indication

For the treatment of Hypertension

pharmacology

Diltiazem, a benzothiazepine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Diltiazem is a non-dihydropyridine (DHP)member of the calcium channel blocker class, along with Verapamil. Diltiazem is similar to other peripheral vasodilators. Diltiazem inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.

mechanism of action

Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, diltiazem, like verapamil, inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

toxicity

LD₅₀=740mg/kg (orally in mice)

biotransformation

Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme.

absorption

Diltiazem is well absorbed from the gastrointestinal tract but undergoes substantial hepatic first-pass effect.

half life

3.0 - 4.5 hours

drug interactions

Amiodarone: Increased risk of cardiotoxicity and arrhythmias

Amlodipine: Diltiazem may increase the serum concentration of amlodipine. Concomitant therapy will result in additive hypotensive effects. Monitor for changes in the hypotensive effect of amlodipine if diltiazem is initiated, discontinued or dose changed.

Aprepitant: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Atazanavir: Atazanavir may increase the therapeutic and adverse effects of diltiazem resulting in increased risk of AV block. Consider alternate therapy, a 50% dose reduction of diltiazem and monitor for changes in the therapeutic and adverse effects of diltiazem if atazanavir is initiated, discontinued or dose changed.

Atenolol: Increased risk of bradycardia

Atorvastatin: Diltiazem may increase the serum concentration of atorvastatin. Atorvastatin may increase the serum concentration of diltiazem. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Bromazepam: Diltiazem may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or a reductin in the bromazepam dose. Monitor for changes in the therapeutic and adverse effects of bromazepam if diltiazem is initiated, discontinued or dose changed.

Buspirone: The calcium channel blocker, diltiazem, increases the effect and toxicity of buspirone.

Carbamazepine: Carbamazepine may decrease the serum concentration of diltiazem by increasing its metabolism. Diltiazem may increase the serum concentration of carbamazepine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if dosages are changed.

Cerivastatin: Diltiazem may increase the serum concentration of cerivastatin. Cerivastatin may increase the serum concentration of diltiazem. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Cilostazol: Diltiazem, a moderate CYP3A4 inhibitor, may increase the serum concentration of cilostazol by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cilostazol if diltiazem is initiated, discontinued or dose changed.

Cisapride: Diltiazem, a moderate CYP3A4 inhibitor, may increase the serum concentration of cisapride by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cisapride if diltiazem is initiated, discontinued or dose changed.

Cyclosporine: Diltiazem may increase the effect and toxicity of cyclosporine.

Dihydroquinidine barbiturate: Increases the effect and toxicity of quinidine

Lovastatin: Diltiazem may increase the serum concentration of lovastatin. Lovastatin may increase the serum concentration of diltiazem. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Metoprolol: Increased risk of bradycardia

Midazolam: The calcium channel blocker, diltiazem, may increase the effect and toxicity of the benzodiazepine, midazolam.

Moricizine: Increased effect/toxicity of moricizine

Pindolol: Increased risk of bradycardia

Propranolol: Increased risk of bradycardia

Quinidine: Diltiazem may increase the serum concentration of quinidine. Monitor for changes in the therapeutic and adverse effects of quinidine if diltiazem is initiated, discontinued or dose changed.

Quinidine barbiturate: Increases the effect and toxicity of quinidine

Quinupristin: This combination presents an increased risk of toxicity

Ranolazine: Diltiazem may increase the serum concentration of ranolazine. Consider alternate therapy or limit ranolazine dose to 500 mg twice daily and monitor for changes in the therapeutic and adverse effects if diltiazem is initiated, discontinued or dose changed.

Rifampin: Rifampin decreases levels of diltiazem

Ritonavir: Ritonavir increases diltiazem levels

Simvastatin: Diltiazem may increase the serum concentration of simvastatin. Simvastatin may increase the serum concentration of diltiazem. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Sirolimus: Increases the effect and toxicity of sirolimus

Tacrolimus: Diltiazem may increase the serum concentration of tacrolimus by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of tacrolimus if diltiazem therapy is initiated, discontinued or dose changed.

Tamsulosin: Diltiazem, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Diltiazem is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Diltiazem. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Diltiazem if Telithromycin is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thiopental: The CYP3A4 inducer, Thiopental, may increase the metabolism and clearance of Diltiazem, a CYP3A4 substrate. Monitor for changes in the therapeutic/adverse effects of Diltiazem if Thiopental is initiated, discontinued or dose changed.

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Timolol: Additive effects of decreased heart rate and contractility may occur. Increased risk of heart block.

Tipranavir: Tipranavir, co-administered with Ritonavir, may alter the concentration of Diltiazem. Monitor for efficacy and adverse/toxic effects of Diltiazem.

Tolterodine: Diltiazem may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Diltiazem may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inhibitor, Diltizem, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Diltiazem is initiated, discontinued or dose changed.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Triazolam: The calcium channel blocker, diltiazem, may increase the effect and toxicity of the benzodiazepine, triazolam.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of diltiazem by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of diltiazem if voriconazole is initiated, discontinued or dose changed.