anxiolytics Flashcards
barbiturates (derivatives of barbital)
amobarbital
pentobarbital
thiopental
phenobarbital
-note al ending (also see -one ending)
historical uses of barbiturates
Anxiolytics
Anticonvulsants
Sedatives/hypnotics
Anaesthetics
barbiturates and overdose
very dangerous in overdose
respiratory depression
when are barbiturates used as anxiolytics and anticonvulsants
in extreme cases
when are barbiturates used as anaesthetics?
for induction or very short procedures
mechanism of action of barbiturates
Mainly positive allosteric modulators of GABAA receptor: prolong channel opening time (make GABA work better)
At higher concentrations can bypass GABA and directly activate the receptor
may also inhibit AMPA receptors, P/Q type voltage sensitive channels (inhibits NT release)
why are barbiturates so dangerous in overdose?
because they can directly activate GABA receptors
general mechanism of action or barbiturates
boost inhibitory transmission
can decrease excitatory transmission
how do barbiturates act on GABA A receptors?
site of action of GABA A receptor is fairly poorly characterised
think they have a binding site in the beta subunit, so they are acting within the membrane domain
some have suggested that the binding site might extend into the neighbouring alpha subunit as well
these are drugs that would need to enter the lipid bilayer to access their binding site
uses of thiopental
general anaesthesia
occasionally used in status epilepticus when a seizure has not responded to benzodiazepines or anticonvulsants (also pentobarbital)
current uses of barbiturates
general anaesthesia
status epilepticus
used to induce comas at higher dioses in medical veterinary euthanasia
used in lethal injections as a dorm of capital punishment
lethal injection common cocktail
sodium thiopental
pancuronium bromide
potassium chloride
purpose of sodium thiopental in lethal injection cocktail
induce loss of consciousness and repress respiratory drive
replacement drugs for lethal injection used since 2011
using pentobarbital or a benzodiazepine/ opioid mixture as a replacement
why did benzodiazepines replace barbiturates?
because they are safer in overdose
what was the first barbiturate synthesised?
chlordiazepoxide
effects of benzodiazepines
anxiolytic
sedative
muscle relaxant
amnesic
anticonvulsant
why are barbiturates use sparingly
used at low dose and short term because tolerance builds up quickly
where is the benzodiazepine binding site on GABA A?
on the interfaces of alpha 1 and gamma 2
benzodiazepine agonists
flunitrazepam
diazepam
temazepam
nitrazepam
mechanism of benzodiazepine agonists
increase GABA a receptor channel opening frequency
can also increase affinity for GABA binding sites
benzodiazepine
flumazenil
pharmacologically fairly inactive
applied alone has little effect on GABA A
what is flumazenil used for?
to block potentiation by flunitrazepam
therefore used to reverse benzodiazepine sedation (overdose)
why is it quite difficult to manage flumazenil?
it isn’t a perfect antagonist
it can show a bit of inverse agonist activity and at other doses can show agonist activity
benzodiazepine inverse agonists
B carbolines (DMCM)
proconvulsant
anxiogenic
decrease channel opening frequency
what can block the action of B carbolines
by flumazenil
SAM meaning
silent allosteric modulator
Two distinct CNS populations defined by binding studies
CL218-872:
High affinity for Cl: Type I benzodiazepine binding sites
Low affinity for Cl: Type II
differ in regional distribution
receptor heterogeneity?
benzodiazepine and alpha 1 subunit
type 1 BDZ binding site - binds classic BDZs
benzodiazepine and alpha 2, 3, 5 subunit
type II BDZ binding site - binds classic BDZs
benzodiazepine and alpha 4, 6 subunit
high affinity for Ro 15-4513, but not for classic BDZs
Ro compound
synthesised by Roche
discovered it was an alcohol antagonist
considered marketing it as an alcohol antagonist and antidote, but decided that the ethical issues were too great
what does pharmacology of benzodiazepine binding site depend on?
the alpha subunit at the alpha gamma interface of a GABA A receptor
use of BDZ when first introduces
first line treatments for anxiety and sleep disorders
also frequently used as anticonvulsants
what are most BDZ used for today?
