Anxiety disorder 1.2.1 (Anxiolytics & Hypnotics) Flashcards
What are the type of anxiety disorders? What do you use to treat them?
- generalised anxiety disorder
- panic disorder
- phobias (social phobia)
- obsessive compulsive disorder
- anxiolytics
Classify the anxiolytics & hypnotics please…
Benzodiazepine
- diazepam, oxazepam, temaxepam
Newer non-benzodiazepine hypnotics
- zolpidem, zoplicone, melatonin, suvorexant
5HT1A receptor agonist anxiolytics
- buspirone
What are the causes of sleep disorders (insomnia)?
What is used to treat sleep disorders?
- illness
- alcohol or drugs
- periodic limbic movement
- sleep apnoea
- psychiatric illness- depression, anxiety
- shift work, flights
- hypnotic drugs
How does serotonin affect anixety? What is there a overactivity of?
- excessive serotonin in limbic region
- overactivity of 5HT1A, 2A & 2C receptors
What is there a deficient inhibition of in many anixety disorders?
- Deficient inhibition of limbic neurotransmission of GABA interneurons
Which are the long acting BZD?
>12 hours
- diazepam
What are the short acting BZD?
1-6 hours
- temazepam
- midazolam
- nitrazepam
- flunitrazepam
- triazolam
- oxazepam
What other drugs are hypnotics?
- melatonin
- choral hydrate
- sedative antidepressant-mirtazapine
- sedative antihistamine- diphenhydramine, doxylamine
What other drugs are anxiolytics?
- propanolol
- antidepressants- venlafaxine, sertraline, paroxetine
What is GABA? What does it do?
- calming neurontransmittor
- Major inhibitory- sedation, insomnia, anxiety sx etc neurotransmitter in CNS
- Widely distributed throughout the brain
- Inhibits synaptic activity by mainly acting postsynaptically
What are GABA pathways & functions?
- All regions
- Motor control, memory, consciousness
What are the two types of GABA receptors? What do GABAA receptors do?
- GABAA Postsynaptic Ligand-gated Clchannel
- GABAB G-protein-coupled receptor, acts via Gi
GABAA receptors mediate most of the fast inhibitory neurotransmission (ligand gated) in the CNS
What are the most widely used anxiolytics & hypnotics?
- benzodiazepines
What is the MOA of benzodiazepines?
- potentiate the actions of GABA- inhibitoruy effects
- act at site closely linked to the GABAA receptor
- acts only in the presence of GABA, GABA needs to be bound to GABAA receptor before benzo can be effective
What does the potentiation of hyperpolarisation (postsynaptic membrane) produced by GABA result in?
- Increased frequency of chloride channel opening –> more chloride enters the channel –> enhances inhibitory effect of GABA
The increase in inhibitory neurotransmission produced by BZDs has potentially useful effects. Explain how for the following:
a) anxiolytic
b) hypnotic
c) skeletal muscle relaxation
d) premedication
A) anxiolytic- actions on the limbic system and hypothalamus
B) hypnotics- reduced sensory input to the reticular activating system
C) skeletal muscle relaxtaion- reduction of muscle tone
D) Intravenous sedation (midazolam), anterograde amnesia produced is useful in this situation
What are the THREE pharmacological effects of BZDs?
- sedation
- amnesia
- anxiolytics
- muscle relaxation
Which BZDs are used as anxiolytics?
DOAC
- diazepam
- oxazepam
- alprazolam
- clobazam
What are the first choice drugs for treating anxiety? Where do they act and how do they work? What is a common precaution?
- benzos
- they rapidly relieve anxiety by potentiating GABA activity in the amygdala and other limbic regions of the brain
- binds to omega 2 receptor subtype to enhance anxiolytic effect of GABA
- avoid long term use
What are the anxiolytic effects of diazepam (long acting)? Include other effects…
- Rapidly absorbed
- Marked initial drowsiness
- Accumulation and residual drowsiness because of its long half-life (30h) and active metabolite formed (60h)
- significant muscle relaxant and anticonvulsant effects
What are the anxiolytic effects of oxazepam (short -acting)? Why is it better than diazepam?
