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Z:\Sergio\Diapositivos\CliniPharmak.ppt
Diferentes nomes para o mesmo problema
Diferentes nomes para o mesmo problema
• Bronquite
• Bronquite alérgica
• Bronquite asmática
• Bronquite
• Bronquite alérgica
• Bronquite asmáticaASMAASMA
Z:\Sergio\Diapositivos\CliniPharmak.ppt
ASMA - DefiniçãoASMA - Definição
É uma doença inflamatória crônica das vias aéreas na qual muitas células desempenham um papel importante, incluindo os mastócitos e os eosinófilos.
Em indivíduos suscetíveis a esta inflamação, ela causa sintomas freqüentemente associados à obstrução ao fluxo aéreo que é reversível com ou sem tratamento.
A inflamação também causa aumento da reatividade brônquica a diversos estímulos.
É uma doença inflamatória crônica das vias aéreas na qual muitas células desempenham um papel importante, incluindo os mastócitos e os eosinófilos.
Em indivíduos suscetíveis a esta inflamação, ela causa sintomas freqüentemente associados à obstrução ao fluxo aéreo que é reversível com ou sem tratamento.
A inflamação também causa aumento da reatividade brônquica a diversos estímulos.
International Conference Report, 1992
Proliferação CelularAumento da Matriz
Extracelular
Proliferação CelularAumento da Matriz
Extracelular
Recrutamento celular
Dano EpitelialModificações
Estruturais Precoces
Recrutamento celular
Dano EpitelialModificações
Estruturais Precoces
Broncoconstrição
Edema
Secreção
Tosse
Broncoconstrição
Edema
Secreção
Tosse
Inflamação Aguda
Inflamação Aguda
Remodelamento das Vias AéreasRemodelamento das Vias Aéreas
Inflamação Crônica
Inflamação Crônica
Processo inflamatório da ASMAProcesso inflamatório da ASMA
Cançado, JE 2000
Estímulos que desencadeim a asma
• Estreitamento das vias aéreas pode ocorrer em resposta aos seguintes estímulos:
– Alergenos
– Infecções
– Dieta/Medicações
– Fatores emocionais (estímulos endógenos)
– Exercício físico
– Ar frio
– Exposição a irritantes
químicos
IndutoresIndutores
AlérgenosAlérgenosAlérgenosAlérgenos
AspirinaAspirinaAspirinaAspirina
Agentes Agentes ocupacionaisocupacionais
Agentes Agentes ocupacionaisocupacionais
VSRVSRVSRVSR
ExercíciosExercíciosExercíciosExercícios
ASMAASMA
ProvocadoresProvocadores
IrritantesIrritantesIrritantesIrritantes
Schematic diagram illustrating the overlapping relationship between syndromes characterized by disordered airway function.
Multi-dimensional phenotyping: towards a new taxonomy for airway disease - Clin Exp Allergy 2005; 35:1254–1262
Asma
AsmaNormal
SADIO
ASMA LEVE
Hyperplasia and erosion
Eosinophil and Lymphocyte Infiltration
Inflamação das Vias Aéreas na ASMAInflamação das Vias Aéreas na ASMA
AsmáticoAsmáticoNormalNormalP Jeffery, in: Asthma, Academic Press 1998
Induced sputum specimens from patients with eosinophilic airway inflammation (A) or neutrophilic airway inflammation (B)
Pharmacological management of mild or moderate persistent asthma - Lancet 2006; 368: 794–803
A B
C D
Sputum cytospins showing the four inflammatory subtypes of asthma: (a) neutrophilic asthma; (b) eosinophilic asthma; (c) mixed granulocytic asthma; (d) paucigranulocytic asthma.
(a) Induced sputum neutrophils and (b) eosinophils in asthma subgroups and healthy controls.
eosinophilic
neutrophilic
mixed granulocytic
paucigranulocytic
healthy
Bars are median with error bars representing the interquartile range.
Schematic diagram illustrating the heterogeneity of airways disease in terms of triggers, pattern of airway inflammation, associated diseases, airway physiology and the specific
underlying pathological abnormality
The reclassification of asthma based on subphenotypes - Lippincott Williams & Wilkins
0 100 200 300 400 500 600 700 800
100
80
60
40
20
0
Days from maintenance
Pro
por
tion
fre
e of
exa
cerb
atio
n (
%) Sputum strategy
Conventional strategy
Number at risk
Sputum strategy 48 41 38 33 27 20 13 5 0
Conventional strategy 52 42 33 26 19 16 12 9 0
Kaplan-Meier survival curve of patients free of asthma exacerbations over 2 years in the Canadian study
Pharmacological management of mild or moderate persistent asthma - Lancet 2006; 368: 794–803
0 1 2 3 4 5 6 7 8 9 10 11 12
120
100
80
60
40
20
0
Guidelines management groupSputum managenment group
Sev
ere
exac
erb
atio
ns
Time (months)
Cumulative asthma exacerbations in a group managed according to standard guidelines, and one managed by identification of eosinophilic inflammation in sputum and adjustment of
treatment where necessary
Asthma: defi ning of the persistent adult phenotypes - Lancet 2006; 368: 804–13
0 1 2 3 4 5 6 7 8 9 10 11 12
120
100
80
60
40
20
0
Sev
ere
exac
erb
atio
ns
(cu
mu
lati
ve n
um
ber
)
Time (months)
6 asthma admissions
BTS guidelines
Sputum guidelines
1 asthma admission
Severe exacerbations in subjects with asthma managed by standard British Thoracic Society (BTS) guidelines vs those managed by an algorithm directed at normalizing the sputum
eosinophil count
Clinical Applications of Induced Sputum- (CHEST 2006; 129:1344–1348)
Cumulative asthma exacerbations during a 12-month randomized trial of asthma management guided at controlling sputum eosinophilia compared
with conventional management
120
100
80
60
40
20
00 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
Several exacerbations (cumulative number) Control management
Sputum guided management
109
35
The reclassification of asthma based on subphenotypes - Lippincott Williams & Wilkins
Resposta Imediata e Tardia da asma
50
25
1 2 3 4 5 6 7 8 9 10 11 12
75
100
Tempo (h)Inalaçãodo
alérgeno
AAR
AAR = Resposta aguda, imediata LAR = Resposta tardia
FE
V1 (
%)
LAR
Z:\Sergio\Diapositivos\CliniPharmak.ppt
ASMA - DefiniçãoASMA - Definição
É uma doença inflamatória crônica das vias aéreas na qual muitas células desempenham um papel importante, incluindo os mastócitos e os eosinófilos.
Em indivíduos suscetíveis a esta inflamação, ela causa sintomas freqüentemente associados à obstrução ao fluxo aéreo que é reversível com ou sem tratamento.
A inflamação também causa aumento da reatividade brônquica a diversos estímulos.
É uma doença inflamatória crônica das vias aéreas na qual muitas células desempenham um papel importante, incluindo os mastócitos e os eosinófilos.
Em indivíduos suscetíveis a esta inflamação, ela causa sintomas freqüentemente associados à obstrução ao fluxo aéreo que é reversível com ou sem tratamento.
A inflamação também causa aumento da reatividade brônquica a diversos estímulos.
