Classification of Antipsychotic Drugs

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Classification of Antipsychotic Drugs




Antipsychotic drugs, also known as neuroleptics or major tranquilizers, are primarily used to treat psychotic disorders such as schizophrenia, bipolar disorder, and other conditions associated with psychosis. These drugs work by altering the activity of neurotransmitters, especially dopamine, in the brain. They are broadly classified into first-generation (typical) and second-generation (atypical) antipsychotics.

1. Pharmacological Classification of Antipsychotic Drugs

Antipsychotic drugs can be classified into two main categories based on their mechanism of action, receptor affinity, and side effect profile:

  • First-Generation Antipsychotics (FGAs) or Typical Antipsychotics: These drugs primarily block dopamine (D2) receptors, which alleviates the positive symptoms of psychosis but can also lead to extrapyramidal side effects (EPS).
  • Second-Generation Antipsychotics (SGAs) or Atypical Antipsychotics: These drugs block both dopamine (D2) receptors and serotonin (5-HT2A) receptors, which leads to fewer extrapyramidal side effects and better control of both positive and negative symptoms of psychosis.

First-Generation Antipsychotics (FGAs)

First-generation antipsychotics are divided into two subcategories based on their potency at the D2 receptor:

  • Low Potency FGAs
  • High Potency FGAs

a) Low Potency First-Generation Antipsychotics

These drugs have a lower affinity for D2 receptors but higher anticholinergic, antihistaminergic, and alpha-adrenergic effects, which lead to more sedation, hypotension, and anticholinergic side effects (dry mouth, constipation, etc.). However, they are less likely to cause severe extrapyramidal side effects.

  1. Chlorpromazine

    • Mechanism of Action: Blocks dopamine D2 receptors.
    • Indications: Used for schizophrenia, mania, and nausea/vomiting.
    • Side Effects: Sedation, orthostatic hypotension, weight gain, and anticholinergic effects (dry mouth, constipation, urinary retention).
    • Clinical Use: One of the earliest antipsychotics, it is less frequently used today due to its side effect profile.

  2. Prochlorperazine

    • Mechanism of Action: Primarily blocks dopamine receptors in the brain.
    • Indications: Mostly used for the treatment of severe nausea and vomiting, but also for psychotic disorders.
    • Side Effects: Similar to other low-potency antipsychotics with a notable risk of sedation and hypotension.

  3. Thioridazine

    • Mechanism of Action: Dopamine receptor antagonist with strong anticholinergic properties.
    • Indications: Previously used for schizophrenia but is less commonly used today due to the risk of cardiac arrhythmias (QT prolongation).
    • Side Effects: Sedation, orthostatic hypotension, and significant cardiac side effects (QT prolongation).

b) High Potency First-Generation Antipsychotics

These drugs have a higher affinity for D2 receptors, resulting in more significant dopamine antagonism and a greater likelihood of causing extrapyramidal side effects (EPS), such as tremors, rigidity, and tardive dyskinesia. However, they are less sedating and have fewer anticholinergic effects than low-potency agents.

  1. Fluphenazine

    • Mechanism of Action: Potent dopamine D2 receptor antagonist.
    • Indications: Schizophrenia and other psychotic disorders.
    • Side Effects: High risk of extrapyramidal side effects, such as dystonia, akathisia, and tardive dyskinesia. Can also cause neuroleptic malignant syndrome (NMS).
    • Clinical Use: Available in oral and long-acting injectable forms.

  2. Haloperidol

    • Mechanism of Action: Strong dopamine D2 receptor antagonist.
    • Indications: Schizophrenia, acute agitation, and delirium. Also used in Tourette syndrome to control tics.
    • Side Effects: High risk of EPS, NMS, and QT prolongation. Minimal sedation and anticholinergic effects compared to low-potency FGAs.
    • Clinical Use: Frequently used due to its potency, particularly in acute settings for controlling agitation or psychosis.

  3. Pimozide

    • Mechanism of Action: Dopamine receptor antagonist with some serotonin blocking activity.
    • Indications: Primarily used to treat Tourette syndrome and other disorders involving motor tics.
    • Side Effects: Similar to other high-potency antipsychotics, with EPS and QT prolongation being major concerns.

  4. Thiothixene

    • Mechanism of Action: Potent dopamine receptor antagonist.
    • Indications: Used in the management of schizophrenia.
    • Side Effects: High risk of EPS, particularly parkinsonism and dystonia, as well as other typical antipsychotic side effects.

Second-Generation Antipsychotics (SGAs)

Second-generation antipsychotics have a broader mechanism of action, as they not only block dopamine receptors but also have significant effects on serotonin receptors (especially 5-HT2A). This results in fewer extrapyramidal symptoms and improved efficacy for both positive and negative symptoms of schizophrenia.

  1. Aripiprazole

    • Mechanism of Action: Partial agonist at dopamine D2 and serotonin 5-HT1A receptors, antagonist at 5-HT2A receptors.
    • Indications: Schizophrenia, bipolar disorder, depression (adjunctive), and irritability in autism.
    • Side Effects: Less risk of EPS and metabolic side effects, but may cause insomnia, restlessness, and akathisia.
    • Unique Feature: "Dopamine stabilizer" due to its partial agonist activity.

  2. Asenapine

    • Mechanism of Action: Antagonist at dopamine and serotonin receptors.
    • Indications: Schizophrenia and bipolar disorder.
    • Side Effects: May cause sedation, dizziness, and weight gain, but has a lower risk of EPS.

