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Anxiolytics Flashcards

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1
Q

What are the two classes of anxiety?

A
  • Physiological
  • Pathological
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2
Q

Outline Physiological Anxiety

A
  • Anticiptation of a stressful event
  • Acts as a stimulus to prepare
  • Focus on “threat”
  • A useful anxiety
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3
Q

Outline Pathological Anxiety

A
  • Anxiety is out of proportion to threat
  • Anxiety without a threat
  • Anxiety interferes with day to day activities
  • Pathological anxiety can be very disabling
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4
Q

What are 4 examples of pathological anxiety?

A
  • Panic attacks
  • Generalized anxiety
  • PTSD
  • OCD

Phobias

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5
Q

What are the 4 psychological symptoms of anxiety?

A
  • Fearful anticipation
  • Minor depressive disorder
  • Irritability
  • Cognitive disturbance
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6
Q

What are the 4 physical symptoms of anxiety?

A
  • Sympathetic arousal
  • Hyperventilation
  • Increased muscle tension
  • Sleep disturbance
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7
Q

What percentage of adults have an anxiety disorder in a given year?

A

10-20%

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8
Q

What is the lifetime prevalence of anxiety disorders?

A

20-30%

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9
Q

What is the cost of general anxiety disorder medication globally?

A

7 billion dollars

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10
Q

What is the projected UK cost of anxiety medication by 2026?

A

14 billion pounds

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11
Q

Per year, how many work days are lost due to anxiety/ depression/ work related stress?

A

18 million in the UK

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12
Q

What are two possible treatments for anxiety?

A
  • Psychological therapy
  • Anxiolytic drugs
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13
Q

What are the 5 criteria for generalised anxiety disorder according to the DSM5?

A
  • Excessive worry/anxiety most of the time for >6 months
  • Worry is about a number of different things
  • Cannot control worry
  • At least three of: restlessness, fatigue, poor concentration, irritable, sleep problems
  • The symptoms must result in poor functioning, cannot be managed by patient and are not due to drugs or other psychiatric conditions
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14
Q

What percentage of the population does GAD affect?

A

2-4% in a year

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15
Q

Is GAD more common in a gender and if so by how much?

A

More common in women by nearly double

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16
Q

What is the median onset for GAD?

A

30 years old, higher prevalence in middle age

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17
Q

What is the heritability of GAD according to twin studies?

A

30%

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18
Q

Is there a GAD gene and if so what is it?

A
  • There is no GAD gene
  • But it links to serotonergic and monoamine transmission genes
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19
Q

What are two risk factors for GAD?

A
  • Childhood trauma
  • Other health conditions e.g. heart attack or stroke
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20
Q

What 3 brain regions is there suggestion that the dysfunction of leads to GAD?

A
  • Amygdala
  • Medial prefrontal cortex
  • Insular
  • These are involved in memory, decision making and emotional reaction, fear and threat perception
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21
Q

What is the NICE 4 step approach to treating GAD?

A
  1. Eduction: may in itself improve symptoms
  2. Individual or group self- or guided-help (based on CBT)
  3. Drug therapy or high intensity CBT
  4. Combinations of drugs (SSRIs, SNRIs, pregabalin, BDZ) and psychological interventions
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22
Q

What is Buspirone’s trade name?

A

Buspar

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23
Q

How does Buspirone act in the synapse?

A

Is a partial agonist at 5HT1A receptors

Therefore modulates the release of 5HT and other neurotransmitters

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24
Q

Where are 5HT1A receptors found?

A

pre (inhibitory autoreceptors or heteroreceptors) and post synaptically

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25
Q

What is a benefit of Busprione?

A

Does not produced pronounced sedation and has relatively mild side-effects

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26
Q

What is the lifetime prevalence of OCD?

A

2.3%

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27
Q

What are the two sets of symptoms for OCD?

A
  • Obsessions
  • Compulsions
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28
Q

What are obsessions characterised by?

A
  • Intrusive/disturbing thoughts
  • Usually have a particular theme
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29
Q

What are compulsions characterised?

