Anxiety and insomia: pathophysiology and pharmacology Flashcards
what is eustress?
acute stress
what is physiological stress?
the body’s response to an external pressure
what is anxiety?
Psychological response to a perceived threat
what is distress?
chronic stress
what is generalised anxiety disorder?
Excessive and persistent anxiety/worry for more than 6 months
what is obsessive compulsive disorders?
- obsessive repetitive thoughts which are often negative
- accompanied with compulsive behaviours providing temporary relief
what is panic disorder?
- Sudden unexpected panic attacks
- Palpitations, tremor dizzy chest pains
- fear of certain places can result in phobic avoidance = Agoraphobia
what are phobic disorders?
An excessive fear that is disproportionate to the specific situation
Generally predictable - thus phobic avoidance `
what is post traumatic stress disorder?
Onset delayed weeks to months following an intense traumatic experience
Re-experience of trauma
what three systems are involved in anxiety?
- CNS
- ANS
- Endocrine system
what is the role of the amygdala in the stress response?
- it integrates information about threat
- then appraises the new stimulus
- then coordinates the behavioural response, the autonomic response and the endocrine response
what happens to the 5-HT1A receptor binding in anxiety disorders?
there is decreased binding
what are the 2 core symptoms of anxiety disorders?
- fear
- avoidance
what happens to the GABA receptor binding in anxiety disorders?
there is reduced binding
what pathway is active whilst awake?
The Ascending Arousal Pathway:
-the Locus coeruleus, Raphe and Tuberomammillary nucleus.
what pathway is inhibited for sleep?
the ascending arousal pathway
what impact does insomia have?
- reduced quality of life
- increased risk of accidents
what can cause insomnia?
- stress
- psychiatric illness
- medical illness
- medications/drugs
what are the three main neurotransmitters in the ascending arousal pathway?
- Histamine from the Tuberomammillary nucleus
- Serotonin (5-HT) from Raphe
- Noradrenaline from Locus coeruleus
first part of sleep is called what?
slow wave sleep
second part of sleep is called what?
rapid eye movement
what does the ventrolateral preoptic nucleus (VLPO) do?
releases GABA which inhibits the arousal pathway.
-however it is not active when awake.
what does the Suprachiasmatic Nucleus (SCN) do?
-active during the day and night to detect whether it is day or night and inhibits the VLPO during the day to prevent it from stopping the ascending arousal pathway.
What effect does adenosine have on the VLPO?
- it builds up during the day in the basal ganglia so when it gets to a certain level, it activates the VLPO
- this inhibits the arousal pathway
what effect does the pineal gland have on the SCN?
-releases melatonin which is active on a night time therefore preventing SCN from inhibiting VLPO so GABA can be released to prevent the arousal pathway.
what risk factor increases chances of insomnia?
- increased age
- female
what are the common side effects with acute use of hypnotics and anxiolytics?
-CNS depression e.g. poor memory and motor-co-ordination
what are the common side effects with chronic use of hypnotics and anxiolytics?
-tolerance/dependence
what is an example of a benzodiazepine?
diazepam
what are the therapeutic uses of anxiolytics?
- short term sedation
- relieve muscle tension
- anxiolysis
- hypnosis (reduces time taken to fall asleep and increase how long you sleep for)
- anticonvulsants
side effects of anxiolytics?
- unwanted sedation
- amnesia
- reduced cognition
- reduced motor-co-ordination
- interactions - barbituates and benzo’s with alcohol
- Decreased rapid eye movement
what are the side effects associated with the chronic use of anxiolytics?
- tolerance
- dependence
- withdrawal symptoms
very short half life anxiolytics are used for what e.g. midazolam?
-conscious sedative, status epilepticus
short half-life anxiolytics are used for what e.g. loprazolam?
hypnotics
intermediate half-life anxiolytics are used for what e.g. alprazolam?
anxiolytic/panic disorders
Long half-life anxiolytics are used for what e.g. lorazepam, diazepam, Chlordiazepoxide?
anxiolytic, acute alcohol withdrawal, panic disorder, anticonvulsants, status epilepticus, muscle spams
why do some anxiolytics have a longer half-life?
because the long-half life ones are metabolised into active metabolites unlike the short half-lives ones
How do Barbituates work?
- Barbiturates act on GABA receptors (inhibitory receptors)
- these receptors have Cl- channels around it which open to let Cl- in which hyperpolarises the cell and dampens down the cell activity.
- the barbituates work in the absence of GABA so aren’t in competition with it.
- GABA inhibits the ascending arousal pathway
how do alcohol and benzodiazepines work?
-work to increase the effects of GABA which inhibits the arousal pathway
why are anxiolytics non-selective?
because there are different GABA receptor subtypes in the brain (e.g. 6 alpha subtypes, 3beta, 3 gamma, 3 sigma etc) so you dampen other activities in the brain.
what are alpha 1 subunits associated with?
sedation
what are alpha 3 subunits associated with?
anxiolysis
what are alpha 5 subunits associated with?
learning and memory
what causes tolerance and dependence?
-long term use of the GABA receptor agonist causes the GABA function to increase but also the receptor to adapt making them ‘resistant’ to the anxiolytic
what are the first line anxiolytics?
SSRIs (selective serotonin reuptake inhibitors)
- SNRIs
- TCAs
- Monoamine oxidase inhibitors
- 5-HT receptor agonist (for anxiety not depression!!)
what is the initial risk of SSRIs?
- increased anxiety
- agitation
- sleeping problems
mechanism of serotonin action?
- 5-HT released from presynaptic neurone and activates excitatory or inhibitory 5-HT receptors on postsynaptic neurone
- autoreceptors on presynaptic neurone will turn off the further release 5HT
- It is taken up by 5HT transporter and metabolised by monoamine oxidase
what drugs inhibit the 5HT transporter?
- SSRIs, TCAs and SNRIs
- this means 5HT remains in the synaptic cleft longer to activate 5HT receptors
what do Monoamine Oxidase inhibitors do?
inhibit monoamine oxidase from metabolising 5HT therefore more 5HT neurotransmission
how does buspirone work?
-as a 5HT receptor agonist (so basically binds to the 5HT receptor since there’s too little 5HT to bind to it)
what do Z-hypnotics do?
- they bind to GABA receptors like benzodiazepines
- but they are more selective fir the GABA 1 receptor unlike benzos
- this causes sedation (helping with insomnia) and may also help with anxiety
how long do Z-hypnotics act?
very fast onset and short duration of action
side effects of Z-hypnotics?
tolerance and dependence
what do antihistamines do?
- antagonise H1 receptors in the cortex inhibiting the histamine arousal pathway
- can use for sedation
what are the side effects to antihistamine use?
- weight gain
- anticholinergic effects
what does melatonin do?
-released at night and acts on melatonin receptors to inhibit the suprachiasmatic nucleus hence allowing the VLPO to release GABA and cause sedation.
what is the only licenced melatonin drug for over 55yr olds in the UK?
circadin
what is the theoretical mechanism underlying the initial increase in anxiety with SSRI administration?
- inhibits 5HT transporter
- causing increasing 5HT levels in synaptic cleft
- that is associated with an increase in anxiety
- this is from its acute use, with time, this becomes therapeutic as the 5HT receptors alter their expression over time
