Mechanism Of Action
The therapeutic effects of diltiazem 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.
Diltiazem 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.
Diltiazem 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 workloads. Diltiazem has been
shown to be a potent dilator of coronary arteries, both epicardial and subendocardial.
Spontaneous and ergonovine-induced coronary artery spasm are inhibited by
In animal models, diltiazem interferes with the slow
inward (depolarizing) current in excitable tissue. Diltiazem causes
excitation-contraction uncoupling in various myocardial. 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.
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
diltiazem. Diltiazem decreases vascular resistance, increases cardiac output
(by increasing stroke volume), and produces a slight decrease or no change in
During dynamic exercise, increases in diastolic pressure
are inhibited, while maximum achievable systolic pressure is usually reduced.
Chronic therapy with diltiazem produces no change or an increase in plasma
catecholamines. No increased activity of the renin-angiotensin-aldosterone axis
has been observed. Diltiazem 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.
Intravenous diltiazem hydrochloride 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 diltiazem
hydrochloride 300 mg 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 diltiazem hydrochloride 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 AND
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%.
Diltiazem undergoes extensive metabolism in which only 2% to 4% of the
unchanged drug appears in the urine. Drugs that 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 diltiazem is 70% to 80%
bound to plasma proteins. Competitive in vitro ligand binding studies have also
shown diltiazem hydrochloride 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 LA Tablets. A single 360 mg dose of
CARDIZEM LA results in detectable plasma levels within 3 to 4 hours and peak
plasma levels between 11 and 18 hours; absorption occurs throughout the dosing
interval. The apparent elimination half-life for CARDIZEM LA Tablets after
single or multiple dosing is 6 to 9 hours. When CARDIZEM LA Tablets were
coadministered with a high fat content breakfast, diltiazem peak and systemic
exposures were not affected indicating that the tablet can be administered
without regard to food. As the dose of CARDIZEM LA Tablets is increased from
120 to 240 mg, area-under-the-curve increases 2.5-fold.
Impact Of Diltiazem On Other Co-Administered Drugs
Anesthetics: The depression of cardiac
contractility, conductivity, and automaticity as well as the vascular dilation
associated with anesthetics may be potentiated by calcium channel blockers.
When used concomitantly, anesthetics and calcium blockers should be titrated
Benzodiazepines: Studies showed that diltiazem
increased the AUC of midazolam and triazolam by 3-to 4-fold and the Cmax by
2-fold, compared to placebo. The elimination half-life of midazolam and
triazolam also increased (1.5-to 2.5fold) during coadministration with
diltiazem. These pharmacokinetic effects seen during diltiazem coadministration
can result in increased clinical effects (e.g., prolonged sedation) of both
midazolam and triazolam.
Beta-blockers: Controlled and uncontrolled
domestic studies suggest that concomitant use of diltiazem and beta-blockers is
usually well tolerated, but available data are not sufficient to predict the
effects of concomitant treatment in patients with left ventricular dysfunction
or cardiac conduction abnormalities.
Administration of diltiazem concomitantly with
propranolol in five normal volunteers resulted in increased propranolol levels
in all subjects and bioavailability of propranolol was increased approximately
50%. In vitro, propranolol appears to be displaced from its binding sites by
diltiazem. If combination therapy is initiated or withdrawn in conjunction with
propranolol, an adjustment in the propranolol dose may be warranted [see WARNINGS
Buspirone: In nine healthy subjects, diltiazem significantly
increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to
placebo. The elimination half-life and Tmax of buspirone were not significantly
affected by diltiazem. Enhanced effects and increased toxicity of buspirone may
be possible during concomitant administration with diltiazem. Subsequent dose
adjustments may be necessary during coadministration, and should be based on
Carbamazepine: Concomitant administration of
diltiazem with carbamazepine has been reported to result in elevated serum
levels of carbamazepine (40% to 72% increase), resulting in toxicity in some
Clonidine: Sinus bradycardia resulting in
hospitalization and pacemaker insertion has been reported in association with
the use of clonidine concurrently with diltiazem. Monitor heart rate in
patients receiving concomitant diltiazem and clonidine.
Cyclosporine: A pharmacokinetic interaction
between diltiazem and cyclosporine has been observed during studies involving
renal and cardiac transplant patients. In renal and cardiac transplant
recipients, a reduction of cyclosporine dose ranging from 15% to 48% was
necessary to maintain cyclosporine trough concentrations similar to those seen
prior to the addition of diltiazem. If these agents are to be administered
concurrently, cyclosporine concentrations should be monitored, especially when
diltiazem therapy is initiated, adjusted, or discontinued. The effect of
cyclosporine on diltiazem plasma concentrations has not been evaluated.