A
  • Driven by the obsession
  • Carrying out the compulsion is uncontrollable and provides temporary releif from the obsession
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30
Q

What is Pure O OCD?

A
  • Obsession dominant OCD
  • May have compulsions but they are minor
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31
Q

What is the heriditability of OCD?

A

50% genetics and epigenetic

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32
Q

What types of medication can trigger OCD?

A

Atypical antipsychotics

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33
Q

What is Trichotillomania?

A
  • Compulsive pulling out of the hair which can sometimes be accompanied by eating it
  • Is classified as a bodily focused repetitive behaviour which has a distinct DSM5 classification
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34
Q

What is Dermatillomania?

A
  • Compulsive picking of the skin
  • Is classified as a bodily focused repetitive behaviour which has a distinct DSM5 classification
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35
Q

What are the treatments for OCD when it causes mild impairment?

A

Low intensity psychological interventions (<10 hour) CBT inc. ERP (Exposure response prevention)

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36
Q

What are the treatments of OCD when it causes moderate impairment?

A

SSRIs or more intense CBT inc. ERP

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37
Q

What is the treatment for OCD when it causes severe impairment?

A

SSRIs and more intense CBT inc. ERP

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38
Q

What is exposure response prevention?

A
  • Similar to the desensitization approach that is sometimes used to treat allergies
  • You expose the person to what they are fearful of in a controlled way, and gradually help them to overcome their fear
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39
Q

What are the most implicated brain areas involved in OCD?

A
  • Orbitofrontal cortex
  • Basal ganglia
  • Cingulate cortex
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40
Q

What is seen in the cingulate cortex with patients experiencing OCD?

A

Anterior portion shows hyperactivity

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41
Q

What is a bilateral cingulotomy?

A
  • Severing the connection to the cingulate cortex
  • Done with the aid of MRI scans
  • Done using electrodes or a gamma knife
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42
Q

What is the recovery time for a bilateral cingulotomy and what percentage of people benefit from the procedure?

A
  • A few days
  • 40%
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43
Q

What are 4 symptoms of panic attacks?

A
  • Physical symptoms
  • Sympathetic activation, parasthesis
  • Psychological symptoms
  • Depersonalization, derealization, fear of losing control or of dying
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44
Q

How many out of the 13 DSM5 symptoms for panic attacks must one experience to be diagnosed?

A

4

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45
Q

What is panic disorder?

A
  • Recurrent panic attacks and
  • A period of at least a month in which there is persistent anxiety about havnig a panic attack and/or
  • Changed behaviour aimed at avoiding panic attacks
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46
Q

What is the treatment for mild to moderal panic disorder?

A
  • Low intensity psychological interventions
  • e.g. self help, support groups
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47
Q

What is the treatment for moderate to severe panic disorder?

A
  • CBT or, if not effective
  • SSRI or SNRI or, if not effective
  • Tricyclic AD
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48
Q

Which two beta blockers can be used to treat panic disorder?

A

Propranolol

Atenolol

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49
Q

How do beta blockers work to aid in panic disorder?

A
  • Beta1 adrenoreceptor antagonists
  • Mask symptoms of sympathetic activation
  • Reduce physical effects of panic attacks
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50
Q

What are the 4 symptoms for phobias?

A
  • Intense fear or panic when confronted with the object of the phobia (sometimes even thinking about it)
  • Knowing that your reaction is out of proportion, but not being able to control it
  • Trying to avoid the object or situation if possible
  • A marked impact on your functioning when confronted with the object of your phobia
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51
Q

What does the NHS suggest in terms of treating for phobias?

A
  • CBT with exposure therapy
  • Some cases, SSRIs, SNRIs, tricyclic AD and moclobemide
  • Short term Benzodiazepines or beta blockers
52
Q

What is the most common type of anxiety disorder?

A

Social anxiety disorder

53
Q

What is the lifetime prevalence of social anxiety disorder?

