anxiolytics and hypnotics Flashcards
what is anxiety and it’s symptoms?
anticipatory fear response - often independent of external events (not a reaction to an actual situation that has happened, but something that could happen)
Symptoms - defensive behaviours, autonomic reflexes (flight or flight) corticosteroid and adrenaline production, negative emotions
name 5 anxiety disorders and there impact
Panic disorder/phobias - an overwhelming fear of something, like agoraphobia, medical intervention may be required ALONGSIDE psychiatric therapy
Social anxiety disorder - can severely impact quality of life
PTSD - not just for war-survivors
OCD - hahaha we know what this one is
Generalised anxiety - no clear reason or focus
how are different animal models used to test anxiolytics?
What conclusion was made about effective anxiolytics?
Elevated plus/cross
Put a mouse in an elevated cross, will it go along the length with walls, or the exposed length of the cross with the risk of falling, normally mouse always picks the walled length
light/dark box is a similar concept - how long does mouse spend in dark side, vs light side (usually prefers to hide in the dark side)
If you treat the rodent with an anxiolytic drug it is equally happy in either situation - reduced fear response
Conclusion - drugs that increased GABA-A reduced fear response
what is the downside of increasing GABA-A to treat anxiety?
while effective, it comes with the often unwanted effect of sedation
GABA-a receptors - describe the structure and the different kind of frugs it has binding sites for
Receptor - ionotropic, 5 protein subunits, with two binding sites for GABA
Has sites for binding other than GABA, such as benzodiazepines, barbiturates, ethanol and neurosteroids
what do GABA receptors do (generally) and how do they vary?
Mediate fast inhibitory transmission
Usually found postsynaptic and are chloride selective (let -ve ions across)
Activation = hyperpolarisation = reduced excitability
Different parts of the brain have receptors with different subunit combinations that may contribute to difference in function
what is an orthosteric agonist of GABA-A receptors?
give an example of an orthosteric antagonist for GABA-A receptors
an orthosteric agonist controls the opening of the receptor by binding at the binding/active site - example = muscimol
an orthosteric (competitive) antagonist for GABA-A receptors = bicuculline
what is picrotoxin?
a GABA-A antagonist that blocks the ion channel. These drugs can lead to seizures as there is a lack of necessary inhibition, so more excitation
what is an allosteric modulator?
alters behaviour/response of the receptor to an agonist of the orthosteric site. Can be positive (increase response) or negative. Cannot open the channel itself, just changes the response to an orthosteric agonist
what are benzodiazepines?
agonists for GABA-A receptors by acting as positive allosteric modulators (they inc. response to orthosteric agonists (including GABA-A itself)
interesting fact - Marilyn Monroe died of an overdose of a benzodiazepine drug combined with alcohol
what is flumazenil?
competitive antagonist for GABA-A receptors (an orthosteric antagonist) that can therefore be used to treat benzodiazepine overdose
GABA-A receptor genes - how many are there? what is most common?
why is this important?
many genes for different subunits
there are 6 genes coding for GABA-A alpha subunits alone (two alpha subunits per receptor)
most abundant GABA-A receptor = a1 (x2) b2 (x2) and y2
important because pharmacology slightly differs - we can use this to increase selectivity of drugs
explain the mouse model showing the importance of the a2 subunit in GABA-A receptors as a target for anxiolytics
histamine was changed to an arginine in the a2 subunits of GABA-A receptors in mice
then treated with diazepam and using the light/dark box experiment, the diazepam had no effect on mutant mice while it did reduce fear response for WT mice
discovered anxiolytic effects of diazepam (a benzodiazepine) completely removed with the mutant a2 subunit
what are the physiological effects of benzodiazepines
?
how are these different effects achieved?
Anxiolytic/sedative
Hypnotic (tho increase stage 2 - non-rem - sleep) and less slow wave sleep which is associated with sleepwalking and night terrors
Anterograde amnesia - prevents memories being formed - rohypnol
Anticonvulsants
Reduce muscle tone - useful in surgery (due to CNS effects not neuromuscular junction effects)
Different GABAA receptor compositions are responsible for different effects
The hope is to produce drugs selective for one of the several effects that occur
what is rohypnol?
