Norvasc Mechanism of Action

Pharmacology: Pharmacodynamics: Amlodipine is a calcium ion influx inhibitor (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 ischemic burden by the following two actions: 1) 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.
2) The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina) and blunts smoking-induced coronary vasoconstriction.
In patients with hypertension, once-daily dosing provides clinically significant reductions in 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 nitroglycerine 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.
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 mg/day to 10 mg/day (calcium channel blocker) or lisinopril 10 mg/day to 40 mg/day (ACE inhibitor) as first-line therapies to that of the thiazide-diuretic chlorthalidone 12.5 mg/day to 25 mg/day in mild to moderate hypertension.
A total of 33,357 hypertensive patients aged 55 or older were randomized and followed up for a mean of 4.9 years. The patients had at least one additional CHD risk factor, including MI or stroke for >6 months or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), high-density lipoprotein-C (HDL-C) <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), or current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal MI. 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. In addition, 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.
Use in Patients with Heart Failure: Hemodynamic 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 in patients with heart failure.
In a follow-up, long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA class III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total or cardiovascular mortality. In this same population, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure compared to placebo.
Use in Pediatric Patients (Aged 6 to 17 years): The efficacy of amlodipine in hypertensive pediatric patients aged 6 to 17 years of age was demonstrated in one 8-week, double-blind, placebo-controlled, randomized withdrawal trial in 268 patients with hypertension. All patients were randomized to the 2.5 mg or 5 mg treatment arms and followed up for 4 weeks after which they were randomized to continue 2.5 mg or 5 mg amlodipine or placebo for an additional 4 weeks.
Compared to baseline, once-daily treatment with amlodipine 5 mg resulted in statistically significant reductions in systolic and diastolic blood pressures. Placebo-adjusted mean reduction in seated systolic blood pressure was estimated to be 5.0 mmHg for the 5 mg dose of amlodipine and 3.3 mmHg for the 2.5 mg dose of amlodipine. Subgroup analyses indicated that younger pediatric patients aged 6 to 13 years had efficacy results comparable to those of the older pediatric patients aged 14 to 17 years.
Pharmacokinetics: Absorption: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6 and 12 hours post-dose. Absolute bioavailability has been estimated to be between 64% and 80%. The volume of distribution is approximately 21 L/kg. Absorption of amlodipine is unaffected by consumption of food.
In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Biotransformation/Elimination: The terminal plasma elimination half-life is about 35 to 50 hours and is consistent with once-daily dosing. Steady-state plasma levels are reached after 7 to 8 days of consecutive dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites, with 10% of the parent compound and 60% of metabolites excreted in the urine.
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. Increases in AUC and elimination half-life in patients with CHF were as expected for the patient age group studied.
Use in Pediatrics: In one clinical chronic exposure study, 73 hypertensive pediatric patients aged 12 months to less than or equal to 17 years received amlodipine at an average daily dose of 0.17 mg/kg. Clearance for subjects with median weight of 45 kg was 23.7 L/h and 17.6 L/h for males and females, respectively. This is in a similar range to the published estimates of 24.8 L/h in a 70 kg adult. The average estimate for volume of distribution for a 45 kg patient was 1130 L (25.11 L/kg). Maintenance of the blood pressure effect over the 24-hour dosing interval was observed with little difference in peak and trough variation effect. When compared to historical adult pharmacokinetics, the parameters observed in this study indicate that once-daily dosing is appropriate.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Rats and mice treated with amlodipine in the diet for 2 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.
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females for 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).
*Based on patient weight of 50 kg.