b1. Histamine.pdf

Overview of Discussion-
Histamine
Synthesis, storage, release and destruction
Histamine receptors
Pharmacological actions
Pathophysiological roles
Uses
Histamine analogue
Histamine releasers

1. Histamine
Mr. Vishal Balakrushna Jadhav
Assistant Professor (Pharmacology)
School of Pharmaceutical Sciences (SOPS), Sandip University, Nashik
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2. Overview of Discussion
Histamine
Synthesis, storage, release and destruction
Histamine receptors
Pharmacological actions
Pathophysiological roles
Uses
Histamine analogue
Histamine releasers
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3. Histamine
Histamine,meaning‘tissueamine’(histos-tissue)
Almostubiquitouslypresentinanimaltissuesandincertain
plants,e.g.stingingnettle.
Closeparallelismwasnotedbetweenitsactionsandthe
manifestationsofcertainallergicreactions.
Implicatedasamediatorofhypersensitivityphenomenaandtissue
injuryreactions(allergyandinflammation),andknownto
playimportantphysiologicalroles(gastricacidsecretion,and
neurotransmissioninpartsofthebrain).
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4. Synthesis
Histamineisanamineformedbythedecarboxylationoftheamino
acidhistidinebytheenzymehistidinedecarboxylase,whichis
expressedincellsthroughoutthebody,includingneurons,gastric
parietalcells,mastcells,andbasophilsasshowninfigure-
Synthesis, storage, release and destruction
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5. Storage
Withinintracellularstoragegranulesofmastcells,histamine
(+charged)isheldbyanacidicproteinandheparin(-charged).
Itisalsopresentinblood,mostbodysecretions,venomsand
pathologicalfluids.Tissuesrichinhistamineareskin,gastricand
intestinalmucosa,lungs,liverandplacenta.Nonmastcell
histamineoccursinbrain,epidermis,gastricmucosaandgrowing
regions.Turnoverofmastcellhistamineisslow,whilethatof
nonmastcellhistamineisfast.
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6. Release
Inresponsetostimulisuchasdestructionofcellsasaresultofcold,
toxinsfromorganisms,venomsfrominsectsandspiders,and
trauma,histamineisreleasedfromintracellularstoragegranulesof
mastcellsbyexocytosiswhereNa
+
ionsine.c.f.exchangewith
histaminetoreleaseitfree.
Allergiesandanaphylaxiscanalsotriggersignificantreleaseof
histamine.
IncreaseinintracellularcAMP(causedbyβ-adrenergicagonistsand
methylxanthines)inhibitshistaminerelease.
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7. Destruction
Histamineisorallyinactiveasliverdegradedallintestinallyabsorbed
histamine.Itisdegradedrapidlybyoxidationcatalyzedbydiamine
oxidaseandmethylationcatalyzedbyN-methyltransferaseas
showninfigure-
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8. Histamine receptors
Histamineisformedinvariouscelltypes(asshowninrectangularbox)
andmediatesnumerousactionsviabindingtofourreceptortypes,
designatedasH
1–H
4,allofwhichareG-proteincoupledreceptors
(GPCRs).
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9. Distribution of histaminergic receptors in body
and actions mediated by histamine
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10. 10

11. Pharmacological actions
Bloodvessels
Markeddilatationofsmallerbloodvessels,includingarterioles,
capillariesandvenules.Ons.c.injectionflushing,especiallyinthe
blusharea,heat,increasedheartrateandcardiacoutput,withlittle
ornofallinBPareproduced.Rapidi.v.injectioncausesfallinBP.
FallinBPduetolargedosesiscompletelyblockedonlybya
combinationofH
1andH
2antagonists.Dilatationofcranialvessels
causespulsatileheadache.
H
1receptormediatingvasodilatationispartlyindirectactionon
theendothelialcellsmediatedthrough‘endotheliumdependent
relaxingfactor’(EDRF/NO)whileH
2receptorsmediating
vasodilatationisdirectactiononthevascularsmoothmuscle.
