Thioridazine
Encyclopedia
Thioridazine is a piperidine
typical (but see next paragraph, below) antipsychotic
drug
belonging to the phenothiazine
drug group and was previously widely used in the treatment of schizophrenia
and psychosis
. Due to concerns about cardiotoxicity
and retinopathy
at high doses this drug is not commonly prescribed, reserved for patients who have failed to respond to, or have contraindications for, more widely used antipsychotics. A serious side effect is the potentially fatal neuroleptic malignant syndrome
. It exerts its actions through a central adrenergic-blocking, a dopamine
-blocking, and minor anticholinergic
activity.
In older references, it is sometimes described as atypical
, but more recently it is usually described as typical, with the term "atypical" usually reserved for agents showing D4 selectivity or serotonin antagonism
.
and anxiety
linked to alcohol withdrawal
and dysphoria
of epileptic
patients. It was even indicated in Europe for the treatment of psychosis in children and adolescents as Melleretten (10 mg to 60 mg daily).
It was also given off-label for the treatment of insomnia
and for alleviation of opiate
withdrawal.
Thioridazine is known to kill multidrug-resistant Mycobacterium tuberculosis
and MRSA at clinical concentrations.
compound with two enantiomer
s, both of which are metabolized, according to Eap et al., by CYP2D6
into (S)- and (R)-thioridazine 2-sulfoxide, better known as mesoridazine
, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine
. Thioridazine is an inhibitor of CYP1A2
and CYP3A2.
The most commonly complained about side effect is akathisia
which is the main reason for low patient compliance
Tardive dyskinesia
characterized by involuntary movements of the lips, mouth, and tongue can be long lasting or irreversible, tremor of the mouth and lips without tongue involvement constitutes Rabbit syndrome
. Neuroleptic malignant syndrome
is potentially fatal.
Central nervous system side effects occur. These are mainly drowsiness, dizziness, fatigue, and vertigo. Early and late extrapyramidal
side effects are seen only infrequently (less than 1% altogether). There is no clear dose-effect relationship, as with higher doses anticholinergic effects of thioridazine become more prominent.
Thioridazine causes also an unusual high incidence of impotence and anorgasmia
due to a strong alpha-blocking
activity. Painful ejaculation or no ejaculation at all is also sometimes seen.
Autonomous side effects (dry mouth, urination
difficulty, obstipation, induction of glaucoma
, postural hypotension, and sinus tachycardia
) occur obviously less often than with most other mildly potent antipsychotics.
Thioridazine is no longer recommended as first-line treatment due its side effect of prolonging the QT interval
on the EKG. Thioridazine-5-sulfoxide is associated with ventricular tachycardia
and torsades de pointes
.
It can also cause sialadenitis
, which is more common in older individuals.
Also, the serious and sometimes fatal blood damage agranulocytosis
is seen more frequently (approximately 1/500 to 1/1,000 patients) with thioridazine than with other typical phenothiazines (1/2,000 to 1/10,000 patients).
Thioridazine if given over a prolonged time and in high doses can be stored in the ocula and the retina
of the eyes and in the heart muscle. Clinical consequences (disturbed or blurred vision) are rare although chromatopsia has been reported.
, insomnia, anxiety). Another neuroleptic may be introduced to the therapeutic regime step by step (overlapping), if needed. If sudden withdrawal of thioridazine is necessary, withdrawal symptoms can also be alleviated with the benzodiazepine
s lorazepam
(Ativan) 1 mg—2 mg, alprazolam
(Xanax) 0,5 mg prn or clonazepam
(Klonopin, Rivotril) 0,5 mg to 2 mg prn (as needed)or Diazepam
(Valium)5 – 10 mg prn for up to 2 weeks (not longer to avoid addiction).
/Sandoz/Wander of the brands of thioridazine, Mellaril in the USA and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.
The usual dosage was 50 mg per day for mild cases to 600–800 mg per day for severely disturbed patients.
Thioridazine may still be available from other manufacturers as a generic drug with the precaution that it is used only in psychotic patients refractory to other forms of drug treatment. ECG-monitoring and frequent white blood cell
counts are required before initiating therapy and in close intervals afterwards.
