Cholinergicsand

Anticholinergics
PHL-358-PHARMACOLOGY AND THERAPEUTICS-I

Mr. D.Raju, M.pharm,

Lecturer

CholinergicDrugs

Parasympathomimeticsorcholinomimetics
Stimulateparasympatheticnervoussystemin
samemannerasdoesacetylcholine
Maystimulatecholinergicreceptorsdirectlyor
slowacetylcholinemetabolismatsynapses
(affecttheenzymeacetylcholinesterase)

CholinergicDrugs

UsefulintreatingAlzheimersDisease,
Myastheniagravisandtotxatonyofthe
smoothmuscleoftheGIsystemorurinary
system

CholinergicDrugs

Normalneuromuscularfunction,acetylcholine
bindstonicotinicreceptorsoncell
membranesofmusclecellstocause
contraction
Myastheniagravisautoantibodiespresumably
destroynicotinicreceptors;thus,acetylcholine
lessabletostimulatemusclecontraction.
Resultsinseveremuscleweakness.

CholinergicDrugs
Acetylcholineimportantneurotransmitteraffecting
cognitivefunctioning,memorystorageandretrieval
InAlzheimersdisease(AD),abnormalitiesofthe
cholinergic,serotonergic,noradrenergic,and
glutaminergicneurotransmissionsystems
Incholinergicsystem,patientwithADfoundtohave
lossofneuronsthatsecreteacetylcholine

CholinergicDrugsGIeffects

Acetylcholinestimulatescholinergicreceptors
intheguttopromotenormalsecretoryand
motoractivity
Cholinergicactivityinthegutwillincrease
peristalsisandfacilitatesmovementofflatus
andfeces
Thesecretoryfunctionsofthesalivaryand
gastricglandsalsostimulated

CholinergicDrugsGUeffects

Acetylcholinestimulatescholinergicreceptors
intheurinarysystemtopromoteurination
Resultsincontractionofthedetrusormuscle
andrelaxationoftheurinarysphincterto
facilitateemptyingoftheurinarybladder

Acetylcholine

OneofthemainneurotransmittersoftheANS
isacetylcholine
Acetylcholineisreleasedatpreganglionic
fibersofboththesympatheticand
parasympatheticnervoussystem
Alsoreleasedfrompostganglionicsympathetic
neuronsthatinnervatethesweatglandsand
frommotorneuronsthatinnervatethe
skeletalmuscles

Acetylcholine

Sympatheticandparasympatheticdivisionsof
theANSareantagonistictoeachother
Whenacetylcholineactsonbodycellsthat
respondtoparasympatheticstimulation,it
interactswithtwotypesofcholinergic
receptors:nicotinicandmuscarinic

Acetylcholine

Nicotinicreceptorsarelocatedinmotor
nervesandskeletalmuscle
Stimulationresultsinmusclecontraction

Acetylcholine

Muscarinicreceptorsarelocatedinmost
internalorgans.Thisincludesthe
cardiovascular,respiratory,gastrointestinal,
andgenitourinary.Stimulationofthe
muscarinicreceptorsmayresultineither
excitationorinhibition,dependingonthe
organinvolved.

MechanismsofAction
DirectActing
Cholinergics
Directactingcholinergics arelipidinsoluble
DonotreadilyentertheCNSsoeffectsare
peripheral
Resistanttometabolismby
acetylcholinesterase
Effectsarelongeractingthanwith
acetylcholine

DirectActingCholinergic
Drugscont.
Widespreadsystemiceffectswhenthey
combinewithmuscarinicreceptorsincardiac
muscle,smoothmuscle,exocrineglandsand
theeye

DirectactingCholinergic
Drugs
Effects
Decreasedheartrate,vasodilation,variableBP
effects
IncreasedtoneandcontractilityinGIsmooth
muscle,relaxationofsphincters,increased
salivaryglandandGIsecretions
Increasedtoneandcontractilityofsmooth
muscleinurinarybladderandrelaxationof
thesphincter

DirectActingCholinergic
Drugscont.
Increasedtoneandcontractilityofbronchial
smoothmuscle
Increasedrespiratorysecretions
Constrictionofpupils(miosis)andcontraction
ofciliarymuscle

DirectActingCholinergics

Bethanecol(Urecholine)givenorally.Not
givenIMorIV.
Usedtotreaturinaryretentionduetobladder
atonyandforpostoperativeabdominal
distentionduetoparalyticileus

IndirectActing
CholinergicDrugs
Actionisbydecreasingtheinactivationof
acetylcholineinthesynapsebytheenzyme
acetylcholinesterase
Accumulationofacetylcholinethenoccurs
whichenhancestheactivationofthenicotinic
andmuscarinicreceptors

IndirectActingor
AnticholinesteraseDrugs
cont.
Anticholinesterasedrugsareeitherreversible
orirreversibleinhibitorsof
acetylcholinesterase
Reversibleagentsaresuchdrugs
as:edrophodium(Tensilon).Usedtodiagnose
myastheniagravisandforreversalofnon
depolarizingneuromuscularblockers

Indirectactingagentscont.

