Chlorprothixene
Encyclopedia
Chlorprothixene is a typical antipsychotic
drug
of the thioxanthene
class and was the first of the series to be synthesized. It was introduced in 1959 by Lundbeck
.
at the following receptor
s:
) and of acute mania
occurring as part of bipolar disorder
s.
Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation due to use of selective serotonin reuptake inhibitor
s for depression
and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.
An intrinsic antidepressant
effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine (intrinsic) analgesic
effects. However, chlorprothixene can be used as comedication in severe chronic pain. Also, like most antipsychotics, chlorprothixene has antiemetic
effects.
side effects. The types of side effects encountered (dry mouth, massive hypotension
and tachycardia
, hyperhidrosis
, substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.
Chlorprothixene is structurally related to chlorpromazine
, with which it shares in principal all side effects. Allergic side effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side effects of chlorprothixene (precipitation of narrow angle glaucoma
, severe obstipation, difficulties in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.
Early and late extrapyramidal side effects
may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).
. In order to avoid lithium intoxication, lithium plasma levels should be monitored closely.
If chlorprothixene is given concomitantly with opioid
s, the opioid dose should be reduced (by approx. 50%), because chlorprothixene amplifies the therapeutic actions and side effects of opioids considerably.
Avoid the concomitant use of chlorprothixene and tramadol
(Ultram). Seizures may be encountered with this combination.
Consider additive sedative effects and confusional states to emerge, if chlorprothixene is given with benzodiazepine
s or barbiturate
s. Choose particular low doses of these drugs.
Exert particular caution in combining chlorprothixene with other anticholinergic drugs (tricyclic antidepressant
s and antiparkinsonian agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus
and glaucoma .
An alternative way of making 2-chlorthioxantone is by making 2-(4-chlorophenylthio)benzoic acid by reacting 2-iodobenzoic acid with 4-chlorothiophenol.
The resulting 2-chlorothioxantone is reacted as a carbonyl
component with either 3-dimethylaminopropylmagnesiumbromide (see Engelhardt above), or with allylmagnesiumbromide, giving the corresponding tertiary alcohol.
Dehydration of the first is accomplished by acylation
of the tertiary hydroxyl group using
acetyl chloride
and the subsequent pyrolysis
of the formed acetate, which leads to the desired chlorprothixene.
In the second case, dehydration of the tertiary alcohol is accomplished by chlorination of the tertiary alcohol group by thionyl chloride
, forming the diene 2-chloro-9-(3-propen-1-
iliden)thioxanthene, the addition to which of dimethylamine
at high temperature forms the desired chlorprothixene.
Typical antipsychotic
Typical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
of the thioxanthene
Thioxanthene
Thioxanthene is a chemical compound in which the oxygen atom in xanthene is replaced with a sulfur atom. It is also related to phenothiazine. Several of its derivatives are used as typical antipsychotics in the treatment of schizophrenia and other psychoses....
class and was the first of the series to be synthesized. It was introduced in 1959 by Lundbeck
Lundbeck
H. Lundbeck A/S is a Danish international pharmaceutical company engaged in the research and development, production, marketing, and sale of drugs for the treatment of disorders in the central nervous system , including depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease,...
.
Pharmacology
Chlorprothixene exerts strong antagonismReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
at the following receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s:
- 5-HT25-HT2 receptorThe 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT2 subfamily consists of three G protein-coupled receptors which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C...
: antipsychotic effects, anxiolysis, weight gain - D1, D2, D3: antipsychotic effects, sedation, extrapyramidal side effects, prolactin increase, depression, apathy/anhedonia, weight gain
- H1H1 receptorThe H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...
: sedation, weight gain - mAChMuscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
: anticholinergic effects, inhibition of extrapyramidal side effects - α1-adrenergicAlpha-1 adrenergic receptorThe alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
: hypotension, tachycardia
Indications
Chlorprothixene's principal indications are the treatment of psychotic disorders (e.g. schizophreniaSchizophrenia
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 of acute mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
occurring as part of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
s.
Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation due to use of selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s for depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.
An intrinsic antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine (intrinsic) analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
effects. However, chlorprothixene can be used as comedication in severe chronic pain. Also, like most antipsychotics, chlorprothixene has antiemetic
Antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
effects.
Side effects
Chlorprothixene has a strong sedative activity with a high incidence of anticholinergicAnticholinergic
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....
side effects. The types of side effects encountered (dry mouth, massive hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
and tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, hyperhidrosis
Hyperhidrosis
Hyperhidrosis is the condition characterized by abnormally increased perspiration, in excess of that required for regulation of body temperature.-Classification:Hyperhidrosis can either be generalized or localized to specific parts of the body...
, substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.
Chlorprothixene is structurally related to chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
, with which it shares in principal all side effects. Allergic side effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side effects of chlorprothixene (precipitation of narrow angle 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...
, severe obstipation, difficulties in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.
Early and late extrapyramidal side effects
Extrapyramidal system
In human anatomy, the extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. The system is called "extrapyramidal" to distinguish it from the tracts of the motor cortex that reach their targets by traveling through...
may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).
Dosage
The initial doses of chlorprothixene should always be as low as possible (e.g. 30 mg at bedtime, 15 mg morning dose) and be increased gradually. Patients receiving 90 mg daily (and more) of the drug should be hospitalized, particularly during the initial phase of treatment. The theoretical maximum is 800 mg daily which can usually not be given due to side effects as stated above. Elderly and pediatric patients should be treated with particular low initial doses. Dose increments should be done slowly. If chlorprothixene is to be withdrawn, it should not be stopped abruptly, but the dose should be decreased steadily.Interactions
Chlorprothixene may increase the plasma-level of concomitantly given lithiumLithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
. In order to avoid lithium intoxication, lithium plasma levels should be monitored closely.
If chlorprothixene is given concomitantly with opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s, the opioid dose should be reduced (by approx. 50%), because chlorprothixene amplifies the therapeutic actions and side effects of opioids considerably.
Avoid the concomitant use of chlorprothixene and tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
(Ultram). Seizures may be encountered with this combination.
Consider additive sedative effects and confusional states to emerge, if chlorprothixene is given with benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s or barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s. Choose particular low doses of these drugs.
Exert particular caution in combining chlorprothixene with other anticholinergic drugs (tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s and antiparkinsonian agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus
Ileus
Ileus is a disruption of the normal propulsive ability of the gastrointestinal tract.Ileus is commonly defined simply as bowel obstruction. However, authoritative sources define it as decreased motor activity of the GI tract due to non-mechanical causes...
and glaucoma .
Chemistry
Chlorprothixene (2-chloro-9[(1-dimethylamino)-3-propyliden]thioxanthene) is made starting from 2-chlorothixantone. 2-Chlorothixantone, in turn, is prepared from 2-mercaptobenzoic acid, the reaction of which with 1-bromo-4-chlorobenzene forms 2-(4-chlorophenylthio)benzoic acid, which upon reaction with phosphorus pentachloride transforms into acid chloride, and further undergoes intramolecular cyclization with the use of aluminum chloride to give 2-chlorthioxantone.- H. Spiegelberg, K. Doeben, (1957).
An alternative way of making 2-chlorthioxantone is by making 2-(4-chlorophenylthio)benzoic acid by reacting 2-iodobenzoic acid with 4-chlorothiophenol.
- E.L. Engelhardt, J.M. Sprague, (1960).
The resulting 2-chlorothioxantone is reacted as a carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
component with either 3-dimethylaminopropylmagnesiumbromide (see Engelhardt above), or with allylmagnesiumbromide, giving the corresponding tertiary alcohol.
- V.P. Petersen, H.O. Trokil, (1963).
- Kefalas Aktieselskab, (1959).
- Kefalas Aktieselskabet, (1959).
Dehydration of the first is accomplished by acylation
Acylation
In chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....
of the tertiary hydroxyl group using
acetyl chloride
Acetyl chloride
Acetyl chloride, CH3COCl, also known as ethanoyl chloride or acyl chloride, is an acid chloride derived from acetic acid. It belongs to the class of organic compounds called acyl halides. It is a colorless liquid. Acetyl chloride does not exist in nature, because contact with water would hydrolyze...
and the subsequent pyrolysis
Pyrolysis
Pyrolysis is a thermochemical decomposition of organic material at elevated temperatures without the participation of oxygen. It involves the simultaneous change of chemical composition and physical phase, and is irreversible...
of the formed acetate, which leads to the desired chlorprothixene.
In the second case, dehydration of the tertiary alcohol is accomplished by chlorination of the tertiary alcohol group by thionyl chloride
Thionyl chloride
Thionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...
, forming the diene 2-chloro-9-(3-propen-1-
iliden)thioxanthene, the addition to which of dimethylamine
Dimethylamine
Dimethylamine is an organic compound with the formula 2NH. This secondary amine is a colorless, flammable liquified gas with an ammonia-like odor. Dimethylamine is generally encountered as a solution in water at concentrations up to around 40%...
at high temperature forms the desired chlorprothixene.