Haloperidol

Mechanism

Chemical and Commercial Profile

Common trade names: Haloperidol, Haldol, Tepazepan.
Group: Typical antipsychotic, derived from butyrophenone.

Mechanism of Action

It exerts a competitive antagonism of extreme potency and affinity on dopamine type 2 receptors (D₂, K_i ≈ 0.5 nM), located preferentially in the mesolimbic and mesocortical pathways.

Mesolimbic Effect (Desired)

Reducing overactive dopaminergic transmission in this pathway effectively mitigates the positive symptoms of psychosis (delusions, audible hallucinations, disorganization of thought).

Nigrostriatal and Tuberoinfundibular Effects (Adverse)

Blockade of the D₂ receptor in these regions produces the extrapyramidal spectrum due to striatal cholinergic imbalance, and induces symptomatic hyperprolactinemia due to cancellation of the pituitary inhibitory tone.

Pharmacokinetics

Pharmacokinetics

• Routes of administration: Oral, rapid intramuscular (IM) and depot (haloperidol decanoate for monthly prolonged release).
• Bioavailability: Oral: 60%. Rapid IM: 100% with a T_max of 10-20 minutes, ideal for controlling acute agitation.
• Metabolism: Hepatic via carbonyl reductase (60%) and isoenzymes CYP3A4 and CYP2D6. Produces inactive metabolites.
• Excretion: Renal (40%) and fecal (60%) mainly in conjugated form.
• Half-life (t_1/2): Oral: 15-30 hours. IM Decanoate: 20-30 days of terminal elimination.

Indicators and dose

Indications

• Schizophrenia and acute chronic psychoses.
• Urgent control of delirium and severe psychomotor agitation (hyperactive delirium).
• Acute manic phase of bipolar disorder type I.
• Severe tics and refractory Gilles de la Tourette syndrome.
• Symptomatic treatment of nausea and vomiting induced by chemotherapy or palliative care of terminal phases.

Dosage and Settings

• Acute psychomotor agitation: 2.5 mg to 5 mg IM (or IV with ECG monitoring), with the dose being repeatable every 4-8 hours up to a usual maximum of 15-20 mg/day.
• Chronic schizophrenia: 2 mg to 10 mg/day orally.
• Renal / Liver Failure: Reduce the initial oral doses by 50% in advanced chronic liver disease or kidney disease. Avoid decanoate preparations in these conditions of systemic fragility.

Security

Contraindications

• Idiopathic Parkinson's disease and Lewy body dementia (extreme risk of catastrophic rigidity and stupor).
• Coma of any etiology or severe depression of the central nervous system.
• Acquired or known long QT syndrome due to increased risk of Torsade de Pointes with intravenous use (a route not formally authorized in the technical data sheet but used in ICUs under continuous monitoring).

Adverse Effects (ADR)

Neuroleptic Malignant Syndrome (NMS)

Potentially lethal idiosyncratic AMR (~10% mortality) characterized by the classic tetrad: extreme hyperthermia (>40°C), severe "lead pipe" extrapyramidal muscle rigidity, fluctuating autonomic instability (tachycardia, HBP, diaphoresis) and altered level of consciousness. Laboratory: Massive elevation of Creatine Kinase (CK >10,000 IU/L) and leukocytosis. Immediate treatment: Absolute suspension of the neuroleptic, intensive support, physical cooling, administration of dantrolene (direct-acting muscle relaxant) and dopamine agonists such as bromocriptine.

• Extrapyramidal Effects (SEP):
  • Acute dystonia: Involuntary muscle spasm of the neck and face (oculogyric crises, torticollis) in the first 48 hours. Treatment: Parenteral anticholinergics (biperiden IM or IV).
  • Akathisia: Subjective and unbearable sensation of psychomotor restlessness that prevents staying still. Treatment: Propranolol at a dose of 40-80 mg/day.
  • Secondary parkinsonism: Inexpressive facies, resting tremor "in counting of coins", rigidity and festinating gait from the first week.
  • Tardive dyskinesia: Involuntary choreoathetotic perioral and lingual movements that appear after years of continued treatment. It may be irreversible.
• Hyperprolactinemia: Galactorrhea, painful gynecomastia, amenorrhea, erectile dysfunction.

Clinical Interactions

• Central depressants: Synergy in sedation and respiratory depression.
• Drugs that prolong QTc: High-risk interaction with amiodarone, erythromycin, and moxifloxacin.

Pregnancy and Breastfeeding

FDA Category: C. It is associated with the risk of transient extrapyramidal symptoms and withdrawal in neonates exposed in the third trimester. Breastfeeding: Compatible with extreme caution. It is excreted in milk in low proportions, but requires monitoring the infant for rigidity, sedation or tics.