International Conference Report, 1992
SlightSlight
FEV1 in patients (HBR)FEV1 in patients (HBR)
SevereSevere ModerateModerate MildMild
NormalNormalNormalNormalCOPDCOPDCOPDCOPD
Dose (Dose (mol)mol)Dose (Dose (mol)mol)
FE
VF
EV
11 (%
FA
LL
) (
% F
AL
L)
FE
VF
EV
11 (%
FA
LL
) (
% F
AL
L)
ASTHMAASTHMAASTHMAASTHMA
6060
5050
4040
3030
2020
1010
00
6060
5050
4040
3030
2020
1010
00
0.01 0.1 1.0 10 100 0.01 0.1 1.0 10 100 0.01 0.1 1.0 10 100 0.01 0.1 1.0 10 100
HISTAMINEHISTAMINEHISTAMINEHISTAMINEMETHACHOLINEMETHACHOLINEMETHACHOLINEMETHACHOLINE
Z:\Sergio\Diapositivos\CliniPharmak.ppt
ASMA ASMA
• É a doença crônica mais comum na infância
• A incidência na população
pediátrica brasileira é de 13%
• 50% a 80% das crianças asmáticas desenvolvem
sintomas antes dos 5 anos de idade
• É a doença crônica mais comum na infância
• A incidência na população
pediátrica brasileira é de 13%
• 50% a 80% das crianças asmáticas desenvolvem
sintomas antes dos 5 anos de idadeNational Institutes of Health, 1997. NIH Publication No. 97-4051.
II Consenso Brasileiro no Manejo da Asma, 1998
Genética da AsmaGenética da Asma
A asma “caminha” pelas gerações das famíliasA asma “caminha” pelas gerações das famílias
Gêmeos monozigóticos apresentam maior Gêmeos monozigóticos apresentam maior concordância que os DZ nas prevalências de asma.concordância que os DZ nas prevalências de asma.
Ainda não esclarecido:Ainda não esclarecido:
A maior prevalência nos meninosA maior prevalência nos meninos
A maior mortalidade na raça negra A maior mortalidade na raça negra
Peter J. Barnes. Asthma Peter J. Barnes. Asthma
TabagismoTabagismo
Strachan & Cook - Thorax 52: 905-14, 1997Cook & Strachan - Thorax 52: 1081-94, 1997
Strachan & Cook - Thorax 53: 117-23, 1998Cook & Strachan - Thorax 53: 295-301, 1998
Strachan & Cook - Thorax 52: 905-14, 1997Cook & Strachan - Thorax 52: 1081-94, 1997
Strachan & Cook - Thorax 53: 117-23, 1998Cook & Strachan - Thorax 53: 295-301, 1998
Meta-análises confirmam:
Tabagismo nos pais aumenta o risco
dos filhos terem maior freqüência
de doenças respiratórias, asma,
tosse crônica e sibilância
Meta-análises confirmam:
Tabagismo nos pais aumenta o risco
dos filhos terem maior freqüência
de doenças respiratórias, asma,
tosse crônica e sibilância
TRATAMENTO
• Categorias de drogas– Agonistas -adrenérgicos– Glicocorticosteróides– Metilxantinas– Anticolinérgicos– Inibidores da lipoxigenase– Antagonistas de receptores de leucotrienos– Monoclonal para IgE– Monoclonal para TNF-alfa– Imunoterapia
• Reduzir ou prevenir a inflamação das vias aéreas e a ação dos mediadores que contribuem para o broncoespasmo.
Agonistas Agonistas 2-adrenérgicos-adrenérgicos
Agonists 2 Adrenérgicos
• Broncodilatadores mais potentes – Aliviam o broncoespasmo
• Duas classes:Curta duração: Fenoterol, salbutamol, terbutalinaLonga duração: Formoterol, salmeterol
• Mecanismo:– Ativam receptores 2 no músculo liso pulmonar– Promovem broncodilatação (aliviam o broncoespasmo)– Efeitos antiinflamatórios discretos
SALBUTAMOL, TERBUTALINASALBUTAMOL, TERBUTALINA
ADRADRISOISO
22
Broncodilatação
RelaxamentoUterino
RelaxamentoVascular
AGONISTAS DE AÇÃO DIRETA
Adrenergic agonist structureAdrenergic agonist structure
NorepinephrineNorepinephrineNorepinephrineNorepinephrine
EpinephrineEpinephrineEpinephrineEpinephrine
IsoproterenolIsoproterenolIsoproterenolIsoproterenol
SalbutamolSalbutamolSalbutamolSalbutamol
CHCH CHCH NHNH
OHOH HH HH
CHCH CHCH NHNH
OHOH HH CHCH33
CHCH CHCH NHNH
OHOH HH CH(CHCH(CH33))33
CHCH CHCH NHNH
OHOH HH C(CHC(CH33))22
HOHO
HOHO
HOHO
HOHO
HOHO
HOHO
HOHHOH22CC
HOHO
-adrenoceptor exosite
-
CH
HO
HO-CH2
-
OH
-- CH
2 NH
-
CH2
---
CH2
CH2
CH2
CH2
-- CH
2 O CH2---- CH2 CH2 CH2
HIPÓTESE: EXOSITE BINDING
HO
HO
OH
CH
O
salmeterol
Beta2 de longa duraçãoBeta2 de longa duração
• Discreta ação anti-inflamatória in vitro.
• Formas de administração: inalatória (formoterol, salmeterol) e oral
(terbutalino)
• Efeitos colaterais:
– estímulo beta-adrenérgico
– tolerância
• Indicação: prevenção de sintomas noturnos
• Discreta ação anti-inflamatória in vitro.
