Haloperidol 52-86-8

History

Haloperidol was discovered by Paul Janssen. It was developed in 1958 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. It was approved by the U. S. Food and Drug Administration on April 12, 1967.

Pharmacology

Haloperidol is a antipsychotic 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 (sold under the brand name Thorazine, among others) on a weight basis (50 mg chlorpromazine is equivalent to 1 mg 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 . 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. However, in some cases Haloperidol may worsen psychomotor agitation via its potent Dopamine receptor antagonism. Dopamine receptor antagonism, notably of the D2 receptor subtype, can cause akathisia, psychomotor agitation, anxiety, and restlessness, which may worsen the condition of some patients. The peripheral antidopaminergic effects of haloperidol account for its strong antiemetic activity. There, it acts at the chemoreceptor trigger zone (CTZ). 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 in both sexes.

Pharmacokinetics

Intramuscular injections

The drug is well and rapidly absorbed and has a high bioavailability. Plasma-levels reach their maximum within 20 minutes after injection. The decanoate injectable formulation is for intramuscular administration only and should never be used intravenously.

Intravenous injections

The bioavailability is 100% and the very rapid onset of action is seen within about ten minutes. The duration of action is 3 to 6 hours. If haloperidol is given as a slow IV infusion, the onset of action is slowed, but the duration prolonged compared to IM injection.

Therapeutic concentrations

Plasma levels of 4 to 25 micrograms per liter are required for therapeutic action. The determination of plasma levels can be used to calculate dose adjustments and to check compliance, particularly 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

A comprehensive review of haloperidol has found it to be an effective agent in treatment of symptoms associated with schizophrenia. Haloperidol is also used in the control of the symptoms of:

• Acute psychosis, such as drug psychosis (LSD, psilocybin, amphetamines, ketamine, and phencyclidine), psychosis associated with high fever or metabolic disease
• Acute manic phases until the concomitantly given first-line drugs such as lithium or valproate are effective
• Hyperactivity, aggression.
• Acute delirium
• Otherwise uncontrollable severe behavioral 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 tic disorders, 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 disorder
• Also used in the treatment of intractable hiccups

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 (e. g. 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 (e. g. 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 was considered indispensable for treating psychiatric emergency situations, although the newer atypical drugs have gained greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005. It is enrolled in the World Health Organization 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. ). With the exception of the highly effective clozapine, the effectiveness of haloperidol against positive symptoms has not been outperformed by newer antipsychotics. 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{{cquote

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status and by some measures improved functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this possibility must be weighed against the unwanted effects of therapy. The current study helps to inform a clinical management strategy for current practice, but the considerable risks of maintenance therapy highlight the urgency of further work to find, develop, and implement safer and more effective treatment approaches for neuropsychiatric symptoms in people with AD.