Download - adrenergicki lekovi
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ADRENERGIČKI LEKOVI
� Adrenergički lekovi deluju na aktivnost simpatičkog- adrenergičkog nervnog sistema preko adrenoreceptorakoji se u fiziološkim uslovima aktiviraju neurotransmiterom noradrenalinom (norepinefrin) a mogu delovati i preko neurona koji oslobañaju neurotransmiter.
Prof. dr Danica Agbaba
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adrenergički lekovi- podela
� simpatomimetici, adrenomimetici, adrenergički stimulansi i/ili agonistiadrenergičkih receptora
� simpatolitici, antiadrenergici iliadrenergički blokatori
PODELA - u zavisnosti od odgovora, odnosno farmakološkog efekta
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Agonisti – mimetici i antagonisti - litici
� mimetici - lekovi koji proizvode farmakološke efekte na efektornimorganima slične efektima koje izazivaju neurotransmiter – noradrenalin oslobodjeniz postganglijskih simpatičkih neurona kao posledica nervne stimulacije i adrenalin –neurohormon, sintetisan u srži nadbubrežne žlezde.
� litici - blokiraju receptor na dejstvo adrenalina i noradrenalina ili.....
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adrenergički receptori- membranski - GPCR
� Alfa receptori se dele na: alfa1 i alfa2
sa podtipovima: alfa1a, alfa1b, alfa1d, alfa2a alfa2b
i alfa2c
� Beta receptori se dele na: beta1, beta2,beta3 i beta4
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Human β2-adrenergic receptor: amino acid sequence of the human β2-receptor showing the seven transmembranedomains (I–VII), the connecting intracellular and extra cellular loops, extracellular glycosylation sites at as paragines6 and 15, and intrachain disulfide bonds between cysteine s 106–184 and 190–191. Also indicated are the aminoacids identified as participating in neurotransmitter b inding—aspartate 113 in transmembrane domain III, whic hbinds the positively charged amine of the neurotransmit ter, and serines 204 and 207 of transmembrane domain V, which form hydrogen-bonds with the catechol hydroxyls. P henylalanine 290 may participate in agonist binding as well. Amino acids 222–229 and 258–270 of the third intr acellular loop are critical for G protein–coupling, andpalmitoylated cysteine 341 is critical for proper adeny lyl cyclase activation.
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GPCR
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GPCR
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GPCR
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GPCR
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adrenergički receptori – distribucija i funkcija
� Strukturabeta1 receptora dominira u srcu ićelijamabubrega i smatra se da utiču na povećanje sekrecijerenina.
� Strukturabeta2 receptora dominira u glatkimmišićima i utiče na relaksaciju glatkih mišića bronhija, arteriola i vena.
� Strukturabeta3 receptora dominira u adipoznomtkivu i utiče na lipolizu.
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adrenergički receptori-distribucija i funkcija
� ubrzanje i pojačanje srčanog rada
� dilatacija vaskularnog sistema (vazodilatacija)
� dilatacija uterusa
� bronhodilatacija
� dilatacija mišića digestivnog trakta i dr.
Efekti koji nastaju posle stimulacije β- adrenergičkihreceptora su:
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adrenergički lekovi – distribucija i funkcija
� Strukturealfareceptora dominiraju u glatkimmišićima arteriola i vena, bronhija i GI trakta.
� Efekti koji nastaju posle stimulacije α- adrenergičkihreceptora su: vazokonstrikcija krvnih sudova, konstrikcija uterusa i bronhija, midrijaza, relaksacijamišića digestivnog trakta i drugi.
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adrenergički lekovi – distribucija i funkcija
� alfa1 i alfa2 - uloga u regulaciji metaboličkihprocesa - sekreciji insulina i glikogenolizi
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Hemija -katehol, kateholetilamin
kateholkatehol(o-difenol)
kateholetilaminkateholetilamin
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Biosinteza A i NA
� U srži nadbubrežne žlezde
� Neuronima adrenergičkog, dopaminergičkogsistema
� CNS i dr.
