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PH3501- Neuropharmacology > Lec 7- Anxiety and Anxiolytics > Flashcards

Lec 7- Anxiety and Anxiolytics Flashcards

1
Q

Anxiety disorders- GAD

General Anxiety disorder

A
  • Prevalence = 5.1%
  • Symptoms= non specific anxiety; palpatations; sweats; shakes; sleep disturbances; agitation
  • Drug= SSRI + benzodiazepine
  • Other= CBT
  • Prognosis= 65-75% recovery
  • No external influence occurs yet anxiety still occurs
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2
Q

Anxiety disorders- PD

Panic disorder

A
  • Prevalence= 3.5%
  • Symptoms= Recurrent panic
  • Drug= SSRI + Alprazolam (Xanax)
  • Other= exposure
  • Prognosis= 25-45%
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3
Q

Anxiety disorders- Phobia (specific)

A
  • Prevalence= 11.3%
  • Symptoms= Specific stimulant
  • Drug= Possibly BZ to allow exposure
  • Other= exposure
  • Prognosis= reduction is common but loss is rare
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4
Q

Anxiety disorder- PHOBIA (social)

A
  • Prevalence= 13.3%
  • Symtoms= social stiuation
  • drug= SSRI
  • Other CBT
  • Prognosis= 35-75% relapse on drug withdrawal
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5
Q

Anxiety disorder- OCD

A
  • Prevalence= 25%
  • Symptoms= repetative irrational
  • Drug= SSRI, CI
  • Other= CBT, surgury
  • Prognosis= 60% improve within a year
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6
Q

Anxiety disorder- PTSD

Post Traumatic Stress Disorder

A
  • Prevalence= 1-3%
  • Symptoms= Sequel to trauma
  • Drug= TCA, SSRI, MAOI
  • Other= surgury
  • Prognosis= <50% leave clinical class
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7
Q

Anxiety disorders: important comments

A
  • DSM IV provides detailed classification characteristics
  • Clinical trials demonstrate that benzodiazepines and all classes of antidepressant are valublein many of subclasses
  • Clinical opinonand usage varies significantly but NICE guidlines now available for GAD and panic disorder
  • District interventions are often patient specific or determined by patient preference
  • CBT valubleand many produce significant improvement in GAD
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8
Q

Generalized Anxiety disorder

A
  • Excessive anxiety or worry occuring more days than not for at least 6 months
  • Anxiety or worry is associated with 3 or more of the following symptoms
    • Restlessness, keyed up or on edge
    • easily fatigued
    • Difficulties concentrating
    • Irritability
    • Muscle tension
    • Sleep disturbance
  • Symptoms cause clinically significant distress
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9
Q

Occurence of GAD

A
  • Lifetime prevalence about 5.1%
  • Onset can occur throughout life
  • Women are about twice as likely to seek help than men
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10
Q

GAD- management

A
  • The interventions that have evidence for the longest duration of effect are in descending order
    • Psychological therapy (CBT)
    • Pharmacologyical therapy (SSRI)
    • Self-help (bibliotherapy- use of written material to help people understand, learn and deal with their psychological problems
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11
Q

GAD: current therapy

A
  • The benzodiazepines are effective and provide rapid relief but should not normally be used for longer than 2-4 weeks: concerns about their potenital withdrawal symptoms has limited their use
  • SSRIs (TCA and MAOIs) provide similar relief at appropriate dose
  • Current therapy is SSRI plus BZ during intial3-4 weeks to control inital exacerbation of symptoms and provide immediate relief
    • BZ then slowly withdrawn with SSRI remaining
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12
Q

Anxiolytics- Drugs that decrease anxiety

A
  • Opiates
  • Barbiturates
  • Alcohol
  • Buspirone- Anxiolytic and sedative
  • BZ
  • SSRI’s
  • Beta-blockers- will reduce physical symtoms (HR, sweating)
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13
Q

History of anxiolytics

A
  • First anxiolytic know to man was alcohol
  • Bromide salts popular at turn of the century but produced CNS toxicity
  • Barbiturates (diethylbarbituric acid) introduced in 1903
  • Meprobamate introduced in 1955
  • Benzodiazepines introdu ced in 1960
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14
Q

