Pimozide
Encyclopedia
Pimozide is an antipsychotic
drug
of the diphenylbutylpiperidine
class. It was discovered at Janssen Pharmaceutica
in 1963. It has a high potency compared to chlorpromazine
(ratio 50-70:1). On a weight basis it is even more potent than haloperidol
. It also has special neurologic indications for Tourette syndrome
and resistant tics. The side effects include akathisia
, tardive dyskinesia
, and, more rarely, neuroleptic malignant syndrome
and prolongation of the QT interval
.
and chronic psychosis
(on-label indications in Europe only), Tourette syndrome and resistant tics (Europe, USA and Canada). In Germany the 1 mg tablet is indicated for the treatment of some forms of reactive depression.
and paranoid personality disorder
.
It has been used for delusions of parasitosis.
Use as a Listeria monocytogenes inhibitor has been described.
may be required to ascertain that the patient is developing adequate plasma levels before withdrawing the drug and attempting other antipsychotics.
Pimozide also inhibits moderately the dopamine transporter
(DAT), accounting for the stimulant properties of the drug. The inhibition of dopamine-reuptake may also explain the synergistic effects of pimozide in the treatment of ADHD when given together with a stimulant.
antagonists pimozide can cause various extrapyramidal side effects, including tardive dyskinesia
and Rabbit syndrome
. The frequency of extrapyramidal side effects is quite high. Neuroleptic malignant syndrome
may also occur.
In particular, pimozide is known for causing the unpleasant extrapyramidal side effect akathisia
(commonly referred to as "restless pacing") in a large percentage of those who take it. This "restlessness" can sometimes be treated with anticholinergic
drugs (mainly benztropine
), beta blockers or benzodiazepine
s, particularly clonazepam
(Klonopin). Unfortunately, in many cases this side effect can be so intense that even large doses of these drugs are unable to counter it, and often is so extreme that self-destructive behaviour, including attempting suicide
, may occur.
Pimozide has no significant sedative properties, but behaves in some patients as a mild stimulant. If the drug is given shortly before bedtime, insomnia
may result. Excitement, agitation, irritability, tension, anxiety, and nightmares have all been seen.
The drug can also cause depression in quite a number of patients, severe enough to result in suicide.
Pimozide has few but nonetheless existing anticholinerg side effects (e.g. dry mouth, obstipation, urinary hesitancy), rarely of clinical importance.
Pimozide may rarely cause seizures of the grand-mal-type. Patients with epilepsia should be counselled to maintain anticonvulsive therapy.
Particularly disturbing is a relatively high incidence of the long QT syndrome
, which may lead to ventricular tachycardia
, torsades de pointes
and death via ventricular fibrillation
.
There is also specific information of carcinogenity both in animals and humans. The carcinogenity in animals has been proven and the carcinogenity in man is strongly suspected (breast cancer and probably liver tumors).
Because of these serious side effects, Pimozide should only be used after the patient has received full information about the drug and agrees to treatment with it despite the risks (fully informed consent
).
Given to a non-psychotic patient, Pimozide can result in severe disabilities, both mental and physical. Loss of ability to lead a conversation is a common side effect. Due to that specific side effect, patients who have been wrongly given Pimozide cannot explain their need to stop taking the medication. Pimozide should be prescribed only after a complete medical examination and consensus between the patient and doctor.
There have been reported cases of irreversible nyctalopia
in healthy patients treated with Pimozide.
Recommended dose ranges are as follows:
Generally human overdoses show exaggerations of the pharmacologic effect of Pimozide. These are : ECG-abnormalities, severe extrapyramidal reactions, hypotension, and comatose state with respiratory depression.
Treatment is largely symptomatic. No specific antidote exists. Induction of emesis, gastric lavage and the repeated application of activated charcoal can all be helpful. Monitor and stabilize, if necessary, the vital functions. Hospitialization and/or admittance to intensive care treatment is in most cases necessary. Due to the long halflife of Pimozide, the symptoms of overdose may last for several days.
