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CNS lectures (Bal) > Module 1.2.1 (Drugs for Anxiety) > Flashcards

Module 1.2.1 (Drugs for Anxiety) Flashcards

1
Q

What are the type of anxiety disorders?

A
  • generalised anxiety disorder
  • panic disorder
  • phobias (social phobia)
  • post-traumatic stress disorder
  • obsessive compulsive disorder
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2
Q

What can anxiety involve?

A

Subjective feeling

  • (worry, a sense of threat) )

Physiological responses

  • (tachycardia, increased blood pressure) )

Behavioural response

  • (avoidance, withdrawal)
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3
Q

What drugs are used to relieve anixety?

A

Anxiolytics

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4
Q

What are the causes of insomnia?

A

illness, alcohol or dugs, periodic limb movement disorder, sleep apnoea, psychiatric illness

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5
Q

What are the drugs used to treat insomnia?

A

Hypnotics

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6
Q

How does serotonin affect anixety? What is there a overactivity of?

A

Excessive serotonin (lesser extent NA) associated with many anxiety syndromes in the limbic region

  • Overactivity of 5HT 1A, 2A & 2C receptors
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7
Q

What is there a deficient inhibition of in many anixety disorders?

A

Deficient inhibition of limbic neurotransmission of GABA interneurons

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8
Q

Provide examples for the following Anxiolytics:

A) Long acting BZDs

B) 5-HT1a agonist

C) Other drugs

A

A)
act on GABA-A

  • Diazepam
  • Lorazepam, bromazepam

B)

  • Buspirone

C)

  • Propranolol
  • Antidepressants (Venlafaxine, sertraline, paroxetine)
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9
Q

Provide examples for the following Hypnotics:

A) Short acting BZDs

B) Non-bezodiazepines

C) Other drugs

A

A)

(act on GABA-A receptor)

  • Temazepam, midazolam, nitrazepam, flunitrazepam (new)

B)

(act on GABA-A receptor)

  • Zolpidem, zopiclone

C)

  • Melatonin, Choral hydrate
  • Sedative antidepressant - mirtazapine
  • Sedative antihistamine – diphenhydramine, doxylamine
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10
Q

What is GABA? What does it do?

A
  • Major inhibitory neurotransmitter in CNS

Widely distributed throughout the brain

  • Inhibits synaptic activity by mainly acting postsynaptically
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11
Q

What are gaba pathways and functions? What are the related conditions?

A

GABA pathways and functions

  • All regions
  • Motor control, memory, consciousness

Related conditions

  • Aberrant behaviour, insomnia, anxiety
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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

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13
Q

What subunits does a major GABA receptor have?

A

A major GABAA receptor isoform throughout the brain has two a1 subunits, two b2 subunits and one y2 subunit.

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14
Q

A) How many GABA binding sites are there on the GABAA receptors?

B) How many enzodiazepine modulatory sites are there on the GABAa receptors?

A

A)

  • Two GABA binding sites on the interfaces between the two a and B subunits.

B)

  • at the interface between the a and y2 subunits
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15
Q

For benzodiazepines (most widely used anxiolytic and hypnotic drugs), provide examples for the following;

A) Anxiolytics

B) Hypnotic

C) Skeletal muscle relaxation

D) Anticonvulsant

E) Premedication

A

A)

  • diazepam, oxazepam, alprazolam

B)

  • temazepam, nitrazepam, oxazepam)

C)

  • diazepam, clonazepam

D)

  • clonazepam, clobazam

E)

  • midazolam
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16
Q

What is the MOA of benzodiazepines? What needs to happen before benzodiazepines can exert its effect?

A

Potentiate the actions of GABA

  • 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

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17
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

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18
Q

The increase in inhibitory neurotransmission produced by BZDs has potentially useful effects. Explain how for the following:

A) Anxiolytic (diazepam, oxazepam, alprazolam)

B) Hypnotic (temazepam, nitrazepam, oxazepam)

C) Skeletal muscle relaxation (diazepam, clonazepam)

D) Premedication

… antivonvulsant (clonazepam, clobazam)

A

A)

  • actions on the limbic system and hypothalamus

B)

  • reduced sensory input to the reticular activating system

C)

  • reduction of muscle tone

D)

  • Intravenous sedation (midazolam), anterograde amnesia produced is useful in this situation
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19
Q

What are the THREE pharmacological effects of BZDs?