Neostigmine(Prostigmine)prototype
anticholinesteraseagent.Usedforlongterm
txofmyastheniagravisandasanantidotefor
tubocurarineandothernondepolarizing
agentsinsurgery.
Poorlyabsorbedorallysorequireslargerdoses
thanwhengivenparenterally.
Candevelopresistancetoitsactionovertime

IndirectActingAgents

Pyridostigmine(Mestinon)isthemaintenance
drugofchoiceforpatientswithMyasthenia
gravis.Slowrelease.

IndirectActing
Reversiblecont.
Physostigmine(Antilirium)only
anticholinesterasecapableofcrossingthe
bloodbrainbarrier.Ismorelipidsoluble.Used
asanantidoteforoverdosageof
anticholinergicssuchas:atropine,
antihistamines,TCA,phenothiazines.Mayalso
beusedintxofglaucoma.

IndirectActingAgents
usedtotreat
Alzheimersdisease
Donepezil(Aricept)saidtodelayprogressionofthe
diseasebyupto55weeks.Doesnotcauseliver
toxicity.
Galantamine(Reminyl)newestkidontheblock
Rivastigmine(Exelon)longacting.Twiceadaydosing.
Tacrine(Cognex)hepatoxic.Elevatedliverenzymes
usu.Within18wks.>inwomen.

SpecificConditions

Distinctionbetweencholinergiccrisisanda
myastheniccrisis
Difficulttoascertainasbotharecharacterized
byrespiratorydifficultyorfailure
Needtodistinguishasrequireopposite
treatmentmeasures

SpecificConditionsCholinergic
vs.Myasthenic Crisis
Myastheniccrisisrequiresmoreanticholinesterase
drugwhereascholinergiccrisisrequires
discontinuationoftheanticholinesterasedrugs
Diagnosiscanbemadebyevaluatingpatientpatient
responsetotheirmedication(s/sonehourafter
medicationoftenischolinergiccrisis,s/s3ormore
hoursaftermedicationoftenismyastheniccrisis

MyastheniaGravis

Ifs/snotclearlyindicativeoftheproblem,
mayhavetointubatepatient,injectdoseofIV
edrophonium.Ifdramaticimprovementin
breathing,diagnosisismyastheniccrisis.If
edrophoniummakess/sworse,thediagnosis
ischolinergiccrisis.Patientmustbeintubated
andassistedwithmechanicalventilationto
performthistest.

ToxicityofCholinergicDrugs

Atropineisthespecificantidotetocholinergic
agents
Atropinereversesonlythemuscariniceffects
ofcholinergicdrugs;heart,smoothmuscle,
andglands.
Atropinecannotreversethenicotiniceffects
ofskeletalmuscleweaknessorparalysisdue
tooverdoseofindirectcholinergicdrugs.

ToxicityofIrreversible
Anticholinesterase Agents
Theseagentsarelipidsoluble
Canenterthebodybytheeye,skin,
respiratorysystemandGItract.
Caseinpoint,organophosphateinsecticides
(malathion,parathion)ornervegases(sarin,
tabun,soman)
Theseagentscauseexcessivecholinergic
stimulation(muscarinic)andneuromuscular
blockade

Anticholinergics

Alsocalledcholinergicblockingagentsor
parasympatholytics
Again,focusisontheparasympathetic
nervoussystem
Parasympatheticsystemactsasarestingand
reparativefunction
Functionsincludedigestion,excretion,cardiac
decelertion,anabolismandnearvision

ParasympatheticNervousSystem
75%ofallparasympatheticnervefibersarein
thevagusnerves
Thesenervessupplythethoracicand
abdominalorgans,whichinnervatetheheart,
lungs,esophagus,stomach,smallintestine,
proximalhalfofthecolon,liver,gallbladder,
pancreasandupperportionsoftheureters

