3. Pharmacology
          3.3. IV anaesthetic agents
              3.3.6. Benzodiazepine Diazepam




Effects by systems

  • Does not increase incidence of nausea and vomiting
  • Minimal effects on ventilation and systemic circulation
    * Similar to other benzodiazepines


  • Minimal decrease in BP, CO, and SVR
  • No direct action on sympathetic nervous system
  • Does not cause orthostatic hypotension


  • Decrease in the slope of CO2 response curve
    * But NO shift to the right as observed with opioid [SH4:p149]

Skeletal muscles

  • Acts on spinal internuncial neurons
    --> Diminishes the tonic facilitatory influence on spinal gamma-neurons
    --> Skeletal muscle relaxation
  • No action on NM junction
  • Tolerance occurs to this skeletal muscle relaxation effect of benzodiazepine




  • IM, IV, Oral
  • Rapid oral absorption



  • Vd = 1-1.5 L/kg
  • Protein-binding = 96-98%
    * Efficacy of haemodialysis in diazepam overdose is reduced
    * Increased sensitivity with decreased albumin (e.g. cirrhosis, renal insufficiency)
  • Rapid uptake into brain
  • Redistribution to inactive tissues, especially fat
  • High lipid solubility
    --> Large Vd [SH4:p147]
  • Women are likely to have larger Vd
    * Due to greater body fat content
  • Readily crosses the placenta
    --> Foetal concentration may be the same level or higher than maternal level


  • Vd is said to be large, but actually not that large. Nothing like propofol.



  • Principally metabolised by hepatic microsomal enzyme
    * By an oxidative pathway of N-demethylation
  • Metabolites
    * Desmethyldiazepam (by N-demethylation of diazepam)
    * Oxazepam (by hydroxylation of desmethyldiazepam)
    * Temazepam (to less extent, by hydroxylation of diazepam)
  • Desmethyldiazepam (aka nordiazepam)
    * Metabolised more slowly than oxazepam
    * Only slightly less potent than diazepam
    * Can cause return of drowsiness 6-8 hours after administration of diazepam
    * Ultimately excreted in urine as oxidized metabolite and glucuronide conjugates
  • Enterohepatic recirculation may contribute to recurrence of sedation


  • Benzodiazepine do NOT cause enzyme induction
  • Cimetidine
    --> Inhibits P450 hepatic microsomal enzymes
    --> Prolongs elimination half-life of diazepam and desmethyldiazepam


  • Elimination half-time of diazepam is increased by
    * Cirrhosis (fivefold increase)
    * Advanced age
  • Elimination half-time for diazepam = 21-37 hours
  • Elimination half-time for desmethyldiazepam = 48-96 hours
    * Longer than diazepam


  • Prolonged elimination in cirrhosis is due to
    * Increased Vd (secondary to decreased protein-binding)
    * Decreased hepatic clearance (decreased hepatic blood flow)
  • Prolonged elimination in elderly is due to
    * Increased Vd
    * Hepatic clearance is UNCHANGED

Action profile

Oral administration

  • Peak concentration
    = 1 hour in adults
    = 15-30 minutes in children

Diazepam vs lorazepam

  • Diazepam has longer elimination half-time
  • Diazepam has SHORTER duration of action
    * Due to faster dissociation from GABAa receptors
    --> Greater redistribution to inactive tissues


  • Diazepam is dissolved in organic solvents (propylene glycol, sodium benzoate)
    * Because it is insoluble in water
    --> IM or IV injection may be painful
    * Unlike midazolam
  • Solution is viscid
  • pH = 6.6 - 6.9
    * [SH4:p147]
  • Diluation causes cloudiness, but does not affect action


  • May also be available in soybean formulation


  • Active: Diazepam 0.5%
  • Inactive:
    * Propylene glycol 53%
    * Ethanol 31%
  • pH = 6.2 - 7.0 [PI on MIMs)



Anticonvulsant activity

  • Diazepam at 0.1mg/kg IV is effective in abolishing seizure produced by
    * Lidocaine
    * Delirium tremens
    * Status epilepticus
  • Anticonvulsant activity by diazepam is due to facilitation of GABA
    --> Selective inhibition of the limbic system (especially the hippocampus)
    * c.f. Anticonvulsive activity of barbiturates is by nonselelctive depression of the CNS


  • May also be used for skeletal muscle relaxation in lumbar disc disease
  • Midazolam is mostly replaced diazepam for IV sedation and preoperative medication of children


  • Despite massive overdoses, serious sequelae (e.g. coma) are unlikely to occur if cardiac and pulmonary functions are supported, and other drugs (e.g. alcohol) are absent [SH4:p150]


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