Anxiolytics, Sedatives and Hypnotics Flashcards
Describe the process of GABA neurotransmission
- Glutamate -> GABA via GAD (Glutamate Decarboxylase)
- GABA can bind to:
- GABA AR on the postsynaptic cell -> hyperpolarise cell (chloride channel)
- GABA BR on pre-synaptic cell ->-ve inhibition of release - GABA can then be re-up-taken by:
- Glial cells – GABA-Transaminase breaks down GABA into SSA (Sunninic Semialdehyde)
- Pre-synaptic cell – GABA-T breaks down GABA into SSA
How is GABA metabolised?
GABA (GABA-T) -> Succinic Semialdehyde (SSA)
(SSDH) -> Succinic Acid
Where are GABA neurotransmission and metabolism enzymes found?
GAD is found in the cytosol whilst GABA-T and SSDH are found in the mitochondrial membrane
What are examples of GABA metabolism inhibitors?
Sodium Valproate, Vigabatrin
lead to more GABA and more inhibition in the brain
What is the GABA a-R made of?
4 main proteins:
- GABA-R Protein
- GABA modulin
- Barbiturate receptor protein
- BDZ (Benzodiazepine) receptor protein
- chloride channel protein in the middle - binding of GABA -> linkage of proetien -> opening of chloride channel -> hyperpolerisation
What are the mechanisms of action of GABAa-Receptor?
Pathway 1 – linkage of GABA-RP, GABA-M and BDZ-RP and opening of Cl—channel - GABA
Pathway 2 – initiation of pathway 1 - BDZ
Pathway 3 – increased affinity of binding of GABA/BDZ (reversible) - GABA, BDZ
Pathway 4 – linkage of Barb-RP and BDZ-RP and opening of Cl—channel - Barb
Pathway 5 – increased affinity of binding of GABA (NOT-reversible) - Barb
Pathway 6 – direct activation of Cl—channel - GABA, Barb
What are some competitive antagonists for GABAa-R?
Bicuculline (GABA) and Flumazenil (BDZ) are competitive antagonists - require GABA to some degree to function
How do Barbs and BZDs affect the channels?
- Barbs increase the FREQUENCY of opening
- BZDs increase the DURATION of opening
Barbs are less selective then BDZs so Barbs have:
- Less excitatory transmission
- Barbs are MORE dangerous:
> More dangerous SEs – induction of surgical anaesthesia and small therapeutic window
What are some clinical uses of barbs and BDZs?
- Anaesthetics - Barbiturates only – Thiopentone
- Anticonvulsants - Diazepam, Clonazepam, Phenobarbital
- Anti-spastics- Diazepam
- Anxiolytics (“Long-acting”) - Diazepam(BDZ)(Valium), Chlordiazepoxide (Librium), Nitrazepam - BDZs only. Oxazepam can also be used if the patient has hepatic impairment
(as the liver will take longer to metabolise the Oxazepam so the half-life will be longer) - Sedatives/Hypnotics (“Short-acting”) Temazepam (BDZ), Oxazepam (BDZ), Amobarbital (Barb)- Barbiturates, BDZ. Nitrazepam can also be used for a hypnotic effect at night
followed by an anxiolytic effect during the day
What are anxiolytics?
remove anxiety without impairing mental or physical activity
What are sedatives?
reduce mental and physical activity without producing a loss of consciousness
What are hypnotics?
induce sleep
What would the ideal drugs have?
have a large therapeutic window, not depress respiration, produce natural sleep, not interact with other drugs, not produce “handovers”, not produce “dependence”
Describe the simple structure of barbs
single ring structure with two R-groups - R groups are – ethyl groups and phenyl/1-methylbutyl
What are the effects of barbs?
- sedative/hypnotic effect – Amobarbital:
- Causes severe intractable insomnia.
- T1/2 = 20-25h.
unwanted effects :
- Small therapeutic windows – depress respiration
- Reduce REM sleep -> “hangovers”
- Induce enzymes
- Potentiate effects of other CNS depressants – alcohol
- Tolerance and dependence become issues
