acts directly on vascular smooth muscle tocause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, butare thought to include the following:
Exertional Angina: In patients with exertional angina, amlodipine reduces the total peripheralresistance (afterload) against which the heart works and reduces the rate pressure product, andthus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore bloodflow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin,and thromboxane A2 analog in experimental animal models and in human coronary vesselsin vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine invasospastic (Prinzmetal’s or variant) angina.
12.2 Pharmacodynamics
Hemodynamics: Following administration of therapeutic doses to patients with hypertension,amlodipine produces vasodilation resulting in a reduction of supine and standing bloodpressures. These decreases in blood pressure are not accompanied by a significant change inheart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenousadministration of amlodipine decreases arterial blood pressure and increases heart rate inhemodynamic studies of patients with chronic stable angina, chronic oral administration ofamlodipine in clinical trials did not lead to clinically significant changes in heart rate or bloodpressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for atleast 24 hours. 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 heightof pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure105-114 mmHg) had about a 50% greater response than patients with mild hypertension(diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significantchange in blood pressures (+1/–2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in adecrease in renal vascular resistance and an increase in glomerular filtration rate and effectiverenal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at restand during exercise (or pacing) in patients with normal ventricular function treated withamlodipine have generally demonstrated a small increase in cardiac index without significantinfluence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamicstudies, amlodipine has not been associated with a negative inotropic effect when administered inthe therapeutic dose range to intact animals and man, even when co-administered with betablockersto man. Similar findings, however, have been observed in normal or well-compensatedpatients with heart failure with agents possessing significant negative inotropic effects.
Electrophysiologic Effects: Amlodipine does not change sinoatrial nodal function oratrioventricular conduction in intact animals or man. In patients with chronic stable angina |
