Preterax Mechanism of Action

Pharmacotherapeutic Group: Perindopril and diuretics. ATC Code: C09BA04.
Pharmacology: Pharmacodynamics: Preterax is a combination of perindopril arginine, an angiotensin-converting enzyme inhibitor, and indapamide, a chlorosulphamoyl diuretic. Its pharmacological properties are derived from each of the components taken separately, in addition to those due to the additive synergistic action of the 2 products when combined.
Mechanism of Action: Linked to Preterax: Preterax produces an additive synergy of the antihypertensive effects of the 2 components.
Linked to Perindopril: 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 resistances 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, perindoprilate. 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 resistances (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.
Linked to Indapamide: 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.
Characteristics of Antihypertensive Action: Linked to Preterax: In hypertensive patients regardless of age, Preterax exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure while supine or standing. This antihypertensive effect lasts for 24 hrs. The reduction in blood pressure is obtained in <1 month without tachyphylaxis; stopping treatment has no rebound effect. During clinical trials, the concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergic nature in relation to each of the products administered alone.
Linked to Perindopril: Perindopril is active in all grades of hypertension: mild to moderate or severe. A reduction in systolic and diastolic arterial pressure is observed in decubitus and in orthostatism.
The antihypertensive activity after a single dose is maximal between 4 and 6 hrs and is maintained over 24 hrs.
There is high degree of residual blocking of angiotensin-converting enzyme at 24 hrs, approximately 80%.
In patients who respond, normalised blood pressure is reached after 1 month and is maintained without tachyphylaxis.
Withdrawal of treatment has no rebound effect on hypertension.
Perindopril has vasodilatory properties and restores elasticity of the main arterial trunks, corrects histomorphometric changes in resistance arteries and produces a reduction in left ventricular hypertrophy.
If necessary, the addition of a thiazide diuretic leads to an additive synergy. The combination of an angiotensin-converting enzyme inhibitor with a thiazide diuretic decreases the hypokalaemia risk induced by the diuretic alone.
Linked to Indapamide: Indapamide, as monotherapy, has an antihypertensive effect which lasts for 24 hrs. This effect occurs at doses at which the diuretic properties are only slight.
Its antihypertensive action is proportional to an improvement in arterial compliance and a reduction in total and arteriolar peripheral vascular resistance. Indapamide reduces left ventricular hypertrophy.
When a dose of thiazide diuretics and thiazide-related diuretics is exceeded, the antihypertensive effect reaches a plateau, whereas the adverse effects continue to increase. If the treatment is ineffective, the doses should not be increased.
Furthermore, it has been shown that in the short-term, mid-term and long-term in hypertensive patients, indapamide has no effect on lipid metabolism (triglycerides, LDL-cholesterol and HDL-cholesterol); has no effect on carbohydrate metabolism, even in diabetic hypertensive patients.
Pharmacokinetics: Linked to Preterax: The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
Linked to Perindopril: Perindopril is rapidly absorbed by the oral route. The quantity absorbed is 65-70% of the dose administered.
It is hydrolysed into perindoprilate which is a specific angiotensin-converting enzyme inhibitor. The quantity of perindoprilate formed is altered by food intake. The peak plasma concentration of perindoprilate is reached after 3-4 hrs. Plasma protein binding is <30% but is concentration-dependent.
After repeated administration of perindopril as a single daily dose, steady state is reached after an average of 4 days. The effective elimination half-life of perindoprilate is approximately 24 hrs.
Plasma concentrations of perindoprilate are significantly higher in patients with creatinine clearance <60 mL/min, whether they are patients with renal insufficiency or elderly. Elimination is also slowed down in patients with cardiac insufficiency.
The clearance of perindopril by dialysis is 70 mL/min.
In cirrhotic patients, the kinetics of perindopril is altered: hepatic clearance of the parent substance is reduced by half. However, the quantity of perindoprilate formed is not reduced and dose adjustment is therefore not necessary.
Angiotensin-converting enzyme inhibitors cross the placenta.
Linked to Indapamide: Indapamide is rapidly and completely absorbed from the digestive tract. The peak plasma level is reached approximately 1 hr after oral administration of the product in humans. Plasma protein binding is 79%.
The elimination half-life is between 14 and 24 hrs (average 18 hrs). Repeated administration does not produce accumulation. Elimination is mainly in the urine (70% of the dose) and faeces (22%) in the form of inactive metabolites.
The pharmacokinetics is unchanged in patients with renal insufficiency.
Toxicology: Preclinical Safety Data: Preterax has slightly increased toxicity than that of its components. Renal manifestations do not seem to be potentiated in rats. However, the combination produces gastrointestinal toxicity in dogs and the toxic effects on the mother seem to be increased in rats (compared to perindopril).
Nonetheless, these adverse effects are shown at dose levels corresponding to a very marked safety margin by comparison to the therapeutic doses used (from 15-50 times the therapeutic dose).