typical antipsychotic

**Mechanism:** Block postsynaptic D2 receptors, mainly in the mesolimbic pathway. This reduces positive symptoms of psychosis. They have little effect on negative symptoms. Low-potency agents also block H1, muscarinic M1, and alpha-1 receptors.

**Classification (potency is inversely related to side-effect profile):** - *High potency* ("try to fly high"): Trifluoperazine, Fluphenazine, Haloperidol, (also pimozide, thiothixene). They cause more neurologic effects: EPS, dystonia. - *Low potency* (Cheating Thieves are low): Chlorpromazine, Thioridazine. They cause more non-neurologic effects: anticholinergic, antihistamine, and alpha-1 blockade effects.

**Dopamine pathway effects and adverse effects:** - Nigrostriatal blockade: extrapyramidal symptoms (EPS). - Timeline: acute dystonia (hours to days; treat with benztropine or diphenhydramine), akathisia (days to weeks; treat with beta-blocker such as propranolol, benztropine, or benzodiazepines), parkinsonism (weeks to months; treat with benztropine or amantadine), and tardive dyskinesia (months to years; often irreversible; treat by switching to a lower-risk agent and with VMAT2 inhibitors such as valbenazine or deutetrabenazine). - Tuberoinfundibular blockade: hyperprolactinemia, which causes galactorrhea, gynecomastia, amenorrhea, and decreased libido. - Mesocortical blockade: may worsen negative and cognitive symptoms. - Neuroleptic malignant syndrome (NMS): fever, rigidity ("lead pipe"), autonomic instability, altered mental status, and elevated CK. Treat by stopping the drug, giving supportive care, and using dantrolene or bromocriptine. - Anticholinergic effects (low potency): dry mouth, constipation, urinary retention, blurry vision. - Antihistamine effects: sedation, weight gain. - Alpha-1 blockade: orthostatic hypotension. - QT prolongation: especially thioridazine and haloperidol, which can cause torsades de pointes. - Drug-specific toxicities: - Thioridazine: retinal deposits (retinitis pigmentosa-like). - Chlorpromazine: corneal deposits, cholestatic jaundice, photosensitivity or blue-gray skin discoloration.

**Clinical uses:** Schizophrenia, acute psychosis, acute agitation (IM haloperidol), Tourette syndrome (haloperidol, pimozide), delirium, and mania. Chlorpromazine is also used as an antiemetic and for intractable hiccups. Long-acting depot forms (haloperidol decanoate, fluphenazine decanoate) improve adherence.

**Typical vs atypical:** - Typical: D2 antagonism, with more EPS and tardive dyskinesia and hyperprolactinemia. - Atypical (-apines, -dones, e.g., olanzapine, risperidone, quetiapine, clozapine): D2 plus 5-HT2A antagonism, with less EPS but more metabolic effects (weight gain, diabetes, dyslipidemia). Clozapine carries a risk of agranulocytosis and seizures but is the most effective option for treatment-resistant schizophrenia.

**Board pearls:** - A young patient with sudden neck or jaw spasm after haloperidol is having acute dystonia. Give IM benztropine. - Fever and rigidity after starting haloperidol suggest NMS (high CK). Serotonin syndrome, by contrast, shows clonus and hyperreflexia with diarrhea. - Amenorrhea or galactorrhea in a patient on antipsychotics reflects hyperprolactinemia (dopamine normally inhibits prolactin). - Pregnancy: use is generally limited to when benefits outweigh risks. - Always check baseline ECG, and monitor for tardive dyskinesia with the AIMS scale.