Chlorpromazine

Indications

• FDA-approved for schizophrenia and for the manic phase of bipolar disorder in adults, and for severe behavioral disturbance in children aged 1 to 12.
• FDA-approved for nausea and vomiting, intractable hiccups, and preoperative restlessness in adults, usually at doses well below antipsychotic range.
• FDA-approved as adjunctive therapy in tetanus and for the acute intermittent porphyria attack, reflecting its long and broad legacy labeling.
• Off-label use for acute agitation when marked sedation is desirable and for refractory nausea in palliative care at low divided doses.
• Off-label option for status migrainosus and severe cyclic vomiting, typically given parenterally with a fluid bolus to offset hypotension.
• No longer a first-line antipsychotic; guidelines favor higher-potency or second-generation agents because of its sedation and autonomic load.

Mechanism of action

• Antagonizes dopamine D2 receptors with only moderate affinity, so effective antipsychotic doses are ten to twenty times those of haloperidol.
• Strong alpha-1 adrenergic blockade produces the orthostatic hypotension, reflex tachycardia, nasal congestion, and priapism seen at higher doses.
• Potent histamine H1 antagonism drives the pronounced sedation and appetite gain that made it useful for agitation before newer agents existed.
• Muscarinic blockade partially offsets striatal D2 antagonism, which is why extrapyramidal symptoms are less frequent than with high-potency agents.
• Blockade of hERG potassium channels and of neuronal sodium channels underlies QT prolongation and its comparatively high seizure-threshold reduction.

Pharmacokinetics

• Oral bioavailability is erratic at roughly 10-30 percent because of heavy first-pass metabolism; intramuscular dosing gives four to ten times higher exposure.
• Terminal half-life is about 30 hours, but numerous active and inactive metabolites prolong tissue effects well beyond plasma clearance.
• Metabolized principally by CYP2D6 with contributions from CYP1A2 and CYP3A4, followed by sulfoxidation and glucuronide conjugation in the liver.
• It is itself a moderate CYP2D6 inhibitor, raising exposure to substrates such as metoprolol, tricyclic antidepressants, and atomoxetine.
• Highly lipophilic and about 95 percent protein bound, with a large volume of distribution and no meaningful renal clearance of parent drug.

Dosing

• For psychosis, start 10-25 mg orally three or four times daily and increase by 20-50 mg every 3-4 days to a usual 200-800 mg/day.
• Severe refractory illness may require up to 2000 mg/day, but exposure at that level markedly increases hypotension, sedation, and seizure risk.
• Acute agitation can be treated with 25 mg IM, repeated at 25-50 mg after one hour if needed, with the patient supine and blood pressure checked.
• Intractable hiccups and nausea respond to 25-50 mg orally three or four times daily, far below the antipsychotic dose range.
• No specific renal adjustment; halve the starting dose and titrate slowly in hepatic impairment, and avoid it entirely in decompensated liver disease.
• Discontinue by tapering over several weeks; abrupt withdrawal provokes cholinergic rebound with nausea, insomnia, sweating, and dyskinesias.

Adverse effects

• Sedation affects the majority of patients early, and orthostatic hypotension is dose-limiting, particularly after the first parenteral doses.
• Anticholinergic burden is high, producing dry mouth, blurred vision, constipation, urinary retention, and delirium risk in older adults.
• Extrapyramidal symptoms occur in roughly 10-20 percent, lower than with haloperidol, but tardive dyskinesia risk still accrues with chronic use.
• Photosensitivity is common and prolonged high-dose therapy can cause blue-gray skin pigmentation plus lens and corneal deposits.
• Cholestatic jaundice occurs in under 1 percent, usually in the first month, and rare agranulocytosis and neuroleptic malignant syndrome are reported.
• It lowers seizure threshold more than most antipsychotics and prolongs the QT interval in a dose-dependent fashion.

Monitoring

• Check supine and standing blood pressure at baseline, after each increase, and before repeat parenteral doses given the alpha-blockade.
• Obtain baseline liver enzymes and repeat if jaundice, pruritus, or malaise appears, since cholestasis clusters in the first four weeks.
• Get a CBC at baseline and whenever fever or sore throat develops; stop the drug for an absolute neutrophil count below 1000 per microliter.
• Perform an AIMS every 6 months and a slit-lamp or ophthalmologic exam periodically for patients on prolonged high-dose therapy.
• ECG at baseline and after dose escalation when QT-prolonging drugs, electrolyte disturbance, or cardiac disease are present.

Interactions

• Epinephrine given for chlorpromazine-induced hypotension can paradoxically lower pressure further; use phenylephrine or norepinephrine instead.
• Additive hypotension with antihypertensives, alpha-blockers, and nitrates, and additive sedation with opioids, benzodiazepines, and alcohol.
• As a CYP2D6 inhibitor it raises levels of metoprolol, tricyclics, and atomoxetine, while CYP1A2 inducers such as smoking lower its own levels.
• Additive QT prolongation with methadone, ondansetron, macrolides, and antiarrhythmics; combined anticholinergics precipitate ileus or delirium.
• Contraindicated with comatose states, severe CNS depression, and known phenothiazine hypersensitivity; avoid in dementia with Lewy bodies.

Special populations

• Pregnancy data are extensive without a clear teratogenic signal, but third-trimester exposure risks neonatal extrapyramidal and withdrawal symptoms.
• Small amounts appear in breast milk; monitor the infant for sedation and poor feeding, and prefer better-studied agents when a choice exists.
• Labeled for children aged 6 months and older; pediatric dosing is 0.55 mg/kg every 4-6 hours as needed, with lower ceilings than adults.
• In older adults it appears on the Beers criteria for anticholinergic and hypotensive burden; use only briefly and at markedly reduced doses.
• Hepatic impairment substantially raises exposure and jaundice risk, while renal impairment requires no dose change for the parent drug.

Clinical pearls

• Never treat its hypotension with epinephrine; unopposed beta-2 vasodilation worsens the drop.
• Counsel sun protection early; photosensitivity burns appear within days of starting therapy.
• Chlorpromazine 100 mg is roughly equivalent to haloperidol 2 mg when converting antipsychotics.