A

12%

54
Q

What is the DSM5 criteria for social anxiety disorder (8)

A
  • Marked fear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others. Examples include social actions and performing in front of others
  • The individual fears that he or she will act in a way or show anxiety symptoms that will be negatively evaluated
  • The social situations are avoided or endured with intense fear or anxiety
  • The social situations almost always provoke fear or anxiety
  • The fear or anxiety is out of proportion to the actual threat posed by the social situation and to the sociocultural context
  • The fear, anxiety or avoidance is persistent, typically lasting for 6 months or more
  • The fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • The symptoms have lasted longer than 6 months or longer and are not better explained by another condition.
55
Q

What is NICE recommendations for social anxiety disorder?

A
  • CBT (individual therapy)
  • If ineffective, then SSRIs in addition to CBT
  • If ineffective, then SNRIs or monoamine oxidase inhibitors
56
Q

What percentage of the US will experience PTSD in their life?

A

7%

57
Q

What are some symptoms of PTSD?

A
  • hypervigilace
  • Aggression
  • Flashbacks to the trauma
  • Cognitive problems
  • Intrusive thoughts and memories
  • Nightmares
58
Q

What is the suicide rate for those with PTSD?

A

9.8X the general population

59
Q

What are the estimates for English and American soldiers developing PTSD after the Iraq war?

A
  • 4-17% for US
  • 3-6% for UK
60
Q

What is the rate of PTSD that occurs in rape survivors?

A

50%

61
Q

What areas of the brain are correlated with PTSD?

A
  • Reductions in volume of the hippocampus and prefrontal cortex
  • Amygdala hyperresponsivenes
  • Responsiveness of the HPA axis (lower plasma cortisol levels and greater response to dexamethasone supression test)
62
Q

What might low levels in cortisol following a traumatic event correlate with?

A
  • Increased noradrenergic signalling in the CNS and periphery
  • When in the locus coeruleus it may result in over-consolidation of fearful memories
63
Q

What does CBT within the month following trauma do for those with acure stress reaction (often a delay before CBT propr establishes)?

A
  • Reduce the rate at which people go onto develop PTSD
  • Lessens the symptoms of those who do develop it
64
Q

What is NICE recommended treatment for PTSD?

A
  • Specialised CBT and for non-combat trauma, Eye movement desensitization and reprocessing (EMDR)
  • In terms of drugs: SSRIs, SNRIs and if psychotic symptoms: atypical antpsychotic such as risperidone may be considered
65
Q

What are the endings of the barbiturates?

A
  • tal
  • one
66
Q

What are the historical uses of the barbiturates?

A
  • Anxiolytics
  • Anticonvulsants
  • Sedatives/hypnotics
  • Anaesthetics
67
Q

When are barbiturates used now?

A
  • In extreme cases
  • For short procedures or induction
68
Q

What is the major issue with the barbiturates

A

VERY dangerous in overdose: respiratory depression

69
Q

What are the mechanisms of action for the barbiturates?

A
  • Positive allosteric modulators of GABAA receptor: prolong opening time
  • At higher concentrations can directly activate the receptor- main reason why they are more lethal in overdose
  • May also inhibit AMPA receptors, P/Q type VSCC (inhibits neurotransmitter release)
70
Q

Where do the barbiturates bind within the receptor?

A
  • Beta subunit within the membrame domain and may extend into the alpha subunit
  • Need to enter the lipid bilayer
71
Q

What are 4 medical ways in which the barbiturates are used?

A
  • General anaesthesia (thiopental/pentobarbital)
  • Status epilepticus when the seizure has not responded to benzodiazepines or anticonvulsants
  • Induce comas
  • Medical and veterinary euthanasia
72
Q

What is the most common cocktail of drugs used for lethal injection?

A
  • Sodium thiopental to induce loss of consciousness and repress respiratory drive
  • Pancuronium bromide; a long acting non-depolarising neuromuscular blocker that paralyses the respiratory muscles
  • Potassium chloride to depolarise the myocardium and bring about cardiac arrest
73
Q

What have the States used as a replacement for the non-exported lethal injection drugs?

A
  • Pentobarbital
  • Benzodiazepine/opioid mixture
74
Q

Why were Benzodiazepines created?

A
  • To replace barbiturates by 70s
  • As safer in overdose
75
Q

What do benzodiazepines do?

