DBB: 15 Barbiturates and benzodiazepines

what group do barbs and benzos fall into

sedative-hypnotics and anxiolytics

• compounds that depress the CNS and behaviour (+ alcohol)

what do these all these have in common (besides being in the same group obvs)

they’re often used as ‘date-rape’ drugs

explain the symptoms that come with increasing the dosage

changing overall state of consciousness

• alertness

• relief from anxiety

• sedation

• sleep

• general anaesthesia

• coma

• death

what is the foundational structure of all barbiturates

barbituric acid (1864)

what are the first developed barbs and what were they used for

• barbital (1903)

• phenobarbital (1912)

important sedatives, anticonvulsants and anaesthetics

barbs have similar effects - but how do they differ give examples

differ in their speed and duration of action (more their redistribution and metabolic pathways)

• pentothal (ultrashort) - high lipid solubility, 30 min duration → intravenous anaesthesia

• amytal (short) - moderate lipid solubility, 40 min duration → surgical anaesthesia

• luminal (long) - low lipid solubility, 1hr+ duration → prolonged sedation/seizure control

what are some medical uses

• sleep induction

• anticonvulsant

• anaesthetics

• sedatives

• alcohol withdrawal

• anxiolytics

• euthanasia

how are barbs abused

recreationally used as ‘downers’

• desirable effects are very similar to alcohol (anxiety relief, loss of inhibition)

• takes edge of other drugs like cocaine

what kind of barbs are more preferable to animals - what has to be considered during animal self administration of barbs

people and animals prefer more rapidly-acting barbs

• have to be careful in experimentation as want to avoid animal taking too much - other wise they’ll be sedated and stop responding

what is a striking effects of barbs in experimentation

enhanced responding that has been suppressed by punishment

• e.g. FR10 schedule food + VR15 electric shock (aka random shock) - creates a conflict schedules → increases responding, maybe because anxiolytic effects)

how do barbs effect sleep

• initially helpful in getting to sleep (why it was thought to be beneficial)

• with repeated use, reduction in both REM and SWS + harder to get to sleep

why might this be the case

because you get quite rapidly developing tolerance

why aren’t barbs prescribed for insomnia and anxiety anymore

too dangerous

• rapid tolerance (dose escalation)

• severe withdrawal (seizures)

• low safety margin (like if you give higher dose, a dose that’s closer to sedation, anaesthetic effects - bad)

how were the therapeutics issues with barbs ‘resolved’

development of anxiolytics (benzos)

• structurally different to barbs but have very similar effects

what is the base structure for all benzos

benzene ring - just different things attached to it

what are some of the first benzos brought to market

• librium (1959) - still used for bipolar

• valium (1963)

what are they widely used for

• anxiolytics; sedatives (calm agitation, induce sleep);

• anticonvulsants; treatment of alcohol withdrawal;

• surgical sedation/amnesia (in combination with other drugs - since benzos cant really induce general anaesthesia unless at very high doses → more for pre surgical sedation)

what is its medical use

• pathological anxiety

• severe emotional distress

• relief from agitation and alcohol

• sedation (sleep-inducing)

• pre-surgery sedation and amnesia

• anticonvulsant

what determines benzo distribution in the brain

they’re all lipid soluble

• depend partly on redistribution to others sites, but also metabolic pathways

what do longer action benzos have

multiple active metabolite steps

give example of both a short acting and long acting benzo and how they’re metabolised

• e.g. lorazepam (HL = 10-24hr) immediately metabolised into an inactive molecule

• but chordiazepoxide (HL = 8-100hr) is metabolised into an active molecule → and then another active molecule - that keep having effects → until it becomes and inactive molecule

and then both are excreted

how would you use both these drug considering if they’re short or long acting

• for someone have a one off panic attack, no history of anxiety → give lorazepam for example

• versus someone with chronic anxiety → makes sense to give them chlordiazepoxide

compared to barbiturate, how are benzos safer

• less tolerance

• less severe withdrawal

• higher TI

much harder to take a lethal dose of benzos (unless in combination with other CNS depressants)

explain the study comparing safety index of benzos and phenobarbital

showed the difference when

• inducing sedation incline screen test (if you’re sedated → you slip off)

• suppression of fighting induced by foot shock

• and blocking convulsion

the LD50s were ranked for each drug and when working out SI → phenobarbital was a lot lower in all cases

where can benzo abuse be seen

• illicit use: when In combination with not other drugs

• date rape drug cases e.g. rohypnol

in what ways does benzo dependence occur - what’s the best way to come off them

ween off - never cold turkey

• withdrawal syndrome: milder form of alcohol, barbiturate withdrawal

• persistent emotional disturbances, following withdrawal from even low doses of benzos - anxiety, tingly feelings, weight loss, oversensitivity to sensations

what’s another sedative hypnotic - how is it synthesised

GHB

• synthesise by chemises looking for GABA replacement that would cross the BBB

• also occurs naturally in the brain (small quantities)

• GHB structure very similar to GABA

what are its effects - what drug does it resemble

subjective effects resemble alcohol: relaxation, social disinhibition etc. with some mild stimulant-like effects too

