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Anxiolytic drugsAnxiolytics: reduce anxiety
Sedatives: decrease activity, calming effect
Hypnotics: induce sleep
Some drugs have anxiolytic and sedative/hypnoticeffects.
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Anxiety disordersExcessive, severe, and prolonged anxiety thatcompromises normal functioning
Prevalence: 2.5-6.5% of general population
Subjective featuresApprehensionWorry AnticipationFear Hypervigilance (‘jumpiness’)RestlessnessImpaired concentrationDepression
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Physiological featuresNeuromuscular e.g. tension, fatigue, tremor Gastrointestinal e.g. dry mouth, difficulty in swallowing Respiratory e.g. hyperventilationCardiovascular e.g. palpitations
Beta-blockerse.g. PropranololOnly treats physiological symptoms (palpitations,tremor and gastrointestinal upset, etc.)Used for performance anxiety
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Anxiolytic drugsBenzodiazepines have dominated for 40 yearsAlpralozam **(Xanax); Chlordiazepoxide ***(Librium); Diazepam ***(Valium); Lorazepam **(Ativan); Chlorazepate * (Tranxene)*Short-acting (3-8 hours)**Intermediate (10-20 hours)*** Long-acting (1-3 days)
Azapirones:Buspirone (Buspar) - partial 5-HT1A agonist
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Sedative/hypnotic drugs
Benzodiazepines:Clonazepam ***(Klonopin); Diazepam***(Valium); Lorazepam **(Ativan); Oxazepam(Serax); Triazolam *(Halcion); Estazolam**(ProSom); Temazepam **(Restoril);Flurazepam ***(Dalmane); Quazepam ***(Doral);Midazolam *(Versed)
Benzodiazepine binding site agonists(but not benzodiazepines): Z drugs
Zaleplon (Sonata); Zolpidem (Ambien)
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Sedative/hypnotic drugs
BarbituratesAmobarbital **(Amytal); Aprobarbital (Alurate);Butabarbital (Butisol); Mephobarbital (Mebaral);Methohexital * (Brevital); Pentobarbital**(Nembutal); Phenobarbital ***(Luminal);Secobarbital **(Seconal); Thiopental* (Pentothal)
*Ultrashort (5-15 min)/induction of anesthesia**Short acting (3-8 hrs)/insomnia/preoperative sedation***Long acting (days) treatment of seizuresNewer GABA receptor activators are also used for anesthesia
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Meprobamate (Miltown) - used as an anxiolytic appearsto have a barbiturate like effect but can also directlyactivate the GABAA receptor
Chloral hydrate (Noctec) - older sedative/hypoticFlunitrazepam (Rohypnol) fast -acting BDZ causesamnesia “date rape”
Alpha2 adrenergic agonist sedation/analgesia/anxiolyticDexmedetomidine (Precedex )
Ramelteon MT1/MT2 melatonin agonist - insomnia(targets a nucleus in the hypothalamus)
OTHERS
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Classifying anxiety disorders
•Generalized anxiety disorder•Phobic anxiety disorder (e.g. agoraphobia, social phobia etc) •Panic disorder•Obsessive-compulsive disorder (OCD)•Post-traumatic stress disorder•Adjustment disorder with anxiety (and sometimes depression),
also known as acute stress disorder•-Comorbid depression and anxiety
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Generalized anxiety disorder (GAD)excessive anxiety and worry most of the time
Phobic anxiety disordersan irrational fear that interferes with normal behavior
Panic disorderdiscrete periods of intense fear
Obsessive-compulsive disorder (OCD)Obsessions: persistent thoughts, ideas, or images thatintrude into conscious awarenessCompulsions are urges or impulses for repetitiveintentional behaviors
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Post-traumatic stress disorderrecurrent anxiety precipitated by exposure to anexceptionally stressful or life threatening event
Acute stress disordera reaction to a recent identifiable stress;lasts less than six months
Comorbid depression and anxietyDepression and anxiety occurring together at thesame time in the same patient
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Molecules(neurotransmitters, receptors, ion channels)
neurons
synapses
Neural networks
?
Higher cortical function (consciousness, cognition, mood)
Psychological treatment
Drug treatment
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‘Fear’ vs ‘Anxiety’
Fear: reaction to immediate perceived threat/critical tosurvival
Anxiety: anticipatory response to an uncertain, potentialthreat
Conditioned fear: reaction to a stimulus that isassociated with a threat
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The amygdala is central
amygdalathalamus
cortex
hippocampus
striatum
brainstem
hypothalamus
Sensoryinput
‘fight or flight’Motor response
Autonomicresponses
(Greatly simplified)hormonalstress response
“expression”“experience”
Limbic System
Functional neuroanatomy of anxiety and fear
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Neurochemistry of anxiety and fear
Corticotropin-releasing hormone/factor (CRH/F)
Glutamate
Norepinephrine
Acetylcholine
Serotonin (5-HT)
Dopamine
Gamma-aminobutyric acid (GABA)
Cholecystokinin (CCK; neuroactive peptide)
neuropeptides
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GABAA receptors
Serotonergic systemSerotonin released in amygdala duringanxiety?5-HT2A, 5-HT 2C, 5-HT1A and 5-HT1B receptors
Noradrenergic systemHyperactive response in anxiety disordersPanic disorder - hypersensitive to anxiogenicalpha2 antagonists
Benzodiazepine antagonists and inverseagonists cause anxiety
Infusion of benzodiazepines into amygdala hasanxiolytic effect (animal studies)
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Ascending arousal system
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Buspironefull agonist
Inhibitoryautoreceptor
Buspirone
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Buspirone metabolite: 1-2-pyrimidinylpiperazine (1-PP)
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BuspironePartial agonist at postsynaptic 5HT1A receptors
Can exacerbate panic attacks in patients with panic disorder(1-PP alpha2 antagonist effect?)
