Download anxiety

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probably among most
common symptoms
for which drug
pharmacotherapy is
prescribed
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Symptoms of
Anxiety
Update as of 2007
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1 in 4 people have met the diagnostic criteria for at
least 1 anxiety disorder
12 month prevalence rate of 19.1%
women have higher prevalence rate than men
affecting approximately 40 million American adults
ages 18 and older
May occur with variety of medical or psychiatric
illness
◦ symptoms similar to anxiety disorders
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hyperthyroidism
hypothyroidism
vitamin b12 deficiency
certain tumors produce E
certain brain lesions (postenecphalitic states)
cardiac arrhthymia – can produce signs
hypoglycemia
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stimulants
anorectics
analgesics
anticholinergics
hallucinogens
sympathomimetics
steroids
neuroleptics
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caffeine
fenfluramine
salicyclates
diphenhydramine
cannabis
ephedrine
prednisone
haloperidol
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GABA
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NE
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5HT
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now recognized as commonly occurring
disorder affecting ~ 2% of the population
1 in 50 of US population
symptoms worsen when coexisting symptoms
of depression or other comorbid conditions
exist
depression is found in 1/3 of patients upon
presentation and 2/3 in lifetime
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Developed from preclinical studies with
animal models
Peripheral SNS activation
◦ Peripheral NS activity are not peculiar to anxiety
disorders; not necessarily correlated with
subjective experience of anxiety although there are
clear exceptions!!!!
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Social interaction
test
Plus maze
Novelty stress
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Anxiolytic drugs
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Probably first treatment –
◦ alcohol
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first agent introduced first as sedative and
soon thereafter as hypnotic
◦ bromide – mid 19th century
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Barbital – introduced in 1903
◦ phenobarbital in 1912
◦ over 2500 barbiturates synthesized and tested in
early 1900’s
◦ ~ 50 distributed commercially
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Currently – most commonly employed
medicinal treatments for clinical anxiety are
antidepressants (SSRIs and SNRIs) BZ and
buspirone
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Benzodiazepine (BZD) = a drug of a specific
chemical structure.
◦ Thus, drugs are structurally, not
pharmacologically, classified.
Figure 6.1 Structures of
some benzodiazepines
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Benzodiazepine (BZD) = a drug of a specific
chemical structure.
◦ Thus, drugs are structurally, not
pharmacologically, classified.
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All are GABA-agonists, increasing chloride
influx into neurons.
Any drug that activates the benzodiazepine
receptor is a benzodiazepine receptor
agonist (BZRA).
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BZD –
◦ chlordiazepoxide (Librium) – introduced in1961
and ushered in use of BZ
◦ all BZ have sedative, anxiolytic, anticonvulsant,
muscle relaxants and amnestic effects
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currently ~ 15 BZ available on the market
◦ most that have reached the marketplace were
selected for high anxiolytic potency (relative to
depression of CNS)
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Diazepam (Valium)
Chlordiazepoxide (Librium)
Flurazepam (Dalmane)
Chlorazepate (Tranxene)
Lorazepam (Ativan)
Quazepam (Dormalin)
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Clonazepam
(Klonopin)
Oxazepam (Serax)
Temazepam (Restoril)
Triazolam (Halcion)
Alprazolam (Xanax)
Estazolam (ProSom)
Halazepam (Paxipam)
Midazolam (Versed)
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Several BZ are first biotransformed into