Anxiolytic BZ

A
  • Chlordiazepoxide- 1st found by serendipity
  • Long half-life- which is dependent on the slight changes of functional groups around the 7 membrane ring
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15
Q

Correlation between binding site affinity and therapeutic dose

A
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16
Q

The behavioural inhibition systems

A
  • Inputs
    • Signals of punishment
    • Signals of non-reward
    • Novel stimuli
    • Inate fear stimuli
  • Behaviour inhibition system (brain stem reticular formation, limbic system)- <= Anti-anxiety drugs impair function
  • Output
    • Behavioural inhibition
    • Increment in arousal
    • Increased attention
17
Q

The reticular formation and the limbic system

A
  • Evidence from behavioural studies and their manipulation with brain lesions and pharmacological intervention is consistent with the notion that the behavioural inhibition system is anatomically associated with the reticular formation and the limbic system
  • It is argued that the brain stem reticular formation is activated by exteroreceptive stimuli which are filtered and passed to the limbic circuit consisting of the fornix, cingulate gyrus, mamillary bodies, hypothalamus, amygdala and hippocampus
  • It is the mismanagement of these inputs which result in inappropriate anxiety
18
Q

Neurophysiology of Anxiety

A
  • PAG= prey aqueductal grey= sympathetic stim= palpitations, sweating etc
    • Flight or fight
  • GABA neurones inhibit all these sites
    • NB every neuron in brain contains GABA/ GABAA receptors
  • 5-HT has complex involvement at most sites
19
Q

Benzodiazepines

A
  • All potentiate GABA by acting on the BDZ site on GABAA/CI-channel macromolecule
  • So inhibit the anxiety systems
  • Differences mainly due to different half-lives
  • Very selective for their receptors, no problem side-effects due to non-selectivity
  • Example: Diazepam
20
Q

Other properties of BDZ

A
  • Sedation
  • Anti-epileptic
  • Amnesia: failure of transfer from working to long-term memory
    • Due to inhibition of forebrain cholinergic neurones
  • Can cause impulsivity and loss of inhibitions due to suppression of the behavioural inhibition systems
  • Dependence risk (4th year)
21
Q

Problems with the barbiturates

A
  • The barbiturates have a low therapeutic index (LD50/ED50 between 3:1 and 30:1) while this ratio for the BDZ is in excess of 300:1
  • Barbiturates cause marked respiratory depression and are fatal in overdose
    • This is not the case for the BDZ
  • Barbiturates show rapid tolerance and are dangerous in withdrawal where convulsions and frequently found; not so for BDZ
  • Barbiturates induce liver microsomal enzymes and thus modify the blood level of other drugs; the BDZ do not induce liver enzymes
22
Q

Alternate Anxiolytics: I

A
  • There is now significant evidence that all classes of antidepressant are useful in the treatment of many sub-classes anxiety disorder
    • SSRIs are currently the most popular
  • They have distinct side-effect profiles, of which you must be aware (see below)
  • Individual patients may prefer, or respond better to a certain class; thus multiple trials with a patient is not uncommon
    • Ensure that appropriate criteria are followed in transferring from one medication to another
23
Q

Importance of 5-HT systems in anxiety

A
  • Increasing evidence has been accumulated for the importance of 5-HT in the anxiety
  • In addition to the use of imipramine (the tertiary amine) in the treatment of anxiety, two additional classes of drugs are finding increasing popularity in the effective control of several classes of anxiety disorders
    • 5-HT1A receptor agonist
    • Selective Serotonin Reuptake Inhibitors
24
Q

Distribution of 5-HT1A receptors

A
  • Lots of 5-HT receptors throughout the limbic system (heavy labelling)
25
Q

Buspirone is a 5-HT1A agonist

A
  • It doesn’t interact with a BDZ site
  • It has a distinct pharmacodynamic profile- it is not anti-convulsant or sedative
  • The onset of the anxiolytic effects of buspirone are delayed- they appear after 3-4 weeks of therapy
26
Q

The anxious phenotype of the 5-HT1A receptor knockout mouse

A
  • All mice in which 5-HT1A receptor gene has been deleted show an anxious phenotype
  • These animals only appeared to more anxious under conditions of high stress
  • The knockout animals exhibit disturbances in the GABAA receptor alpha-1 and 2 subunit expression in the amygdala
27
Q

