Trifluoperazine

Indications

• FDA-approved for the treatment of schizophrenia in adults, where it is a high-potency phenothiazine comparable in efficacy to haloperidol.
• FDA-approved for short-term treatment of generalized non-psychotic anxiety, capped at 6 mg/day and at 12 weeks of continuous use.
• The label explicitly states it is not the drug of first choice for anxiety, given the risk of tardive dyskinesia from any duration of exposure.
• Labeled for schizophrenia in hospitalized or closely supervised children aged 6 to 12 years, an unusual pediatric allowance for this class.
• Not approved for dementia-related psychosis, where the boxed warning of increased mortality applies to the whole antipsychotic class.
• Used off-label as an antiemetic and for intractable nausea, though prochlorperazine is the phenothiazine normally chosen for that purpose.

Mechanism of action

• Potent postsynaptic dopamine D2 receptor antagonist of the piperazine phenothiazine subclass, with high affinity and low sedation.
• Mesolimbic D2 blockade suppresses hallucinations and delusions, while nigrostriatal blockade produces parkinsonism, dystonia and akathisia.
• Blockade of D2 receptors in the chemoreceptor trigger zone accounts for the antiemetic effect shared across phenothiazines.
• Tuberoinfundibular blockade raises prolactin, producing galactorrhea, menstrual disturbance and sexual dysfunction.
• Anticholinergic, antihistaminic and alpha-1 blocking activity is modest compared with chlorpromazine but still causes orthostasis and dry mouth.

Pharmacokinetics

• Oral absorption is variable with substantial first-pass metabolism, so plasma levels differ widely between patients on the same dose.
• Elimination half-life averages about 13 h with a range of 7-18 h, which supports once- or twice-daily dosing at steady state.
• Metabolized in the liver, principally by CYP1A2 with a CYP2D6 contribution, so smoking and CYP inhibitors shift levels appreciably.
• Highly protein bound and lipophilic with a large volume of distribution, so effects persist for days after the last dose.
• No validated therapeutic plasma concentration range exists, so titration is guided by symptom response and extrapyramidal signs.

Dosing

• Schizophrenia in adults: start 2-5 mg twice daily; most patients respond in the 15-20 mg/day range within two to three weeks.
• A minority require more than 40 mg/day, but every increase above 20 mg/day should be weighed against a steep rise in extrapyramidal effects.
• Non-psychotic anxiety: 1-2 mg twice daily, never exceeding 6 mg/day, and never continuing beyond 12 weeks of treatment.
• Children 6 to 12 years who are hospitalized or closely supervised: 1 mg once or twice daily, titrated slowly and rarely above 15 mg/day.
• Start older adults at the lowest available dose and titrate slowly, because parkinsonism, orthostasis and falls emerge quickly.
• Taper over several weeks when stopping, since abrupt withdrawal produces cholinergic rebound, insomnia and withdrawal dyskinesias.

Adverse effects

• Extrapyramidal symptoms are the leading problem: akathisia, drug-induced parkinsonism and acute dystonic reactions, especially in young men.
• Tardive dyskinesia accrues with cumulative exposure at roughly 5% per year in adults and much faster in the elderly.
• Hyperprolactinemia produces galactorrhea, amenorrhea, gynecomastia, sexual dysfunction and long-term reduction in bone density.
• Phenothiazine-specific effects include photosensitivity, blue-gray skin pigmentation, cholestatic jaundice and pigmentary retinopathy.
• Agranulocytosis and other blood dyscrasias are rare but require immediate discontinuation and a complete blood count if fever or sore throat appears.
• Neuroleptic malignant syndrome, QT prolongation, seizures and orthostatic hypotension complete the list of serious risks.

Monitoring

• Abnormal Involuntary Movement Scale at baseline and every 6 months, or every 3 months in older and other high-risk patients.
• Complete blood count whenever fever, sore throat or other infection appears, and liver function tests if jaundice or pruritus develops.
• Weight, fasting glucose and lipids at baseline and periodically, plus prolactin when endocrine symptoms are reported.
• ECG at baseline in patients with cardiac disease, electrolyte abnormality or concurrent QT-prolonging drugs.
• Ophthalmologic examination after prolonged high-dose therapy to detect lenticular, corneal or retinal pigmentary changes.

Interactions

• CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin raise levels, while smoking induces the same enzyme and lowers them.
• CYP2D6 inhibitors including paroxetine, fluoxetine and bupropion increase exposure and can precipitate extrapyramidal symptoms.
• Additive QT prolongation with methadone, citalopram, ondansetron, macrolides and fluoroquinolones warrants ECG review.
• Antagonizes levodopa and dopamine agonists, so avoid it in Parkinson disease and in dementia with Lewy bodies.
• Alcohol, benzodiazepines and opioids add sedation, and antihypertensives compound orthostatic hypotension and fall risk.

Special populations

• Pregnancy: third-trimester exposure can cause neonatal extrapyramidal signs and withdrawal, so document the risk-benefit discussion.
• Lactation: phenothiazines pass into human milk; watch the infant for sedation, poor feeding and abnormal movements.
• Pediatric: labeled from age 6 years for hospitalized or closely supervised children, though second-generation agents are usually preferred.
• Geriatric: the boxed mortality warning applies in dementia, and tardive dyskinesia and orthostatic falls are far more common.
• Hepatic impairment calls for lower doses and closer observation, and treatment should stop if cholestatic jaundice appears.

Clinical pearls

• The anxiety indication caps at 6 mg/day for 12 weeks; it is not a first-line anxiolytic.
• Counsel sunscreen and covering clothing; phenothiazine photosensitivity is common and severe.
• Never use it for dementia-related psychosis; the boxed mortality warning is the reason.