L11: Benzodiazepines and Barbiturates

what are sedative-hypnotic drugs

drugs that produce dose-dependent depression of CNS activity

what effects occur as sedative-hypnotic dose increases

• sedation

• anxiolysis

• hypnosis

• anticonvulsant effects

• anaesthesia

• respiratory depression

which drug classes are sedative-hypnotics

• alcohol

• benzodiazepines

• barbiturates

• general anaesthetics

what are barbiturates

sedative-hypnotic drugs derived from barbituric acid that depress CNS activity

how are barbiturates classified

by duration of action:

• ultra-short

• short/intermediate

• long acting

what determines duration of action of barbiturates

lipid solubility

how does lipid solubility affect barbiturate action

high lipid solubility = rapid brain entry and rapid redistribution into fat = short action

clinical uses of barbiturates

• sedation

• hypnosis

• anaesthesia

• anticonvulsant therapy

which barbiturate is still commonly used for epilepsy

phenobarbital

what is the major problem with barbiturates

narrow therapeutic range

why are barbiturates dangerous in overdose

high doses depress medullary respiratory centres causing respiratory depression

what is tolerance

reduced drug response after prolonged exposure requiring higher doses

why is tolerance dangerous with barbiturates

tolerance develops for desired effects but not respiratory depression and so reduced safety margin

what is drug dependence

physical and/or psychological compulsion to continue drug use

how do barbiturates produce psychological dependence

increase dopamine release from VTA neurons in the mesolimbic reward pathway

why is exam barbiturate withdrawal dangerous

can cause:

• severe seizures

• excitotoxicity

• arrhythmias

• death

why do barbiturates have high abuse potential

they produce euphoria, disinhibition and reduced anxiety at low doses

why is combining barbiturates with alcohol dangerous

both are CNS depressants and so greatly increased overdose risk

why are barbiturates rarely used today

because of overdose risk, tolerance and dependence

what are current uses of barbiturates

• anaesthesia

• epilepsy treatment

• euthanasia/lethal injection

what are benzodiazepines (BZDs)

sedative-hypnotic drugs that enhance GABA-A receptor activity

first benzodiazepine

chlordiazepoxide (librium)

why did benzodiazepines replace barbiturates

they are much safer and have a larger therapeutic index

effects of benzodiazepines

• sedation

• anxiolysis

• anticonvulsant effects

• anterograde amnesia

why are benzodiazepines safer than barbiturates

they produce much less respiratory depression and are difficult to overdose on alone

what are clinical uses of benzodiazepines

• anxiety disorders

• insomnia

• epilepsy

• alcohol withdrawal

• sedation before surgery

what problems occur with long-term benzodiazepine use

• tolerance

• dependence

• abuse potential

why do benzodiazepine produce dependence

increase dopamine release in mesolimbic reward pathways

what is the function of GABA-A receptors

main inhibitory receptors in the brain, allowing Cl- influx causing hyperpolarisation

how do barbiturates and benzodiazepines act on GABA-A receptors

positive allosteric modulators PAMs that enhance GABA-mediated inhibition

how do benzodiazepines affect GABA-A channels

increase frequency of channel opening

how do barbiturates affect GABA-A channels

increase duration of channel opening

what can barbiturates do at very high concentration

directly activate GABA-A receptors even without GABA

which GABA-A subunits are sensitive to benzodiazepines

a1, a2, a3 and a5

which GABA-A subunits are insensitive to benzodiazepines

a4 and a6

which GABA-A subunit mediates anxiolysis

a1

which GABA-A subunit mediates sedation

a1

which GABA-A subunit mediates anxiolysis

a2

what are Z-drugs

non-benzodiazepine drugs that bind the same GABA-A site and act as hypnotics

examples of Z-drugs

• Zolpidem

• Zopiclone

• Zaleplon

what is flumazenil

a competitive antagonist at the benzodiazepine binding site

what is flumazenil used for

reversal of benzodiazepine sedation/overdose

compare barbiturates and benzodiazepines

• both enhance GABA-A mediated inhibition and produce sedation, anxiolysis and anticonvulsant effects

• barbiturates are more dangerous - they have narrow therapeutic range, can directly activate GABA-A receptors at high concentrations causing severe respiratory depression

• benzodiazepines are safer due to greater receptor specificity and lower overdose risk