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HISTAMINERGIC RECEPTORS

Classification : 4 types

1) H1 (Ash and Schil 1!"")

#) H# ( $lac% et al 1!&#)

') H' ( Aan et al1!*&)4) H4 ( H+,h #--1)

H1 receptor

History

• The .ist H1/antihista0ine disc+eed 2as pipe+3an y 5e.. 6+nea, and 7aniel

$+et (1!'') in thei e..+ts t+ deel+p a ,inea pi ani0al/0+del .+

anaphyla3is at Ryes+n 8niesity9 $+et 2ent +n t+ 2in the 1!& N+el Pi;e in

Physi+l+y + Medicine .+ his c+nti,ti+n9

• Hista0ineic ecept+s 2ee classi.ied y Asch and Schild int+ H1 and H# :

th+se l+c%ed y then aailale antihista0ines 2ee laelled H1

Pharmacology

Hista0ine H1 ecept+ ae G/p+tein/c+,pled ecept+s e3pessed th+,h+,t the +dy

speci.ically in s0++th 0,scles +n asc,la end+thelial cells in the heat and in the

cental ne+,s syste09 The H1 ecept+ is lin%ed t+ an intacell,la  G/p+tein (G<) 2hichactiates ph+sph+lipase C and the ph+sphatidylin+sit+l (PIP#) sinallin path2ay9

Recept+ Si;e / 4*& AA

Function

1)Visceral Smooth muscle— 

  Hista0ine ca,ses +nch+c+nsticti+n ,inea pis and patients +. asth0a aehihly sensitie9

  It ca,ses ad+0inal ca0ps and c+lic y inceasin intestinal c+ntacti+ns9

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  2) Blood vessels

  Hista0ine ca,ses 0a%ed dilatati+n +. s0alle l++d essels incl,din atei+les

capillaies and en,les9 =as+dilatati+n ca,sed y hista0ine is patly indiect 0ediatedth+,h >end+theli,0 dependent ela3in .act+? : the ecept+ ein l+cated +n the

end+thelial cells9

  @ae ateies and eins ae c+nsticted y hista0ine : 0ediated y H1 ecept+

+n asc,la s0++th 0,scle9

!)Sensory nerve endings

Sti0,lati+n/ itchin

")#utonomic ganglia $ adrenal medulla

  Release +. catech+la0ines 2hich can ca,se sec+nday ise in $P9

%)Brain

• Hista0ine H1 ecept+s ae actiated y end+en+,s hista0ine 2hich is eleased

 y ne,+ns 2hich hae thei cell +dies in the t,e+0a0illay ne,+ns +. thehyp+thala0,s9 

• The hista0ineic ne,+ns +. the t,e+/0a00illay n,cle,s ec+0e actie

d,in the 2a%e cycle .iin at app+3i0ately #H;B

• 7,in sl+2 2ae sleep this .iin ate d+ps t+ app+3i0ately -9H;9

• 6inally d,in REM sleep hista0ineic ne,+ns st+p .iin all t+ethe9

  It has een ep+ted that hista0ineic ne,+ns hae the 0+st 2a%e/

selectie .iin patten +. all %n+2n ne,+nal types (Passani et al 9 #--4)9

  Th,s Hista0ine actin +n H1/ecept+s p+d,ces p,it,s as+dilatati+n

hyp+tensi+n .l,shin headache tachycadia +nch+c+nsticti+n inceases asc,la

 pe0eaility p+tentiates pain and 0+e9 (Si0+ns #--4)

#gonist

 # /0ethylhista0ine 

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 #ntagonists

First-generation H 1-receptor antagonists

• +ldest antihista0ineic d,s and ae elatiely ine3pensie

• 0+deately t+ hihly p+tent 0,scainic acetylch+line ecept+ /anta+nists

(antich+lineic) aents as 2ell9

• als+ c+00+nly hae acti+n at /adeneic ecept+s andD+  /HT ecept+s

Ethylenediamines

• 0epya0ine (pyila0ine)