• Formas de administração: inalatória (formoterol, salmeterol) e oral
(terbutalino)
• Efeitos colaterais:
– estímulo beta-adrenérgico
– tolerância
• Indicação: prevenção de sintomas noturnos
0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
100100
9090
8080
7070
6060
100100
9090
8080
7070
6060
HoursHoursHoursHours
FE
VF
EV
11 (%
of
(%
of
Pre
dic
ted
Pre
dic
ted
FE
VF
EV
11 (%
of
(%
of
Pre
dic
ted
Pre
dic
ted
Salmeterol 42 mcg twice daily (n=178)Salmeterol 42 mcg twice daily (n=178) Salbutamol 180 mcg four times daily (n=176)Salbutamol 180 mcg four times daily (n=176) Placebo (n=181)Placebo (n=181)
Salmeterol 42 mcg twice daily (n=178)Salmeterol 42 mcg twice daily (n=178) Salbutamol 180 mcg four times daily (n=176)Salbutamol 180 mcg four times daily (n=176) Placebo (n=181)Placebo (n=181)
FEVFEV11, as percent of Predicted, From two large, as percent of Predicted, From two large
12-Week Clinical Trials12-Week Clinical TrialsFirst Treatment dayFirst Treatment day
ofdahl and Svedmyr, Allergy 1989
Duração do efeito: formoterol vs salbutamol
TEMPO (h)
Cap
acid
ade
Bro
nco
dil
atad
ora
(%
) Formoterol 6 µg
Salbutamol 100 µg
-20
20
60
100
0 2 4 6 8
09 pacientes asmáticosVia Inalatória
Agonistas 2-adrenérgicos
Salbutamol, Terbutalina, Bitolterol
• Forma preferida como terapia broncodilatadora
• Via inalatória
• Complicações decorrentes do uso
• Automedicação
• Efeitos colaterais (cardíacos) a longo prazo
• Não reduzem hiperreatividade brônquica
Agonistas 2-adrenérgicos
• Efeitos Adversos
– Preparação Inalação• Mínimos• Uso prolongado pode causar mortalidade• Efeitos sistêmicos: taquicardia, angina, tremores
– Preparação Oral• Ativa o receptor 1 no coração• Sobredose pode causar intensa estimulação de 1 cardíacos,
levando a angina pectoris e taquiarritmias• Tremores (estimulação de 2)
Glicocorticóides
SlightSlight
FEV1 in patients (HBR)FEV1 in patients (HBR)
SevereSevere ModerateModerate MildMild
NormalNormalNormalNormalCOPDCOPDCOPDCOPD
Dose (Dose (mol)mol)Dose (Dose (mol)mol)
FE
VF
EV
11 (%
FA
LL
) (
% F
AL
L)
FE
VF
EV
11 (%
FA
LL
) (
% F
AL
L)
ASTHMAASTHMAASTHMAASTHMA
6060
5050
4040
3030
2020
1010
00
6060
5050
4040
3030
2020
1010
00
0.01 0.1 1.0 10 100 0.01 0.1 1.0 10 100 0.01 0.1 1.0 10 100 0.01 0.1 1.0 10 100
HISTAMINEHISTAMINEHISTAMINEHISTAMINEMETHACHOLINEMETHACHOLINEMETHACHOLINEMETHACHOLINE
Steroid treatmentSteroid treatment
SlightSlightSevereSevere ModerateModerate MildMild
Histamine Dose (Histamine Dose (mol)mol)Histamine Dose (Histamine Dose (mol)mol)
FE
VF
EV
11 (%
FA
LL
) (
% F
AL
L)
FE
VF
EV
11 (%
FA
LL
) (
% F
AL
L)
6060
5050
4040
3030
2020
1010
00
6060
5050
4040
3030
2020
1010
00
0.001 0.01 0.1 1.0 10 0.001 0.01 0.1 1.0 10 0.001 0.01 0.1 1.0 10 0.001 0.01 0.1 1.0 10
InitialInitial(2.0)(2.0)
InitialInitial(2.0)(2.0)
4 months4 months(3.0)(3.0)
4 months4 months(3.0)(3.0)
6 months6 months(2.6)(2.6)
6 months6 months(2.6)(2.6)
7 months7 months(3.0)(3.0)
7 months7 months(3.0)(3.0)
Relação Estrutura Química e Atividade Farmacológica
MODIFICAÇÕES NA ESTRUTURA MOLECULAR DOS GLICOCORTICÓIDESMODIFICAÇÕES NA ESTRUTURA MOLECULAR DOS GLICOCORTICÓIDESMODIFICAÇÕES NA ESTRUTURA MOLECULAR DOS GLICOCORTICÓIDESMODIFICAÇÕES NA ESTRUTURA MOLECULAR DOS GLICOCORTICÓIDES
C OC OC O
OOO
OHOHOH
CH2OHCHCH22 OHOH
HOHOHO
222
111
333
444555
999
101010
666777
888
191919
FFF
121212111111
141414
131313171717
151515
161616
181818
CH3CHCH33
CH3CHCH33
212121
202020
OO
OO
ESTRUTURA MOLECULAR DE ALGUNS CORTICOSTERÓIDESESTRUTURA MOLECULAR DE ALGUNS CORTICOSTERÓIDES ESTRUTURA MOLECULAR DE ALGUNS CORTICOSTERÓIDESESTRUTURA MOLECULAR DE ALGUNS CORTICOSTERÓIDES
C OC O
OHOH
CHCH2 2 OHOH
HOHO
CortisolCortisol
OHOH
CHCH2 2 OHOH
C OC O
OO
CortisonaCortisona
OHOH
CHCH2 2 OHOH
C OC O
HOHO
PrednisolonaPrednisolona
OHOH
CHCH2 2 OHOH
C OC O
PrednisonaPrednisona
OO
OHOH
CHCH2 2 OHOH
C OC O
HOHO
MetilprednisolonaMetilprednisolona BetametasonaBetametasona
DexametasonaDexametasona
OHOH
CHCH2 2 OHOH
C OC O
HOHO
TriamcinolonaTriamcinolona
OHOH
CHCH2 2 OHOH
C OC O
HOHO
FludrocortisonaFludrocortisona
OO
CHCH33
OHOH
CHCH2 2 OHOH
C OC O
HOHOCHCH33
FF
OHOH
FF FF
OO
OOOO
OOOO
Glucocorticóides inalatórios
CORTICOTERAPIA SISTÊMICACORTICOTERAPIA SISTÊMICATabela de EquivalênciaTabela de Equivalência
Fármaco Potência Dose Fármaco Potência Dose
AntiinflamatóriaAntiinflamatória Equivalente (mg) Equivalente (mg)
Cortisol (HC) Cortisol (HC) 1 201 20 CortisonaCortisona 0,8 25 0,8 25 Prednisona 4 5Prednisona 4 5Prednisolona 4 5Prednisolona 4 5MetilprednisolonaMetilprednisolona 5 4 5 4Triamcinolona 5 4Triamcinolona 5 4Betametasona 20-30 0,75Betametasona 20-30 0,75Dexametasona 20-30 0,75Dexametasona 20-30 0,75
% deposição pulmonar
Metabolismo da ciclesonida
Deposição pulmonar (HFA)
CORTICOTERAPIACORTICOTERAPIA SISTÊMICASISTÊMICA
Meia-vida Meia-vida Duração do efeito Duração do efeitoFármacoFármaco (h) (h)
Cortisol (HC)Cortisol (HC) 8 - 12 8 - 12 curta curtaCortisonaCortisona 12 12 curta curtaPrednisonaPrednisona 12 - 36 12 - 36 intermediáriaintermediáriaPrednisolonaPrednisolona 12 - 36 12 - 36 intermediáriaintermediáriaMetilprednisolona 12 - 36Metilprednisolona 12 - 36 intermediária intermediária TriamcinolonaTriamcinolona 12 - 36 12 - 36 intermediáriaintermediáriaBetametasonaBetametasona 24 - 72 24 - 72 prolongada prolongadaDexametasonaDexametasona 24 - 72 24 - 72 prolongada prolongada
Citoplasma
Núcleo
Membrana celular
Membrana nuclear
Proteínas e Enzimas
Cortisol
Cortisol
Receptor(proteína plasmática)
Elementos responsivos ao GC
Complexo GC-Receptor
CROMATINA
mRNA
Estimula Transcrição
mRNA
Síntese
Resposta ao GC
GCS
RG
hsp90
núcleo ERGn ERG+
Gene alvoresponsivo ao corticóide
X
CitocinasiNOSCOX-2PLA2
RNAm
Lipocortina-1-receptor
CORTICOSTERÓIDESCORTICOSTERÓIDES
INIBIÇÃO da liberação /ação de mediadores inflamatórios:
Prostaglandinas e leucotrienosCitocinasAminas vasoativasRadicais livres de oxigênio
Inibição da indução de enzimas (iNOS, COX-2)
CÉLULAS MÚSCULO LISO: AÇÕES DOS GLICOCORTICÓIDES
INIBIÇÃO MECANISMOS PRODUTORES DE CONTRAÇÃO
Redução da conc. Ca2+ intracelular
Redução expressão receptores muscarínicos
Desacoplamento receptores H1 histamina
CÉLULAS MÚSCULO LISO: AÇÕES DOS GLICOCORTICÓIDES
POTENCIAÇÃO MECANISMOS PRODUTORES DE RELAXAMENTO
Redução dessensibilização receptores 2-adrenérgicos
Aumento número receptores 2-adrenérgicos
Aumento atividade adenil-ciclase
Vias de Administração
Oral Aerossol Intra-muscular Endovenosa Intra-articular Conjuntival Nasal Percutânea
Glicocorticóides: Toxicidade
Síndrome de Cushing (c/ eritema facial)
Diminuição da massa muscular
Osteoporose (fraturas ósseas)
Hipertensão arterial
Hepatomegalia
Hiperglicemia / Hiperproteinemia
Úlceras pépticas
Retardo no crescimento
GlicocorticóidesGlicocorticóides1. Para cada paciente e doença, a dose apropriada é determinadapor tentativa e erro;