A
  • Anxiolytic
  • Sedative
  • Muscle relaxant
  • Amnesic
  • Anticonvulsion
76
Q

Why are the Benzodiazepines now used sparingly?

A
  • Used in low dose for short term
  • Addiction and tolerance are now recognised
77
Q

Where are GABA binding sites on the GABA A receptor?

A

The interfaces of beta and alpha

78
Q

Where are the Benzodiazepines binding sites on the GABA A receptor?

A

Interface of gamma 2 and alpha

79
Q

How do compounds that enhance GABA A receptor function act?

A
  • Anxiolytic
  • Sedative
  • Muscle relaxant
  • Amnesic
  • Anticonvulsant
80
Q

How do compounds that decrease GABA A receptor function act?

A

Pro-convulsants

81
Q

How can ligands at the Benzodiazepine site modulate the function of the GABA A receptor?

A
  • Positively
  • Neutrally
  • Negatively
82
Q

How to the Benzodiazepine agonists work at the GABA A receptor?

A

Increase GABA A receptor channel opening frequency and therefore the affinity of GABA

83
Q

Give 4 examples of a Benzodiazepine agonist

A
  • Flunitrazepam (rohypnol)
  • Diazepam (valium)
  • Temazepam
  • Nitrazepam (mogadon)
84
Q

What effects do the Benzodiazepine agonsits produce?

A
  • Anxiolytic
  • Sedative
  • Hypnotic
  • Amnesia inducing
85
Q

Give an example of a Benzodiazepine antagonist

A

Flumazenil

86
Q

How does flumazenil work?

A
  • Competes wit agonists for the same binding site
  • Pharmacologically fairly inactive
  • Little effect on GABA A
87
Q

When would flumazenil be used?

A
  • To reverse Benzodiazepine sedation (overdose)
  • Receptor acitvation blocks potentiation by the agonists
88
Q

Give an example of a Benzodiazepine inverse agonist

A

Beta-carbolines DMCM

89
Q

How do the Benzodiazepine inverrse agonists act?

A
  • Act at the same site as flunitrazepam
  • Actions can be blocked by flumazenil
  • Decrease channel opening frequency
90
Q

What do the Benzodiazepine inverse agonists do?

A
  • Proconvulsant
  • Anxiogenic
91
Q

What are the two distinct populations of Benzodiazepine binding sites?

A

High affinity- Type 1

Low affinity- Type 2

92
Q

What compound was used to find the pharmacological heterogeneity of the Benzodiazepine sites?

A

CL218-872

93
Q

What does the pharmacology of the Benzodiazepine site depend on?

A

The alpha subunit

94
Q

What is alpha subunit 1’s receptor type?

A

Type 1- binds classic Benzodiazepines

95
Q

What is alpha subunit 2, 3 and 5’s receptor type?

A

Type 2- binds classic Benzodiazepines

96
Q

What is alpha 4 and 6’s receptor type?

A

High affinity for Ro 15-4513 but not classic Benzodiazepines

97
Q

What are the 4 most licenced Benzodiazepines and what do they do?

A
  • Midazolam- sedative for surgery
  • Chlordiazepoxide- alcohol withdrawal
  • Clobazam and clonazepam- epilepsy
  • Diazepam- muscle spasms
98
Q

What does the term Benzodiazepine refer to?

A
  • A type of chemical structure
  • Only drugs with this structure should be termed Benzodiazepines
  • Other drugs should be termed Benzodiazepine site ligands
99
Q

What are Z drugs used for?

A

Sleep disorders: hypnotics or sleeping tablets

100
Q

Why are the Z drugs useful for sleep disorders?

A
  • They have a short plasma half-life of 1-6 hours
  • This can help avoid the hangover effect with drugs such as diazepam (half-life of 48 hours)
101
Q

What is the oppositional tolerance model?

A

In response to a drug, the brain will adjustthe neurochemistry to try and maintain the status quo

102
Q

How does one build a tolerance to the Benzodiazepines?

A
  • GABAergic transmission is potentiated so the reaction of the brain is to down-regulate GABAergic transmission
  • This also leads to withdrawal symptoms when it is stopped
103
Q

What is the maximum amount of days the Benzodiazepines can be prescribed for?

