Bioprexum Mechanism of Action

Pharmacotherapeutic Group: ACE inhibitor, plain. ATC Code: C09AA04.
Pharmacology: Pharmacodynamics: Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II [angiotensin-converting enzyme (ACE)]. The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (eg, cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.
Hypertension: Perindopril is active in all grades of hypertension: Mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions is observed.
Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral blood flow increases, with no effect on heart rate. Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually unchanged. The antihypertensive activity is maximal between 4 and 6 hrs after a single dose and is sustained for at least 24 hrs: Trough effects are about 87-100% of peak effects.
The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and persists without the occurrence of tachyphylaxis.
Discontinuation of treatment does not lead to a rebound effect.
Perindopril reduces left ventricular hypertrophy.
In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and decreases the media:lumen ratio of small arteries.
An adjunctive therapy with a thiazide-diuretic produces an additive-type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.
Heart Failure: Perindopril reduces cardiac work by a decrease in pre- and afterload. Studies in patients with heart failure have demonstrated decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index.
In comparative studies, the 1st administration of perindopril arginine 2.5 mg to patients with mild to moderate heart failure was not associated with any significant reduction of blood pressure as compared to placebo.
Patients with Stable Coronary Artery Disease: The EUROPA trial was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting 4 years.
Twelve thousand two hundred and eighteen (12,218) patients >18 years were randomised to perindopril tert-butylamine 8 mg (equivalent to perindopril arginine 10 mg) (n=6110) or placebo (n=6108).
The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or a previous coronary revascularisation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid-lowering agents and β-blockers.
The main efficacy criterion was the composite of cardiovascular mortality, nonfatal myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with perindopril tert-butylamine 8 mg (equivalent to perindopril arginine 10 mg) once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% [relative risk reduction (RRR) of 20%, 95% CI (9.4; 28.6); p<0.001].
In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% [95% CI (12.0; 31.6); p<0.001] in the primary endpoint was observed by comparison to placebo.
Pharmacokinetics: 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.
It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
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).
Dialysis clearance of perindoprilat is equal to 70 mL/min.
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 (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: 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, ACE inhibitors, as a class, have been shown to induce adverse effects on late foetal development, resulting in foetal death and congenital effects in rodents and rabbits. Renal lesions and an increase in peri- and postnatal mortality have been observed.
No carcinogenicity has been observed in long-term studies in rats and mice.