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台灣常用的高血壓藥物 -- 脈優錠
脈優 (Amlodipine, Norvasc)
Amlodipine (Norvasc (Pfizer) and generics) (as besylate, mesylate or maleate) is a long-acting calcium channel blocker dihydropyridine (DHP) class used as an antihypertensive and in the treatment of angina pectoris. Like other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in the arterial wall, decreasing total peripheral resistance thereby reducing blood pressure; in angina, amlodipine increases blood flow to the heart muscle (although DHP-class calcium channel blockers are more selective for arteries than the muscular tissue of the heart (myocardium), as the cardiac calcium channels are not of the dihydropyridine-type).
Amlodipine is used in the management of hypertension and coronary artery disease.
(1). Breast feeding
(2). Cardiogenic shock
(3). Unstable angina
(4). Aortic stenosis: Amlodipine causes vasodilation, which can result in reduced cardiac output in patients with severe aortic stenosis.
Adverse side effects of the use of amlodipine may be:
● Very often: peripheral edema in 8.3% of users, fatigue in 4.5% of users
● Often: dizziness; palpitations; muscle-, stomach- or headache; dyspepsia; or nausea - in one in 100 users
● Sometimes: blood disorders, development of breasts in men (gynecomastia), impotence, depression, insomnia, tachycardia, or gingival enlargement - in one in 1,000 users
● Rarely: erratic behavior, hepatitis, jaundice - in one in 10,000 users
● Very rarely: hyperglycemia, tremor, Stevens–Johnson syndrome - in one in 100,000 users
The acute oral toxicity (LD50) of amlodipine in mice is 37 mg/kg.
● Hepatic impairment
● 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. This phenomenon usually occurs when first starting amlodipine, or at the time of dosage increase.
● Excessive lowering of blood pressure during initiation of amlodipine treatment can occur, especially in patients already taking another medication for lowering blood pressure. In rare instances, congestive heart failure has been associated with amlodipine, usually in patients already on a beta blocker.
● Amlodipine is primarily metabolyzed 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.
The most recent study indicates that long-term use (10 yrs) of calcium channel blockers to control hypertension lead to a 10 fold increase in risk to develop breast cancer.
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.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Amlodipine also acts as a functional inhibitor of acid sphingomyelinase (FIASMA). Sphingomyelin is involved in signal transduction and apoptosis, or cell death.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include:
Exertional angina -- In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, so lowers myocardial oxygen demand, at any given level of exercise.
Vasospastic angina -- Amlodipine has been demonstrated to block constriction 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 vasospastic (Prinzmetal's or variant) 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 of approximately 60%. Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. 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.