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, NORVASC 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: NORVASC 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 NORVASC in vasospastic (Prinzmetal's
or variant) angina.
Pharmacokinetics and Metabolism: After oral administration of therapeutic
doses of NORVASC, absorption produces peak plasma concentrations between 6 and 12
hours. Absolute bioavailability has been estimated to be between 64 and 90%. The
bioavailability of NORVASC 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 30–50 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 40–60%, 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 NORVASC between 1.25 mg and 20 mg. Weight-adjusted clearance and volume
of distribution were similar to values in adults.
Pharmacodynamics
Hemodynamics Following administration of therapeutic doses to patients with
hypertension, NORVASC 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 NORVASC
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 NORVASC
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 NORVASC 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, NORVASC 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 normals or well-compensated patients with heart failure
with agents possessing significant negative inotropic effects.
Electrophysiologic Effects: NORVASC 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 NORVASC and concomitant beta-blockers. In clinical
studies in which NORVASC 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, NORVASC therapy did
not alter electrocardiographic intervals or produce higher degrees of AV blocks.