anxiety and anxiolytics

8/10/2019 Anxiety and Anxiolytics

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Anxiety and Anxiolytics


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Anxiety disordersLife time

prevalenceSymptoms Drug Other Prognosis

GAD 5.1% Non specific Anxiety

SSRI(+ benzo)

CBT 65-75%recover

PD 3.5% Recurrentpanic

SSRI Alprazolam

Exposure 25-45%improve

PHOBIA(specific)

11.3% Specificstimulant

Possibly BZto allowexposure

Exposure Reductioncommon butloss rare

PHOBIA(social)

13.3% Socialsituation

SSRI CBT 35-75%relapse ondrugwithdrawal

OCD 2.5% Repetitiveirrational

SSRICI

CBTsurgery

60% improvewithin 1 year

PTSD 1-3% Sequel totrauma

TCA, SSRI,MAOI

CBT


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Anxiety disorders: important comments

DSM IV provides detailed classification characteristics. Clinical trials demonstrate that benzodiazepines and all

classes of antidepressant are valuable in many of sub-classes (at appropriate dose).

Clinical opinion and usage varies significantly but NICEguidelines now available for GAD and Panic Disorder.

Distinct interventions are often patient specific ordetermined by patient preference.

CBT valuable and may produce significantimprovement in GAD.


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Generalized Anxiety Disorder

Excessive anxiety or worry occurring more days thannot for at least 6 months

Anxiety or worry is associated with 3 or more of thefollowing symptoms:

restlessness, keyed up or on-edge easily fatigued difficulties with concentration irritability muscle tension sleep disturbance

Symptoms cause clinically significant distress


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Occurrence of GAD

Lifetime prevalence about 5.1%

Onset can occur throughout life

Women are about twice as likely to seek helpthan men


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GAD: management The interventions that have evidence for the

longest duration of effect are, in descendingorder:

Psychological therapy (cognitive behaviouraltherapy, CBT)

Pharmacological therapy (SSRI)

Self-help (bibliotherapy use of written material tohelp people understand, and learn to deal with,their psychological problems)

www.nice.org.uk/CG022


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GAD: current therapy

The benzodiazepines are effective and provide rapidrelief but should not normally be used for longer than2-4 weeks: concern about their potential withdrawalsymptoms has limited their use

SSRIs (TCAs and MAOIs) provide similar relief atappropriate dose

Current therapy is SSRI plus benzodiazepine duringinitial 3-4 weeks to control initial exacerbation ofsymptoms and provide immediate relief.Benzodiazepine then slowly withdrawn with SSRIremaining.


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ANXIOLYTICS Drugs that decrease anxiety

Opiates Barbiturates Alcohol Buspirone Benzodiazepines SSRIs Beta-blockers


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History of anxiolytics First anxiolytic know to man was alcohol Bromide salts popular at the turn of this

century but produced CNS toxicity Barbiturates (diethylbarbituric acid)

introduced in 1903

Meprobamate introduced in 1955 Benzodiazepines introduced in 1960


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Anxiolytic benzodiazepines

N

N

Cl

NHCH 3

N

N

Cl

CH 3O

N

N

N

NH 3 C

Cl

N

N

Cl

HO

OH

N

N

N

Br

HO

N

N

Cl

HO

COOK

N

N

Cl

CH 3O

O

O

H 3 C

N

N

Cl

HO

OH

Cl

KetazolamDiazepam

Alprazolam

Lorazepam Oxazepam

O

Bromazepam Chlordiazepoxide Clorazepate


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Correlationbetween

binding siteaffinity andtherapeutic

dose

A v e r a g e

t h e r a p e u t

i c d o s e

m o

l / d a y

1

10

100

1000

1 10 100 1000

Affinity for benzodiazepine site, K i (nM)

triaz

clnfnz

lor

diaz nit

flr brm

oxzcdp


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The behavioural inhibition system

Behaviouralinhibition

system} {Inputs Outputs

signals of punishment behavioural inhibition

increment in arousal

increased attentioninate fear stimuli

novel stimuli

signals of non-reward

Anti-anxiety drugsimpair function


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The reticular formation and the limbic system

Evidence from behavioural studies, and theirmanipulation with brain lesions and pharmacologicalintervention, is consistent with the notion that thebehavioural inhibition system is anatomicallyassociated with the reticular formation and the limbicsystem

It is argued that the the brain stem reticular formation is activated by exteroceptive stimuli which are filteredand passed to the limbic circuit consisting of thefornix, cingulate gyrus, mamillary bodies,hypothalamus, amygdala and hippocampus

It is the mismanagement of these inputs which result

in inappropriate anxiety


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Neurophysiology of Anxiety

Sympathetic

activation

Flight

Amygdala

Limbic system andcortex

BehaviouralInhibition

System AvoidanceCaution

GABA neurones inhibit allthese sites

5-HT has complexinvolvement at most sites

Perception of being anxious

PAG


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Benzodiazepines All potentiate GABA by acting on the BDZ site

on the GABA A/Cl - channel macromolecule

So inhibit the anxiety systems

Differences mainly due to different half-lives

Very selective for their receptors, no problemside-effects due to non-selectivity

Example: Diazepam


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Other properties of Benzodiazepines

Sedation Anti-epileptic Amnesia: failure of transfer from

working to long-term memory. Due toinhibition of forebrain cholinergicneurones

Can cause impulsivity and loss ofinhibitions due to suppression of theBehavioural Inhibition System

Dependence risk (4th year)


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Problems with The Barbiturates

The barbiturates have a low therapeutic index (LD50 /ED 50 between 3:1 and 30:1) while this ratio forthe benzodiazepines is in excess of 300:1

