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Dúvidas Arquivo Sistema Respiratório Site Dúvidas Arquivo Sistema Respiratório Site

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Apresentação em tema: "Dúvidas Arquivo Sistema Respiratório Site Dúvidas Arquivo Sistema Respiratório Site"— Transcrição da apresentação:

1 Dúvidas Arquivo Sistema Respiratório Site Dúvidas Arquivo Sistema Respiratório Site

2

3 Diferentes nomes para o mesmo problema Bronquite Bronquite alérgica Bronquite asmática Bronquite Bronquite alérgica Bronquite asmática ASMA

4 ASMA - 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

5 Proliferação Celular Aumento da Matriz Extracelular Proliferação Celular Aumento da Matriz Extracelular Recrutamento celular Dano Epitelial Modificações Estruturais Precoces Recrutamento celular Dano Epitelial Modificações Estruturais Precoces Broncoconstrição Edema Secreção Tosse Broncoconstrição Edema Secreção Tosse Inflamação Aguda Remodelamento das Vias Aéreas Inflamação Crônica Processo inflamatório da ASMA Cançado, JE 2000

6 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

7 Indutores AlérgenosAlérgenos AspirinaAspirina AgentesocupacionaisAgentesocupacionaisVSRVSR ExercíciosExercícios ASMA Provocadores IrritantesIrritantes

8 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

9 Asma

10 Normal

11 SADIO ASMA LEVE Hyperplasia and erosion Eosinophil and Lymphocyte Infiltration

12 Inflamação das Vias Aéreas na ASMA Asmático Normal P Jeffery, in: Asthma, Academic Press 1998

13 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

14 AB CD Sputum cytospins showing the four inflammatory subtypes of asthma: (a) neutrophilic asthma; (b) eosinophilic asthma; (c) mixed granulocytic asthma; (d) paucigranulocytic asthma.

15 (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.

16 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

17 Days from maintenance Proportion free of exacerbation (%) Sputum strategy Conventional strategy Number at risk Sputum strategy Conventional strategy 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

18 Guidelines management group Sputum managenment group Severe exacerbations 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

19 Severe exacerbations (cumulative number) 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)

20 Cumulative asthma exacerbations during a 12-month randomized trial of asthma management guided at controlling sputum eosinophilia compared with conventional management Time (months) Several exacerbations (cumulative number) Control management Sputum guided management The reclassification of asthma based on subphenotypes - Lippincott Williams & Wilkins

21 Resposta Imediata e Tardia da asma Tempo (h) Inalação do alérgeno AAR AAR = Resposta aguda, imediata LAR = Resposta tardia FEV 1 (%) LAR

22

23 ASMA - 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

24 Slight FEV1 in patients (HBR) SevereModerateMild NormalNormalCOPDCOPD Dose ( mol) FEV 1 (% FALL) ASTHMAASTHMA HISTAMINEHISTAMINE METHACHOLINEMETHACHOLINE

25 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 idade National Institutes of Health, NIH Publication No II Consenso Brasileiro no Manejo da Asma, 1998

26 Genética da Asma A asma caminha pelas gerações das famílias Gêmeos monozigóticos apresentam maior concordância que os DZ nas prevalências de asma. Ainda não esclarecido: A maior prevalência nos meninos A maior mortalidade na raça negra A maior mortalidade na raça negra Peter J. Barnes. Asthma

27 Tabagismo Strachan & Cook - Thorax 52: , 1997 Cook & Strachan - Thorax 52: , 1997 Strachan & Cook - Thorax 53: , 1998 Cook & Strachan - Thorax 53: , 1998 Strachan & Cook - Thorax 52: , 1997 Cook & Strachan - Thorax 52: , 1997 Strachan & Cook - Thorax 53: , 1998 Cook & Strachan - Thorax 53: , 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

28 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.

