Covinace Mechanism of Action

Pharmacology: Perindopril is a converting enzyme inhibitor (CEI) of angiotensin I into angiotensin II.
Perindopril acts through its active metabolite perindoprilat and the other metabolites are inactive.
Hypertension: The usual effective dose in mild to moderate hypertension is 4 mg per day given in a single dose. Efficacy is maintained throughout the 24-hour cycle and the peak antihypertensive effect is reached 4 to 6 hours after a single dose of perindopril.
Fall in blood pressure is rapidly obtained and, in responding patients, normal values are reached within 1 month and are maintained without therapeutic escape.
There is no rebound effect on withdrawal of treatment.
In man, perindopril has vasodilator properties, it restores the elastic qualities of the large arteries and reduces left ventricular hypertrophy.
Combination with a diuretic potentiates the antihypertensive effect.
Congestive heart failure: In congestive heart failure, the reduced renal blood flow stimulates the renin-angiotensin system, which at the same time causes: the increased levels of angiotensin II, a very potent vasopressor agent, which impedes cardiac work by increasing peripheral resistance.
increased aldosterone secretion which leads to volume overload due to salt-and-water retention, and results in the same effect.
This causes increased impedance (resistance) to left ventricular ejection flow (afterload), and increased preload (blood volume to be ejected). Heart failure 1 is made worse by the activation of the renin-angiotensin system. By inhibiting the converting enzyme, Perindopril prevents the vicious circle being established, and improves haemodynamic efficiency. But the structural properties of Perindopril on the myocardium itself are essential, since they suggest that early treatment could confer great benefit with regard to protection of myocardial function.
Pharmacokinetics: Perindopril is rapidly and considerably absorbed after oral dosing; peak levels are reached in one hour and the bioavailability is from 65% to 70%. Perindopril is transformed into its active metabolite perindoprilat. The plasma half-life of perindopril is one hour. The degree of biotransformation into perindoprilat is about 20% and peak plasma perindoprilat levels are reached in 3 to 4 hours.
Apart from active perindoprilat, perindopril gives rise to 5 inactive metabolites. Perindoprilat is eliminated in the urine and the half-life of its free fraction is about 3 to 5 hours. The dissociation of the perindoprilat-angiotensin-converting enzyme complex gives an "effective" elimination half-life of 25 hours. Perindoprilat elimination is delayed in elderly subjects and in patients with cardiac and renal failure. The dosage must be adjusted according to the reduction in creatinine clearance.
The dialysis clearance of perindopril is 70 mL/min.