Benzodiazepines 120115103433 Phpapp02

8/16/2019 Benzodiazepines 120115103433 Phpapp02

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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

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Benzodiazepines 120115103433 Phpapp02