29 Agonistas -adrenérgicos Agonistas 2 -adrenérgicos

30 Agonists 2 Adrenérgicos Broncodilatadores mais potentes – Aliviam o broncoespasmo Duas classes: Curta duração: Fenoterol, salbutamol, terbutalina Longa duração: Formoterol, salmeterol Mecanismo: –Ativam receptores 2 no músculo liso pulmonar –Promovem broncodilatação (aliviam o broncoespasmo) –Efeitos antiinflamatórios discretos

31

32 SALBUTAMOL, TERBUTALINA ADRISO 2 Broncodilatação Relaxamento Uterino Relaxamento Vascular AGONISTAS DE AÇÃO DIRETA

33 Adrenergic agonist structure NorepinephrineNorepinephrine EpinephrineEpinephrine IsoproterenolIsoproterenol SalbutamolSalbutamol CH CHNH OH H H CH CHNH OH H CH 3 CH CHNH OH H CH(CH 3 ) 3 CH CHNH OH H C(CH 3 ) 2 HO HO HO HO HO HO HOH 2 C HO

34 -adrenoceptor exosite - CH HO HO-CH 2 - OH - - CH 2 NH - CH O HIPÓTESE: EXOSITE BINDING

35 HO OH CH O salmeterol

36 Beta 2 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

37 HoursHours FEV 1 (% of Predicted l Salmeterol 42 mcg twice daily (n=178) s Salbutamol 180 mcg four times daily (n=176) n Placebo (n=181) l Salmeterol 42 mcg twice daily (n=178) s Salbutamol 180 mcg four times daily (n=176) n Placebo (n=181) FEV 1, as percent of Predicted, From two large 12-Week Clinical Trials First Treatment day

38 ofdahl and Svedmyr, Allergy 1989 Duração do efeito : formoterol vs salbutamol TEMPO (h) Capacidade Broncodilatadora (%) Formoterol 6 µg Salbutamol 100 µg pacientes asmáticos Via Inalatória

39 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

40 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 )

41 Glicocorticóides

42 Slight FEV1 in patients (HBR) SevereModerateMild NormalNormalCOPDCOPD Dose ( mol) FEV 1 (% FALL) ASTHMAASTHMA HISTAMINEHISTAMINE METHACHOLINEMETHACHOLINE

43 Steroid treatment Slight SevereModerateMild Histamine Dose ( mol) FEV 1 (% FALL) Initial(2.0)Initial(2.0) 4 months (3.0) (3.0) 6 months (2.6) (2.6) 7 months (3.0) (3.0)

44 Relação Estrutura Química e Atividade Farmacológica

45 MODIFICAÇÕES NA ESTRUTURA MOLECULAR DOS GLICOCORTICÓIDES C O O O O OH CH 2 OH CH 2 2 OH HO F F F CH

46 O O ESTRUTURA MOLECULAR DE ALGUNS CORTICOSTERÓIDES

47 Glucocorticóides inalatórios

48 CORTICOTERAPIA SISTÊMICA Tabela de Equivalência Fármaco Potência Dose Antiinflamatória Equivalente (mg) Antiinflamatória Equivalente (mg) Cortisol (HC) 1 20 Cortisona 0,8 25 Prednisona 4 5 Prednisolona 4 5 Metilprednisolona 5 4 Triamcinolona 5 4 Betametasona ,75 Dexametasona ,75

49 % deposição pulmonar

50 Metabolismo da ciclesonida

51 Deposição pulmonar (HFA)

52 CORTICOTERAPIA SISTÊMICA Meia-vida Duração do efeito Meia-vida Duração do efeito Fármaco (h) Cortisol (HC) curta Cortisona 12 curta Prednisona intermediária Prednisolona intermediária Metilprednisolona intermediária Triamcinolona intermediária Betametasona prolongada Dexametasona prolongada

53 Citoplasma Núcleo Membrana celular Membrana nuclear Proteínas e Enzimas Cortisol Receptor (proteína plasmática) Elementos responsivos ao GC Complexo GC-Receptor CROMATINA mRNA Estimula Transcrição mRNA Síntese Resposta ao GC

