Anxiety disorder 1.2.1 (Anxiolytics & Hypnotics) Flashcards
(49 cards)
1
Q
What are the type of anxiety disorders? What do you use to treat them?
A
- generalised anxiety disorder
- panic disorder
- phobias (social phobia)
- obsessive compulsive disorder
- anxiolytics
2
Q
Classify the anxiolytics & hypnotics please…
A
Benzodiazepine
- diazepam, oxazepam, temaxepam
Newer non-benzodiazepine hypnotics
- zolpidem, zoplicone, melatonin, suvorexant
5HT1A receptor agonist anxiolytics
- buspirone
3
Q
What are the causes of sleep disorders (insomnia)?
What is used to treat sleep disorders?
A
- illness
- alcohol or drugs
- periodic limbic movement
- sleep apnoea
- psychiatric illness- depression, anxiety
- shift work, flights
- hypnotic drugs
4
Q
How does serotonin affect anixety? What is there a overactivity of?
A
- excessive serotonin in limbic region
- overactivity of 5HT1A, 2A & 2C receptors
5
Q
What is there a deficient inhibition of in many anixety disorders?
A
- Deficient inhibition of limbic neurotransmission of GABA interneurons
6
Q
Which are the long acting BZD?
>12 hours
A
- diazepam
7
Q
What are the short acting BZD?
1-6 hours
A
- temazepam
- midazolam
- nitrazepam
- flunitrazepam
- triazolam
- oxazepam
8
Q
What other drugs are hypnotics?
A
- melatonin
- choral hydrate
- sedative antidepressant-mirtazapine
- sedative antihistamine- diphenhydramine, doxylamine
9
Q
What other drugs are anxiolytics?
A
- propanolol
- antidepressants- venlafaxine, sertraline, paroxetine
10
Q
What is GABA? What does it do?
A
- calming neurontransmittor
- Major inhibitory- sedation, insomnia, anxiety sx etc neurotransmitter in CNS
- Widely distributed throughout the brain
- Inhibits synaptic activity by mainly acting postsynaptically
11
Q
What are GABA pathways & functions?
A
- All regions
- Motor control, memory, consciousness
12
Q
What are the two types of GABA receptors? What do GABAA receptors do?
A
- 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
13
Q
What are the most widely used anxiolytics & hypnotics?
A
- benzodiazepines
14
Q
What is the MOA of benzodiazepines?
A
- 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
15
Q
What does the potentiation of hyperpolarisation (postsynaptic membrane) produced by GABA result in?
A
- Increased frequency of chloride channel opening –> more chloride enters the channel –> enhances inhibitory effect of GABA
16
Q
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
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
17
Q
What are the THREE pharmacological effects of BZDs?
A
- sedation
- amnesia
- anxiolytics
- muscle relaxation
18
Q
Which BZDs are used as anxiolytics?
DOAC
A
- diazepam
- oxazepam
- alprazolam
- clobazam
19
Q
What are the first choice drugs for treating anxiety? Where do they act and how do they work? What is a common precaution?
A
- 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
20
Q
What are the anxiolytic effects of diazepam (long acting)? Include other effects…
A
- 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
21
Q
What are the anxiolytic effects of oxazepam (short -acting)? Why is it better than diazepam?
A
- 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.
22
Q
A) What are short acting/medium acting (DOA) benzodiazepines used for?
B) What are medium/long acting (DOA) benzodiazepines used for?
A
A) difficulty getting to sleep
B) problems waking up too early
23
Q
Which BZDs are used as hypnotics for insomnia? What do they do?
(TNFC)
A
- 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.
24
Q
How do benzodizepines as hypnotics work? How do they alter the sleep cycle? What are the negatives to using this?
A
- 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
25
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
26
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
27
How do you get BZD tolerance?
* with prolonged use
28
What does the severity of BZD withdrawal depend on?
* dose dependant
* DOA
* duration of treatment
29
What are the symptoms of BZD withdrawal?
* anxiety
* tremor
* insomnia
* restlessness
* sometimes paranoia
* panic
* delirium
* convulsions
30
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
31
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
32
Can BZD be used in pregnancy & lactation?
* it should be avoided
* to minimise adverse effects on the foetus & newborn
33
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
34
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
35
What are TWO examples of non-benzodiazepines (hypnotics)?
Hypnotic- insomnia
* zolpidem
* zoplicone
36
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
37
What is zolpidem used for?
* short term treatment of insomnia
38
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)
39
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
40
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
41
What does stimulation of postsynaptic 5-HT1A receptors in limbic and corticalregions do?
* reduces anxiety
42
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
43
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
44
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
45
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
46
What are the TWO other hypnotics used?
* melatonin
* suvorexant
47
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
48
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
49
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