2. Uma única dose de corticóide nunca é perigosa, mesmo que elevada;
3. Poucos dias de terapia com corticóide é improvável que produzaefeitos indesejáveis, exceto com altas dosagens;
4. Se a terapia com corticóide for prolongada (semanas / meses), a incidência de efeitos colaterais aumenta;
5. A terapia com corticóide não é específica nem curativa, massomente paliativa.
GlicocorticóidesBeclometasona, Triamcinolona, Flunisolide
Formulações de aerossol
Diminuem a hiperreatividade brônquica
Uso inalatório: Redução de efeitos sistêmicos
Previnem a fase tardia
Efeitos adversos associados ao uso inalatório Supressão do eixo H-H-Adrenal (não importante)
Osteoporose (relativamente importante)
Metabolismo de carboidratos e lipídeos (insignificante)
Disfonia, candidíase (riscos pequenos)
Retardo no crescimento
Lipid-soluble, inhaled corticisteroids
Beclomethasone
Fluticasone
Triamcinolone
Spacer
Metered-dose inhaler
Large aerosol particles are deposited in chamber rather patient’s mouth
Inhaled portion consists of small particles which travel to small airways
Netter’s Illustrated Pharmacology – fig 7-19
Corticosteroids: Clinical Uses
EspaçadoresEspaçadores• Reduzem a velocidade das partículas
• Aumentam a distância percorrida pelo jato
• Aumentam a relação partículas pequenas vs. grandes inspirada
• Diminuem a deposição oral e nas grandes vias aéreas
• Reduzem a velocidade das partículas
• Aumentam a distância percorrida pelo jato
• Aumentam a relação partículas pequenas vs. grandes inspirada
• Diminuem a deposição oral e nas grandes vias aéreas
Medida de Inflamação Pulmonar: Agonista 2 vs
Corticóide
1. Catarro– Leucócitos totais e diferenciais– Proteína catiônica do eosinófilo (ECP)– Triptase
2. Broncoscopia
3. Óxido nítrico exalado
Lazarus et al., 2001, JAMA [164 pacientes, 12-65 anos, asma persistente]
Óxido Nítrico Exalado
15
20
25
30
35
0 6 12 18 24
Weeks
Triamcinolone
Salmeterol
Placebo
Run-In Double-Blind Treatment
0.0215
MeanFENO(ppb)
Eosinófilos
1
2
3
4
5
6
7
8
0 6 12 18 24
Weeks
Triamcinolone
Salmeterol
Placebo
Run-In Double-Blind Treatment
0.0003
0.0007
MeanSputum Eos (%)
Proteína Catiônica do Eosinófilo
50
110
290
170
230
350
0 6 12 18 24
Weeks
Triamcinolone
Salmeterol
Run-In Double-Blind Treatment
MedianSputum ECP (µg/L)
Placebop=0.0054
Triptase
0
5
10
15
0 6 12 18 24
Weeks
Triamcinolone
Salmeterol
Placebo
Run-In Double-Blind Treatment Run-Out
MeanSputumTryptase (ng/ml)
1-0
0-8
0-6
0-4
0-2
0-0
Optima A Optima B Facet
PlaB20
0
B200 +
For
9B20
0B40
0
B400 +
For
9B20
0
B200 +
For
18B80
0
B800 +
For
18
Rat
e of
exa
cerb
atio
ns
(nu
mb
er p
er p
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nt
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Rate of severe asthma exacerbations in OPTIMA and FACET studies
Pharmacological management of mild or moderate persistent asthma - Lancet 2006; 368: 794–803
Sensitivity of Hypothalamic-Pituitary-Adrenal Axis Function Tests
Function Sensitivity of test
AUC0-24h plasma cortisol
24-Hour urinary free cortisol
Overnight urinary free cortisol
Urinary cortisol metabolites
CRH stimulation
Low-dose cosyntropin (0.5-1 µg)
Insulin tolerance test
Morning cortisol
Standard-dose cosyntropin (250 µg)
Most sensitive
Least sensitive
The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006
0700 1100 1500 1900 2300 0300 0700
20
16
12
8
4
0
Time (hours)
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(µ
g/d
L)
Morning dose
evening dose
PBO bidCIC 640 µg qd AM and PBO PMCIC 640 µg qd PM and PBO AMCIC 320 µg bid
20 22 0 2 4 6 8 10 12 14 16 18 20
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450
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350
300
250
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100
50
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Time (hours)
Pla
sma
cort
isol
(n
mol
/L)
PBOCIC 640 µg bidFP 440 µg bid
CIC 320 µg qdCIC 640 µg bidFP 880 µg bid
A, Mean 24-hour serum cortisol level profiles in healthy volunteers receiving ciclesonide (CIC) or placebo (PBO).68 This figure has been reproduced with permission from The
Endocrine Society (copyright 2002, The Endocrine Society).58 B, Mean plasma cortisol concentrations more than 24 hours after 9 days of treatment with PBO, CIC, or fluticasone
propionate (FP).69 bid indicates twice daily; qd, once daily.
A B
The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006
Mean percent change in 24-hour urinary free cortisol profile and plasma cortisol area under the concentration time curve (AUC0 –24h)69 (*P .0001 vs
placebo; #P .0003 vs placebo).
0
-10
-20
-30
-40
-50
-60
-70Urinary cortisol
Plasma cortisol
Ch
ange
in c
orti
sol c
once
ntr
atio
n
vers
us
pla
ceb
o (%
)
CIC320 CIC640 CIC1280 FP880 FP1760
The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006
30
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0Placebo CIC40 CIC80 CIC160
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ly a
lbu
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l use
(p
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Effect of ciclesonide (40, 80, and 160 g/day) from baseline to week 12 on (A) AM PEF, (B) asthma symptom
scores, and (C) daily albuterol use in children with all severities of asthma
(values expressed as least squares mean and standard error).
Mean percent change from baseline to week 4 in serum cortisol 24-hour area under the concentration time curve (AUC0–24h).
PBO CIC640 CIC1280 FP880 FP1760
20
10
0
-10
-20
-30
-40
-50
Ser
um
cor
tiso
l AU
C0-
24h
Per
cen
tage
ch
ange
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The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006
Mean change from baseline to week 12 in peak serum cortisol levels after low-dose (1 g) cosyntropin stimulation.
PBO CIC320 CIC640 FP880
Mea
n c
han
ge f
rom
bas
elin
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p
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ser
um
cor
tiss
ol (
µg/
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2.0
1.1
0
-1.0
-2.0
-3.0
-4.0
The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006
Mean provocative concentration required to produce a 20% decrease in lung function (PC20) forced expiratory volume in 1 minute for adenosine triphosphate (AMP) after at least 9 days
of treatment69 (*P .001 vs placebo).
