Pharmacology of Antipsychotics

Introduction

• Antipsychotics are drugs primarily used to treat psychotic disorders:
  • Schizophrenia
  • Mania due to bipolar disorder
  • Severe depression

Dopamine's Role in Psychosis

• Dopamine Hypothesis: Unusual behavior and experiences in psychosis explained by changes in dopamine function.
• Major Dopamine Pathways:
  1. Mesolimbic Pathway: Hyperactive in schizophrenia; mediates positive symptoms (delusions, hallucinations).
  2. Mesocortical Pathway: Underactive in schizophrenia; mediates negative symptoms (loss of motivation, social withdrawal).
  3. Nigrostriatal Pathway: Controls motor function; deficiency leads to dystonia and parkinsonism, while excess leads to hyperkinetic movements (tics, dyskinesias).
  4. Tuberoinfundibular Pathway: Controls prolactin secretion; dopamine inhibits prolactin release.

Dopamine Receptors

• Five primary types: D1, D2, D3, D4, and D5.
• D2 Receptors: Most clinically relevant; main targets of antipsychotic drugs.

Types of Antipsychotics

First-Generation (Typical) Antipsychotics

• Mechanism: Block D2 receptors across multiple pathways.
• Benefits: Reduce positive symptoms (delusions, hallucinations).
• Drawbacks:
  • Worsen negative symptoms (diminished energy, lack of motivation).
  • Extrapyramidal side effects (tardive dyskinesia, parkinson's-like symptoms).
  • Increased prolactin levels (galactorrhea, gynecomastia, sexual dysfunction).
• Subclassification:
  • High Potency:
    • Examples: Haloperidol, Fluphenazine, Prochlorperazine, Trifluoperazine.
  • Low Potency:
    • Example: Chlorpromazine.

Second-Generation (Atypical) Antipsychotics

• Mechanism: Block both D2 receptors and serotonin 2A receptors.
• Benefits:
  • Lower incidence of extrapyramidal side effects.
  • Decrease negative symptoms and improve cognition.
• Examples: Aripiprazole, Clozapine, Lurasidone, Olanzapine, Quetiapine, Risperidone, Ziprasidone.

Side Effects of Atypical Antipsychotics

• Varies by Drug: Based on receptor binding profile.
• Key Side Effects:
  • Strong affinity for serotonin 2C: Weight gain, hyperglycemia, dyslipidemia (Clozapine, Olanzapine).
  • Strong affinity for H1: Sedation, weight gain (Clozapine, Olanzapine, Quetiapine).
  • Significant affinity for alpha-1: Orthostatic hypotension (Clozapine, Risperidone).
• Risperidone: Strongest affinity for D2; highest potential for extrapyramidal side effects and hyperprolactinemia.
• Clozapine: Risk of agranulocytosis; requires periodic blood cell counts.

Conclusion

• Understanding the pharmacology of antipsychotics is crucial for effective treatment of psychotic disorders.
• Stay tuned for more information in future lectures.