Vasalat Mechanism of Action

Pharmacology: Mechanism of Action: Amlodipine is a dihydropyridine calcium-channel blocker which is also known as calcium antagonists, calcium-entry blockers and slow-channel blockers. It inhibits the cellular movements of calcium ions across cell membranes. It acts primarily via inhibition of calcium into vascular smooth muscle and to lesser extent cardiac muscle. As a result, amlodipine produces peripheral arterial vasodilation and lowers blood pressure, with relatively little negative inotropic effect. Amlodipine interacts with calcium ion channels by an ongoing association/dissociation with the receptor binding site, producing a gradual onset of action.
Amlodipine has a greater selectivity for vascular smooth muscle than for myocardium and therefore their main effect is vasodilation. It has little or no action at the sinoatrial (SA) or atrioventricular (AV) nodes and negative inotropic activity is rarely seen at therapeutic doses. It is used for antihypertensive and antianginal properties.
Amlodipine reduces the work of the heart by dilating peripheral arteries and also act on the coronary circulation preventing spasm.
Pharmacodynamics: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressures are accompanied by a significant change in the heart rate of plasma catecholamine levels with chronic dosing. Although the acute IV administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressure in normotensive patients with angina.
With chronic once-daily oral administration of amlodipine, antihypertensive effectiveness is maintained for at least 24 hrs. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pre-treatment elevation, these individuals with moderate hypertension (diastolic pressure 101-114 mm Hg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mm Hg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mm Hg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine 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 have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular and diastolic pressure or volume. In hemodynamic studies, amlodipine 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 β-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: Amlodipine does not change SA nodal function or AV conduction in intact animals or man. In patients with chronic stable angina, IV 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 and concomitant β-blockers. In clinical studies in which amlodipine was administered in combination with β-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Pharmacokinetics: Amlodipine is well-absorbed following oral administration with peak blood concentrations occurring during 6-12 hrs. The bioavailability is about 64-90%. Absorption is not affected by administration with food. Amlodipine is widely distributed, with a volume of distribution of 12-16 L/kg. Amlodipine is reported to be about 97.5% bound to plasma proteins. It has a prolonged terminal elimination t_½ of 35-50 hrs and steady-state plasma concentrations are not achieved until after 7-8 days of administration. Amlodipine is extensively metabolized in the liver and oxidation to the pyridine analogue represent a major step. Metabolites are mostly excreted 0.4 L/hr/kg. Patients with hepatic dysfunction may have a delayed clearance of drug. Doses should be reduced in these patients to account for this delay. No dosage adjustment is necessary for patients with renal dysfunction. Amlodipine is not removed by dialysis.