4
3
2
1
0
Ch
ange
in P
C20
AM
P(d
oub
lin
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nce
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PBO CIC320 CIC640 CIC1280 FP880 FP1760
The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006
METILXANTINASTeofilina
• Componente natural (chá) com propriedade broncodilatadora
• Usada desde 1930 para o tratamento da asma.
Camellia sinensisThea sinensis
Nativas do Tibet, Índia e China
Teofilina (Teolong, Talofilina)
Inibição da fosfodiesterase do AMPc e GMPc
Antagonista de receptores de adenosina
Inibidor direto da mobilização de Ca2+
Inibidor da quimiotaxia de neutrófilos
Xantinas de longa duraçãoXantinas de longa duração• Discreta ação anti-inflamatória
• Forma de administração: oral (teofilina, bamifilina)
• Dose terapêutica próxima da dose tóxica
• Nível sérico errático
• Efeitos colaterais: GI, convulsão
• Indicação: terapia adicional
• Discreta ação anti-inflamatória
• Forma de administração: oral (teofilina, bamifilina)
• Dose terapêutica próxima da dose tóxica
• Nível sérico errático
• Efeitos colaterais: GI, convulsão
• Indicação: terapia adicional
Broncodilatador Anticolinérgico
• Efeito broncodilatador máximo em 90 min, permanecendo por até 6 h
• Usado em associação com agonista 2 adrenérgico de
curta duração
• Não costuma ser utilizado de forma isolada.
Brometo de Ipratrópio (Atrovent)
Ipratropium bromide (Atrovent)Ipratropium bromide (Atrovent)
BrBr-- H H22OOBrBr-- H H22OO
HHHH
HH33CCHH33CC CH(CHCH(CH33))22CH(CHCH(CH33))22
NN++NN++
HHHH
HHHHCCCC
OCOCOCOC
OOOO
CHCHCHCH
CHCH22OHOHCHCH22OHOH
Cochrane Database Syst Rev. 2003;(3):CD003535. Department of Paediatric Emergency Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London, UK, SW10 9NH.
Anticholinergic therapy for chronic asthma in children over two years of age.
McDonald NJ, Bara AI.
BACKGROUND: In the intrinsic system of controlling airway calibre, the cholinergic (muscarinic) sympathetic nervous system has an important role. Anticholinergic, anti muscarinic bronchodilators such as ipratropium bromide are frequently used in the management of childhood airway disease. In asthma, ipratropium is a less potent bronchodilator than beta-2 adrenergic agents but it is known to be a useful adjunct to other therapies, particularly in status asthmaticus. What remains unclear is the role of anticholinergic drugs in the maintenance treatment of chronic asthma. OBJECTIVES: To determine the effectiveness of anticholinergic drugs in chronic asthma in children over the age of 2 years. SEARCH STRATEGY: The Cochrane Airways Group trials register and reference lists of articles were searched in January 2002. SELECTION CRITERIA: Randomised controlled trials in which anticholinergic drugs were given for chronic asthma in children over 2 years of age were included. Studies including comparison of: anticholinergics with placebo, and anticholinergics with any other drug were included. DATA COLLECTION AND ANALYSIS: Eligibility for inclusion and quality of trials were assessed independently by two reviewers. MAIN RESULTS: Eight studies met the inclusion criteria.Three papers compared the effects of anticholinergic drugs with placebo, and a meta-analysis of these results demonstrated no statistically significant benefit of the use of anticholinergic drugs over placebo in any of the outcome measures used. The results of one of these trials could not be included in the meta-analysis but the authors did report significantly lower symptom scores with inhaled anticholinergics compared with placebo. However, there was no significant difference between ipratropium bromide and placebo in the percentage of symptom-free nights or days.Two trials studied the effects of anticholinergics on bronchial hyper responsiveness to histamine, by measuring the provocation dose of histamine needed to cause a fall of 20 % in FEV1 (PD 20). One study (comparing anticholinergics with placebo) reported a statistically significant increase in PD 20 but this was not found in another study (comparing anticholinergics with a beta-2 agonist). Both trials also examined the effect of anticholinergic drugs on diurnal variation in peak expiratory flow rate (PEFR) and reported no significant effect.Two studies compared the addition of an anticholinergic drug to a beta-2 agonist with the beta-2 agonist alone. Both trials failed to show any significant benefit from the long term use of combined anticholinergics with beta-2 agonists compared with beta-2 agonists alone. One trial compared the effects of oral and inhaled anticholinergic drugs with placebo. No statistically significant differences were found in any of the outcome measures except for a higher FEV1 / VC ratio and RV / TLC ratio with oral anticholinergic therapy when compared with placebo. REVIEWER'S CONCLUSIONS: The present review summarises the best evidence available to date. Although there were some small beneficial findings in favour of anticholinergic therapy, there is insufficient data to support the use of anticholinergic drugs in the maintenance treatment of chronic asthma in children.
Cochrane Database Syst Rev. 2002;(4):CD00390Center for Clinical Health Policy Research, Duke University Medical Center, 2200 W. Main St., Suite 230, Durham, NC 27705, USA. [email protected]
Anti-cholinergic bronchodilators versus beta2-sympathomimetic agents for acute exacerbations of chronic obstructive pulmonary disease.
McCrory DC, Brown CD.
BACKGROUND: Inhaled bronchodilators form the mainstay of treatment for acute exacerbations of COPD. Two types of agent are used routinely, either singly or in combination: anticholinergic agents and beta2-sympathomimetic agonists. OBJECTIVES: To assess the effect of anti-cholinergic agents on lung function and dyspnea in patients with acute exacerbations of COPD, compared with placebo or short-acting beta-2 agonists. SEARCH STRATEGY: A comprehensive search of the literature was carried out on MEDLINE, EMBASE, CINAHL and the Cochrane COPD Trials Register, using the terms: bronchodilator* OR ipratropium OR oxitropium. References listed in each included trial were searched for additional trial reports. SELECTION CRITERIA: Studies were included if the participants were adult patients with a known diagnosis of COPD and had symptoms consistent with criteria for acute exacerbation of COPD. All randomized controlled trials that compared inhaled ipratropium bromide or oxitropium bromide to appropriate controls were considered. Appropriate control treatments included placebo, other bronchodilating agents, or combination therapies. Studies of acute asthma or ventilated patients were excluded. DATA COLLECTION AND ANALYSIS: All trials that appeared to be relevant were assessed by two reviewers who independently selected trials for inclusion. Differences were resolved by consensus. MAIN RESULTS: Four trials compared the short-term effects of ipratropium bromide vs. a beta2-agonist. Short-term changes in FEV1 (up to 90 minutes) showed no significant difference between beta2-agonist and ipratropium bromide treated patients. The differences were similar among the studies and when combined: Weighted Mean Difference (WMD) 0.0 liters (95% Confidence Interval (95% CI) -0.19, 0.19). There was no significant additional increase in change in FEV1 on adding ipratropium to beta2-agonist: WMD 0.02 liter (95% CI -0.08, 0.12). Long-term effects (24 hours) of the ipratropium bromide and beta2-agonist treatment combination were similar: WMD 0.05 liters (95%CI -0.14, 0.05). Neither of two studies found significant changes in PaO2, either short- or long-term, with ipratropium vs. beta-agonist, although one showed an increase in PaO2 in subjects receiving ipratropium bromide at 60 minutes. Adverse drug reactions included dry mouth and tremor. REVIEWER'S CONCLUSIONS: There was no evidence that the degree of bronchodilation achieved with ipratropium bromide was greater than that using a short-acting beta2-agonist. The combination of a beta2-agonist and ipratropium did not appear to increase the effect on FEV1 more than either used alone.