A multi-year UK study by the Alzheimer's Research Trust suggested that this and other neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse. The study concluded that
Piperidine
Piperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
typical (but see next paragraph, below) antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
drug
Psychoactive drug
A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...
belonging to the phenothiazine
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
drug group and was previously widely used in the treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. Due to concerns about cardiotoxicity
Cardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...
and retinopathy
Retinopathy
Retinopathy is a general term that refers to some form of non-inflammatory damage to the retina of the eye. Frequently, retinopathy is an ocular manifestation of systemic disease.-Pathophysiology:Causes of retinopathy are varied:...
at high doses this drug is not commonly prescribed, reserved for patients who have failed to respond to, or have contraindications for, more widely used antipsychotics. A serious side effect is the potentially fatal neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
. It exerts its actions through a central adrenergic-blocking, a dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
-blocking, and minor anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
activity.
In older references, it is sometimes described as atypical
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
, but more recently it is usually described as typical, with the term "atypical" usually reserved for agents showing D4 selectivity or serotonin antagonism
Serotonin antagonist
A serotonin antagonist is a drug used to inhibit the action at serotonin receptors.Many of the most important medications of this class selectively act at the 5-HT3 receptor, and thus are known as 5-HT3 antagonists...
.
Indications
Previous additional indications were agitated depression, tensionStress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
and anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
linked to alcohol withdrawal
Alcohol withdrawal syndrome
-Protracted withdrawal:A protracted alcohol withdrawal syndrome occurs in many alcoholics where withdrawal symptoms continue beyond the acute withdrawal stage but usually at a subacute level of intensity and gradually decreasing with severity over time. This syndrome is also sometimes referred to...
and dysphoria
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
of epileptic
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
patients. It was even indicated in Europe for the treatment of psychosis in children and adolescents as Melleretten (10 mg to 60 mg daily).
It was also given off-label for the treatment of insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
and for alleviation of opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
withdrawal.
Thioridazine is known to kill multidrug-resistant Mycobacterium tuberculosis
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a pathogenic bacterial species in the genus Mycobacterium and the causative agent of most cases of tuberculosis . First discovered in 1882 by Robert Koch, M...
and MRSA at clinical concentrations.
Metabolism
Thioridazine is a racemicRacemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
compound with two enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s, both of which are metabolized, according to Eap et al., by CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
into (S)- and (R)-thioridazine 2-sulfoxide, better known as mesoridazine
Mesoridazine
Mesoridazine is a piperidine neuroleptic drug belonging to the class of drugs called phenothiazines, used in the treatment of schizophrenia. It is a metabolite of thioridazine...
, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine
Sulforidazine
Sulforidazine a typical antipsychotic and a metabolite of thioridazine; it and mesoridazine are more potent than the parent compound, whose pharmacological effects are believed by some to be largely due to its metabolism into sulforidazine and mesoridazine.- References :...
. Thioridazine is an inhibitor of CYP1A2
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
and CYP3A2.
Side effects
For further information see: PhenothiazinePhenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
The most commonly complained about side effect is akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
which is the main reason for low patient compliance
Tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
characterized by involuntary movements of the lips, mouth, and tongue can be long lasting or irreversible, tremor of the mouth and lips without tongue involvement constitutes Rabbit syndrome
Rabbit syndrome
Rabbit syndrome is a rare form of extrapyramidal side effect of antipsychotic drugs in which perioral tremors occur at a rate of 5 Hz. Rabbit syndrome is characterized by involuntary, fine, rhythmic motions of the mouth along a vertical plane, without involvement of the tongue...
. Neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
is potentially fatal.
Central nervous system side effects occur. These are mainly drowsiness, dizziness, fatigue, and vertigo. Early and late extrapyramidal
Extrapyramidal
Extrapyramidal can refer to:* Extrapyramidal system* Extrapyramidal symptoms...
side effects are seen only infrequently (less than 1% altogether). There is no clear dose-effect relationship, as with higher doses anticholinergic effects of thioridazine become more prominent.