• also a date-rape drug (pops up as a ‘club drug’)

explain the study looking at tolerance to the behavioural effects of GHB

mice given 200mg/kg GHB for 14 days

• locomotor activity measured 30-60 minutes following each dose

found:

• initial decreased locomotor activity compared to control

• over the two weeks increased - highlighting tolerance

why might this have been the case

sedative effects (maybe anxiolytic effects - less anxious in environment so doesn’t run)

what receptors does GHB act on

• agonist at two types of GPCRs

• low-affinity agonist at GABAb receptors (appears to be critical for most behavioural effects)

what do GABAb receptor knockout mice show

do not display the typical behavioural responses to GHB (particularly sedative-hypnotic effects)

what were early thoughts about mechanism of action for these types of drugs (alcohol, benzos, barbs)

have such widespread sedative effects - thought to affects several neurotransmitters

• many transmitter systems implicated

• nonspecific membrane effects

• potentiation of GABA effects

what was discovered in 1977 concerning benzo binding sites

• concentrated in newly evolved structures (cortex, hippocampus, amygdala)

• correlate with anxiolytic effects

• closely related to GABAa receptor sites

what does a coronal slice showing sedative-hypnotic drug effects

you see binding in a lot of places but not everywhere

• lots of binding in hippocampus, but not the whole of it

• widespread but selective nonetheless

what is GABA - its importance in the brain

• most important inhibitory NT in the adult, vertebrate brain

• found throughout the brain in high concentrations

• synthesised from glutamate

how is GABA synthesised

glutamate inside the cell is converted into GABA by enzyme glutamic acid (decarboxylase)

• glutamate → GABA (done through regular excitosis)

• GABA is then stored in vesicles transported by vGATs - vesticular GABA transporter

• which is then released through conventional mechanisms likes excitosis to then bind GABA to receptors

• is now taken back up into the same cell through transporters to be converted back to glutamate

what do astrocytes have to do with this process also

not just GABA being taken back up into the presynaptic cell

• it also has a process where its taken up by astrocytes which convert it to glutamate → and then transported back to the cell to be resynthesised into GABA again

explain the 2 types GABA receptors

GABAa and GABAb

both post synaptic and presynaptic (GABAa mostly ‘post’ and GABAb mostly ‘pre’)

• GABAa (and GABAc) - ionotropic receptors (ligand gated Cl- channels)

• GABAb - metabotropic receptors (G-protein-coupled)

how many subunits do GABAa receptors consist of

5 - they surround a central pore (Cl- ion channel)

how many ‘types’ of GABAa subunits have been identified

as of 2008 - 18 different types

• most GABAa receptors have 2alpha +2beta + a (gamma/theta)

what do these differences mean

question comes in - are there different drug effects at different receptors

where are these different subunit combinations found - what does it mean

found in different parts of the brain - even on the same neuron (just in different locations)

• e.g alpha(1,2,3) beta gamma → synaptic receptors mediating phasic inhibition

• e.g alpha5 beta gamma + alpha(4,6) beta theta → extrasynpatic receptors mediating tonic inhibition

what’s a GABAa receptor agonist

muscimol

what’s a GABAa receptor antagonist - how does it work

bicuculline

• blocks the effects of GABA not the effects of benzo/barbiturates

• because benzo/barbiturates bind to a different site separate from the GABA binding site

explain - how most drug act as non-competitive antagonists

since they compete for the same site as GABA bu they do change the effect of GABA (in order to inhibit cells)

what do all sedative-hypnotics appear to do to GABA

enhance the ability of GABA to cause chloride influx through GABAa receptors

• cell becomes more negative → inhibition

so explain this image - are barbiturates the same

benzos dont do much by themselves they are influencing the effect of GABA - cant do anything without GABA

• barbiturates seem to have some effects by themselves by again its primarily their influence on changing the gate to allow more Cl- influx

give an example of what GABA + benzo/barbiturates on GABAa channels

• in the presence of GABA + diazepam → GABAa channels open more frequently than with GABA alone

• in the presence of GABA + phenobarbital → GABAa channels stay open for longer than with GABA alone (barbiturate may also have some direct agonist effects)

do similar things but in different ways

what about a binding site for alcohol

we don’t know yet

why does the GABAa receptor have benzo binding sites?

endogenous ligands for the benzo binding site

• steroid metabolites of progesterone and deoxycorticosterone

• may regulate anxiety at times of stress e.g. childbirth

so the suggestion that this may indulge in this pathway that regulate through the benzo site sort of stress responses and potentially in childbirth

how can you test the behavioural effects of benzos separately

generate knock-in mice with point mutations of the benzos binding site, in specific GABAa alpha subtypes

these mice are then selectively insensitive to benzo effects

what receptor subunits are requires for the sedative effects and anxiolytic effects

• sedative effects - require alpha1 containing receptors (also a3 - as they're located in recticular activating systems - related to more general states of awareness)

• anxiolytic effects - require alpha2 containing receptors → so alpha2 is a very attractive target for drug development (because a2 receptors are specifically located in the limbic regions - striatal regions)