Anxiety Disorders And Their Treatment(+FXS) Flashcards
What is FXS?
It’s a mental condition which is hereditary and arises on chromosome x
What are prominent characteristics of FXS?
Elongated face
Large or protruding ears
Low muscle tone- particularly in the face
What causes FXS?
Expansion of the CGG trinucleotide repeat affecting the fragile x mental retardation 1 gene -FMR1
Prevents the expression of the fragile x mental retardation protein FMRP- this is needed for normal development
Which sex is more affected with FXS ?
Males
The mutation occurs on the X chromosome and the males only have one X chromosomes
What is the “full mutation” for FXS?
> 200 CGG
This mutation occurs in the promoter region of the FMR1 gene and causes a methylated promoter region - this shuts down the gene so little or no mRNA is produced so no protein available
What is the mGluR theory ?
Used to explain many aspects of the clinical symptoms present in patients with FXS and in FMR1 KO mouse
What are the clinical symptoms found in FXS patients and FmR1 KO mice ?
- higher density of spines and more immature spines compared to normal
- electrophysiological deficits in FmR1 mice
- exaggerated dendritic protein in FmR1 KO nice after activation of mGluR5
- behavioural phenotype in patients with FXS and FmR1 KO mice
What does the mGluR theory state ?
That AMPA receptor internalisation triggered by group 1 mGluR stimulation is exaggerated in FXS
What are AMPA receptors do ?
Essential for long term synaptic plasticity
What does FMRP do ?
It negatively regulates transcription and reduces internalisation of AMPA receptors
what is characteristic of neurones from patients with FXS?
they have increased internalisation of AMPA receptors in the absence of FMRP - this reduces long term synaptic plasticity
what happens when mGluR5 is activated ?
they signal through protein kinase c
leads to activation of SRC family tyrosine kinases
what happens when group 1 mGluRs are activated ?
causes the up regulation of protein synthesis and this has been implicated in playing a role in FRMP dependent synaptic plasticity
it is thought that using these receptors as a target, could be a treatment for FXS
what are therapeutic substances for FXS?
negative modulators of mGluR5
what is MPEP and what does it do ?
1st negative modulator of mGluR5 - classed as an mGluR5 antagonist
interacts with transmembrane domain 7
why is MPEP not used in clinical trials?
causes toxicity and had a short half life
what beneficial effects did MPEP have ?
suppressed audiogenic seizures and rescued deficits in prepulse inhibition of acoustic startle in FRM1 KO mice
what is anxiety ?
normal biological process
- apprehension, tension and fearfulness
what is the difference between normal anxiety and chronic anxiety ?
chronic anxiety is debilitating
how common are anxiety disorders and what are some different types ?
18% of population in USA have anxiety disorders general anxiety disorder social anxiety disorder obsessive compulsive disorder panic disorder
what are the types of symptoms of anxiety disorders ?
psychological and somatic (physical)
what do the symptoms of anxiety disorders depend on ?
depends on the particular anxiety disorder
depends on the individual
what are the causes of anxiety disorders ?
most often the causes are unknown
PTSD is often a cause though
what are some examples of somatic symptoms of anxiety disorders ?
tachycardia
sweating
trembling
what are some examples of psychological symptoms of anxiety disorders ?
worry
panic
exaggerated fear
how are anxiety disorders diagnosed?
diagnostic and statistical manual of mental disorders, 4th edition
what is the pathophysiology underlying anxiety disorders ?
unknown however stress is thought to be involved and the levels of catecholamines
how does stress contribute to anxiety disorders ?
causes a heightened physiological response - normally emotional stress
- increases catecholamine levels
- thought that the hypothalamic-pituitary-adrenal axis is implicated because its involved in the release of catecholamines
which neurotransmitters are influence the HPA axis and/or involved in the pharmacological treatment of anxiety disorders ?
serotonin
GABA
noradrenaline
what regions of the brain have been hypothesized to have implications in anxiety disorders ?
disturbances in the cerebral cortex - especially the limbic system including the amygdala
what are the types of anxiolytics ?
benzodiazepines- GABAergic
Beta blockers- noradrenergic
SSRIs/buspirone- Serotonin
SNRIs- serotonin and noradrenaline
what do benzodiazepines do ?
bind to GABAa receptors
they have a specific binding site on these receptors
it enhances the influx of chloride ions when GABA binds
what do GABAa receptors look like ?
mutlisubunit receptors - 19 different types
pentameric - combination of alpha beta and gamma subunits- combinations are different in different brain regions
where does benzodiazepine bind on GABAa receptors ?
binds at the interface between alpha and gamma subunits
what happens to the electrophysiological recordings in GABA receptors when a mutation is induced ?
the mutation caused the receptor to become insensitive to diazepam
the alpha-2,3,and 5 receptors were rendered insensitive to diazepam when histidine is replaced by arginine at 101
what are the actions of benzodiazepines ?
sedative hypnotic anxiolytic anticonvulsant muscle relaxant amnesic
what are some other examples of benzodiazepines ?
alprazolam
chlordiazepoxide
lorazepam
oxazepam
why are lorazepam and oxazepam useful ?
they have a shorter action
good for patients with hepatic impairment
what are the pharmacokinetics of benzodiazepines ?
normally taken orally
rapidly absorbed
peak concentration after one hour
highly protein bound and highly lipid soluble so sequestered into body fat
how are benzodiazepines metabolised?
mainly by N-desmethylation - can lead to an active metabolite- desmethyldiazepam - 70 hour half life
phase 2 by glucuronide- the shorting acting ones goes straight to this phase
what happens if you overdose on benzodiazepines?
generally safe
not lethal- prolonged sleep
when can benzodiazepine administration be dangerous ?
if they are taken with other CNS depressants
if they are taken with ethanol- respiratory depression
what is used to treat a benzodiazepine overdose?
flumazenil
- benzodiazepine site antagonist
what are the unwanted effects of benzodiazepines ?
drowsiness
confusion
amnesia
poor coordination
do people suffer from tolerance when taking benzodiazepines?
tolerance to anxiolytic effects have been seen in animals but not humans
- more pronounced tolerance to anticonvulsant and sedative effects
why are benzodiazepines not used for chronic administration ?
dependence
there are marked withdrawal symptoms - anxiety, tremor and dizziness
it is difficult to wean patients off them if they have been used for a long time
withdrawal has to be slow and tapering
how do beta blockers work and what do they do ?
antagonist of beta-1 and 2 adrenoreceptors
act on autonomic system
they are used to treat the somatic symptoms
they have no effect on psychological effects however the reduction in the somatic symptoms may reduce worry and fear
what is buspirone ?
serotonin 1a agonist
how does buspirone work ?
it is a partial agonist
stimulates serotonin 1a receptors at low serotonin levels
inhibits serotonin 1a receptors at high serotonin levels
also binds to D2 and 5HT 2a receptors
they are presumed to alter serotonergic transmission
what anxiety disorders can busprione be used to treat and which can it not treat ?
used to treat generalised anxiety disorder
cant treat panic disorder or OCD
not thought to show tolerance to therapeutic effects but it does show tolerance to adverse effects
only for acute treatment
how do SNRIs work ?
they have combined selectively for both serotonergic and noradrenergic uptake mechanisms
e,g venlafaxine
when are SSRIs and SNRIs used ?
for the management of chronic anxiety - 4or more weeks
can sometimes initally worsen the effects
can be taken with benzodiazepines to relieve the initial worsening of symptoms