54 GCS RG hsp90 núcleo ERGnERG+ Gene alvo responsivo ao corticóide X Citocinas iNOS COX-2 PLA2 RNAm Lipocortina-1 -receptor

55 CORTICOSTERÓIDES INIBIÇÃO da liberação /ação de mediadores inflamatórios: Prostaglandinas e leucotrienos Citocinas Aminas vasoativas Radicais livres de oxigênio Inibição da indução de enzimas (iNOS, COX-2)

56 CÉLULAS MÚSCULO LISO: AÇÕES DOS GLICOCORTICÓIDES INIBIÇÃO MECANISMOS PRODUTORES DE CONTRAÇÃO Redução da conc. Ca 2+ intracelular Redução expressão receptores muscarínicos Desacoplamento receptores H 1 histamina

57 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

58 Vias de Administração Oral Aerossol Intra-muscular Endovenosa Intra-articular Conjuntival Nasal Percutânea

59 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

60 Glicocorticóides 1.Para cada paciente e doença, a dose apropriada é determinada por 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 produza efeitos 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, mas somente paliativa.

61 Glicocorticóides Beclometasona, 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

62 Lipid-soluble, inhaled corticisteroids Beclomethasone Fluticasone Triamcinolone Spacer Metered-dose inhaler Large aerosol particles are deposited in chamber rather patients mouth Inhaled portion consists of small particles which travel to small airways Netters Illustrated Pharmacology – fig 7-19 Corticosteroids: Clinical Uses

63 Espaçadores 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

64 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, anos, asma persistente]

65 Óxido Nítrico Exalado Weeks Triamcinolone Salmeterol Placebo Run-InDouble-Blind Treatment Mean FENO (ppb)

66 Eosinófilos Weeks Triamcinolone Salmeterol Placebo Run-In Double-Blind Treatment Mean Sputum Eos (%)

67 Proteína Catiônica do Eosinófilo Weeks Triamcinolone Salmeterol Run-In Double-Blind Treatment Median Sputum ECP (µg/L) Placebo p=0.0054

68 Triptase Weeks Triamcinolone Salmeterol Placebo Run-In Double-Blind Treatment Run-Out Mean Sputum Tryptase (ng/ml)

69 Optima AOptima BFacet PlaB200B200 + For9B200B400B400 + For9B200B200 + For18B800B800 + For18 Rate of exacerbations (number per patient per year) Rate of severe asthma exacerbations in OPTIMA and FACET studies Pharmacological management of mild or moderate persistent asthma - Lancet 2006; 368: 794–803

70 Sensitivity of Hypothalamic-Pituitary-Adrenal Axis Function Tests FunctionSensitivity of test AUC 0-24h 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

71 Time (hours) Serum cortisol concentration (µg/dL) Morning dose evening dose PBO bid CIC 640 µg qd AM and PBO PM CIC 640 µg qd PM and PBO AM CIC 320 µg bid Time (hours) Plasma cortisol (nmol/L) PBO CIC 640 µg bid FP 440 µg bid CIC 320 µg qd CIC 640 µg bid FP 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. AB The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006

72 Mean percent change in 24-hour urinary free cortisol profile and plasma cortisol area under the concentration time curve (AUC 0 –24h ) 69 (*P.0001 vs placebo; #P.0003 vs placebo) Urinary cortisol Plasma cortisol Change in cortisol concentration versus placebo (%) CIC320CIC640CIC1280FP880FP1760 The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006

73 PlaceboCIC40CIC80CIC160 Mean chenge from baseline in AM PEF (L/min) PlaceboCIC40CIC80CIC Mean chenge from baseline in asthma symptom scores PlaceboCIC40CIC80CIC Mean chenge from baseline in daily albuterol use (puffs) 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).

