Amlodipine (Norvasc (Pfizer) and generics) (as besylate, mesylate or maleate) is a medication used to lower blood pressure and prevent chest pain. It belongs to a group of medications known as long-acting dihydropyridine-type calcium channel blockers. Like other medications in this group, amlodipine lowers blood pressure by relaxing the muscles controlling the diameter of blood vessels in the body. Widening of these blood vessels lowers blood pressure. In angina, amlodipine increases blood flow to the heart muscle to relieve pain due to angina.
In patients with severe coronary artery disease, amlodipine can increase the frequency and severity of angina or actually cause a heart attack on rare occasions.
Excessive lowering of blood pressure during initiation of amlodipine treatment can occur, especially in patients already taking another medication for lowering blood pressure. This includes medications for erectile dysfunction, such as sildenafil, which can also lower blood pressure. In rare instances, congestive heart failure has been associated with amlodipine, usually in patients already on a beta blocker.
Amlodipine is primarily metabolized by the liver, via the cytochrome P450 isoenzyme CYP3A4. As a result, serum levels can potentially be affected by drugs which inhibit or activate CYP3A4. Grapefruit juice can inhibit the cytochrome P450 system, but the predicted interaction risk with amlodipine is low. Eating pomegranate or drinking pomegranate juice might cause similar side effects.
Mechanism of action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells. Experimental data suggest amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects, or decreased heart muscle contractility, can be detected in vitro, but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa = 8.6), and its interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
In patients with stable (exertional) angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, thereby lowering myocardial oxygen demand, at any given level of exercise.
Amlodipine has been demonstrated to block spasm of the coronary arteries and restore blood flow in coronary arteries and arterioles in response to calcium, potassium, epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in Prinzmetal's angina.
Pharmacokinetics and metabolism
The metabolism and excretion of amlodipine have been studied in healthy volunteers following oral administration of 14C-labelled drug. amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%. It is extensively metabolized in the liver to inactive metabolites via CYP3A4. The half-life of amlodipine is about 30-50 hours, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing. Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. However, renal impairment does not significantly influence amlodipine elimination. The major metabolite identified was 2-([4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl- 2-pyridyl]methoxy) acetic acid, and this represented 33% of urinary radioactivity. Amlodipine concentrations in plasma declined with a mean half-life of 33 h, while elimination of total drug-related material from plasma was slower.
Amlodipine is a chiral calcium antagonist, currently on the market and in therapeutic use as a racemate [1:1 mixture of (R)-(+)- and (S)-(–)-amlodipine]. A method for the semipreparative chromatographic purification of the enantiomers (S)-(–)-amlodipine and (R)-(+)-amlodipine has been reported.
Pfizer's patent protection on Norvasc lasted until 2007. Total patent expiration occurred later in 2007. A number of generic versions are available.
In the United Kingdom, tablets of amlodipine from different suppliers may contain different salts. The strength of the tablets is expressed in terms of amlodipine base, i.e., without the salt. Tablets containing different salts are therefore considered interchangeable.
The efficacy and tolerability of a fixed-dose combination of amlodipine 5 mg and perindopril 4 mg, an angiotensin converting enzyme inhibitor, have recently been confirmed in a prospective, observational, multicentre trial of 1250 hypertensive patients.
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