DILTIAZEM HCL

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

Storage, Stability, Compatibility

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

Pharmacology - DILTIAZEM HCL

Diltiazem is a calcium-channel blocker similar in action to drugs such as verapamil 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 notalter 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.

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 - DILTIAZEM HCL

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 entersmaternal milk in concentrations approximating those found in the plasma. Diltiazem is rapidly andalmost 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 patientswith 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.

Adverse Effects, Warnings

Experience in both dogs and cats is limited. At usual doses, bradycardia 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. Symptomsnoted after overdosage may include heart block, bradycardia, hypotension, and heart failure.
Treatment should consist of gut emptying protocols when warranted, and supportive andsymptomatic 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 blockmay 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 slowintravenous calcium infusion (1 ml/10 kg body weight of 10% calcium gluconate) may also beuseful for severe acute toxicity.

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). Additional y, 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.