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The focus is on drugs used to treat schizophrenia, specifically the first generation (typical) and second generation (atypical) antipsychotics.
At the end of this session, students should be able to:
- Describe the mechanism of action of first and second generation antipsychotics.
- Understand the adverse effects associated with these medications.

Strong antagonists at the D2 dopamine receptors.
Effects:
- Reduce positive symptoms of schizophrenia including hallucinations, delusions, and paranoia.
- No effect on negative symptoms (e.g., lack of motivation, social withdrawal) or cognitive deficits, which are often viewed as the core of the disorder.

Exhibit dirty pharmacology:
  - Antagonize multiple receptor types:
    - Muscarinic receptors
    - Histamine H1 receptors
    - Alpha adrenergic receptors
This broad activity leads to a wide range of adverse effects.

Extrapyramidal Side Effects (EPSEs):
  - Parkinsonian symptoms (e.g., tremors, rigidity).
  - Dystonias (involuntary movements, muscle spasms).
  - Akathisia (restlessness).
  - Tardive dyskinesia (rhythmic involuntary movements, lip smacking), which may be irreversible with strong antagonists like haloperidol.
Therapeutic Response:
- Reduction of psychotic symptoms appears to be due to decreased dopamine levels in the mesolimbic system.
Impact on Other Pathways:
  - Nigrostriatal pathway:
    - Blocking dopamine receptors leads to movement disorders (Parkinson's-like symptoms).
  - Tuberoinfundibular pathway:
    - Leads to elevated prolactin levels causing:
      - Sexual dysfunction.
      - Gynecomastia (breast development in men), change in menstrual cycles.

Antimuscarinic Effects:
- Dry mouth, urinary retention, blurred vision, constipation.
Antihistaminergic Effects:
- Sedation, increased appetite, potential weight gain.
Alpha Adrenergic Effects:
- Hypotension due to vasodilation.

Young patients may find the adverse effects of the medications more troubling than the disorder itself, impacting their willingness to adhere to treatment.

Developed to minimize the adverse effects of first generation drugs, particularly extrapyramidal side effects.
Examples include: Clozapine, Olanzapine.

Weaker antagonism at D2 dopamine receptors but stronger antagonism at serotonin receptors.
Reduced psychotic symptoms with some potential to address negative symptoms, though cognitive deficits remain unaffected.

Variable antagonist actions can influence side effects based on specific drugs chosen.
Adverse effects: Lower incidence of EPSEs due to less potent antagonism at D2 receptors combined with serotonin antagonism, which helps stimulate dopamine in the striatum, thus improving motor control.

Weight Gain:
- Particularly prominent with Olanzapine due to blocking of histamine H1 and serotonin receptors leading to increased appetite and metabolic dysfunction (e.g., increased risk of diabetes, heart disease).

Exciting research suggests that addressing muscarinic receptors may provide effective treatment options for schizophrenia.
New Drug Combination:
- Zanomaline: Muscarinic receptor agonist that does not affect dopamine receptors, reduces psychotic symptoms.
- Trospium: Pan muscarinic receptor antagonist that does not cross the blood-brain barrier.
This combination allows stimulation of central muscarinic receptors while blocking peripheral one's effects that could cause side effects.
Approved by the FDA in 2004, but not yet available in Australia.

Continuous exploration of pharmacology is crucial for improving treatment options for schizophrenia, balancing efficacy with side effects, and enhancing patient compliance.