apnes3

• CNS Depressants


  Drugs that enhance GABAergic synaptic transmission and therefore neuronal inhibition
• Drugs targeting the GABA synapses


  • GABAA receptor allosteric modulation
  • GABAA receptor agonism
  • GABAB receptor agonism
  • GABA transporter inhibition
  • GABA transaminase inhibition

  
• GABA


  • Inhibitory neurotransmitter
  • ~20% of neurons are GABAergic
  • Most are short interneurons
  • Some long GABAergic tracts (e.g. striatum to substantia nigra and globus pallidus)
  • Hyperpolarization of neurons
  • Making the membrane potential more negative
  • Less likely to fire action potential

  
• GABAA receptors


  • Ligand-gated ion channel (ionotropic)
  • Selectively permeable to Cl- ions
  • Cl- enter the cells: hyperpolarization
  • Reduce the neuronal excitability

  
• GABAB receptors


  • G protein-coupled receptors (metabotropic)
  • Inhibit adenylyl cyclase via Gi/Go
  • Reduced production of cAMP
  • Open the potassium channel: reduce postsynaptic excitability

  
• GABAA receptors


  • Primarily located postsynaptically
  • Fast and tonic postsynaptic inhibition
  • Pentamer made up of different subunits
  • 19 known subunits now
  • In general, two α, two β, one γ in a sequence α-β-α-β-γ
  • GABA bind at α/β interface
  • Benzodiazepines bind at α/γ interface (subunit determine drug sensitivity)

  
• GABAB receptors


  • Located pre- and postsynaptically
  • Require second messenger: cAMP
  • Dimer: B1 and B2 are seven-transmembrane subunit
  • B1: binds to GABA (Venus fly trap)
  • B2: interact and activate G protein

  
• Benzodiazepines (BZDs)


  • Bind at α/γ interface (subunit determine drug sensitivity)
  • BZDs have NO agonist activity
  • NO direct action on ion flow
  • BZDs are positive allosteric modulators
  • Binding of BZDs to α/γ interface induces a conformational change of GABAA receptors
  • Enhance its affinity to GABA

  
• Benzodiazepines (BZDs)


  • Only α1, α2, α3 and α5 are sensitive to BZDs
  • α1 and α5 induce sedation and hypnosis (at higher doses) to increase relaxation for improved focus and concentration
  • α2 and α3 induce anxiolytic/calming and muscle-relaxant effects
  • α1, α2, α3 and α5 subunits exhibit anticonvulsant activity (suppress the excessive rapid firing of neurons during seizures)
  • NO subunit-specific BDZs: unwanted side effects
  • α4 and α6 are insensitive to BDZs
• Subunit selectivity of various BZDs
• Diazepam


  • Fast-acting, long-lasting BZDs
  • Used to treat: Muscle spasm, Convulsions, Anxiety, Symptomatic relief of alcohol withdrawal
• Lorazepam


  • Fast-acting (1-3 min), short-lived BZDs
  • Used to treat: Short-term relief of anxiety symptoms, Short-term use for anxiety-associated insomnia, Anaesthesia premedication, Convulsions
• Midazolam


  • Fast-acting (water soluble), ultrashort-lived BZDs
  • Used to treat: Convulsions, Sedation, Adjunct to antipsychotic for confusion and restlessness in palliative care
• Clonazepam


  • Fast-acting, long-lived BZDs
  • Used to treat: Broad spectrum of epilepsy, Short-term management of panic disorders, Acute treatment of panic attacks
• Alprazolam


  • Fast-acting, medium-lived BZDs
  • Used to treat: Short-term use for treating anxiety, Panic disorders with or without agoraphobia
• Side effects of BZDs (short-term)


  • Drowsiness - avoid driving or operating machinery
  • Confusion, especially in the elderly
  • Amnesia - memory impairment
  • Ataxia and muscle weakness
  • Potentiation of sedative effects of other CNS depressants - severe depression of respiratory and cardiovascular centres in the brainstem (fatal)
  • Paradoxical increase in aggression - suppress cortical inhibition of limbic areas of the brain that normally modulate social behaviour or conventions

  
• Side effects of BZDs (long-term)


