Pharm 101: Chlorpromazine

Class

First generation antipsychotic (FGA)

Pharmacodynamics

• Aliphatic phenothiazine derivative
• Greater blockade of D2 receptors than 5-HT-2a receptors (high D2/5-HT2A ratio)
• Alpha1-receptor, M receptor and H1 receptor blockade (especially extensive alpha1 blockade, causing many autonomic adverse effects)
• Clinical effects:
  • Low clinical potency
  • Medium extrapyramidal toxicity
  • High sedative action
  • High hypotensive action

Pharmacokinetics of antipsychotic drugs (general)

• Characteristics of most antipsychotic drugs:
  • Readily but incompletely absorbed
  • Significant first-pass metabolism
  • Highly lipid soluble and protein bound (92-99%)
  • Large volumes of distribution (usually > 7L/kg)
  • Much longer duration of action than estimated from their plasma half-lives
  • Hepatic metabolism by oxidation or demethylation, catalysed by CYP450 enzymes

Clinical uses

• Schizophrenia (alleviates positive symptoms)
• Bipolar disorder (manic phase)
• Antiemetic
• Agitation

Adverse effects of antipsychotic drugs

• Muscarinic cholinoceptor blockade:
  • Loss of accomodation, dry mouth, difficulty urinating, constipation
  • Tachycardia
  • Toxic-confusional state
• Alpha-adrenoceptor blockade:
  • Postural hypotension
  • Impotence, failure to ejaculate
• Dopamine-receptor blockade:
  • Parkinson’s syndrome
  • Akathisia, dystonias
  • Neuroleptic malignant syndrome
  • Amenorrhoea, galactorrhoea, infertility, impotence due to hyperprolactinaemia resulting from dopamine receptor blockade
• Supersensitivity of dopamine receptors:
  • Tardive dyskinesia
• H1 receptor blockade:
  • Sedation
• Combined H1 and 5-HT2 blockade:
  • Weight gain
• Specific to chlorpromazine:
  • Extensive alpha blockade causing hypotension
  • Seizures
  • Corneal deposits

Precautions/contraindications

• Combination with other drugs producing extrapyramidal dysfunction, sedative effects, alpha-blockade, anti-cholinergic effects

Further reading

• Buttner R. Pharm 101: Olanzapine. LITFL
• Buttner R. Pharm 101: Haloperidol. LITFL

References

• Katzung BG. Basic and Clinical Pharmacology. 14e. 2018: 515-529