b2. H1-Antagonists.pdf

Overview of Discussion-
H1 -antagonists
Classification of H1 -antagonists
Pharmacological actions
Pharmacokinetics
Adverse effects
Second generation antihistaminics
Therapeutic uses

1. H
1-Antagonists
Mr. Vishal Balakrushna Jadhav
Assistant professor (Pharmacology)
School of Pharmaceutical Sciences (SOPS), Sandip University, Nashik
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2. Overview of Discussion
H
1 -antagonists
Classification of H
1 -antagonists
Pharmacological actions
Pharmacokinetics
Adverse effects
Second generation antihistaminics
Therapeutic uses
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3. H
1 -antagonists
Conventionalantihistaminicscompetitivelyantagonizeactionsof
histamineattheH
1receptorsandalsohaveinverseagonistic
potency.
Clinicallyusedagentsarelesssedating/non-sedatingsecond
generationH
1antihistamines.
Havediversechemicalstructures,butmajorityhaveasubstituted
ethylaminesidechain.
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4. Classification of H
1 -antagonists
Includesfirst-andsecondgenerationdrugs(asshowninfigure).
Theolderfirst-generationdrugsarestillwidelyusedbecausetheyare
effectiveandinexpensive.TheypenetratetheCNSandcausesedation,tendto
interactwithotherreceptors,producingavarietyofunwantedadverseeffects.
Incontrast,thenewersecond-generationagentsarespecificforperipheral
H
1receptors,polarinnature(presenceofcarboxylgroups,forexample,
cetirizine),donotpenetratetheblood–brainbarrier,causinglessCNS
depression(sedation)thanthefirstgenerationdrugs.
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5. Fig. Classification of H
1 –antagonists
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6. Pharmacological actions
Actionsarequalitativelysimilar,butquantitativedifferent,especiallyin
concernwiththesedativeproperty.
1.Antagonismofhistamine
2.Antiallergicaction
3.Centralnervoussystem(CNS)
4.Anticholinergicaction
5.Localanaesthetic
6.Bloodpressure(BP)
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7. 1.Antagonismofhistamine-H1–antagonists-
Blockshistamineinducedbronchoconstriction,contractionofintestinaland
othersmoothmuscleandtripleresponse-especiallywheal,flareanditch.
BlocksfallinBPproducedbylowdosesofhistamine,butadditionalH
2
antagonistsarerequiredforcompleteblockadeofthatcausedbyhigherdoses.
Pretreatmentwiththesedrugsprotectsanimalsfromdeathduetoi.v.injection
oflargedosesofhistamine.
Inhibitsthereleaseofadrenaline(Adr)fromadrenalmedullainresponseto
histamine.
Antagonizeconstrictionoflargerbloodvesselbyhistamine.
Actionofhistamineongastricsecretionissingularlynotaffectedbythese
drugs(H
2blockersmayrequired).
Cyproheptadinehadadditional5-HT
2receptorblockingactivity.
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8. 2.Antiallergicaction-H1–antagonists-
Suppressmanifestationsofimmediatehypersensitivity(typeIreactions)→
urticaria,itchingandangioedemaarewellcontrolled.
PreventpartiallyanaphylacticfallinBP.
Human asthmaispracticallyunaffected,thoughanaphylactic
