26. Anxiolytic, sedative and hypnotic drugs

Question 1

what is one of the functions of glial cells?

Answer 1

to envelope the synapse and surround GABA (the most important inhibitory NT in the brain) so that it can be ‘mopped up’

Question 2

why is the precursor of GABA strange?

Answer 2

the precursor of GABA is glutamate which is the single most important excitatory NT in the brain

it is acted on by glutamate decarboxylase –> GABA

Question 3

what is the difference between GABA-A and GABA-B receptors?

Answer 3

GABA-A receptors sit on the post-synaptic membranes and are chloride ionophores (ion channel-linked)

GABA-B receptors exist on pre-synaptic terminals and are type 2 receptors (G-protein coupled)

Question 4

what happens when GABA-A receptors are stimulated by GABA?

Answer 4

1. the ion channel changes conformation to become a chloride ion channel
2. chloride is negative so they hyperpolarise the post-synaptic cell
3. if the cell has a very negative potential, it is harder to excite –> this is how GABA dampens down activity

Question 5

how is GABA metabolised?

Answer 5

1. GABA transaminase converts GABA –> succinic semialdehyde
2. succinic semialdehyde dehydrogenase (SSDH) converts succinic semialdehyde –> succinic acid
3. succinic acid goes back into the TCA cycle in the cells
4. glutamate arises from the TCA cycle which forms a GABA shunt

Question 6

what can the inhibition of GABA metabolism result in?

Answer 6

• large increases in brain GABA levels

- this enhances the release of GABA in the CNS –> anticonvulsant/anti-epileptic effects

Question 7

name 2 GABA metabolism inhibitors

Answer 7

1. sodium valproate (epilim) is a GABA-T and SSDH inhibitor and Na blocker
2. vigabatrin (sabril) is a GABA-T inhibitor

Question 8

what 4 main proteins are GABA-A receptors composed of?

Answer 8

• GABA receptor protein
• benzodiazepine receptor protein
• barbiturate receptor protein
• chloride channel protein

Question 9

what causes the opening of the chloride channel protein when the GABA-A receptor is stimulated?

Answer 9

• when GABA binds to the GABA-A receptor it binds to the GABA receptor protein
• when this happens, GABA receptor protein and benzodiazepine receptor protein link together
• this is mediated by a peptide called GABA modulin
• this results in a momentary opening of the chloride channel protein –> hyperpolarisation

Question 10

what is bicuculline?

Answer 10

a competitive antagonist for the GABA-A receptor

Question 11

what effects on GABA neurotransmission do benzodiazepines have?

Answer 11

1. facilitates GABA mediated opening of the Cl- channel
2. facilitates GABA binding to its own receptor (reciprocated - in the presence of GABA binding there is facilitation of benzodiazepine binding)

Question 12

what is flumezanil?

Answer 12

competitive benzodiazepine antagonist

Question 13

what effects on GABA neurotransmission do barbiturates have?

Answer 13

• facilitate GABA mediated opening of the Cl- channel
• facilitate GABA binding to its receptor (not reciprocated)
• at higher concentrations they have a direct action on the chloride channel

Question 14

what does the ‘allosteric action’ of benzodiazepines and barbiturates mean?

Answer 14

they have no activity alone - they are working to enhance the action of GABA, they are not direct GABA agonists by themselves

Question 15

what is the difference between benzodiazepines and barbiturates?

Answer 15

• benzodiazepines increase the frequency of chloride channel opening
• barbiturates increase the duration of chloride channel opening
• barbiturates are less selective than benzodiazepines
• barbiturates also reduce excitatory transmission

Question 16

what are the clinical uses of benzodiazepines and barbiturates?

Answer 16

BARBITURATES ONLY

• anaesthetics (thiopentone)

BENZODIAZEPINES ONLY

• anti-spastics (diazepam)

BOTH

• anticonvulsants (benzodiazepines: diazepam, clonazepam and barbiturates: phenobarbital)
• anxiolytics
• sedatives/hypnotics

Question 17

what do anxiolytics do?

