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1 Dúvidas Arquivo Sistema Respiratório Site


3 Asthma Pharmacotherapy
A. Immunologic response A. Antigen Sensitized mast cell Antigen-antibody reaction Release of pharmacologic mediators (histamine, SRS-A, etc) Anti-1gE antibody Mast cell degranulation blocker Chemotaxins, chemokines Direct action on end organs (glands, smooth muscle, blood vessels) Infection Metabolites Adenylyl cyclase deficiency Drug B. β-adrenergic blockade caused by: C. Cholinergic dominance D. β-adrenergic amine deficiency Sympathetic nerves β2-Adrenergic agonist Vagus efferent Block Muscarinic antagonist Vagus nerves Central influences Antiinflammatory agents (eg, glucocorticoids) Airway inflammation, airway hyperreactivity, epithelial damage Recruitment of TH2 cells, activation of inflammatory cells (eg, eosinophils) Late Phase Asthma Pharmacotherapy Netter’s Illustrated Pharmacology – fig 7-8

4 Anti-IgE Antibodies Sensitization Pollen Antigen Light chain
Heavy chain Disulfide bonds Fc fragment Fab fragment IgE A. Genetically atopic patient exposed to especific antigen (ragweed pollen illustrated) C. Mast cells and basophils sinsitized by attachment of IgE to cell membranes Rhumab-E25 (anti-IgE) prevents binding of IgE to mast cells Rhumab-E25 B. Plasma cells in lymphoid tissue of respiratory mucosa release immunoglobulin E (IgE) Netter’s Illustrated Pharmacology – fig 7-9

5 Mast cell degranulation blockers
ALLERGIC REACTION D. Reexposure to same antigen E. Antigen reacts with antibody (IgE) on membrane of sensitized mast cells and/ or basophils, wich respond by secreting pharmacologic mediators Mast cell degranulation blockers Vagus nerve Mucous gland hypersecretion Smooth muscle contraction Increased capillary permeability and inflammatory reaction Eosinophil attraction F. End-organ (airway) response compound by nonspecific reactions (cilistasis, particle retention, and cell injury) Histamine SRS-A (slow-reacting substance of anaphylaxis) ECF-A (eosinophil chemotactic factor of anaphylaxis)) Prostaglands Serotonin Kinins Cromolyn Nedocromil Mast Cell Degranulation Blockers Netter’s Illustrated Pharmacology – fig 7-10

6 Respiratory System - Bronchodilators
B2-Agonists + Theophylline - ATP AMP Adenylyl cyclase Phospho-diesterase cAMP Muscarinic antagonists Bronchospasm Bronchial tone Bronchodilation Adenosine Acetylcholine Netter’s Illustrated Pharmacology – fig 7-11

7 Block by methylxanthine
Theophylline CH3 Bronchial smooth muscle cell β receptor Sympathetic fibers Block by methylxanthine (aminophylline) increases effective concentration of cyclic 3’, 5’-AMP, leading to relaxation Adenosine receptor Vagus fiber Muscarinic receptor Theobromine Caffeine Cyclic GMP Adenylyl cyclase Cyclic 3’,5’-AMP Mg2+ ATP 5’-ATP Degradation by phospho-diesterase Relaxation Contraction β-Blockade by: Infection Metabolites Functional deficiency of adenylyl cyclase Propranolol Cell membrane Myofibrils Ca2+ PGE Prosta-glands PGF2α β –Blockade causes muscle to become more sensitive to pharmacologic mediators and to vagal and possibly α-adrenergic influences Vagus n. and α β Methylxanthines Netter’s Illustrated Pharmacology – fig 7-12

8 Methylxanthine: Adverse Effects
Methylxanthines Brain Lungs Heart Live and gastrointestinal tract Skeletal muscle Kidney Increased cortical arousal Increased alertness Fatigue deferral Nervousness Bronchodilation Increased cardiac output Increased blood flow Decreased blood viscosity Increased heart rate Increased gastric acid and digestive enzyme secretion Increased contractility Slight diuresis Methylxanthine: Adverse Effects Netter’s Illustrated Pharmacology – fig 7-13

9 β-Adrenergic Agonists
Catecholamine Action on α and β Receptors of Heart and Bronchial Tree Epinephrine Norepinephrine Isoproterenol Specific β2 stimulators Action on bronchial tree Action on heart β1 Sinus node α β1 α Constriction and increased secretion of mucus Muscle β2 β1 Rate and force of contraction increased β2 Dilatation and decreased secretion of mucus Netter’s Illustrated Pharmacology – fig 7-14

10 β-Adrenergic Agonists (cont)
ATP Bronchodilation β2-Agonists Adenylyl cyclase + cAMP + Phospho-diesterase AMP Bronchial tone + Adenosine + Acetylcholine Bronchospasm Netter’s Illustrated Pharmacology – fig 7-14