A
  • Sedation and amnesia (omega 1 receptor subtype)
  • Anxiolysis (omega 2 receptor subtype)
  • Muscle realaxation (omega 3 receptor subtype)
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20
Q

What are the two phases of metabolism of BZDs?

A
  1. Phase 1 metabolism (activation)
  2. Phase II metabolism (inactivation)

Leads to forming glucoronide and urinary excretion

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21
Q

What metabolite has a long half life for BZDs?

A

Diazepam –> nordazepam. Very long half life >40 hours, phase I metabolites are active for a long time and have a long DOA.

22
Q

Which benzodiazipnes bypass phase 1 metabolism? What are these drugs useful for?

A

Lorazepam, temazepam, ozaxepam

  • Bypasses phase 1 metabolism, doesn’t have active metabolites –> used in elderly as phase II metabolism doesnt decline with age.
23
Q

What benzodiazepines are used as anxiolytics?

A

Diazepam, oxazepam, alprazolam, clobazam

24
Q

What is the first choice drug for anxiety? Where do they act and how do they work? What is a common precaution

A

Benzodiazepines are first-choice drug for anxiety

  • 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

> Precuation: avoid long term use = physical dependence

25
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

26
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.

27
Q

A) What are short acting/medium acting benzodiazepines used for?

B) What are medium/long acting benzodiazepine used for?

A

A) Difficulty getting to sleep

B) Problem waking up too early

28
Q

Which BZDs are used as hpynotics for insomnia?

A

Tamezapem, nitrazepam, flunitrazepam, clobazam

29
Q

What happens to sleep in patients with insomnia?

A
  • 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
30
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
31
Q

What BZDs are used for short-term treatment of insomnia? How do they work? What is the maximum period of time they should be used for?

A
  • Temazepam, nitrazepam, flunitrazepam and clobazam
  • Produce hypnotic effect with minimal residual drowsiness the following morning
  • Should not be used for longer than 1-2 weeks for insomnia
32
Q

Describe the adverse effects of the following BZDs

A) CNS depression

B) Anterogade Amnesia

C) Paradoxical Effects

D) Respiratory Depression

E) Disinhibition

F) Other AE

A

A)

  • drowsiness, lethargy, impaired coordination, muscle weakness

B)

  • impaired recall events that take place after dosing esp with triazolam –> been discontinued

C)

  • insomnia, excitation, euphoria, heightened anxiety

D)

  • weak depression, but to avoid combining with other CNS depressants

E)

  • may lead to rage, violence and antisocial acts

F)

  • vertigo, nausea, headache
33
Q

Describe the tolerance that can develop to some effects of BZDs

> Minimal tolerance

> Significant tolerance

> Cross tolerance

A
  • Minimal tolerance to anxiolytic & hypnotic effects
  • Significant tolerance to anti-seizure effect
  • Cross tolerance with other CNS depressants

Tolerance develops to most of the adverse efefcts

34
Q

What does the severity of BZD withdrawal depend on? What are the symptoms?

A

Severity of withdrawal depends on the doses taken, duration of action of BZDs and duration of treatment

Withdrawal symptoms

  • anxiety, tremor, insomnia, restlessness and sometimes paranoia, panic, delirium and convulsions.
35
Q

Why are the withdrawal symptoms with diazepam less severe than those with oxazepam and other short acting BZDs?

A

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
36
Q

What are the CI for benzodiazepines? Can it be used in pregnancy and lactation?

A
  • History of drug abuse
  • Sleep apnoea
  • Respiratory depression, disease
  • Renal and hepatic impairment
  • Myasthenia gravis
  • Elderly with cognitive problems

Avoid use in pregnancy and lactation

  • BZDs readily cross placenta barrier
  • Avoid use in first trimester
  • Pregnant and breastfeeding women should avoid repeated doses of BZDs to minimise adverse effects on the foetus and newborn
37
Q

Benzodiazepine overdoses are rarely serious, what are some cautions and symptoms of overdose? What is the antidote?

A

Caution: additive effects with other CNS depressants such as alcohol or heroin

Symptoms: drowsiness, lethargy, confusion

Benzodiazepine overdose can be treated with the competitive benzodiazepine receptor antagonist, flumazenil

38
Q

What is IV flumazenil used for specifically in BZD overdose? What is the DOA? What is the AE?