bronchoconstrictioninguineapigislargelyprevented→thistissueandspecies
dependenceresponseprobablyreflectsextentofinvolvementofhistamine.Itis
nowwellestablishedthatleukotrienes(C
4andD
4)andPAFaremore
importantmediatorsforhumanasthma.
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9. 3.Centralnervoussystem(CNS)
Becauseofpenetrationacrossblood-brainbarrierandaffinityforthecentral
(comparedtoperipheral)H
1receptors,olderfirstgeneration
antihistaminicsproducesvariabledegreeofCNSdepression(sedation).
IntersubjectvariationmaydeveloptoCNSeffect→samedruganddosemay
sedatesomesubjects,whileothersmayremainalert.
Accordingtosedativepotential,agentsareclassifiedas-
a)Highlysedative(e.g.Diphenhydramine,Dimenhydrinate,Promethazine,
Hydroxyzine),b)Moderatelysedative(e.g.Pheniramine,Cyproheptadine,
Meclozine,Cinnarizine),andc)Mildsedative(e.g.Chlorpheniramine,
Dexchlorpheniramine,Triprolidine,Clemastine).Someindividualsalso
experienceCNSstimulanteffectslikerestlessnessandinsomnia.
Excitementandconvulsionsarefrequentlyseenattoxicdoses.
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10. Thesecondgenerationantihistaminicsarepracticallynon-sedating.
Promethazine,diphenhydramine,dimenhydrinateandmeclozineareeffectivein
preventingmotionsickness.Itisnotclearwhetherthisisduetoantagonism
ofhistamineinthebrainorreflectsantimuscarinicpropertyofthesedrugs.
Promethazinealsocontrolsvomitingofpregnancyandothercauses.
Promethazineandfewotherantihistaminicsreducetremor,rigidityand
sialorrhoeaofparkinsonismbecauseofanticholinergicandsedative
properties.
Cyproheptadine,haveappetitestimulatingeffect.
SomeH
1antihistaminesarealsoeffectiveantitussives.
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11. 4.Anticholinergicaction
ManyH
1blockersinadditionantagonizemuscarinicactionsofACh.The
anticholinergicactioncanbegradedas:
Concurrentadministrationwithatropineoritssubstitutes,phenothiazines,
tricyclicantidepressantsordisopyramide→additiveanticholinergic
action.
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12. 5.Localanaesthetic
Pheniramine,promethazineanddiphenhydraminehavestrongwhileothershave
weakmembrane stabilizingproperty.However,theyarenotused
clinicallyaslocalanaestheticbecausetheycauseirritationwheninjecteds.c.
Membranestabilizingactivityconfersantiarrhythmicpropertytothese
compounds.
6.Bloodpressure(BP)
Promethazinecausedirectsmoothmusclerelaxationorα-adrenergic
blockade→fallinBPoni.v.injection.However,thisisnotevidentonoral
administration.
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13. TheconventionalfirstgenerationH
1antihistaminicsarewellabsorbed
fromoralandparenteralroutes,metabolizedintheliverandexcretedin
urine.Theyarewidelydistributedinthebodyandenterbrain.
Thenewersecondgenerationcompounds penetratebrainpoorly
accountingfortheirlow/absentsedatingaction.
Durationofactionofmostagentsis4–6hours,exceptmeclozine,
chlorpheniramine,mesolastine,loratadine,cetirizineandfexofenadinewhich
actfor12–24hoursormore.
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Pharmacokinetics