11 Epinephrine Ephedrine Isoproterenol
β receptor Adenosine receptor Muscarinic receptor Vagus fibers Sympathetic fibers Cyclic GMP Adenylyl cyclase β ATP Mg2+ Cyclic ’, 5’-AMP Degradation by phospho-disterase 5’-AMP Relaxation Contraction Cell membrane Myofibrils Ca2+ Bronchial smooth muscle cell Give aqueous epinephrine 1:1000 subcutaneously. If initial response is inadequate, repeat at 30 to 60 minute intervals as needed; oxygen as indicated Epinephrine Ephedrine Isoproterenol Nonselective β-Adrenergic Agonist If response to epinephrine is inadequate or if patient becomes refractory, give aminophylline intra venously very slowly; administer oxygen. If necessary, corticosteroids, which act more slowly, also can be given Netter’s Illustrated Pharmacology – fig 7-15

12 Selective β2-Adrenergic Agonists
Epinephrine Norepinephrine Isoproterenol Selective β2-adrenergic agonist Action on heart Action on bronchial tree Rate and force of contraction increased Dilatation and decreased secretion of mucus Constriction and increased secretion of mucus α β1 β2 Muscle Sinus node Catecholamine Action on α and β Receptors of Heart and Bronchial Tree Netter’s Illustrated Pharmacology – fig 7-16

13 Antimuscarinic Antagonists
Ipratropium Atropine N+ Sympathetic fibers Cholinergic fibers Contraction Relaxation ATP Adenylyl cyclase Mg2+ Cyclic 3’,5’-AMP 5’-AMP Degradation by phospho-diesterase Cyclic GMP Acetylcholine Muscarinic receptor Adenosine receptor β receptor β Cell membrane Myofibrils Ca2+ Bronchial smooth muscle cell Muscarinic antagonists Antimuscarinic Antagonists Netter’s Illustrated Pharmacology – fig 7-17

14 Corticosteroids Corticosteroid Action in Bronchial Athma Supra cortex
Lysosome stabilization Antiinflamammatory effect Inhibition of antibody formation Possible inhibition of histamine formation / storage Steroid-resistant patients may require higher and continuous dosage In chronic steroid administration, if dosage is withdrawn or suboptimal, severe asthmatic exacerbations may occur Plasma clearance Vagus nerves Sympathetic nerves During acute episode some patients may have relative suprarenal insufficiency Supra cortex Corticisteroids Potentiation of β-adrenergic receptor Possible antagonism of cholinergic (vagal) actions Relaxation of bronchospasm Decreased mucus secretion Corticosteroid Action in Bronchial Athma Corticosteroids Netter’s Illustrated Pharmacology – fig 7-18

15 Corticosteroids: Clinical Uses
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

16 Corticosteroids: Adverse Effects
Increased appetite Mood alterations Insomnia Headache Brain Corticosteroids: Adverse Effects Reduced bronchial reactivity Reduced asthma attack frequency Reduced severity of asthmatic symptoms Decreased inflammation No direct muscle relaxation Lungs Increased hypertension Corticosteroids Heart Diarrhea Liver and gastrointestinal tract Osteoporosis Netter’s Illustrated Pharmacology – fig 7-20 Bone Increased salt retention Kidney

17 Prostaglandins (PGE, PGF)
Phospholipids Phospholipase A2 Angiotension Corticosteroids Arachidonic acid COOH PGG2 NSAIDs Cyclooxygenase (COX) OOH Thromboxane (TXA2) Prostaglandins (PGE, PGF) Prostacyclin (PGl2) INFLAMMATION 5-HPETE H 5-Lipoxygenase Leukotrienes (LTB4, LTC4, LTD4) Cell membrane Leukotrienes Netter’s Illustrated Pharmacology – fig 7-21

18 Leukotriene Antagonists
Netter’s Illustrated Pharmacology – fig 7-22

19 Infectious Agents Causing Pneumonia
Bacteria Streptoccus pneumoniae Streptococcus pyogeneses Staphylococcus aureus Klesbsiella pneumoniae Pseudomonas aeruginosa Escherichia coli Yersinia pestis Legionnaires bacillus Peptostreptococcus, Peptococcus Bacteroides Fusobacterium Veillonella Actinomyces israelii Nocardia asteroides Coccidioides immitis Histoplasma capsulatum Blastomyces dermatitidis Aspergillus Phycomycetes Coxiella burnetti Chlamydia psittaci Mycoplasma pneumoniae Influenza virus, adenovirus, respiratory Syncytial virus, etc Pneumocystis carinii Actinomycetes Fungi Rickettsia Chlamydia Mycoplasma Viruses Protozoa Bacterial pneumonias Legionnaires disease Aspiration (anaerobic) pneumonia Pulmonary actinomycosis Pulmonary nocardiosis Coccidioidomycosis Histoplasmosis Blastomycosis Aspergillosis Mucormycosis Q ferver Psittacosis Ornithosis Mycoplasmal pneumonia Viral pneumonia Pneumocystis pneumonia (plasma cell pneumonia) Class Etiologic Agent Type of Pneumonia


