Pharm 26 - Anxiolytic, Sedative and Hypnotic drugs

Question 1

What is the most important inhibitory neurone and what is its precursor

Answer 1

GABA - precursor is glutamate

GABA is an AA

Question 2

How is glutamate converted into GABA?

What happens to the GABA after it is formed

Answer 2

GAD converts glutamate into GABA

gabs then stored in vesicles in presynaptic terminal until it is time to be exocytosed (when Ca influx)

Question 3

GABA are mostly ……….. interneurons that dampen firing of …..

Answer 3

Short interneurons

Dampen firing of e.g. glutamate neurons

Question 4

What are the 2 types of GABA receptors?

Answer 4

GABAa receptors - located post-synaptically and ion-channel linked; it causes Cl influx causing hyperpolarisation

GABAb receptors - these are presynaptic (auto receptors). They are self regulatory, G protein coupled (type 2)

Question 5

How is GABA inactivated

Answer 5

1. GABA reuptake (primary method) - by GABAb receptors

2. Reuptake by glial cells

Question 6

Where does Glutamate come from? Where does succinate go?

Answer 6

TCA Cycle (GABA shunt)

GABA removed from TCA Cycle and inputted back in

Question 7

The conversion of GABA to succinic acid (succinate) is 2 step. Explain this reaction

Answer 7

1. GABA —–> Succinic semialdehyde (via GABA transaminase (GABA-T))
2. Succinic semialdehyde —–> Succinic acid (via Succinic semialdehyde dehydrogenase (SSDH)).

Succinic acid then goes back into TCA

Question 8

What structure are GABA-T and SSDH enzymes associated with?

Answer 8

They are mitochondrial enzymes

Question 9

Where is GAD enzyme found and only in what type of neurones?

GAD converts glutamate to GABA

Answer 9

Found in cytoplasm and only in GABAnergic neurones

Question 10

What happens if you inhibit GABA metabolism (i.e. by inhibiting SSDH or GABA-T)

Answer 10

Increase in brain GABA levels

Question 11

Name 2 drugs that inhibit GABA metabolism?

These drugs are both??

Answer 11

1. Sodium valproate (Epilim) - inhibits GABA-T and SSDH. (also acts as a VGSC blocker)
2. Vigabatrin (Sabril) - selective to GABA-T (non-competitive)

Sodium valproate has more mixed action as less selective

These are both anti-convulsants

Question 12

What are the 4 main proteins in the GABA receptor

Answer 12

1. GABA receptor protein
2. Benzodiazepine receptor (BDZ receptor)
3. BARB receptor protein (barbiturates)
4. Cl channel protein

Question 13

Explain how the GABAa receptor complex works

Answer 13

1. GABA binds to the GABAaR
2. This causes GABAaR and BDZ receptor protein linkage (modulated by GABA modulin)
3. This causes a transient opening of Cl- channels

Question 14

Give an example of reciprocal binding in the GABAaR

Answer 14

If BDZ binds to the BDZ receptor - normal GABA action is enhanced (on CL- channel). Binding/affinity of GABA also enhanced.

This also works the other way - GABA binding enhances affinity of BDZ binding

Question 15

Give an example of non-reciprocal binding at the GABAaR

Answer 15

BARB enhances GABA binding (affinity) and action at Cl channel - but this does not work the other way as with the BDZ receptor

Question 16

At high doses, what can BARBs do?

Answer 16

Directly stimulate the Cl channel

Question 17

What is bicuculline

Answer 17

A competitive GABAa receptor antagonist

Question 18

What is flumazenil

Answer 18

Competitive BDZ antagonist

Question 19

Benzodiazepines (BDZs) and Barbs have no activity alone because?

They are allosteric, meaning?

Answer 19

Because they work by enhancing GABA

Allosteric meaning they work at a site different to the GABA receptor - they are not direct GABA agonists)

Question 20

What is the difference in mechanism between BARBS and BDZ

BDZ and BARBS have different binding sites and mechanisms

Answer 20

BDZ increases the frequency of Cl channel openings

BARBS increase the duration of Cl channel openings

Question 21

Which is less selective, BARBs or BDZ?

Answer 21

Barbs are less selective - they decrease excitatory transmission and also have other membrane effects (at higher doses)

This may explain why they have a lower margin of safety and why they can induce surgical anaesthesia

Question 22

What is a clinical usage for only Barbs and not BDZ

Answer 22

Anaesthesia - thiopentone is used

Question 23

What are the clinical uses for BDZ and Barbs

Answer 23

1. Anticonvulsants - diazepam, clonazepam, phenobarbital
2. Anti-spastics - diazepam
3. Anxiolytics
4. Sedatives / hypnotics

Question 24

What is the difference between anxiolytics and sedatives

Answer 24

Anxiolytics - remove anxiety but don’t impair mental or physical activity

Sedatives - reduce mental and physical activity without loss of consciousness

(Hypnotics - induce sleep. Same type of drugs as sedatives but different doses)

Question 25

What are 6 ideal features of anxiolytics, sedatives and hypnotics?