  3. Clozapine

    • Mechanism of Action: Dopamine receptor antagonist, also has strong serotonin receptor blocking activity.
    • Indications: Treatment-resistant schizophrenia and schizophrenia with a high risk of suicidal behavior.
    • Side Effects: Agranulocytosis (requires regular blood monitoring), weight gain, diabetes, sedation, and drooling.
    • Unique Feature: Considered the most effective antipsychotic but is reserved for treatment-resistant cases due to its side effect profile.

  4. Iloperidone

    • Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
    • Indications: Schizophrenia.
    • Side Effects: May cause dizziness, orthostatic hypotension, and weight gain but has a relatively low risk of EPS.

  5. Lurasidone

    • Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
    • Indications: Schizophrenia and depressive episodes associated with bipolar disorder.
    • Side Effects: Relatively low risk of metabolic side effects, but may cause EPS, especially akathisia.

  6. Olanzapine

    • Mechanism of Action: Antagonist at dopamine and serotonin receptors.
    • Indications: Schizophrenia and bipolar disorder, including manic and mixed episodes.
    • Side Effects: Significant risk of weight gain, diabetes, and sedation. Lower risk of EPS compared to FGAs.
    • Clinical Use: Effective but often avoided due to its metabolic side effects.

  7. Quetiapine

    • Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
    • Indications: Schizophrenia, bipolar disorder (including depression), and major depressive disorder (adjunctive).
    • Side Effects: Sedation, weight gain, and metabolic syndrome are common. Lower risk of EPS.
    • Unique Feature: Also used off-label for sleep disorders due to its sedative properties.

  8. Paliperidone

    • Mechanism of Action: Dopamine D2 and serotonin 5-HT2A receptor antagonist.
    • Indications: Schizophrenia and schizoaffective disorder.
    • Side Effects: Similar to risperidone, with EPS, weight gain, and metabolic effects. Available as a long-acting injectable.

  9. Risperidone

    • Mechanism of Action: Antagonist at dopamine D2 and serotonin 5-HT2A receptors.
    • Indications: Schizophrenia, bipolar disorder, and irritability associated with autism.
    • Side Effects: Higher risk of EPS compared to other SGAs, particularly at higher doses. Also associated with weight gain and hyperprolactinemia.
    • Clinical Use: Commonly used due to its availability in oral and long-acting injectable forms.

  10. Ziprasidone

  • Mechanism of Action: Dopamine D2 and serotonin 5-HT2A receptor antagonist.
  • Indications: Schizophrenia and bipolar disorder.
  • Side Effects: Lower risk of metabolic side effects but may cause QT prolongation and sedation.









The mnemonic ISHADE is a helpful tool for remembering the common side effects of antipsychotic medications. Here's how these side effects come about:

1. Impotence

  • Cause:
    Antipsychotic medications, particularly first-generation antipsychotics (FGAs), can cause sexual dysfunction, including impotence, due to their effect on dopamine and prolactin levels. Dopamine blockade in the tuberoinfundibular pathway leads to increased prolactin levels, which can inhibit sexual function.

2. Sedation and Seizures

  • Cause (Sedation):
    Many antipsychotics, especially low-potency FGAs and some second-generation antipsychotics (SGAs) like clozapine, have antihistamine effects due to H1 histamine receptor blockade. This can cause sedation.

  • Cause (Seizures):
    Antipsychotics, particularly clozapine, lower the seizure threshold. This occurs because of their action on GABAergic pathways and dopamine blockade, which can disturb the balance of excitatory and inhibitory neurotransmitters in the brain, leading to an increased risk of seizures.

3. Hypotension

  • Cause:
    Antipsychotics block alpha-1 adrenergic receptors, which leads to vasodilation and a reduction in blood pressure. This can cause orthostatic hypotension, where the patient feels dizzy or light-headed when standing up. Low-potency antipsychotics, like chlorpromazine, are more likely to cause this side effect.

4. Akathisia (Inability to sit still)

  • Cause:
    Akathisia is a type of extrapyramidal symptom (EPS) associated with the dopamine receptor blockade in the nigrostriatal pathway. This leads to motor restlessness, making it difficult for the patient to sit still. Akathisia is more common with high-potency first-generation antipsychotics such as haloperidol.

5. Dermatological Side Effects

  • Cause:
    Some antipsychotics, especially chlorpromazine, can cause photosensitivity and pigmentation changes in the skin due to their chemical structure and interaction with UV light. Long-term use can also result in dermatitis or other skin reactions.

6. Extrapyramidal Reactions

  • Cause:
    Extrapyramidal symptoms (EPS), such as acute dystonias, rigidity, tremor, and tardive dyskinesia, occur due to the dopamine blockade in the nigrostriatal pathway. This pathway is involved in the coordination of movement, and its disruption leads to the motor side effects characteristic of first-generation antipsychotics.

  • Tachycardia may be a result of anticholinergic activity or compensatory responses to the sedative effects of the drugs.

Summary of ISHADE:

  • Impotence: Increased prolactin due to dopamine blockade
  • Sedation/Seizures: Histamine receptor blockade and seizure threshold reduction
  • Hypotension: Alpha-1 adrenergic blockade
  • Akathisia: Dopamine blockade in the nigrostriatal pathway
  • Dermatological effects: Chemical interactions with UV light, leading to skin sensitivity
  • Extrapyramidal reactions: Dopamine receptor blockade leading to movement disorders

Each of these side effects arises from the broad receptor activity of antipsychotic drugs, particularly their action on dopaminergic, adrenergic, histaminergic, and cholinergic systems.





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