Diltiazem

Diltiazem is an antihypertensive agent belonging to Calcium Channel Blocker.

Diltiazem is a calcium channel blocker used to treat hypertension and to manage chronic stable angina.

Almost completely absorbed from the gastrointestinal tract after oral administration. The Bioavailability of Diltiazem is approximately 40%. Time to peak plasma concentration of immediate-release, extended-release tablet and extended-release capsule of Diltiazem is about 2-4 hours, 11-18 hours and 10-14 hours respectively. The Plasma protein binding of Diltiazem is approximately 70-80%. The Volume of distribution is found to be 3-13 L/kg. Undergoes extensive first-pass metabolism by CYP450 and conjugation to N-monodesmethyldiltiazem, desacetyldiltiazem, desacetyl-N-monodesmethyldiltiazem, desacetyl-O-desmethyldiltiazem and desacetyl-N,O-desmethydiltiazem.

Excreted via urine (2-4% as unchanged drug) and feces.

Diltiazem shows common side effects like Body aches or pain, congestion, cough, dryness or soreness of the throat, fever, hoarseness, runny nose, tender or swollen glands in the neck, trouble swallowing, voice changes, etc.

Diltiazem is available in the form of Oral Tablet, Oral capsule, Injectable solution, Powder for injection.

Diltiazem is available in India, US, UK, Canada, France, Russia, Finland and Italy.

Diltiazem belonging to the Calcium Channel Blocker acts as an antihypertensive agent.

Mechanisms of Action for Hypertension

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.

Mechanisms of Action for Angina

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 diltiazem.

The time taken for Diltiazem to show its effect is 30-60 minutes (by oral immediate release tablet) and 3 minutes (by IV Bolus).

The Duration of action of Diltiazem is approximately 1-3 hours (by IV Bolus).

The Tmax was found within 2-4 hours (by immediate release), 10-14 hours (by extended-release capsule) and 11-18 hours (extended-release tablet) of following the administration.

Diltiazem is available in the form of Oral Tablet, Oral capsule, Injectable solution, Powder for injection.

Diltiazem tablet and capsule are taken orally, Powder for injection and Injectable solution taken Intravenously as single or several doses.

Diltiazem is used for the prevention and long-term treatment of hypertension and angina pectoris which is a type of heart disease characterized by chest pain or pressure and heaviness in the chest.

Diltiazem is an antihypertensive agent belonging to Calcium Channel Blocker.

Diltiazem, a benzothiazepine calcium channel blocker, inhibits the influx of Calcium ions during depolarization of the vascular smooth muscles and myocardium thereby producing relaxation of coronary vascular muscles and coronary vasodilation and increases myocardial oxygen delivery.

Diltiazem is approved for use in the following clinical indications

• Hypertension

Diltiazem is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications.

• Angina Pectoris

Diltiazem is used for the prevention and treatment of angina pectoris which is a type of heart disease characterized by chest pain or pressure and heaviness in the chest. It may be caused by various factors including emotional stress, smoking, coronary artery disease, etc.

Although not approved, there have been certain off-label indications. These include

• Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndrome
• Pediatric hypertension
• Chronic ventricular rate control
• Non-sustained ventricular tachycardia or ventricular premature beats, symptomatic
• Pulmonary arterial hypertension (group 1)
• Supraventricular tachycardia (eg. atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal atrial tachycardia, multifocal atrial tachycardia)
• Pediatric atrial tachyarrhythmias, rate control

• Hypertension

Adult Oral Dose:

12-hour (twice-daily) formulations

Initial: 60 to 120 mg twice daily; increase dose as needed after ~7 to 14 days.

Usual dose: 240 to 360 mg/day in 2 divided doses.

24-hour (once-daily) formulations

Initial: 120 to 240 mg once daily; increase dose as needed after ~7 to 14 days.

Usual dose: 120 to 360 mg once daily.

Pediatric Dose (off-label use):

Infants and Children:

Oral Dose:

Immediate-release formulations:

Initial dose: 1.5 to 2 mg/kg/day in 3 to 4 divided doses; increase gradually, at 1- to 2-day intervals until optimum response is obtained.

Maximum daily dose: 3.5 mg/kg/day; some experts recommend a higher maximum daily dose of 6 mg/kg/day up to 360 mg/day; whichever is less.

Adolescents:

Oral Dose:

Immediate-release formulations: 30 to 120 mg/dose administered 3 to 4 times daily; usual daily dosage range: 180 to 360 mg/day

Extended-release formulations:120 to 300 mg/day or in 2 divided doses.

• Angina pectoris:
• Chronic stable angina

Oral:

Immediate release:

Initial: 30 mg 4 times daily; increase as needed at 1- to 2-day intervals to effective antianginal dose.

Usual effective dose: 240 to 360 mg/day in 3 to 4 divided doses.

