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[email protected]

Arquivo

Sistema Respiratório

Site

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[email protected]

Arquivo

Sistema Respiratório

Site

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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


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.




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

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


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


ASMA - DefiniçãoASMA - Definição







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


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




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)






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


0.0003

0.0007

MeanSputum Eos (%)

Proteína Catiônica do Eosinófilo

50

110

290

170

230

350

0 6 12 18 24

Weeks

Triamcinolone

Salmeterol


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

atie

nt

per

yea

r)

Rate of severe asthma exacerbations in OPTIMA and FACET studies


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)

Ser

um

cor

tiso

l con

cen

trat

ion

(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

500

450

400

350

300

250

200

150

100

50

0

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


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

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)

CIC320 CIC640 CIC1280 FP880 FP1760


30

20

10

0Placebo CIC40 CIC80 CIC160

Mea

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rom

bas

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F (

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Placebo CIC40 CIC80 CIC1600

-0.5

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Placebo CIC40 CIC80 CIC1600

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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

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ch

ange

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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

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bas

elin

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p

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um

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ol (

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dL

)

2.0

1.1

0

-1.0

-2.0

-3.0

-4.0


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

g co

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PBO CIC320 CIC640 CIC1280 FP880 FP1760


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.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=12917970

http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3058&uid=12917970&db=pubmed&url=http://dx.doi.org/10.1002/14651858.CD003535

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

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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

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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

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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




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)





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)


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

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Mean change from baseline in total asthma symptom scores and numbers of puffs of rescue medication (salbutamol) per day

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Children

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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 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)

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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

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