Singapore Drugs Database

Indication

For the treatment of schizophrenia [L2016] For the treatment of acute psychosis in acutely agitated schizophrenic patients with moderately severe to very severe symptoms [L2016] For the treatment of severe behavioral or psychological symptoms of dementia [L2016] For the treatment of delirium in the pediatric intensive care unit [L2016] For the treatment of agitation or delirium [L2016] For agitation† or delirium in adult patients with no underlying psychiatric illness [L2016] For use as a second-line agent for rescue treatment of chemotherapy-induced nausea/vomiting [L2016] For the treatment of irritability associated with autistic disorder [L2016] For the treatment of tics and vocal utterances associated with Tourette's syndrome [L2016] For the treatment of severe behavioral problems associated with oppositional defiant disorder or other disruptive behavioral disorders, or for the treatment of attention-deficit hyperactivity disorder (ADHD) in pediatric patients who show excessive motor activity with accompanying conduct disorders [L2016]

Mechanism of Action

Haloperidol inhibits the effects of dopamine and increases its turnover, however, the exact mechanism of action is not fully understood [FDA label]. Dopamine overactivity can be presynaptic (an excess of dopamine release from dopamine nerve terminals) or post-synaptic (an increase in the density of D2 receptors or an increase in post-receptor action) [L2017]. Traditional antipsychotics, such as haloperidol, bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine [A4962]. It is believed that haloperidol competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. It acts primarily on the D2-receptors and has some effect on 5-HT2 and α1-receptors, with negligible effects on dopamine D1-receptors. The drug also exerts some blockade of α-adrenergic receptors of the autonomic system [L2022]. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity [L1996]. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain [L2018]. Clinical brain-imaging findings show that haloperidol remains tightly bound to D2 dopamine receptors in humans undergoing 2 positron emission tomography (PET) scans with a 24h pause in between scans [A4962]. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to the tight binding of haloperidol to the dopamine D2 receptor [FDA label]. Further information is found in the "Toxicity" section of this drug profile. Due to the risk of unpleasant and sometimes lifelong extrapyramidal symptoms, newer antipsychotic medications than haloperidol have been discovered and formulated. Rapid dissociation of drugs from dopamine D2 receptors is a plausible explanation for the improved EPS profile of atypical antipsychotics such as [DB00734]. This is also consistent with the theory of a lower affinity for D2 receptors for these drugs [L2018]. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms [A4962], and therefore should only been used when necessary.

Pharmacokinetics

Absorption

Haloperidol is well-absorbed from the gastrointestinal tract when ingested orally, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40 - 75% [L1996]. Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects. The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days. Steady-state plasma concentrations are achieved after the third or fourth dose [FDA label]. Serum concentration peaks 0.5 to 4 hours after an oral dose [L1996].

Distribution

The apparent volume of distribution is about 20 L/kg, in concordance with the high lipophilicity of the drug [L1996], and largely depends on the subject [L2028]. Haloperidol is rapidly distributed to various tissues and organs, as indicated by the large volume of distribution (mean values 8 to 21 L/kg after intravenous dosing). Haloperidol readily crosses the blood-brain barrier. It also crosses the placenta and is excreted in breast milk [L2028].

Metabolism

Its metabolic fate has not been clearly established, it appears that haloperidol is primarily metabolized in the liver [L1996]. The drug is thought to be metabolized primarily by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming _hydroxyhaloperidol_. Some data suggest that the reduced metabolite, hydroxyhaloperidol, has some pharmacologic activity, although its activity appears to be inferior to that of haloperidol. Urinary metabolites in rats include _p-fluorophenaceturic acid_, _beta-p-fluorobenzoylpropionic acid_, and several unidentified acids [L1996]. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase and uridine di-phosphoglucose glucuronosyltransferase enzymes. The greatest proportion of the intrinsic hepatic clearance of haloperidol is performed by glucuronidation and followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of cytochrome-mediated disposition in vitro, CYP3A4 appears to be the major isoform of the enzyme responsible for the metabolism of haloperidol in humans. The intrinsic clearance of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude. This suggests that the same enzyme system is responsible for the above three metabolic reactions [L1996]. Haloperidol is a substrate of _CYP3A4_ and an inhibitor, as well as a stimulator, of _CYP2D6_ [L1996].