Answer 17

remove anxiety without impairing mental or physical activity

Question 18

what do sedatives do?

Answer 18

reduce mental and physical activity without producing loss of consciousness

Question 19

what do hypnotics do?

Answer 19

induce sleep

Question 20

what should anxiolytics, sedatives and hypnotics ideally do?

Answer 20

• have wide margins of safety
• not depress respiration
• produce natural sleep
• not interact with other drugs
• not produce ‘hangovers’
• not produce dependence

Question 21

what is the general structure of barbiturate molecules?

Answer 21

• 6-membered ring in the middle
• differ in the substituent groups
• has 4 carbons and 2 nitrogens in the ring

Question 22

what are the unwanted effects of barbiturates?

Answer 22

• possess low safety margins (depress respiration –> lethal if overdosed)
• alter natural sleep –> hangovers and irritability
• enzyme inducers
• potentiate effect of other CNS depressants (e.g. alcohol)
• tolerance
• dependence: withdrawal symptoms of insomnia, anxiety, tremor, convulsion and death

Question 23

what is the general structure of benzodiazepine molecules?

Answer 23

• tricyclic: classic 3-ring structure
• around 20 available
• all have similar potencies and profiles and have the same mechanism

Question 24

what are 3 key benzodiazepines?

Answer 24

• diazepam
• oxazepam
• temazepam

Question 25

how are benzodiazepines administered?

Answer 25

• well absorbed orally
• peak plasma concentration is reached after an hour
• sometimes given via IV

Question 26

how are benzodiazepines distributed, metabolised and excreted?

Answer 26

DISTRIBUTION

• bind plasma proteins strongly
• highly lipid soluble

METABOLISM

• extensively in the liver

EXCRETED

• in the urine as glucuronide conjugates

Question 27

what is the duration of action of benzodiazepines?

Answer 27

• varied
• drugs are classified as either short-acting or long-acting
• long-active drugs have slower metabolism or generate active metabolites

Question 28

give examples of short-acting benzodiazepines and how they are metabolised

Answer 28

OXAZEPAM: metabolised in the liver to its inactive glucuronide

TEMAZEPAM: metabolised to oxazepam –> inactive glucuronide

Question 29

give an example of a long-acting benzodiazepine and how it is metbolised

Answer 29

DIAZEPAM: metabolised via temazepam and oxazepam to the inactive glucuronide

Question 30

which benzodiazepines are used as anxiolytics?

Answer 30

the longer acting benzodiazepines:

• diazepam
• chlordiazepoxide
• nitrazepam

Question 31

when would a shorter-acting benzodiazepine be used?

Answer 31

when a patient has hepatic impairment - the metabolism of the drug is slowed so a shorter-acting drug can be used (usually oxazepam)

Question 32

which benzodiazepines are usually used as sedatives/hypnotics?

Answer 32

the shorter acting benzodiazepines:

• temazepam
• oxazepam

Question 33

what are the advantages of benzodiazepines

Answer 33

• wider margin of safety than barbiturates - overdose –> prolonged sleep (but this is rousable)
• mild effect on REM sleep –> do not induce the hangover effect
• do not induce liver enzymes

Question 34

what are the unwanted effects of benzodiazepines?

Answer 34

• sedation: when used as anxiolytics the patient will feel drowsy
• confusion, ataxia
• potentiate other CNS depressants
• tolerance
• dependence (associated with withdrawal symptoms)

Question 35

how can free plasma concentration of benzodiazepines be increased?

Answer 35

by giving aspirin and heparin: they are plasma protein bound and compete with benzodiazepines

Question 36

what is zopiclone?

Answer 36

• short acting
• acts at benzodiazepine receptor but is not a benzodiazepine
• enhances GABA-mediated neurotransmission by binding to the BZ binding site
• it is a cyclopyrrolone
• similar efficacy to benzodiazepines
• minimal hangover effects
• dependency is a slight problem