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PHAR2005 > Anxiolytics > Flashcards

Anxiolytics Flashcards

1
Q

What are anxiolytics and hypnotics used for ?

What is their main site of action ?

A
  • Drug treatment of anxiety, stress and sleep disorders

* Act mostly in the central nervous system

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2
Q

What is anxiety ?

A

Excessive fear response and worry that disrupts everyday function and causes distress.

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3
Q

Name 6 anxiety and stress disorders you know.

A

Panic disorders (PD) = unexpected panic attack, worry over future attack, symptoms of racing heart rate, short breath, paresthesia, irrational fear. Agoraphobia.
Phobias = Excessive fear triggered by an object (food) or environment (tall buildings, cliffs)
Social anxiety disorder (SAD) = Fear of social gatherings, judgement by others, embarrassment
Generalised anxiety disorder (GAD) = Persistent worry and apprehension from diverse sources, cognitive dysfunction.
Post-traumatic stress disorder (PTSD) = Follows significant trauma, injury, threat to personal well-being typified by re-living trauma, flashbacks, negative mood, disrupted cognition
Obsessive-Compulsive disorder (OCD) = Disturbing worrying thoughts (terrible event will occur) and need for perfection that are offset by engaging in repetitive,
ritualistic behaviour

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4
Q

What are the 3 main types of sleep disorders (insomnia) ?

A 
Transient = noise related factors / shift work patterns / jet lag 
Intermediate = Emotional or illness related episode
Chronic = Psychiatric disorders – anxiety, depression, drugs, alcohol
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5
Q

What brain structures/circuits are affected in anxiety and stress disorders ?

A
  • mPFC
  • cortex (e.g. sensory system (arousal)
  • thalamus
  • hypothalamus
  • limbic system = amygdala + hyppocampus (emotion)
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6
Q

Which NT levels are increased in anxiety and stress disorders ?
Therefore, how are these disorders treated ?

A

Increased glutamatergic activity –> Physiology: Heart, Respiration rate, Behaviour
Treatment –> Increase inhibition

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7
Q

Which NTs are involved in anxiety ?

A

GABA :
- Major inhibitory transmitter via GABA-A and GABA-B Rs
- Site of action for barbiturates and BDZs
- Increasing GABAergic activity reduces anxiety
- Ubiquitous distribution throughout brain
- Drug target
Glutamate :
- Major excitatory transmitter via AMPA(R), NMDA(R) and mGluRs
- Complex, both potentiation/inhibition of NMDARs confers anxiolysis
- No approved drugs
- 5-HT :
- Projections from the Raphe Nucleus to forebrain
- Increased serotonergic drive reduces anxiety
- Large receptor family (14 subtypes)
- Agonists at 5-HT-1A Rs are anxiolytic
NA :
- Projections from Locus Coeruleus (pons) to forebrain
- Upregulated in anxiety – mediates ‘physiology of anxiety’
- Antagonists of β-adrenoceptors are anxiolytic

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8
Q

Which receptors are preferentially targeted for the treatment of anxiety ?

A

GABA-A Rs > 5-HTRs > Adrenoceptors

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9
Q

When are BDZs used ?

How do they work ?

A

BDZs –> used to treat anxiety and insomnia

BDZs –> bind to GABA-A Rs and increase the frequency of the channel opening –> increase inhibition at synapses

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10
Q

Where do BDZs bind on the GABA-A R ?

A

Between the alpha and gamma subunits.

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11
Q

What does it mean to say that BDZ are positive allosteric odulators at GABA-A Rs?

A

This means that BDZs can potantiate the action of GABA when it binds to its receptor, but cannot activate the GABA-AR alone.

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12
Q

What is beta-carboline ?

A

Beta-carboline is a BDZ inverse agonist :

  • it competitively displaces BDZ from its binding site
  • it prevents GABA from activating the receptor if it is not already present
  • it closes the channel if GABA is already present
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13
Q

What is flumazenil ?

What is the difference between this coumpound and beta-carboline ?

A

Flumazenil is a BDZ antagonist :
- it competitively displaces BDZ from its binding site, but has no effect on the ability of GABA to activate the receptor (unlike beta-carboline)

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14
Q

What are the effects of BDZs ?

A
  • Sedation (anxiolytic)
  • Hypnosis
  • Muscle relaxation
  • Anti-convulsant
  • Amnesia
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15
Q

What are the different uses of BDZs ?

What difference in action do these different uses reflect ?

A

Amnesic, pre-med, surgery (endoscopy) :
- midazolam (duration ~ 4hrs)
Anxiolytic, hypnotic :
- lorazopam, oxazepam, temazepam (~15hrs)
Axiolytic, panic attacks, hypnotics :
- alprazolam, nitrazepam (~24hrs)
Anxiolytic, muscle relax, anti-convulsant :
- chlordiazepoxide (Librium), diazepam (Valium) (~48hrs)
Anticonvulsant, anxiolytics :
- clonazepam, flurazepam (~60hrs)

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16
Q

What are Z drugs ?

A

Drugs that act as anxiolytics, sedative or hypnotics, and that bind at the BDZ binding site of the the GABA-AR.

17
Q

Give examples of Z-drugs.

