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Pharmacotherapeutic Group: Perindopril and diuretics. ATC Code: C09BA04.
Pharmacology: Mechanism of Action: Bioprexum Plus produces an additive synergy of the antihypertensive effects of the two components.
Pharmacodynamics: Bioprexum Plus is a combination of perindopril arginine salt, an ACE 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 synergistic action of the 2 products when combined.
Perindopril: Perindopril is an 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 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; and 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, therefore having a reduction in preload; by reduction of the total peripheral resistance, therefore having a reduction in afterload.
Studies carried out on patients with cardiac insufficiency have shown a reduction in left and right ventricular filling pressures and total peripheral vascular resistance, an increase in cardiac output and regional blood flow in muscle and an improvement in the cardiac index. Exercise test results also showed improvement.
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: Bioprexum Plus: In hypertensive patients regardless of age, Bioprexum Plus exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure whilst 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 synergistic nature in relation to each of the products administered alone.
PICXEL, a multicenter, randomised, double-blind active controlled study has assessed on echocardiography the effect of perindopril/indapamide combination on left ventricular hypertrophy (LVH) versus enalapril monotherapy.
In PICXEL, hypertensive patients with LVH, defined as left ventricular mass index (LVMI) >120 g/m2 in male and >100 g/m2 in female) were randomised either to perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg)/indapamide 0.625 mg or to enalapril 10 mg once a day for a 1-year treatment. The dose was adapted according to blood pressure control, up to perindopril tert-butylamine 8 mg (equivalent to perindopril arginine 10 mg) and indapamide 2.5 mg or enalapril 40 mg once a day. Only 34% of the subjects remained treated with perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg)/indapamide 0.625 mg (versus 20% with enalapril 10 mg).
At the end of treatment, LVMI had decreased significantly more in the perindopril/indapamide group (-10.1 g/m2) than in the enalapril group (-1.1 g/m2) in all the randomised patients population. The between group difference in LVMI change was -8.3 [95% CI (-11.5, -5), p<0.0001].
A better effect on LVMI was reached with higher perindopril/indapamide doses than those licensed for Bioprexum Plus.
Regarding blood pressure, the estimated mean between group differences in the randomised population were -5.8 mm Hg [95% CI (-7.9, -3.7), p<0.0001] for systolic blood pressure and -2.3 mm Hg [95% CI (-3.6, -0.9), p=0.0004] for diastolic blood pressure respectively, in favor of the perindopril/indapamide group.
Perindopril: Perindopril is active in all grades of hypertension, from 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 between 4 and 6 hrs and is maintained over 24 hrs.
There is a high degree of residual blocking of ACE at 24 hrs, approximately 80%.
In patients who respond, normalized 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 LVH.
If necessary, the addition of a thiazide diuretic leads to an additive synergy.
The combination of an ACE inhibitor with a thiazide diuretic decreases the hypokalemia risk associated with the diuretic alone.
Indapamide: Indapamide, as monotherapy, has an antihypertensive effect which lasts for 24 hrs. 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 treatment in hypertensive patients, indapamide has no effect on lipid metabolism eg, triglycerides, LDL- and HDL-cholesterol and carbohydrate metabolism, even in diabetic hypertensive patients.
Pharmacokinetics: The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
Perindopril: After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hr. The plasma half-life of perindopril is equal to 1 hr.
Perindopril is a prodrug. Twenty seven percent (27%) of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields 5 metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3-4 hrs.
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.
A linear relationship between the dose of perindopril and its plasma exposure has been demonstrated.
The volume of distribution is approximately 0.2 L/kg for unbound perindoprilat. Protein-binding of perindoprilat to plasma proteins is 20%, principally to ACE, but is concentration-dependent.
Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hrs, resulting in steady state within 4 days.
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 (CrCl)].
Dialysis clearance of perindoprilat is equal to 70 mL/min.
Perindopril kinetics are modified in patients with cirrhosis because 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 (see Dosage & Administration and Precautions).
Indapamide: Indapamide is rapidly and completely absorbed from the digestive tract.
The peak plasma level is reached in humans approximately 1 hr after oral administration of the product. Plasma protein-binding is 79%.
The elimination half-life is between 14 and 24 hrs (average of 18 hrs). 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.
The pharmacokinetics are unchanged in patients with renal insufficiency.
Toxicology: Preclinical Safety Data: Bioprexum Plus has slightly increased toxicity than that of its components. Renal manifestations do not seem to be potentiated in the rat. However, the combination produces gastrointestinal 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 are shown 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.
