Diltiazem

By | 2011-08-17

Diltiazem Hydrochloride

Chemistry

A calcium channel blocker, diltiazem HCl occurs as a white to off-white crystalline powder having a bitter taste. It is soluble in water and alcohol. Potencies may be expressed in terms of base (active moiety) and the salt. Dosages are generally expressed in terms of the salt. Diltiazem is also known as latiazem HCl.

Storage – Stability – Compatibility

Diltiazem oral products should be stored at room temperature in tight, light resistant containers.

Diltiazem: Pharmacology

Diltiazem is a calcium-channel blocker similar in action to drugs such as vera-pamil or nifedipine. While the exact mechanism is unknown, diltiazem inhibits the transmembrane influx of extracellular calcium ions in myocardial cells and vascular smooth muscle, but does not alter serum calcium concentrations. The net effects of this action is to inhibit the cardiac and vascular smooth muscle contractility, thereby dilating main systemic and coronary arteries. Total peripheral resistance, blood pressure and cardiac afterload are all reduced.

Diltiazem also has effects on cardiac conduction. It slows AV node conduction and prolongs refractory times. Diltiazem rarely affects SA node conduction, but in patients with Sick Sinus Syndrome, resting heart rates may be reduced.

Although diltiazem can cause negative inotropic effects, it is rarely of clinical importance (unlike verapamil or nifedipine). Diltiazem apparently does not affect plasma renin or aldosterone concentrations nor affect blood glucose or insulin concentrations.

Diltiazem: Uses – Indications

Diltiazem may be useful in the treatment of atrial fibrillation, supraventricular tachycardias, and hypertrophic cardiomyopathy. For specific information, refer to the Dosages section.

Pharmacokinetics

After an oral dose, about 80% of the dose is absorbed rapidly from the gut, but because of a high first pass effect only about half of that absorbed reaches the systemic circulation. Approximately 75% of the drug is bound to serum proteins in humans. Diltiazem enters maternal milk in concentrations approximating those found in the plasma. Diltiazem is rapidly and almost completely metabolized in the liver. Serum half lives in humans range from 3.5 to 10 hours. Renal impairment may only slightly increase half lives.

Contraindications – Precautions – Reproductive Safety

Diltiazem is contraindicated in patients with severe hypotension (<90 mm Hg systolic), sick sinus syndrome or 2nd or 3rd degree AV block (unless a functioning pacemaker is in place), acute MI, radiographically documented pulmonary congestion, or if the patient is hypersensitive to it.

Diltiazem should be used with caution in geriatric patients or those with heart failure (particularly if also receiving beta blockers), or hepatic or renal impairment.

High doses in rodents have resulted in increased fetal deaths and skeletal abnormalities. Use during pregnancy only when the benefits outweigh the potential risks.

Diltiazem: Adverse Effects – Warnings

Experience in both dogs and cats is limited. At usual doses, brady-cardia is the most prominent side effect reported in dogs thus far. Specific adverse effects in cats are not well described. Potentially, GI distress, hypotension, heart block or other rhythm disturbances, CNS effects, rashes, or elevations in liver function tests could occur in either species.

Overdosage – Acute Toxicity

The oral LD50 in dogs has been reported as >50 mg/kg. Symptoms noted after overdosage may include heart block, bradycardia, hypotension, and heart failure. Treatment should consist of gut emptying protocols when warranted, and supportive and symptomatic treatment. Atropine may be used to treat bradycardias or 2nd or 3rd degree AV block. If these do not respond to vagal blockade, isoproterenol may be tried (with caution). Fixed block may require cardiac pacing. Inotropics (e.g., dobutamine, dopamine, isoproterenol) and pressors (e.g., dopamine, norepinephrine) may be required to treat heart failure and hypotension. A slow intravenous calcium infusion (1 ml/10 kg body weight of 10% calcium gluconate) may also be useful for severe acute toxicity.

Diltiazem: Drug Interactions

While data conflicts regarding whether diltiazem affects digoxin pharmacokinetics, diligent monitoring of digoxin serum concentrations should be performed. Diltiazem may increase the likelihood of bradycardia, AV block or CHF developing in patients also receiving beta blockers (including ophthalmic beta blockers). Additionally, diltiazem may substantially increase the bioavailability of propranolol. Cimetidine may increase plasma diltiazem concentrations; increased monitoring of diltiazem’s effects are warranted. Ranitidine may also affect diltiazem concentrations, but to a lesser extent. Diltiazem may affect cyclosporin or quinidine serum concentrations; increased monitoring and dosage adjustments may be required.

Diltiazem: Doses

Doses for dogs:

For treatment of supraventricular tachyarrhthymias:

a) 0.5 – 1 (up to 1.5) mg/kg PO q8h (PionZZZ

b) For atrial fibrillation with rapid ventricular response in dogs with dilated cardiomyopathy: 0.4 – 0.5 mg/kg PO tid; increase dosage gradually every 2-3 days while patient is observed for deterioration of cardiovascular function. Dosages above 1 mg/kg are not recommended.

c) Initially give a 0.25 mg/kg IV bolus over 2 minutes. Repeat 0.25 mg/kg IV bolus every 15 minutes until conversion occurs or total dosage of 0.75 mg/kg has been given.

For supraventricular arrhythmias, hypertrophic cardiomyopathy, hypertension:

a) 0.5 – 1.5 mg/kg PO q8h; titrate upwards to effect

Doses for cats:

For treatment of supraventricular tachyarrhythmias:

a) 0.5 – 1 (up to 1.5) mg/kg PO q8h

For treatment of hypertrophic cardiomyopathy:

a) 7.5 mg PO tid

b) 1.75 – 2.5 mg/kg PO tid

c) Initially 7.5 mg (l/4th of a 30 mg tablet) PO q8h; may be given as initial therapy in asymptomatic cats or added to therapy in cats responding poorly to furosemide or enalapril.

For supraventricular arrhythmias, hypertrophic cardiomyopathy, hypertension: a) 0.5 – 2.5 mg/kg PO q8h

Monitoring Parameters

1) ECG/Heart Rate; 2) Blood Pressure; 3) Adverse Effects

Client Information

Inform clients of potential adverse effects. Stress compliance.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:

None

Human-Approved Products:

Diltiazem Tablets 30 mg, 60 mg, 90 mg, and 120 mg; Cardizem® (Hoechst Marion Roussel) (Marion Merrell Dow, generic; (Rx)

Diltiazem Extended-Release Tablets: 120 mg, 180 mg, & 240 mg; Tiamate® (Hoechst Marion Roussel) (Rx)

Diltiazem Oral Capsules Extended Release 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg; Cardizem® SR (Hoechst Marion Roussel); (Rx);Cardizem CD® (Hoechst Marion Roussel) (Rx);Dilacor XR® (Rhone-Poulenc Rorer) (Rx);Tiazac® (Forest) (Rx); generic (Rx)

Diltiazem Injection 5 mg/ml in 5 ml & 10 ml vials; Cardizem® (Hoechst Marion Roussel); Diltiazem (Bedford Labs) (Rx)