(See also: droperidol
)
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
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
of the diphenylbutylpiperidine
Diphenylbutylpiperidine
Diphenylbutylpiperidines are a class of typical antipsychotic drugs which were all synthesized, developed, and marketed by Janssen Pharmaceutica.They include:* Clopimozide * Fluspirilene * Pimozide...
class. It was discovered at Janssen Pharmaceutica
Janssen Pharmaceutica
Janssen Pharmaceutica is pharmaceutical company, established in Belgium in 1953 by Paul Janssen. Its headquarters are located in Beerse, in the Campine region of the province of Antwerp, Belgium. It was created not as a subsidiary of a chemical factory but solely with the aim of conducting...
in 1963. It has a high potency compared to chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
(ratio 50-70:1). On a weight basis it is even more potent than haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
. It also has special neurologic indications for Tourette syndrome
Tourette syndrome
Tourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...
and resistant tics. The side effects include 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...
, tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
, and, more rarely, 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...
and prolongation of 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...
.
Uses
Pimozide is used in its oral preparation in 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 chronic 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"...
(on-label indications in Europe only), Tourette syndrome and resistant tics (Europe, USA and Canada). In Germany the 1 mg tablet is indicated for the treatment of some forms of reactive depression.
Off-label use
Pimozide has been used in the treatment of delusional disorderDelusional disorder
Delusional disorder is an uncommon psychiatric condition in which patients present with circumscribed symptoms of non-bizarre delusions, but with the absence of prominent hallucinations and no thought disorder, mood disorder, or significant flattening of affect...
and paranoid personality disorder
Paranoid personality disorder
Paranoid personality disorder is a psychiatric diagnosis characterized by paranoia and a pervasive, long-standing suspiciousness and generalized mistrust of others....
.
It has been used for delusions of parasitosis.
Use as a Listeria monocytogenes inhibitor has been described.
Pharmacokinetics
Plasma levels of pimozide can vary widely between patients, and in insufficient response therapeutic drug monitoringTherapeutic drug monitoring
- Background :Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed...
may be required to ascertain that the patient is developing adequate plasma levels before withdrawing the drug and attempting other antipsychotics.
Pharmacodynamics
Pimozide blocks the following postsynaptic receptors according to Bezchlinyk-Butler and Jeffries:- Extremely strong: D2
- Strong: D3, 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...
, 5-HT2A5-HT2A receptorThe mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such... - Moderate: D1, D4, α2-adrenergicAlpha-2 adrenergic receptorThe alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
- Weak: mAChMuscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
, 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... - Extremely weak: 5-HT1A5-HT1A receptorThe 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
Pimozide also inhibits moderately the dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT), accounting for the stimulant properties of the drug. The inhibition of dopamine-reuptake may also explain the synergistic effects of pimozide in the treatment of ADHD when given together with a stimulant.
Contraindications and precautions
- Contraindicated in patients taking citalopram citalopramCitalopramCitalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa) and escitalopram escitalopramEscitalopramEscitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
(Lexapro) due to prolongation of the QTc interval, as per the FDA. - Patients with prominent agitation or anxiety
- Depressed patients
- Severe intoxication with alcohol, opiates, and psychoactive drugs (e.g. antidepressants, benzodiazepines)
- Preexisting Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
- Comedication with nefazodoneNefazodoneNefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, clarithromycinClarithromycinClarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
and vetoconazol (see below under interactions) - Caution: Anticonvulsive treatment in epileptic patients should not be interrupted. Pimozide may in principle lower the seizure-threshold.
- Caution: Patients under 18 yrs. of age. Side effects may be particularly frequent and severe. Treatment should be started with low initial dose and the dose increased very slowly.
Side effects
Pimozide can have severe, potentially fatal side effects. As with other dopamineDopamine
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...
antagonists pimozide can cause various extrapyramidal side effects, including tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
and 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...
. The frequency of extrapyramidal side effects is quite high. 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...
may also occur.
In particular, pimozide is known for causing the unpleasant extrapyramidal side effect 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...
(commonly referred to as "restless pacing") in a large percentage of those who take it. This "restlessness" can sometimes be treated with 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....
drugs (mainly benztropine
Benztropine
Benzatropine , also known as benztropine , is an anticholinergic marketed under the trade name Cogentin which is used in the treatment of Parkinson's disease, parkinsonism, akathisia, and dystonia.- Indications :...
), beta blockers or benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s, particularly 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). Unfortunately, in many cases this side effect can be so intense that even large doses of these drugs are unable to counter it, and often is so extreme that self-destructive behaviour, including attempting suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
, may occur.
