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 ,
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 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 amlodipine 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, amlodipine 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 amlodipine 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
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 end 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 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 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 amlodipine 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 therapy did not alter
electrocardiographic intervals or produce higher degrees of AV blocks.
Clinical StudiesEffects in HypertensionAdult Patients:
The antihypertensive efficacy of amlodipine has 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 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 in
exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind
clinical trials of up to 6 weeks duration involving 1038 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 10 mg, and averaged 7.9% (38 sec) for amlodipine 5 mg. Amlodipine
10 mg also increased time to 1 mm ST segment deviation in several studies and
decreased angina attack rate. The sustained efficacy of amlodipine 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 therapy decreased attacks by approximately
4/week compared with a placebo decrease of approximately 1/week (p less than 0.01). Two
of 23 amlodipine and 7 of 27 placebo patients discontinued from the study due to
lack of clinical improvement.
Effects in Documented Coronary Artery Disease:
In PREVENT, 825 patients with angiographically documented
coronary artery disease were randomized to amlodipine (5 to 10 mg once daily) or
placebo and followed for 3 years. Although the study did not show significance
on the primary objective of change in coronary luminal diameter as assessed by
quantitative coronary angiography, the data suggested a favorable outcome with
respect to fewer hospitalizations for angina and revascularization procedures in
patients with CAD.
CAMELOT enrolled 1318 patients with CAD recently documented by angiography,
without left main coronary disease and without heart failure or an ejection
fraction less than 40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites,
89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44%
with a stent) were randomized to double-blind treatment with either amlodipine
(5 to 10 mg once daily) or placebo in addition to standard care that included
aspirin (89%), statins (83%), beta-blockers (74%), nitroglycerin (50%),
anti-coagulants (40%), and diuretics (32%), but excluded other calcium channel
blockers. The mean duration of follow-up was 19 months. The primary endpoint was
the time to first occurrence of one of the following events: hospitalization for
angina pectoris, coronary revascularization, myocardial infarction,
cardiovascular death, resuscitated cardiac arrest, hospitalization for heart
failure, stroke/TIA, or peripheral vascular disease. A total of 110 (16.6%) and
151 (23.1%) first events occurred in the amlodipine and placebo groups
respectively for a hazard ratio of 0.691 (95% CI: 0.540-0.884, p= 0.003). The
primary endpoint is summarized in Figure 1 below. The outcome of this study was
largely derived from the prevention of hospitalizations for angina and the
prevention of revascularization procedures (see Table 1). Effects in
various subgroups are shown in Figure 2.
In an angiographic substudy (n=274) conducted within CAMELOT, there was no
significant difference between amlodipine and placebo on the change of atheroma
volume in the coronary artery as assessed by intravascular ultrasound.
|
| Figure 1: Kaplan-Meier analysis of composite clinical outcomes for amlodipine
versus placebo |
|
| Figure 2 - Effects on primary endpoint of amlodipine versus placebo across
sub-groups |
Table 1 below summarizes the significant clinical outcomes from the composites
of the primary endpoint. The other components of the primary endpoint including
cardiovascular death, resuscitated cardiac arrest, myocardial infarction,
hospitalization for heart failure, stroke/TIA, or peripheral vascular disease
did not demonstrate a significant difference between amlodipine and placebo.
Table 1. Incidence of Significant Clinical Outcomes for CAMELOTClinical Outcomes N (%)
| Amlodipine (N=663)
| Placebo (N=655)
| Risk Reduction (p-value)
|
Composite CV Endpoint
| 110 (16.6)
| 151 (23.1)
| 31% (0.003)
|
Hospitalization for Angina*
| 51 (7.7)
| 84 (12.8)
| 42% (0.002)
|
Coronary revascularization*
| 78 (11.8)
| 103 (15.7)
| 27% (0.033)
|
* Total patients with these events
Studies in Patients with Congestive Heart
Failure:
Amlodipinehas been compared to placebo in four 8-12 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 5 to10
mg in 1153 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 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 (n=827) and followed
them for a mean of 33 months. There was no statistically significant difference
between amlodipine and placebo in the primary endpoint of all cause mortality
(95% confidence limits from 8% reduction to 29% increase on amlodipine ). With
amlodipine there were more reports of pulmonary edema.