A 
Imidazopyridines : 
- zolpidem (hypnotic)
Cyclopyrrolones 
- zopiclone (hypnotic)
- eszepiclone (hypnotic)
- pagoclone (anxiolytic)
- suproclone (anxiolytics)
Pyrazolopyrimidines
- zaleplon (hypnotic)
18
Q

What is the half-life of Z drugs ?

How can they be reversed ?

A

All Z drugs are relatively short acting (half-life ~ 2-7hrs).
All are reversed by flumazenil.

19
Q

What are the adverse effects of BDZs ?

A 
Unwanted side-effects: 
• Confusion
• Drowsiness
• Forgetful
• Muscle incoordination
• Day after impairment
• Driving, manual skills
Toxic adverse effects:
• Overdose
• Prolonged sleep
• Less dangerous cf. barbiturates
• Respiratory depression with EtOH
• Safeguard of flumazenil
Tolerance:
• Factor of receptor occupancy
• Factor of dose duration
• Surface receptor numbers?
Dependence:
• Major problem in clinical use
• Rebound anxiety
• Tremor
• Loss of appetite
• Disrupted sleep
• Slow onset cf. opioids
• Limited craving
• Gradual withdrawal
20
Q

Are there natural anxiolytics in the brain ?

Which cells release these ?

A

Yes, these are called neurosteroids, such as tetrahydro-deoxycorticosterone and allopregnanolone.
These are released by glial cells.

21
Q

How do neurosteroids work ?

What effects do they have ?

A 
They are positive allosteric modulators of the GABA-AR.
Effects : 
- Anxiolytic
- Sedative/hypnotic
- Anticonvulsant
- Motor incoordination
22
Q

When are neurosteroids released ?

A
  • Stress responses
  • Premenstr. stress disorder
  • Sleep regulation
  • Neuronal development
  • Ethanol/Drug intoxication
  • Catamenial epilepsy
  • Depression, pain
23
Q

What is diazepam binding inhibitor protein (DBI, 10kDa) ?

A

DBI = a protein that is regulated by hormones and is involved in lipid metabolism and the displacement of beta-carbolines and BDZs

24
Q

What are endozepines ?

A

Endozepines are endogenous pepyides (4-6kDa) compounds with BDZ like effects (bind the same site of the GABA-AR.
Their expression is particularly high in the thalamic reticular nucleus (nRT).

25
Q

What is the main serotonergic nucleus in the brain ?

Where does it projects ?

A

The raphe nuclei in the brainstem.
It projects to a variety of areas, including cerebral cortex, cerebellum, basal ganglia, thalamus, hypothalamus, hippocampus and amygdala.

26
Q

Which 5-HT R is targeted in the treatment of anxiety ?

A

The 5HT-1A R = inhibitory auto-receptor, causes psotsynaptic inhibition (Gi/o, inhibits AC)

27
Q

What is an example of anxiolytic acting at the 5HT-1A R ?

A 
Buspirone = 5HT-1A R partial agonist
• Desensitises presynaptic 5HT-1A Rs?
• Very slow onset (weeks)
• Effective for generalised anxiety disorder
• Not for phobias
• Less problematic side effects cf. to BDZs :
• Dizziness
• Headache
• Nausea
28
Q

What is the main adrenergic nucleus in the brain ?

Where does it project ?

A

The nucleus coeruleus.

It projects to the cerebellum, hippocampus, amygdala, thalamus and cingulate gyrus.

29
Q

Which drugs action of the adrenergic system can be used as anxiolytics ?
Is what particular contexts are these drugs used ?

A

Propranolol = a beta-AR antagonist
Used to treat anxiety with clear physical signs
• Sweating
• Tremor
• Tachycardia
Used to regulated peripheral autonomic effects

30
Q

What other hypnotic is used only for the elderly ?

Why ?

A
  • Chlormethiazole (acts via GABA receptors)

* Used as hypnotic only for elderly because there is no hangover effect

31
Q

What general advice is given to patients taking hypnotics ?

A
  • Short term treatment with hypnotics preferred
  • Tolerance develops over 2 weeks
  • Withdrawal – rebound insomnia, vivid dreams - over weeks
32
Q

What other historical drugs have been used as anxiolytics/hypnotics and are no longer used as such ?

A
  1. Barbiturates – Act via GABA-ARs (can directly activate receptor)
    • Anaesthesia (thiopental)
    • Severe intractable insomnia (amylobarbitone, secobarbital, butobarbital)
    • Epilepsy (phenobarbitone)
    Respiratory depression
    Not for elderly
    Not for sedation
  2. Meprobamate – Acts via GABA-ARs
    Not recommended, similar to barbiturates, less potent than BDZs, more toxic (respiratory depression, coma) – MHRA recommendation to avoid use.
33
Q

How are barbiturates different from BDZ in terms of their actions on the GABA-AR ?

A

Barbiturates : Positive allosteric modulators & Direct activators of GABA-ARs
Barbiturates –> increase the duration of opening of the channel (and not the frequency c.f. BDZs)

34
Q

What other non-prescription anxiolytics/sedatives exist ?

A 
Antihistamines – H1 R antagonists – Sedation, Hypnotic
• Diphenhydramine
• Promethazine
Problem = v rapid tolerance (~2 days)
Valarian extract (Valerianaofficinalis)
– Valerenic acid 
– potentiates GABAR function

PHAR2005 (24 decks)

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