L13 - anxiolytics and hypnotics Flashcards
what is anxiety?
can be a normal fear response
beneficial in some cases to keep us safe
when is anxiety an issue
when the source and intensity of the anxiety become abnormal
- anxiety becomes chronic, constant and irrational - triggered by situations / events that it shouldnt be
- when it leads to avoidance behaviours, social disturbances, insomnia etc
what are the
psychological
physiological (physical)
symptoms of anxiety
psychological
- worry
- stress
- nervousness
physiological
- increased HR and breathing
- dizziness and headaches
- flushing
- sweating
- feelings of sicknes
- insomnia
list some possible causes of anxiety
- past childhood experiences
- everyday life (work, financial problems, exams)
- diet (coffee and sugar)
- drugs and medication (alcohol, antimalarials)
- physical and mental health (co-morbidities)
- genetic
what drugs have been associated with causing anxiety?
alcohol
antimalarials
drugs of abuse
define GAD - generalised anxiety of disorder
constant (sometimes low level) anxiety with an unclear source
list soome types of anxiety disorders
specific phobias
separation anxiety
OCD
Social phobias
PTSD
panic disorder
describe panic disorder
a disorder when individuals suffer from panic attacks with no apparent triggers
what symptoms of anxiety are treated by anxiolytics
some treat psychological (nervousness etc)
some treat pysiological symptoms (agitation, palpitations, sweating, GI disturbances, high HR)
what symptoms of anxiety do hypnotics treat?
insomnia
list the types of drugs used to treat anxiety (and briefly how they work)
what type of drugs have no anxiolytic effect at low dose/potency
Z drugs
high dose/potency used as hypnotic
BRIEFLY how do barbiturates, benzodiazepines and Z drugs act, to treat anxiety / insomnia
GABA(A) receptor modulators
what is the most common subunit conformation of the GABA(A) receptor
(2x a) + (2x B) + (y)
are GABA(A) receptors mainly found pre or post synaptically?
post
name the transporter that re-uptakes GABA from cleft
GAT
where is the GABA binding site on GABA(A)
between a and B subunits
also site of other agonists and antagonists
where on the GABA(A) receptor do the BZDs bind?
between a and y subunits
where on the GABA(A) receptor do the barbiturates bind
allosterc site
what are barbiturates and what is their mechanism of action.
positive allosteric modulators
- bind to allosteric site of GABA(A) found in the inner pore
- this binding holds the channel open for longer, so more Cl- can flow through channel
- increasing inhibition
list the off target effects of barbitruaates
- at high doses, they can act as direct GABA(A) agonists
- stabilise the glycine receptor (also holding it open for longer)
- block nAChRs and 5-HT3 receptors
- block AMPA and kainate receptors
- block Ca2+ dependant NT release (hyperpolarisation)
what have barbiturates been replaced with and why
BZDs
less side effects and have a lower risk of OD, also have an OD antidote where barbiturates do not
what are barbiturates still used to treat
epilepsy
euthanasia
capital punishment
what is the OD antidote for BZDs
flumazeil
competitive antagonist for BZD binding site
what are BZDs and what is their mechanism of action
positive modulators
- bind to binding site between a and y subunits of GABA(A)
- stabilise the receptor (into shape that can better bind to GABA) and so increase the receptor affinity for GABA
what is useful about the mechanism of action of BZDs
they only work in the presence of GABA
what GABA(A) receptors can the BZDs not bind to ?
those containing alpha subunits 4/6 because they have an arginine residue in the binding pocket instead of histidine
a1 a2 a3 a5 are fine
what are the effects of BZDs on synptoms
anxiolytic
sedative and hypnotic effect
also reduce muscle tone (anticonvulsants)
briefly talk about the different types of BZDs
there are different options depending on duration of action
short acting potent ones are preffered for hypnotics so that sedative effects arent experienced during the day
longer acting less potent ones used as anxiolytics
what type of BZDs are used as hypnotics?
short acting (short half life) potent
how long should BZDs be used to treat anxiety for and why?
no longer than 6 weeks as they can lead to neuroadaptations - which can then lead to addiction
where do Z drugs bind on the GABA(A) receptor
the same binding site as BZDs
between alpha and y subunit
give an example of a Z drug
zolpidem
what symptoms of anxiety / insomnia are Z drugs used to treat
insomnia only
they have no low dose anxiolytic effects, only high dose hypnotic
describe the 5-HT1A receptor
GPCR/ LGIC?
pre / post?
