Haloperidol BP injection 5mg/ml

Indications

• Schizophrenia
• Acute psychomotor agitation associated with psychotic disorders
• Manic episodes of bipolar I disorder
• Prophylaxis of postoperative nausea and vomiting

Mechanism of action

Haloperidol exerts its antipsychotic effects primarily through strong antagonism of dopamine D2 receptors located in the mesolimbic and mesocortical pathways of the brain. By competitively blocking these receptors, haloperidol reduces dopamine neurotransmission, which is often overactive in conditions like schizophrenia. This mechanism helps alleviate positive symptoms such as hallucinations and delusions. Additionally, haloperidol has some activity at serotonin receptors (5-HT2) and alpha-adrenergic receptors, although its primary action is on dopamine receptors.

Pharmacodynamics

Haloperidol is effective in managing the positive symptoms of schizophrenia, including hallucinations and disorganized behavior. However, its use is often associated with extrapyramidal side effects (EPS), such as drug-induced parkinsonism and akathisia, due to its strong dopamine blockade. While haloperidol is considered to have a lower incidence of sedation and weight gain compared to other antipsychotics, it still poses a significant risk for movement disorders, particularly at higher doses or with prolonged use.

Pharmacokinetics

Haloperidol is well absorbed after oral administration, with peak plasma concentrations occurring within 2 to 6 hours. It has a high volume of distribution and is extensively metabolized in the liver, primarily by cytochrome P450 enzymes. The elimination half-life of haloperidol ranges from 14 to 26 hours, allowing for once or twice daily dosing in most cases. The drug is excreted mainly in urine as metabolites, with less than 1% excreted unchanged. Renal and hepatic function can significantly affect haloperidol clearance, necessitating dose adjustments in patients with impaired function.

Contra-indications

• Hypersensitivity to haloperidol or any of its components
• Severe central nervous system depression
• Comatose states
• Parkinson's disease

Adverse effects

• Extrapyramidal symptoms (EPS)
• Sedation
• Weight gain
• Hyperprolactinemia
• Akathisia
• Dystonia
• Tardive dyskinesia
• Hypotension
• Dry mouth
• Constipation
• Blurred vision
• Restlessness
• Angioedema
• Severe cutaneous adverse reactions

Interactions

• Dopamine receptor agonists (decreases effects of haloperidol)
• Antiepileptics (increases risk of overheating and dehydration)
• Zonisamide (increases risk of overheating and dehydration)
• Fluvoxamine (increases haloperidol concentration)
• Levodopa (decreases effects of haloperidol)
• Mitotane (decreases haloperidol concentration)
• Clozapine (additive effect)
• Other second-generation antipsychotics (additive effect)
• Itraconazole (increases haloperidol concentration)

Precautions

• Careful monitoring in elderly patients
• Use with caution in patients with a history of seizures
• Evaluate benefit-risk for prolonged use
• Gradually adjust doses based on response
• Monitor for signs of neuroleptic malignant syndrome

Pregnancy

Manufacturer advises it is preferable to avoid use during pregnancy; moderate data indicates no malformative or fetal/neonatal toxicity, but there are isolated case reports of birth defects.

Breast-feeding

Haloperidol is excreted in breast milk; caution is advised, and alternative treatments should be considered.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Tablets (oral)
• Oral solution
• Intramuscular injection
• Subcutaneous infusion
• Continuous intravenous infusion

Mechanism of action

While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain. Schizophrenia is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain. Dopamine-antagonizing medications such as haloperidol, therefore, are thought to improve psychotic symptoms by halting this over-production of dopamine. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain. While the exact mechanism is not entirely understood, haloperidol is known to inhibit the effects of dopamine and increase its turnover. 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. 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. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities. 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. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to this tight binding of haloperidol to the dopamine D2 receptor. 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. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms, and therefore should only been used when necessary. Haloperidol has less prominent autonomic effects than do other antipsychotic drugs. It has little anticholinergic activity ... it blocks activation of alpha receptors by sympathomimetic amines but is much less potent than chlorpromazine in this action. Although the complex mechanism of the therapeutic effect is not clearly established, haloperidol is known to produce a selective effect on the central nervous system (CNS) by competitive blockade of postsynaptic dopamine (D2) receptors in the mesolimbic dopaminergic system and an increased turnover of brain dopamine to produce its tranquilizing effects. With subchronic therapy, depolarization blockade, or diminished firing rate of the dopamine neuron (decreased release) along with D2 postsynaptic blockade results in the antipsychotic action.

Pharmacodynamics

Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation. However, this class is limited by the development of movement disorders such as drug-induced parkinsonism, akathisia, dystonia, and tardive dyskinesia, and other side effects including sedation, weight gain, and prolactin changes. Compared to the lower-potency first-generation antipsychotics such as [DB00477], [DB01624], [DB00623], and [DB01403], haloperidol typically demonstrates the least amount of side effects within class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension. The balance between the wanted drug effects on psychotic symptoms and unwanted side effects are largely at play within dopaminergic brain pathways affected by haloperidol. Cortical dopamine-D2-pathways play an important role in regulating these effects and include the nigrostriatal pathway, which is responsible for causing extrapyramidal symptoms (EPS), the mesolimbic and mesocortical pathways, which are responsible for the improvement in positive schizophrenic symptoms, and the tuberoinfundibular dopamine pathway, which is responsible for hyperprolactinemia. A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.