Anxiolytics, Sedatives and Hypnotics Flashcards
what is the main inhibitory neurotransmitter in the CNS?
GABA
what is GABA derived from?
glutamate (happens to be the excitatory neurotransmitter of CNS also)
conversion via Glutamate Decarboxylase (GAD) during the GABA shunt
GAD found in cytosol
where does GABA bind post-synaptically? what effect does this have?
GABAa receptor
hyperpolarises the cell by Cl- influx
where does GABA bind pre-synaptically? what effect does this have?
GABAb receptor (autoreceptor)
regulates the release of GABA (inhibition of release)
which two locations can GABA be reuptaken?
1) at glial cells (found lateral to the pre-synaptic neurone)
2) the pre-synaptic neurone itself
what breaks down GABA in glial cells and pre-synaptic neurones?
GABA-Transaminase
what is GABA broken down into by GABA-T?
Succinic Semialdehyde
what is succinic semialdehyde broken down into? by what?
succinic acid
by succinic semialdehyde dehydrogenase
what is overall formation and deactivation pathway of GABA?
formation:
- Glutamate
- GABA
(via glutamate decarboxylase)
metabolism:
- succinic semialdehyde
(via GABA transaminase)
- succinic acid
(via succinic semialdehyde dehydrogenase)
where is GAD found?
found in the cytosol
where is GABA-T and SSDH found?
found in the mitochondrial membrane.
how can the action of GABA be enhanced?
1) by using Inhibitors of GABA metabolism
- ->so GABA is increased leading to more inhibition in the brain
2) by stimulating GABA receptors (increasing Cl- influx)
- use of barbs and BDZs
what are examples of inhibitors of GABA metabolism?
Sodium Valproate (epilim) Vigabatrin (sabril)
what is sodium valproate used for?
anti-convulsive i.e. epileptic seizures
what is vigabatrin used for?
epilepsy where GABA inhibition is not at its optimal
reduce GABA metabolism
how does sodium valproate work?
inhibitor of GABA metabolism:
it is a weak inhibitor of GABA-T and SSDH
nb GABA-T and SSDH are found in the mitochondria
also binds to sodium channels
has a complex MoA
how does vigabatrin work?
inhibitor of GABA-T therefore metabolism
binds covalently, therefore irreversibly
what are the 4 proteins that make up GABAa receptor (post-synaptic)?
o GABA receptor Protein.
o GABA modulin.
o Barbiturate receptor protein.
o BDZ (Benzodiazepine) receptor protein.
there is a chloride channel protein in the middle
what is the effect of GABA on the Chloride channel?
the domains are linked so
opens the Cl-channel causing hyperpolarisation of the membrane
what is the effect of BDZ binding to GABAa?
binds to BDZ receptor protein
- this enhances the GABA affinity
- leads to chloride influx and therefore hyperpolarisation
- the binding of GABA improves BDZ binding aswell (reciprocity)
what is the effect of Barbs biding to GABAa?
enhances GABA’s
but the action is not reciprocated by GABA for Barbs
what effect does higher concentrations of Barbs have on the GABAa receptor?
has a direct activating effect on the Cl- channel (like GABA can aswell)
Name competitive antagonists of GABA and BDZs for GABAa receptor
- Bicuculline compete with GABA
- Flumazenil compete with BDZ
what overall effect do BZDs have on GABAa Chloride channel?
increases the frequency of its opening
[BDZ treat convulsions with frequent spasms]
what overall effect do Barbs have on GABAa chloride channel?
increase the duration of its opening
[barbed fences–> more time in jail]
why do barbs cause less excitatory transmission that BDZs? what does this mean for barbs?
they are less selective
this means barbs are more dangerous and have more dangerous side effects: small therapeutic window (low safety margin)
what does the low selectivity of barbs enable its usage for?
induction of surgical anaesthesia
what role does GABA play for the action of Barbs and BDZs?
They are not independent of GABA, GABA is required for their MoA
how can you describe barbs and BDZ in terms of binding to GABA?
allosteric
what is used for anaesthetics?
Barbiturates only
– e.g. Thiopentone.
what can be used as anti-convulsants?
Diazepam, Clonazepam, Phenobarbital.
what can be used as anti spastics?
