Pharmacotherapeutic group: 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.
Clinical efficacy and safety: 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.
In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and decreases the media:lumen ratio of small arteries.
Stable coronary artery disease: The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting 4 years.
Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised 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 a previous coronary revascularisation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid lowering agents and beta-blockers.
The main efficacy criterion was 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% (relative risk reduction 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.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) clinical trial data: Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.
Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
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).
Clinical efficacy and safety: 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 1mm 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.
Coronary artery disease (CAD): The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-center, randomized, double-blind, placebo-controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT).
Of these patients, 663 were treated with amlodipine 5-10 mg, 673 patients were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard care of statins, beta-blockers, diuretics and aspirin, for 2 years. The key efficacy results are presented in Table 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.
Click on icon to see table/diagram/image
Heart failure: Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.
A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.
In a follow-up, long term, placebo controlled study (PRAISE-2) of 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): A randomized double-blind 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/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension.
A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional 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(0.90-1.07) 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 [1.25-1.52] 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 [0.89-1.02] p=0.20).
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: 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 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.
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.
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.
Elderly, Heart Failure, Renal Failure: 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.
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 (see Dosage & Administration and Precautions).
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 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 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.
Amlodipine: Reproductive toxicology: 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.
Impairment of fertility: 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.
Carcinogenesis, mutagenesis: 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