Cochrane Database Syst Rev. 2002;(1):CD001279Department of Paediatrics, Sheffield Children's Hospital, Western Bank, Sheffield, UK, S10 2TH.
Anticholinergic drugs for wheeze in children under the age of two years.
Everard ML, Bara A, Kurian M, Elliott TM, Ducharme F.
BACKGROUND: Wheeze in infancy and early childhood is common and appears to be increasing though the magnitude of any increase is unclear. Most wheezing episodes in infancy are precipitated by respiratory viral infections. Treatment of very young children with wheeze remains controversial. Anti-cholinergics are often prescribed but practice varies widely and the efficacy of this form of therapy remains the subject for debate. OBJECTIVES: Wheeze in infancy and early childhood is common and appears to be increasing. Most wheezing episodes in infancy are a result of viral infection. Bronchodilator medications such as beta2-agonists and anti-cholinergic agents are often used to relieve symptoms, but patterns of use vary. The objective of this review was to assess the effects of anti-cholinergic therapy in the treatment of wheezing infants. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and the reference lists of articles. We contacted researchers in the field and industry sources. SELECTION CRITERIA: Randomised trials that compared anti-cholinergic therapy with placebo or beta2-agonists in wheezing children under two years of age. Children with acute bronchiolitis and chronic lung disease were excluded. DATA COLLECTION AND ANALYSIS: Eligibility for inclusion and quality of trials were assessed independently by two reviewers. MAIN RESULTS: Six trials involving 321 infants in three different settings were included. Compared with beta2-agonist alone, the combination of ipratropium bromide and beta2-agonist was associated with a reduced need for additional treatment, but no difference was seen in treatment response, respiratory rate or oxygen saturation improvement in the emergency department. There was no significant difference in length of hospital stay between ipratropium bromide and placebo; or between ipratropium bromide and beta2-agonist combined compared with beta2-agonist alone. However, combined ipratropium bromide and beta2-agonist compared to placebo showed significantly improved clinical scores at 24 hours. Parents preferred ipratropium bromide over nebulised water or placebo for relief of their children's symptoms at home. REVIEWER'S CONCLUSIONS: There is not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits.
Cochrane Database Syst Rev. 2004;(3):UK Cochrane Centre, Summertown Pavilion, Middle Way, Oxford, Oxfordshire, UK, OX2 7LG.
Anticholinergic agents for chronic asthma in adults.Westby M, Benson M, Gibson P.
BACKGROUND: Anticholinergic agents such as ipratropium bromide are sometimes used in the treatment of chronic asthma. They effect bronchodilation and have also been used in combination with beta2-agonists in the management of chronic asthma. OBJECTIVES: To examine the effectiveness of anticholinergic agents versus placebo and in comparison with beta2-agonists or as adjunctive therapy to beta2-agonists. SEARCH STRATEGY: The Cochrane Airways Group asthma and wheeze database was searched with a pre-defined search strategy. Searches were current as of August 2003. Reference lists of articles were also examined. SELECTION CRITERIA: Randomised trials or quasi-randomised trials were considered for inclusion. Studies assessing an anticholinergic agent versus placebo or in combination/comparison with beta2-agonists were included. In practice, all beta2-agonists were short acting. Short-term (less than 24 hours duration) and longer-term studies were separated; the latter are reported in this review and the former in the review, "Anticholinergic agents for chronic asthma in adults short term". DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed abstracts for retrieval of full text articles. Papers were then assessed for suitability for inclusion in the review. Data from included studies were extracted by two reviewers and entered into the software package (RevMan 4.2). We contacted authors for missing data and some responded. Adverse effect data were analysed if reported in the included studies. MAIN RESULTS: The studies analysed were in two groups: those comparing anticholinergics with placebo and those comparing the combination of anticholinergics with short acting beta2-agonists versus short acting beta2-agonists alone. The former group had 13 studies involving 205 participants included in this review, and the latter 9 studies involving 440 patients. Generally methodological quality was poorly reported, and there were some reservations with respect to the quality of the studies.Despite the limited number of studies that could be combined, anticholinergic agents in comparison with placebo resulted in more favourable symptom scores particularly in respect of daytime dyspnoea (WMD -0.09 (95%CI -0.14, -0.04, 3 studies, 59 patients). Daily peak flow measurements also showed a statistically significant improvement for the anticholinergic (e.g. morning PEF: WMD =14.38 litres/min (95%CI 7.69, 21.08; 3 studies, 59 patients). However the clinical significance is small and in terms of peak flow measurements equates to approximately a 7% increase over placebo. The more clinically relevant comparison of a combination of anticholinergic plus short acting beta2-agonist versus short acting beta2-agonist alone gave no evidence in respect of symptom scores or peak flow rates of any significant differences between the two regimes. Again there are reservations with respect to the quality of the information from which these conclusions are drawn. REVIEWERS' CONCLUSIONS: Overall this review provides no justification for routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. This does not exclude the possibility that there may be a sub-group of patients who derive some benefit and a trial of treatment in individual patients may still be justified. The role of long term anticholinergics such as tiotropium bromide has yet to be established in patients with asthma and any future trials might draw on the messages derived from this review.