ParasympatheticNervousSystem
Alsosupplythemusclesoftheeyes,lacrimal,
nasal,submaxillary,andparotidglands;
descendingcolonandrectum;lowerportions
oftheureters,bladderandgenitalia
Allareregulatedbyacetylcholineexerts
excitatoryeffectsatnervesynapsesand
neuromuscularjunctions;andinhibitory
effectsatperipheralsitese.g.heart

Anticholinergics

Mostanticholinergicdrugsinteractwiththe
muscarinicreceptorsinthebrain,secretory
glands,heart,andsmoothmuscle
Afewcanalsoaffectthenicotinicreceptors.
Glycopyrrolate(Robinul)isanexample

MechanismofActionandEffects
Actbyoccupyingreceptorsitesat
parasympatheticnerveendings,thereby
leavingfewerreceptorsitesfreetorespondto
acetylcholine
Distributionofreceptorsisbroadsoeffectsof
anticholinergics willbediffuse.

EffectsonBodyTissues

1. CNSstimulationfollowedbydepression,can
resultincomaanddeath(atropine,
antiparkinsons)
2. Decreasedcardiovascularresponsetovagal
stimulationresultingintachycardia.
Increasesvagaltone.Ex.Atropine.
3. Bronchodilationanddecreasedrespiratory
tractsecretions.

EffectsonBodyTissues

AntispasmoticsofGItractduetodecreased
toneandmotility.
Mydriasisandcyclopegia.Normallydonot
increaseIOPbutcautionascanprecipitate
acuteglaucoma.
Cancausedecreasedoralsecretions,
decreasedsweating,relaxationofurinary
bladder

IndicationsforUse

UsesincludeGI,GU,ophthalmicand
respiratorydisorders,bradycardiaandin
Parkinsonsdisease.
Usedpreoperatively

UseInGIDisorders

Helpfulintreatingirritablecolonorcolitis
Usefulingastritis,pylorospasmandulcerative
colitisastheyslowmotility

UseinGUdisorders

Antispasmoticeffectsseeninoveractive
bladderandinurinaryincontinence

Ophthalmology

Mydriaticandcycloplegiaforexaminations
andsurgery

Respiratory

Inbronchospasmwhetherrelatedtoasthma
orCOPD
Atroventveryusefulforitsbronchodilating
effects

Cardiology

Atropineisusedtoincreaseheartratein
symptomaticbradycardiasandhigherblocks

ParkinsonsDisease

Usefulinthosewithminimalsideeffects
ThosewhocannottakeLevodopa
Helpfulindecreasingsalivation,spasticityand
tremors

Preop

Helppreventvagalstimulationandpotential
bradycardia
Reducerespiratorysecretionsaswell

Contraindications

BPH
Myastheniagravis
Hyperthyroidism
Glaucoma
Tachydysrhythmias
Notinsituationswherebydelayingofgastric
emptyingisaconcern

IndividualAnticholinergicDrugs
Atropineprototype.Antidote.Belladonnaalkaloid.
Ipratropium(Atrovent).Usefulinrhinorrhea.Also
excellentbronchodilator.
Scopolamine,similartoatropine.DepressesCNSand
causesamnesia,drowsiness,euphoria,relaxation
andsleep.Alsogoodformotionsickness.Given
parenterally,orallyandtransdermally.

CentrallyActing
Anticholinergics

Benztropine(Cogentin)temporaryusein
Parkinsonsdisease.Usefulfordystonic
reactionscausedbyantipsychotics.
Trihexyphenidyl(Trihexy)alsousedfortxing
EPSbysomeantipsychotics.Contraindicated
inglaucoma.

UrinaryAntispasmotics
Flavoxate(Urispas)relievesdysuria,urgency,
frequency,andpainwithGUinfections
Oxybutynin(Ditropan)hasdirectantispasmodic
effectsonsmoothmuscleandanticholinergiceffects.
Decreasesfrequencyofvoiding.
Tolterodine(Detrol)iscompetitive,antimuscuranic
anticholinergicthatinhibitscontraction.More
selectiveforthisareathanelsewhereinthebody.

ToxicityofAnticholinergics

Anticholinergicoverdosesyndromeis
characterizedby:Hyperthermia,delirium,dry
mouth,tacycardia,ileus,urinaryretention.
Seizures,comaandrespiratoryarrestmay
occur.
Txactivatedcharcoal,Antilirium,cooling
agents(icebags,coolingblankets,tepid
baths).