Anxiolytics, sedative and hypnotic drugs

Question 1

What are the inhibitory and excitatory transmitters in the CNS?

Answer 1

Inhibitory: GABA, Glycine
Excitatory: Glutamate, Aspartate

Question 2

How is GABA synthesised?

Answer 2

Synthesised from Glutamate (from Krebs cycle) -> GABA
Using GAD (glutamate decarboxylase)

Question 3

What are the post-synaptic receptors of GABA called?

Answer 3

GABAa receptors: post synaptic Cl- channel

Question 4

What is the reuptake mechanism of GABA?

Answer 4

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.

Question 5

What is the mechanism whereby not to overproduce GABA?

Answer 5

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.)

Question 6

What are some drugs which are used as anti-convulsants and by what mechanism?

Answer 6

Inhibit breakdown of GABA
Sodium valproate: targets SSDH and GABA-T, voltage sensitive Na channels
Vigabatrin: selective GABA-T antagonist, binds covalently (irreversible)

Question 7

What is an example of a GABAb agonist and it’s clinical impact?

Answer 7

Baclofen: competitive agonist
Modulatory on GABA release
Used as a muscle relaxant in spinal cord and spasmolytic for cerebral palsy and MS.

Question 8

What is the MOA of GABA on the GABAa receptor?

Answer 8

GABA binds to the GABA receptor protein and via GABA modulin is linked to the BDZ receptor proteins.
Stimulates Cl-channel opening.

Question 9

What is the MOA of Benzodiazepines on the GABAa receptor?

Answer 9

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).

Question 10

What is the MOA of Barbiturates on the GABAa receptor?

Answer 10

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.

Question 11

What is the difference in action on Cl- channels by BDZ vs BARBs?

Answer 11

Benzodiazepines increase the frequency of the opening of Cl-channels.
Barbiturates increase the duration for which the Cl-channels open.

Question 12

Which type of GABAa receptor agonist can be used as a surgical anaesthetic and why?

Answer 12

Barbiturates:
Less selective than BDZs
Lower margin of safety as it has other membrane effects
(Decreases excitatory transmission).

Question 13

Give the name of a drug whose clinical use is in surgical anaesthesia (BARB or BDZ)?

Answer 13

BARBs only: Thiopentone

Question 14

Give the name of drugs whose clinical use is as anticonvulsants?

Answer 14

BARB: phenobarbital
BDZ: diazepam

Question 15

Give the name of drugs whose clinical use is as antispastics?

Answer 15

Diazepam

Question 16

What is meant by an anxiolytic?

Answer 16

Remove anxiety without impairing mental or physical activity. They are long-acting.

Question 17

What is meant by a sedative?

Answer 17

Reduce mental and physical activity without losing consciousness.

Question 18

What is the name of the barbiturate given as a sedative/hypnotic?

Answer 18

Amobarbital
Given in severe intractable insomnia
Half-life: 20-25hrs

Question 19

What are the unwanted effects of using barbiturates as sedative/hypnotics?

Answer 19

• 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

Question 20

What are the classic signs of withdrawal syndrome?

Answer 20

Insomnia
Anxiety
Tremors
Convulsions
Death

Question 21

Name a GABAa receptor antagonist?

Answer 21

Bicuculline

Question 22

Name a BDZ receptor antagonist

Answer 22

Flumazenil

Question 23

What is the administration, distribution and excretion mechanisms of benzodiazepines?

Answer 23

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

Question 24

Give examples of long and short-acting BDZs and their metabolism

Answer 24

Long-acting: Diazepam (32h) -> Nordiazepam (60h active metabolite) -> oxazepam
Short-acting: Oxazepam (8h) -> glucuronide conj.
Temazepam (8h) -> oxazepam -> glucuronide conj.

Question 25

Give examples of BDZs used as anxiolytics

Answer 25

Diazepam
Nitrazepam
Oxazepam (used in patients with hepatic impairment)

Question 26

Give examples of BDZs used as sedative/hypnotics

Answer 26

Oxazepam, Temazepam

Question 27

What are the advantages of using BDZs as sedatives/hypnotics?

Answer 27

Higher margin of safety -> induces rousable sleep
Antagonist: flumazenil
Less effect on REM sleep
Does not induce liver enzymes

Question 28

What are the disadvantages of using BDZs as sedatives/hypnotics?

Answer 28

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.

Question 29

Name a sedative/hypnotic which is not a BDZ or BARB

Answer 29

Zopiclone
Short acting (half-life: 5hrs)
Acts at BDZ receptors.
Dependency still a problem.

Question 30

Name some other examples of anxiolytics which are not BDZs or BARBs

Answer 30

Propanalol: non-selective beta antagonist
Improves symptoms of tachycardia (beta1) and tremor (beta2)
Buspirone: 5HT1a agonist, fewer side effects, slow onset of action