Which action of Buspirone causes its anxiolytic effect

A
  1. Postsynaptic agonist(good) balance
    • Increases transmission through 5-HT1A receptors- an immediate effect that continues
  2. Presynaptic agonist (bad) - balance
    • At cell-body autoreceptors so inhibits 5-HT transmission by reducing firing and release but immediate effect that wears off
    • 1 +2 balance out why we dont see effect within 3 weeks
  3. Presynaptic down-regulation
    • Effect 1 wears off in 3 weeks due to receptor down-regulation
    • Leaves 5-HT neurones less regulated (so more responsive)
    • A delayed effect that matches onset of action
28
Q

xOther alternate anxiolytics

A
  • The beta-blockers are useful in the treatment of performance anxiety (propranolol is the drug of choice
  • Sedative antihistamine (hydroxyzine and diphenhydramine) can be useful in the treatment of anxiety, particularly in patients with dermatological disorders
  • Barbiturates and meprobamate are now rarely used as anxiolytics
29
Q

Co-morbidity of anxiety and depression

A
  • If you have Major depression you are 2.6% more likely to have anxiety disorder etc
  • Shows many disorders are interlinked
30
Q

Panic attack

A
  • Panic attacks are characterised by a discrete period of intense fear or discomfort in which the symptoms develop abruptly and peak within 10 minutes
    • Palpitations or accelerated heart rate, sweating, trembling or shaking
    • Sensations of shortness of breath or smothering, feeling of choking, chest pain or discomfort
    • Nausea or abdominal distress, feeling dizzy, lightheaded or faint
    • Derealisation or depersonalization, feeling of losing control or going crazy, fear of dying
    • Numbness or tingling sensations, chills or hot flushes
31
Q

Panic disorder

A
  • Panic disorder is defined as 4 or more panic attacks in a period of 4 weeks
  • Lifetime prevalence of 3.5%
  • Most frequently occurs for the first time in the early 20s
  • Women are more prone than men to suffer from panic disorder (5:2)- oestrogens bind to GABAA steroid receptors
  • Patients with panic disorder frequently develop agoraphobia (95% of cases)
32
Q

Panic disorder with or without agoraphobia: management

A
  • The interventions that have evidence for the longest duration of effect, in descending order are
    • Psychological therapy (CBT)
    • Pharmacological therapy (SSRI)
    • Self-help (Bibliotherapy- use of written material to help people understand, and learn to deal with their psychological problems)
33
Q

Pharmacological intervention in panic disorder

A
  • Although panic disorder is classified with the anxiety disorders, only one BDZ, alprazolam is approved for its treatment
  • However, all BDZ are effective but high doses are required and their therapeutic effectiveness is slower than in GAD
  • The condition is frequently and effectively treated with antidepressants
    • SSRI
    • Tricyclic antidepressants
    • MOAI, phenelzine
    • The response time is slower than for GAD
34
Q

Obsessive-compulsive disorder

A
  • Characterised by repetitive fruitless physical activity e.g. washing of hands
  • Intrusive and repetative thoughts that cause distress
  • NICE guidlines were introduced for OCD and body dysmorphic disorder in 2005: CG031
35
Q

Intervention in OCD

A
  • CBT offered to alleviate the condition
  • If the patient is unable to effectively engage in CBT or there is no adequate response an SSRI is introduced
  • Clomipramine may be used as an alternative if the patient has previously responsed to this intervention; note the cardiotoxicity of this drug
  • TCAs in general are not recommended
36
Q

Treatment of other anxiety disorders

A
  • Simple phobia (fear of insects etc) treat with behaviour therapy but if immediate help is required (must travel by air) BDZ can be used
  • Social phobia (fear of being scrutinized in public): Beta-blockers as the symptoms are peripheral rather than central (propanolol drug of choice
  • Post-traumatic stress disorder: anti-depressants
    • NICE guidelines for PTSD were introduced in 2005: CG026
  • Alcohol withdrawal is best treated with the BDZ
37
Q

General anxiety and symptoms

A
  • No external influence occurs yet anxiety still occur

PH3501- Neuropharmacology (28 decks)

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