Amlodipine pharmacokinetics and molecular data

Description
Amlodipine besylate is the besylate salt of Amlodipine, a long-acting calcium channel blocker.

Amlodipine besylate is chemically described as 3 - ethyl - 5 - methyl(±) - 2 - [(2 - aminoethoxy)methyl] - 4 - (2 - chlorophenyl) - 1,4 - dihydro - 6 - methyl - 3,5 - pyridinedicarboxylate, monobenzenesulphonate. Its structural formula is:



C20H25CIN2O5·C6H6O3S M.W. 567.1

Amlodipine besylate is a white crystalline powder. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate tablets are formulated as white to off-white tablets equivalent to 2.5, 5, and 10 mg of Amlodipine for oral administration. In addition to the active ingredient, Amlodipine besylate, each tablet contains the following inactive ingredients: calcium phosphate dibasic anhydrous, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

Mechanism of Action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) 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. Negative inotropic effects 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 kinetic 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.

The precise mechanisms by which Amlodipine relieves angina have not been fully delineated, but are thought to include the following:

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, and thus 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
After oral administration of therapeutic doses of Amlodipine besylate tablets, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Amlodipine besylate tablets 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. Ex vivo 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 half-life of about 30 to 50 hours. Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily dosing.

The pharmacokinetics of Amlodipine are 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 AUC of approximately 40 to 60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.

Pediatric Patients
Sixty-two hypertensive patients aged 6 to 17 years received doses of Amlodipine besylate tablets between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.

Hemodynamics
Following administration of therapeutic doses to patients with hypertension, Amlodipine besylate tablets produce 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 Amlodipine besylate tablets is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 to 114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90 to 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 Amlodipine besylate tablets 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 Amlodipine besylate tablets 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, Amlodipine besylate tablets have not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when coadministered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Electrophysiologic Effects
Amlodipine besylate tablets do 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 Amlodipine besylate tablets and concomitant beta-blockers. In clinical studies in which Amlodipine 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, Amlodipine besylate tablet therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Effects in Hypertension

 * Adult Patients

The antihypertensive efficacy of Amlodipine besylate tablets have been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on Amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24 hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the reduction in supine and standing blood pressures was dose-related within the recommended dosing range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black patients and in white patients.


 * Pediatric Patients

Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first to Amlodipine besylate tablets 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or to placebo for another 4 weeks. Patients receiving 5 mg at the end of 8 weeks had lower blood pressure than those secondarily randomized to placebo. The magnitude of the treatment effect is difficult to interpret, but it is probably less than 5 mmHg systolic on the 5 mg dose. Adverse events were similar to those seen in adults.

Effects in Chronic Stable Angina
The effectiveness of 5 to 10 mg/day of Amlodipine besylate tablets in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1,038 patients (684 Amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8 studies significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for Amlodipine besylate tablets 10 mg, and averaged 7.9% (38 sec) for Amlodipine besylate tablets 5 mg. Amlodipine besylate tablets 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate. The sustained efficacy of Amlodipine besylate tablets in angina patients has been demonstrated over long-term dosing. In patients with angina there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).

Effects in Vasospastic Angina
In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50 patients, Amlodipine besylate tablet therapy decreased attacks by approximately 4/week compared with a placebo decrease of approximately 1/week (p < 0.01). Two of 23 Amlodipine and 7 of 27 placebo patients discontinued from the study due to lack of clinical improvement.

Studies in Patients With Congestive Heart Failure
Amlodipine besylate tablets have been compared to placebo in four 8 to 12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or left ventricular ejection fraction. In a long-term (follow-up at least 6 months, mean 13.8 months) placebo-controlled mortality/morbidity study of Amlodipine besylate tablets 5 to 10 mg in 1,153 patients with NYHA classes III (n = 931) or IV (n = 222) heart failure on stable doses of diuretics, digoxin, and ACE inhibitors, Amlodipine had no effect on the primary endpoint of the study which was the combined endpoint of all-cause mortality and cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure), or on NYHA classification, or symptoms of heart failure. Total combined all-cause mortality and cardiac morbidity events were 222/571 (39%) for patients on Amlodipine besylate tablets and 246/583 (42%) for patients on placebo; the cardiac morbid events represented about 25% of the endpoints in the study.

Another study (PRAISE-2) randomized patients with NYHA class III (80%) or IV (20%) heart failure without clinical symptoms or objective evidence of underlying ischemic disease, on stable doses of ACE inhibitor (99%), digitalis (99%), and diuretics (99%), to placebo (N = 827) or Amlodipine besylate tablets (N = 827) and followed them for a mean of 33 months. There was no statistically significant difference between Amlodipine besylate tablets and placebo in the primary endpoint of all cause mortality (95% confidence limits from 8% reduction to 29% increase on Amlodipine). With Amlodipine besylate tablets there were more reports of pulmonary edema.