- More slowly absorbed
- Less initial drowsiness
- Short half-life
- Inactivated by glucuronidation
- Short duration of action with minimal residual drowsiness
- Better than diazepam in the eldery as it less likely to reduce alertness and phase II metabolism is less impaired in elderly.
A) What are short acting/medium acting (DOA) benzodiazepines used for?
B) What are medium/long acting (DOA) benzodiazepines used for?
A) difficulty getting to sleep
B) problems waking up too early
Which BZDs are used as hypnotics for insomnia? What do they do?
(TNFC)
- tamazepem
- nitrazepam
- flunitrazepam
- clobazam
- Produce hypnotic effect with minimal residual drowsiness the following morning
- Should not be used for longer than 1-2 weeks for insomnia.
How do benzodizepines as hypnotics work? How do they alter the sleep cycle? What are the negatives to using this?
- Reduce sleep onset, reduce awakening and increase sleep duration
- Decrease the proportion of REM sleep and stages 3 & 4 of NREM sleep
- Increase the proportion of stages 1&2 NREM sleep
Negatives
- some tolerance may develop to these effects after 1-2 weeks
- rebound insomnia can become a problem after prolonged use of benzodiazepines
What happens to sleep in patients with insomnia?
- time required to fall asleep (sleep latency) is usually prolonged
- one or more awakenings during the night
- total sleep time is decreased –> reduced amount of slow-wave sleep
What are the ADV of BZDs?
- CNS depression- drowsiness, lethargy, impaired coordination, muscle
weakness
- Anterograde amnesia- impaired recall events that take place after dosing esp w triazolam
- Paradoxial effects- insomnia, excitation, euphoria, heightened anxiety
- Respiratory depression- weak depression, but to avoid combining with other CNS depressants
- disinhibition- rage, violence, antisocial acts
- others- vertigo, nausea, headache
How do you get BZD tolerance?
- with prolonged use
What does the severity of BZD withdrawal depend on?
- dose dependant
- DOA
- duration of treatment
What are the symptoms of BZD withdrawal?
- anxiety
- tremor
- insomnia
- restlessness
- sometimes paranoia
- panic
- delirium
- convulsions
Why are the withdrawal symptoms with diazepam less severe than those with oxazepam and other short acting BZDs?
- because both it and its active metabolite, nordazepam have long half-lives
- Oxazepam is directly converted to glucoronide metabolite via phase II –> shorter acting –> more severe withdrawal symptoms
What are the CI for benzodiazepines?
- History of drug abuse
- Sleep apnoea
- Respiratory depression, disease
- Renal and hepatic impairment
- Myasthenia gravis
- Elderly with cognitive problems
Can BZD be used in pregnancy & lactation?
- it should be avoided
- to minimise adverse effects on the foetus & newborn
Is a BZD overdose serious? What happens in BZD OD? Can it be treated- with what?
- no, rarely serious
- symptoms include: drowsiness, lethargy, confusion
- yes, with competitive BZD receptor antagonist, flumazenil
How does flumazenil work in BZD OD?
- reverse rapidly excessive respiratory depression produced by BZD
- DOA is relatively brief
- 1/2 life is 1h
- repeated injc may be required
- major adv is convulsion
What are TWO examples of non-benzodiazepines (hypnotics)?
Hypnotic- insomnia
- zolpidem
- zoplicone
How does zolpidem work?
- Binds selectively to type-1a benzodiazepine receptors omega1 subtype to produce hypnotic effect
- has minimal anxiolytic, muscle relaxant and anticonvulsant effects
- A rapid and short-acting hypnotic. It has a duration of action of 4-6 h because it is rapidly inactivated by hepatic enzymes
What is zolpidem used for?
- short term treatment of insomnia
What are the adverse effects of of zolpidem? What is the antidote?