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12. VasoconstrictionoflargerarteriesandveinsbyhistamineisH
1
receptormediatedactiononvascularsmoothmuscle.
Histaminealsocausesincreasedcapillarypermeabilitydueto
separationofendothelialcells→exudationofplasma.Thisis
primarilyaH
1response.
Injectedintradermally,itelicitsthetripleresponseconsistingof:1)
Redspot:duetointensecapillarydilatation,2)Flare:i.e.
rednessinthesurroundingareaduetoarteriolardilatation
mediatedbyaxonreflex,and3)Wheal:duetoexudationoffluid
fromcapillariesandvenulesasshowninfigure-
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13. Heart
Directeffectsofhistamineoninsituheartarenotprominent,butH
1
mediatednegativedromotropic effect(slowingofA-V
conduction),andH
2mediatedpositiveinotropicand
chronotropiceffect(increasedrateandforceofcontraction)has
beendemonstratedontheisolatedheart,especiallyofguineapig.
Visceralsmoothmuscle
Histaminecausesbronchoconstriction;guineapigsandpatientsof
asthmaarehighlysensitive.Largedosescauseabdominalcramps
andcolicbyincreasingintestinalcontractions.Guineapiguterusis
contractedwhilethatofratisrelaxed;humanuterusisnotmuch
affectedasaremostothervisceralsmoothmuscles.Smooth
musclecontractionisaH
1response.InfewinstancesH
2
mediatedrelaxationisalsoseen,e.g.bronchialmuscleofsheep,
humanbronchiafterH
1blockade.
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14. Glands
Histaminecausesmarkedincreaseingastricsecretion-primarily
ofacidandpepsin.Thisisadirectactionexertedonparietalcells
throughH
2receptorsandismediatedbyincreasedcAMP
generation,whichinturnactivatesthemembrane proton
pump(H
+
-K
+
-ATPase).Histaminecanincreaseothersecretions
also,buttheeffectishardlydetectable.
Sensorynerveendings
Itchingoccurswhenhistamineisinjectedi.v.orintracutaneously.
Higherconcentrationsinjectedmoredeeplycausepain.Theseare
reflectionsofthecapacityofhistaminetostimulatenerveendings.
Autonomic ganglia andadrenal medulla
These structures are stimulatedand release of Adr occurs, which
can cause a secondary risein BP.
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15. CNS
Histaminedoesnotpenetratebloodbrainbarrier(BBB)-no
centraleffectsareseenoni.v.injection.
However,intracerebroventricularadministrationproduces
riseinBP,cardiacstimulation,behaviouralarousal,hypothermia,
vomitingandADHrelease.
TheseeffectsaremediatedthroughbothH
1andH
2receptors.
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16. Pathophysiological roles
Gastricsecretion
Histaminehasdominantphysiologicalroleinmediatingsecretionof
HClinthestomach.Nonmastcellhistamineoccursingastric
mucosa,possiblyincellscalled‘histaminocytes’situatedclose
totheparietalcells.Thishistaminehashighturnoverrate.Itis
releasedlocallyundertheinfluenceofallstimulithatevokegastric
secretion(feeding,vagalstimulation,cholinergicdrugsandgastrin)
andactivatestheprotonpump(H
+
K
+
ATPase)throughH
2
receptors.
Acetylcholine(ACh)andgastrinalongwithhistamineactivate
thesameprotonpump(H
+
K
+
ATPase)intheparietalcell
membrane,butthroughtheirownreceptorsi.e.muscarinicand
gastrin/cholecystokinin(CCK2)receptorsrespectively.
H
2blockers not only suppress acid secretion induced by histamine
but also markedly diminish that in response to ACh and gastrin.
