anxiolytics & hypnotics

Question 1

how is GAMA synthesised

Answer 1

from glutamate to GABA via glutamate decarboxylase enzyme

Question 2

how is GABA metabolised?

Answer 2

GABA reuptake back into presynaptic neurones or into surrounding glial cells

GABA is then metabolised to succinicsemialdehyde (SSA) by GABA transaminase. the SSA is converted to succinic acid by succinic semialdehyde dehydrogenase. the succinic acid then goes into the TCA cycle in the cell.

Question 3

how is GABA release regulated?

Answer 3

by the -ve feedback effect of the GABA B receptors

Question 4

what is the MOA of Vigabatrin?

Answer 4

GABA transaminase inhibitor.

binds covalently

enhancing the release and effectiveness of GABA

Question 5

what is the MOA of sodium valproate?

Answer 5

inhibits both breakdown enzymes of GABA

binds to multisensitive sodium channels
contributes to its anti-convulsive drugs

Question 6

what is the normal physiological action of GABA?

Answer 6

GABA binds via route 1,
and changes the conformation of the chloride channel protein
to increase chloride flux.

the Cl- hyperpolarises the cell and reduces the AP

Question 7

how do benzodiazepines work?

Answer 7

bind to benzodiazepine receptor on GABA receptor complex

in the presence of benzodiazapien, the binding of GABA is enhanced and that response is reciprocated

only work in the presence of GABA 
allosteric action (own binding site)

Benzodiazepines increase the frequency of chloride channel
openings.

Question 8

how do barbiturates work?

Answer 8

binds to its ow barbiturate binding protein
enhances the normal action of GABA
increase the infinity of GABA binding (but not reciprocated)
can get a direct action on the chloride channel to allow Cl- influx

only work in the presence of GABA 
allosteric action (own binding site)
not classed as agonists 

Barbiturates increase the duration of chloride channel
openings.

Question 9

what is the difference in the effect between barbs and BZs

Answer 9

BARBs are less selective than BZs which may explain why:

barbituates have a lower margin of safety than benzodiazepines

barbituates can induce surgical anaesthesia but benzodiaazepines cannot

Question 10

what are the clinical uses of BARBs and BZs?

Answer 10

anaesthetia (Barbiturates only: Thiopentone);

anticonvulsants
(Diazepam, Clonazepam, Phenobarbital);

anti-spastics (Diazepam),

anxiolytics,
sedatives
hypnotics.

Question 11

define anxiolytics

Answer 11

remove anxiety without impairing mental or physical activity (‘minor tranquilisers’)

lytic- ‘dissolving anxiety’

Question 12

define sedatives

Answer 12

reduce mental and physical activity without producing loss of consciousness

Question 13

define hypnotics

Answer 13

induces sleep

Question 14

what are the clinical uses of BARBS

Answer 14

general anaesthetics eg. Thiopentone

anticonvulsants eg. Phenobarbital

sedatives/hypnotics eg. Amobarbital

Question 15

what are the unwanted effects of BARBS

Answer 15

depress respiration
overdosing is lethal
alter natural sleep (decrease REM)
enzyme inducers
potential other CNS depressant effects when interacting with other drugs (eg.alcohol)
can develop tolerance
can develop dependence and withdrawal symptoms

Question 16

what is the pharmokinetics of BZs

Answer 16

They are well absorbed orally, and reach their peak plasma concentration after
about an hour (Oxazepam is slower).

They can be given intravenously in the
treatment of Status Epilepticus (repeated seizure activity).

Benzodiazepines bind to plasma proteins strongly, and are highly lipid soluble. This
gives them a very wide distribution in the body. Metabolism is usually extensive,
and mostly in the liver. Excretion is by the kidney in the urine, with glucuronide
conjugates.

split into two groups:
long acting (slow metabolism or active metabolites)
short acting

Question 17

which drugs are used for anxiolytics?

Answer 17

long acting:
eg,
Diazepam (valium)
nitrazepam

Question 18

which drugs are used as sedatives/ hypnotics?

Answer 18

short acting:
eg
temazepam
oxazepam

Question 19

what are the advantages of BZs?

Answer 19

wide margin of safety
-overdose–> prolonged sleep which is rousable

mild effect on REM sleep

do not induce liver enzymes

Question 20

what are the unwanted effects of BZs?

Answer 20

sedation (when being used as an anxiolytic), confusion, amnesia, ataxia (impaired manual skills)

potentiate other CNS depression in combination with other drugs

tolerance

dependence - withdrawal (similar but less intense than BARBS)

free plasma conc of BZs increased by aspirin and heparin (displace from binding sites to plasma proteins)

Question 21

what is an example of another seditive/ hypnotic? and describe

Answer 21

zopiclone

short acting (1/2~5hrs)
acts at BZ receptors to inhance action of GABA 

similar efficacy to BZs

minimal hangover effect but still dependency

Question 22

what is an example of another anxiolytic drug?

Answer 22

selective serotonin reuptake inhibitors (antidepressant drug has some useful anxiolytic effects)

propranolol (improves symptoms of anxiety eg tachycardia and tremor)

5HT