Amlodipine is used in the management of hypertension and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress) or vasospastic angina (where it occurs in cycles) and without heart failure. It can be used as either monotherapy or combination therapy for the management of hypertension or coronary artery disease. Amlodipine can be administered to adults and children 6–17 years of age. Calcium channel blockers, including amlodipine, may provide greater protection against stroke than other classes of blood pressure-lowering medications.
Amlodipine along with other calcium channel blockers are considered the first choice in the pharmacological management of Raynaud's phenomenon.
Amlodipine can be given as a combination therapy with a variety of medications:
Amlodipine/atorvastatin, where amlodipine is given for hypertension or CAD and atorvastatin prevents cardiovascular events, or if the person also has high cholesterol.
Amlodipine's safety in pregnancy has not been established, although reproductive toxicity at high doses is known. Whether amlodipine enters the milk of breastfeeding mothers is also unknown.
Those who have heart failure, or recently had a heart attack, should take amlodipine with caution.
Some common dose-dependent adverse effects of amlodipine include vasodilatory effects, peripheral edema, dizziness, palpitations, and flushing. Peripheral edema (fluid accumulation in the tissues) occurs at rate of 10.8% at a 10-mg dose (versus 0.6% for placebos), and is three times more likely in women than in men. It causes more dilation in the arterioles and precapillary vessels than the postcapillary vessels and venules. The increased dilation allows for more blood, which is unable to push through to the relatively constricted postcapillary venules and vessels; the pressure causes much of the plasma to move into the interstitial space. Amlodipine-association edema can be avoided by adding ACE inhibitors or angiontensin II receptor antagonist. Of the other dose-dependent side effects, palpitations (4.5% at 10 mg vs. 0.6% in placebos) and flushing (2.6% vs. 0%) occurred more often in women; dizziness (3.4% vs. 1.5%) had no sex bias.
Amlodipine-associated gingival overgrowth is a relatively common side effect with exposure to amlodipine. Poor dental health and buildup of dental plaque are risk factors.
Amlodipine may increase the risk of worsening angina or acute myocardium infarction, especially in those with severe obstructive coronary artery disease, upon dosage initiation or increase. However, depending on the situation, Amlodipine inhibits constriction and restores blood flow in coronary arteries as a result of its property that works directly on vascular smooth muscle causing reduction in peripheral vascular resistance and consequent reduction in blood pressure.
Although rare, amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate. Toxicity is generally managed with fluid replacement monitoring ECG results, vital signs, respiratory system function, glucose levels, kidney function, electrolyte levels, and urine output. Vasopressors are also administered when low blood pressure is not alleviated by fluid resuscitation.
Several drugs interact with amlodipine to increase its levels in the body. CYP3A inhibitors, by nature of inhibiting the enzyme that metabolizes amlodipine, CYP3A4, are one such class of drugs. Others include the calcium-channel blocker diltiazem, the antibiotic clarithromycin, and possibly some antifungals. Amlodipine causes several drugs to increase in levels, including cyclosporine, simvastatin, and tacrolimus (the increase in the last one being more likely in people with CYP3A5*3 genetic polymorphisms). When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases. Giving amlodipine with Viagra increases the risk of hypotension.
Amlodipine is a long acting calcium channel antagonist that selectively inhibits calcium ion influx across cell membranes. It targets L-type calcium channels in muscle cells and N-type calcium channels in the central nervous system which are involved in nociceptive signalling and pain perception. Amlodipine has an inhibitory effect on calcium influx in smooth muscle cells to inhibit contraction.
Amlodipine ends up significantly reducing total vascular resistance without decreasing cardiac output expressed by pressure-rate product and cardiac contractability in comparison with verapamil, a non-dihydropyridine. In turn, following treatment lasting a month, with amlodipine, cardiac output was significantly enhanced. Unlike verapamil which has efficacy in moderation of emotional arousal and reduces cardiac load without lowering cardiac output demands, amlodipine increases the cardiac output response concomitantly with increased functional cardiac load.
Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals at therapeutic doses. Among the two stereoisomers [R(+), S(–)], the (–) isomer has been reported to be more active than the (+) isomer. Serum calcium concentration is not affected by amlodipine. And it specifically inhibits the currents of L-typeCav1.3 channels in the zona glomerulosa of the adrenal gland.
The mechanisms by which amlodipine relieves angina are:
Stable 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 and one of its major metabolites: The nitrogen-containing ring is oxidized, and two of the side chains are hydrolyzed.
Amlodipine has 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%; the half-life of amlodipine is about 30 h to 50 h, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing. In the blood it has high plasma protein binding of 97.5%. Its long half-life and high bioavailability are largely in part of its high pKa (8.6); it is ionized at physiological pH, and thus can strongly attract proteins. It is slowly metabolized in the liver by CYP3A4, with its amine group being oxidized and its side ester chain being hydrolyzed, resulting in an inactive pyridine metabolite. 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. 20-25% of the drug is excreted in the faeces.
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 salts. Tablets containing different salts are therefore considered interchangeable. Fixed-dose combination of amlodipine and perindopril, an angiotensin converting enzyme inhibitor are also available.
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