anxiolytics and hypnotics

Question 1

what is anxiety and it’s symptoms?

Answer 1

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

Question 2

name 5 anxiety disorders and there impact

Answer 2

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

Question 3

how are different animal models used to test anxiolytics?
What conclusion was made about effective anxiolytics?

Answer 3

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

Question 4

what is the downside of increasing GABA-A to treat anxiety?

Answer 4

while effective, it comes with the often unwanted effect of sedation

Question 5

GABA-a receptors - describe the structure and the different kind of frugs it has binding sites for

Answer 5

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

Question 6

what do GABA receptors do (generally) and how do they vary?

Answer 6

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

Question 7

what is an orthosteric agonist of GABA-A receptors?

give an example of an orthosteric antagonist for GABA-A receptors

Answer 7

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

Question 8

what is picrotoxin?

Answer 8

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

Question 9

what is an allosteric modulator?

Answer 9

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

Question 10

what are benzodiazepines?

Answer 10

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

Question 11

what is flumazenil?

Answer 11

competitive antagonist for GABA-A receptors (an orthosteric antagonist) that can therefore be used to treat benzodiazepine overdose

Question 12

GABA-A receptor genes - how many are there? what is most common?
why is this important?

Answer 12

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

Question 13

explain the mouse model showing the importance of the a2 subunit in GABA-A receptors as a target for anxiolytics

Answer 13

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

Question 14

what are the physiological effects of benzodiazepines
?
how are these different effects achieved?

Answer 14

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

Question 15

what is rohypnol?

Answer 15

a benzodiazepine, also known as flunitrazepam

the date rape drug - causes anterograde amnesia and muscle relaxation

Question 16

how do benzodiazepines work? include the possibilities for allosteric regualtors

Answer 16

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

Question 17

describe the experiments used to discover how diazepam (benzodiazepine) works

Answer 17

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)

Question 18

how do barbiturates work?

Answer 18

these are also positive allosteric regulators of GABA-A receptors, but work by prolonging channel opening, not frequency of channel opening

Question 19

explain the two state model

Answer 19

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

Question 20

what is a negative allosteric modulator of GABA-A receptors and what does it do?

Answer 20

b-carboline, it increases awareness (sort of the opposite of retrograde amnesia) but will also be pro-anxiolytic and proconvulsant

Question 21

why is zolpidem useful as a hypnotic/sleeping tablet?

Answer 21

this is a benzodiazepine that has a short half life and is therefore short acting

Question 22

what is intravenous diazepam used for?

Answer 22

someone seizing/status epilepticus

Question 23

what makes diazepam a good anxiety treatment compared to other benzodiazepines?

Answer 23

it is metabolised to produce active intermediates resulting in it being quite long-acting. also used as a muscle relaxant

Question 24

when it comes to benzodiazepines, what is the industry now looking for?

Answer 24

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

Question 25

adverse effects/ issues with benzodiazepines?

Answer 25

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

Question 26

how can withdrawal from benzodiazepines be managed?

Answer 26

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)

Question 27

why are benzodiazepines usually safer than barbiturates?

Answer 27

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)

Question 28

so, which drugs are used to treat which kind of anxiety? (name a drug for PTSD)

Answer 28

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

Question 29

what is propanolol?

Answer 29

Propranolol - beta-blocker, blocks adrenaline effects, physically calms

Question 30

what is olanzapine?

Answer 30

an atypical antipsychotic used for PTSD and general anxiety

Question 31

what recent developments have been made in the treatment of PTSD?

Answer 31

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

Question 32

what drugs are used to treat insomnia?

Answer 32

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

Question 33

what is buspirone?

Answer 33

partial agonist of serotonin receptor (5HT-1)

used for anxiety, no sedation (YAYYYYYY)
not suitable for immediate relief, not all kinds of anxiety responds

Question 34

what is promethazine?

Answer 34

an antihistamine - so used as a sedative/ to treat insomnia

Question 35

ketamine?

Answer 35

an anaesthetic, acts as an antagonist of NMDA receptors involved in pain signals
causes a dissociative state

looking at using it as an antidepressant