Haloperidol

<!-- Definition and uses -->

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. It may be used by mouth or injection into a muscle or a vein. When taken during pregnancy it may result in problems in the infant. It should not be used by people with Parkinson's disease. prepared as part of a structure-activity relationship investigation into analogs of pethidine (meperidine). It is on the World Health Organization's List of Essential Medicines. It is the most commonly used typical antipsychotic. In 2020, it was the 303rd most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Haloperidol is used in the control of the symptoms of:

• Acute psychosis, such as drug-induced psychosis caused by ketamine, and phencyclidine, and psychosis associated with high fever or metabolic disease. Some evidence has found haloperidol to worsen psychosis due to psilocybin.
• Adjunctive treatment of alcohol and opioid withdrawal
• Agitation and confusion associated with cerebral sclerosis
• Alcohol-induced psychosis
• Hallucinations in alcohol withdrawal
• As chemical restraint in acute care psychiatry, mainly for violent and self-harming patients (controversial use but very commonly found in movies). However, the newer atypical drugs have gained a greater role in a number of situations, as outlined in a series of consensus reviews published between 2001 and 2005.

In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13–16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone. A 2013 systematic review compared haloperidol to placebo in schizophrenia:

{| class="wikitable"

! Summary

|-

|Haloperidol often causes troublesome adverse effects. If there is no other antipsychotic drug, using haloperidol to offset the consequences of untreated schizophrenia is justified. Where a choice of drug is available, however, an alternative antipsychotic with less likelihood of adverse effects such as parkinsonism, akathisia and acute dystonias may be more desirable.

Pregnancy and lactation

Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Reports in pregnant women revealed possible damage to the fetus, although most of the women were exposed to multiple drugs during pregnancy. In addition, reports indicate neonates exposed to antipsychotic drugs are at risk for extrapyramidal and/or withdrawal symptoms following delivery, such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential fetal risk.

Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.

Other considerations

class=skin-invert-image|thumb|right|[[Skeletal formula of haloperidol decanoate. The decanoate group is highlighted in .]]

During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually. In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects. Patients responded with doses under even 2&nbsp;mg in first-episode psychosis. For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.

• Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.

The decanoate ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose is given by intramuscular injection once every two to four weeks. The IUPAC name of haloperidol decanoate is [4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl] decanoate.

Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.

Adverse effects

Sources for the following lists of adverse effects:

As haloperidol is a high-potency typical antipsychotic, it tends to produce significant extrapyramidal side effects. According to a 2013 meta-analysis of the comparative efficacy and tolerability of 15 antipsychotic drugs it was the most prone of the 15 for causing extrapyramidal side effects. Haloperidol may be neurotoxic.

Prolonged use of the drug can lead to mental dependence.

Common (>1% incidence)

• Extrapyramidal side effects including:
• Akathisia (motor restlessness)
• Dystonia (continuous spasms and muscle contractions)
• Muscle rigidity
• Parkinsonism (characteristic symptoms such as rigidity)
• Hypotension
• Anticholinergic side effects such as: (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine.)
• Blurred vision
• Constipation
• Dry mouth
• Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis.
• Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients. Most of the causes of death were either cardiovascular or infectious in nature. It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients. The drug bears a boxed warning about this risk. or dementia with Lewy bodies

Interactions

• Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).
• Amphetamine and methylphenidate: counteracts increased action of norepinephrine and dopamine in patients with narcolepsy or ADD/ADHD
• Epinephrine: action antagonized, paradoxical decrease in blood pressure may result
• Guanethidine: antihypertensive action antagonized
• Levodopa: decreased action of levodopa
• Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.
• Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects
• Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased. In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
• Other drugs metabolized by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels Some studies report an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume. Haloperidol irreversibly blocks the sigma σ¹ receptor. It may exert deleterious effects on the dorsolateral prefrontal cortex (DLPFC) by attenuating brain-derived neurotrophic factor (BDNF) transcription and expression, associated with an increase in the long non-coding RNA BDNF-AS in the DLPFC. Besides the preceding mechanisms, haloperidol metabolizes into HPP⁺, a monoaminergic neurotoxin related to MPTP. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped. but in general the prognosis after overdose is good, provided the person has survived the initial phase.

Pharmacology

thumb|Haloperidol, 10-mg oral tablet

Haloperidol is a typical butyrophenone-type antipsychotic that exhibits high-affinity dopamine D₂ receptor antagonism and slow receptor dissociation kinetics. It has effects similar to the phenothiazines. The drug binds preferentially to D₂ and α₁ receptors at low dose (ED₅₀ = 0.13 and 0.42&nbsp;mg/kg, respectively), and 5-HT₂ receptors at a higher dose (ED₅₀ = 2.6&nbsp;mg/kg). Given that antagonism of D₂ receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT₂ receptors on the negative symptoms, this characteristic underlies haloperidol's greater effect on delusions, hallucinations and other manifestations of psychosis. Haloperidol's negligible affinity for histamine H₁ receptors and muscarinic M₁ acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms.

{| class="wikitable sortable"

|+ Haloperidol binding profile

! data-sortable | Receptor !! Action !! K_i (nM)

|-

|D₁

|silent antagonist

|45

|-

|D₅

|silent antagonist

|Unknown efficiency

|-

|D₂

|inverse agonist

|0.7

|-

|D₃

|inverse agonist

|0.2

|-

|D₄

|inverse agonist

|5–9

|-

|σ₁

|(irreversible inactivation by haloperidol metabolites)

|3

|-

|σ₂

|agonist

|54

|-

|5-HT_1A

|agonist

|1927

|-

|5-HT_2A

|silent antagonist

|53

|}

Pharmacokinetics

By mouth

The bioavailability of oral haloperidol ranges from 60 to 70%. However, there is a wide variance in reported mean T_max and T_1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.

Intramuscular injections

thumb|right|Haldol Decanoate for injection into muscle

The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The T_max is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T_1/2 is 20.7 hours.

Intravenous injections

The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T_1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg. which may explain the slow disappearance of side effects when the medication is stopped.

Distribution and metabolism

Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolized in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4.

Chemistry

Haloperidol is a crystalline material with a melting temperature of 150&nbsp;°C. This drug has very low solubility in water (1.4&nbsp;mg/100&nbsp;mL), but it is soluble in chloroform, benzene, methanol, and acetone. It is also soluble in 0.1&nbsp;M hydrochloric acid (3&nbsp;mg/mL) with heating.

History

Haloperidol was discovered by Paul Janssen. It was developed in 1958 at the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.

Haloperidol was approved by the U.S. Food and Drug Administration (FDA) on 12 April 1967; it was later marketed in the U.S. and other countries under the brand name Haldol by McNeil Laboratories.

Names

Haloperidol is the INN, BAN, USAN, AAN approved name.

It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halol, Halosten, Keselan, Linton, Peluces, Serenace Norodol (Turkey) and Sigaperidol.

Research

Haloperidol was under investigation for the treatment of depression. It was employed as a short-term low-dose dopamine receptor antagonist to upregulate dopamine receptors and produce receptor supersensitivity followed by drug withdrawal as a means of treating depression.

References