Pimozide (sold as Orap®) is an antipsychotic drug. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weight basis it is even more potent than haloperidol. As it has severe side effects, it is considered a drug of last resort, typically prescribed only after the patient has failed to respond to other medications. It also has special neurologic indications for Gilles de la Tourette syndrome and resistant tics. The side effects include akathisia, tardive dyskinesia, neuroleptic malignant syndrome and long QT syndrome. It is also strongly suspected that pimozide is carcinogenic in humans. CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Atomic mass 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number fluorine, F, 9 Chemical series halogens Group, Period, Block 17, 2, p Appearance pale greenish-yellow gas Atomic mass 18. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless Atomic mass 14. ... General Name, Symbol, Number oxygen, O, 8 Chemical series Nonmetals Group, Period, Block 16, 2, p Appearance colorless Atomic mass 15. ... The molecular mass of a substance (less accurately called molecular weight and abbreviated as MW) is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... Excretion is the biological process by which an organism chemically separates waste products from its body. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother. ... The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... The term antipsychotic is applied to a group of drugs used to treat psychosis. ... A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. ... Chlorpromazine was the first antipsychotic drug, used during the 1950s and 1960s. ... Haloperidol (sold as Aloperidin®, Bioperidolo®, Brotopon®, Dozic®, Einalon S®, Eukystol®, Haldol®, Halosten®, Keselan®, Linton®, Peluces®, Serenace®, Serenase®, Sigaperidol®) is a conventional butyrophenone antipsychotic drug. ... Georges Gilles de la Tourette Tourette syndrome (also called Tourettes syndrome, Tourettes disorder, Gilles de la Tourette syndrome, GTS or TS) is an inherited neurological disorder with onset in childhood, characterized by the presence of multiple motor tics and at least one phonic tic, which characteristically wax and... A tic is a repeated, impulsive action, almost reflexive in nature, which the actor feels powerless to control or avoid. ... Akathisia (or acathisia) is an often extremely unpleasant subjective sensation of inner restlessness that manifests itself with an inability to sit still or remain motionless, hence the origin of its name: Greek a (without) + kithesia (to sit). ... Tardive dyskinesia is a serious neurological disorder caused by the long-term and/or high-dose use of dopamine antagonists, usually antipsychotics and among them especially the typical antipsychotics. ... Neuroleptic malignant syndrome (NMS) is a life-threatening, neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. ... The long QT syndrome (LQTS) is a heart disease in which there is an abnormally long delay between the electrical excitation (or depolarization) and relaxation (repolarization) of the ventricles of the heart. ...

Uses

Pimozide is used in its oral preparation in schizophrenia and chronic psychosis (on-label indications in Europe only), Gilles de la Tourette syndrome and resistant tics (Europe, USA and Canada). In Germany the 1mg tablet is indicated for the treatment of some forms of reactive depression. This article is about the mental state. ... Georges Gilles de la Tourette Tourette syndrome (also called Tourettes syndrome, Tourettes disorder, Gilles de la Tourette syndrome, GTS or TS) is an inherited neurological disorder with onset in childhood, characterized by the presence of multiple motor tics and at least one phonic tic, which characteristically wax and... A tic is a repeated, impulsive action, almost reflexive in nature, which the actor feels powerless to control or avoid. ...

Off-label use

ADHD (Attention Deficite Hyperactivity Disorder) in children and adolescents not controlled by monotherapy with a stimulant The image on the left illustrates areas of activity in the brain of a person without ADHD. The image on the right illustrates the areas of activity of the brain of someone with ADHD. There is some controversy over the research by Dr. Alan Zametkin that produced these images. ...

Chemistry

Pimozide is a diphenylbutylpiperidine derivative.

Pharmacology

Pharmacokinetics

Plasma levels of pimozide can vary widely between patients, and in insufficient response therapeutic drug monitoring may be required to ascertain that the patient is developing adequate plasma levels before withdrawing the drug and attempting other antipsychotics. Therapeutic drug monitoring is a branch of clinical chemistry that specialises in the measurement of medication levels in blood. ...

Pharmacodynamics

Pimozide blocks the folling postsynaptic receptors according to Bezchlinyk-Butler and Jeffries:

• Extremely strong: D2
• Strong: D3, ALPHA1, 5-HT2A
• Moderate to moderately strong: D1, D4, ALPHA2
• Weak: ACH, H1
• Extremely weak: 5-HT1A

Pimozide also inhibits moderately the dopamine-reuptake from the synaptic cleft, 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 ADHS when given together with a stimulant.

