Thioridazine

Absorption

60%

Toxicity

LD50=956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock

Description

An antipsychotic drug of the phenothiazine class. It is of particular interest because of its “atypical” properties, some of which may be due to its extensive bioconversion to active metabolites. The therapeutic and side effects of thioridazine and its metabolites involve blockade of brain dopamine receptors, but also actions mediated via blockage of muscarininc cholinergic and α-adrenergic receptors.

Chemical properties

Colorless crystals. Soluble in water and alcohol.

Originator

Mellaril,Sandoz,US,1959

The Uses of Thioridazine

Mellaril(Novartis).

The Uses of Thioridazine

In terms of antipsychotic activity, thioridazine is inferior to aminazine. It is most effective in mental and emotional disorders accompanied by fear, stress, and excitement. It is prescribed for various forms of schizophrenia, psychosis, and neurosis.

Background

A phenothiazine antipsychotic used in the management of psychoses, including schizophrenia, and in the control of severely disturbed or agitated behavior. It has little antiemetic activity. Thioridazine has a higher incidence of antimuscarinic effects, but a lower incidence of extrapyramidal symptoms, than chlorpromazine. (From Martindale, The Extra Pharmacopoeia, 30th ed, p618).
Thioridazine was withdrawn worldwide in 2005 due to its association with cardiac arrythmias.

Definition

ChEBI: A phenothiazine derivative having a methylsulfanyl subsitituent at the 2-position and a (1-methylpiperidin-2-yl)ethyl] group at the N-10 position.

Indications

For the treatment of schizophrenia and generalized anxiety disorder.

Manufacturing Process

N-(m-methylmercapto-phenyl)-aniline (MP 59° to 61°C) is prepared by condensing m-methylmercapto-aniline (BP 163° to 165°C/16 mm Hg) with the potassium salt of o-chloro-benzoic acid and decarboxylating the resultant N- (m-methylmercapto-phenyl)-anthranilic acid (MP 139° to 141°C) by heating, and then distilling.
9.87 parts of N-(m-methylmercapto-phenyl)-aniline are heated with 2.93 parts of sulfur and 0.15 part of powdered iodine for 15 minutes in a bath at about 160°C. Upon termination of the ensuing evolution of hydrogen sulfide, animal charcoal is added to the reaction mixture and recrystallization carried out first from 40 parts by volume of chlorobenzene, and then from 25 to 30 parts by volume of benzene at the boiling temperature. The obtained citronyellow 3-methylmercapto-phenothiazine has a MP of 138° to 140°C.
17.82 parts of 2-methylmercapto-phenothiazine, 3.4 parts of finely pulverized sodamide and 80 parts by volume of absolute xylene are heated to boiling for two hours at a bath temperature of 180°C under a reflux condenser and while stirring the reaction mixture. Without interrupting the heating, a solution of 13.2 parts of 2-(N-methyl-piperidyl-2')-1chloro-ethane in 40 parts by volume of absolute xylene is then added dropwise in the course of 1 1/2 hours. After further heating for 3 hours, the reaction mixture is cooled and, after the addition of 5 parts of ammonium chloride, is shaken three times with water, using 25 parts by volume each time. The xylene solution is extracted once with 35 parts by volume of 3 normal acetic acid and then three times, each time with 15 parts by volume of the said acid, after which the acetic acid extract is washed with 60 parts by volume of ether and is then made phenolphthalein-alkaline by means of 25 parts by volume of concentrated aqueous caustic soda solution.
The precipitated oily base is taken up in a total of 100 parts by volume of benzene. The benzene layer, dried over potassium carbonate, is filtered and then evaporated under reduced pressure. The residue from the evaporation is distilled in a high vacuum; after separating a preliminary distillate which passes over up to 228°C under a pressure of 0.92 mm Hg, the principal fraction, 2-methylmercapto-10-[2'-(N-methyl-piperidyl-2'')-ethyl- 1']phenothiazine, which distills over at 228° to 232°C under the lastmentioned pressure, is collected. The analytically pure base has a BP of 230°C/0.02 mm Hg.

Therapeutic Function

Tranquilizer

Pharmacokinetics

Thioridazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Thioridazine has not been shown effective in the management of behaviorial complications in patients with mental retardation.

Synthesis

Thioridazine, 10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methylthio)phenothiazine (6.1.9), is synthesized in an analogous manner by alkylating 2-methylthiophenothiazine with 2-(2-chloroethyl)-1-methylpiperidine [29,30].

Metabolism

Hepatic