Pharmacology: Mechanism of Action: Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that 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. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6) and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of 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 a decrease in blood pressure.
Pharmacokinetics: After oral administration of therapeutic doses of amlodipine, peak plasma concentrations are reached between 6-12 hrs. Absolute bioavailability has been estimated to be between 64% and 90%. Amlodipine's bioavailability is not altered by the presence of food. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination t½ of about 30-50 hrs. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive dosing.
The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Patients with renal failure may therefore, receive the usual initial dose. Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in area under the curve (AUC) of approximately 40-60%, and a lower initial dose may be required.
Treatment of hypertension and prophylaxis of angina.
Hypertension, Stable Angina, Prinzmetal's Angina: Adults: Usual Dose: 5 mg. Maximum Dose: 10 mg, if necessary.
Chronic Stable or Vasospastic Angina: 5-10 mg.
Coronary Artery Disease: 5-10 mg.
Children (6-17 years): 2.5-5 mg once daily. Adjust dosage according to patient's age and symptom or as prescribed by the physician.
Elderly and Patients with Hepatic Insufficiency: 5 mg.
Administration: All doses are given once daily.
Symptoms: Excessive peripheral vasodilation and possibly a reflex tachycardia.
Treatment: If massive overdose should occur, institute active cardiac and respiratory monitoring. Frequent blood measurements are essential. Initiate cardiovascular support including elevation of the extremities and judicious fluid administration should hypotension occur. If hypotension remains unresponsive to these conservative measures, administration of vasopressors should be considered with attention to circulating volume and urine output. Calcium gluconate IV may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Hypersensitivity to amlodipine or any dihydropyridine calcium antagonist; advanced aortic stenosis because the drug can worsen the abnormal valve pressure gradient associated with this condition; pregnant women, women of childbearing potential or breastfeeding mothers; severe liver failure; known history of shock.
Rarely, patients particularly those with severe obstructive coronary disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Use with caution in patients with severe bradycardia, heart failure (particularly in combination with a β-blocker), cardiogenic shock because of the risk of a slight negative inotropic effect and potent hypotensive effects.
Monitor signs and symptoms of worsening heart failure in patients with left ventricular dysfunction who are receiving amlodipine for the treatment of angina.
Although hemodynamic studies and a controlled trial in NYHA class II-III 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, studies have not been performed in patients with NYHA class IV heart failure. In general, all calcium channel blockers should be used with caution in patients with heart failure.
Amlodipine decreases peripheral resistance and can worsen hypotension; hence, it should not be used in patients with systolic blood pressure <90 mm Hg. Dizziness induced by hypotensive effect may occur.
Amlodipine is not a β-blocker and therefore gives no protection against the dangers of abrupt β-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of β-blocker.
Use with caution in patients with hepatic disease. The amlodipine plasma elimination t½ is prolonged (56 hrs) in patients with hepatic disease and dosage adjustment is recommended.
Effects on the Ability to Drive or Operate Machinery: Patients should observe caution while driving, operating machinery or performing other tasks requiring alertness.
Use in pregnancy: Pregnancy Category C: Amlodipine has been shown to be fetotoxic in laboratory animals. No adequate or well-controlled studies have been done in humans. Amlodipine should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.
Use in lactation: It is not known whether amlodipine is excreted into human milk, so clinicians should consider risk/benefit ratio for breastfeeding women.
Use in children: The effect of amlodipine on blood pressure in patients <6 years is not known.
Use in the elderly: Elderly patients are more likely to experience a delayed clearance of amlodipine and can be at greater risk for toxicity. Observe caution in amlodipine dose selection for an elderly. Start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Elderly patients have decreased amlodipine clearance with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required.
Use in pregnancy:
Pregnancy Category C: Amlodipine has been shown to be fetotoxic in
laboratory animals. No adequate or well-controlled studies have been
done in humans. Amlodipine should only be used during pregnancy if the
potential benefit justifies the potential risk to the fetus.
Use in lactation: It is not known whether amlodipine is
excreted into human milk, so clinicians should consider risk/benefit
ratio for breastfeeding women.
Treatment with amlodipine is well tolerated. In controlled clinical trials comparing amlodipine to placebo, the most common side effects are as follows: Autonomic Nervous System:
Central and Peripheral Nervous System:
Vertigo, headache, drowsiness.
Abdominal pain, nausea.
Concomitant oral administration of amlodipine and other 1,4-dihydropyridine-derivative calcium channel blocking agents (eg, nifedipine) with grapefruit juice should be avoided since potential clinically important increases in hemodynamic effects can result.
Store at temperatures not exceeding 30°C.
C08CA01 - amlodipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
Tab 5 mg (white, round tablet, 5/16" in diameter, beveled-edged, with bisection on one side) x 50's. 10 mg (white, round plain tablet, 3/8" in diameter, bisected on one side) x 50's.