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Receptors, Neurons, Systems
Anxiolytic and Hypnotic Clinical Efects
Mechanisms o Sleep and Wakeulness
Selectie and Nonselectie A!ents
Aderse Efects
BENZODIAZEPINESAnd "ther Anxiolytic and Hypnotic
A!ents
Adonis Sfera, MD
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Benzodiazepines Augment theEects of ABA
#$A%A is the main inhi&itory neurotransmitter
in the &rain'
#$A%A neurons are inter(neurons'
#%en)odia)epines au!ment the efect o $A%A'
#*hey exert their action only in the presence o
$A%A + or this reason they are
called positi!e a""osteric modu"ators -AMs.'
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A""osteric Modu"ators#PAMs$ ofABA%A &eceptors
Allosteric sites are all receptor sites /here $A%Aitsel does not &ind'Allosteric modulators can &e positie or ne!atie'
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ABA 'e""s are Inter%neurons
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'ortica" and "im(ic ABA Inter%Neurons are0mplicated in Neurodeelopmental 1isordersschi)ophrenia, autism, and epilepsy.'
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*he 0nterest in %en)odia)epines
0ncreased oer the -ast 1ecade
SE3EC*040*56
7or diferent $A%A neurons
7or diferent receptor su&types
7or the tonic $A%A 8rin!
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Su(units
$A%A A receptors containin!alpha 9 su&units are inoled insleep'
$A%A A receptorscontainin!
alpha : or alpha ; su&unitsare
inoled in anxiety'
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A"pha * Se"ecti!e +)pnotics %Za"ep"on and Zo"pidem
*he hypnotics )aleplon and )olpidem &ind selectiely to $A%A(A receptorsthat contain the a"pha * su(unit #s"eep$' *his su&unit is important orsedation and possi&ly or anticonulsant and amnesic actions'
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Eisting Benzodiazepines are Non%se"ecti!e
%en)odia)epines &ind to $A%A(A alpha su&units6 a"pha *, a"pha
-, a"pha . and a"pha /0 Each o these su&units is associated /ith diferent efects, and thus
&en)odia)epines not only cause sedation &ut are also anxiolytic,cause muscle relaxation, and hae alcohol potentiatin! actions'
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Se"ecti!it) for Phasic ABA Inhi(ition %A!oiding Addiction
%en)odia)epine sensitie $A%A A
receptors contain !amma and
a"pha #* through .$ and a"pha /
su(units are intra(synaptic and
mediate phasic inhi&ition tri!!ered
&y peak concentrations osynaptically released $A%A'
$A%A A receptors containin!
a"pha 1, a"pha 2 , gamma * orde"ta su&units are located
extrasynaptically and
re!ulate tonic inhi&ition
tonic inhi&ition is not addictie.'
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AN3IO456I' E77E'68 %en)odia)epines inhi&it theactiation o amy!dala, &y &indin! at $A%A( A receptors inthe am)gda"a'
+5PNO6I' E77E'66 %en)odia)epines promote sleep &y&indin! at $A%A(A receptors in the 94PO, causin!sleepiness'
enzo azep nes are no ) cas
:e"" as +)pnotic Drugs
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Acti!ation of the Am)gda"a ()the En!ironment
Monoamines rom the locuscoeruleusactiate amy!dala causin! anxiety,
panic attacks, tremors, s/eatin!,tachicardia, hyperarousal andni!htmares'
%en)odia)epines inhi&it actiationo amy!dala silence the shout oamy!dala.'
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Shout of Am)gda"a
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*raumatic memories stored in the hippocampus can actiate theamy!dala, causin! the amy!dala in turn to actiate thehippocampus and !enerate a ear response,&EE3PE&IEN'IN-*S1.'
&eeperiencing % Acti!ation ofthe Am)gda"a () Inner 'ues
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the Am)gda"a () the+ippocampus
7ear acti!ated am)gda"a0
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+)pnotic Eect of Benzodiazepines
Benzodiazepines are a"so h)pnotic drugs0
*he hypothalamus containsthe s"eep and :a;efu"ness
promoters6
94PO sleep promoter.
6MN /akeulness promoter.'
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Arousa" Spectrum *he state o arousal is more complex than
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=hat >eeps ?s A:a;e@
+istamine ;eeps the(rain a:a;e'
+IS6AMINE #6MN$
Histamine promotes the CA3M/akeulness that helps pro&lem
solin!, creatiity and co!nitionunlike the monoamines .'
