anxiolytics, sedatives, hypnotics Flashcards
how is GABA formed?
glutamate –> GABA via glutamate decarboxylase (GAD)
what can GABA bind to?
- GABAaR on postsynaptic cell –> hyperpolarize cell
- GABAbR on presynaptic cell —> -ve inhibtion of release
what can GABA be re-uptaken by?
- glial cells: GABA transaminase breaks down GABA into SSA
- pre-synaptic cell: GABA-T breaks down GABA into SSA
describe GABA metabolism
- GABA –> SSA by GABA-T
- SSA –> succinic acid by SSDH
where are these enzymes found?
- GAD: cytosol
- GABA-T and SSDH: found in mitochondrial membrane
what do inhibitors of GABA metabolism lead to?
- more GABA and more inhibition in brain
e. g. sodium valproate, vigabatrin
What is GABAaR made up of?
4 main proteins:
- GABA-R protein
- GABA modulin
- Barbiturate receptor protein
- benzodiazepine receptor protein
what are bicuculline and flumazenil?
competitive antagonist
- bicucline (GABA)
- flumazenil (BDZ)
what do BDZ and barb need?
require GABA to function
what are the 6 MoA of GABAa-receptor? which ones use each?
- linkage of GABA-RP, GABA, M, BDZ-RP and opening of Cl- channel (GABA)
- initiation of pathway 1 (BDZ)
- inc. affinity of binding of GABA/BDZ - reversible (GABA, BDZ)
- linkage of Barb-RP and BDZ-RP and opening of Cl- channels
- inc. affinity of binding of GABA (Barb)
- direct activation of Cl- channel (GABA, Barb)
what do Barbs and BZDs do to the GABAaR?
- barbs inc. frequency of opening
- BZDs inc. duration of opening
which is less selective? what does that mean?
- barbs are less selective than BDZs
- so barbs have less excitatory transmission
- Barbs are more dangerous = small therapeutic window
what are the clinical uses of BDZs and Barbs?
- anaesthetics: Barbs only
- Anticonvulsants: diazepam, clonazepam, phenobarbital
- anti-spastics: diazepam
- anxiolytics (long acting): BDSz only, diazepam, oxazepam
- sedatives/hypnotics (short acting): Barbs and BDZ, oxazepam, amobarbital
when is oxazepam used?
if pt has a hepatic impairment
define anxiolytics
remove anxiety without impairing mental or physical activity
define sedative
reduce mental and physical activity without producing a loss of consciousness
define hypnotic
induce sleep
ideally what should these drugs do?
- large therapeutic window
- not depress resp
- produce natural sleep
- not interact with other drugs
- not produce hangovers
- not produce dependence
what do the drug names of barbiturates end in?
- tone
- tal
- tol
describe the structure of barbiturates
- single ring structure with 2 R-groups
- R groups are -ethyl groups and phenyl/1-methylbutyl
- drugs have sedative/hypnoticeffet
name a barbiturate
amobarbital
why aren’t these drugs first line?
- small therapeutic window (depress resp)
- reduce REM sleep = hangovers
- induce enzymes
- potentiate effects of other CNS depressants (alcohol)
- tolerance and dependence issues
describe the structure of benzodiazepines
triple ring structure
what do benzodiazepine drug names end in?
- epam
- epate
what do benzodiazepines act on?
all GABAa receptors
not GABAb
describe the pharmacokinetics of benzodiazepines
- oral/IV admin
- peak plasma conc at 1 hour
- extensive liver metabolism
- excretion in urine (glucuronide conjugates)
what are the long and short acting?
- diazepam long acting = 32hr half life
- temazepam (8 hrs) and oxazepam (8 hrs) = short acting
what are the advantages of BDZs?
- wide therapeutic window
- overdose = prolonged sleep
- flumazenil is BDZ anatgonist so can reverse effect
- mild effect on REM sleep
- does not induce liver enzymes
what are the unwanted effects of BDZs?
- sedation, confusion, amnesia, ataxia (impaired manual skills)
- potentiates other CNS depressants
- tolerance and dependence
with which drugs does the free plasma conc. inc. with?
aspirin
heparin
what is zopiclone?
- sedative/hynotic
- Z-drug
- short acting
- acts on BDZ receptor
- not BDZs
- minimal hangover effects but dependency problems
what are other anxiolytics?
- antidepressants (SSRIs)
- anti-epilpetics (valproate)
- antipsychotic’s (olanzapine)
- propanolol (improves physical symptoms of anxiety)
- buspirone (5HT1a receptor agonist with fewer side effects)
