D4-receptor antagonists
Summary
Drugs blocking dopamine D4 receptors, a subtype of D2-like receptors enriched in the prefrontal cortex and limbic system. Clozapine is the classic high-affinity D4 antagonist.
Detail
D4 receptors belong to the D2-like family (Gi-coupled, inhibit adenylyl cyclase) and are concentrated in prefrontal cortex, hippocampus, and limbic regions but largely absent from the nigrostriatal pathway. This anatomic distribution underlies the therapeutic rationale: D4 blockade may treat positive psychotic symptoms with minimal extrapyramidal side effects. Clozapine is the prototypical atypical antipsychotic with high D4 affinity (plus 5-HT2A blockade), reserved for treatment-resistant schizophrenia due to risk of agranulocytosis (mandatory ANC monitoring), myocarditis, seizures, and metabolic syndrome. Boards: clozapine = D4/5-HT2A antagonist, treatment-resistant schizophrenia and reduces suicidality, agranulocytosis risk.
Sources
- First Aid for USMLE Step 1 2024
- Sketchy Pharmacology
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