intermediate, pharmacologically active
products
metabolized extensively by CYP450 enzymes
active drug
active metabolites
Diazepam
Chlordiazepoxide
Chlorazepate
Halazepam
Prazepam
nordiazepam
oxazepam
inactive
metabolite
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drugs active at BZ site divided into 4
categories (based on ½ life)
◦ ultra short acting
◦ short-acting (1/2 life less than 6 hours) – includes
triazolam, zopiclone
◦ intermediate (1/2 life – 6 – 24 hr)
◦ long-acting (greater than 24 hr) – flurazepam,
diazepam, quazepam
Trade Name
Generic
Dosage f
Active
metabolite
½ life
Valium
diazepam
Oral, p
Yes
Nordiazepam
24 (20-50)
60 (50-100)
Librium
chlordiazepoxi Oral
de
Yes
nordiazepam
10 (8-24)
60 (50-100)
Dalmane
flurazepam
yes
80 (70-160)
oral
Trade Name
Generic
Dosage f
Active
metabolite
½ life
Ativan
lorazepam
Oral, p
no
15 (10-24)
Klonopin
clonazepam
Oral
no
30 (18-50)
Dormalin
quazepam
oral
yes
desalkylfluraz
epam
35(25-50)
80 (70-160)
Trade Name
Generic
Dosage f
Active
metabolite
½ life
Versed
midazolam
injection
no
2.5 (1.5-4.5)
Serax
oxazepam
oral
no
8 (5-15)
Halcion
triazolam
oral
no
2.5 (1.5-5)
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Treatment of debilitating anxiety
Treatment of insomnia
Treatment of muscle spasm and “tension”
Symptomatic treatment of panic attacks
Nonspecific treatment of anxiety that may
accompany other psychological disorders
Treatment of alcohol dependence
presurgical txt
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frequent use is likely a reflection of their
effectiveness, their rapid onset of anxiolytic effect
and their tolerability
therapeutic tolerance?
◦ probably not
Advantages of BZs
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SAFE! Very low toxicity, unlike barbiturates or
alcohol
Do not induce metabolic enzymes; do not
accelerate their own metabolism.
Act on CNS and peripheral organs (e.g., liver)
are not impaired.
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BZ side effects –
◦ most common include sedation and
impairment of cognition and fine motor function
(motor appears more impaired),
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BZDs, even at low, normal clinical doses impair
real-world driving performance.
◦ 1 mg alprazolam impaired driving comparable to a
BAC of 0.15 mg %
◦ Women more affected than men
◦ Significant detrimental effects on driving, memory,
and divided attention
◦ Clinical implications are enormous – who is
responsible?
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Source: Verster, et al. (2002). Effects of alprazolam on driving ability,
memory functioning and psychomotor performance: A randomized,
placebo-controlled study. Neuropsychopharmacology, 27, 260–269.
CONCLUSION: Benzodiazepine users were found to be at a significantly
increased risk of motor vehicle collisions compared to nonusers, and these
differences may be accounted for by a difficulty in maintaining road position.
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BZ side effects –
◦ most common include sedation and
impairment of cognition and fine motor function
(motor appears more impaired),
◦ in elderly (particularly) – common cause for
confusion, delirium and falls (with fractures)
Figure 6.4 Concentration curve and clinical end points for young and
elderly male volunteers receiving continuous infusion of midazolam
Julien: A Primer of Drug Action, Eleventh Edition
Copyright © 2008 by Worth Publishers
Am J Geriatr Psychiatry. 2008
Aug;16(8):686-92.
CONCLUSIONS: Benzodiazepine exposure in the elderly increases the risk of hip
fractures. This is true even with modest dosage, short-acting agents and short-term
exposures. Clinicians should prescribe benzodiazepines judiciously with the elderly to
minimize drug-related hip fractures.
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BZ side effects –
◦ most common include sedation and
impairment of cognition and fine motor function
(motor appears more impaired),
◦ in elderly (particularly) – common cause for
confusion, delirium and falls (with fractures)
◦ confusion, anterograde amnesia
Amnesia
 more likely observed if high doses; or
adm iv
 Anterograde
 Primarily for episodic memory
 May be useful for presurgical preparation.
 May not be a problem if taken for sleep.