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17. Allergicphenomena
Mediationofhypersensitivityreactionswasthefirstroleascribedto
histamine.Itisanimportant,butonlyoneofthemediatorsof
suchphenomena.ReleasedfrommastcellsfollowingAG:AB
reactionontheirsurface(involvingIgEtypeofreaginic
antibodies)inimmediate typeofhypersensitivity
reactions,histamineiscausativeinurticaria,angioedema,
bronchoconstrictionandanaphylacticshock.TheH
1
antagonistsareeffectiveincontrollingthesemanifestationstoa
considerableextent,exceptasthmaandtoalesserextent
anaphylacticfallinBPinwhichleukotrienes(especially
LTD
4)andPAFappeartobemoreimportant.
Histamineisnotinvolvedindelayedorretardedtypeofallergic
reactions.
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18. Astransmitter
Histamineisbelievedtobetheafferenttransmitterwhich
initiatesthesensationofitchandpainatsensorynerveendings.
Nonmastcellhistamineoccursinbrain,especiallyhypothalamus
andmidbrain.Itisinvolvedinmaintainingwakefulness;H
1
antihistaminicsinducedtheirsedativeactionthroughblockade
ofthisfunction.
InthebrainH
1agonismsuppressesappetite.Thismayexplainthe
appetitepromotingactionofcertainH
1antagonists.
Histamineasatransmitterregulatingbodytemperature,
cardiovascularfunction,thirst,andpossiblyotherfunctions,
mainlythroughH
2(postsynapticreceptors)andH
3(presynaptic
autoreceptors).
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19. Inflammation
Histamineisamediatorofvasodilatationandotherchangesthat
occurduringinflammation.Itpromotesadhesionofleukocytesto
vascularendotheliumbyexpressingadhesionmoleculeP-
selectinonendothelialcellsurface,sequestratingleukocytesat
theinflammatorysite.Itmayalsoregulatemicrocirculation
accordingtolocalneeds.
Tissuegrowthandrepair
Becausegrowingandregeneratingtissuescontainhigh
concentrationsofhistamine,ithasbeensuggestedtoplayan
essentialroleintheprocessofgrowthandrepair.
Headache
Histaminehasbeenimplicatedincertainvascularheadaches,but
thereisnoconclusiveevidence.
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20. Uses
Histaminehasnoclinicalapplications.
Inthepasthistaminehasbeenusedtotest-
Acidsecretingcapacityofstomach,
Bronchialhyperreactivityinasthmatics,and
Fordiagnosisofpheochromocytoma,
Thesepharmacologicaltestsareriskyandobsoletenow.
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21. Histamine analogue
Betahistine
Itisanorallyactive,somewhatH
1selectivehistamineanalogue,
whichisusedtocontrolvertigoinpatientsofMeniere’s
disease:possiblyactsbycausingvasodilatationintheinternal
ear.
Itiscontraindicatedinasthmaticsandulcerpatients.
MarketedpreparationVERTIN8mgtab.,1/2to1tab.QID.
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22. Histamine releasers
Avarietyofmechanical,chemicalandimmunologicalstimuli
arecapableofreleasinghistaminefrommastcells.
Tissuedamage:trauma,stingsandvenoms,proteolyticenzymes,
phospholipaseA.
Antigen:antibodyreactioninvolvingIgEantibodies.
Polymerslikedextran,polyvinylpyrrolidone(PVP).
Some basicdrugs-tubocurarine,morphine,atropine,
pentamidine,polymyxinsB,vancomycinandevensome
antihistaminicsdirectlyreleasehistaminewithoutan
immunologicalreaction.
SurfaceactingagentslikeTween80,compound48/80etc.
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23. Theprimaryactionofthesesubstancesisreleaseofhistamine
frommastcells,thereforetheyarecalled‘histamine
liberators’.
Theseagentsproducean‘anaphylactoidreaction’-itchingand
burningsensation,flushing,urticaria,fallinBP,tachycardia,
headache,colicandasthma.Mostofthesesymptomsare
controlledbyaH
1blocker,combinationwithH
2blockerisbetter.
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