anxiolytics & hypnotics Flashcards
how is GAMA synthesised
from glutamate to GABA via glutamate decarboxylase enzyme
how is GABA metabolised?
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.
how is GABA release regulated?
by the -ve feedback effect of the GABA B receptors
what is the MOA of Vigabatrin?
GABA transaminase inhibitor.
binds covalently
enhancing the release and effectiveness of GABA
what is the MOA of sodium valproate?
inhibits both breakdown enzymes of GABA
binds to multisensitive sodium channels
contributes to its anti-convulsive drugs
what is the normal physiological action of GABA?
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
how do benzodiazepines work?
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.
how do barbiturates work?
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.
what is the difference in the effect between barbs and BZs
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
what are the clinical uses of BARBs and BZs?
anaesthetia (Barbiturates only: Thiopentone);
anticonvulsants
(Diazepam, Clonazepam, Phenobarbital);
anti-spastics (Diazepam),
anxiolytics,
sedatives
hypnotics.
define anxiolytics
remove anxiety without impairing mental or physical activity (‘minor tranquilisers’)
lytic- ‘dissolving anxiety’
define sedatives
reduce mental and physical activity without producing loss of consciousness
define hypnotics
induces sleep
what are the clinical uses of BARBS
general anaesthetics eg. Thiopentone
anticonvulsants eg. Phenobarbital
sedatives/hypnotics eg. Amobarbital
what are the unwanted effects of BARBS
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
what is the pharmokinetics of BZs
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
which drugs are used for anxiolytics?
long acting:
eg,
Diazepam (valium)
nitrazepam
which drugs are used as sedatives/ hypnotics?
short acting:
eg
temazepam
oxazepam
what are the advantages of BZs?
wide margin of safety
-overdose–> prolonged sleep which is rousable
mild effect on REM sleep
do not induce liver enzymes
what are the unwanted effects of BZs?
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)
what is an example of another seditive/ hypnotic? and describe
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
what is an example of another anxiolytic drug?
selective serotonin reuptake inhibitors (antidepressant drug has some useful anxiolytic effects)
propranolol (improves symptoms of anxiety eg tachycardia and tremor)
5HT