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Biosinteza endogenih kateholamina
[O]tirozin oksidaza
dopa dekarboksilaza
-CO2
[O]
dopamin-β oksidazametilovanje
N-metil transferaza
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Metabolizam
� aktivni transport vraća deo NA u presinaptički neuron (neuralnimetabolizam- MAo) a deo se koristi kao neurotransmiter
� ekstra neuralni metabolizam u jetri i krvnim pločicama
Enzimi:� COMT – katehol-O-metiltransferaza
� MAO – monoaminooksidaza -
R C NH2
MAOR C NH
H2OR C
O
H
NH3+
H
H H
• 3 – O – glukuronid/sulfat u intestinumu
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metabolizam kateholetilamina
COMT
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hemija i stabilnost adrenalina i noradrenalina
4-[(1-hidroksi-2-(metilamino)etil]-1,2-benzendiol
(bitartarat)
4-[(2-amino-1-hidroksietil)]-1,2-benzendiol
(hlorid, bitartarat)
Adrenalin
Noradrenalin
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Adranalin (A) i noradrenalin
� Sintetski lekovi – totalna sinteza - racemati� Koriste se soli , STABILNIJE i rastvorne u vodi� KATEHOL – nestabilnost, vodeni rastvori soli nestabilne� pH of 3 -4, stabilni rastvori� Fotosenzitivni, lako oksidišu (katehol), u baznoj sredini, u
prisustvu (Cu, Zn, Fe), u prisusvu kiseonika iz vazduha.� U rastvore adrenalina i noradrenalina se dodaju antioksidansi
kao natrijum bisufit , vit. C i dr, � Oba su polarna jedinjenja , pKa za A katjon je 8.7 i 9.9 (fenol
i protonovan amin). Na pH 7.4, 95% je prisutan kao katjon, 3% kao cviterjon ; samo 2% egzistira u nejonskoj formi.
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mehanizam oksidacije kateholamina
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PRIMENA
-Kod srčanog bloka ili cirkulatornog kolapsa - injekciono,ne može per os
-Lokalno –dodatak lokalnim anesteticima, midrijatik u kapima za oči
Dipivefrin – dipivaliladrenalinLipofilniji – efikasniji u nižim koncentracijama
-Pro drug-Tretman glaukoma
O
O
(H3C)3C
O(H3C)3C
OHHN
CH3
HO
OH
OHHN
CH3
+
O
2(CH3)3CCOOH
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Karakteristike-razlog za sintezu novih lekova
� In vivo
� Niska bioraspoloživost (oralno neaktivni) � Niska lipofilnost� Biološko poluvreme 1-2 min primenjen infuziono.� Brz metabolizam dejstvom MAO i COMT (jetra), 3-O-
glukuronid/sulfat (intestinum)
� In vitro
� NestabilnI kao baze i soli� Inaktivni - per os � Neselektivni
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CILJ
� Dejstvo duže i selektivnije� Stabilniji in vitro i in vivo� Per os primena leka
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Sintetski lekovi
� agonisti adrenergičkih receptora su derivati:
1. Feniletilamina ( α i β agonisti)
2. Arilimidazolina ( α agonisti)
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Hemijske promene na strukturi feniletilamina
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� Promene na benzenu
� Promene na azotu amino grupe
� Promene naα-C atomu
Hemijske promene na strukturi feniletilamina
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zamena α + β
QSAR Ariletilamini
pp
mm
RRααββ
mm,, p p - OH α + β
m, p p - OH
eliminacija αm, p p - OHzamena βm, mm - OH
� CH2OH polarna grupa� CH2-CH2- 2C maksimalna aktivnost
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QSAR Ariletilamini
pp
mm
RRααββ
ββCC - OH R(-) uslov za aktivnost
ααCC – CH3 stabilnost-MAO PEROS
α + β
CNSafinitet α2 + β2
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Stereohemijske modifikacije i dejstvo
� Alkilovanje alfa-C2 atoma hiralni centar – konfiguracija na C2 = uticaj na vezivanje za receptor.
