first-generation antipsychotic

**Mechanism:** Block postsynaptic D2 receptors, especially in the mesolimbic pathway, which reduces positive symptoms. They have little effect on negative symptoms. Potency correlates with D2 affinity. Efficacy is similar across agents, so the choice is based on side-effect profile.

**Classification (phenothiazines and others):** - *High-potency* ("Try to Fly high"): Trifluoperazine, Fluphenazine, Haloperidol. Adverse effects are mainly neurologic (EPS, dystonia). Haloperidol is also a butyrophenone. - *Low-potency* ("Cheating Thieves are low"): Chlorpromazine, Thioridazine. Adverse effects are mainly non-neurologic: anticholinergic (dry mouth, constipation, urinary retention), antihistamine (sedation, weight gain), α1-blockade (orthostatic hypotension). - Other: Pimozide (Tourette syndrome), Loxapine, Thiothixene.

**Dopamine pathways and adverse effects:** - Nigrostriatal blockade → EPS: acute dystonia (hours to days; treat with benztropine or diphenhydramine), akathisia (days to weeks; treat with β-blocker such as propranolol, or benzodiazepine, or reduce the dose), parkinsonism (weeks; bradykinesia, rigidity, tremor; treat with benztropine or amantadine), and tardive dyskinesia (months to years; orofacial movements; stop the drug or switch to a second-generation agent; treat with VMAT2 inhibitors such as valbenazine or deutetrabenazine). - Tuberoinfundibular blockade → hyperprolactinemia: galactorrhea, gynecomastia, amenorrhea, decreased libido, osteoporosis. - Mesocortical blockade may worsen negative symptoms.

**Other toxicities:** - *Neuroleptic malignant syndrome (NMS):* fever, "lead-pipe" rigidity, autonomic instability, altered mental status, elevated CK. Treat by stopping the drug and giving dantrolene, bromocriptine, and supportive care. Onset is usually within days to weeks. - *QT prolongation* (thioridazine, haloperidol) → torsades de pointes. - *Thioridazine:* retinal deposits (retinitis pigmentosa-like). - *Chlorpromazine:* corneal deposits, blue-gray skin discoloration, cholestatic jaundice. - Lower seizure threshold. - *Increased mortality in elderly patients with dementia-related psychosis* (boxed warning).

**Clinical uses:** Schizophrenia, acute psychosis and agitation (IM haloperidol), schizophreniform and brief psychotic disorder, Tourette syndrome (haloperidol, pimozide), delirium, and mania. Chlorpromazine is also used for intractable hiccups and nausea. Long-acting depot injections (haloperidol decanoate, fluphenazine decanoate) are used for nonadherence.

**Comparison with second-generation (atypical) agents:** Atypicals (e.g., risperidone, olanzapine, clozapine) combine D2 with 5-HT2A antagonism. They cause fewer EPS but more metabolic effects (weight gain, diabetes, dyslipidemia). Typicals remain high-yield for EPS and NMS questions.

**Board pearls:** - A patient with sudden neck twisting or oculogyric crisis after haloperidol has acute dystonia → give benztropine. - Restlessness and inability to sit still means akathisia → give propranolol. - Fever, rigidity, and elevated CK after starting an antipsychotic means NMS (compare with serotonin syndrome, which has clonus, hyperreflexia, and diarrhea, and malignant hyperthermia, which follows inhaled anesthetics or succinylcholine). - High-potency agents cause more EPS, and low-potency agents cause more anticholinergic effects.