Answer 25

1. Wide margin of safety 2. No respiratory depression 3. Natural sleep 4. No other drug interactions 5. No hangovers 6. No dependence

Question 26

Barbs have what kind of structure?

Answer 26

Single ring structure

Question 27

Give an example of a major use of barbiturates

Answer 27

Sedative/hypnotic - Amobarbital given for severe intractable insomnia (after 1st line BDZ given) Amobarbital has a half life of 20-25 hrs

Question 28

What are the SEs of barbs

Answer 28

1. Low safety margins (can cause respiratory depression) 2. Alters natural sleep (less REM) - causing hangovers or irritability 3. Enzyme inducers 4. Potentiates effect of other CNS depressants (e.g. alcohol) 5. Tolerance 6. Dependence, causing withdrawal symptoms (e.g. insomnia, anxiety, convulsions, etc) Hence, Barbs are no longer first line

Question 29

What is the structure of BDZ? How many BDZs are there?

Answer 29

3 ring structure - about 20 available They ALL act on GABA receptors, with similar potency

Question 30

Describe the administration of BDZ

Answer 30

1. Well absorbed orally 2. Peak plasma conc after 1 hr 3. Given IV if status epilepticus

Question 31

Describe the distribution of BDZ

Answer 31

BDZ binds plasma proteins very strongly They are highly lipid soluble so have a wide distribution

Question 32

How are BDZs metabolised

Answer 32

BDZ metabolised by liver microsomal enzymes and excreted in urine as glucuronide conjugates

Question 33

BDZ can be short acting or long acting. They are long acting if?

Answer 33

If they have slow metabolism or they produce active metabolites

Question 34

Name 4 long acting BDZ

Answer 34

1. Diazepam (Important) 2. Nordiazepam 3. Nitrazepam 4. Chlordiazepoxide

Question 35

Name the short acting BDZs

Answer 35

1. Temazepam (important) 2. Oxazepam - important - (except if they have hepatic impairment - then slower metabolism) 3. Lorazepam

Question 36

What are the clinical uses of BDZs?

Answer 36

1. Anxiolytics (long acting) - Diazepam (valium) / chlordiazepoxide / (nitrazepam) However, if the patient has hepatic impairment, give Oxazepam instead for anxiolytic- b/c slower metabolism 2. Sedative/hypnotics (short acting)- Temazepam - Oxazepam NB - nitrazepam can be used as BOTH a sedative and anxiolytic if you want a daytime anxiolytic effect and a night time sedative effect

Question 37

What are the advantages of BDZs?

Answer 37

1. Wide margin of safety (OD causes prolonged sleep but can be roused) 2. They do not induce liver enzymes - fewer drug interactions (unlike barbs which are enzyme inducers)

Question 38

What can be given if there is a BDZ OD

Answer 38

Flumazenil

Question 39

What are the unwanted effects of BDZ

Answer 39

1. Sedation/confusion/amnesia/ataxia 2. Potentiate other CNS depressants (e.g. alcohol, Barbs) 3. Tolerance (but less than barbs and tissue only, not liver) 4. Dependence causing withdrawal symptoms - not as bad as Barbs, but must withdraw slowly 5. Free plasma conc can increase if other drugs e.g. aspirin/heparin present, that compete w/ plasma protein binding

Question 40

Name and describe another sedative/hypnotic that is used

Answer 40

Zopiclone - short acting (5hrs half life) - acts at BDZ receptor and has similar efficacy to BDZ , has minimal hangover effects. - Dependency still a problem. Zopiclone is a cyclopyrrolone, NOT A BENZODIAZEPINE

Question 41

Name and describe another anxiolytic

Answer 41

Certain antidepressants can be used - e.g. SSRIs - They have less of a sedative effect may cause dependence. They also have a delayed response - However, they are useful in the long term treatment of e.g. anxiety

Question 42

Name another anti epileptic drug (anxiolytic)

Answer 42

Valproate, tiagibine

Question 43

Name some antipsychotic drugs (anxiolytic)

Answer 43

Olanzapine, quetiapine

Question 44

What can propranolol be used for?

Answer 44

It can remove some of the symptoms of anxiety - e.g. tachycardia, tremor

Question 45

What is buspirone

Answer 45

A 5-HTA agonist, with fewer side effects (less sedation), but has a slower onset of action as an anxiolytic