Axiolytics, sedative, hypnotics Flashcards
Describe GABA-ergic synapse
GABA formed from Glu (GAD enzyme)
Release into synapse-Acts on GABAR(a) - Cl- ion channel
after Reuptaken by pre-synaptic neuron-GAG-. Then GABA-Transaminase makes it into SuccinucSemiAldehyde
Also can be uptaken by Glial cells, where GABAT act again (make into SSA)
Presynaptic nerve terminal also have few autoreceptors-> similar to a2 adrenergic receptor -> act as feedback and downregulates if excess released
What types of neurons use GABA?
Tend to be short axon interneurons that act locally-downregulate close to what activates them
Have some long on- cortical-substantia nigra pathway (part of action of parkinsons
What is the fate of GABA after reuptake?
reuptake via GAG
Intracellular breakdown of GABA
inital-GABA transaminase to SSA
Then SSDH enzymes generates Succinic Acid with it -> Kreps cycle —GABA shunt
Both are mitochondrial enzymes
Inhbition of GABA metabolism cause large increase of brain GABA (2 exemples-sodium Valproate (Epilim) and Vigabatrin(Sabril))
What does sodium valoprate act on? And Vigabatrin?
Vigabatrin inhbit GABA-T -> increase GABA action, used as anti-epilectic
Sodium Valpoate-> weak inhbitor of GABAT, and inhbits SSDH. But also discovered to act on sodium channels (inhbit) -> anti-epiletic
GABA(a) Receptor in brain structure?
4 main proteins-Benzodiazepine receptor protein, barbituate receptor protein, GABA receptor protein and Chloride channel
When GABA binds-link of GABA protein to BDZ receptor protein (uses Gaba modulin) -> brief Cl- channel opening-enought to hyperpolarise
How do benzodiazepines and barbituates act on GABAa
NEITHER ARE GABA AGONIST-they need GABA, and just enhance its action
Both are allosteric => positive allosteric modulators (bind different place to GABA)
Benzodiazepine bind its own receptor-> cause ehanced chloride intake -increase frequency of opening
Also increases GABA affinity for the receptor (reciprical -GABA also increase affinity of BZD to receptor)
Barbituates-bind to their own receptor protein-> enhance intake of Cl in channel, and intake length of opening
enhance GABA binding to receptor (but not reciprocal-GABA doesnt increase barbituate binding)
At higher concentration, can cause direct opening of Cl channels
-> less selective than BZD
What is Bicuculline and flumazenil and their action of GABA
Bicuculline-competitive GABA antagonist -not used in any treatment
Flumazenil- competitive BDZ antagonist-to treat BDZ
What are the clincal uses of BZD and Barbituates? give a good exemple of each
aneastetics (barb only) Anticovulsants Anti spastics Axiolytics Sedative/Hypnotics
Barbituate-Amorbarbital-sedative/hypnotic
BZD-diazepam, oxazepam, temazepam
Define anxiolytic, sedative and hypnotics?
Anxiolytic-remove anxiety without impairing mental/physical activity-mild tranquiliser
Sedatives-Reduce mental/physical activity without loss of conciousness
Hypnotics-induces sleep
need to be sure not to stop resp but can produce natural sleep
No hangovers,no interaction, not cause dependence
What are the main side effects of barbituates like amorbarbital
Why barbs are not 1st line
Low safety margins _> depress respiration -overdosing lethal
Alter natrual sleep-irratable/hangovers
enzyme induces -> activate liver enzymes
Potentiate effects of other CNS depressants
Tolerance is also an issue
cause dependence via withdrawal syndrome (anxiety, temor, convultion, death)
Pharmacokinetics of BDZ
All act the same way and have similar activity prolife
Generally well absorbed orally. Peak conc in 1h
IV can be given-for status epilepticus (mal épileptique)
Bind plasma protein
Highly lipid soluble
Liver metabolised, excreted in urine with glucoronide conjugates
Duration of action varies: Long acting and short acting
(long acting are either metabolised slowly or produce active metabolism)
Temazepam, made to oxazepam, then glucorinide
Oxazepam-directly to gluco
Diazepam-to nordiazepam-> to oxazepam-> glucoronide
How are BDZ metabolised
Long acting and short acting
(long acting are either metabolised slowly or produce active metabolism)
Short acting:
Temazepam, made to oxazepam, then glucorinide
Oxazepam-directly to gluco
long acting
Diazepam-to nordiazepam-> to oxazepam-> glucoronide
Which BDZ are used for what? what are the advantages of these drugs?
Anxiolytic-usually long acting ones-diazepam (valium)
one exception- oxazepam can be used as anxiolytic if hepatic impairment
Sedative/hypnotics-usually short acting onesTemazepan, oxazepam exception Nitrazepam (long acting-if need sleep + anxiolytic)
BDZ advantages: Wide marge of safetty- Overdose-prolongedsleep but antidote exist (Flumazenil) Mild effects on REM sleep Does NOT induce liver enzymes
Which BDZ are used for what? what are the advantages of these drugs?
Anxiolytic-usually long acting ones-diazepam (valium)
one exception- oxazepam can be used as anxiolytic if hepatic impairment
Sedative/hypnotics-usually short acting onesTemazepan, oxazepam exception Nitrazepam (long acting-if need sleep + anxiolytic)
BDZ advantages: Wide marge of safetty- Overdose-prolongedsleep but antidote exist (Flumazenil) Mild effects on REM sleep Does NOT induce liver enzymes
What are the unwanted effects of BDZ?
Sedation, confusion, amnesia, ataxia
Potentiate other CNS depressants,
Tolerance-less than Barbs-tissue tolerance obly
Dependence-withdrawal symptoms similar to barb but less intense, -> withdraw slowly
Protein bound BDZ in plasma can be freed/displaced by aspirin, heparin-can cause sharp increase
