is achieved by 5 mg and that lower doses may be useful in clinical practice.

The effect of age on the pharmacodynamic responses to converting enzyme inhibitors, enalapril and enalaprilat was investigated in nine young (22‐30 years) and nine sex‐matched elderly (65‐73 years), healthy volunteers. The groups differed in baseline blood pressure, young 121/64 mmHg, elderly 142/75 mmHg (P less than 0.01), but not in sodium intake or body weight. Both enalapril and enalprilat produced significant falls in blood pressure in both groups but no increase in heart rate in the supine or erect posture. The blood pressure fall was significantly greater in the elderly on both treatments and in both erect and supine posture. The greater fall in blood pressure in the elderly was associated with a more prolonged inhibition of plasma angiotensin converting enzyme activity. The apparent age‐related difference in response appears to be due to the difference in baseline blood pressures between the groups. Further study of the usefulness of chronic dosing with angiotensin converting enzyme inhibitors in hypertension in the elderly is indicated.

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