REVIEW OF STUDIES ON THE CLINICAL PHARMACODYNAMICS OF CILAZAPRIL

Several studies were performed to evaluate the degree of inhibition of angiotensin-converting enzyme (ACE) by an ACE inhibitor by assessing the blood pressure response to a continuous i.v. infusion of increasin g doses of angiotensin I in healthy volunteers. We assessed pharmacoki netic and pharmacodynamic interactions of the ACE inhibitor cilazapril and the beta-blocker propranolol in healthy volunteers and patients w ith essential hypertension. We also evaluated the effect of cilazapril on aortic compliance in hypertension by pulse-wave velocity along the aorta. We showed that single oral doses of cilazapril 4 mg, captopril 25 mg, or enalapril 10 mg shifted the angiotensin I dose-effect curve to the right and determined a pharmacologic half-life of about 4 h fo r cilazapril. Increasing single oral doses (1.25, 3.75, 10, and 30 mg) of cilazapril reduced diastolic blood pressure dose-dependently and s hifted the angiotensin I dose-response curves to the right. The dose r epresenting 50% inhibition of ACE activity (apparent K-i dose) was abo ut 0.6 mg 3 h after cilazapril administration. Cilazapril and proprano lol did not exhibit significant pharmacokinetic interaction in healthy volunteers; each drug reduced diastolic and systolic blood pressure b y about 7 mm Hg, and this was doubled by the combination. Monotherapy with each drug reduced blood pressure, and combined administration enh anced the antihypertensive effect. The reduction in cardiac output and the increase in total peripheral resistance induced by propranolol we re attenuated by the cilazapril-propranolol combination. In comparison with hydrochlorothiazide, the ACE inhibitor at the same degree of blo od pressure reduction seems to have a more intense effect on aortic co mpliance. Therefore, ACE inhibition by cilazapril, in addition to its effects on blood pressure, could provide further benefit in hypertensi ve patients.