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Dependence/withdrawal
Abuse
Potentiation of other sedative-hypnotics
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BZ withdrawal – cannot discontinue suddenly
–
those predisposed to substance abuse have
increased risk for BZ abuse
lack antidepressant efficacy and can induce
or amplify comorbid depression
rebound anxiety
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1998 – advocates initiating pharmacotherapy for
panic disorders with SSRI and BZ for acute anxiety
management rather than long-term treatment
BZ continue to be prescribed frequently for a
variety of anxiety disorders (Stevens and Pollack,
2005 review)
alprazolam – single most prescribed anxiolytic
agent
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Not anxiolytic
Most bind to GABA1A receptor.
Currently 3 are on the market.
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Currently 3 on the market:
◦ Zolpidem (Ambien):
◦ Zaleplon (Sonata):
◦ Eszopiclone (Lunesta):
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zolpidem (Ambien)
◦ binds to GABAA receptor
◦ acts mostly as a sedative (rather than anxiolytic)
◦ Half-life of 2–2.5 hours.
◦ Overdoses not fatal even at very high doses.
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definition: binds and activates a receptor,
but with only partial efficacy at the receptor
relative to a full agonist
partial GABAA agonist advantage of partial agonist
◦ less withdrawal; less physical dependence;
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Zaleplon (Sonata)
◦ nonBZ agonist binding to GABA1A
◦ released late 1999 for clinical use as a hypnotic
drug
◦ ½ life is less than 1 hr; only about 30% reaches
bloodstream
◦ does not appear to affect psychomotor function,
driving… the next morning
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Eszopiclone (Lunesta)
◦ Similar to zolpidem and traditional BZs.
◦ Long half life (5–7 hours), increased risk of nextday sedation.
◦ Only non-benzodiazepine BZRA approved for
longer-term use in treating insomnia.
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FDA 2007 requirement of warning of
“sleep driving”
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FDA 2007 requirement of warning of
“sleep driving”
◦ Driving while not fully awake and having no
memory of the event.
◦ Extends to making phone calls, preparing and
eating food, etc?
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Blood levels of drug sufficient to block
memory formation in absence of sleep
state.
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beta blockers
◦ propanolol – reduces physiological symptoms of
arousal (useful for subtypes of anxiety like
performance anxiety, social anxiety, etc)
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Anxiety may result, in part, from defects in
serotonin transmission.
All six clinically available SSRI
antidepressants are widely prescribed for
anxiety disorders.
◦ Actually considered to be first choice drugs for
anxiety.
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unique class of anxioselective drugs
does not cause sedation, hypnosis,
anticonvulsant effects or muscle relaxation
takes 3 – 6 weeks to achieve maximum
anxiolytic effects
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mechanism of action of buspirone is not clear
In vitro preclinical studies - has a high affinity
for serotonin (5-HT1A) receptors (probably
works on both pre and post)
has no significant affinity for BZ receptors
doesn’t affect GABA binding
may bind to DA2?
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SSRIs and SNRIs
◦ first line treatment for GAD
◦ paroxetine (Paxil, Paxil CR), escitalopram (Lexapro)
◦ venlafaxine (Effexor XR) – first FDA approved drug
for both depression and GAD
 both an SSRI and an SNRI
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tricyclic antidepressants
◦ can be used for treating panic disorders
 imipramine, desipramine, amitrypityline, trazadone
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MAO inhibitors -
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gabapentin (Neurontin)
◦ anticonvulsant – used to treat social anxiety
disorder
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Retigabine –
◦ novel antiepileptic drug that opens K+ channels reduces anxiety in rodent models
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pregabalin
◦ GABA agonist –
◦ may be useful for GAD
◦ new agent -
http://www.neurotransmitter.net/newdrugs.html
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Ramelteon: a selective melatonin receptor
agonist
◦ Melatonin is regulated by pineal gland on a 24-hour
cycle, with levels increasing towards bedtime.
◦ Nonaddictive
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antidepressants have emerged as more
effective treatments
clomipramine (Anafranil) and SSRIs
buspirone – more often used as adjunct with
SSRIs
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increasingly recognized as prevalent
psychiatric disorder
antidepressants
◦ TCAs and MAOIs; maybe SSRIs