1-(2,6-Dimethylphenoxy)-2-propanamine

Absorption

Well absorbed (bioavailability 90%) from the gastrointenstinal tract.

Toxicity

Symptoms of overdose include nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, AV heart block, asystole, ventricular tachyarrythmia, including ventricular fibrillation, cardiovascular collapse, and coma.

Description

Mexiletine is effective both parenterally and orally , . Because the substance has a large distribution volume, a high initial dose is necessary.

Originator

Mexitil,Boehringer Ingelheim,US,1976

The Uses of 1-(2,6-Dimethylphenoxy)-2-propanamine

Cardiac depressant (anti-arrhythmic).

The Uses of 1-(2,6-Dimethylphenoxy)-2-propanamine

Mexiletine is used for ventricular extrasystole and ventricular tachycardia, and ventricular fibrillation (including during the severe period of myocardial infarction).

The Uses of 1-(2,6-Dimethylphenoxy)-2-propanamine

Mexiletine is a useful analgesia.It is used in treatment of amyotrophic lateral sclerosis comprising administering a bile acid and a phenylbutyrate compound and an additional therapeutic agent.

Indications

For the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation.

Background

Antiarrhythmic agent pharmacologically similar to lidocaine. It may have some anticonvulsant properties.

Definition

ChEBI: An aromatic ether which is 2,6-dimethylphenyl ether of 2-aminopropan-1-ol.

Manufacturing Process

The sodium salt of dimethyl phenol was reacted with chloroacetone and this product with hydroxylamine to give the starting material.
245 g of this 1-(2',6'-dimethyl-phenoxy)-propanone-(2)-oxime were dissolved in 1,300 cc of methanol, and the solution was hydrogenated at 5 atmospheres gauge and 60°C in the presence of Raney nickel. After the calculated amount of hydrogen had been absorbed, the catalyst was filtered off, the methanol was distilled out of the filtrate,and the residue, raw 1-(2',6'-dimethylphenoxy)-2-amino-propane, was dissolved in ethanol. The resulting solution was acidified with ethereal hydrochloric acid, the acidic solution was allowed to cool, and the precipitate formed thereby was collected by vacuum filtration. The filter cake was dissolved in ethanol and recystallized therefrom by addition of ether. 140.5 g (51.5% of theory) of a substance having a melting point of 203°C to 205°C were obtained, which was identified to be 1-(2',6'- dimethyl-phenoxy)-2-anino-propane hydrochloride.

brand name

Mexitil (Boehringer Ingelheim).

Therapeutic Function

Antiarrhythmic

Pharmacokinetics

Mexiletine is a local anesthetic, antiarrhythmic agent (Class Ib), structurally similar to lidocaine, but orally active. Mexiletine has fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. It shortens the action potential duration, reduces refractoriness, and decreases Vmax in partially depolarized cells with fast response action potentials. Mexiletine either does not change the action potential duration, or decreases the action potential duration.

Clinical Use

Mexiletine (Mexitil) is an antiarrhythmic agent with pharmacological and antiarrhythmic properties similar to those of lidocaine and tocainide. Like tocainide,mexiletine is available for oral administration.
Mexiletine is useful as an antiarrhythmic agent in the management of patients with either acute or chronic ventricular arrhythmias.While it is not at present an indication for use, there is interest in using mexiletine to treat the congenital long QT syndrome when an abnormality in the SCN5A gene (LQTS 3) has been found.

Side Effects

A very narrow therapeutic window limits mexiletine use. The first signs of toxicity manifest as fine tremor of the hands, followed by dizziness and blurred vision. Hypotension, sinus bradycardia, and widening of the QRS complex have been noted as the most common unwanted cardiovascular effects of IV mexiletine. The side effects of oral maintenance therapy include reversible upper gastrointestinal distress, tremor, lightheadedness, and coordination difficulties. These effects generally are not serious and can be reduced by downward dose adjustment or administering the drug with meals. Cardiovascular adverse effects, which are less common, include palpitations, chest pain, and angina or anginalike pain.

Synthesis

Mexiletine is 1-methyl-2-(2,2-dimethylphenoxy)ethylamine (18.1.11). Mexiletine is synthesized by reacting the sodium salt of 2,6-dimethylphenol with chloroacetone, forming 1-(2,6-dimethylphenoxy)-2-propanone (18.1.9). Reacting this with hydroxylamine gives the corresponding oxime (18.1.10). Reduction of the oximine group using hydrogen over Raney nickel gives mexiletine (18.1.11).

Drug interactions

An upward adjustment in dose may be required when mexiletine is administered with phenytoin or rifampin, since these drugs stimulate the hepatic metabolism of mexiletine, reducing its plasma concentration.

Metabolism

Primarily hepatic (85%) via CYP2D6 and CYP1A2 (primarily CYP2D6).

Precautions

Mexiletine is contraindicated in the presence of cardiogenic shock or preexisting second- or third-degree heart block in the absence of a cardiac pacemaker. Caution must be exercised in administration of the drug to patients with sinus node dysfunction or disturbances of intraventricular conduction.