Ethanolamines

• diphenhyda0ine 

• cain+3a0ine

• d+3yla0ine 

• cle0astine

• di0enhydinate

Alkylamines

• chl+phena0ine (chl+phenia0ine)

• de3chl+phena0ine 

•  +0phenia0ine

• tip+lidine

Piperazines

• cycli;ine

• chl+cycli;ine 

• hyd+3y;ine 

• mecli&ine

Tricyclics

7+3apine HCl

Phen+thia;ines

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P+0etha;ine HCl

Pipeidines

Cyp+hepltadine HCl

Pheninda0ine tatate

Sec+nd/eneati+n H1/ecept+ anta+nists Ne2e d,s that ae 0,ch 0+e selectie .+ peipheal H1 ecept+s in pe.eence t+the cental ne+,s syste0 hista0ineic and ch+lineic ecept+s9

Systemic

• cetii;ine

• l+atadine 

• 0i;+lastine 

• te.enadine (2ithda2n .+0 0+st 0a%ets d,e t+ is% +.  cadiac ahyth0ias and

eplaced 2ith .e3+.enadine)

• Eastine

Topical

• a;elastine

• le+caastine

Thid/eneati+n H1/ecept+ anta+nists19 Actie enanti+0e  (le+cetii;ine) + 0eta+lite (desl+atadine

.e3+.enadine) deiaties +. sec+nd/eneati+n d,s intended t+ hae

inceased e..icacy 2ith .e2e adese d, eacti+ns9#9 A eie2 y the C+nsens,s G+,p +n Ne2 Geneati+n Antihista0ines

c+ncl,ded that n+ne +. the c,ently aailale antihista0ines can eclassi.ied as t,e  Thid/eneati+n H1/ecept+ anta+nists 2hich they

de.ine as lac%in in cadi+t+3icity d,/d, inteacti+ns andCNS e..ects2ith p+ssile ene.icial e..ects ( e99 antiin.la00at+y)9

• @e+cetii;in

• desl+atadine 

• .e3+.enadine 

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H2 receptor

History

Sir 'ames (lac *1+,2) deel+ped the .ist H# l+c%e ,i0a0ide and c+n.i0ed H#

ecept+9

Pharmacology

H2 receptors p+sitiely c+,pled t+ adenylate cyclase ia Gs9 It is a p+tent sti0,lant +.cAMP p+d,cti+n9 It inceases the intacell,la Ca#F c+ncentati+ns and elease Ca#F

.+0 intacell,la st+es

Recept+ Si;e / '! AA

 Location and Function

• Gastic paietal cells (+3yntic cells) /// acid seceti+n

• =asc,la s0++th 0,scle // dilatati+n

• Cental ne+,s syste0 /// tans0itte 

• Heat /// Fe ch+n+t+py Fe in+t+py

• 8te,s (Rat) // Rela3ati+n

 Response

• Sti0,lati+n +. astic acid seceti+n

• S0++th 0,scle ela3ati+n

• Inhiit anti+dy synthesis T/cell p+li.eati+n and cyt+%ine p+d,cti+n

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 Agonist 

  7i0apit

  #ntagonistsci0etidine

anitidine

 .a0+tidine

ni;atidineR+3atidine

@+3atidine

H! receptorHistory

• H' ecept+ 2as p+st,lated y sch2at;(1!*')

• H! receptor -as localised in a variety of cells using R//0ethylhista0ine  a

selectie H' a+nist and thi+pea0ide an anta+nist ( Aan et al1!*&)

