Pathophysiology
Clinical meaning
Antipsychotic side effect profiles are determined by their receptor binding affinities across multiple neurotransmitter systems. Dopamine D2 receptor blockade is the primary therapeutic mechanism for reducing positive psychotic symptoms (hallucinations, delusions) but also produces extrapyramidal symptoms (EPS) when nigrostriatal D2 occupancy exceeds 80% and hyperprolactinemia when tuberoinfundibular D2 receptors are blocked. Serotonin 5-HT2A receptor antagonism, characteristic of second-generation antipsychotics, reduces EPS risk by disinhibiting dopamine release in the nigrostriatal and mesocortical pathways while potentially improving negative symptoms and cognition. Histamine H1 receptor blockade causes sedation and weight gain through increased appetite. Muscarinic M1 receptor blockade produces anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, cognitive impairment). Alpha-1 adrenergic blockade causes orthostatic hypotension, dizziness, and reflex tachycardia. First-generation antipsychotics (FGAs) are classified as high-potency (haloperidol, fluphenazine—strong D2 binding with high EPS and low sedation/anticholinergic effects) or low-potency (chlorpromazine, thioridazine—weaker D2 binding with lower EPS but significant sedation, anticholinergic, and hypotensive effects). SGAs achieve limbic selectivity through combined D2 and 5-HT2A blockade, producing antipsychotic efficacy with reduced EPS.