Anxiolytics, sedative and hypnotic drugs Flashcards
What are the inhibitory and excitatory transmitters in the CNS?
Inhibitory: GABA, Glycine
Excitatory: Glutamate, Aspartate
How is GABA synthesised?
Synthesised from Glutamate (from Krebs cycle) -> GABA Using GAD (glutamate decarboxylase)
What are the post-synaptic receptors of GABA called?
GABAa receptors: post synaptic Cl- channel
What is the reuptake mechanism of GABA?
Taken up by selective carrier molecules on glial cells or pre-neuronal terminal.
GABA via GABA transaminase -> Succinic semialdehyde via succinic semialdehyde dehydrogenase -> Succinic acid
In the pre neuronal terminal this can be reused in the TCA cycle.
What is the mechanism whereby not to overproduce GABA?
Autoreceptors (GABAb) on the pre-synaptic terminal have a negative feedback on GABA release. They can sense when there is too much GABA in the synaptic cleft (g-protein coupled.)
What are some drugs which are used as anti-convulsants and by what mechanism?
Inhibit breakdown of GABA
Sodium valproate: targets SSDH and GABA-T, voltage sensitive Na channels
Vigabatrin: selective GABA-T antagonist, binds covalently (irreversible)
What is an example of a GABAb agonist and it’s clinical impact?
Baclofen: competitive agonist
Modulatory on GABA release
Used as a muscle relaxant in spinal cord and spasmolytic for cerebral palsy and MS.
What is the MOA of GABA on the GABAa receptor?
GABA binds to the GABA receptor protein and via GABA modulin is linked to the BDZ receptor proteins.
Stimulates Cl-channel opening.
What is the MOA of Benzodiazepines on the GABAa receptor?
BDZ binds to BDZ receptor protein.
Acts to enhance GABA effect on Cl- channel.
Enhances the affinity of GABA for the GABA receptor protein (reciprocated action).
What is the MOA of Barbiturates on the GABAa receptor?
BARB bind to BARB receptor protein.
Acts to enhance GABA effect on Cl- channel.
Enhances the affinity of GABA for the GABA receptor protein (not reciprocated).
In high conc. of BARB there is direct action on the Cl- channel to stimulate receptor opening.
What is the difference in action on Cl- channels by BDZ vs BARBs?
Benzodiazepines increase the frequency of the opening of Cl-channels.
Barbiturates increase the duration for which the Cl-channels open.
Which type of GABAa receptor agonist can be used as a surgical anaesthetic and why?
Barbiturates:
Less selective than BDZs
Lower margin of safety as it has other membrane effects
(Decreases excitatory transmission).
Give the name of a drug whose clinical use is in surgical anaesthesia (BARB or BDZ)?
BARBs only: Thiopentone
Give the name of drugs whose clinical use is as anticonvulsants?
BARB: phenobarbital
BDZ: diazepam
Give the name of drugs whose clinical use is as antispastics?
Diazepam
What is meant by an anxiolytic?
Remove anxiety without impairing mental or physical activity. They are long-acting.
What is meant by a sedative?
Reduce mental and physical activity without losing consciousness.
What is the name of the barbiturate given as a sedative/hypnotic?
Amobarbital
Given in severe intractable insomnia
Half-life: 20-25hrs
What are the unwanted effects of using barbiturates as sedative/hypnotics?
- Depress respiration
- Lethal overdose
- Alter natural sleep (decrease in REM) -> hangovers/irritability
- Enzyme inducers; co-administered drugs may be metabolised quicker so need to adjust dosage
- Potentiate effects of other CNS depressants
- Tolerance e.g. tissue and pharmacokinetic
- Dependence -> withdrawal syndrome
What are the classic signs of withdrawal syndrome?
Insomnia Anxiety Tremors Convulsions Death
Name a GABAa receptor antagonist?
Bicuculline
Name a BDZ receptor antagonist
Flumazenil
What is the administration, distribution and excretion mechanisms of benzodiazepines?
Admin: Orally, use IV in emergencies e.g. status epileptics. Reaches peak plasma conc. in 1hr.
Distribution: binds strongly to plasma proteins
highly lipid soluble -> wide distribution
Excretion: metabolised in the liver into glucuronide conjugates -> excreted through urine
Give examples of long and short-acting BDZs and their metabolism
Long-acting: Diazepam (32h) -> Nordiazepam (60h active metabolite) -> oxazepam
Short-acting: Oxazepam (8h) -> glucuronide conj.
Temazepam (8h) -> oxazepam -> glucuronide conj.
Give examples of BDZs used as anxiolytics
Diazepam
Nitrazepam
Oxazepam (used in patients with hepatic impairment)
Give examples of BDZs used as sedative/hypnotics
Oxazepam, Temazepam
What are the advantages of using BDZs as sedatives/hypnotics?
Higher margin of safety -> induces rousable sleep
Antagonist: flumazenil
Less effect on REM sleep
Does not induce liver enzymes
What are the disadvantages of using BDZs as sedatives/hypnotics?
CNS effects: sedation, confusion, amnesia, ataxia
Potentiate CNS depressants
Tolerance (less than BARBs)
Dependence
Free plasma concentration increases with aspirin/heparin, as they compete with the BDZ.
Name a sedative/hypnotic which is not a BDZ or BARB
Zopiclone
Short acting (half-life: 5hrs)
Acts at BDZ receptors.
Dependency still a problem.
Name some other examples of anxiolytics which are not BDZs or BARBs
Propanalol: non-selective beta antagonist
Improves symptoms of tachycardia (beta1) and tremor (beta2)
Buspirone: 5HT1a agonist, fewer side effects, slow onset of action