Thioridazine causes also an unusual high incidence of impotence and anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
due to a strong alpha-blocking
Alpha blocker
Alpha-1 blockers constitute a variety of drugs which block α1-adrenergic receptors in arteries and smooth muscles.-Pharmacology:...
activity. Painful ejaculation or no ejaculation at all is also sometimes seen.
Autonomous side effects (dry mouth, urination
Urination
Urination, also known as micturition, voiding, peeing, weeing, pissing, and more rarely, emiction, is the ejection of urine from the urinary bladder through the urethra to the outside of the body. In healthy humans the process of urination is under voluntary control...
difficulty, obstipation, induction of glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
, postural hypotension, and sinus tachycardia
Sinus tachycardia
Sinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
) occur obviously less often than with most other mildly potent antipsychotics.
Thioridazine is no longer recommended as first-line treatment due its side effect of prolonging the QT interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
on the EKG. Thioridazine-5-sulfoxide is associated with ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
and torsades de pointes
Torsades de pointes
Torsades de pointes, or simply torsades, is a French term that literally means "twisting of the points". It was first described by Dessertenne in 1966 and refers to a specific, rare variety of ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram .- Presentation...
.
It can also cause sialadenitis
Sialadenitis
Sialadenitis is inflammation of a salivary gland. It may be subdivided temporally into acute, chronic and recurrent forms.Alternate spelling:Sialoadenitis-Acute Form:Predisposing factors:* decreased flow * poor oral hygiene...
, which is more common in older individuals.
Also, the serious and sometimes fatal blood damage agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
is seen more frequently (approximately 1/500 to 1/1,000 patients) with thioridazine than with other typical phenothiazines (1/2,000 to 1/10,000 patients).
Thioridazine if given over a prolonged time and in high doses can be stored in the ocula and the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
of the eyes and in the heart muscle. Clinical consequences (disturbed or blurred vision) are rare although chromatopsia has been reported.
Discontinuation
It is advisable to withdraw thioridazine gradually and not abruptly to avoid unpleasant withdrawal symptoms (agitationPsychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, insomnia, anxiety). Another neuroleptic may be introduced to the therapeutic regime step by step (overlapping), if needed. If sudden withdrawal of thioridazine is necessary, withdrawal symptoms can also be alleviated with the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s lorazepam
Lorazepam
Lorazepam is a high-potency short-to-intermediate-acting 3-hydroxy benzodiazepine drug that has all five intrinsic benzodiazepine effects: anxiolytic, amnesic, sedative/hypnotic, anticonvulsant, antiemetic and muscle relaxant...
(Ativan) 1 mg—2 mg, alprazolam
Alprazolam
Alprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
(Xanax) 0,5 mg prn or clonazepam
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
(Klonopin, Rivotril) 0,5 mg to 2 mg prn (as needed)or Diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
(Valium)5 – 10 mg prn for up to 2 weeks (not longer to avoid addiction).
History
The manufacturer NovartisNovartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
/Sandoz/Wander of the brands of thioridazine, Mellaril in the USA and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.
The usual dosage was 50 mg per day for mild cases to 600–800 mg per day for severely disturbed patients.
Thioridazine may still be available from other manufacturers as a generic drug with the precaution that it is used only in psychotic patients refractory to other forms of drug treatment. ECG-monitoring and frequent white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
counts are required before initiating therapy and in close intervals afterwards.
A multi-year UK study by the Alzheimer's Research Trust suggested that this and other neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse. The study concluded that
Chemistry
Thioridazine, (10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methylthio)phenothiazine) is synthesized by alkylating 2-methylthiophenothiazine with 2-(2-chloroethyl)-1-methylpiperidine.- J. Renz, J.P. Bourquin, G. Gamboni, G. Schwarb, (1966).
External links
- PubChem Substance Summary: Thioridazine National Center for Biotechnology Information,.
- Antipsychotic Mellaril Removed from Market Schizophrenia Daily News Blog.
- U.S. National Library of Medicine: Drug Information Portal - Thioridazine