� 1R, 2S = maksimalno direktno dejstvo na receptor� 1R, 2R = primarno indirektno dejstvo na R (oslobadja
endogeni NA) � 2S = SELEKTIVNOST ZA α 2 RECEPTOR� 2R- agonistiα1 postsinaptički-vazokonstriktor-poveëava krvni pritisak� 2S- agonistiα2 presinaptički R - smanjuje krvni pritisak
NHCH3RS
CH3
OH
α
β
1
2 OH
NHCH3SS
CH3
α
β
1
2
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QSAR Ariletilamini
pp
mm
RRααββ
1o ili 2 o amin (pka=8.5-10)
β
RR
R R – CH3 αR R – račvast:
,
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Derivati feniletilamina
OH
R
N
H
R1
H
HO
+X -
CH3CH3Oksilofrin
CH3HOksedrin
HHOktopamin
R1RNaziv
X=tartarat, hlorid
VAZOKONSTRIKTORI
� Para-monofenoli
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Derivati feniletilamina
� Meta-monofenoli
HHNorfenefrin
HCH3Metarminol
C2H5HEtilefrin
CH3HFenilefrin
R1RNaziv
X=tartarat, hloridOH
R
N
H
R1
H
HO
+X -
STABILNIJI, DUŽE DEJSTVO, SELEKTIVNI ZA α1 RECEPTOR,NEMA DEJSTVA NA CNS
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nefenoli – efedrinska grupa
OH
NHCH3SS
CH3
D(-)-1R,2S-α-[(metilamino)etil]benzenmetanol
Efedrin - D(-)-1R,2S-eritro
L(+) 1S,2S-treo
Pseudoefedrin
NHCH3RS
CH3
OH
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Efedrin
� Efedrin – alkaloid� Neselektivan� Nestabilan� Deluje na CNS� Stabilan na MAO i COMT-duže deluje� Deluje direktno (malo i indirektno - racemat)� Primena kod alergija i vazokonstriktor� (Alergije (β receptor), kijavica, hipotenzija (α receptor)
� Oralno,lokalno i parenteralno
NHCH3R
S
CH3
OH
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Pseudoefedrin
� Deluje indirektno – oslobadja endogeninoradrenalin
� Nema dejstvo na CNS ?� Bronhodilatator� Primena kod astmatične kijavice� Vazokonstriktor, midrijatik� Primena- oralno, lokalno� Kombinuje se sa antihistaminicima � OPREZ kod hipertenzije
OH
NHCH3SS
CH3
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Sintetski lekovi
� agonisti adrenergičkih receptora su derivati:
1. Feniletilamina ( α i β agonisti)
2. Arilimidazolina ( α agonisti)
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2---- Arilmetilimidazolini
- Strukturna sličnost sa kateholaminima- Dva C atoma izmedju aril i protonovanog azota (pKa 10 -11).- Di-orto supstitucija na aril radikalu >> alfa 1 i alfa 2 receptoru-Voluminozan radikal u para položaju (terc. butil) >>>selektivnost na alfa 1 vs. alfa 2 receptoru- Parcijalni agonisti na alfa 1 i alfa 2 receptoru.
N
N
H
12
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2- Arilmetilimidazolini
HO
HO
HOH
H H
H H
Cl
Cl
N
HNNHN
Noradrenalin KlonidinNA CLONIDINE
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derivati 2-arilimidazolina
� opšta strukturna formula derivata 2-arilimidazolina/2-arilmetilimidazolina
KsilometazolinKsilometazolin:: 2-[[4-(1,1-dimetiletil)-2.6-dimetil fenil]metil]-4.5-dihidro-1H-imidazolOksimetazolinOksimetazolin:: 3-[(4.5-dihidro-1H-imidazol-2-il) metil]-6-[1.1-dimetiletil]-2.4-dimetil-fenol
NafazolinNafazolin::4,5-dihidro-2(1-naftalenilmetil)-1H-imidazol
R grupa:
TetrahidrozolinTetrahidrozolin :: 4.5-dihidro-2-(1,2,3,4-tetrahidro-1-naftalenil)-1H-imidazol
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derivat 2-aminoimidazolina
TramazolinTramazolin4,5-dihidro-N-(5,6,7,8-tetrahidro-1-naftalenil)-1H-imidazol-2-amin.
