14.4: Antipsychotic Drugs: Typical and Atypical Agents

Antipsychotic drugs are classified into first-generation (typical) drugs including phenothiazines; and second-generation (atypical) drugs. Chlorpromazine hydrochloride (Thorazine), a phenothiazine derivative, broadly impacts the central, autonomic, and endocrine systems. This drug, along with typical agents like haloperidol (Haldol), primarily works by antagonizing D₂ receptors, thus reducing dopaminergic neurotransmission. However, typical antipsychotics can cause side effects such as sedation and blurred vision.

On the other hand, atypical agents like clozapine (Clozaril), risperidone (Risperdal), sulpiride (Dogmatil), olanzapine (Zyprexa), quetiapine (Seroquel), and lurasidone (Latuda) demonstrate weaker D₂ antagonism but potent 5-HT_2A antagonism. Their complex pharmacology allows them to alter 5-HT_2A receptor activity effectively, leading to anxiolytic effects. Clozapine's unique efficacy in refractory schizophrenia may be attributed to its activity at glutamatergic sites, especially the NMDA receptor. Despite their different chemical structures and receptor activities, all antipsychotics undergo significant first-pass metabolism and are readily absorbed. Their metabolites can be excreted weeks after the last dose, and long-acting formulations can block D₂ receptors for weeks. Abrupt discontinuation of drugs like clozapine can lead to rapid and severe symptom relapse.

All effective antipsychotics block D₂ receptors, but the extent of this blockade varies across drugs. Most second-generation and some first-generation antipsychotics are as effective at blocking 5-HT_2A receptors as they are at blocking D₂ receptors. Aripiprazole and brexpiprazole act as partial agonists at D₂ receptors. Drugs like clozapine and quetiapine mainly exhibit α₁ adrenoceptor antagonism while risperidone, olanzapine, and aripiprazole show varying degrees of α₂ adrenoceptor antagonism.

Finally, while structure-function relationships were once paramount, receptor binding and functional assays have become more clinically relevant for understanding these drugs' mechanisms of action. For instance, partial agonist antipsychotics, such as aripiprazole, require higher D₂ occupancy levels, even though the exact mechanism, based on their structure, is not fully understood.

Antipsychotic drugs can be categorized as first-generation or typical and second-generation or atypical agents.

All antipsychotic drugs act by inhibiting dopamine receptors, although the extent of this inhibition varies significantly among different drugs.

Typical antipsychotics like chlorpromazine and haloperidol primarily target D₂ receptors in the brain.

Clinical efficiency typically corresponds to receptor occupancy ranging from 60 to 75%. However, receptor occupancy exceeding 78% can lead to extrapyramidal side effects.

In contrast, atypical agents such as risperidone and lurasidone block both D₂ receptors and 5HT_2A receptors.

These agents are also partial 5HT_1A receptor agonists, producing anxiolytic effects.

Drugs like clozapine and risperidone additionally show varying degrees of α₂ adrenoceptor antagonism.

Antipsychotics are generally lipophilic, resulting in their distribution and accumulation in well-vascularized tissues, including the brain.

They can also cross into fetal circulation and breast milk, posing potential risks during pregnancy and lactation.