Coversyl Plus Mechanism of Action

Pharmacology: Pharmacodynamics: Perindopril arginine + Indapamide (Coversyl Plus) is a combination of perindopril arginine salt, an angiotensin converting enzyme inhibitor, and indapamide, a chlorosulphamoyl diuretic. Its pharmacological properties are derived from those of each of the components taken separately, in addition to those due to the additive synergic action of the two products when combined.
Mechanism of action: Perindopril arginine + Indapamide (Coversyl Plus) produces an additive synergy of the antihypertensive effects of the two components.
Perindopril is an inhibitor of the angiotensin converting enzyme (ACE inhibitor) which converts angiotensin I to angiotensin II, a vasoconstricting substance; in addition the enzyme stimulates the secretion of aldosterone by the adrenal cortex and stimulates the degradation of bradykinin, a vasodilatory substance, into inactive heptapeptides.
This results in: a reduction in aldosterone secretion; an increase in plasma renin activity, since aldosterone no longer exercises negative feedback; a reduction in total peripheral resistance with a preferential action on the vascular bed in muscle and the kidney, with no accompanying salt and water retention or reflex tachycardia, with chronic treatment.
The antihypertensive action of perindopril also occurs in patients with low or normal renin concentrations.
Perindopril acts through its active metabolite, perindoprilat. The other metabolites are inactive.
Perindopril reduces the work of the heart: by a vasodilatory effect on veins, probably caused by changes in the metabolism of prostaglandins: reduction in pre-load; by reduction of the total peripheral resistance: reduction in afterload.
Studies carried out on patients with cardiac insufficiency have shown: a reduction in left and right ventricular filling pressures; a reduction in total peripheral vascular resistance; an increase in cardiac output and an improvement in the cardiac index; an increase in regional blood flow in muscle.
Exercise test results also showed improvement.
Indapamide is a sulphonamide derivative with an indole ring, pharmacologically related to the thiazide group of diuretics. Indapamide inhibits the reabsorption of sodium in the cortical dilution segment. It increases the urinary excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urine output and having an antihypertensive action.
Pharmacokinetics: The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
Linked to perindopril: After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour.
The plasma half-life of perindopril is equal to 1 hour.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.
The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent.
Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.
Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 4 days.
Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.
It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
Special populations: Elderly: Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.
Renal impairment: Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).
In case of dialysis: Dialysis clearance of perindoprilat is equal to 70 ml/min.
Cirrhosis: Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required.
Linked to indapamide: Indapamide is rapidly and completely absorbed from the digestive tract.
The peak plasma level is reached in humans approximately one hour after oral administration of the product.
Plasma protein binding is 79 %.
The elimination half-life is between 14 and 24 hours (average 18 hours). Repeated administration does not produce accumulation. Elimination is mainly in the urine (70 % of the dose) and feces (22 %) in the form of inactive metabolites.
Special populations: Renal impairment: The pharmacokinetics are unchanged in patients with renal insufficiency.