Barbiturate and Benzodiazepine

BARBITURATE AND BENZODIAZEPINE POISONing
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Barbiturates
Depressants of the central nervous system (CNS) that impair
or reduce the activity of the brain by acting as a Gamma
Amino Butyric Acid (GABA) potentiators.
As an unfortunate fallout, barbiturate overdose became fairly
common so much so that it constituted one of the leading
causes for self-induced mortality (suicidal or accidental
ingestion) in the western countries, and to a great extent in
india also.
The increase in the abuse of barbiturates may be due to the
popularity of stimulating drugs such as cocaine and
methamphetamines.
The barbiturates ("downers") counteract the excitement and
alertness obtained from the stimulating drugs.
Classification
Longacting:(durationofaction612hrs)
barbitone,phenobarbitone,mephobarbitone
Intermediateacting:(durationofaction36hrs)
Amylobarbitone,butobarbitone,aprobarbitone,
amobarbitone
Shortacting:(durationofaction<3hrs)
Pentobarbitone,secobarbitone,hexobarbitone
Ultrashortacting:(durationofaction<1520
min)
Thiopentone
Uses
1.Sedativehypnotic(especiallyintermediateand
shortactingbarbiturates)
2.Anticonvulsant(especiallylongacting
preparation)
3.Inductionofanaesthesia(thiopentone)
4.Antidoteforconvulsantpoisons.
5.Anxietydisorders
6.Musclerelaxant
7.Sleepdisorders
MechanismofAction
BarbituratespotentiatetheeffectofGABAbybindingtotheGABAA
receptoratanearbysiteandincreasingthechlorideflowthroughthe
channel.
BarbituratesalsoblocktheAMPAreceptorwhichissensitivetoglutamate,
theexcitatoryneurotransmitter.
GlutamateperformstheoppositeeffectfromGABArestrictingionflowand
increasingthetransmembraneactionpotentialoftheneuron.
ByblockingthisactionBarbituratesservetoincreasethedurationofthe
receptorresponsetoGABAandextendthedepressedconditionofthecell.
GABAbindingsite
Barbituratebindingsite
GABA
MechanismofAction
Bindswithbenzodiazepinereceptors.
EnhancesbindingofGABAwithits
receptors
OpensClionchannels.
IncreasesInfluxofClions
Causeshyperpolarization
Inhibitsformationofactionpotential
Inhibitionofneuronalfiring
Introduction to GABA
GABA is the main inhibitory neurotransmitter in the brain.