  • Dependence with physical and psychological withdrawal syndromes
  • Rebound anxiety, insomnia, nausea, and cognitive, perceptual and mood changes
  • Aggravate depression - provoke suicide
  • Apathy - emotional anaesthesia, decreased motivation
  • Development of epileptic-like seizures if sudden withdrawal - anticonvulsant properties of BZDs
  • Gradual withdrawal over a number of weeks or months
• BZD antagonist - Flumazenil


  • Fast-onset, competitive inhibitor - interact with BZD receptors site
  • Reverse the binding of BZD to BZD receptors
  • Reversal agents for BZDs
  • Reversal of postoperative sedation from BZD anesthetics
  • Reversal of benzodiazepine overdose
• Non-benzodiazepines allosteric modulators of GABAA receptors


  • Zaleplon, Zolpidem, Zopiclone (Z-drugs)
  • All Z-drugs bind to the regulatory site that is close to, but distinct from BZD binding site
  • Potentiate Cl- influx to the cells
  • Zaleplon has a high binding affinity to α1 receptors, with much lower affinity for α2/3
  • Zolpidem has a high binding affinity to α1 receptors, with much lower affinity for α2/3. No affinity for α5
  • Zopiclone has a higher affinity for α1 and α5 receptors, but still some modulation for α2/3

  
• Non-benzodiazepines allosteric modulators of GABAA receptors


  • Strong hypnotic (sedative) effects
  • Weak anxiolytic, myorelaxant, and anticonvulsant properties
  • Very short duration of action; very short half-life
  • Short-term use for the treatment of insomnia
• Barbiturates (Thiopental & Phenobarbital)


  • Act as positive allosteric modulators (low conc.) of GABAA receptors
  • Increase the duration of opening of Cl- channels (BZDs increase the frequency of opening of Cl- channels)
  • Function as direct agonists (high conc.) of GABAA receptors: activation of GABAA receptors
  • Inhibit the actions of glutamate by binding to the AMPA receptor

  
• Barbiturates (Thiopental & Phenobarbital)


  Clinical indications: Extensive use as an antiepileptic drug (status epilepticus), Induction of anaesthesia, Induction of coma for increased intracranial pressure in patients with traumatic brain injury (under ventilation controlled)
• Etomidate


  • Binds to β2 and β3 subunits of GABAA receptors
  • Act as positive allosteric modulators (clinical dose) of GABAA receptors to enhance the effects of endogenous GABA in inducing both synaptic and extrasynaptic (tonic) currents
  • Function as direct agonists (above clinical dose) of GABAA receptors: activation of GABAA receptors
  • Use for induction of general anaesthesia

  
• Baclofen - GABAB receptor agonist


  • Agonist at GABAB receptors expressed in presynaptic terminals of glutamatergic axons
  • Neuronal inhibition of glutamatergic axons
  • Inhibit adenylyl cyclase - decrease cAMP
  • Activate potassium channels
  • Inhibit voltage-gated calcium channel
  • Reduced glutamate release: inhibition
  • Used to treat muscle spasms caused by multiple sclerosis and spinal cord injury or in palliative care

  
• Tiagabine - blocker of GABA transporter 1


  • GABA transporter (GAT) facilitates the reuptake of GABA to the presynaptic terminals and glial cells
  • Lowering GABA availability in the synapses for synaptic transmission (neuronal inhibition)
  • Tiagabine blocks the functions of GAT1 (predominant GAT in neocortex and hippocampus)
  • Increase the amount of GABA in the synapses
  • Prolong the duration of GABA to its receptors - increase synaptic transmission for neuronal inhibition
  • Used as an adjunctive treatment for epilepsy

  
• Vigabatrin - blocker of GABA transaminase


  • GABA transaminase (GABA-T) is the main degradative enzyme of GABA
  • Fewer GABA is available for synaptic transmission (neuronal inhibition)
  • Vigabatrin serves as an irreversible inhibitor of GABA-T - long-lasting effects
  • Block the breakdown of GABA by GABA-T
  • Increase GABA content in the synapses
  • More GABA is available in the releasable pool
  • Enhance inhibitory transmission
  • Used as an adjunctive treatment for resistant epilepsy