14. First-generationH
1-receptorblockershavealowspecificity,
interactingnotonlywithhistaminereceptorsbutalsowithmuscarinic
cholinergicreceptors,α-adrenergicreceptors,andserotoninreceptors.
Natureofthesideeffectsvarieswiththestructureofthedrugandextent
ofinteractionwiththesereceptors.
Somesideeffectsmaybeundesirable,andothersmaybeoftherapeutic
value.Furthermore,theincidenceandseverityofadversereactionsfora
givendrugvariesbetweenindividualsubjects.
InteractionofH
1-receptorblockerswithabovementionedreceptorsand
possiblesideeffectsisshownbelow-
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Adverse effects

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16. 16Figure-Someadverseeffectsobservedwithantihistamines

17. Second generation antihistaminics
IdealpropertiesofsecondgenerationH
1-blockers-
AbsenceofCNSdepressantproperty(less/nosedativepotency).
HigherH
1selectivity→noanticholinergicsideeffects.
Additionalantiallergicmechanismsapartfromhistamineblockade→some
alsoinhibitlatephaseallergicreactionbyactingonleukotrienesorby
antiplateletactivatingfactoreffect.
Noimpairmentofpsychomotorperformance(drivingetc.neednotbe
contraindicated),producenosubjectiveeffects,nosleepiness,donot
potentiatealcoholorbenzodiazepines.
Somepatientsdocomplainofsedation,butincidenceissimilartothatwith
placebo.
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18. SecondgenerationH
1-blockershaveanarrowspectrumoftherapeutic
useandareindicatedforthetreatmentof-
Allergicrhinitisandconjunctivitis,hayfever,pollinosis→controlsneezing,
runnybutnotblockednose,andred,watering,itchyeyes,
Urticaria,dermographism,atopiceczema,and
Acuteallergicreactionstodrugsandfoods.
Theyhavepoorantipruritic,antiemeticandantitussiveactions.
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19. Therapeutic uses
TheusesofH
1antihistaminicsarebasedontheirabilitytoblockcertaineffectsof
histaminereleasedendogeneously,aswellasonsedativeand
anticholinergicproperties.Theindicationsare-
1.Allergicdisorders 9.Cough
2.Otherconditions 10.Acutemuscledystonia
3.Pruritides 11.Assedative,hypnotic,anxiolytic
4.Commoncold
5.Motionsickness
6.Vertigo
7.Preanaestheticmedication
8.Parkinsonism
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20. 1.Allergicdisorders
DonotsuppressAG:ABreaction,butblocktheeffectsofreleasedhistamine-
areonlypalliative.
Effectivelycontrolcertainimmediatetypeofallergies,e.g.itching,urticaria,
seasonalhayfever,allergicconjunctivitisandangioedemaoflips,eyelids,etc.
IVantihistaminicmayhaveadjuvantvalueinlaryngealangioedema,andhave
asecondaryplacetoAdrinanaphylacticshock.
Benefitsarelessmarkedinperennialvasomotorrhinitis,atopicdermatitis
andchronicurticarias→combinationwithanH2antagonistmayrequired.
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21. Theantihistaminicsareineffectiveinbronchialasthma:reasonsmaybe—
(i)Leukotrienes(C4,D4)andPAFaremoreimportantmediatorsthan
histamine,and(ii)Concentrationofantihistaminesattainedatthesitemay
notbesufficienttoblockhighconcentrationofhistaminereleasedlocallyin
thebronchi.
Cetirizinehaveadjuvantroleinseasonalasthma.
Ineffectiveinothertypesofhumoralandcellmediatedallergiesbecause
histamineisnotinvolved.
Suppressurticariaandswellingsinserumsickness.
TypeIhypersensitivityreactionstodrugs(exceptasthmaandanaphylaxis)
aresuppressed.Someskinrashesalsorespond.
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22. 2.Otherconditionsinvolvinghistamine
Blocksymptomsproducedbyhistamineliberators;affordsymptomaticrelief
ininsectbiteandivypoisoning.
Suppressedabnormaldermographism.
Haveprophylacticvalueinblood/salineinfusioninducedrigor.
3.Pruritides
AntipruriticactionindependentofH
1antagonism.
Olderantihistaminicschlorpheniramine,diphenhydramine,cyproheptadine
remainthefirstchoicedrugsforidiopathicpruritus.
4.Commoncold
Affordsymptomaticreliefbyanticholinergic(reducerhinorrhoea)and
sedativeactions.Newernonsedatingantihistaminesarelesseffective.
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23. 5.Motionsickness
Promethazine,diphenhydramine,dimenhydrinateandmeclozinehave
prophylacticvalueinmildertypesofmotionsickness;shouldbetakenone
hourbeforestartingjourney.
Promethazinecanalsobeusedinmorningsickness,druginducedand
postoperativevomiting,radiationsickness.
6.Vertigo
CinnarizineistheH
1antihistaminehavingadditionalanticholinergic,anti-5-
HT,sedativeandvasodilatorpropertieswhichhasbeenwidelyusedin
vertigo.ItmodulatesCa
2+
fluxesandreducesvasoconstrictoractionofmany
endogenousmediators.
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24. Cinnarizineinhibitsvestibularsensorynucleiintheinnerear,suppresses
postrotatorylabyrinthinereflexes,possiblybyreducingstimulatedinfluxof
Ca
2+
fromendolymphintothevestibularsensorycells.Beneficialeffectshave
beenreportedinMeniere’sdiseaseandothertypesofvertigo.
Sideeffectsaresedationandmildg.i.upset.
Dimenhydrinateisanothereffectiveantivertigoantihistaminic.
7.Preanaestheticmedication
Promethazinehasbeenusedforitsanticholinergicandsedativeproperties.
8.Parkinsonism
Becauseofanticholinergicandsedativeproperty,promethazineandsome
othersaffordmildsymptomaticreliefinearlycases.
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25. 9.Cough
Chlorpheniramine,diphenhydramineandpromethazineareconstituentsof
manypopularcoughremedies.Theyhavenoselectivecoughsuppressant
action,butmayaffordsymptomaticreliefbysedativeandanticholinergic
property.
10.Acutemuscledystonia
Because0fcentralanticholinergicaction,parenteralpromethazine,
diphenhydramineorhydroxyzinerelieveacutemuscledystoniacausedby
antidopaminergic-antipsychoticdrugs.
11.Assedative,hypnotic,anxiolytic
AntihistamineswithCNSdepressantactionhavebeenusedassedativeandto
inducesleep,especiallyinchildren.Anxietyassociatedwithautonomic
manifestationsistreatedbyhydroxyzine. 25

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