74 Mean percent change from baseline to week 4 in serum cortisol 24-hour area under the concentration time curve (AUC0–24h). PBOCIC640CIC1280FP880FP Serum cortisol AUC0-24h Percentage change from baseline The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006

75 Mean change from baseline to week 12 in peak serum cortisol levels after low-dose (1 g) cosyntropin stimulation. PBOCIC320CIC640FP880 Mean change from baseline in peak serum cortissol (µg/dL) The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006

76 Mean provocative concentration required to produce a 20% decrease in lung function (PC 20 ) forced expiratory volume in 1 minute for adenosine triphosphate (AMP) after at least 9 days of treatment 69 (*P.001 vs placebo) Change in PC20 AMP (doubling concentrations) PBOCIC320CIC640CIC1280FP880FP1760 The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide - ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY - VOLUME 97, AUGUST, 2006

77 METILXANTINAS Teofilina Componente natural (chá) com propriedade broncodilatadora Usada desde 1930 para o tratamento da asma. Camellia sinensis Thea sinensis Nativas do Tibet, Índia e China

78 Teofilina (Teolong, Talofilina) Inibição da fosfodiesterase do AMPc e GMPc Antagonista de receptores de adenosina Inibidor direto da mobilização de Ca 2+ Inibidor da quimiotaxia de neutrófilos

79 Xantinas 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

80 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)

81 Ipratropium bromide (Atrovent) Br - H 2 O HH H3CH3CH3CH3C H3CH3CH3CH3C CH(CH 3 ) 2 N+N+N+N+ N+N+N+N+ HH HH CC OCOC OO CHCH CH 2 OH

82 Cochrane Database Syst Rev. 2003;(3):CD 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 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.

83 Cochrane Database Syst Rev. 2002;(4):CD00390 Center for Clinical Health Policy Research, Duke University Medical Center, 2200 W. Main St., Suite 230, Durham, NC 27705, USA. 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.

84 Cochrane Database Syst Rev. 2002;(1):CD Department 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.

85 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 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 (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.

86 Fosfolípides de membranas (PC, PS, PE) Ácido Araquidônico Fosfolipase A 2 COX Lipoxigenase PGE 2, PGD 2, PGF 2 TXA 2 PGI 2 Leucotrienos Others Isoprostanos Cit. P450 produtos

87 Locais de ação dos antileucotrienos Ácido aracdônico 5-HPETE Leucotrieno A4 LTC4 LTD4 LTE4 LTB4 Inibição de 5-lipoxigenase ou de FLAP Antagonista do receptor CysLT1 Efeitos dos leucotrienos: liberação de citoquinas, quimiotaxia, broncoconstrição, edema e produção de muco

88 Fosfolípedes de Membrana Fosfolipase A 2 Ácido Aracdônico Ciclooxigenase 5-lipoxigenase Prostaglandina e Tromboxanes Eosinófilo Mastócito Basófilo ATP Ca ++ FLAPATP FLAP Leucotrieno A 4 LTC4 Sintase LTA Hidrolase Neutrófilo Macrófago Monócito Leucotrieno C 4 Leucotrieno E 4 Leucotrieno D 4 g Glutamil transpeptidase Dipeptidase Leucotrieno B 4

89 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

90 Zafirlukast (Accolate) NN CH 3 HH OO OCH 3 OO NN NN HH OO OO SS OO

91 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

92 Montelukast Sodium (Singulair) COO Na + HOHO H3CH3CH3CH3C H3CH3CH3CH3C H3CH3CH3CH3C H3CH3CH3CH3C ClCl NN SS

93 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

94 Effect of Singulair on FEV Weeks in treatment Mean percent change from Baseline Mean percent change from Baseline PlaceboPlaceboSingulairSingulair WashoutWashout

95 Effect of Singulair on FEV Weeks in treatment Mean percent change from Baseline Mean percent change from Baseline PlaceboPlacebo SingulairSingulair BeclometasoneBeclometasone WashoutWashout

96 Busse, w. et al. J Fam Pract 2001; 50:

97 Indicações 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

98 Leukotriene Inhibitors for the Treatment of Allergy and Asthma DrugAge and recommended oral dose Therapeutic issuesAppromiximate 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 $ (4 mg, 5mg, or 10-mg) Leukotriene Inhibitors in the Treatment of Allergy and Asthma - Volume 75, Number 1 January 1, 2007

