Description: Diltiazem Hydrochloride is a calcium ion influx inhibitor ( slow channel blocker or calcium channel antagonist). Chemically, diltiazem hydrochloride is (+)-5-[2- (Dimethylamino)ethyl]-cis-2,3-dihydro-3-hydroxy-2-(p-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one acetate (ester) monohydrochloride. Diltiazem Hydrochloride Injection is for direct intravenous bolus injection and continuous intravenous infusion.

Pharmacological effects: Diltiazem inhibits the influx of calcium (Ca) ions during membrane depolarization of cardiac and vascular smooth muscle. The therapeutic benefits of diltiazem in supraventricular tachycardias are related to its ability to slow AV nodal conduction time and prolong AV nodal refractoriness. Diltiazem exhibits frequency (use) dependent effects on AV nodal conduction such that it may selectively reduce the heart rate during tachycardias involving the AV node with little or no effect on normal AV nodal conduction at normal heart rates. Diltiazem slows the ventricular rate in patients with a rapid ventricular response during atrial fibrillation or atrial flutter. Diltiazem converts paroxysmal supraventricular tachycardia (PSVT) to normal sinus rhythm by interrupting the reentry circuit in AV nodal reentrant tachycardias and reciprocating tachycardias, e.g., Wolff-Parkinson-White syndrome (WPW). Diltiazem prolongs the sinus cycle length. It has no effect on the sinus node recovery time or on the sinoatrial conduction time in patients without SA nodal dysfunction. Diltiazem has no significant electrophysiologic effect on tissues in the heart that are fast sodium channel dependent, e.g., His-Purkinje tissue, atrial and ventricular muscle, and extranodal accessory pathways.Like other calcium channel antagonists, because of its effect on vascular smooth muscle, diltiazem decreases total peripheral resistance resulting in a decrease in both systolic and diastolic blood pressure.

Pharmacokinetics: In patients with cardiovascular disease, diltiazem hydrochloride administered intravenously in single bolus doses, followed in some cases by a continuous infusion, reduced blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance and increased coronary blood flow. In a limited number of studies of patients with compromised myocardium (severe congestive heart failure, acute myocardial infarction, hypertrophic cardiomyopathy), administration of intravenous diltiazem produced no significant effect on contractility, left ventricular end diastolic pressure, or pulmonary capillary wedge pressure. The mean ejection fraction and cardiac output/index remained unchanged or increased. Maximal hemodynamic effects usually occurred within 2 to 5 minutes of an injection. However, in rare instances, worsening of congestive heart failure has been reported in patients with preexisting impaired ventricular function.Following a single intravenous injection in healthy male volunteers, diltiazem hydrochloride appears to obey linear pharmacokinetics over a dose range of 10.5 to 21 mg. The plasma elimination half-life is approximately 3.4 hours. The apparent volume of distribution of diltiazem is approximately 305 L. Diltiazem is extensively metabolized in the liver with a systemic clearance of approximately 65 L/h.After constant rate intravenous infusion to healthy male volunteers, diltiazem exhibits nonlinear pharmacokinetics over an infusion range of 4.8 to 13.2 mg/h for 24 hours. Over this infusion range, as the dose is increased, systemic clearance decreases from 64 to 48 L/h while the plasma elimination half-life increases from 4.1 to 4.9 hours. The apparent volume of distribution remains unchanged (360 to 391 L). In patients with atrial fibrillation or atrial flutter, diltiazem systemic clearance has been found to be decreased compared to healthy volunteers. In patients administered bolus doses ranging from 2.5 mg to 38.5 mg, systemic clearance averaged 36 L/h. In patients administered continuous infusions at 10 mg/h or 15 mg/h for 24 hours, diltiazem systemic clearance averaged 42 L/h and 31 L/h, respectively.


Indications: Diltiazem hydrochloride injection is indicated for Atrial Fibrillation or Atrial Flutter.

Precautions: The use of diltiazem hydrochloride injection should be undertaken with caution when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium. For either indication and particularly when employing continuous intravenous infusion, the setting should include continuous monitoring of the ECG and frequent measurement of blood pressure. A defibrillator and emergency equipment should be readily available. Diltiazem hydrochloride injection rarely converts atrial fibrillation or atrial flutter to normal sinus rhythm. Following administration of one or two intravenous bolus doses of diltiazem hydrochloride injection, response usually occurs within 3 minutes and maximal heart rate reduction generally occurs in 2 to 7 minutes. Heart rate reduction may last from 1 to 3 hours. If hypotension occurs, it is generally short-lived, but may last from 1 to 3 hours.A 24-hour continuous infusion of diltiazem injection in the treatment of atrial fibrillation or atrial flutter maintained upon discontinuation of infusion, heart rate reduction may last from 0.5 hours to more than 10 hours (median duration 7 hours). Hypotension, if it occurs, may be similarly persistent.Diltiazem hydrochloride is extensively metabolized by the liver and excreted by the kidneys and in bile. The drug should be used with caution in patients with impaired renal or hepatic function. High intravenous dosages (4.5 mg/kg tid) administered to dogs resulted in significant bradycardia and alterations in AV conduction. Should a dermatologic reaction persist, the drug should be discontinued. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy of and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic blood levels.

Adverse reaction: Adverse events were generally mild and transient. Hypotension was the most commonly reported adverse event during clinical trials. Asystole, atrial flutter, AV block first degree, AV block second degree, bradycardia, chest pain, congestive heart failure, sinus pause, sinus node dysfunction, syncope, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia. Pruritus, sweating.Constipation, elevated SGOT or alkaline phosphatase, nausea, vomiting. Dizziness, paresthesia. Amblyopia, asthenia, dry mouth, dyspnea, edema, headache have also been reported.