Digitalis: Administration of diltiazem with
digoxin in 24 healthy male subjects increased plasma digoxin concentrations
approximately 20%. Another investigator found no increase in digoxin levels in
12 patients with coronary artery disease. Monitor digoxin levels when
initiating, adjusting, and discontinuing diltiazem therapy to avoid possible
over-or under-digitalization [see WARNINGS AND PRECAUTIONS].
Quinidine: Diltiazem increases the AUC (0-∞)
of quinidine by 51%, elimination half-life by 36%, and decreases its oral
clearance by 33%. Monitor for quinidine adverse effects and adjust the dose
Statins: Diltiazem has been shown to increase
significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis
with statins metabolized by CYP3A4 may be increased with concomitant use of
diltiazem. When possible, use a non-CYP3A4-metabolized statin together with
diltiazem; otherwise, dose adjustments for both diltiazem and the statin should
be considered along with close monitoring for signs and symptoms of any statin
related adverse events.
In a healthy volunteer cross-over study (N=10),
co-administration of a single 20 mg dose of simvastatin at the end of a 14 day
regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean
simvastatin AUC versus simvastatin alone. Subjects with increased average
steady-state exposures of diltiazem showed a greater fold increase in
simvastatin exposure. Computer-based simulations showed that at a daily dose of
480 mg of diltiazem, an 8-to 9-fold mean increase in simvastatin AUC can be
expected. If co-administration of simvastatin with diltiazem is required, limit
the daily doses of simvastatin to 10 mg and diltiazem to 240 mg.
In a ten-subject randomized, open label, 4-way cross-over
study, co-administration of diltiazem (120 mg BID diltiazem SR for 2 weeks)
with a single 20 mg dose of lovastatin resulted in 3-to 4-fold increase in mean
lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was
no significant change in 20 mg single dose pravastatin AUC and Cmax during
diltiazem coadministration. Diltiazem plasma levels were not significantly
affected by lovastatin or pravastatin.
Impact Of Other Co-Administered Drugs On Diltiazem Include, But Not Limited To:
Coadministration of rifampin with diltiazem lowered the
diltiazem plasma concentrations to undetectable levels. Coadministration of
diltiazem with rifampin or any known CYP3A4 inducer should be avoided when
possible, and alternative therapy considered.
Cimetidine and Ranitidine
A study in six healthy volunteers has shown a significant
increase in peak diltiazem plasma levels (58%) and AUC (53%) after a 1-week
course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg.
Ranitidine produced smaller, non-significant increases. The effect may be
mediated by cimetidine's known inhibition of hepatic cytochrome P450, the
enzyme system responsible for the first-pass metabolism of diltiazem. Patients
currently receiving diltiazem therapy should be carefully monitored for a
change in pharmacological effect when initiating and discontinuing therapy with
cimetidine. An adjustment in the diltiazem dose may be warranted.
In a randomized, double-blind, parallel-group,
dose-response study involving 478 patients with essential hypertension, evening
doses of CARDIZEM LA 120, 240, 360, and 540 mg were compared to placebo and to
360 mg administered in the morning. The mean reductions in diastolic blood
pressure by ABPM at roughly 24 hours after the morning (4 AM to 8 AM) or
evening (6 PM to 10 PM) administration (i.e., the time corresponding to
expected trough serum concentrations) are shown in the table below:
Mean Change in Trough Diastolic Pressure by ABPM
A second randomized, double-blind, parallel-group,
dose-response study (N=258) evaluated CARDIZEM LA following morning doses of
placebo or 120, 180, 300, or 540 mg. Diastolic blood pressure measured by
supine office cuff sphygmomanometer at trough (7 AM to 9 AM) decreased in an
apparently linear manner over the dosage range studied. Group mean changes for
placebo, 120 mg, 180 mg, 300 mg and 540 mg were -2.6, -1.9, -5.4, -6.1, and
-8.6 mm Hg, respectively.
Whether the time of administration impacts the clinical
benefits of antihypertensive treatment is not known.
Postural hypotension is infrequently noted upon suddenly
assuming an upright position. No reflex tachycardia is associated with the
chronic antihypertensive effects.
The effects of CARDIZEM LA on angina were evaluated in a
randomized, double-blind, parallel-group, dose-response trial of 311 patients
with chronic stable angina. Evening doses of 180, 360, and 420 mg were compared
to placebo and to 360 mg administered in the morning. All doses of CARDIZEM LA
administered at night increased exercise tolerance when compared with placebo
after 21 hours. The mean effect, placebo-subtracted, was 20 to 28 seconds for
all three doses, and no dose-response was demonstrated. CARDIZEM LA, 360 mg,
given in the morning, also improved exercise tolerance when measured 25 hours
later. As expected, the effect was smaller than the effects measured only 21
hours following nighttime administration. CARDIZEM LA had a larger effect to
increase exercise tolerance at peak serum concentrations than at trough.