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Primena
- Vazokonstriktori – lokalno na sluzokoži zaustavljanje krvarenja
- Vazokonstriktori – lokalno u kapima za nos
- Kod hipotonije i šoka - Kombinovano sa lokalnim anesteticima
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Derivat 2-amino, 2-metilimidazolina -tautomerija
2 – aminoimidazolini su selektivni agonisti alfa 2 rece ptora(locirani u CNS, inhibiraju oslobadjanje endogenog NA, deluju preko receptora u CNS-u, antihipertenzivi
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Hemijske promene na strukturi feniletilamina
AGONISTI ββββ2 - RECEPTORA
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Efekti stimulacije beta receptora
� Stimulacija beta1 receptora →aktivira rad srčanog mišića
� Stimulacija beta 2 receptora →bronhodilatacija, dilatacija uterusa i vazodilatacija
Cilj:� Beta 2 selektivni lekovi – bronhodilatatori
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Beta adrenergički agonisti - ariletanolamini
IzoprenalinIzoprenalin4-[1-hidroksi-2-[(1-metiletil)-amino]etil]-1.2 benzendiol
NESELEKTIVAN, NISKA BIORASPOLOŽIVOST, BRZ METABOLIZAMKoristi se za inhalacije, injekciono i sublingvalno
� Orto-difenoli
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SAR – selektivnost za beta2 receptor + stabilnost na COMT
Promene na aril radikalu
� m – OH - zamena sa polarnim grupama� Položajni izomer katehola – rezorcinol
� Estri katehola – lipofilnije jedinjenje i duže dejstvo
� Račvast radikal na azotu – izopropil → terc. butil >>> selektivnost na beta2 receptoru, arilalkoksialkil >>> lipofilnist i dužinu dejstva
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Beta adrenergički agonisti - ariletanolamini
IzoIzoetarinetarinStabilan na MAOStabilan na MAONestabilan na COMTNestabilan na COMT
SoterenolSoterenol–– metabolimetaboliččkikistabilnijistabilniji
CH2
NCH
HOH
HO
HOCH3
CH3
CH3
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Beta adrenergički agonisti
AlbuterolAlbuterol ((SalbutamolSalbutamol))R R izomerizomer 68 x aktivniji68 x aktivnijiSlabije izraSlabije izražžen sporedni en sporedni efekat na KVSefekat na KVS
PirbuterolPirbuterolfarmakinetifarmakineti ččkeke osobine osobine -- promenjenepromenjene
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STEREOSELEKTIVNI METABOLIZAM -ALBUTEROLA
� Registrovan u 26 zemalja kao racemat� Metabolički stabilan na COMT and O-sulfonovanje
�� R R izomerizomer 68 x aktivniji68 x aktivniji� Manje ispoljeno dejstvo na beta 1 receptor, selektivniji
� CHIRALITY SWITCH-LEVALBUTEROL –R(-)
� R(-) – levalbuterol- brz metabolizam, manju oralnu bioraspoloživost, i brzu eliminaciju
� S(+) – sporiji metabolizam i veće conc. u plazmi koje se zadržavaju ( ispoljava neželjeno dejstvo)
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Beta adrenergički agonisti - ariletanolamini
KarbuterolKarbuterol
Albuterol, pirbuterol i karbuterolimaju duže poluvreme eliminacije(6–8 h)
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Beta adrenergički agonisti - ariletanolamini
HO
N
OH H
(CH2)5 O (CH2)4
CH2OH
SalmeterolSalmeterol –– inhalaciona primenainhalaciona primenaParcijalni Parcijalni agonistagonist , radikal na azotu pove, radikal na azotu pove ććava ava lipofilnostilipofilnosti ( Log P 3,88) ( Log P 3,88) i vezivanje van aktivnog mesta i vezivanje van aktivnog mesta receptora. Spora receptora. Spora disocijacijadisocijacija leklek --receptorreceptor →→→→→→→→tt1/21/2 oko 12 h.oko 12 h.
