Mechanism of Action of Typical Antipsychotics (First-Generation)

Introduction

Typical antipsychotics, also known as first-generation antipsychotics (FGAs), are primarily used to treat schizophrenia, acute psychosis, and manic episodes. Their therapeutic effect is mainly due to dopamine D2 receptor antagonism in the brain. However, this same action also causes many extrapyramidal side effects (EPS) and hyperprolactinemia.

Common FGAs include:

• Haloperidol
• Chlorpromazine
• Fluphenazine
• Thioridazine
• Trifluoperazine
• Perphenazine

These drugs are frequently covered in USMLE, NCLEX, NEET-PG, and GPAT pharmacology sections.

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Stepwise Mechanism of Action of Typical Antipsychotics

1. Blockade of dopamine D2 receptors in mesolimbic pathway
   The antipsychotic effect comes from D2 receptor antagonism in the mesolimbic tract, which reduces positive symptoms (e.g., hallucinations, delusions) of schizophrenia.
2. D2 receptor blockade in other brain regions
   • Nigrostriatal pathway: causes EPS (e.g., parkinsonism, dystonia, akathisia).
   • Tuberoinfundibular pathway: causes increased prolactin levels (galactorrhea, gynecomastia).
   • Mesocortical pathway: may worsen negative symptoms and cognitive dysfunction.
3. Additional receptor blockade (especially low-potency FGAs)
   • Alpha-1 adrenergic blockade: orthostatic hypotension
   • H1 histamine blockade: sedation, weight gain
   • Muscarinic blockade: dry mouth, constipation, urinary retention

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Pharmacokinetic Parameters of Typical Antipsychotics

Drug	Potency	Half-life	Metabolism	Notes
Haloperidol	High	12–36 hrs	Hepatic (CYP3A4)	Most used in acute settings
Chlorpromazine	Low	~30 hrs	Hepatic	More sedating, anticholinergic
Fluphenazine	High	~15–30 hrs	Hepatic	Available in depot form
Thioridazine	Low	~12–24 hrs	Hepatic	Causes retinal pigmentation
Trifluoperazine	High	~18 hrs	Hepatic	Potent antipsychotic

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Clinical Uses of Typical Antipsychotics

• Schizophrenia (positive symptoms)
• Acute psychosis
• Mania
• Tourette syndrome (haloperidol)
• Delirium (short-term)
• Severe agitation in ICU
• Nausea and vomiting (prochlorperazine, a related drug)

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Adverse Effects of Typical Antipsychotics

• Extrapyramidal symptoms (EPS)
  • Acute dystonia
  • Akathisia
  • Parkinsonism
  • Tardive dyskinesia (long-term)
• Hyperprolactinemia
  • Galactorrhea, gynecomastia, amenorrhea
• Neuroleptic Malignant Syndrome (NMS)
  • Rigidity, hyperthermia, altered mental status
• Sedation (H1 blockade)
• Anticholinergic effects – dry mouth, constipation
• Orthostatic hypotension (α1-blockade)
• QT prolongation
• Retinal deposits (thioridazine)

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Comparative Analysis: Typical vs Atypical Antipsychotics

Feature	Typical Antipsychotics	Atypical Antipsychotics
D2 blockade	Strong	Moderate
5-HT2A blockade	Minimal	Prominent
EPS risk	High	Lower
Effect on negative symptoms	Minimal or worsens	Better effect
Sedation and weight gain	Higher with low-potency	Variable

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Practice MCQs

Q1. Typical antipsychotics primarily act on which receptor?
a. 5-HT2A
b. D2 dopamine receptor ✅
c. GABA-A
d. NMDA receptor

Q2. Which pathway is responsible for EPS in FGAs?
a. Mesolimbic
b. Tuberoinfundibular
c. Nigrostriatal ✅
d. Mesocortical

Q3. Hyperprolactinemia is due to blockade of D2 in which pathway?
a. Nigrostriatal
b. Mesolimbic
c. Tuberoinfundibular ✅
d. Cortical

Q4. Which of the following is a high-potency FGA?
a. Chlorpromazine
b. Haloperidol ✅
c. Thioridazine
d. Olanzapine

Q5. Tardive dyskinesia occurs after:
a. One dose
b. Few days
c. Long-term use ✅
d. Overdose

Q6. A life-threatening complication of FGAs is:
a. EPS
b. Neuroleptic Malignant Syndrome ✅
c. Hypertension
d. Anemia

Q7. Which receptor blockade causes sedation in FGAs?
a. D2
b. H1 ✅
c. Alpha-2
d. GABA-B

Q8. What visual side effect is associated with thioridazine?
a. Myopia
b. Retinal deposits ✅
c. Optic neuritis
d. Cataract

Q9. Haloperidol is preferred in:
a. Sleep disorders
b. Chronic depression
c. Acute psychosis ✅
d. OCD

Q10. FGAs are more effective in controlling:
a. Hallucinations ✅
b. Social withdrawal
c. Blunted affect
d. Cognitive symptoms

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FAQs

Q1: Do typical antipsychotics treat both positive and negative symptoms?
Primarily effective for positive symptoms only. Negative and cognitive symptoms may worsen.

Q2: Are FGAs safe in pregnancy?
Some are used with caution. Haloperidol has the most safety data.

Q3: Which side effect needs immediate discontinuation of the drug?
Neuroleptic Malignant Syndrome – a medical emergency.

Q4: Can FGAs be used long-term?
Yes, but with monitoring for EPS and tardive dyskinesia.

Q5: Which FGA is available in depot form for long-term use?
Fluphenazine and haloperidol decanoate.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK557852/