Amlodipine (Norvasc®)
Amlodipine
Brand Names: AmVaz™, Norvasc®
Classification:
Cardiovascular Agents
» Antianginals
» Calcium-channel blockers
Cardiovascular Agents
» Antihypertensive Agents
» Calcium-channel blockers
Description: Amlodipine is an oral calcium-channel blocker. It is used for the treatment of hypertension, chronic stable angina pectoris, and Prinzmetal’s variant angina. Amlodipine is considered less effective than ACE inhibitors or AII-receptor antagonists in slowing the progression of renal disease in patients with diabetic nephropathy or hypertensive renal disease. Amlodipine is a potent peripheral vasodilator, similar to nifedipine and other members of the dihydropyridine class, although amlodipine has the longest half-life of the group, thus allowing for once-daily dosing. Amlodipine besylate (Norvasc®) was approved by the FDA in July 1992. The FDA has withdrawn the 2003 approval for amlodipine maleate (AmVaz®); this drug was a different salt form of amlodipine (not generically equivalent to amlodipine besylate) and was initially approved on November 2, 2003. The US Federal Court has ruled that AmVaz® infringes on patent rights held by Pfizer for Norvasc® (March, 2004). Sepracor has conducted Phase I and II studies with the S-isomer of amlodipine for the treatment of hypertension. In theory, less potential for peripheral edema may exist with S-amlodipine. The FDA has approved amlodipine for use in patients with recently documented coronary artery disease (CAD) by angiography and without heart failure (September 2005). The CAMELOT trial has demonstrated that amlodipine use in patients with documented CAD results in reduced coronary revascularization procedures and reduced hospitalizations due to angina.
Mechanism of Action: Amlodipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. Amlodipine inhibits this influx, and the resultant decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries. As with other calcium-channel blockers of the dihydropyridine class, amlodipine exerts its effects mainly on arteriolar vasculature. It has no significant effect on sinus node function or cardiac conduction, nor does it possess negative inotropic effects at clinical doses. Because it has a gradual onset, reflex tachycardia does not occur, a side effect that is common with other peripheral vasodilators. Amlodipine therapy usually does not affect hemodynamic parameters in patients with normal ventricular function.
 Norvasc Tablets (Tab 5 mg)
Amlodipine reduces coronary vascular resistance and increases coronary blood flow. These actions increase oxygen delivery to the myocardial tissue. Myocardial oxygen consumption is also reduced. Thus, amlodipine’s beneficial effects in the treatment of angina are a result of multiple actions. In general, calcium-channel blockers exert favorable effects on LVH, and do not worsen insulin resistance or exert detrimental effects on the lipid profile.
Pharmacokinetics: Amlodipine is administered orally and is slowly but almost completely absorbed. Oral bioavailability ranges from 52 - 88%. Peak plasma concentrations are achieved between 6 - 9 hours post-dose, and maximum hypotensive effects are correspondingly delayed. Food does not appear to influence these parameters significantly; however, grapefruit juice may increase amlodipine bioavailability by inhibiting cytochrome P450 enzymes. Like other calcium-channel blockers, amlodipine is primarily metabolized by CYP3A4 isoenzymes. The drug is approximately 93% bound to plasma proteins, but drug interactions secondary to displacement from binding sites have not been documented. Amlodipine is extensively metabolized to inactive compounds, and 10% of the parent compound and 60% of the inactive metabolites are excreted in the urine. The mean terminal half-life of amlodipine is 35 hours following single dose administration, which is significantly longer than dihydropyridines which are currently available.
Special Populations: The pharmacokinetics of amlodipine are not affected by renal impairment. In the elderly population, the elimination half-life of single 5 mg oral doses is significantly prolonged (48 vs 35 hours). In elderly patients, amlodipine clearance is reduced and AUC is increased by approximately 40 - 60%. In patients with cirrhosis, the elimination half-life is also significantly prolonged (60 vs 34 hours).
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References
. Kuschnir E, Acuna E, Sevilla D, Vasquez J, Bendersky M, Resk J, Glazer R. Treatment of patients with essential hypertension: amlodipine 5 mg/benazepril 20 mg compared with amlodipine 5 mg, benazepril 20 mg, and placebo. Clin Ther 1996;18:1213 - 24.
. Agodoa LA, Appel L, Bakris GL, et al. Effect of ramipril vs. amlodipine on renal outcomes in hypertensive nephrosclerosis. JAMA 2001;285:2719 - 28.
. Lewis E, Hunsicker L, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851 - 60.
. Norvasc® (amlodipine) package insert. New York, NY: Pfizer Labs; 2005 Mar.
. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217 - 25.
[ Revised 2/4/2006 7:03:00 PM ]
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