Combination of three antihypertensive components with complementary mechanisms to control blood pressure in patient with hypertension. Perindopril is an angiotensin converting enzyme inhibitor, indapamide, a chlorosulphamoyl diuretic and amlodipine, a calcium ion flux inhibitor of the dihydropyridine group.
The pharmacological properties of perindopril/indapamide/amlodipine are derived from those of each of the components taken separately. In addition, the combination of perindopril/ indapamide 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:
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:
Studies carried out on patients with cardiac insufficiency have shown:
Exercise test results also showed improvement.
Indapamide is a sulfonamide 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.
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
In hypertensive patients regardless of age, the perindopril/indapamide combination exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure whilst supine or standing. 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.
Perindopril is active in all grades of hypertension: mild to moderate or severe. A reduction in systolic and diastolic arterial pressure is observed in the lying and standing position. The antihypertensive activity after a single dose is maximal at between 4 and 6 hours and is maintained over 24 hours.
There is a high degree of residual blocking of angiotensin converting enzyme at 24 hours, approximately 80%. In patients who respond, normalised blood pressure is reached after one 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 associated with the diuretic alone.
Indapamide, as monotherapy, has an antihypertensive effect which lasts for 24 hours. This effect occurs at doses at which the diuretic properties are minimal.
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 diuretic 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 dose should not be increased.
Furthermore, it has been shown that in the short-term, mid-term and long-term in hypertensive patients, indapamide:
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions:
Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal’s or variant angina).
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration. Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
The co-administration of perindopril/indapamide and amlodipine does not change their pharmacokinetic properties by comparison to separate administration.
After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour (perindopril is a prodrug and perindoprilat the active metabolite). 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 concentrationdependent.
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.
It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.
Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).
clearance of perindoprilat is equal to 70 mL/min.
Perindopril pharmacokinetics is modified, 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.
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 faeces (22%) in the form of inactive metabolites.
The pharmacokinetics is unchanged in patients with renal insufficiency.
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%.
The bioavailability of amlodipine is not affected by food intake.
The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing.
The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.
Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.
In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage.
No mutagenicity has been observed in in vitro or in vivo studies.
Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxicity or teratogenicity. However, angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on late fetal development, resulting in fetal death and congenital effects in rodents and rabbits: renal lesions and an increase in peri- and postnatal mortality have been observed. Fertility was not impaired either in male or in female rats.
No carcinogenicity has been observed in long term studies in rats and mice.
The highest doses administered orally to different animal species (40 to 8000 times the therapeutic dose) have shown an exacerbation of the diuretic properties of indapamide. The major symptoms of poisoning during acute toxicity studies with indapamide administered intravenously or intraperitoneally were related to the pharmacological action of indapamide, i.e. bradypnoea and peripheral vasodilation. Indapamide has been tested negative concerning mutagenic and carcinogenic properties.
Fertility was not impaired either in male or female rats.
The perindopril/indapamide combination has slightly increased toxicity than that of its components. Renal manifestations do not seem to be potentiated in the rat. However, the combination produces gastro-intestinal toxicity in the dog and the toxic effects on the mother seem to be increased in the rat (compared to perindopril). Nonetheless, these adverse effects appear at dose levels corresponding to a very marked safety margin by comparison to the therapeutic doses used. Preclinical studies performed separately with perindopril and indapamide did not show genotoxic, carcinogenic or teratogenic potential.
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg. There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m² basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m² basis) was close to the maximum tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
* Based on patient weight of 50 kg
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