a benzodiazepine, also known as flunitrazepam
the date rape drug - causes anterograde amnesia and muscle relaxation
how do benzodiazepines work? include the possibilities for allosteric regualtors
its a positive allosteric regulator so increases receptor response to GABA-A or other orthosteric agonists, this response being an increase in Cl- current (which is inhibitory)
positive allosteric regulators can work by keeping channels open for longer, increasing conductance, or increasing affinity of the receptor for the orthosteric agonist
diazepam shows more frequent opening of the channels in the same length of time
describe the experiments used to discover how diazepam (benzodiazepine) works
Single channel patch clamp recordings were used to view activity of a single GABAA receptor with an electrode
Each deflection = opening and closing of the channel. Size of deflection is a measure of conductance (which is fixed)
Diazepam shows more frequent opening of the channels (for same amount of time)
how do barbiturates work?
these are also positive allosteric regulators of GABA-A receptors, but work by prolonging channel opening, not frequency of channel opening
explain the two state model
PAM (positive allosteric modulators) stabilize the receptor in a state with increased affinity for GABA, effectively causes leftward shift in concentration response curve
NAM (negative allosteric modulators) stabilize the receptor in such a state that has reduced affinity for GABA and therefore effectively remains closed/harder to open
what is a negative allosteric modulator of GABA-A receptors and what does it do?
b-carboline, it increases awareness (sort of the opposite of retrograde amnesia) but will also be pro-anxiolytic and proconvulsant
why is zolpidem useful as a hypnotic/sleeping tablet?
this is a benzodiazepine that has a short half life and is therefore short acting
what is intravenous diazepam used for?
someone seizing/status epilepticus
what makes diazepam a good anxiety treatment compared to other benzodiazepines?
it is metabolised to produce active intermediates resulting in it being quite long-acting. also used as a muscle relaxant
when it comes to benzodiazepines, what is the industry now looking for?
Benzodiazepines with selectivity for receptor subtypes or partial agonists (less sedation likely)
Have noted that some benzo derivatives have antiCCK activity, CCK has been implicated as biological substrate for anxiety, so there is a search for antagonists
adverse effects/ issues with benzodiazepines?
People can develop a tolerance, which can be overcome by increasing dose
The CNS can have changes in how responsive it is to benzodiazepines (unknown how)
Physical dependence/withdrawal - when removed there can be increased anxiety, insomnia, convulsions and CNS excitability
Drugs with short half lives have this issue, some sleeping pills may cause daytime anxiety
how can withdrawal from benzodiazepines be managed?
by using a slower acting drug - it’s drugs with short half-lives commonly cause withdrawal/dependence (which is why SSRIs are the first port of call for depression, not benzodiazepines)
why are benzodiazepines usually safer than barbiturates?
Barbiturates, at high doses act as agonists, increase CNS depression to point of death.
Benzodiazepines on their own show plateau effect…can’t do more than put you into deep sleep. BUTTTTT
They add with other CNS depressants eg. alcohol to give fatal results.
*Flumazenil (benzodiazepine antagonist) can be used to treat overdose on benzodiazepines (not barbiturates)
so, which drugs are used to treat which kind of anxiety? (name a drug for PTSD)
Benzodiazepines - used for short term anxiety purposes/before surgery
Used for the time it takes for antidepressants to work
Antidepressants - SSRIs useful for generalised anxiety and OCD
Atypical antipsychotics - have been used for generalised anxiety and for PTSD e.g. olanzapine
Anti-epileptic drugs have also been used for generalised anxiety
what is propanolol?
Propranolol - beta-blocker, blocks adrenaline effects, physically calms
what is olanzapine?
an atypical antipsychotic used for PTSD and general anxiety
what recent developments have been made in the treatment of PTSD?
found a small molecule to interfere with the way a memory was created rather than the consequences of the memory. Essentially erasing the memory wtf
Psychedelics have also been looked at for treating PTSD
what drugs are used to treat insomnia?
the drug of choice depends on whether the issue is chronic or short term
melatonin agonists
orexin receptor antagonists
antihistamines (H1 receptor antagonists) which is why allergy medication can be drowsy
what is buspirone?
partial agonist of serotonin receptor (5HT-1)
used for anxiety, no sedation (YAYYYYYY)
not suitable for immediate relief, not all kinds of anxiety responds
what is promethazine?
an antihistamine - so used as a sedative/ to treat insomnia
ketamine?
an anaesthetic, acts as an antagonist of NMDA receptors involved in pain signals
causes a dissociative state
looking at using it as an antidepressant