GABA is formed from glutamate , by the action of GAD
(glutamic acid decarboxylase ). Its action is terminated
mainly by deamination , catalysed by GABA-transaminase.
There are two types of GABA receptor ,
GABAA and
GABAB
Neusteroids,includingendogenousprogesterone
metabolites,andother
CNSdepressants,suchasbarbiturates,which
facilitatetheactionofGABA
GABABreceptors
TheseareGproteincoupledreceptors,linkedto
inhibitionofcAMPformation.
Theycausepreandpostsynapticinhibitionbyinhibiting
Ca2+channelopeningandincreasingk +conductance.
BaclofenisaGABABreceptoragonist,usedtotreate
spasticity.GABABantagonistarenotyetinclinicaluse.
GABAAreceptor:mainlyoccurspostsynaptically,and
directlycoupledtochloridechannels,openingofwhich
reducesmembraneexcitability.
MuscimolisaspecificGABAAagonistandtheconvulsant
.
Bicucullineisanantagonist.
OtherdrugsthatinteractwithGABAAreceptorand
channelinclude:
Benzodiazepines
Glycineisaninhibitorytransmittermainlyinthespinal
cord,actingonitsownreceptors,whichfunctionally
resembletheGABAAreceptor.
SignandSymptoms
1stStage
Excitement
Talkativeness
Hallucination
Confusion
LackofCoordination
2ndStage:Unconsciousness.Pupilfixed.
Respirationslow.Reflexesarediminished.
3rdStage:Coma
CLINICALFEATURES
Atlowerdoses,areductioninrestlessnessand
emotionaltensionoccurs.
Atincreasinglyhigherdoses,sedationisfollowedby
increasinglevelsofanesthesiaandeventuallydeath.
Inlargeoverdose,thereisaCNSdepressionranging
fromlethargytocoma,hypotension,pulmonary
edema.
Italsocauseshypothermiaandventilatory
depression,pupilsareusuallyconstricted.
Withphenobarbitolsignsoftoxicityusuallyappear
serumconcentrationexceedsover4mg/dl.
Pharmacologyofbarbiturates
1.CNS:confusion,vertigo,ataxia,slurredspeech,coma.
Hypothermiaiscommon.
2.EYE:pupilsareatfirstconstricted,butlatertheydilate.
3.CVS:tachycardia,hypotension,circulatoryfailure.
4.RESPIRATORYSYSTEM:slow,sighingrespirations
progressingtorespiratoryfailure.
5.SKIN:cold,clammy,cyanotic.Bullouslesionsoccurina
asmallpercentageofcomatosecases,seencommonlyonthe
fingersandmedialaspectsofkneesandankles.Theyare,
however,seenincomaduetootherpoisonsalso,e.g.carbon
monoxide,amitriptyline,methadone,meprobamate,
nitrazepam,etc.
Toxicity
1. Overdosedeathduetorespiratory
failure
2. Pupildilated
3. Pulseweakandrapid
4. Reflexdisappear
5. Skincoldandcyanotic
Giveartificialrespirationwith100%
O2
Chronicpoisoning:resultsfromregular
intakeoflargedoses
Andismainlycharacterisedbysomnolence,
confusion,slurredspeech,etc.abrupt
withdrawalcanprovokeanabstinence
syndromecomprisinganxiety,agitation,
confusion,tremor,ataxia,convulsions,
delusionsandhallucination.
Thereisalsofrequently,insomniaand
vomiting
TREATMENT
Respiratorydepressionmustbetreatedwith
oxygenadministration,intubationandassisted
ventilation.
IVfluids(Ringerslactateinhypotensivecases).
Stomachwash(canbedoneupto8hourspost
ingestion).
Activatedcharcoal(1gm/kg),followedbya
suitablecathartic.
Diuretics
Forcedalkalinediuresis(notveryusefulin
intermediateandshortactingbarbiturates).
haemodiallysis(forlongacting)and
haemoperfusion(forintermediateandshort
actingbarbiturates).
Supportivemeasures.
Forchronicpoisoning,gradualwithdrawal
mustbeundertakentogetherwith
symptomaticmanagementofadverse
manifestations.
LethalDoses
1gm,forshortacting
2gm,forintermediateactingand
3gm,forlongactingbarbiturates
FatalBloodLevels
Fasteracting23mg/100ml
Longacting48mg/100ml
BENZODIAZEPINES
Benzodiazepines
Introducedin1960.
Sedativehypnoticdependingondoseandcompound.
Minortranquillizers.
Mostwidelyusedinhumanlessinveterinarypractice.
Moreeffectiveandsafeascomparedtobarbiturates
Theyhavehightherapeuticindex.
Theseareamongthemostcommonlyprescribeddrugstodayinindia,
andaremainlyusedtorelieveanxiety.Fortunately,theyarerelatively
safedrugsandrarelycausetoxicity.