Fosfolípides de membranas (PC, PS, PE)
Ácido Araquidônico
Fosfolipase A2
COX
Lipoxigenase
PGE2, PGD2, PGF2
TXA2
PGI2
LeucotrienosOthers
IsoprostanosCit. P450produtos
Locais de ação dos antileucotrienosLocais de ação dos antileucotrienosÁcido aracdônicoÁcido aracdônico
5-HPETE5-HPETE
Leucotrieno A4Leucotrieno A4
LTC4LTC4
LTD4LTD4
LTE4LTE4
LTB4LTB4
Inibição de 5-lipoxigenase Inibição de 5-lipoxigenase ou de FLAPou de FLAP
Antagonista do Antagonista do receptor CysLT1receptor CysLT1
Efeitos dos leucotrienos: liberação de citoquinas, quimiotaxia, Efeitos dos leucotrienos: liberação de citoquinas, quimiotaxia, broncoconstrição, edema e produção de mucobroncoconstrição, edema e produção de muco
Fosfolípedes de MembranaFosfolípedes de MembranaFosfolipase A2 Fosfolipase A2
Ácido Aracdônico Ácido Aracdônico
Ciclooxigenase Ciclooxigenase 5-lipoxigenase5-lipoxigenase
Prostaglandina e Tromboxanes
Prostaglandina e Tromboxanes
EosinófiloMastócitoBasófilo
EosinófiloMastócitoBasófilo
ATPATPCaCa++++
FLAPFLAP
ATPATPCaCa++++
FLAPFLAP
Leucotrieno ALeucotrieno A44 Leucotrieno ALeucotrieno A44
LTC4 Sintase LTC4 Sintase LTA Hidrolase LTA Hidrolase
NeutrófiloMacrófagoMonócito
NeutrófiloMacrófagoMonócito
Leucotrieno CLeucotrieno C44 Leucotrieno CLeucotrieno C44
Leucotrieno ELeucotrieno E44 Leucotrieno ELeucotrieno E44
Leucotrieno DLeucotrieno D44 Leucotrieno DLeucotrieno D44
Glutamil transpeptidase Glutamil transpeptidase
Dipeptidase Dipeptidase
Leucotrieno BLeucotrieno B44 Leucotrieno BLeucotrieno B44
Antileucotrienos Antileucotrienos
• Apresentam ação anti-inflamatória
• Forma de administração: oral
• Excelente tolerabilidade
• Melhor adesão ao tratamento
• Apresentam ação anti-inflamatória
• Forma de administração: oral
• Excelente tolerabilidade
• Melhor adesão ao tratamento
Zafirlukast (Accolate)Zafirlukast (Accolate)
NNNN
CHCH33CHCH33
HHHH
OOOO
OCHOCH33OCHOCH33OOOO NNNN
NNNN
HHHH OOOO
OOOO
SSSS
OOOO
Zafirlucast (Accolate®)Zafirlucast (Accolate®)Posologia: 20mg 2x/dia em adultos
10mg 2x/dia em crianças de 7 a 14 anos (Interação com alimentos pode reduzir biodisponibilidade) Efeitos colaterais: elevação das enzimas hepáticas (rara) Interações medicamentosas importantes:
– concentração de aspirina– concentração de eritromicina– concentração de teofilina
Posologia: 20mg 2x/dia em adultos 10mg 2x/dia em crianças de 7 a 14 anos
(Interação com alimentos pode reduzir biodisponibilidade) Efeitos colaterais: elevação das enzimas hepáticas (rara) Interações medicamentosas importantes:
– concentração de aspirina– concentração de eritromicina– concentração de teofilina
Montelukast Sodium (Singulair)Montelukast Sodium (Singulair)
COO NaCOO Na++COO NaCOO Na++
HOHOHOHO
HH33CCHH33CCHH33CCHH33CC
ClClClCl NNNN
SSSS
Montelucaste (Singulair®)Montelucaste (Singulair®)Posologia:
2 a 5 anos - 4 mg - 1 comp ao deitar 6 a 14 anos - 5 mg - 1comp ao deitar > 15 anos - 10 mg - 1 comp ao deitar
(Não tem interação com alimentos)
Efeitos colaterais: semelhantes ao placebo
Interação medicamentosa:
– concentração de fenobarbital
Posologia: 2 a 5 anos - 4 mg - 1 comp ao deitar
6 a 14 anos - 5 mg - 1comp ao deitar > 15 anos - 10 mg - 1 comp ao deitar
(Não tem interação com alimentos)
Efeitos colaterais: semelhantes ao placebo
Interação medicamentosa:
– concentração de fenobarbital
Effect of Singulair on FEV1Effect of Singulair on FEV1
0 0 3 6 3 6 9 9 12 1512 150 0 3 6 3 6 9 9 12 1512 15
1515
1010
55
00
1515
1010
55
00
Weeks in treatmentWeeks in treatmentWeeks in treatmentWeeks in treatment
Mea
n p
erce
nt
chan
geM
ean
per
cen
t ch
ange
from
Bas
elin
efr
om B
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ine
Mea
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per
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from
Bas
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asel
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PlaceboPlaceboPlaceboPlacebo SingulairSingulairSingulairSingulair
WashoutWashoutWashoutWashout
Effect of Singulair on FEV1Effect of Singulair on FEV1
0 0 3 3 6 6 9 9 12 15 12 150 0 3 3 6 6 9 9 12 15 12 15
1515
1010
55
00
1515
1010
55
00
Weeks in treatmentWeeks in treatmentWeeks in treatmentWeeks in treatment
Mea
n p
erce
nt
chan
geM
ean
per
cen
t ch
ange
from
Bas
elin
efr
om B
asel
ine
Mea
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erce
nt
chan
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ean
per
cen
t ch
ange
from
Bas
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efr
om B
asel
ine
PlaceboPlaceboPlaceboPlacebo
SingulairSingulairSingulairSingulair
BeclometasoneBeclometasoneBeclometasoneBeclometasone
WashoutWashoutWashoutWashout
Busse, w. et al. J Fam Pract 2001; 50:595-602
IndicaçõesIndicações
• Pacientes com asma leve a moderada (monoterapia) e pacientes pediátricos
• Na asma grave, como poupador de corticosteróide (terapia adicional)
• Pacientes com co-morbidades (rinite alérgica, urticária)
• Broncoconstrição induzida por exercício
• Asma induzida por aspirina
• Pacientes com asma leve a moderada (monoterapia) e pacientes pediátricos
• Na asma grave, como poupador de corticosteróide (terapia adicional)
• Pacientes com co-morbidades (rinite alérgica, urticária)
• Broncoconstrição induzida por exercício
• Asma induzida por aspirina
Leukotriene Inhibitors for the Treatment of Allergy and Asthma
Drug Age and recommended oral dose
Therapeutic issues Appromiximate monthly cost
Montelukast (Singulair)
Adults: 10 mg before bed
Children six to 14 years: 5 mg before bed
Children two to five years: 4 mg before bed
Renal adjustments: none
Hepatic adjustments: in mild to moderate disease
$ 104.40 (4 mg, 5mg, or 10-mg)
Leukotriene Inhibitors in the Treatment of Allergy and Asthma - Volume 75, Number 1 January 1, 2007
Leukotriene Inhibitors for the Treatment of Allergy and Asthma
Drug Age and recommended oral dose
Therapeutic issues Appromiximate monthly cost
Zafirlukast (Accolate)
Patients older than 11 years 20 mg twice daily
Children seven to 11 years: 10 mg twice daily
Renal adjustments: none
Hepatic adjustments: not defined
Monitor hepatic enzymes every two to three months
Administration with meals decreases bioavailability; take at least one hour before meals or two hours after
Inhibits metabolism of warfarin (coumadin, increasing prothrombin time
$ 88,10 (10 mg, or 20 mg)
Leukotriene Inhibitors in the Treatment of Allergy and Asthma - Volume 75, Number 1 January 1, 2007
Leukotriene Inhibitors for the Treatment of Allergy and Asthma
Drug Age and recommended oral dose
Therapeutic issues Appromiximate monthly cost
Zileuton (Zyflo)
Patients older than 12 years: 600 mg four times daily
Can inhibit metabolsim of warfarin, theophylline, and propranolol (Inderal)
Monitor hepatic enzymes every two to three months
$ 273,75 (600 mg)
Leukotriene Inhibitors in the Treatment of Allergy and Asthma - Volume 75, Number 1 January 1, 2007
BroncodilatadoresBroncodilatadores AntiinflamatóriosAntiinflamatórios Beta-2 agonistasBeta-2 agonistas Ação curta: Ação curta: SalbutamolSalbutamol
FenoterolFenoterol
TerbutalinaTerbutalina Ação prolongada: Ação prolongada: SalmeterolSalmeterol
FormoterolFormoterol
Anticolinérgicos:Anticolinérgicos: IpratrópioIpratrópio
Xantinas:Xantinas: TeofilinaTeofilina
AminofilinaAminofilina
BamifilinaBamifilina
Corticosteróides:Corticosteróides: Inalatórios: Inalatórios: BeclometasonaBeclometasona
BudesonidaBudesonida
FlunisolidaFlunisolida
FluticasonaFluticasona
TriancinolonaTriancinolona Sistêmicos: Sistêmicos: PrednisonaPrednisona
DeflazacortDeflazacort
Cromonas:Cromonas: CromoglicatoCromoglicato
NedocromilNedocromil
Antileucotrienos:Antileucotrienos:
MontelukastMontelukast
ZafirlukastZafirlukast
Drogas no tratamento da Asma
TRATAMENTO
• Categorias de drogas– Agonistas -adrenérgicos– Glicocorticosteróides– Metilxantinas– Anticolinérgicos– Inibidores da lipoxigenase– Antagonistas de receptores de leucotrienos– Monoclonal para IgE– Monoclonal para TNF-alfa– Imunoterapia
• Reduzir ou prevenir a inflamação das vias aéreas e a ação dos mediadores que contribuem para o broncoespasmo.