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'reati!e =a;efu"ness % +istamine
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6u(eromammi"ar) Nuc"eus #6MN$ of+)potha"amus is the =a;efu"ness Promoter#the coee% house of the (rain$
*MN o hypothalamus contains histamine producin! neuronsthat are acti!ated &y !lutamate and inhi(ited &y $A%Aand %en)odia)epines'
*hese neurons are the /akeulness promoter'
#3ateralhypothalamuscontainsoreinh)pocretin neurons thatpromote /ei!ht loss
in addition to/akeulness'
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9entro%4atera" Preoptic Nuc"eus ofthe +)potha"amus#94PO$ % the
S"eep Promoter43-" nucleus contains $A%A neurons that
inhi&it *MN and thus promote sleep'
%en)odia)epines au!ment the action o $A%Ain 43-" nucleus'
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6he Ba"ance of S"eep and=a;efu"ness
*MN SCN43-"
IN6E&NA4 '4O'>8Suprachiasmaticnucleus o thehypothalamus +6+ES=I6'+ actiated
&y li!ht, melatonin.'0t can promote either
=A>E P&OMO6E&6 *u&eromammillarynucleus +*MN(o thehypothalamuspromotes /akeulnessproduces histamine .
S4EEP
P&OMO6E&84entrolateralpreoptic area +43-"(o thehypothalamuspromotes sleep
produces $A%A.
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M) Net 'up of 'oee
Skinny Histamine Macchiato /ith orexinsprinkles
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Eogenous ABA Does Not 'rossthe B"ood Brain Barrier#BBB$
$A%A is produced in the $A%A(er!ic neurons rom theexcitatory neurotransmitter g"utamate &y the en)yme$A1 !lutamic acid decar&oxilase.'
SA4E8*-0CC
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Benzodiazepines 7DA Indications
0n addition to anxiety, &en)odia)epines areindicated or muscle tension, insomnia, status
epilepticusdia)epam., myoclonic
epilepsyclona)epam., preoperatie anesthesia,
and alcohol /itdhra/al'
*/o &en)odia)epines6 alpra)olam andlora)epam hae 71A indication or aniet)
associated :ith depression0
Clona)epam and Alpra)olam are indicated in the
treatment o panic disorder'
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Benzodiazepines Ad!erse Eects
Sedation
3ethar!y
1ependency>Withdra/alRespiratory depression
-ossi&le co!nitie impairment'
Sae in oerdose6 up to . times the normal daily dose' ?sual
symptoms o oerdose include sedation, dro/siness, ataxia, andslurred speech' May result in respiratory depression incom&ination /ith other CNS depressants' Mana!ement includes!astric laa!e, orced emesis, and assisted entilation'
1ru! interactions69' dru!s that increase &en)odia)epine leels include -@B;A@
inhi&itors, ketocona)ole, ucona)ole, nea)odone'
:' dru!s that decrease &en)odia)epine leels include -@B;A@inducers such as car&ama)epine'
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=hat are Pro%Drugs@
*hree &en)odia)epines are pro(dru!s,theyare inactie, &ut orm actie meta&olites inthe &ody.6
pra)epam,
clora)epate
hala)epam
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Ocar(azepine#pro%drug$ is 'on!ertedto 4icar(azepine #acti!e drug$
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4isdeamfetamine# 9)!anse$ %a Pro%Drug
3isdexametamine a pro(dru!. is conerted inthe
intestin to d(amphetamine actie orm.'
F4isdeamphetamine is the on") drug that has 7DAappro!a" for adu"t AD+D0
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Benzodiazepines % Su(c"asses
-%;eto chlordia)epoxide, clona)epam, clora)epate, dia)epam,hala)epam, pra)epam, and ura)epam.'
*he :(keto dru!s and their actie meta&olites are oxidi)ed in the lier,and &ecause this process is relatiely s"o:, these compounds ha!e
re"ati!e") "ong ha"f%"i!es0
.%h)dro)lora)epam, oxa)epam, tema)epam.
*he ;(hydroxy compounds are meta&oli)ed ia direct conDu!ation /itha !lucuronide radical, a process that is more rapid than oidationand does not in!o"!e the formation of acti!e meta(o"ites'
6riazo"o alpra)olam, adina)olam, esta)olam, and tria)olam.