Diazepam (into spinal cord to reduce muscle tone)
what are the uses of BDZs and barbs?
o Anaesthetics (Barbs only)
o Anticonvulsants (both)
o Anti-spastics (both)
o Anxiolytics (“Long-acting”, BDZs only)
o Sedatives/Hypnotics (“Short-acting”; both)
what are anxiolytics?
remove anxiety without impairing mental or physical activity.
what are sedatives?
reduce mental and physical activity without producing a loss of consciousness
what are hypnotics?
induce sleep.
what is the order of drugs in order of decreasing wakefulness?
anxiolytics
sedatives (higher dose has hypnotic effect)
hypnotics
what would the ideal properties of anxiolytics,
sedatives and hypnotics be?
- have a large therapeutic window, high safety margin
- not depress respiration
- produce natural sleep
- not interact with other drugs
- low drowsiness
- not produce “dependence”.
describe Barbiturates structure
[-tone, -tol, -tal]
- tend to have a single ring structure with two R-groups and an X group
- R groups are – ethyl groups and phenyl/1-methylbutyl
- a sedative/hypnotic effect
amobarbital and its use
Amobarbital for severe intractable insomnia
T1/2 = 20-25h
what are the unwanted side effects of Barbs leading to it being superseded by BDZs?
o Small therapeutic windows – depress respiration.
o Reduce REM sleep
- “hangovers”
o Induce enzymes (chronic use) so co-administration needs to be careful
o Potentiate effects of other CNS depressants
– alcohol so OD is easier
o Tolerance and dependence become issues (withdrawal syndrome)
describe benzodiazepines [-epam, -epate] structure
- Usually a triple-ring structure (R1-R4)
- bind to all GABAa receptors
- different drugs have difference pharmacokinetics so that determines their use (duraction of action varies)
describe the pharmacokinetic of BDZs
o Administration
– orally or IV, peak plasma at ~1h.
o Binds plasma proteins strongly, high lipid solubility.
o Extensive liver metabolism.
o Excretion – urine (glucuronide conjugates).
o Duration of action – varies greatly
how do BDZs vary in duration of action?
there are long acting and short acting BDZs
long acting BDZs have slower metabolism and/or active metabolites–> use as anxiolytics
give examples of long acting BDZs
locating acting drugs used for anxiolytic effect
- diazepam (valium) 32h
- nitrazepam 28h
- Chlordiazepoxide (Librium) 12h
nitrazepam due to long DOA can be used as a hypnotic at night and anxiolytic by day at the same time
give examples of short acting BDZs
- Temazepam (becomes oxazepam) 8h
- Oxazepam 8h–> liver impairment anxiolytic however
- Lorazepam 12h
these get into the urine quickly
NB anxiolytics need long acting drugs
what BDZ should be given to those with hepatic impairment?
Oxazepam (short acting)
impaired liver will take longer to metabolise the oxazepam so the half-life will be longer
what BDZ is given for a hypnotic effect at night
followed by an anxiolytic effect during the day (daytime anxiety)?
Nitrazepam (long acting)
will have a longer effect, not just for the night
what is the final excreted product of BDZs?
glucuronide conjugates
what is the advantage of using BDZs over Barbs in terms of overdose?
what is the antidote for reversal?
has a wider therapeutic window so an overdose leads to just prolonged sleep i.e. safer in overdose
An antidote is available:
Flumazenil (BDZ antagonist)
can reverse effect
what other advantages are there to using BDZs over barbs?
o Mild effect on REM sleep.
o Does not induce liver enzymes.
unlike barbs
what are the unwanted effects of BDZs?
o Sedation, confusion, amnesia, ataxia
– all impaired manual skills.
o Potentiates other CNS depressants.
o Tolerance (less than barbs and includes “tissues only”)
o Dependence (less intense than barbs).
o Free plasma concentration increases when co-administered with aspirin, heparin.
What is Zopiclone? describe it use and effects
- short acting cyclopyrrolones
- sedative/hypnotic
- bind to BDZ receptor protein(NOT a BDZ however)
- minimal hangover effects
- dependency issue
what is an advantage and disadvantage of SSRIs as antidepressants?
A: less sedation and dependence, safer in OD
D: have a delayed response (a week), not effective against more severe condition
name anti-epileptics
- Valproate (GABA-T inhibitor)
- Tiagabine (GABA reuptake inhibitor GAT-1)
these enhance GABA transmission
name anti-psychotics
Olanzapine
Quetiapine
what can be used to treat the physical symptoms of anxiety?
beta blocker propranolol
name a drug for anxiety disorder
Buspirone
– 5HT1A-Receptor agonist (serotonin)
- with fewer side effects (less sedation)
- but has a slow onset of action.
what type of drug is used to treat insomnia?
BDZ like temazepam
