Benzodiazepine Use

Pharmacology

  • Sedative-hypnotic class
  • Act on the GABAA receptors (inhibitory) in the brain facilitating GABA binding and enhanced GABA neurotransmission
  • CNS: sedation, striated muscle relaxation, anxiolysis, anticonvulsant
  • PNS: decreased cardiac contractility, vasodilation, increased perfusion
  • Absorption
    • When taken orally the absorption depends on lipophilicity, with those with greater lipophilicity being absorbed more rapidly with a faster onset of action, however due to redistribution (i.e. to adipose tissue) these drugs have a shorter duration of action
  • Metabolism
    • Liver oxidation with the metabolites being conjugated to be excreted in the urine
    • Oxazepam, Lorazepam and Temazepam are directly conjugated (safer in those with liver disease, alcoholics)
    • Many metabolites are active with significant half-lives
  • Pregnancy: benzodiazepines cross the placenta and are present in breast milk

Drugs

  • Long acting
    • Diazepam (Valium)
      • Active metabolites (erratic availability IM)
      • 5 mg PO (2-40 mg/day)
    • Chlordiazepoxide (Librium)
      • Active metabolities (erratic availability IM)
      • 10-20 mg PO (5-300 mg/day)
    • Clonazepam (Rivotril)
      • 0.25-4 mg/day
    • Flurazepam (Dalmane)
      • 15-30 mg/day
  • Short acting
    • Lorazepam (Ativan)
      • No active metabolities
      • 1-2 mg PO/SL; 0.5-2 mg IV (0.5-6 mg/day)
    • Alprazolam (Xanax)
      • Rapidly absorbed orally
      • 0.25-0.5 mg PO (0.25-4 mg/day)
    • Temazepam (Restoril)
      • 7.5-30 mg/day

Benzodiazepines are commonly used for treating the acute manifestations of Panic Disorder and General Anxiety Disorder (see psychiatry notes).  They are recommended for short term use, and should be discontinued slowly in a tapering schedule.



 

Uses

  • Seizure control
  • Anxiety
  • Alcohol withdrawal
  • Insomnia
  • Agitation control
  • Muscle relaxants
  • Amnesia (i.e. procedural sedation)

Abuse potential

  • Short acting benzodiazepines have a higher abuse potential due to the rapid onset of action
  • Tolerance – requiring increased amount of drug to achieve a similar effect with ongoing use
    • May be due to down regulation of receptors in the brain
  • Dependence – requiring ongoing use of drug to prevent withdrawal symptoms

Toxicity

  • The toxicity of benzodiazepines is related to its cardiorespiratory depression and CNS depression

Withdrawal

  • Withdrawal symptoms include psychomotor dysfunction, autonomic dysfunction (tachycardia, diaphoresis, HTN, tremors), insomnia, sensory hypersensitivity
  • Seizures and delirium tremens may occur in abrupt discontinuation of benzodiazepines
  • Protracted abstinence syndrome
    • Believed to be due to chronic use and the resultant neuroadaptation
    • Symptoms of anxiety, depression, insomnia, physical manifestations (GI, MSK, Neuro)
    • Can last for months
    • May occur despite slow tapering

Antagonist

  • Flumazenil
    • Competitive antagonist with high affinity for benzodiazepine receptor
    • Short half-life relative to most benzodiazepines, thus multiple doses may be required
    • Adverse effects include agitation, confusion, dizziness, nausea

Panic attack symptoms

  • Tachycardia
  • Diaphoresis
  • Tremulousness
  • Shortness of breath
  • Feeling of choking
  • Chest pain
  • GI distress
  • Dizziness
  • Feelings of unreality
  • Fear of losing control
  • Fear of dying
  • Paresthesias
  • Chills or hot flashes

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