Elimination

Clearance

Haloperidol clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of C_YP2D6_ enzyme. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia [L2028].

Toxicity

Acute oral toxicity (LD50): 71 mg/kg in rats [MSDS]. Toxicity of haloperidol may be divided into several categories, according the FDA label: **Cardiovascular Effects** The incidence of sudden death, QT-prolongation, and Torsades de Pointes has been reported in patients treated with this drug. Higher than usual doses of any formulation and intravenous (IV) administration of haloperidol have shown to be associated with a higher risk of QT-prolongation and Torsades de Pointes [FDA label]. Caution is advised in treating patients with other cardiac QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs which prolong the QT interval, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). Depot haloperidol is not to be administered by the IV route [FDA label]. **Extrapyramidal Symptoms** Extrapyramidal symptoms are comprised of a group of movement disorders which may include dystonia, akathisia, tardive dyskinesia and parkinsonism. Drug-induced extrapyramidal symptoms have been common knowledge for decades, yet the use of these drugs is still common. Despite this, these symptoms may prove to be long-lasting, and therefore, caution is warranted in the prevention of extrapyramidal symptoms [L2021]. **Tardive Dyskinesia** This is a consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs and is known as an _extrapyramidal_ symptom [FDA label]. Although the prevalence of the syndrome appears to be high among the elderly, this is a particularly common occurrence in elderly women [FDA label] The risk of developing tardive dyskinesia and the risk that it may be irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient over time. However, the syndrome can develop, although much less commonly, after brief periods of treatment at lower doses [FDA label]. There are no known treatments for established cases of tardive dyskinesia. The syndrome may remit, partially or completely, if antipsychotic treatment is removed [FDA label]. Antipsychotic drugs should be prescribed in a manner that is most likely to minimize the occurrence of If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome [FDA label]. **Neuroleptic Malignant Syndrome (NMS)** A potentially fatal condition, sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been demonstrated in association with antipsychotic drugs treatment. Clinical signs and symptoms of NMS are hyperpyrexia, muscle rigidity, alterations in mental status (including catatonia) and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Other signs include elevated creatine phosphokinase (CPK), myoglobinuria (rhabdomyolysis) and acute kidney failure [FDA label]. **General** In addition to the above toxicities, number of cases of bronchopneumonia, some fatal, have followed the use of antipsychotic drugs, including haloperidol. One theory suggests that lethargy and decreased sensation of thirst due to central inhibition may lead to dehydration, hemoconcentration and reduced pulmonary ventilation. Therefore, if the above signs and symptoms appear, especially in the elderly, the physician should institute remedial therapy promptly. **Hematologic Effects** Reports have been made of the occurrence of mild, usually transient leukopenia and leukocytosis, minimal decreases in red blood cell counts, anemia, or a tendency toward monocytosis. Agranulocytosis has rarely been reported to have occurred with the use of haloperidol, and then only in association with other medication [FDA label]. **Liver Effects** Impaired liver function and/or jaundice may occur. **Dermatologic Reactions** Maculopapular and acne-like skin reactions and isolated cases of photosensitivity and loss of hair. **Endocrine Disorders** Lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia [FDA label] **Gastrointestinal Effects** Anorexia, constipation, diarrhea, hypersalivation, dyspepsia, nausea and vomiting [FDA label] **Autonomic Reactions** Dry mouth, blurred vision, urinary retention, diaphoresis and priapism [FDA label] **Respiratory Effects** Laryngospasm, bronchospasm and increased depth of respiration [FDA label] **Special Senses** Cataracts, retinopathy and visual disturbances [FDA label]

Active Ingredient/Synonyms

1-(3-p-fluorobenzoylpropyl)-4-p-chlorophenyl-4-hydroxypiperidine | 4-(4-(para-chlorophenyl)-4-hydroxypiperidino)-4'-fluorobutyrophenone | 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one | 4'-fluoro-4-(4-(p-chlorophenyl)-4-hydroxypiperidinyl)butyrophenone | 4'-fluoro-4-(4-hydroxy-4-(4'-chlorophenyl)piperidino)butyrophenone | Haloperidolum | γ-(4-(p-chlorophenyl)-4-hydroxpiperidino)-p-fluorbutyrophenone | Haloperidol |