A

9Intravenous flumazenil is used to reverse rapidly excessive respiratory depression produced by benzodiazepines

  • Flumazenil - Duration of action is relatively brief, half-life is about 1 h.
  • Re-sedation can occur with long-acting benzodiazepines –> diazepam
  • Repeated injections of flumazenil may be required

> Major adverse effects of flumazenil is convulsion

39
Q

What are TWO examples of non-benzodiazepines (hypnotics)?

> short term management of insomnia

A
  • Zolpidem
  • Zopiclone
40
Q

For Zolpidem;

A) what is it

B) what does it bind to

C) What minimal effects does it have

D) What does it share with BZDs

E) How is it dfferent from BZDs

F) DOA

G) What is it useful for

A

A)

  • Zolpidem is a non-benzodiazepine hypnotic

B)

  • Binds selectively to type-1a benzodiazepine receptors omega1 subtype to produce hypnotic effect

C)

  • Minimal anxiolytic, muscle relaxant and anticonvulsant effects.

D)

  • Hypnotic effect similar to BZDs

E)

  • Less effects on REM sleep and stages 3 & 4 of NREM sleep than BZDs
  • Zolpidem has little effect on sleep architecture

F)

  • A rapid and short-acting hypnotic. It has a duration of action of 4-6 h because it is rapidly inactivated by hepatic enzymes.

G)

  • Useful for the short-term treatment of insomnia
41
Q

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

A)

  • Sedation
  • Amnesia

B

  • Anxiolysis

C)

  • No effect
42
Q

What are the adverse effects of of zolpidem? What is the antidote?

A
  • Adverse effects: diarrhoea, impaired alertness, drowsiness headache, sleep walking
  • Tolerance and dependence can develop to zolpidem, but to a lesser extent than with benzodiazepines
  • 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, if it is required.
43
Q

What is the MOA of Buspirone as anxiolytic?

A
  • Buspirone affects serotonin (5-HT) activity in the brain by acting as a partial agonist on 5-HT1A receptors.

> not hypnotic or anticonvulsant or muscle relaxant like benzos

> may also have antidepressant acivity

44
Q

What is buspirone used for and not used for?

A

Used for:

  • Effective for generalised anxiety disorder

Not used for

  • Panic disorder
  • acute anxiety because its anxiolytic effect requires about 1-3 weeks to develop
45
Q

What does stimulation of postsynaptic 5-HT1A receptors in limbic and corticalregions do?

A

REDUCTION IN ANXIETY

46
Q

Why does buspirone take 1-3 weeks to develop?

A

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 Æ reduces 5‐HT release.

47
Q

What is the long term effect of buspirone?

A
  • 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

48
Q

What are the adverse effects of buspirone?

A

Buspirone does not cause excessive drowsiness, impaired coordination unlike benzo and zolpidem

> NOT associated with dependence, withdrawal & abuse

Main adverse effects include tachycardia, palpitations, nausea, dizziness, headaches & restlessness

> relatively safe if an overdose is taken

> safety in pregnancy not established

49
Q

Why is the non-selective beta blocker used in social phobia where there is sympathetic over activity?

A

Disabling symptoms include tremors, palpitations, sweating

  • Treat the prominent sympathetic symptoms of acute anxiety disorder and social phobia
  • 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.

50
Q

For Melatonin (hypnotic)

A) What age group is it used for?

B) What is the MOA and PK

C) What are the drug interactions?

D) Common AE

A

A)

Only indicated for > 55yrs (insomnia – short term)

B)

  • Acts at melatonin MT1 & MT2 receptors –> G-protein coupled receptors
  • Melatonin secretion –> high at night & low by day
  • Given orally, well absorbed
  • T1/2 of about a few minutes (hence Circadin® is CR)

C)

  • Drowsiness increased with others that cause drowsiness
  • Fluvoxamine (STRONG CYP1A2 inhibitor) –> inhibits melatonin metabolism – may increase drowsiness

D)

  • Back pain, arthralgia (joint pain)
51
Q

For suvurexant (hypnotic);

A) Who is it indicated for?

B) What is the MOA

C) What are the AE

D) What are the drug interactions

A

A)

  • Indicated for chronic insomnia

B)

  • Orexin receptor antagonist that blocks binding of wakepromoting orexin A and B neuropeptides

C)

  • somnolence, headache (common)
  • abnormal dreams, fatigue, dizziness, hallucination during sleep

D)

  • Avoid using with drugs that are moderate or strong inhibitors of CYP3A4 and with drugs that are strong inducers of CYP3A4.

CNS lectures (Bal) (29 decks)

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