Pimozide has no significant sedative properties, but behaves in some patients as a mild stimulant. If the drug is given shortly before bedtime, 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:...
may result. Excitement, agitation, irritability, tension, anxiety, and nightmares have all been seen.
The drug can also cause depression in quite a number of patients, severe enough to result in suicide.
Pimozide has few but nonetheless existing anticholinerg side effects (e.g. dry mouth, obstipation, urinary hesitancy), rarely of clinical importance.
Pimozide may rarely cause seizures of the grand-mal-type. Patients with epilepsia should be counselled to maintain anticonvulsive therapy.
Particularly disturbing is a relatively high incidence of the long QT syndrome
Long QT syndrome
The long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation...
, which may lead to ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
, 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...
and death via ventricular fibrillation
Ventricular fibrillation
Ventricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...
.
There is also specific information of carcinogenity both in animals and humans. The carcinogenity in animals has been proven and the carcinogenity in man is strongly suspected (breast cancer and probably liver tumors).
Because of these serious side effects, Pimozide should only be used after the patient has received full information about the drug and agrees to treatment with it despite the risks (fully informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...
).
Given to a non-psychotic patient, Pimozide can result in severe disabilities, both mental and physical. Loss of ability to lead a conversation is a common side effect. Due to that specific side effect, patients who have been wrongly given Pimozide cannot explain their need to stop taking the medication. Pimozide should be prescribed only after a complete medical examination and consensus between the patient and doctor.
There have been reported cases of irreversible nyctalopia
Nyctalopia
Nyctalopia is a condition making it difficult or impossible to see in relatively low light. It is a symptom of several eye diseases. Night blindness may exist from birth, or be caused by injury or malnutrition...
in healthy patients treated with Pimozide.
Interactions
- Central Depressants: Action of the other drug may be increased.
- Drugs competing for the same cytochrome subenzymes: Risk of mutual and uncontrollable increased action. NefazodoneNefazodoneNefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, ClarithromycinClarithromycinClarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, FluconazoleFluconazoleFluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
and Vetoconazol all lead to increased pimozide plasma levels and to a higher incidence of (potentially serious) side effects of pimozide. - Grapefruit juice: Elimination of Pimozide is inhibited. Avoid drinking grapefruit juice during treatment with Pimozide.
Dosage
Due to its long halflife pimozide is usually given once a day (preferably in the morning, because pimozide may have a rather stimulating effect).Recommended dose ranges are as follows:
- Acute psychotic disorders: usually 2 to 12 mg daily starting with low doses, then slowly increasing. More than 20 mg daily should be avoided, because the benefit-risk ratio is unclear
- Chronic psychotic disorders: for maintenance of acute results 6 mg daily is the usual dose
- Tics: 1 to 16 mg daily in slowly increasing doses
- Reactive Depression: 1 to 2 mg daily
- ADHD: not clearly established, start with very small doses (e.g. 0.5 to 1.0 mg) and increase slowly according to the clinical reaction and the side effects encountered.
Animal toxicity and human overdose
The precise lethal dose in humans is unknown. The oral LD50 is 228 mg/kg in mice, 5120 mg/kg in rats, 188 mg/kg in guinea pigs, and 40 mg/kg in dogs.Generally human overdoses show exaggerations of the pharmacologic effect of Pimozide. These are : ECG-abnormalities, severe extrapyramidal reactions, hypotension, and comatose state with respiratory depression.
Treatment is largely symptomatic. No specific antidote exists. Induction of emesis, gastric lavage and the repeated application of activated charcoal can all be helpful. Monitor and stabilize, if necessary, the vital functions. Hospitialization and/or admittance to intensive care treatment is in most cases necessary. Due to the long halflife of Pimozide, the symptoms of overdose may last for several days.
Chemistry
Pimozide is a diphenylbutylpiperidine derivative.- Janssen, P. A. J.; Soudijn,W.; VanWijngaarden, I.; Dreese A.; Arzneimittel-Forsch. 1968, 18, 282.
- P. Meisel, H.-J. Heidrich, H.-J. Hansch, E. Kretzschman, S. Henker, G. Laban, Ger. (Dem.) (1987).
- P.A.J. Janssen, (1965).
- P. Janssen, (1963).
(See also: droperidol
Droperidol
Droperidol is an antidopaminergic drug used as an antiemetic and antipsychotic...
)