Mexiletine hydrochloride, like class I antiarrhythmic agents, blocks the fast Na+ channel in cardiac cells. It is especially effective on the Purkinje fibers in the heart. The drug increases the threshold of excitability of myocardial cells by reducing the rate of rise and amplitude of the action potential and decreases automaticity.
Mexiletine hydrochloride is used for long-term oral prophylaxis of ventricular tachycardia. The drug is given in 200- to 400-mg doses every 8 hours.
Tocainide Hydrochloride. Tocainide hydrochloride, 2-amino-2',6'-propionoxyxylidide hydrochloride (Tonocard) (pKa 7.7), is an analog of lidocaine. It is orally active and has electrophysiological properties like those of lidocaine.36 Total body clearance of tocainide hydrochloride is only 166 mL/min, suggesting that hepatic clearance is not large. Because of low hepatic clearance, the hepatic extraction ratio must be small; therefore, tocainide hydrochloride is unlikely to be subject to a substantial first-pass effect. The drug differs from lidocaine, in that it lacks two ethyl groups, which provides tocainide hydrochloride some protection from first-pass hepatic elimination after oral ingestion. Tocainide hydrochloride is hydrolyzed in a manner similar to that of lidocaine. None of its metabolites is active.
Tocainide hydrochloride is classed as a IB antiarrhyth-mic agent and used orally to prevent or treat ventricular ec-topy and tachycardia. The drug is given in 400- to 600-mg doses every 8 hours.
Flecainide Acetate. Flecainide acetate, n-(2-piperidinyl-methyl)-2,5-bis (2,2,2-trifluoroethoxy)benzamide monoacetate (Tambocor), is a class IC antiarrhythmic drug with local anesthetic activity; it is a chemical derivative of benza-mide. The drug undergoes biotransformation, forming a meta-O-dealkylated compound, whose antiarrhythmic properties are half as potent as those of the parent drug, and a meta-O-dealkylated lactam of flecainide with little pharmacological activity.37 Flecainide acetate is given orally to suppress chronic ventricular ectopy and ventricular tachycardia. It has some limitations because of CNS side effects.
phenothiazine derivative used for the treatment of malignant ventricular arrhythmias. It is categorized as a class IC antiarrhythmic agent, blocking the Na+ channel with 1:1 stochiometry. The drug has higher affinity for the inactivated state than the activated or resting states. It appears to bind to a site on the external side of the Na+ channel membrane.38 It has been used to suppress life-threatening ventricular arrhythmias.
Propafenone. Propafenone, 2-[2'-hydroxy-3-(propyl-amino)propoxy]-3-phenylpropiophenone (Rythmol), a class IC antiarrhythmic drug, contains a chiral center and is marketed as the racemic mixture. Therapy with the racemic mixture of propafenone produces effects that can be attributed to both (S) and (R) enantiomers. Although (R) and (S) enantiomers exert similar Na+ channel-blocking effects, the (S) enantiomer also produces a ^-adrenergic blockade. As a result, the (S) enantiomer is reported to be 40-fold more potent than the (R) enantiomer as an antiarrhythmic agent.39 The enantiomers also display stereoselective disposition characteristics. The (R) enantiomer is cleared more quickly. Hepatic metabolism is polymorphic and determined genetically. Ten percent of Caucasians have a reduced capacity to hydroxylate the drug to form 5-hydroxypropafenone. This polymorphic metabolism accounts for the interindividual variability in the relationships between dose and concentration and, thus, variability in the pharmacodynamic effects of the drug. The 5-hydroxy metabolites of both enantiomers are as potent as the parent compound in blocking Na+ channels. Propafenone also depresses the slow inward current of Ca2+ ions. This drug has been used for acute termination or long-term suppression of ventricular arrhythmias. It is bound in excess of 95% to ^i-acid glycoprotein in the plasma. It is absorbed effectively, but bioavailability is estimated to be less than 20% because of first-pass metabolism. Less than 1% is eliminated as unchanged drug. Therapy with propafenone may produce effects that can be attributed to both (S) and (R) enantiomers. Thus, the effects may be modulated because of an enantiomer-enantiomer interaction when patients are treated with the racemate.40
Moricizine. Moricizine, ethyl 10-(3-morpholino-propionyl)phenothiazine-2-carbamate (Ethmozine), is a
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