Mexiletine

Structural formula
1: 1 mixture of ( R ) -isomer (top) and ( S ) -isomer (bottom)
General
Non-proprietary name	Mexiletine
other names	( RS ) -1- (2,6-dimethylphenoxy) propan-2-amine rac -1- (2,6-dimethylphenoxy) propan-2-amine DL -1- (2,6-dimethylphenoxy) propan-2-amine (±) -1- (2,6-Dimethylphenoxy) propan-2-amine
Molecular formula	C 11 H 17 NO
External identifiers / databases
CAS number 31828-71-4 (free base) 5370-01-4 (mexiletine hydrochloride ) EC number 250-825-7 ECHA InfoCard 100.046.190 PubChem 4178 ChemSpider 4034 DrugBank DB00379 Wikidata Q420377
Drug information
ATC code	C01 BB02
Drug class	Class Ib antiarrhythmic
Mechanism of action	Blockade of fast sodium channels
properties
Molar mass	179.26 g mol −1
Physical state	firmly
Melting point	203–205 ° C (mexiletine hydrochloride)
solubility	Water: 8.25 g l −1 (25 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302 P: no P-phrases
Toxicological data	320 mg kg −1 ( LD 50 ,  mouse ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Half-life	9-12 (8-20) hours
Bioavailability	~ 90%
Plasma protein binding	~ 70%
elimination	liver
Volume of Distribution	5.5–9.5 l kg −1
Metabolism	CYP2D6

Mexiletine is a drug against ventricular cardiac arrhythmias from the group of antiarrhythmics Ib according to Vaughan-Williams. It is similar to the structure of lidocaine and tocainide . It was originally introduced as an appetite-reducing and anti-epileptic agent until its anti-arrhythmic effects were discovered. The drug was marketed in Germany by Boehringer until September 2009 under the name Mexitil ^® . Since January 2019, it is for the treatment of non- dystrophic myotonia in adults under the name Namuscla ^® available in Germany.

Electrophysiological effects

Like all class I antiarrhythmics, mexiletine inhibits the rapid sodium channel . It shortens the action potential of the heart chamber and stabilizes the membrane potential. Mexiletine does not prolong the QT time and is therefore an alternative if drug-induced ventricular tachycardia of the torsade de pointes type has occurred or if there is a long QT syndrome in which other antiarrhythmics such as quinidine , sotalol , and procainamide exist or disopyramide are contraindicated. Since the effectiveness of mexiletine on its own is quite modest, it is often successfully administered in combination with quinidine, propranolol , procainamide or amiodarone , whereby lower doses of the substances used are required and thus the frequency of side effects can be reduced.

Hemodynamic effects and indication

Mexiletine has little effect on the force of contraction of the heart or the circulatory system in patients with heart failure. Mexiletine is used to treat ventricular arrhythmias. A therapy attempt is also useful if lidocaine has shown no effectiveness. It is applicable to QT prolongation. The only indication for which it is currently available is the symptomatic treatment of myotonia in adult patients with non-dystrophic myotonic disease.

application

A slow dose increase in the first few days is recommended until the desired effect on the cardiac arrhythmia has occurred or side effects such as tremor do not allow a further dose increase. The maintenance dose varies widely from person to person and should be clarified by level determinations. In the case of congenital CYP2D6 deficiency , kidney failure, severe liver disease or heart failure, the dose must be reduced or the intake is contraindicated.

unwanted effects

Mexiletine side effects are dose-dependent and neurological in nature. They include tremors , blurred vision, dizziness, mood swings, and nausea. Thrombocytopenia is rare . When syndrome sick sinus node is the danger of bradycardia , or an extension of the sinus node recovery time (SKEZ). If a new bundle branch block occurs, it should be withdrawn. The function of the heart muscle is not inhibited by oral mexiletine, but this is said to occur with intravenous administration.

Interactions

The substances phenytoin , phenobarbital and rifampicin heat up the metabolism of mexiletine in the liver and thus weaken its effect. If one of these active ingredients is discontinued and mexiletine is administered at the same time, the effective dose can change into a toxic dose because the rate of degradation of mexiletine is lower. Mexiletine may make theophylline more effective . Quinidine inhibits CYP2D6 and thus slows down the breakdown of mexiletine. Antacids and atropine reduce absorption in the intestine, while metoclopramide increases it.

Stereoisomerism

Mexiletine contains a stereocenter , so it is chiral . The racemate , a 1: 1 mixture of the isomeric ( R ) form and the ( S ) form, was used as the drug .

literature

• RL Woosley, JH Indic: Antiarrhythmic Drugs. In: V. Fuster, W. Alexander, RA O'Rourke (ed.): Hurst's The Heart. 11th edition. McGraw-Hill, New York 2004, ISBN 0-07-142264-1 , pp. 949-973.

Individual evidence

1. ↑ ^{a b c} Entry on mexiletine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
2. ↑ ^{a b} Datasheet Mexiletine hydrochloride from Sigma-Aldrich , accessed on April 10, 2011 ( PDF ).
3. ↑ E. Mutschler, M. Schäfer-Korting: drug effects. Textbook of pharmacology and toxicology. 7th edition. Wissenschaftliche Verlagsgesellschaft, Stuttgart 1996, ISBN 3-8047-1377-7 .
4. ↑ Discontinuation of mexiletine (Mexitil) ( Memento from September 3, 2012 in the web archive archive.today )
5. ↑ https://www.apotheke-adhoc.de/nachrichten/detail/pharmazie/hormosan-bringt-namuscla-nicht-dystrophe-myotonie/

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