A

28 days

104
Q

What are some side-effects of Benzodiazepine withdrawal?

A
  • Hallucinations
  • Increased anxiety
  • Insomnia
  • Photophobia
104
Q

What were the Benzodiazepines modified in order to do?

A

Maintain anxiolytic effects but avoid sedation

105
Q

What 3 drugs were made in the first wave of developing anxioselective Benzodiazepines?

A
  • Bretazenil
  • Alpidem
  • Ocinaplon
106
Q

Outline the development of Bretazenil

A
  • Animal studies suggested anxiolysis but little sedation
  • Human phase 1 trials: profound sedation and stronger interaction with ethanol than diazepam
107
Q

Outline Alpidem and Ocinaplon development

A
  • Worked in animals
  • Good evidence of anxiolysis
  • Evidence of reduced sedation vs diazepam in humans
  • Ocinaplon failed in phase 3, Alpidem withdrawn after licensing (both: liver toxicity)
108
Q

What are 4 animal behavioural tests?

A
  • Elevated plus maze (anxiety)
  • Vogel water-lick conflict test (anxiety)
  • Rotorod test (motor activity)
  • Morris water maze (memory)
109
Q

What was the hypothetical ancestor of the GABA A receptor?

A

A homopentamer- a single type of subunit arranged in the normal subunit configuration

When the subunits, they have 2 faces; a plus and a minus, to form a binding site we need contributions from a neighbouring negative and positive.

110
Q

How did the GABA A receptor evolve?

A
  • The ancestral subunit X duplicated
  • The redundant X subunit can then mutate to form subunit Y
111
Q

How many GABA ligands can bind to a GABA A receptor?

A

2, to the alpha and beta positive and negative interface

112
Q

What is an issue with knockout studies?

A

Alpha 6
- Cerebellar expression

  • Compensatory expression other GABA A receptors and K channels

Beta 3 and gamma 2
- pernatally lethal

113
Q

What was the strategy for Benzodiazepine subunit knockout studies?

A

Eliminate individual subunits from genome. Does this alter sedative or anxiolytic properties of the Benzodiazepines?

114
Q

What happens if you mutate alpha 1, 2, 3 and 5 (type 1 and 2 GABA A receptors) for histidine to an argenine?

A

You convert the classic Benzodiazepine binding receptor to a low affinity type alpha 4 and 6 GABA A receptor

115
Q

What happened to the GABA A receptor after mutation conserved alpha histadine to argenine in Benzodiazepine site?

A
  • No change in GABA sensitivity
  • No change in receptor assembly
  • Complete loss of classic Benzodiazepine binding
116
Q

How does transgenic knock-in occur?

A

In vivo replacement of single amino acid in defined gene

117
Q

What type od knock-in mice were generated and what was their phenotype?

A
  • Alpha 1, 2 and 3
  • Generally normal phenotype and responses to GABA
118
Q

What effects were lost in the alpha 1 knock-in mice?

A
  • Lost amnesic effects and sedative effects
  • But retained anxiolysis
119
Q

What effects were lost in alpha 2 knock-in mice?

A
  • Lost anxiolytic effect
  • Maintained sedation and amnesia
120
Q

What effects were lost in alpha 3 knock-in mice?

A

NONE

121
Q

What, in theory would alpha 2 selective drugs do?

A

Anti-anxiety without sedation

122
Q

What was suprisingly found in the alpha 2 knock-in mice?

A
  • Alpha 3 selective compounds anxiolytic
  • So alpha 3 is important?
123
Q

Outline the effects of TPA023B (selective for alpha 2 subunit)

A
  • Zero efficacy at alpha 1 but moderate efficacy at alpha 2 and 3 containing receptors
  • Anxiolytic in rodents and primates
  • No sedating in animals
  • But, phase 1 trials (humans) was highly sedative
124
Q

What are the reasons for failure in the knock-in alpha 2 subunit approach?

A
  • Species differences between rodents/primates and man
  • heterogeneity of alpha subunits within a receptor
125
Q

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A

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