99 Leukotriene Inhibitors for the Treatment of Allergy and Asthma DrugAge and recommended oral dose Therapeutic issuesAppromiximate 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

100 Leukotriene Inhibitors for the Treatment of Allergy and Asthma DrugAge and recommended oral dose Therapeutic issuesAppromiximate 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

101 BroncodilatadoresAntiinflamatórios l Beta-2 agonistas Ô Ação curta: Salbutamol Fenoterol Fenoterol Terbutalina Terbutalina Ü Ação prolongada: Salmeterol Formoterol Formoterol l Anticolinérgicos: Ipratrópio l Xantinas: Teofilina Aminofilina Aminofilina Bamifilina Bamifilina l Corticosteróides: Ü Inalatórios: Beclometasona Budesonida Budesonida Flunisolida Flunisolida Fluticasona Fluticasona Triancinolona Triancinolona Ü Sistêmicos: Prednisona Deflazacort Deflazacort l Cromonas: Cromoglicato Nedocromil Nedocromil l Antileucotrienos: Montelukast Montelukast Zafirlukast Zafirlukast Drogas no tratamento da Asma

102 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.

103 Classificação Asma intermitente Asma persistente leve Asma persistente moderada Asma persistente grave GINA/NIH

104 Simplified schematic of the IgE receptor (FceRI) signaling pathway Manipulation of signaling to control allergic inflammation - Lippincott Williams & Wilkins

105 Efeito do omalizumab (300mg s.c. de 30/30d) em asmáticos Median free IgE (ng/mL) Day 0 = screening (n = 93) Days not to scale Day 1 post-dose

106 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

107 Stable steroid phaseSteroid-reduction phase Symptom score range 0-9 Asthma ScoresRescue Medication Omalizumab Placebo Omalizumab Placebo *** * ** * *** ** * * * * p<0.5 ** p<0.01 *** p<0.001 Change from baseline Mean change from baseline in total asthma symptom scores and numbers of puffs of rescue medication (salbutamol) per day Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma J ALLERGY CLIN IMMUNOL VOLUME 108, NUMBER 2

108 Adults and adolescents (protocol 008) Adults and adolescents (protocol 009) Adults and adolescents (protocol 009) Children (protocol 010) Children (protocol 010) Omalizumab Placebo Omalizumab Placebo Omalizumab Placebo Number treated Mean (range) age (years) 39 (12-73) 39 (12-74) 40 (12-76) 39 (12-72) 9 (5-12) 10 (6-12) Mean (range) duration of asthma (years) 21 (1-61) 23 (2-60) 20 (2-68) 19 (1-63) 6 (1-12) Mean serum total IgE (IU/ml) Mean (range) FEV 1 (% 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) 679 ( ) 679 ( ) 676 ( ) 676 ( ) 769 ( ) 769 ( ) 772 ( ) 772 ( ) 338 ( ) 338 ( ) 318 ( ) 318 ( ) Severe asthma (%) Características dos pacientes

109 Adults and adolescents (protocol 008) Adults and adolescents (protocol 009) Children (protocol 010) Omalizumab Placebo Omalizumab Placebo Omalizumab Placebo Number treated Corticosteroid-stable phase (%) with > 1 exacerbation P=0.009 P<0.001 P=0.095 Corticosteroid-withdrawal phase (%) with > 1 exacerbation P=0.004 P<0.001 Median % reduction in BDP dose P<0.001 P=0.001 Effect of omalizumab on ICS treatment

110 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

111 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 reclassification of asthma based on subphenotypes - Lippincott Williams & Wilkins

112 The mechanisms, diagnosis, and management of severe asthma in adults - Lancet 2006; 368: 780–93 Algorithm of possible strategies and recommendations for managing patients with difficulties to control asthma despite maximum combination treatment

113 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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