The therapeutic effects of CARDIZEM CD are believed to be
related to its ability to inhibit the cellular influx of calcium ions during
membrane depolarization of cardiac and vascular smooth muscle.
Mechanisms Of Action
CARDIZEM CD produces its antihypertensive effect
primarily by relaxation of vascular smooth muscle and the resultant decrease in
peripheral vascular resistance. The magnitude of blood pressure reduction is
related to the degree of hypertension; thus hypertensive individuals experience
an antihypertensive effect, whereas there is only a modest fall in blood
pressure in normotensives.
CARDIZEM CD has been shown to produce increases in
exercise tolerance, probably due to its ability to reduce myocardial oxygen
demand. This is accomplished via reductions in heart rate and systemic blood
pressure at submaximal and maximal work loads. Diltiazem has been shown to be a
potent dilator of coronary arteries, both epicardial and subendocardial.
Spontaneous and ergonovineinduced coronary artery spasm are inhibited by
In animal models, diltiazem interferes with the slow
inward (depolarizing) current in excitable tissue. It causes
excitation-contraction uncoupling in various myocardial tissues without changes
in the configuration of the action potential. Diltiazem produces relaxation of
coronary vascular smooth muscle and dilation of both large and small coronary
arteries at drug levels which cause little or no negative inotropic effect. The
resultant increases in coronary blood flow (epicardial and subendocardial)
occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases
in systemic blood pressure and decreases in peripheral resistance.
Hemodynamic And Electrophysiologic Effects
Like other calcium channel antagonists, diltiazem
decreases sinoatrial and atrioventricular conduction in isolated tissues and
has a negative inotropic effect in isolated preparations. In the intact animal,
prolongation of the AH interval can be seen at higher doses.
In man, diltiazem prevents spontaneous and
ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral
vascular resistance and a modest fall in blood pressure in normotensive individuals
and, in exercise tolerance studies in patients with ischemic heart disease,
reduces the heart rate-blood pressure product for any given work load. Studies
to date, primarily in patients with good ventricular function, have not
revealed evidence of a negative inotropic effect; cardiac output, ejection fraction,
and left ventricular end diastolic pressure have not been affected. Such data
have no predictive value with respect to effects in patients with poor
ventricular function, and increased heart failure has been reported in patients
with preexisting impairment of ventricular function. There are as yet few data on
the interaction of diltiazem and beta-blockers in patients with poor
ventricular function. Resting heart rate is usually slightly reduced by
In hypertensive patients, CARDIZEM CD produces
antihypertensive effects both in the supine and standing positions. In a
double-blind, parallel, dose-response study utilizing doses ranging from 90 to 540
mg once daily, CARDIZEM CD lowered supine diastolic blood pressure in an
apparent linear manner over the entire dose range studied. The changes in
diastolic blood pressure, measured at trough, for placebo, 90 mg, 180 mg, 360
mg, and 540 mg were -2.9, -4.5, -6.1, -9.5, and -10.5 mm Hg, respectively.
Postural hypotension is infrequently noted upon suddenly assuming an upright
position. No reflex tachycardia is associated with the chronic
anti-hypertensive effects. CARDIZEM CD decreases vascular resistance, increases
cardiac output (by increasing stroke volume), and produces a slight decrease or
no change in heart rate. During dynamic exercise, increases in diastolic
pressure are inhibited, while maximum achievable systolic pressure is usually
reduced. Chronic therapy with CARDIZEM CD produces no change or an increase in
plasma catecholamines. No increased activity of the
renin-angiotensin-aldosterone axis has been observed. CARDIZEM CD reduces the
renal and peripheral effects of angiotensin II. Hypertensive animal models
respond to diltiazem with reductions in blood pressure and increased urinary
output and natriuresis without a change in urinary sodium/potassium ratio.