• 1!** H' ecept+ .+,nd t+ 0ediate inhiiti+n +. se+t+nin elease in at ain

c+te39

• 1!!& H' ecept+s sh+2n t+ 0+d,late ische0ic n+epinephine elease in ani0als9

• 1!!! H' ecept+ cl+ned

• #--- H' ecept+s called ne2 .+ntie in 0y+cadial ische0ia

Locations & Functions of H 3 receptors

19 Central nervous system/ they act as a,t+ecept+s in pesynaptic

hista0ineic ne,+ns and c+nt+l hista0ine t,n+e y .eedac% inhiiti+n

+. hista0ine synthesis and elease as 2ell9Th,s it ca,ses sedati+n9

#9 Heart  //depess e3aeated catech+la0ines elease in the heat e99 d,in

ische0ia9

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'9 .ungs   inhiit H1 0ediated +nc+c+nsticti+n9

49 /astrointestinal tract   In the ente+c+0a..in li%e cells +. the st+0ach

H' ecept+s inhiit astin ind,ced elease +. hista0ine and thee.+e

decease HCl seceati+n 0ediated y H# ecept+9

9 Spleen 0 sin  decease hsta0ine c+ntent

Pharmacology 

• @i%e all hista0ine ecept+s the H' ecept+ is a G/p+tein c+,pled ecept+ 9 The

H' ecept+ is c+,pled t+ the Gi G/p+tein s+ it leads t+ inhiiti+n +. the

.+0ati+n +. cAMP9

• The  and J s,,nits inteact 2ith N/type +ltae ated calci,0 channels t+

ed,ce acti+n p+tential 0ediated in.l,3 +. calci,0 and hence ed,ce

ne,+tans0itte elease9

Recept+ Si;e / '&''"44 AA

Isoforms

At least si3 H' ecept+  is+.+0s in h,0an is identi.ied9

H3-receptor Agonists

C,ently n+ theape,tic p+d,cts selectie .+ H' ecept+s9 S+0e th+,h n+t t+tally

selectie ae:

• R//0ethylhista0ine

• I00epip 

• i0etit

o Additi+n +. 0ethy +,ps t+ the and side chain +. hista0ine can es,lt

in p+tent H'/ecept+ a+nists9

H3-receptor Antagonists

• Thi+pea0ide

• Cl+enp+pit

H" receptor

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History

The H4 histamine receptor 2as disc+eed y H+,h 21

  @i%e the +the thee hista0ine ecept+s it is als+ a G p+tein/c+,pled ecept+9

Recept+ Si;e / '!- AA

Location

H4 is hihly e3pessed in +ne 0a+2 and 2hite l++d cells ( cells +. he0at+p+ietic

+iin)and e,lates ;y0+san/ind,ced ne,t+phil elease .+0 +ne 0a+29 It is als+e3pessed in the c+l+n lie l,n s0all intestine spleen testes thy0,s t+nsils and

tachea9

Functions

They hae een sh+2n t+ 0ediate 0ast cell che0+ta3is

#gonists KCl+enp+pit (patialL )

Antagonists—JNJ7777!"

  Thi+pea0ide

Reference

• Randal A9S9 Ein G9E9: Hista0ine $ady%inin And thei Anta+nists in

G++d0an Gil0an s The Pha0ac+l+ical $asis +. THERAPE8TICS 11th

editi+n "#!/"#

• $ehai+al Chaactei;ati+n +. Mice @ac%in Hista0ine H' Recept+s 

• Passani M$ @in 5S Hanc+c% A C+chet S $landina P9 The hista0ine H' 

ecept+ as a n+el theape,tic taet .+ c+nitie and sleep dis+des9 Tends

Pha0ac+l Sci9 #--4 7ecB#(1#):"1*/#9

• T,an N,yen 7aid A9 Shapi+ S,san R9 Ge+e =incent Set+la 7ennis 9

@ee Reina Chen @a,a Ra,se Sa0,el P9 @ee ein R9 @ynch $yan @9R+th and $ian 69 O7+2d 7isc+ey +. a N+el Me0e +. the Hista0ine

Recept+ 6a0ily The Journal of Molecular Pharmacology =+l9 ! Iss,e ' 4#&/

4'' Mach #--1