*he tria)olo compounds are also oxidi)ed, ho/eer they hae a more
"imited acti!e meta(o"ites and thus shorter ha"f%"i!es0
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7ie &en)odia)epines are 71A approed or insomnia are8
Gurazepam and Huazepam, ultra(lon! hal(lies.
triazo"am ultra(short hal(lie.
estazo"am and temazepam moderate hal(lies.'
7DA Appro!ed Benzodoazepine +)pnotics
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Benzodiazepine Properties
*he efects o &en)odia)epines depend ontheir properties6
9' hal(lie
:' liposolu&ility
;' receptor aFnity
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3iposolu&ility
Hi!hly lipophilic &en)odia)epines such asdia)epam enter the &rain more Guickly,
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&e"ati!e &eceptor Anit)
*he hi!her their aFnity or $A%A(A receptors,the more intense /ithdra/al symptoms theycause'
Hi!h potency &en)odia)epines such aslora)epam and alpra)olam hae hi!h receptoraFnity + intense :ithdra:a" s)mptoms0
"xa)epam has lo/ receptor aFnity + fe:er:ithdra:a" s)mptoms0
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Memor) Impairment #fact or m)th$
3ucki et al' 9IJ. conducted a study on lon!(term&en)odia)epine treatment' 0t fai"ed to sho/si!ni8cant co!nitie impairment on psychometrictests'
*he most recent controlled study in this area fai"ed to 8nd si!ni8cant lon!(term co!nitie efects oralpra)olam KR in panic disorder patients $ladsDo etal' :BB9.'
0n spite o these studies some inesti!ators &elieethat co!nitie impairment can occur, particularly in
elderly patients'
' M I i t
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'ause Memor) Impairmentin E"der")
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+o: Addicti!e are Benzodiazepines@
Ho/ lon! does one hae to take a &en)odia)epine&eore /ithdra/al is seen /ith discontinuationL
Studies in animals hae indicated that
&en)odia)epines can reinorce use and can producephysical dependence and tolerance'
Aaila&le data seem to reeal that &en)odia)epinesare rarely sou!ht ater or craed in the sense that
heroin or cocaine are' Rather, they are used as part oa polysu&stance a&use pattern to modulate the efectso primary dru! o a&usee'!' cocaine. or as a &ackupdru! /hen more euphoriant dru!s are not aaila&le'
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Benzodiazepines Potentiate the Eect of A"coho"
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6apering o BenzodiazepinesRecommended reduction rate6 no more than 9B per day'
Common symptoms o /ithdra/al include Jitteriness,aniet), pa"pitations, c"amminess, s:eating, nausea,confusion and heightened sensiti!it) to "ight andsound0
Seizures represent the most /orrisome o /ithdra/alreactions, &ut ortunately they are rare'
Sei)ures /ith a&rupt dia)epam /ithdra/al occur a&out /%Kda)s ater the dru! is stopped'
With shorter actin! dru!s e'!' lora)epam, alpra)olam./ithdra/al symptoms emer!e more rapidly( - or . days'
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Dicu"t =ithdra:a"
7actors that make &en)odia)epine /ithdra/almore diFcult include higher dai") dose,shorter ha"f%"ife, "onger duration of prior
(enzodiazepine therap), and more rapidtaper'
At the patient leel, a dia!nosis o panicdisorder, higher pretaper "e!e"s ofaniet) or depression, more persona"it)disorder, and concomitant a"coho" orsu(stance a(use make taperin! morediFcult
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Panic 'ontro" 6reatment #'B6 L !er) s"o: taper$
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-artial a!onists that are se"ecti!e for the a"pha - or. su(units o the $A%A(A receptors ( anxiolytic /ithoutcausin! sedation and /ithout causin! dependence'
Inhi(ition of the ABA transporter $A*. has &eensho/n to proide anxiolytic efects like theanticonulsant *0A$A%0NE.'
0t is possi&le that $A%A(% receptors may hae a role in
anxiety, thus positie modulators o those receptors arepotential therapeutic a!ents the only $A%A(% a!ents/e use today are %acloen and sodium oxy&ate.'
No!e" ABA%A Anio")tic Drugs
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+app) 6ha;sgi!ing
?pon a da) apart,
6o praise the 4ord :ith feast and songIn than;fu"ness of heart0Arthur $uiterman, The First Thanksgiving