## Extrapyramidal Side Effects and Antipsychotic Classification **Key Point:** Haloperidol is a typical (first-generation) antipsychotic with high D₂ dopamine receptor blockade in the basal ganglia, making it the highest-risk agent for EPS among the options listed. ### Mechanism of EPS Extrapyramidal side effects arise from dopamine antagonism in the basal ganglia and nigrostriatal pathway. The degree of EPS risk correlates directly with: - Potency of D₂ blockade - Lipophilicity and CNS penetration - Ratio of D₂ to other receptor blockade ### Antipsychotic Risk Stratification for EPS | Agent | Class | D₂ Potency | EPS Risk | Mechanism | |-------|-------|-----------|----------|----------| | **Haloperidol** | Typical | Very high | **Highest** | Potent, selective D₂ antagonist | | Aripiprazole | Atypical | High | Low–moderate | Partial D₂ agonist; less basal ganglia penetration | | Quetiapine | Atypical | Low | Very low | Rapid D₂ dissociation; high 5-HT₂A blockade | | Clozapine | Atypical | Low | Very low | Loose D₂ binding; high 5-HT₂A/muscarinic blockade | **High-Yield:** Atypical antipsychotics (quetiapine, clozapine, aripiprazole) have intrinsically lower EPS risk due to either loose D₂ binding, rapid dissociation, or partial agonism. Haloperidol's tight, sustained D₂ blockade in the nigrostriatal tract is the primary driver of acute dystonia, akathisia, parkinsonism, and tardive dyskinesia. **Clinical Pearl:** Among atypical agents, aripiprazole carries slightly higher EPS risk than quetiapine or clozapine because it is a partial D₂ agonist with higher D₂ occupancy in motor circuits, yet it remains far safer than haloperidol. **Warning:** Do not confuse "potency" (ability to block D₂) with "selectivity" (preference for D₂ over other receptors). Haloperidol is both potent and selective for D₂, which is why EPS is so pronounced.
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