Lecture 4

• Traditional anxiolytics


  Historically grouped with hypnotics and sedatives - CNS depression + poor memory, poor motor coordination
• Traditional anxiolytics


  Common side effects with chronic use (tolerance + dependence)
• Traditional anxiolytics


  • Alcohol
  • Barbiturates
  • Benzodiazepines
• Alcohol


  • Self medicated, non-specific CNS depressant
  • High solubility - rapid effect
  • Blood alcohol conc dependent on many factors
• Alcohol pharmacodynamics


  Allosteric modulator of GABA
• Barbiturates


  • Early 1900s, popular in 1960s
  • Effective but small therapeutic window - death from respiratory + cardiovascular failure
  • 10-100x clinical dose for anxiolysis
  • Effects potentiated by alcohol
  • No longer used for anxiety
• Barbiturates pharmacodynamics


  • MOA not well understood
  • Can open Cl- channel in absence of GABA (so not as safe in overdose as BDZs)
  • Reduces excitability of Na+ channels to prevent action potential generation
• Benzodiazepines


  • Many derivatives including diazepam (Vallium)
  • 49% of psychoactive drugs in the US
• Benzodiazepines


  • Therapeutic uses: Short-term sedation, Relieve muscle tension, Anxiolysis (short-term), Hypnosis, Anticonvulsant
  • Side effects: Acute - Unwanted sedation/drowsiness, Reduced motor coordination, Amnesia, Reduced cognition; Chronic - Tolerance, Dependence, Withdrawal
• Benzodiazepines pharmacokinetics


  • Very short t1/2 = Midazolam (2-4hrs) - conscious sedative, epilepsy
  • Long t1/2 = lorazepam (8-24hrs) - epilepsy, anticonvulsant, panic disorder
  • Plasma concentrations of diazepam and desmethyldiazepam = cumulative over time (elderly) - slow elimination of both compounds
• Benzodiazepines pharmacodynamics

  • Agonists at BDZ receptor on the GABAA Rs
  • Allosteric modulators of GABAA Rs
  • GABAA receptor currents enhanced in the presence of diazepam
• GABA


  • Pentametric ion channel that increases Cl- permeability + hyperpolarises neurone
  • GABAA receptor subtypes = 2α, 2β and 1γ subunit
  • GABAA = 6 α subunits, 3 β subunits, 3 γ subunits, 3 p subunits, d subunit, ε subunit, π subunit, θ subunit
• Anxiety disorders and GABA dysfunction


  • v binding at BDZ site on GABAA receptor/BDZ complex in anxiety disorders
  • = inhibitory transmission is reduced so non-selective CNS depressants counteract this
• GABAA receptor subunits and brain regions

  • α1 - Cerebral + cerebellar cortex, BL amygdala
  • α2 - Hippocampus, central amygdala, striatum
  • α3 - Monoaminergic neurons of brain stem, basal forebrain cholinergic neurons, reticular nucleus of thalamus
  • α5 - Hippocampus
• α1 GABAA receptor subtype

  In the cerebral cortex - involved in wakefulness — receives ascending arousal signal pathways (INHIBITED BY BDZ)
• α2/α3 GABAA receptor subtypes

  • α2 — Largely expressed in the hippocampus, central amygdala and striatum = anxiolysis
  • α3 — monoaminergic neurones of the brain stem, basal forebrain cholinergic neurones, reticular nucleus of the thalamus = anxiolysis
• α5 GABAA receptor subtype

  Hippocampus and spinal cord — learning and memory, muscle relaxation
• Animal tests for GABAA α1 subunit


  • α1(H101R) - Breed mice with GABAA receptors containing α1 still expressed at normal levels sensitive to GABA but insensitive to diazepam
  • Passive avoidance task to evaluate learning and memory - α1 subunit modified mice were insensitive to diazepam-induced amnesia
• Animal tests for GABAA α5 subunit

  • Horizontal wire test - Measure muscle relaxation by assessing grasping reflex - diazepam increases relaxation, α5 mutation reduces diazepam-induced muscle relaxation
• Animal test for BDZ tolerance

  • GABAA chronic use — synaptic plasticity, Expression increase of low BDZ affinity GABAA receptors, Expression decrease of high BDZ affinity GABAA receptors — tolerance and rebound anxiety
• Studies on α1 subtype changes with chronic BDZ treatment


  • Rhesus monkeys injected with α1 selective positive allosteric modulator zolpidem - similar pattern = α1 GABAA receptor subtype responsible for tolerance
  • Mice administered lorazepam - 50% decrease in the levels of cortical α1 subunit mRNA after 14 or 28 days, no decrease in hippocampal mRNA
  • Cell culture treated with flurazepam - no change in α1 subunit density, decrease in efficacy of GABA to enhance [3H]flunitrazepam binding to BDZ site
• BDZ metabolism

  Hepatic metabolism

  A) Chlordiazepoxide

  B) Desmethylchlordiazepoxide

  C) Demoxepam

  D) Diazepam

  E) Alprazolam

  F) Alpha-hydroxy metabolites

  G) Lorazepam

  H) Conjugation

  I) Excretion

  J) Desmethyldiazepam

  K) Oxazepam

  L) Cytochrome P450

  M) Oxidative