The barbiturates cause marked respiratory

depression and are fatal in overdose. This is not thecase for the benzodiazepines Barbiturates show rapid tolerance and are dangerous

in withdrawal where convulsions are frequently found;not so for benzodiazepines

Barbiturates induce liver microsomal enzymes andthus modify the blood level of other drugs; thebenzodiazepines do not induce liver enzymes


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Alternate anxiolytics: I There is now significant evidence that all classes of

antidepressant are useful in the treatment of manysub-classes of anxiety disorder. SSRIs are currentlymost popular

They have distinct side-effect profiles, of which youmust be aware (see below)

Individual patients may prefer, or respond better to acertain class; thus multiple trials with a patient is notuncommon: ensure that appropriate criteria arefollowed in transferring from one medication toanother


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Alternate anxiolytics

N

N

NNN

H 3 C

O

H 2 NO

O NH 2

O

N

N

Cl

OOH

Buspirone

Meprobamate

Hyroxyzine

(5-HT 1A receptor agonist)

(Barbiturate-like)

(Sedative antihistamine)


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Importance of 5-HT systems in anxiety

Increasing evidence has been accumulatedfor the importance of 5-HT in the anxiety. In

addition to the use of imipramine (the tertiaryamine) in the treatment of anxiety, twoadditional classes of drugs are findingincreasing popularity in the effective control of

several classes of anxiety disorders: 5-HT 1A receptor agonists S elective S erotonin Reuptake Inhibitors


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Distribution of 5-HT 1A receptors

differentiallabelling incortical layers

heavy labellingin the amygdala

heavy labellingin hippocampus


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Buspirone is a 5-HT 1A agonist ; it does notinteract with benzodiazepine site. It has adistinct pharmacodynamic profile - it is notanti-convulsant or sedative. The onset ofthe anxiolytic effects of buspirone aredelayed - they appear after 3-4 weeks of

therapy.


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Anxious phenotype of the 5HT 1A receptorknockout mouse

All mice in which the 5HT 1A receptor gene hasbeen deleted show an anxious phenotype

These animals only appeared to me moreanxious under conditions of high stress

The knockout animals exhibit disturbances in the

GABA A receptor a 1 and a 2 subunit expressionin the amygdala


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Which action of Buspirone causes its anxiolyticeffect?

1.Postsynaptic agonist increases transmission through5-HT1A receptors

immediate effect that continues

2.3.Presynaptic down-regulator

effect 1 wears off in 3 weeks due toreceptor down-regulation leaves 5-HT neurones less regulated(so more responsive?) delayed effect that matches onset ofaction

Presynaptic agonist at cell-body autoreceptorsso inhibits 5-HT transmissionby reducing firing and releasebut immediate effectthat wears off


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Other alternate anxiolytics The -blockers are useful in the treatment of

performance anxiety (propranolol is the drug ofchoice)

Sedative antihistamines (hydroxyzine anddiphenhydramine) can be useful in the treatment ofanxiety, particularly in patients with dermatologicaldisorders

Barbiturates and meprobamate are now rarely usedas anxiolytics.


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Co-morbidity of anxiety and depression

Anxiety

Panicdisorder

MajorDepression

x 9.4

x 5.2 (phobic)(phobic) x 2.6

x 26.5


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Panic attack Panic attacks are characterised by a discrete period of

intense fear or discomfort in which the symptomsdevelop abruptly and peak within 10 minutes:

palpitations or accelerated heart rate, sweating, trembling orshaking

sensations of shortness of breath or smothering, feeling ofchoking, 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


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Panic disorder

Panic disorder is defined as four or more panicattacks in a period of 4 weeks

Lifetime prevalence of 3.5%

Most frequently occurs for the first time in early 20s

Women are more prone than men to suffer frompanic disorder (5:2)

Patients with panic disorder frequently developagoraphobia (95% of cases)


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Panic disorder with or withoutagoraphobia: management

The interventions that have evidence for thelongest duration of effect, in descending orderare:

Psychological therapy (cognitive behavioural therapy,CBT)

Pharmacological therapy (SSRI) Self-help (bibliotherapy use of written material to

help people understand, and learn to deal with, their

psychological problems)

www.nice.org.uk/CG022NICEguideline


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Pharmacological intervention inpanic disorder

Although panic disorder is classified with the anxietydisorders, only one benzodiazepine, alprazolam, isapproved for its treatment. However, allbenzodiazepines are effective but high doses arerequired and their therapeutic effectiveness is slowerthan in GAD.

The condition is frequently, and effectively treated withantidepressants:

Selective Serotonin Reuptake Inhibitors (SSRIs) tricyclic antidepressants monoamine oxidase inhibitor, phenelzine The response time is slower than for GAD


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Obsessive compulsive disorder

Characterised by repetitive fruitless physicalactivity e.g. washing of hands

Intrusive and repetitive thoughts that causedistress

NICE guidelines were introduced for OCD and

body dysmorphic disorder in 2005: CG031


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Intervention in OCD

CBT offered to alleviate the condition

If the patient is unable to effectively engage in CBT orthere is no adequate response an SSRI is introduced

Clomipramine may be used as an alternative if thepatient has previously responded to this intervention;note the cardiotoxicity of this drug

TCAs in general are not recommended


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Treatment of other anxiety disorders

Simple phobia (fear of insects etc): treat withbehaviour therapy but if immediate help is required(must travel by air) benzodiazepines can be used

Social phobia (fear of being scrutinized in public): -blockers as the symptoms are peripheral rather thancentral (propranolol drug of choice)

Post-traumatic stress disorder: antidepressants

NICE guidelines for PTSD were introduced in 2005: CG026

Alcohol withdrawal is best treated with thebenzodiazepines

anxiety and anxiolytics

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