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β-adrenergic agonisti-β2 -agonisti – dugo dejstvoInterakcija sa receptorom – moguëe objašnjenje
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β-adrenergički agonisti-β2 -agonisti – long lasting
HO
HNCH
NH
O
OH
CH 3
OCH 3
Formoterol- formanilid (log P =1.6)Racemat (R,R; S,S)R,R ima 1000-puta veëi affinitet za β2 – receptor Dejstvo leka 12 h.Manje lipofilan ali je aktivniji, 12 µµµµg vs. 50 µg of salmeterolNestabilan na vlagu i temperaturuInhalaciona primena
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Hidroliza bitolterola
BitolterolBitolterol mezilatmezilat((TornalatTornalat ))InfalacionaInfalaciona primenaprimena
+ 2
kolterol
HOH
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Osobine - BitolterolBitolterol mezilatmezilat
� PRODRUG –� Estar je lipofilniji� Hidrolizuju ga esteraze u pluëima i drugim
tkivima do aktivnog kolterol-a.� Ima duže dejstvo 5 - 8 časova.� Metaboliše – dejstvom COMT-a i
conjugacijom.� Koristi se kao inhalacija
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Heksoprenalin, ritodrin – dilatacija uterusa
HeksoprenalinHeksoprenalin
RitodrinRitodrin
Primena – per os i infuzije
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m – difenoli,rezorcinoli
HO
OH
N
H
R
OH
Stabilni na COMT i reakcije oksidacijeSelektivni za beta 2 receptorManje sporednih efekataOralna primenaMetabolišu reakcijama konjugacije
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Meta-difenoliHO
OH
N
H
R
OH
CH3
CH3
CH3
CH3
CH3
CH3
OH
N
N
N
NCH3
OO
CH3
propil teofilin
4. Reproterol
3. Fenoterol
2. Terbutalin
1. MetaproterenolOrciprenalin
R
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Para-monofenoli - vazodilatatori
BametanBametan––Periferni Periferni vazodilatatorvazodilatator
BufeninBufenin –– parcijalni parcijalni agonistaagonistana alfana alfa11 i i beta beta receptorreceptor
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Para-monofenoli - vazodilatatori
�� BametanBametan--�� PeriferniPerifernivazodilatatorivazodilatatori
�� BufeninBufenin--NN--arilalkilarilalkil ↑↑afinitetafinitet zaza
αα--receptor receptor –– parcijalniparcijalni agonist agonist
Poveëava krvni pritisakKontrakcija glatkih mišiëaα
Arteriole glatkih mišiëa ( not supply muscle)
Konstrikcija KS i poveëva krvnipitisaka suprotno naβ2 .
Kontrakcija glatkih mišiëa
Relaksacija glatkih mišiëaα, β2fight and flight
VENE
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Drugi mehanizmi bronhodilatacije
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Antagonisti adenozinskih receptora-derivati ksantina
OH
OH
12
3
32
1CH3
OH3. Proksifilin
2. Diprofilin
H1. Teofilin
R
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Antagonisti holinergičkih receptora
IpratropijumIpratropijum bromidbromid
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Antagonisti histaminskih H1-receptora
benzobenzo[4,5]ciklohepta[1,2[4,5]ciklohepta[1,2--b]tiofenb]tiofen
4.94.9--dihidrodihidro --44--(1(1--metilmetil --44--piperidiniliden)piperidiniliden) --10H10H--benzobenzo[[[[[[[[4,54,5]]]]]]]] cikloheptaciklohepta[[[[[[[[1,21,2--bb]]]]]]]]tiofentiofen--1010--onon
� ketotifen
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Ostali mehanizmi
GlikokortikoidiInhibitori biosinteze prostanglandina – MontelukastNovi – Inhibitori fosfodiesteraze