Contraindications and precautions

• Patients with prominent agitation or anxiety
• Depressed patients
• Severe intoxication with alcohol, opiates, and psychoactive drugs (e.g. antidepressants, benzodiazepines)
• Preexisting Parkinson's disease
• Preexisting breast carcinoma
• Comedication with nefazodone, clarithromycin 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 particular 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 dopamine antagonists pimozide can cause various extrapyramidal side-effects, including tardive dyskinesia. The frequency of extrapyramidal side-effects is quite high. Neuroleptic malignant syndrome may also occur. Dopamine is a chemical naturally produced in the body. ... 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. ... Tardive dyskinesia is a serious neurological disorder caused by the long-term and/or high-dose use of dopamine antagonists, usually antipsychotics and among them especially the typical antipsychotics. ... Neuroleptic malignant syndrome (NMS) is a life-threatening, neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs. ...

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 benzodiazepines, 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. Akathisia (or acathisia) is an often extremely unpleasant subjective sensation of inner restlessness that manifests itself with an inability to sit still or remain motionless, hence the origin of its name: Greek a (without) + kithesia (to sit). ... An anticholinergic agent is a member of a class of pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system. ... Benztropine (Cogentin) is an anticholinergic drug used to treat muscle-rigidity, restlessness, and stiffness. ... Beta blockers or beta-adrenergic blocking agents are a class of drugs used to treat a variety of cardiovascular conditions and some other diseases. ... The benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsant, amnestic and muscle relaxant properties. ... Clonazepam (marketed by Roche under the trade-name Klonopin® in the United States and Rivotril® in Canada and Europe) is an anticonvulsant sedative-hypnotic anxiolytic (anti-anxiety drug), and a member of the benzodiazepine class of drugs. ... It has been suggested that Suicide and culture be merged into this article or section. ...

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. It has been suggested that Primary insomnia be merged into this article or section. ...

The drug can also cause depression in quite a number of patients, severe enough to result in suizide.

Pimozide has few but nonetheless existing anticholinerg side-effects (e.g. dry mouth, obstipation, urinay 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. The long QT syndrome (LQTS) is a heart disease in which there is an abnormally long delay between the electrical excitation (or depolarization) and relaxation (repolarization) of the ventricles of the heart. ... Tachycardia is an abnormally rapid beating of the heart, defined as a resting heart rate of over 100 beats per minute. ... Torsades de pointes is a medical condition, the name of which means in French twisting of the points. It is a potentially deadly form of ventricular tachycardia. ... Ventricular fibrillation (V-fib or VF) is a cardiac condition which consists of a lack of coordination of the contraction of the muscle tissue of the large chambers of the heart that eventually leads to the heart stopping altogether. ...

There is also specific information of carcinogenity both in animals und 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 is a legal condition whereby a person can be said to have given consent based upon an appreciation and understanding of the facts and implications of any actions. ...

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. Nefazodone, Clarithromycin and Vetoconazol all lead to increased pimozide plasma levels and to a higher incidence of (potenially serious) side-effects of pimozide.
• Grapefruit juice: Elimination of Pimozide is inhibited. Avoid drinking grapefruit juice during treatment with Pimozide.

// Introduction Serzone (nefazodone) Serzone ( Nefazodone HCl ) is an antidepressant drug formerly marketed by Bristol-Myers Squibb. ... Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia (especially atypical pneumonias associated with Chlamydia pneumoniae or TWAR), skin and skin structure infections, and, in HIV and AIDS patients to prevent, and to treat, disseminated Mycobacterium avium complex or...

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 12mg daily starting with low doses, than slowly increasing. More than 20mg daily should be avoided, because the benefit-risk ratio is unclear
• Chronic psychotic disorders: for maintaince of acute results 6mg daily is the usual dose
• Tics: 1 to 16 mg daily in slowly increasing doses
• Reactive Depression: 1 to 2mg daily
• ADHS: not clearly established, start with very small doses (e.g. 0.5 to 1.0mg) 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.

References

• Van Vloten WA. Pimozide: Use in Dermatology. Dermatol Online J 2003;9(2):3 (fulltext)
• AFHS Database

External links

• http://www.mentalhealth.com/drug/p30-o01.html (A medical white paper on its use)