12-hour (twice-daily) formulations (off label):

Initial: 60 mg twice daily; increase as needed at 7- to 14-day intervals to effective antianginal dose.

Usual effective dose: 240 to 360 mg/day in 2 divided doses.

24-hour (once-daily) formulations:

Initial 120 to 180 mg once daily; increase as needed at 7- to 14-day intervals to effective antianginal dose.

Usual effective dose: 240 to 360 mg/day.

• Vasospastic angina:

Oral:

Immediate release:

Initial: 30 mg 4 times daily; increase as needed at 1- to 2-day intervals to effective antianginal dose.

Usual effective dose: 240 to 360 mg/day in 3 to 4 divided doses.

12-hour (twice-daily) formulations (off label):

Initial: 60 mg twice daily; increase as needed at 7- to 14-day intervals to effective antianginal dose.

Usual effective dose: 240 to 360 mg/day in 2 divided doses.

24-hour (once-daily) formulations:

Initial 120 to 180 mg once daily; increase as needed at 7- to 14-day intervals to effective antianginal dose.

Usual effective dose: 240 to 360 mg/day.

• Chest pain associated with cocaine ingestion, with or without evidence of acute coronary syndrome (off-label use)

Atrial fibrillation or atrial flutter, rate control

• Acute ventricular rate control:

IV Bolus dose: 0.25 mg/kg (actual body weight) over 2 minutes (average dose: 20 mg); if rate control is insufficient after 15 minutes, a repeat bolus dose of 0.35 mg/kg over 2 minutes may be given (average dose: 25 mg). Patients who respond after 1 or 2 bolus doses can be started on a continuous infusion.

Continuous infusion following bolus(es):

Initial: 5 to 10 mg/hour; infusion rate may be increased in 5 mg/hour increments according to ventricular response, up to a maximum of 15 mg/hour. In general, the use of a continuous infusion >24 hours or >15 mg/hour is not recommended due to potential for drug accumulation.

• Chronic ventricular rate control (off-label use):

Oral:

Immediate release:

Initial: 30 mg 4 times daily; increase as needed to achieve ventricular rate control.

Usual dose: 120 to 480 mg/day in 3 or 4 divided doses.

Extended release:

Initial: 120 mg once daily or in 2 divided doses depending on formulation; increase as needed to achieve ventricular rate control.

Usual dose: 120 to 480 mg/day.

• Nonsustained ventricular tachycardia or ventricular premature beats, symptomatic (alternative agent) (off-label use)

Oral

Initial: 120 to 180 mg once daily or in divided doses depending on the drug formulation.

Usual effective dose: 240 to 360 mg/day.

Maximum dose: 480 mg/day.

• Pulmonary arterial hypertension (group 1) (alternative agent) (off-label use)

Oral

24-hour (once-daily) formulations:120 mg once daily; titrate gradually and with close hemodynamic monitoring; reported daily dose range: 240 to 720 mg/day.

• Supraventricular tachycardia (eg, atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, focal atrial tachycardia, multifocal atrial tachycardia)
• Acute treatment:

IV Bolus dose: 0.25 mg/kg (actual body weight) over 2 minutes (average dose: 20 mg); if response is insufficient after ≥15 minutes, a repeat bolus dose of 0.35 mg/kg over 2 minutes may be given (average dose: 25 mg). If bolus(es) does not terminate the arrhythmia, consider alternative therapy.

• Chronic maintenance (off-label use):

Oral:

Immediate release:

Initial: 30 mg 4 times daily; increase as needed for heart rate control.

Usual effective dose: 360 mg/day in divided doses.

Extended release:

Initial: 120 mg once daily or in 2 divided doses depending on formulation; increase as needed for heart rate control.

Usual effective dose: 360 mg/day.

• Pediatric atrial tachyarrhythmias, rate control (off-label use):

Infants ≥6 months, Children, and Adolescents:

IV Dose:

Initial bolus: 0.25 mg/kg over 5 minutes (maximum dose: 20 mg/dose) followed by a continuous IV infusion; reported rate range in one study was 0.05 to 0.15 mg/kg/hour.

• Conversion between dosage forms:

Conversion from immediate-release to extended-release formulations: Patients stabilized on a maintenance regimen between 120 and 360 mg of immediate-release tablets may be switched to an extended-release formulation at the same daily dose administered in 1 or 2 divided doses depending on formulation. In some patients, the dosage of the extended-release formulation may require adjustment following conversion.

Conversion from IV infusion to oral: Immediate release can be started ~1 hour before stopping infusion. Oral daily dose may be estimated from the IV infusion rate by using the equation below. Round oral doses to the nearest appropriate strength and formulation.

Oral dose (mg per day) = [infusion rate (mg/hour) × 3 + 3] × 10

5 mg/hour = 180 mg/day.

10 mg/hour = 300 to 360 mg/day.

