Prinivil

[lisinopril]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

PRINIVIL ® (lisinopril tablets, Merck Frosst Std.) is an ACE inhibitor which is used in the treatment of hypertension, congestive heart failure and following myocardial infarction in haemodynamically stable patients.

Angiotensin-converting enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the pressor substance, angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion. Although the latter decrease is small, it results in a small increase in serum K + . In patients treated with PRINIVIL ® and a thiazide diuretic there was essentially no change in serum potassium (see PRECAUTIONS).

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ACE is identical to kininase II. Thus, PRINIVIL ® may also block the degradation of bradykinin, a potent vasodilator peptide. However, the role that this plays in the therapeutic effects of PRINIVIL ® is unknown. While the mechanism through which PRINIVIL ® lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, PRINIVIL ® also lowers blood pressure in
patients with low-renin hypertension.

Pharmacodynamics

Administration of PRINIVIL ® to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of PRINIVIL ® has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of lisinopril, the onset of antihypertensive activity is seen at one hour with peak reduction of blood pressure achieved by six hours.

Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was six hours after dosing. On occasion, achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy.

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