Drug Monograph: Amlodipine (Norvasc)
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- May be used alone or in combination with other antihypertensive and antianginal agents
- Treatment of hypertension
- Treatment of coronary artery disease (chronic stable angina, vasospastic angina [Prinzmetal's or variant angina], and angiographically documented coronary artery disease in patients without heart failure or an ejection fraction < 40%.)
- Hypertension:
- Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps.
- (Adults): 5 mg once daily with maximum dose 10 mg once daily.
- (Pediatrics): 2.5 mg to 5 mg once daily.
- Symptomatic hypotension - particularly in patients with severe aortic stenosis
- Worsening angina and acute myocardial infarction -
particularly in patients with severe obstructive coronary artery disease
- Severe hepatic impairment - titrate slowly
- Edema - occurs in dose related manner (usually to the lower extremities)
- Fatigue
- Nausea
- Abdominal pain
- Somnolence
- Excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia may be expected.
- Initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential.
- Hypotension: provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension unresponsive to these measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output.
- Hemodialysis is not likely to be of benefit.
- Simvastatin: Increases exposure to simvastatin. Do not exceed doses greater than 20 mg daily of simvastatin.
- CYP3A4 Enzymes:
- Substrate: Amlodipine is a substrate of CYP3A4
- Inhibitors of CYP 3A4 (e.g., ketoconazole, itraconazole, ritonavir) - may increase the plasma concentrations of amlodipine to a greater extent
- Pregnancy: Pregnancy Category C
- Labor and Delivery: None
- Nursing Mothers: It is not known whether the drug is excreted in human milk. It is recommended that nursing be discontinued during treatment.
- Renal Impairment: None
- Hepatic Impairment: Adjust dosage
- Pediatric Patients: Effective in lowering blood pressure in patients 6 to 17 years. The effect in patients less than 6 years of age is not known.
- Geriatric Patients: In general, dose selection for an elderly patient should be cautious, usually starting 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. A lower initial dose may be required.
- It is not known whether the drug is excreted in human milk. It is recommended that nursing be discontinued during treatment
- Scientific Name: 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate
- Empirical Formula:
C20H25CIN2O5•C6H6O3S
- Molecular Weight: 567.1
- Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions primarily peripheral vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
- The precise mechanisms for reducing angina is thought to be from:
- Reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
- Vasospastic angina by inhibiting 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.
- Hemodynamics: Following administration of therapeutic doses to patients with hypertension, amiodpine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
- With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amiodpine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
- In hypertensive patients with normal renal function, therapeutic doses of amiodpine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
- As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amiodpine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies amiodpine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
- Electrophysiologic Effects: Amiodpine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amiodpine and concomitant beta-blockers. In clinical studies in which amiodpine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amiodpine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
- Absorption: Absolute bioavailability has been estimated to be 64 and 90% and is not altered by the presence of food.
- Metabolism: 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.
- Protein Binding: Ex vivo studies have shown that approximately 93%
- Elimination: Biphasic with a terminal elimination half-life of about 30-50 hours.
- Steady-state plasma levels: Are reached after 7 to 8 days of consecutive daily dosing.
- Renal & Hepatic Impairment: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
- Advise patients to read the information provided with amiodpine before starting treatment and each time their prescription is refilled.
- Advise patients to tell their doctor about any prescription and non-prescription medicines they are taking, including natural or herbal remedies.
- Advise patients to tell their doctor if they have ever had heart disease, liver problems, are pregnant, or plan to become pregnant, and are breast-feeding.
- Advise patients to take amiodpine once a day, with or without food. If they miss a dose, take it as soon as they remember. Do not take amiodpine if it has been more than 12 hours since they missed the last dose. Wait and take the next dose at their regular time.
- Advise patients of the possible side effects of amiodpine. Although most side effects are mild or moderate, advise patients to call their doctor right away or go directly to a hospital emergency room if they have a heart attack or their angina gets worse.
- Drug Monograph: Felodipine (Plendil)
- Drug Monograph: Nicardipine (Cardene)
- Drug Monograph: Nimodipine (Nymalize)
- Drug Monograph: Amiodarone (Cordarone; Pacerone)
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