GPCR
Gi/o coupled
presynaptic
what is the function of the 5-HT1A receptor
negative feedback to inhibit serotonin release ( via inhibition of Ca2+ channel opening)
give an example of a 5-HT1A receptor agonist used in the treatment of anxiety/insomnia
buspirone - treats Generalised anxiety disorder
describe the mechanism of action of 5-HT1A agonists (buspirone)
how is this similar/ different to SSRIs
- buspirone activates 5-HT1A receotors to a much greater extent than what theyre used to
- this causes downregulation of receptors at the pre-synaptic membrane
- fewer 5-HT1A receptors means less negative feedback and more 5-HT release into synaptic cleft
- higher level of receptor activation - enhanced effects of 5-HT
both SSRIs and 5-HT1A receptors result in increased 5-HT in synaptic cleft but via different mechanisms
describe the receptor trafficking that occurs with SSRIs and why theyre still effective treatments
- they block 5-HT reuptake and increase the [5-HT] in the synaptic cleft, greatly activating pre and post synaptic receptors
- this causes down regulation of both pre and post synaptic receptors
they are still effective treatments because the effect of SERT blockade and 5-HT1A downregulation outweighs the effect of less post synaptic 5-HT receptors
describe B adrenoreceptors
GPCRs coupled to Gs
post synaptic
what effects do B adrenoceptor antgonists have in the treatment of anxiety / insomnia
- decrease HR, conductance, and contratility
- decrease renin release in RAA system (reduce B.P)
treats peripheral symptoms of anxiety
example of B blocker for anxiety treatment
propranalol
describe antihistamine mechanims of action in treatmment of anxiety / insomnia
- cross BBB and are antagonists at H1 receptors in CNS (which are usually responsible for ‘wakefullness’ and consciousness
treat insomnia
examples of histamine antagonists for insomnia treatment
nytol
day&night cold and flu tablets
how does barbiturates and BZD use cause addiction?
- Patients experiencing anxiety have a natural imbalance between excitation and inhibition of Glutamate and GABA (more excitatory-glutamate)
- Taking these drugs balances the imbalance (increases inhibition or decreases excitation) however, this is not what the body is used to so it up regulates excitatory receptors
- This creates a higher level imbalance, so more drug is needed
- Process keeps repeating Until there is a very big imbalance between excitatory and inhibitory receptors
- This means complete stoppage of taking the drug can cause seizures (much more excitatory receptors than inhibitory)
describe why BZDs and barbiturates are addicting
pleasurable or withdrawl?
mainly addicting to avoid the unpleasant withdrawal response - no pleasurable effect
addiction to what other drug can cause seizures if drug use is stopped immediately
alcohol
explain why BZDs are used to treat alcohol dependance
- Alcohol causes increased stimulation of GABA (inhibitory) receptors
- This is abnormal for the body, so it up-regulates Glutamate receptors to balance this back out
- Stopping alcohol means there’s much more excitatory receptors than inhibitory signalling, which could cause seizures
- So barbiturates / BZDs are given to gradually balance this back out (as they cause inhibition) until they can also stop being taken
why is BZD use in alcohol dependence useful?
an alcoholic will struggle to titrate or gradually reduce alcohol intake over a prolonged period, so BZDs are given so they can completely stop alcohol intake without the severe withdrawal effects
summarise the classes of drugs that are used as anxiolytics, hypnotics and tolerance/withdrawal
