Barbiturates: Mechanism of Action and Classification

Barbiturates

• Classified according to their durations of action
• Site of action: depress neurons and synapses of the mesenocephalic reticular activating system (RAS), reducing electrical activity of the cortex
• Mechanism of action:
  • GABA potentiators, enhancing GABA effect or stimulating its release
  • Activate inhibitory GABAA receptors
  • Promote GABA-induced chloride current
  • Increase duration of GABA-gated channel openings
  • May be GABA-mimetic (high concentration) by direct activation of chloride channels through binding sites distinct from benzodiazepines (BDZ) binding sites
• Pharmacokinetics:
  • Absorption: well absorbed
  • Distribution: thiobarbitone is highly lipid soluble and crosses BBB rapidly to the brain and then redistributed in less vascular tissues
  • Excretion: phenobarbitone is excreted unchanged in the urine and its excretion is increased significantly by alkalinization of urine

Effects of Barbiturates

• Depression of CNS:
  • At low doses: sedation
  • At high doses: hypnosis, anesthesia, coma, and death
• Respiratory depression:
  • Lethal dose: suppresses hypoxic and chemoreceptor response to CO2, and overdose is followed by respiratory depression and death
• CVS:
  • High dose: hypotension due to suppression of ganglionic transmission and suppression of VMC
• Liver:
  • Enzyme inducer and decreases effect of many drugs

Therapeutic Uses of Barbiturates

• Anesthesia: selection of a barbiturate is strongly influenced by the desired duration of action
• Sedative/hypnotic: used to relieve anxiety, nervous tension, and insomnia
• Anticonvulsant: phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus, and eclampsia

Adverse Effects of Barbiturates

• CNS: drowsiness and mental confusion
• Hangover: hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes
• Porphyrin synthesis: increases porphyrin synthesis and is contraindicated in patients with acute intermittent porphyria
• Abuse and dependence: tolerance develops on repeated use, and abrupt withdrawal may cause tremors, anxiety, weakness, restlessness, nausea, and vomiting, seizures, delirium, and cardiac arrest

Benzodiazepines

• Advantages:
  • Wide safety margin
  • Little CV and respiratory depression
  • Fewer drug interactions
  • Lower abuse liability and least to alter sleep pattern
  • Specific antagonist flumazenil
• Mechanism of action:
  • Targets GABAA receptors
  • GABAA receptors are composed of a combination of five α, β, and γ subunits that span the postsynaptic membrane
• Pharmacokinetics:
  • Absorption and distribution: lipophilic, rapidly and completely absorbed after oral administration, and distribute throughout the body and penetrate into the CNS
  • Duration of action: half-lives of benzodiazepines are important clinically, as the duration of action may determine the therapeutic usefulness

Actions of Benzodiazepines

• Reduction of anxiety:
  • At low doses, benzodiazepines are anxiolytic
  • Reduce anxiety by selectively enhancing GABAergic transmission in neurons having the α2 subunit in their GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain
• Sedative/hypnotic:
  • All benzodiazepines have sedative and calming properties, and some can produce hypnosis at higher doses
• Anticonvulsant:
  • Mediated by α1-GABAA receptors
• Muscle relaxant:
  • At high doses, benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located

Therapeutic Uses of Benzodiazepines

• Anxiolytic (in GAD, panic disorders)
• Insomnia (triazolam)
• Anticonvulsants (clonazepam, lorazepam, and diazepam)
• Preanesthetic medication (amnesia)
• Muscle spasm (diazepam)
• Alcohol withdrawal syndrome

Adverse Effects of Benzodiazepines

• Drowsiness and confusion
• Cognitive impairment
• Ataxia
• Triazolam: dose-dependent change in sleep pattern: dec REM and inc NREM and tolerance
• Impairment of mental and motor functions
• All of these effects can greatly impair driving and other psychomotor skills, especially if combined with ethanol
• Rebound insomnia
• Hypotension and respiratory depression
• Dependence and abuse

New Anxiolytics and Hypnotics

• Atypical anxiolytics:
  • Buspirone
  • Ipsapirone
  • Gepirone
• Buspirone:
  • Relieves anxiety without causing marked sedative, hypnotic, or euphoric effects
  • No anticonvulsant or muscle relaxant properties
  • Acts as a partial agonist at brain 5-HT1A receptors
  • Anxiolytic effects take more than a week
  • Unsuitable for management of acute anxiety states
  • No rebound anxiety or withdrawal signs on abrupt discontinuation
  • Minimal abuse liability
• Other hypnotics:
  • Z compounds (zolpidem, zaleplon, and zopiclone)
  • Melatonin receptor agonists (ramelteon and tasimelteon)
  • Suvorexant (orexin receptor antagonist)