In a double-blind, parallel dose-response study of doses
from 60 mg to 480 mg once daily, CARDIZEM CD increased time to termination of
exercise in a linear manner over the entire dose range studied. The improvement
in time to termination of exercise utilizing a Bruce exercise protocol, measured
at trough, for placebo, 60 mg, 120 mg, 240 mg, 360 mg, and 480 mg was 29, 40,
56, 51, 69, and 68 seconds, respectively. As doses of CARDIZEM CD were
increased, overall angina frequency was decreased. CARDIZEM CD, 180 mg once
daily, or placebo was administered in a double-blind study to patients
receiving concomitant treatment with long-acting nitrates and/or beta-blockers.
A significant increase in time to termination of exercise and a significant
decrease in overall angina frequency was observed. In this trial the overall
frequency of adverse events in the CARDIZEM CD treatment group was the same as
the placebo group.
Intravenous diltiazem in doses of 20 mg prolongs AH
conduction time and AV node functional and effective refractory periods by
approximately 20%. In a study involving single oral doses of 300 mg of CARDIZEM
in six normal volunteers, the average maximum PR prolongation was 14% with no instances
of greater than first-degree AV block. Diltiazem-associated prolongation of the
AH interval is not more pronounced in patients with first-degree heart block.
In patients with sick sinus syndrome, diltiazem significantly prolongs sinus
cycle length (up to 50% in some cases).
Chronic oral administration of CARDIZEM to patients in
doses of up to 540 mg/day has resulted in small increases in PR interval and on
occasion produces abnormal prolongation (see WARNINGS).
Pharmacokinetics And Metabolism
Diltiazem is well absorbed from the gastrointestinal
tract and is subject to an extensive first-pass effect, giving an absolute
bioavailability (compared to intravenous administration) of about 40%. CARDIZEM
undergoes extensive metabolism in which only 2% to 4% of the unchanged drug
appears in the urine. ÃÂ Drugs which induce or inhibit hepatic microsomal enzymes
may alter diltiazem disposition.
Total radioactivity measurement following short IV
administration in healthy volunteers suggests the presence of other
unidentified metabolites, which attain higher concentrations than those of
diltiazem and are more slowly eliminated; half-life of total radioactivity is
about 20 hours compared to 2 to 5 hours for diltiazem.
In vitro binding studies show CARDIZEM is 70% to 80%
bound to plasma proteins. Competitive in vitro ligand binding studies have also
shown CARDIZEM binding is not altered by therapeutic concentrations of digoxin,
hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin.
The plasma elimination half-life following single or multiple drug
administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also
present in the plasma at levels of 10% to 20% of the parent drug and is 25% to
50% as potent as a coronary vasodilator as diltiazem. Minimum therapeutic
plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL.
There is a departure from linearity when dose strengths are increased; the
half-life is slightly increased with dose. A study that compared patients with
normal hepatic function to patients with cirrhosis found an increase in
half-life and a 69% increase in bioavailability in the hepatically impaired
patients. A single study in nine patients with severely impaired renal function
showed no difference in the pharmacokinetic profile of diltiazem compared to
patients with normal renal function.
CARDIZEM CD Capsules
When compared to a regimen of CARDIZEM tablets at
steady-state, more than 95% of drug is absorbed from the CARDIZEM CD
formulation. A single 360-mg dose of the capsule results in detectable plasma
levels within 2 hours and peak plasma levels between 10 and 14 hours;
absorption occurs throughout the dosing interval. When CARDIZEM CD was coadministered
with a high fat content breakfast, the extent of diltiazem absorption was not
affected. Dose-dumping does not occur. The apparent elimination half-life after
single or multiple dosing is 5 to 8 hours. A departure from linearity similar
to that seen with CARDIZEM tablets and CARDIZEM SR capsules is observed. As the
dose of CARDIZEM CD capsules is increased from a daily dose of 120 mg to 240 mg,
there is an increase in the area-under-the-curve of 2.7 times. When the dose is
increased from 240 mg to 360 mg, there is an increase in the
area-under-the-curve of 1.6 times.