Diazepam

[SH4:p147]

Pharmacodynamics

Effects by systems

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

CVS

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

Respiratory

• 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

 

Pharmacokinetics

Absorption

• IM, IV, Oral
• Rapid oral absorption

 

Distribution

• 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

NB:

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

Metabolism

[SH4:p147]

• 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

NB:

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

Elimination

• 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

NB:

• 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

Pharmaceutics

• 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

NB:

• May also be available in soybean formulation

Composition

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

Clinical

Usages

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

Others

• 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

Overdose

• 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]