Classificação
Asma intermitente
Asma persistente leve
Asma persistente moderada
Asma persistente grave
GINA/NIH - 1997
Simplified schematic of the IgE receptor (FceRI) signaling pathway
Manipulation of signaling to control allergic inflammation - Lippincott Williams & Wilkins
Efeito do omalizumab (300mg s.c. de 30/30d) em asmáticos
300
200
100
00 1 3 7 14 112 168 252 336
Med
ian
free
IgE
(ng
/mL
)
Day 0 = screening (n = 93)
Days not to scale
Day 1 post-dose
80
70
60
50
40
30
20
10
0 Median dose reduction (%)
Pts (%) with >50% dose
reduction
Pts (%) with complete
BDP withdrawal
Omalizumab (n=268)
Placebo (n=257)
19.1%
39.6%
54.9%
72.4%
50%
75%
Effect of treatment on ICS use.
Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma - J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 2
0.0
-0.5
-1.0
-1.5
-2.0
-2.50-4 4-8 8-12 12-16 16-18 18-20 20-22 22-24 24-26 26-28
Stable steroid phase Steroid-reduction phaseSymptom score range 0-9
Asthma Scores Rescue MedicationOmalizumab
PlaceboOmalizumab
Placebo
****
*** ** * ** ******
**
****
** ****
*
* p<0.5
** p<0.01
*** p<0.001
Ch
ange
fro
m b
asel
ine
Mean change from baseline in total asthma symptom scores and numbers of puffs of rescue medication (salbutamol) per day
Om
aliz
um
ab, a
nti
-IgE
rec
omb
inan
t h
um
aniz
ed m
onoc
lon
al a
nti
bod
y, f
or t
he
trea
tmen
t of
sev
ere
alle
rgic
ast
hm
a J
AL
LE
RG
Y C
LIN
IM
MU
NO
L V
OL
UM
E 1
08, N
UM
BE
R 2
Adults and adolescents(protocol 008)
Adults and adolescents(protocol 008)
Adults and adolescents(protocol 009)
Adults and adolescents(protocol 009)
Children
(protocol 010)
Children
(protocol 010)
Omalizumab Omalizumab Placebo Placebo Omalizumab Omalizumab Placebo Placebo Omalizumab Omalizumab Placebo Placebo
Number treatedNumber treated 268268 257257 274274 272272 225225 109109
Mean (range) age (years)Mean (range) age (years) 39 (12-73)39 (12-73) 39 (12-74)39 (12-74) 40 (12-76)40 (12-76) 39 (12-72)39 (12-72) 9 (5-12)9 (5-12) 10 (6-12)10 (6-12)
Mean (range) duration of asthma (years)Mean (range) duration of asthma (years)
21 (1-61)21 (1-61) 23 (2-60)23 (2-60) 20 (2-68)20 (2-68) 19 (1-63)19 (1-63) 6 (1-12)6 (1-12) 6 (1-12)6 (1-12)
Mean serum total IgE (IU/ml)Mean serum total IgE (IU/ml)
172172 186186 223223 206206 348348 323323
Mean (range) FEV1 (%
predicted)
Mean (range) FEV1 (%
predicted)
68(30-112)
68(30-112)
68(32-111)
68(32-111)
70(30-112)
70(30-112)
70(22-109)
70(22-109)
84(49-129)
84(49-129)
85(43-116)
85(43-116)
Mean (range) BDP dose (g/day)Mean (range) BDP dose (g/day)
679(500-1200)
679(500-1200)
676(400-1000)
676(400-1000)
769(500-1600)
769(500-1600)
772(200-2000)
772(200-2000)
338(200-800)
338(200-800)
318(200-600)
318(200-600)
Severe asthma (%)Severe asthma (%) 2222 2121 2222 2222 99 66
Características dos pacientes
Adults and adolescents(protocol 008)
Adults and adolescents(protocol 008)
Adults and adolescents
(protocol 009)
Adults and adolescents
(protocol 009)
Children(protocol 010)
Children(protocol 010)
OmalizumabOmalizumab PlaceboPlacebo OmalizumabOmalizumab PlaceboPlacebo OmalizumabOmalizumab PlaceboPlacebo
Number treatedNumber treated 268268 257257 274274 272272 225225 109109
Corticosteroid-stable phase (%) with > 1 exacerbationCorticosteroid-stable phase (%) with > 1 exacerbation 14.614.6 23.323.3 12.812.8 30.530.5 15.615.6 22.922.9
P=0.009P=0.009 P<0.001P<0.001 P=0.095P=0.095
Corticosteroid-withdrawal phase (%) with > 1 exacerbationCorticosteroid-withdrawal phase (%) with > 1 exacerbation 21.321.3 32.332.3 15.715.7 29.829.8 18.218.2 38.538.5
P=0.004P=0.004 P<0.001P<0.001 P<0.001P<0.001
Median % reduction in BDP doseMedian % reduction in BDP dose7575 5050 8383 5050 100100 6767
P<0.001P<0.001 P<0.001P<0.001 P=0.001P=0.001
Effect of omalizumab on ICS treatment
The mechanisms, diagnosis, and management of severe asthma in adults - Lancet 2006; 368: 780–93
Possible cellular targets for TNFα in severe corticosteroid refractory asthma
Concentration of inhaled methacholine causing a 20% decrease (PC20) in the forced expiratory volume (FEV1) (a) and asthma quality-of-life scores (b) before, during and after 10 weeks of etanercept or placebo and the cumulative mean (RSE) change in FEV1 after the inhalation of 200mg of albuterol each week during the 10-week treatment trial (c)
The
rec
lass
ific
atio
n of
ast
hma
base
d on
sub
phen
otyp
es -
Lip
pinc
ott W
illi
ams
& W
ilki
ns
Th
e m
ech
anis
ms,
dia
gnos
is, a
nd
man
agem
ent
of s
ever
e as
thm
a in
ad
ult
s -
Lan
cet 2
006;
368
: 78
0–93
Algorithm of possible strategies and
recommendations for managing patients with
difficulties tocontrol asthma despite maximum combination
treatment
Hallmarks of aspirin-sensitive asthma
● Worsening of symptoms in response to non-steroidal anti-inflammatory drugs
● Severe chronic rhinosinusitis and nasal polyps
● Adult onset
● Poor response to corticosteroids
● Raised cysteinyl leukotriene concentrations in urine or lung
Asthma: defi ning of the persistent adult phenotypes - Lancet 2006; 368: 804–13