Sedative-Hypnotics: Barbiturates and Benzodiazepines

what are sedative-hypnotics & anxiolytics

diverse group of compounds that depress CNS and behaviour

• alcohol

• barbiturates

• non-barbiturate hypnotics e.g. GHB

• anxiolytics (tranquillisers)

• also other, structurally-unrelated drugs with similar effects - e.g. Methaqualone (Quaaludes - date rape drug)

dose-dependent effects of sedative hypnotics

barbiturates - history and use

• von Baeyer (1864) first made barbituric acid - foundation of all barbiturates

• first drugs to be marketed:

  • barbital (1903)

  • phenobarbital (1912)

• sedatives, anticonvulsants and anaesthetics

• became widely used, still used in veterinary medicine

duration of action and uses of major barbiturates

all barbiturates have very similar effects, but differ primarily in their speed and duration of action

pharmacokinetic factors: high lipid solubility so reach the brain fast, but then get redistributed to body fat stores so brief duration (differences between drugs mainly occur in distribution and metabolic pathways)

ultrashort duration barbiturates

thiopental (Pentothal), methohexital (Brevital)

• high lipid solubility

• onset:10-20s

• duration: 20-30mins

• use: IV anaesthesia

short/intermediate duration barbiturates

amobarbital (Amytal), secobarbital (Seconal), pentobarbital (Nembutal)

• moderate lipid solubility

• onset: 20-40mins

• duration: 5-8 hours

• use: surgical anaesthesia and sleep induction

long duration barbiturates

phenobarbital (Luminal), mephobarbital (Mebral)

• low lipid solubility

• onset: over 1 hour

• duration: 10-12 hours

• use: prolonged sedation and seizure control

barbiturate use and abuse

“downers”

desirable effects are very similar to alcohol i.e. relief of anxiety, loss of inhibitions, “take the edge off” other drugs such as cocaine

street names associated with colour of pill e.g. blue angels, barbiturates in general called e.g. downers, stumblers, idiot pills

barbiturates and operant behaviour

• barbiturates are readily self-administered by animals

• both people and lab animals prefer the more rapidly acting barbiturates

• have to be careful not to give too much so that the animal is sedated e.g. FR160 lever-press schedule with 3 hour time-out after each injection

• another striking effect of barbiturates: they enhance responding that has been suppressed by punishment (e.g. FR10 schedule for food, VR15 for electric shock, barbiturates will reduce withdrawal behaviour / conflict)

barbiturates: medical uses (past and current)

• sleep induction

• anticonvulsants

• anaesthetics

• sedatives

• alcohol withdrawal

• anxiolytics

barbiturates and sleep

disrupt sleep regulation

• initially helpful in getting to sleep

• but with repeated use, reduction in both REM sleep and deep (slow-wave) sleep - plus harder to get to sleep

(slow wave = stage 2/3)

problems with barbiturates

• rapid tolerance (dose escalation)

• severe withdrawal (seizures)

• low safety margin (therapeutic index and safety index both poor)

barbiturates are no longer widely prescribed for insomnia and anxiety because they are too dangerous

barbiturate overdose - common means of suicide / euthanasia (used for capital punishment in US)

still sometimes used for convulsions, brain surgery (but rarely)

benzodiazepines - anxiolytics

• widely used:

  • anxiolytics

  • sedatives (calm agitation, induce sleep)

  • anticonvulsants

  • treatment of alcohol withdrawal

  • surgical sedation / amnesia (in combination with other drugs) - presurgical sedation

• progressively replaced barbiturates for many of these uses

  • difference between barbiturates and benzodiazepines: pre surgery sedation rather than anaesthesia

• first drugs to market: Librium (~1959), Valium (1963)

medical uses for benzodiazepines

• pathological anxiety

• severe emotional distress

• relief from agitation and alcohol withdrawal

• sedation (sleep-inducing)

• pre-surgery sedation and amnesia

• anticonvulsants

benzodiazepine metabolism

• benzodiazepines are also primarily chosen by duration of action

• duration in brain again depends partly on redistribution to other sites, but also metabolic pathways

• longer-acting BZs are those with multiple metabolite steps

benzodiazepines compared to barbiturates: safety

• benzodiazepines are much safer than barbiturates

• compared to barbiturates: less tolerance, less safety withdrawal, higher therapeutic index

• it is much harder to take a lethal overdose of benzodiazepines - very rare in humans unless taken in combination with other CNS depressants (which is quite common)

abuse of benzodiazepines

• BZs are clearly less liable to being abused by humans than barbiturates

• illicit use: usually in combination with other drugs

• they are also much harder to get animals to self-administer (but rapid onset BZs are easier)