No dependency
Hippocampus site of anxiolytic action?
Chronic buspirone -> desensitize presynaptic 5-HT1A->increased serotonergic activity
Full agonist at presynaptic 5HT1A receptors
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Antidepressants
Effective in treating anxiety and comorbid depression
Take several weeks to have beneficial effect -desensitization of presynaptic autoreceptors -
mechanism will be covered in detail
Can initially make anxiety symptoms worse
Monoamine oxidase inhibitorsTricyclic antidepressants
Selective serotonin reuptake inhibitors
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Benzodiazepines
•Risk of classic tolerance and dependence
Modulate GABAA receptorIncrease potency but not efficacy of GABANo intrinsic agonist activity- can not open the Cl- channelAmygdala site of anxiolytic action?
•Sedative, hypnotic, muscle relaxants, anticonvulsant andanxiolytic•Hypnosis and stupor at high doses•Preferred over barbiturates - when used alone - rarely causefatal CNS depression (additive depression with ethanol)•Flumazenil is a competitive BDZ antagonist - no clinicaleffect alone
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GABAA receptors
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GABAA receptors
Benzodiazepines (BZD)Barbiturates (BRB)Zolpidem (Zol)
Zaleplon (Zal)Meprobamate (Mep)chloral hydrate (ChH)
Anxiolytics/sedatives/hypnotics that bind to GABAAreceptors:
Increase GABAA receptor activity
‘agonists’ / positive allosteric modulators
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Sedative/hypnoticsdeath
surgicalanesthesia
coma
sleep
sedation
Drug dose
Mostnon-benzodiazepinesedative/hypnotics
Benzodiazepines,Zolpidem, Zaleplon
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Anxiolytic?Sedative/hypnotic?
Lethal inoverdose?
Yes (variable) Yes (variable) No
Yes
Yes
Yes
BZD
BRB
Zol
Zal
Mep
ChH
Tolerance/dependence?
Yes Yes
No Yes Not supposed to No
Yes No
YesYes
Yes YesYes?
YesYes
No Not supposed to
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GABAA receptors are heteropentamersGABAA receptor subtypes
Extracellular
Intracellular
Plasma membrane
Cl- ions
Hyperpolarization
Individual subunit
Five subunits combine to form achannel through the membrane
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Subunit class isoformsalphabeta
gammadelta
epsilonpi
rho
1-6l-41-4111
1-3
α1β3γ2
α2β3γ2α3β3γ2
α5β3γ2
α6βxγ2
α6βxδ
α1α6βγ2
α4βxγ2
α4βxδα2β1γ1θ
α2β1γ1αxβxε
αxβxγ3 α1α3βxγ2
Subunit composition
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Subunit compositionpreferred pentameric combination:2 alpha, 2 gamma, 1 beta, or2 alpha, 2 beta, 1 gamma
alpha(1, 2, 3 or 5)
beta
alpha beta orgamma
gamma 2pore
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Distribution of subunits in the brain
Different subunits have distinctive patterns of distributionin the brain
alpha-1 subunit predominantly in the cerebellum
For example:
gamma-1 subunit predominantly in amygdala and septum
The stoichiometry (subunit combination) of GABAAreceptor subtype probably varies among different brainregions
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The sensitivity profile of a GABAA receptor to differentbenzodiazepenes depends on the identity of its alphasubunits.
Differential drug sensitivity
For example:
The common benzodiazepines bind to GABAA receptorsthat contain alpha-1, alpha-2, alpha-3 or alpha-5 subunits(not alpha-4 or alpha-6)Zolpidem and zaleplon are specific for receptorscontaining the alpha-1 subunitReceptors containing the gamma-1 subunit have lowaffinity for most of the benzodiazepine site ligands
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Different drug actions may be mediated bydifferent GABAA receptor subtypes
Transgenic - ‘knock-in’ mouse
GABAA receptor with‘wild-type’ alpha-1subunit
Diazepam-sensitive
GABAA receptor withmutant alpha-1subunit
Diazepam-insensitive
The benzodiazepine binding site is made up withresidues from the α and γ subunits
Not all GABAA receptors bind benzodiazepines
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Effects of Diazepam
Sedation
Memory impairment
Anticonvulsant activity (suppress tonic seizures)
Myorelaxant activity (muscle-relaxing effect)
Motor impairment (uncoordinated movement)
Anxiolytic effect
Potentiates the sedative effects of ethanol
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Summary
Knock-in mice resistant to sedative and amnesic effects, andpartially resistant to anticonvulsant effects of diazepam
Myorelaxant, motor control impairment, ethanol-potentiating and anxiolytic actions of diazepam notchanged in knock-in mice
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Conclusion
The sedative, amnesic and some of the anticonvulsiveeffects of diazepam are mediated by GABAA receptorsthat contain the alpha-1 subunit
The other effects of diazepam are mediated by GABAAreceptors that contain the alpha-2, alpha-3 or alpha-5subunits
The selective sedative effect of zolpidem andzaleplon may be due to their specificity forGABAA receptors that contain the alpha-1 subunit
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Another mechanism of selective drug effects :partial BZD agonists
(newer agents)
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Benzodiazepine receptor partial agonistsAnxiolytic, but less sedation
motor impairmentdependencetolerance
than diazepam
AbecarnilAlpidem – withdrawn in Europe – hepatotoxicityBretazenilSuridoneImidazenil
None available clinically in USA
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Main points
Many anxiolytics and sedative/hypnotics act at GABAAreceptors
Different GABAA drugs have different spectra of effects
Selectivity
Mode of action
Partial agonists
Receptor subtypes, stoichiometry