Anxiolytics and Hypnotics

Question 1

Give a summary of GABA neurotransmission

Answer 1

Glu converted to GABA via glutamate decarboxylase (GAD)
GABA release into the synapse
Binds to postsynaptic Cl- ionophore receptor (GABAa)

Question 2

What are the ways in which GABA is taken back up from the synapse

Answer 2

Uptake into glial cell or pre-synaptic terminal

Conversion to SSA via GABA-T

Question 3

Explain how GABA is metabolised

Answer 3

GABA converted to succinic semialdehyde by GABA transaminase (GABA-T)
SSA converted to succinic acid by succinic semialdehyde dehydrogenase (SSDH)

Question 4

What is the effect of GABA metabolism inhibitors and give examples

Answer 4

Inhibitors of GABA metabolism - large increase in brain GABA
Sodium valproate
Vigabatrn

Question 5

Describe the action of Benzodiazepines and Barbiturates at the GABA-a receptor complex

Answer 5

No activity alone (allosteric actin)

Different binding sites and different mechnaisms

Question 6

What are the mechanisms of Benzodiazepines and Barbiturates at the GABA-a receptor complex

Answer 6

BZs - increase frequency of Ca2+ channel openings

BARB - increase duration of Ca2+ channel openings

Question 7

Compare Benzodiazepines and Barbiturates

Answer 7

BARBs are less selective than BZs

This causes a decrease in excitatory transmission and other membrane effects

Question 8

What effects of barbiturates are explained by its differences form benzos

Answer 8

decrease in excitatory transmission and other membrane effects

Induction of surgical anaesthesia
Low margin of safety

Question 9

What are the clinical uses of Benzodiazepines and Barbiturates

Answer 9

Anaesthetics (BARB: thiopentone)
Anticonvulsant (diazepam, clonazepam, phenobarbital)
Anti-spastics (diazepam)
Anxiolytics
Sedative/hypnotic

Question 10

Define anxiolytics

Answer 10

Removes anxiety without impairing mental or physical activity (minor tranquillisers)

Question 11

Define sedatives

Answer 11

Reduce mental and physical activity without producing loss of conscioussness

Question 12

Define hypnotic

Answer 12

Induces sleep

Question 13

What are the ideal features of anxiolytics, sedative and hypnotics

Answer 13

Have a wide margin of safety
Not depress respiration 
Produce natural sleep
Not interact with other drugs
Not produce hangovers
Not produce dependence

Question 14

Give an example of a barbiturate used as a sedative/hypnotic, stating what its used for and its half life

Answer 14

Amobarbital
Severe intractable insomnia
20-25h half life

Question 15

What are the unwanted effects of barbiturates

Answer 15

Low safety margins -> depress respiration, overdose is lethal
Alters natural sleep
Leads to hangovers and irritability
Enzyme inducers
Potentiates effects of other CNS depressants e.g. alcohol
Tolerance
Withdrawal syndrome

Question 16

What re the symptoms of withdrawal syndrome

Answer 16

Insomnia
Anxiety 
Tremor
Convulsions
Death

Question 17

Describe benzodiazepines

Answer 17

Around 20 available, all act at GABA-A receptors
All have similar potencies and profiles
Pharmacokinetics largely determine its use

Question 18

Describe the administrative and absorptive pharmacokinetics of benzodiazepines

Answer 18

Well absorbed PO
Peak in plasma = 1 hour
IV vs status epilepticus

Question 19

Describe the distributive pharmacokinetics pf benzodiazepines

Answer 19

Binds plasma proteins strongly

Highly lipid soluble - wide distribution

Question 20

Describe the metabolic and excretory pharmacokinetics of benzodiazepines

Answer 20

Usually extensive metabolisms by the liver

Excreted in the urine (glucuronide conjugates)

Question 21

What is the duration of action for benzodiazepines

Answer 21

Varies greatly
Short action or long acting

Long due to slow metabolism and/or active metabolites

Question 22

Describe the metabolism of diazepam, lorazepam and nitrazepam (diagram)

Answer 22

Refer to notes

Both lorazepam and nitrazepam are metabolised directly into glucuronide

Question 23

Give an example of anxiolytics (long acting)

Answer 23

Diazepam (valium)
Chlordiazepoxide (librium)
Nitrazepam

Question 24

What is the half life of oxazepam and give a side effect

Answer 24

8 hours

Hepatic impairment

Question 25

Give examples of sedative/hypnotics (short acting)

Answer 25

Temazepam

Oxazepam

Question 26

What is the half life of temazepam

Answer 26

28 hours

Question 27

What are the advantages of benzodiazepines

Answer 27

Wide margin of safety 
Overdose - prolonged sleep (rousable) 
Flumazenil 
Mild effect on REM sleep 
Does not induce liver enzymes

Question 28

What are the unwanted effects of benzodiazepines

Answer 28

Sedation
Confusion and amnesia 
Ataxia (impaired manual skills)
Potentiates other CNS depressants (alcohol, BARBs)
Tolerance (less than BARBs)
Dependence
Free [plasma] by aspirin, heparin

Question 29

Describe the dependence from benzodiazepines

Answer 29

Withdrawal syndrome similar to BARBs

Withdraw slowly

Question 30

Describe zopiclone

Answer 30

Short actin sedative (5h half life)
Acts as Bz receptors
Similar efficacy to BZs
Minimal hangover effect but dependency is still a problem

Question 31

What are the advantages and disadvantages of SSRIs as an antidepressant drug compared to others

Answer 31

Less sedation and dependence
Long term treatment

Delayed response

Question 32

Give examples of antiepileptic drugs

Answer 32

Valproate

Tiagabine

Question 33

Give examples of antipsychotic drugs

Answer 33

Olanzapine

Quetiapine

Question 34

What is busiprone

Answer 34

5HT-1A agonist

Fewer side-effects (

Question 35

Where are the enzymes involved in GABA synthesis and metabolism found

Answer 35

GAD - cytoplasmic

GABA-T and SSDH - mitochondrial