Mexiletine and Tocainide - Antiarrhythmic Cardiovascular Poison

Mexiletine and Tocainide

Mexiletine (mexiletene) and tocainide are analogues of ligno-caine with modified structures (to enable them to be adminis-tered orally for long periods). Both drugs have been used for ventricular arrhythmias with varying degree of success. They can be combined with quinidine. Mexiletine is a primary amine similar to lignocaine, but orally active. Its primary use is as a Class 1B antiarrhythmic drug with electrophysiologic proper-ties in man similar to lignocaine, but dissimilar from quinidine, procainamide, and disopyramide. Tocainide is an orally bioavail-able derivative of lignocaine. Tocainide is rarely employed in practice because of the potential risk of bone marrow aplasia and pulmonary fibrosis. Mexiletine was originally introduced as an anorectic agent but is no more used for that purpose today.

Mexiletine is rapidly and well absorbed (greater than 90%) when administered orally. Peak levels are obtained 2 to 3 hours after ingestion. The half-life is 12 to 13 hours. Mexiletine is highly protein-bound (70%), and also has a high volume of distribution (5.5–12 L/kg). Metabolism of this drug is accelerated by phenobarbitone, rifampicin, and phenytoin, but slowed by cimetidine, INH, and disulfiram. 7.5 to 15% is excreted unchanged in the urine within 72 hours. Elimination is increased by acid urine and decreased by alkaline urine.

Adverse Effects and Clinical (Toxic) Features (Mexiletine)

·      Therapeutic serum level is 1 to 2 mcg/ml.

·      Chronic effects:

o     Bradycardia, hypotension (IV), hepatotoxicity, GI distress, vertigo, tremor, ataxia.

o     Skin eruptions may occur as a result of hypersensitivity syndrome.

o     Rare cases of severe hepatic necrosis have been reported during therapeutic use of mexiletine.

·      Acute overdose:

§   a Vertigo, paraesthesias, hypotension, nausea, drowsiness, disorientation, bradycardia, heart block, torsades de pointes, asystole, convulsions, hypokalaemia. Paraesthesias of the tongue often occur as an early symptom of overdose.

§   ECG changes may include those related to heart block (increased PR interval) or conduction delay (increased QRS interval).

§   Agitation and hallucinations have been reported.

Treatment (Mexiletine)

·      Stomach wash, activated charcoal.

·      Atropine (1 mg intravenously and repeat in 3 to 5 minutes if asystolic cardiac arrest persists) for bradycardia. Insertion of a temporary pacemaker is the treatment of choice for bradyarrhythmias induced by drugs of this class.

·      Benzodiazpines for convulsions. If seizures persist or recur administer phenobarbitone.

·      IV fluids.

·      For hypotension: Infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy.

·      Although urinary acidification will enhance the renal clear-ance of mexiletine, it is unlikely to be of clinical signifi-cance, and risks aggravating acidaemia and other adverse renal effects in convulsing patients outweigh theoretical benefit.