anxiety or sleep disorders (or both)
Some are used as sedatives for minor surgical procedures (especially midazolam),
to aid with alcohol withdrawal (chlordiazepoxide) or
epilepsy (clobazam, clonazepam)
Diazepam is also used for muscle spasms
use of midazolam
sedative for minor surgical procedure
use of chlordiazepoxide
to aid with alcohol withdrawal
use of clobazam and clonazepam
treatment of epilepsy
use of diazepam
treat muscle spasms
what are the z deugs
zaleplon
zopiclone
zolpidem
what are z drugs used for
primarily for the treatment of sleep disorders
-hypnotics or sleeping tablets
features of z drugs
tolerance and dependence can develop (though more slowly that drugs like diazepam)
Normally only prescribes in low doses for a short period of time e.g., 14-28 days
They have short plasma half lives
-most useful for people who have trouble falling asleep
-zapelon: 1hr, zolpidem: 2.5hrs, zopiclone: up to 6 hrs
Their rapid elimination can help avoid ‘hangover’ effects that are seen with older drugs like diazepam (half life 48 hrs)
oppositional tolerance model with reference to benzodiazepines
GABAergic transmission is potentiated so the reaction of the brain is to down-regulate GABAergic transmission
causes tolerance to the drug to develop and results in withdrawal symptoms if the person using the drug abruptly stops taking it
tolerance and dependence with BDZ
Can develop rapidly and this is one of the reasons that they are recommended only for short term use (28 days maximum)
withdrawal effects BDZ
Withdrawal effects can develop rapidly, especially with drugs with a short half life such as alprazolam (Xanax)
said to be harder than coming of heroin and can involve a wide range of unpleasant side effects:
-hallucinations, increased anxiety, insomnia through to photophobia (abnormal sensitivity to light)
why do we want to develop anxioselective BDZ ligands?
Fundamental premise: we have different types of GABA A receptors involved with anxiolytic effects compared with those involved with the sedative effects of BDZ agonists
different subunit compositions in these receptors
Aim to develop BDZ that produces anxiolytic effects, while avoiding sedative effects. Or visa versa
drugs in first wave of studies
bretazenil
alpiden and ocinaplon
bretazenil
Animal studies suggested anxiolysis but little sedation.
Human phase I trials: profound sedation and stronger interaction with ethanol than diazepam
Points to a difference in GABA A receptors in humans and animals
interaction between bretazenil ethanol
found to be stronger than that of ethanol and diazepam
alpidem, ocinaplon
Worked in animals
Good evidence of anxiolysis and reduced sedation
Evidence of reduced sedation vs diazepam in humans
Ocinaplon failed in Phase III, Alpidem withdrawn after licensing (both: liver toxicity)
what did olcinaplon and alpidem provide evidence of?
that it is possible to separate anxiolytic and sedative effects in humans
elevated plus maze quantifies
anxiety
what does the vogel water lick conflict test quantify
anxiety
what does the rotorod test quantify
motor activity
what does the morris water maze quantify?
memory
what is the vogel water-lick test?
In the Vogel test a rodent is deprived of water for 18 hours and then placed in a chamber with a water bottle. The animal will start to drink from the bottle, and the apparatus records the number of licks of the bottle. This is repeated on a subsequent day but on the third day, the animal is given a mild electric shock every 20 licks. It is now conflicted between satisfying its thirst and the fear of receiving a shock, which results in a decreased rate of licking. If the animal is given anxiolytic drugs it will not show as marked a decrease in the rate of licking because its fear will be diminished by the anxiolytic.
how is sedation measured
reduction in motor activity
how did BDZ binding site occur given it has no natural ligand
originally would haver been agonist binding sites but mutations accumulated mean that they can no longer bind GABA
Happened to find a class of drug that fit into one of the redundant binding sites
As it was originally an agonist binding site, it potentially retained some of the machinery that is in the ancestral agonist binding site and changes the conformational change that brings about channel opening??
knock out of alpha 6 subunit
a 6 has cerebellar expression
compensatory expression other GABAA receptors + K channels
- both inhibitory
limited utility
knockout of beta 3 and gamma 2 GABA A subunits
perinatally lethal (death)
limited utility
α105: conserved histamine residue H in α1,2,3,5
very high affinity for diazepam
α105: arginine (R) present in α4,6
very low affinity for diazepam
how to get low affinity for diazepam at a1, 2, 3, 5
mutate histidine to arginine
H105R
mutation conserved a his to arg in BDZ
No change in GABA sensitivity
No change in receptor assembly
-expression levels of the receptor are completely normal
Complete loss of classic BDZ binding
-BZN binding site no longer has a high affinity for diazepam and compounds like flunitrazepam
allows use of knock in transgenic animals
knock in
in vivo replacement of single amino acid in a defined gene
a1, a2, a3 histamine to arginine mutation knock in mice
generally normal phenotype
normally responses to GABA
H-R knock in alpha 1
reduced amnesia
reduced sedation
increased anxiety
A1 probably involved in amnesic and sedative effects
H-R knock in alpha 2
decreased anxiety
increase sedation and amnesia
alpha 2 probably involved in anxiolytic effects
treatment using a1 selevtive drugs?
sleeping tablets?
treatment using a2 selective drugs?
anti anxiety without sedation?
a3 subunit
a3 selective compounds anxiolytic in a2 know in mice
is a3 also important?
TPA023B
zero efficacy at α1 but moderate efficacy at α2, 3 containing receptors.
Anxiolytic in rodents and primates
Not sedating in animals
BUT!! Phase I trials (humans): highly sedating
reasons for failure of specific BDZs
Species differences between rodents/primates and man?
Heterogeneity of alpha subunits within a receptor?