- diarrhoea, impaired alertness, drowsiness headache, sleep walking
- Tolerance and dependence can develop to zolpidem, but to a lesser extent than with
- Zolpidem should not be used for more than 1-2 weeks
- An overdose of zolpidem can be dangerous if combined with other CNS depressants
- Flumazenil can be used to reverse excessive respiratory depression produced by zolpidem (OD)
What are the mechanisms of action of non-BZDs on GABAA receptor:
A) Omega 1 receptor sybtype
B) Omega 2 receptor subtype
C) Omegae 3 receptor subtype
A) Omega 1 receptor sybtype- sedation, amnesia
B) Omega 2 receptor subtype- anxiolysis
C) Omegae 3 receptor subtype- no effect
Non selective benzodiazepines= A, B, C
Zolpidem= A
Zoplicone= A, B
What is the MOA of Buspirone as anxiolytic?
- 5-HT 1A Agonist
- affects serotonin (5-HT) activity in the brain by acting as a partial agonist on 5-HT1A receptors
- unsuitable for acute anxiety because its anxiolytic effect requires about 1-3 weeks to develop
- effective for generalised anxiety disorder
- ineffective for panis disorder
- may also have antidepressant activity
What does stimulation of postsynaptic 5-HT1A receptors in limbic and corticalregions do?
- reduces anxiety
Why does buspirone take 1-3 weeks to develop?
- Anxiolytic action of buspirone on postsynaptic 5‐HT1A receptors is less than expected
- This is because increased activation of 5‐HT1A autoreceptors on the soma and dendrites which reduces 5‐HT release
What are the ADV E of buspirone?
- Buspirone does not cause excessive drowsiness, impaired coordination
- Its use is NOT associated with dependence, withdrawal & abuse
- The main adverse effects include: tachycardia, palpitations, nausea, dizziness, headaches & restlessness
- Is relatively safe if an overdose is taken
- Safety in pregnancy not established
What is the long term effect of buspirone?
- After 1‐3 weeks, buspirone produces desensitisation of presynaptic but NOT postsynaptic HT1A receptors
- Desensitisation of the autoreceptors reduces inhibitory effect on 5‐HT release from the nerve terminals = elevation of serotonin cell body and dendrites
- The need to desensitise somato‐dendritic 5‐HT1A receptors could thus explain in part the slow onset of buspirone
Why is the non-selective beta blocker (propanolol) used in social phobia’s when there is sympathetic over activity?
- treats the prominent sympathetic symptoms of acute
anxiety disorder and social phobia
- disabling symptoms include tremors, palpitations, sweating
- does not directly relieve the mental aspects of SP
- avoid in patients with asthma or severe peripheral vascular disease and heart failure
- use with caution in patients with diabetes
What are the TWO other hypnotics used?
- melatonin
- suvorexant
Indication for melatonin?
What is the MOA of melatonin?
Common ADV?
Drug interactions?
- Indication
- 55 y0 and above
- for short term insomnia
- MOA
- acts at melatonin MT1 & MT2 receptors
- melatonin secretion is high at night & low by day
- given PO, well absorbed
- 1/2 life is around a few mins, hence circadin used
- ADV
- back pain, arthralgia
- Drug interactions
- drowsiness, increased with others that cause drowsiness
- fluvoxamine–> inhibits melatonin metabolism- more melatonin in body- increase drowsiness
What is the indication of suvorexant?
What is the MOA?
Common adverse effects?
Drug interactions?
- Indicated for chronic insomnia
- MOA- orexin receptor antagonist that blocks binding of wake- promoting orexin A and B neuropeptides
- ADV
- somnolence, headache (common)
- abnormal dreams, fatigue, dizziness, hallucination during sleep
- Drug Interactions
- avoid using with drugs that are moderate or strong inhibitors of CYP3A4 and with drugs that are strong inducers of CYP3A4
How can BZD improve sleep?
- reduces sleep onset, reduce awakening & increase sleep duration
- decrease the proportion of REM sleep & stages 3 & 4 of NREM sleep
- increase the proportion of stages 1 & 2 NREM sleep
- stage 3- deep sleep, difficult to wake person up
