Pharmacology - ANTIPSYCHOTICS (MADE EASY)

Introduction to Antipsychotics

• Antipsychotics are drugs used primarily to treat psychotic disorders, including:

  • Schizophrenia

  • Mania due to bipolar disorder

  • Severe depression

Understanding Dopamine and Psychosis

• Dopamine plays a crucial role in the dopamine hypothesis related to psychosis, suggesting that behavioral changes in psychosis stem from altered dopamine function.

• Major dopamine pathways in the brain:

  1. Mesolimbic pathway

     • Hyperactivity linked to schizophrenia.

     • Mediates positive symptoms like delusions and hallucinations.

  2. Mesocortical pathway

     • Underactivity associated with schizophrenia.

     • Mediates negative symptoms such as loss of motivation and social withdrawal.

  3. Nigrostriatal pathway

     • Controls motor function and movement.

     • Deficiency can lead to dystonia and Parkinsonian symptoms; excess can cause hyperkinetic movements.

  4. Tuberoinfundibular pathway

     • Regulates prolactin secretion, inhibiting its release.

     • Prolactin is involved in milk production, sexual desire, and immune system regulation.

Dopamine Receptors

• Five primary types of dopamine receptors: D1, D2, D3, D4, and D5.

• D1 and D2 receptors are most concentrated in pathways related to psychosis, with D2 being the most clinically relevant as they are the main focus of antipsychotic drugs.

Types of Antipsychotics

First-Generation Antipsychotics (Typical Antipsychotics)

• All aim to block D2 receptors regardless of the pathway:

  • Positive effects include reduction of delusions and hallucinations.

  • Negative consequences can include worsening of negative symptoms (e.g., lack of motivation), extrapyramidal symptoms (e.g., tremors, rigidity), and increased prolactin levels leading to side effects like galactorrhea and gynecomastia.

• Potency classifications:

  • High Potency Examples: Haloperidol, Fluphenazine, Prochlorperazine, Trifluoperazine

  • Low Potency Example: Chlorpromazine

  • High potency agents have stronger effects at lower doses but more side effects; low potency agents have broader receptor interaction leading to varied side effect profiles:

    • Alpha-adrenergic blockage can cause orthostatic hypotension.

    • Muscarinic receptor blockade leads to anticholinergic symptoms (e.g., dry mouth, constipation).

    • H1-histamine receptor blockade causes sedation and potential weight gain.

Second-Generation Antipsychotics (Atypical Antipsychotics)

• Block both D2 and serotonin subtype 2A receptors, which may enhance dopamine levels in areas of need:

  • Allow for normal dopamine functioning due to transient receptor occupancy, resulting in fewer extrapyramidal side effects and improved cognition.

• Examples of Atypical Antipsychotics: Aripiprazole, Clozapine, Lurasidone, Olanzapine, Quetiapine, Risperidone, Ziprasidone.

• Additional receptor interactions can lead to varied side effects based on each drug's binding profile:

  • Clozapine and Olanzapine (strong 5-HT2C affinity) potentially cause metabolic side effects (weight gain, hyperglycemia).

  • Clozapine and Risperidone may cause orthostatic hypotension due to alpha-1-adrenergic receptor affinity.

  • Risperidone shown to have a strong D2 receptor affinity leading to increased risk for extrapyramidal side effects and hyperprolactinemia.

  • Clozapine can lead to agranulocytosis, necessitating regular blood tests due to its serious risk of lowering white blood cells.

Conclusion

• Understanding the pharmacology and receptor interactions allows for better management of psychotic disorders, optimizing treatment with an emphasis on balancing efficacy with minimizing side effects.