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Hist&Antis 07ho
Hist&Antis 07ho
November19,2007
AntihistaminesmeansclassicalH1receptor
antagonistsunlessotherwisespecified
Druglistitems
cetirizine(Zyrtec)
chlorpheniramine(ChlorTrimeton)
diphenhydramine(Benadryl)
disodiumcromoglycate(cromolyn,Intal)**
fexofenadine(Allegra)
histamine
hydroxyzine(Atarax)
loratadine(Claritin)
promethazine(Phenergan)
scopolamine(TransdermScop)**
tripelennamine(PBZ)
Autacoids
(shortactingendogenousmediators,usually
actingaspartofaninflammatoryresponse)
Bradykinin
Eicosanoids
Prostaglandins,thromboxanes,leukotrienes
Histamine
Kallidin
Plateletactivatingfactor(PAF)
Serotonin(5hydroxytryptamine,5HT)
TeresaTrubbel
4yearoldfemalestartedactingstrangelyin
apartmentofherdivorced,singleparent,mother2
yearoldsiblingseemsnormal
Wired,notatallsleepyatbedtime,pupilswidely
dilated,actingstrangely,twitching
Foreheadfeltveryhotanddry
Teresasuncle,whohappenedtobeapharmacist,
arrivedforavisitandsuggestedimmediate
transportationofTeresatotheEmergency
Departmentofthenearesthospital.
TeresaintheER
4yearoldfemale,incoherent,pupilswidelydilated
equally,sluggishresponsetolight
Fever(103+F),tachycardia,BP129/89,shallowrapid
respiration
Skinflushedanddry
MotheradmittedthatTeresahadgottenintoherpurseand
hadtakenaprescriptionofcoldmedicine,(12time
releasecapsulesofchlorpheniramine([Teldrin]),butI
didntthinkitwoulddoanythingbad.
Teresawastreatedsymptomaticallyandreleasedthenext
day.
Histamine(tissueamine,alsoenteramine):
anotherpotentbiogenicamine
(normallyactslocally,anautacoid)
Synthesizedbydecarboxylationfromanamino
acidprecursor,histidine
Storedingranulesincertaincells(mastcells,
basophils,enterocytes)
Releasedinresponsetocertainstimuli(Ca
dependentexocytosis)
Eliminatedbyoxidativedeaminationand/or
transmethylation
Synthesisandmetabolismofhistamine
Histaminereceptors
H1smoothmuscle,exocrineglands,vascular
endothelium,brain;coupledtophospholipaseC,
leadingtoIP3anddiacylglycerol(DAG)
H2parietalcells,heart,vascularsmoothmuscle,
mastcells,brain;coupledtocAMPproduction
H3presynaptic,brain,myentericplexus
(notherapeuticapplications,yet)
Effectsofhistamine
Decreasedperipheralvascularresistance
(mediatedbyH1andH2)(flushing,headache!)
EffectofIVhistamineonbloodpressure
(simulationfromtheWebSiteforCardiovascularandAutonomicPharmacology)
MediatedbyH1receptorsonendothelium
MediatedbyH2receptorson
onvascularsmoothmuscle
Effectsofhistamine
Decreasedperipheralvascularresistance
(mediatedbyH1andH2)(flushing,headache!)
Increasedvascularpermeability,especially
postcapillaries,localedema(H1)
Histamineintheskin:
theTripleResponseofLewis
Redspot
Flare
Wheal
Effectsofhistamine
Decreasedperipheralvascularresistance
(mediatedbyH1andH2)(flushing,headache!)
Increasedvascularpermeability,especially
postcapillaries,localedema(H1)
Stimulationofnerveendings(pain!)
Effectsofhistamine
Decreasedperipheralvascularresistance
(mediatedbyH1andH2)(flushing,headache!)
Increasedvascularpermeability,especially
postcapillaries,localedema(H1)
Stimulationofnerveendings(pain!)
Tachycardia,direct(H2)andreflex
Effectsofhistamine
Decreasedperipheralvascularresistance
(mediatedbyH1andH2)(flushing,headache!)
Increasedvascularpermeability,especially
postcapillaries,localedema(H1)
Stimulationofnerveendings(pain!)
Tachycardia,direct(H2)andreflex
Increasedgastricacidsecretion(H2)andGI
motility(H1)
Histaminerelease:Promotedbymanycompounds
Therapeutic:
morphine,dtubocurarine,aminoglycosides
(rememberRednecksyndrome??)
Experimental:
compound48/80(wastestedasantihypertensive)
Unknown:
causeofhivesisrarelydetermined
Antigenantibodyreactions
Anaphylaxis
TypeIallergicresponse
(immediatehypersensitivityreaction)
MediatedbyIgEantibodies
IgEbindstoreceptorsonmastcellsandbasophils
Fabportionofantibodybindsantigenandcauses
(moderatetomassive)releaseof:
histamine
leukotrienes
prostaglandins
etc.,etc.
