Anxiolytics and hypnotics

Question 1

What is the main ascending tract associated with GABA transmission in the brain?

Answer 1

Nigrostriatal

Question 2

Describe the descending GABA pathways in the brain

Answer 2

Mostly localised control neurons

Question 3

Recall the subunits of the GABA receptor

Answer 3

1. Cl- channel protein
2. GABA modulin - links GABA and BDZ receptor proteins
   Receptor proteins for:
3. GABA
4. BARBs
5. BDZs

Question 4

How does binding of BARBs to the BARB receptor protein of the GABAR affect GABA receptor activity?

Answer 4

1. Enhances GABA action by increasing affinity of GABA binding
2. At high concentrations, increases DURATION of Cl- channel opening

Question 5

How does binding of BDZs to the BDZ receptor protein of the GABAR affect GABA receptor activity?

Answer 5

1. Increases affinity of GABARP for GABA
2. Increases FREQUENCY of opening of Cl- channel
3. at high conc. can directly open Cl- channel

Question 6

How does binding of GABAs to the GABA receptor protein of the GABAR affect BARBRP and BDZRPs?

Answer 6

1. No effect on the BARBRP

2. Reciprocally activates the BDZRP

Question 7

Where is GABA modulin found and what is its funcion?

Answer 7

Joining the GABARP and the BDZRP

Opens the Cl- channel

Question 8

What sort of action do BARBs and BDZs show at the GABA receptor?

Answer 8

Allosteric only- NO activity alone

Question 9

Compare the selectivity of barbiturates and benzodiazepines.

Answer 9

BARBs = less selective than BDZs as they have other membrane effects eg can directly open Cl- ion channel opening and can also act as glutamate receptor antagonist

This is why BARBs have an anaesthetic effect and a low margin of safety

Question 10

Where can GABA be metabolised?

Answer 10

Glia

Pre-synaptic terminals

Question 11

Recall the reactions and enzymes involved in GABA production and metabolism

Answer 11

Production:
Glutamate to GABA via GAD (glutamate decarboxylase)
Metabolism:
GABA --> SSA --> succinic acid
Enzyme 1 = GABA-transaminase
Enzyme 2 = SSA-dehydrogenase

Question 12

Recall 2 drugs capable of inhibiting GABA metabolism.

Answer 12

Vigabatrin

Sodium valporate

Question 13

Where are the enzymes that produce and metabolise GABA located?

Answer 13

GABA-T and SSA dehydrogenase are Mitochondrial enzymes

GAD is cytoplasmic

Question 14

Recall an example of a barbiturate drug

Answer 14

Amobarbital and phenobarbital (you need to know the first one)

Question 15

Recall 2 uses of amobarbital

Answer 15

1. Sedative

2. Hypnotic- In severe intractable insomnia

Question 16

What is the main distinguishing factor between BDZ drugs?

Answer 16

benzodiazepines all have similar MOA and potency (similar PD) but vary in terms of their PK

Question 17

ROA for benzodiazepines?

Answer 17

Oral or IV (for status epilepticus)

Question 18

Describe the degree of plasma protein binding for benzodiazepines and its degree of distribution in the body

Answer 18

HIGH Plasma protein binding

Lipophilic- extensive distribution

Question 19

How are BDZ drugs usually classified?

Answer 19

Long or short acting

Question 20

What might make a BDZ long-acting?

Answer 20

• Slow metabolism

- Metabolites are active

Question 21

Recall examples for each of long- and short-acting BDZs

Answer 21

Long: diazepam
Short: oxazepam. temazepam

Question 22

Which class of BDZs are preferable for use as anxiolytics?

Answer 22

Long-acting

Question 23

Which class of BDZs are preferable for use as sedatives?

Answer 23

Short-acting

Question 24

Recall 3 advantages of BDZ drug use over BARBs

Answer 24

1. Less effect on REM sleep (so less hangover effect)
2. OD is safer: wide margin of safety + we have antidote Flumazenil
3. Does not induce CYP450 (barbiturates do)

Question 25

Other than BARBs and BDZs, give an example of a drug that may be used as a sedative, its general MOA and an advantage of using it

Answer 25

Zopiclone (cyclopyrrolones)
Short-acting BDZ agonist
Minimal hangover effects

Question 26

Recall 4 drugs that may be used as anxiolytics other than BARBs and BDZs

Answer 26

anti-depressants- SSRIs
Anti-epileptics- Valproate
Anti-psychotics
Propanolol
Busiprone

Question 27

Why might propanolol be used in anxiety?

Answer 27

Improves physical symptoms of tachycardia and tremor (does not directly affect anxiety)

Question 28

Recall the MOA of busiprone, and one advantage and disadvantage for its use

Answer 28

MOA: 5HT1A agonist
Ad: fewer side effects
Dis: Slow onset of action

Question 29

What can BARBs be used for clinically that BDZs cannot?

Answer 29

Anaesthetic use

Question 30

Give an example of a BARB drug that may be used for its anaesthetic effect?

Answer 30

Thiopentone

Question 31

Give 4 clinical uses of BARB/BDZ drugs

Answer 31

1. Anticonvulsants
2. Antispastics
3. Anxiolytics
4. Sedatives/hypnotics

Question 32

What is the difference between a sedative and a hypnotic drug?

Answer 32

 Sedative should reduce mental/ physical activity without producing loss of consciousness
 Hypnotics should induce sleep
 Use same drugs for both just at different dosages

Question 33

Summarise the side effect profile of BARB drugs

Answer 33

1. Low margins of safety
2. Alter natural sleep and may cause Irritability the next day
3. Induce liver enzymes
4. Tolerance (tissue and Pk)
5. Potentiate other CNS depressants such as alcohol
6. Dependence- withdrawal syndrome

Question 34

Recall 4 symptoms of BARB withdrawal

Answer 34

Anxiety
Tremor
Convulsions
Insomnia

Question 35

What might increase the plasma concentration of BDZs and why?

Answer 35

Aspirin and Heparin coadministration

Due to high plasma protein binding

Question 36

What does diazepam get metabolised into?

Answer 36

Diazepam is a long acting BDZ, metabolized into temazepam and nordiazepam which are both active metabolites , they then get further metabolized into oxazepam and eventually excreted in urine as glucuronide

Question 37

What does temazapam get metabolised into?

Answer 37

oxazepam then glucoronide in the urine