Coveram Mechanism of Action

Pharmacotherapeutic Group: ACE inhibitors and calcium channel blockers. ATC Code: C09BB
Pharmacology: Mechanism of Action: Perindopril: 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, normalization is achieved within a month and persists without the occurrence of tachyphylaxis. Discontinuation of treatment dose 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.
Patients With Stable Coronary Artery Disease: The EUROPA study was a multicentre, international, randomized, double-blind, placebo-controlled clinical trial lasting 4 years.
Twelve thousand two hundred and eighteen (12,218) patients >18 years of age were randomized to 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) (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 cardiac arrest with successful revascularization. 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 8 mg perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of 20%, 95% Cl [9.4; 28.6] - p <0.001).
In patients with a history of myocardial infarction and/or revascularization, an absolute reduction of 2.2% corresponding to a RRR of 22.4% (95% Cl [12; 31.6] - p<0.0001) in the primary endpoint was observed by comparison to placebo.
Amlodipine: 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.
The mechanism of 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 ischemic burden by the following 2 actions:
Amlodipine dilates peripheral arterioles and thus, reduces 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 dilation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilation 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-hr interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once-daily administration of amlodipine increases total exercise time, time to angina onset and time to 1 mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
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.
A randomized double-blinded morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: Amlodipine 2.5-10 mg/day (calcium channel blocker) or lisinopril 10-40 mg/day (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/day in mild to moderate hypertension.
A total of 33,357 hypertensive patients ≥55 years of age were randomized and followed for a mean of 4.9 years. The patients had at least one CHD risk factor, including: Previous myocardial infarction or stroke >6 months prior to enrollment or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 [95% CI (0.9-1.07) p=0.65]. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs. 7.7%. RR 1.38, (95% CI [1.25-1.53] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy, RR 0.96 [95% CI (95% (0.89-1.02) p=0.2].
Pharmacokinetics: The rate and extent of absorption of perindopril and amlodipine from Coveram are not significantly different, respectively, from the rate and extent of absorption of perindopril and amlodipine from individual tablet formulations.
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 is achieved within 3-4 hrs.
As ingestion of food decreases conversion to perindoprilat increases, hence more bioavailable. Perindopril arginine should be administered orally in a single daily dose in the morning before a meal. A linear relationship has been demonstrated between the dose of perindopril and 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 angiotensin converting enzyme, 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 (see Dosage & Administration). Therefore, the usual medical follow-up will include frequent monitoring of creatinine and potassium.
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).
Amlodipine: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hrs post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 L/kg. Its bioavailability is not influenced by food. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The terminal plasma elimination half-life is about 35-50 hrs and is consistent with once daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites. About 60% of the administered dose is excreted in the urine, 10% as unchanged amlodipine.
Use in the Elderly: 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. The recommended dosage regimen for the elderly is the same, although increasing the dose should take place with caution. Use in Patients with Renal Failure: (See Dosage & Administration.)
Use Patients with Impaired Hepatic Function: As with all calcium antagonists, amlodipine's half-life is prolonged with impaired liver function.
Toxicology Preclinical Safety Data: Perindopril: 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 signs of embryotoxicity or teratogenicity. However, ACE 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.
No carcinogenicity has been observed in long-term studies in rats and mice.
Amlodipine: Toxicological studies in animal reveal no special hazards for human regarding safety pharmacology, genotoxicity, carcinogenicity, fertility and studies with repeated dosing. Reproductive toxicology studies in rats showed a prolonged duration of pregnancy and an increase in peri- and postnatal mortality.