Product Description

Haloperidol (sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol, Halosten, Keselan, Linton, Peluces, Serenace, Serenase, Sigaperidol) is a conventional butyrophenone antipsychotic drug. It was developed in 1957 by the Belgian company Janssen Pharmaceutica and submitted to first clinical trials in Belgium in the same year. After being rejected by U.S. company Searle due to side effects, it was later marketed in the U.S. by McNeil Laboratories.

Chemistry

Haloperidol is an odourless white to yellow crystalline powder. Its chemical name is 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone and its empirical formula is C21H23ClFNO2

Pharmacology

Haloperidol is a neuroleptic and a butyrophenone. Due to its strong central antidopaminergic action, it is classified as a highly potent neuroleptic. It is approximately 50 times more potent than chlorpromazine on a weight basis (50mg chlorpromazine are equivalent to 1mg haloperidol). Haloperidol possesses a strong activity against delusions and hallucinations, most likely due to an effective dopaminergic receptor blockage in the mesocortex and the limbic system of the brain. It blocks the dopaminergic action in the nigrostriatal pathways, which is the probable reason for the high frequency of extrapyramidal-motoric side-effects (dystonias, akathisia, pseudoparkinsonism). It has minor antihistaminic and anticholinergic properties, therefore cardiovascular and anticholinergic side-effects such as hypotension, dry mouth, constipation, etc., are seen quite infrequently, compared with less potent neuroleptics such as chlorpromazine. Haloperidol also has sedative properties and displays a strong action against psychomotor agitation, due to a specific action in the limbic system. It therefore is an effective treatment for mania and states of agitation. Additionally, it can be given as an adjuvant in the therapy of severe chronic pain.

The peripheral antidopaminergic effects of haloperidol account for its strong antiemetic activity. There, it acts at the CTZ (Chemical Trigger Zone). Haloperidol is useful to treat severe forms of nausea/emesis such as those resulting from chemotherapy. The peripheral effects lead also to a relaxation of the gastric sphincter muscle and an increased release of the hormone prolactin, with the possible emergence of breast enlargement and secretion of milk (lactation) in both sexes.

Oral dosing

Haloperidol is well absorbed after oral dosing. There is a first pass metabolism leading to a reduced oral bioavailability of the drug (60 to 70%). Peak plasma-levels are observed after 3 to 6 hours.

Therapeutic concentrations

Plasma levels of 4 micrograms per liter to 20 (up to 25) micrograms per liter are required for therapeutic action. The determination of plasma levels can be used to decide about dose adjustments and to check compliance, particular in long-term patients. Plasma levels in excess of the therapeutic range may lead to a higher incidence of side-effects or even pose the risk of haloperidol intoxication.

Uses

Haloperidol is used in the control of the symptoms of:
- Acute psychosis, such as drug psychosis (LSD, amphetamines, PCP), psychosis associated with high fever or metabolic disease
- Acute and chronic schizophrenia
- Acute manic phases until the concomitantly given first-line drugs such as lithium or valproate are effective
- Hyperactivity, aggression
- Acute delirium
- Otherwise uncontrollable severe behavioural disorders in children and adolescents
- Agitation and confusion associated with cerebral sclerosis
- Adjunctive treatment of alcohol and opioid withdrawal
- Treatment of neurological disorders such as tics, Tourette syndrome, and chorea
- Treatment of severe nausea/emesis (postoperative, side-effects of radiation and cancer chemotherapy)
- Adjunctive treatment of severe chronic pain, always together with analgesics
- Therapeutic trial in personality disorders such as borderline personality disorders

Some weeks or even months of treatment may be needed before a remission of schizophrenia is evident.

In some clinics the use of atypical neuroleptics (eg. clozapine, risperidone, olanzapine, ziprasidone) is generally preferred over haloperidol, because these drugs have an appreciably lower incidence of extrapyramidal side-effects. Each of these drugs, however, has its own spectrum of potentially serious side-effects (eg. agranulocytosis with clozapine, weight gain with increased risk of diabetes and of stroke). Atypical neuroleptics are also much more expensive and have recently been the subject of increasing controversy regarding their efficacy in comparison to older products and side effects.

Haloperidol is considered indispensable for treating psychiatric emergency situations. It is enrolled in the World Health organisation "List of Essential Medicines".

As is common with'typical neuroleptics, haloperidol is by far more active against "positive" psychotic symptoms (delusions, hallucinations etc.) than against "negative" symptoms (social withdrawal, autism etc.). The effectiveness of haloperidol against positive symptoms has not been outperformed by newer antipsychotics.

Contraindications
- Absolute
- Preexisting coma
- Severe intoxication with alcohol or other central depressant drugs
- Known allergy against haloperidol or other butyrophenones or other drug ingredients

Special caution needed
- Preexisting Parkinson's disease
- Patients at special risk for the development of QT-Time-Prolongation (hypokalema, concomittant use of other drugs causing the QT-Syndrome)
- Compromised liver-function (as haloperidol is metabolized and eliminated mainly by the liver, dose reductions and/or spaced intervalls may be needed)
- Haloperidol may decrease the seizure-threshold. Treat patients with epilepsy and those with risk factors for the development of seizures (alcohol withdrawal, encephalopathy) with caution. Maintain existing anticonvulsive therapy.
- Patients with hyperthyreosis; the action of haloperidol is intensified and side-effcts are more likely. Initiate an effective therapy of hyperthyreosis.
- IV injections: inject slowly to avoid hypotension or orthostatic collapse. Avoid IV injections in cardiovascular unstable patients (preexisting hypotension, shock, concomitant antihypertensive therapy, heart insufficience). Prefer in these cases moderate oral or IM doses.

Side-effects

The drug is noted for its strong early and late extrapyramidal side-effects. The risk of tardive dyskinesia is around 4% per year in younger patients, higher than with most other antipsychotic drugs. In patients over the age of 45, the percentage of those afflicted can be even higher. Other predispositive factors may be female gender, prexisting affective disorder and cerebral dysfunction. See chlorpromazine for further details.

Other side effects include dry mouth, lethargy, muscle-stiffness, muscle-cramping, restlessness, tremors, and weight-gain; side effects like these are more likely to occur when the drug is given in high doses and/or during long-term treatment. Depression, severe enough to result in suicide, is quite often seen during long-term treatment. Care should be taken to detect and treat depression early in course. Sometimes the change from haloperidol to a mildly potent neuroleptic (eg. chlorprothixene or chlorpromazine), together with appropriate antidepressant therapy, does help. Sedative and anticholinergic side-effects occur more frequently in the elderly.

Neuroleptic malignant syndrome (NMS) is a significant possible side effect. Haloperidol and fluphenazine are the two drugs which cause NMS most often. Allergic and toxic side-effects are uncommon. Skin rash and photosensitivity both occur in less than 1% of patients.

Children and adolescents are particularly sensitive to the early and late extrapyramidal side-effects of haloperidol. It is recommended to treat paediatric patients only if clearly needed and if the psychiatric or neurologic disorder is substantial.

QT prolongation with sudden death is rarely seen. Likewise, the development of thromboembolic complications are also rare.

Haloperidol has a negative impact on vigilance and decreases the ability of the patient to drive or operate a machine, particularly initially.