15 mg/hour = 480 mg/day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance.

Diltiazem is available in various strengths as 30mg, 60mg, 90mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg, 5mg/mL and 100mg.

Diltiazem is available in the form of Oral Tablet, Oral capsule, Injectable solution, Powder for injection.

Consumption of grapefruit juice is not recommended during treatment with Diltiazem due to the increased risk of severe adverse effects such as dizziness, headache, swelling of hands and feet, etc.

Diltiazem is contraindicated in patients with:

● Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker.

● Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker.

● Patients with hypotension (less than 90 mm Hg systolic).

● Patients who have demonstrated hypersensitivity to the drug.

● Patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.

• Cardiac Conduction

Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (13 of 3290 patients or 0.40%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem.

• Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24%± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of diltiazem in combination with betablockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.

• Hypotension

Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

Diltiazem is not recommended for use in pregnant women unless absolutely necessary. The risks and benefits should be considered before taking Diltiazem.

Consumption of grapefruit juice is not recommended during treatment with Diltiazem due to the increased risk of severe adverse effects such as dizziness, headache, swelling of hands and feet, etc.

Common Adverse effects

• Edema, Headache, Dizziness, AV block, Peripheral edema, Bradyarrhythmia, Headache, Hypotension (2-4%), Nausea, Vomiting, Vasodilation, Extrasystoles Flushing, Drug-induced gingival hyperplasia, Myalgia, Diarrhea, Constipation, Bronchitis, Sinus congestion, Dyspnea, Congestion.

Rare Adverse effects

• Increased Alkaline phosphatase as well as ALT and AST, CHF, Thrombocytopenia, Toxic epidermal necrolysis, Hemolytic anemia, Photosensitivity, Extrapyramidal symptoms, Syncope.

• 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 carefully.

• 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 2.5-fold) 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.

• Buspirone

In nine healthy subjects, Diltiazem significantly increased the mean buspirone AUC 5.5-fold and Cmax 4.1-fold compared to placebo. The T1/2 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 clinical assessment.

• 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 cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

• Cimetidine

A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, 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.

• 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. Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Diltiazem therapy to avoid possible over- or underdigitalization.

• Quinidine.

Diltiazem significantly increases the AUC (0 →∞) of quinidine by 51%, T1/2 by 36%, and decreases its Oral Clearance by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.

• Rifampin.

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.

• Statins.

Diltiazem is an inhibitor of CYP3A4 and 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 nonCYP3A4-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.

The common side effects of Diltiazem include the following

Common

● Body aches or pain, congestion, cough, dryness or soreness of the throat, fever, hoarseness, runny nose, tender or swollen glands in the neck, trouble swallowing, voice changes.

Rare

● Chest pain, discomfort, or tightness, chills, diarrhea, difficult or labored breathing, feeling faint, dizzy, or lightheaded, feeling of warmth or heat flushing or redness of the skin, especially on the face and neck, general feeling of discomfort or illness, headache, joint pain, loss of appetite, muscle aches and pains, nausea, shivering, slow or irregular heartbeat, sweating, swelling of the hands, ankles, feet, or lower legs, trouble sleeping, unusual tiredness or weakness, vomiting.

• Pregnancy

Pregnancy Category C

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from five to ten times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was an increased incidence of stillbirths at doses of 20 times the human dose or greater. There are no well-controlled studies in pregnant women; therefore, use diltiazem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Events observed following diltiazem overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block.

Management: Fluids and vasopressors were used to maintain blood pressure and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium. Evidence of the effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose was conflicting.

• Pharmacodynamic

Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization. Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate). It is also considered a rate-control drug as it reduces heart rate. Diltiazem is exerting hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow. Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In supraventricular tachycardia, diltiazem prolongs AV nodal refractories.

• Pharmacokinetics

Absorption

Almost completely absorbed from the gastrointestinal tract after oral administration. The Bioavailability of Diltiazem is approximately 40%. Time to peak plasma concentration of immediate-release, extended-release tablet and extended-release capsule of Diltiazem is about 2-4 hours, 11-18 hours and 10-14 hours respectively.

Distribution

The Plasma protein binding of Diltiazem is approximately 70-80%. The Volume of distribution is found to be 3-13 L/kg.

Metabolism and Excretion

Undergoes extensive first-pass metabolism by CYP450 and conjugation to N-monodesmethyldiltiazem, desacetyldiltiazem, desacetyl-N-monodesmethyldiltiazem, desacetyl-O-desmethyldiltiazem and desacetyl-N,O-desmethydiltiazem.

Elimination half-life: Oral: 3-4.5 hours (immediate-release); 6-9 hours (extended-release tab); 4-9.5 hours (extended-release cap). IV: Approx 3-4 hours; 4-5 hours (continuous infusion). Excreted via urine (2-4% as unchanged drug) and feces.

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