Pharm 101: Diazepam

Class

Benzodiazepine

Pharmacodynamics

• Benzodiazepines binds to GABA-A receptor in neuronal membranes in CNS (y subunit of the pentamer). This receptor is a chloride ion channel.
• Enhance inhibitory effect of GABA through membrane hyperpolarisation. This increases frequency of chloride channel opening
  • Do not substitute for GABA
  • Do not directly activate GABA-A receptor or open chloride channels
• Cause sedation, hypnosis, anxiolysis, amnesia, anticonvulsant effect, muscle relaxation, and at higher doses, anaesthesia and cardiorespiratory depression

Pharmacokinetics

• IV, PO, PR, IM (erratic bioavailability)
• Bioavailability 100%
• Hepatic metabolism to active metabolites desmethyldiazepam, and subsequently oxazepam
  • Undergo mirosomal oxidation (phase 1)
  • Subsequent conjugation (phase 2) by glucuronidation
• Time to peak blood level 1-2 hours
• Half-life 20-80 hours
• Renal excretion

Clinical uses

• Anxiety and sleep disorders
• Sedative-hypnotic
  • Sedation of agitated patients
  • Procedural sedation (also has amnesic effect)
  • Anaesthesia adjunct
• Seizure disorders
• Alcohol withdrawal
• Neuromuscular disorders
• Treatment of various toxidromes

Adverse effects

• Dependence and tolerance
• Other are extension of CNS depressant effects
• Excess sedation
• Respiratory depression:
  • Can be profound even at therapeutic doses in patients with pulmonary disease
  • Effects are dose-related
  • Depression of medullary respiratory centre is usual cause of death in overdose
• Cardiovascular depression:
  • May occur at normal dose in hypovolaemic states and heart failure
  • Toxicity causes depression of both myocardial contractility and vascular tone leading to circulatory collapse

Precautions/contraindications

• Additive CNS depression with ethanol and other depressant drugs
• Respiratory or cardiovascular disease due to depressant effects on these organ systems
• Dose reduction in liver failure

References

• Katzung BG. Basic & Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education; 2018. 384-393 p.