HistamineandAntihistamines

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).