Moricizine

Absorption

Well absorbed, absorption is complete within 2 to 3 hours. Significant first-pass metabolism results in an absolute bioavailability of approximately 38%. Administration within 30 minutes after a meal slows the rate, but does not affect the extent of absorption, although peak plasma concentrations are reduced.

Toxicity

Symptoms of overdose include vomiting, unconsciousness, and severe low blood pressure.

Originator

Ethmozine,Bristol-Myers Squibb

The Uses of Moricizine

Moricizine, is Phenothiazine (P318040) derivative, which It was used as an Antiarrhythmic agent. It is also shown that moracizine is effective in suppressing premature ventricular contractions, couplets, and nonsustained ventricular tachycardia.

The Uses of Moricizine

Cardiac depressant (anti-arrhythmic).

Background

An antiarrhythmia agent used primarily for ventricular rhythm disturbances.

Indications

Used to treat irregular heartbeats (arrhythmias) and maintain a normal heart rate.

Definition

ChEBI: A phenothiazine substituted on the nitrogen by a 3-(morpholin-4-yl)propanoyl group, and at position 2 by an (ethoxycarbonyl)amino group.

Manufacturing Process

To a solution of 10 g (0.035 mole) of ethyl phenthiazine-2-carbamate in 30 ml of anhydrous toluene is added dropwise 5.3 g (0.042 mole) of 3- chloropropionyl chloride, and the mixture is refluxed at 110-120°C for 4 hours, followed by clarifying the mixture with activated carbon and cooling it to room temperature. A precipitate of ethyl 10-(3-chloropropionyl)- phenthiazine-2-carbamate is removed by filtration. The yield is 10.2 g (77.5% of the theoretical amount), M.P. 169-170°C.
10.2 g of ethyl 10-(3-chloropropionyl)-phenthiazine-2-carbamate ester is dissolved in 50 ml of toluene, 4.72 g of morpholine is added thereto, and the mixture is refluxed at 110-120°C for a period of 3 hours. A precipitate of morpholine hydrochloride is removed by filtration, and the filtrate is washed with water in order to remove excess morpholine, followed by acidulating with dilute hydrochloric acid to adjust the pH of the filtrate is adjusted at 3. The acidic aqueous layer is separated, clarified by treatment with activated carbon and made alkaline until the pH equals 8-9. This procedure yields the free base of ethyl 10-(β-morpholylpropionyl)-phenthiazine-2-carbamate, M.P. 156- 157°C.
The free base thus obtained is extracted with toluene, the extract is dried over magnesium sulphate and to the anhydrous toluene solution is added an anhydrous ethereal solution of hydrogen chloride until the precipitation of the target compound is complete. This procedure yields 9.53 g (76.2% of the theoretical amount) of ethyl 10-(β-morpholylpropionyl)-phenthiazine-2- carbamate hydrochloride. After recrystallization from dichloroethane, the target compound melts at 189°C. (decomp.).

brand name

Ethmozine (Roberts Pharmaceutical).

Therapeutic Function

Antiarrhythmic

General Description

Moricizine, ethyl 10-(3-morpholinopropionyl)phenothiazine-2-carbamate (Ethmozine), is aphenothiazine derivative used for the treatment of malignantventricular arrhythmias. It is categorized as a class ICantiarrhythmic agent, blocking the Na⁺ channel with 1:1stochiometry. The drug has higher affinity for the inactivatedstate than the activated or resting states. It appearsto bind to a site on the external side of the Na channelmembrane. It has been used to suppress life-threateningventricular arrhythmias.

Pharmacokinetics

Moricizine is used to treat irregular heartbeats (arrhythmias) and to maintain a normal heart rate. It acts on the heart muscle to improve the heart's rhythm. Moricizine has potent local anesthetic activity and membrane stabilizing effect. Decreases excitability, conduction velocity, and automaticity as a result of slowed atrioventricular (AV) nodal and His-Purkinje conduction. Decreases the action potential duration (APD) in Purkinje fibers; also decreases the effective refractory period (ERP) but to a lesser extent than the APD, so the ERP/APD ratio is increased. Decreases the maxiumum rate of Phase 0 depolarization (V max ), but does not affect action potential amplitude or maximum diastolic potential. Does not affect atrial, AV nodal, or left ventricular refractory periods and has minimal effect on ventricular repolarization (evidenced by the overall decrease in JT interval). Has no effect on sinoatrial (SA) nodal or intra-atrial conduction and only minimal effect on sinus cycle length and sinus node recovery time. In the Vaughan Williams classification of antiarrhythmics, moricizine is considered to be a class I agent. It has properties of class IA, IB, and IC agents but does not clearly belong to any of the three subclasses. It has less effect on the slope of phase 0 and a greater effect on action potential duration and effective refractory period than class IC agents.

Clinical Use

Moricizine (Ethmozine) is an antiarrhythmic used to treat documented life-threatening arrhythmias.
Moricizine is indicated for the treatment of documented ventricular arrhythmias, particularly sustained ventricular tachycardia. Moricizine was evaluated in the CAST II clinical trial for the prevention of postinfarction ventricular premature complexes. It was ineffective and found to be proarrhythmic. Patients in the moricizine arm of the trial exhibited a greater incidence of sudden cardiac death than did controls.

Side Effects

The principal adverse gastrointestinal effect of moricizine is nausea (7%). Abdominal discomfort has also been reported. Dizziness (11%) is the most frequently reported CNS-related adverse effect. Such reactions increase in frequency with prolonged drug administration. As with other antiarrhythmic drugs, moricizine has proarrhythmic activity, which may manifest as new ventricular ectopic beats or a worsening of preexisting ventricular arrhythmias. These effects are most common in patients with depressed left ventricular function and a history of congestive heart failure. Cardiovascular effects requiring drug withdrawal include conduction defects, sinus pauses, junctional rhythm, and A-V block.

Drug interactions

Clinically significant interactions with moricizine do not appear to exist.

Metabolism

Hepatic and extensive, to at least 26 metabolites, none accounting for as much as 1% of the administered dose. Two metabolites may be pharmacologically active but are present in extremely small quantities. Moricizine induces its own metabolism (it induces hepatic cytochrome P-450 activity).

Precautions

Patients with preexisting second- or third-degree A-V block, cardiogenic shock, or drug hypersensitivity should not be treated with moricizine.