Uses
Anxiolytic:diazepam,lorazepam,
oxazepam,alprazolam
Sedativehypnotic:flurazepam,
nitrazepam,triazolam
Anticonvulsant:Diazepam,clonazepam
Musclerelaxant:Diazepam
Benzodiazepines
Nonbenzobenzo
Benzodiazepines
zolpidem(Ambien
diazepam(Valium))
buspirone(BusPar
midazolam(Versed))
alprazolam(Xanax)
lorazepam(Atiavan)
triazolam(Halcion)
Barbiturates
Subgroup Prototype Typical
Indication
Ultra-short thiopental Anesthesia
acting (Pentothol)
Short acting secobarbital Insomnia
(Seconal)
Long acting phenobarbital Seizures
(Luminal)
Modeofaction:
Thesecompoundsactbystimulatingthe
GABAAreceptors,therebyopeningupthe
chlorideionchannelinthereceptorcomplex,
resultingintheincreasedconductionof
chlorideionacrossthenervecellmembrane.
Thislowersthepotentialdifferencebetween
theinteriorandexteriorofthecell,blocking
theabilityofthecelltoconductnerve
impulses.
GABAARhavingtwosubunits(16)
Twosubunits(13)
Onesubunit(13)
2,3receptorsareresponsibleforanxiolyticaction.
2isassociatedwithriskforalcoholdepndence,nicotine,cannabis
1,forsedativeactionandinparttheanticonuvulsantactionare
mediated.
4,6subunitsarecompletelyinsensitevetoBenzodiazepines.
currentresearchinthisarefocusedmainlyonproducing
selectiveagonistasanticonvulsantwhichlackthesideeffectsof
olderdrugssuchassedation,amnesia.
Signsandsymptoms
Acutepoisoning
Sedationandsomnolence
Diplopia
Dysarthria
Ataxia
Amnesia
Chronicpoisoning
Longterm,highdosetherapy(e.g.30to40mgofdiazepamdaily),
mayproducewithdrawalreactionwhenthedrugisabruptly
stopped.
Symptoms:
anxiety,
Insomnia,
Headache,
musclespasm,anorexia,
Vomiting,
Tremor,
Weakness,etc.
rarely,theremaybeconvulsionsandpsychiatricdisturbance
Treatment
Decontamination,(stomachwashor
emesis,medicinalcharcoaland
cathartics).
Doxapram(100mg,IV)and
physostigminehavebeensuggestedas
antidotes,butserioussideeffectslimit
theiruse.
Themodeofactioniscompetitive
antagonism.
FLUMAZENIL
Flumazenil (Romazicon) is a specific drug that acts by competitively
blocking benzodiazepine receptors thereby preventing benzodiazepine-
receptor interactions.
Flumazenil'shalflifeisshorterthanthoseexhibitedby
benzodiazepinesandasaresultitwouldbepossibletoreverse
benzodiazepinesmediatedrespiratorydepressiononlytohaveit
reoccuruponflumazenil'selimination.
Consequentlyeitherrepetitiveflumazenildosingorcontinues
infusion(0.51ug/kg/min.)mayberequiredtoensuresustained
recoveryfrombenzodiazepinesmediatedeffects.
Flumazenilreversaltendstohaveagreatereffectonrespiratory
depressionandsedationthanonbenzodiazepineamnestic
properties.
Supportivemeasures.dialysisisnotuseful
Forwithdrawalreactioninchronicabuses,
diazepamitselfisgivenIV5mgeveryfew
hoursandthentaperedoff.
Antidepressantsmayhelp.
Propranolol(10to40mg,6thhourly)is
calimedtobeeffectivebysomeinvestigators.
Benzodiazepinesvs.Barbiturates
Criteria BZ Barb.
Relative Safety High Low
Maximal CNS depression Low High
Respiratory Depression Low High
Suicide Potential Low High
Abuse Potential Low High
Antagonist Available Yes No
Effects of benzodiazepines and
barbiturates on GABA
Both drugs bind to GABAA receptor subunits, but at
different sites.
Neither one binds to the agonist site
Benzodiazepines increase the frequency of channel
opening, but do not alter conductance or duration of
opening
Barbiturates prolong the duration of channel opening
Reference
VVPillay,ModernMedicalToxicology
3rdeditionpgno:193196,217220.
KDTripathi,EssentialsofMedical
Pharmacologypgno:391
H.P.Rang,M.M.Dale,J.M.Ritter,4th
EditionPharmacologypgno:479
www.ncbi.nlm.nih.gov
www.williams.edu
Thankyou

Barbiturate and Benzodiazepine

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BARBITURATE AND BENZODIAZEPINE POISONing

GABA is the main inhibitory neurotransmitter in the brain.

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