Commoncausesofanaphylacticand
anaphylactoidreactions
IgEmediated
Anaphylaxis
NonIgEmediated
Anaphylactoid
Peanuts,seafood,eggs,milk,
grains
Venoms
Foreignproteins
Someexerciseinduced
bronchospasm
NMJblockers,opioids,plasma
expanders
Aminoglycosides
Protamine
Radiocontrastmedia
Urticariaofcold,heat,sun
Someexercisedinduced
bronchospasm
Anaphylaxis:EffectsandTreatment
(mayinvolvereleaseofmediatorsinadditiontohistamine)
Decreasedbloodpressure
Decreasedcardiacoutput
Bronchoconstrictionandincreasedpulmonarysecretions
Pruritis
Treatment:Epinephrinenotinitiallyantihistamines
(epinephrineisaphysiologicalantagonistofhistamine,
notapharmacologicalantagonist)
(alpha1vasoconstriction,beta1increasedHR,
beta2bronchodilation)
Threemechanisticallydifferentapproachesto
minimizehistaminereactions
Physiologicalantagonism(e.g.,epinephrine)
Inhibitthereleaseofhistamine(e.g.,cromolyn)
Pharmacologicalantagonism(antihistamines)
disodiumcromoglycate(cromolyn,Intal)
Decreaseshistaminereleasefrommastcells
(anddecreasesreleaseofSRSA)
Administration:inhalationofnebulizedsolution
(formerlypowder,irritating)
Maybeusefulinprophylaxisofhistaminerelease,but
doesnotantagonizetheeffectsofhistamine
Similarmechanismandeffectsbynedocromil(Tilade)
Cromolyn(Intal)
Indications:
Adjunctintreatmentofsevereperennialasthma
Preventionandtreatmentofallergicrhinitis
Preventionofexerciseinducedbronchospasm
Systemicmastocytosis(mastcelldumping)
Allergicoculardisorders
Contraindications
Acuteasthma
Bronchospasm
Cromolyn:Adversereactions
Cough
Wheezing
Headache
Rash
Nausea
H1antihistamines:diverse
pharmacologicalproperties
AntagonizeH1receptors()
Prophylaxisofmotionsickness&vomiting
Inhibitionofallergicrhinitis
Usefulsymptomaticrelief
pollinosis,conjunctivitis,urticaria(butdonot
usetopically!)
Generalpropertiesoffirstgeneration
H1antihistamines
LipidsolubleCNSpenetrationandeffects
Wellabsorbed
Metabolizedintheliver
Halflifeabout56hours
Adversereactions
SEDATION,DROWSINESS
headache,nausea&vomiting
cough
constipation,diarrhea
drymouth,blurredvision,urinaryretention
H1antihistamines:overdosage
Fever
Excitement
Pupillarydilatation
Hallucinations
Convulsions
pA2
values
ofsome
clinically
useful
drugs
pA2valuesofsomeantihistaminesversus
clonedhumanmuscarinicreceptors*
*bydisplacementof[3H]Nmethylscopolamine
Yasuda&Yasuda,1999
H1antihistamines:overdosage
Fever
Excitement
REMEMBER
Pupillarydilatation
Hotasastove
Hallucinations
Redasabeet
Convulsions
Dryasabone
Madasahatter
Somesecondgeneration(nondrowsy)
H1antihistamines
terfenadine(Seldane),thepioneerofthissecond
generation(NOWWITHDRAWN)
astemizole(Hismanal)(NOWWITHDRAWN)
fexofenadine(Allegra)
(activemetaboliteofterfenadine)
cetirizine(Zyrtec)
loratadine(Claritin)
Secondgenerationantihistaminesarerecommendedasthefirst
lineintreatmentofallergicrhinitisbyTheAmericanCollege
ofAllergyAsthmaandImmunology(Ann.AllergyAsthma&
Immunology,Nov.1998).Avoidsdrowsinessoffirst
generationantihistaminesandmajoradversereactionsof
injectedcorticosteroids.
Terfenadine(Seldane)blocksKchannels:
Maycausetorsadesdepointes
Thereisnormallyalargefirstpasseffectresulting
increationofcarboxyterfenadine(fexofenadine)
byCYP3A4
Erythromycin,ketoconazoleandotherdrugsthat
inhibitCYP3A4promoteaccumulationof
unchangedterfenadineand,thus,increasedthe
riskoftorsadedepointespromptingwithdrawal
ofterfenadine(similareffectswithastemizole,
Hismanal,alsowithdrawn)
Generalpropertiesofsecondgeneration
H1antihistamines
Lipidsolublestructurewithahighlyionized
functionalgrouplessCNSpenetrationmore
selectiveforperipheralH1antagonism(lessuseful
inotherindications)
Wellabsorbed
Metabolizedintheliver
Halflifeabout56hours
(Hugepotentialmarket,
directconsumeradvertising)
Indicationsforantihistamineexamples
Firstgeneration
promethazine
Secondgeneration
fexofenadine
Rhinitis
Urticaria&angioedema
Allergicconjunctivitis
Anaphylaxis(withEPI)
Pre/postopsedation
PreventionofN&V
Preventionofmotionsickness
Adjuncttopainmeds(esp.hydroxyzine)
(localanesthetic)
Seasonalallergicrhinitis
Urticaria,chronic
Inputandintegrationofthevomitingreflex
Clinicallyimportantrelief(CIR)producedby
antihistaminesinallergicrhinitis
AdaptedfromDayetal.,AnnalsofAllergy,AsthmaandImmunology,79:163171
FinancialsupportfromNordicMerrillDow,Canada
Worthnoting...
Firstgenerationantihistaminesarevirtuallywithoutvaluein
thetreatmentofasthma;mayberelativelycontraindicated.
Themainbenefitinpruritismaybesedationonthe
otherhand,amaincauseofdriverdrowsinessmaybetraced
toantihistamines.
Secondgenerationsantihistaminesmaybeuseful(offlabel)
insomepatientswithasthma(e.g.,20mgofcetirizinehasa
bronchodilatoractionadditivetothatofalbuterolinsubjects
withFEV1of5080%ofpredicted,Spectoretal.,1995).