Amopril Mechanism of Action

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; ACE inhibitors and calcium channel blockers. ATC code: C09BB04.
Pharmacology: Pharmacodynamics: Perindopril: Mechanism of action: 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 (e.g. cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.
Pharmacodynamic effects: 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 hours after a single dose and is sustained for at least 24 hours: 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.
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: From the available efficacy data on the composite of cardiovascular mortality, non-fatal 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%. In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2% was observed in the primary endpoint compared to placebo.
Amlodipine: Mechanism of 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.
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).
Pharmacodynamic effects: 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.
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.
Use in patients with heart failure: Amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology in New York Heart Association (NYHA) Class II-IV heart failure patients.
Amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure in patients with NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors.
Amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema.
Treatment to prevent heart attack trial (ALLHAT): From the available data on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), there was no significant difference for amlodipine-based therapy and chlorthalidone-based therapy in composite of fatal coronary heart disease or non-fatal myocardial infarction. In contrast, incidence of heart failure (component of a composite combined cardiovascular endpoint) showed to be significantly higher in amlodipine-based therapy compared to chlorthalidone-based therapy. However, there was no significant difference reported in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy.
Pharmacokinetics: The rate and extent of absorption of perindopril and amlodipine from the combination of perindopril and amlodipine are not significantly different, respectively, from the rate and extent of absorption of perindopril and amlodipine from individual tablet formulations.
Perindopril: Absorption: After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to 1 hour.
Perindopril is a pro-drug. 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.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril 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.
Distribution: 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.
Elimination: 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.
To achieve equimolar quantities and plasma concentrations of perindoprilat, a dosage of perindopril arginine 5 mg replaces perindopril-tert-butylamine 4 mg and a dosage of perindopril arginine 10 mg replaces perindopril-tert-butylamine 8 mg. Preclinical experiments found perindopril arginine and perindopril-tert-butylamine to be comparable in terms of their absorption, distribution, metabolism, and elimination characteristics. Their bioavailability was also found to be similar [Telejko 2007].
Elderly, Heart Failure, Renal Failure: Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure. Therefore, the usual medical follow-up will include frequent monitoring of creatinine and potassium.
Hepatic impairment: 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.
Amlodipine: Absorption, distribution, plasma protein binding: 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 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.
The bioavailability of amlodipine is not affected by food intake.
Biotransformation/elimination: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised by the liver by the cytochrome P450 system, mainly via CYP 3A4 isoenzyme to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
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. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.
Hepatic impairment: 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%.
Toxicology: Preclinical safety data: Perindopril: In animal studies, perindopril shows no sign of embryotoxicity or teratogenicity. However, for angiotensin-converting enzyme inhibitors class, animal studies in rodents and rabbits shows induced adverse effects on late foetal development, resulting in foetal death and congenital effects. In addition, renal lesions and increased of peri- and postnatal mortality also observed.
Amlodipine: In the animal studies, amlodipine shows 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. Amlodipine shows no effect on the fertility of rats at doses up to 10 mg/kg/day. Animal studies in rats when dosed with human dose for 30 days shows decreased plasma follicle-stimulating hormone and testosterone, decreases in sperm density and number of mature spermatids and sertoli cells. Animal studies in rats and mice when dose with amlodipine for two years daily at 0.5, 1.25 and 2.5 mg/kg shows no evidence of carcinogenicity.
Mutagenicity studies shows Amlodipine does not effects gene or chromosome levels.