21 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 Dados de 1999 apontam para a existência de de asmáticos no mundo. Nos Estados Unidos esse número é de, aproximadamente, 15 a 17 milhões, dos quais 5 milhões são crianças. É a doença crônica mais comum em crianças e acredita-se que, nos EUA, haja uma perda de 10 milhões de dias escolares por ano, por causa da asma. National Institutes of Health, NIH Publication No II Consenso Brasileiro no Manejo da Asma, 1998

22 A Situação Brasileira 350.000 hospitalizações pelo SUS/96
4% das causas de hospitalização terceiro > custo (2,8% dos gastos) = $77 milhões 70% dos óbitos ocorrem no hospital e 22% destes chegaram agônicos só 0,8% morrem em UTI os BD são as medicações mais prescritas enquanto os anti-inflamatórios são as menos prescritas A asma é um problema de saúde pública. A sua incidência está aumentando de forma rápida em todo o mundo. Esse trabalho realizado pelo Dr. Hisbelo Campos mostra que os números da asma no Brasil são bastante elevados. Apesar de corresponder a apenas 4% das causas de hospitalização, é responsável pelo terceiro maior custo. Um outro dado relevante é que os broncodilatadores são as medicações mais prescritas, enquanto os antiinflamatórios são as menos prescritas. Isso demonstra que precisamos enfatizar a importância de esclarecer que a asma é uma doença inflamatória e os pacientes precisam ser tratados com drogas antiinflamatórias. Campos, HS Pulmão RJ 2000; 9 (1): 14-43

23 Diferentes nomes para o mesmo problema
Bronquite Bronquite alérgica Bronquite asmática A asma é denominada de diferentes formas. O importante é que o saibamos que a asma é uma doença inflamatória crônica. A inflamação das vias aéreas tem um papel fundamental na patogênese da doença e, portanto, o tratamento deve ser voltado para reverter e prevenir esta alteração. ASMA

24 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. A asma é uma doença inflamatória das vias aéreas. Não importa a causa que está levando aos sintomas, a via final comum é um conjunto semelhante de fenômenos que ocorre nas vias aéreas. Dentre as várias células importantes no desencadeamento da crise, talvez, os mastócitos e os eosinófilos sejas as mais relevantes. Das enzimas eosinofílicas, a catiônica, é capaz de descamar a mucosa brônquica, tornando-a muito sensível à pequenos estímulos, como dar risada ou respirar rápido. Hiperresponsividade das vias aéreas é um estado do brônquio dos asmáticos de apresentar uma resposta exagerada de constrição à estímulos internos ou externos. International Conference Report, 1992

25 FEV1 in patients (HBR) FEV1 (% FALL) Dose (mmol) 60 50 40 30 20 10
METHACHOLINE HISTAMINE ASTHMA FEV1 (% FALL) Severe Moderate Mild Slight COPD Normal Dose (mmol)

26 ASMA Indutores Provocadores Alérgenos VSR Agentes ocupacionais
Exercícios Irritantes Aspirina Provocadores

27 A maior prevalência nos meninos A maior mortalidade na raça negra
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 Peter J. Barnes. Asthma

28 Fenótipo = Genótipo + meio ambiente
Genética da Asma Rinite alérgica Asma Dermatite atópica Infecções Poeira domiciliar Pólen Fenótipo = Genótipo + meio ambiente IgE total IgE específica HRB Idade, dieta , tabagismo Mudanças de temperatura Umidade, poluição, creches

VÍRUS Airway epithelial injury Socioeconomic factors Passive smoking Inflamation Bronchoconstriction Age Airway narrowing in a susceptible host Host susceptibility Mediators Cytokines Sex Immune response Underlying lung function Wheeze Multifactorial association betwen respiratory viruses and wheezing

30 Tabagismo Meta-análises confirmam: Tabagismo nos pais aumenta o risco
dos filhos terem maior freqüência de doenças respiratórias, asma, tosse crônica e sibilância Strachan & Cook - Thorax 52: , 1997 Cook & Strachan - Thorax 52: , 1997 Strachan & Cook - Thorax 53: , 1998 Cook & Strachan - Thorax 53: , 1998

31 Processo inflamatório da ASMA Remodelamento das Vias Aéreas
Inflamação Aguda Inflamação Crônica Remodelamento das Vias Aéreas A asma é uma doença inflamatória crônica das vias aéreas que se manifesta por exacerbações (crises), caracterizadas por falta de ar, chiado no peito, tosse e aumento da expectoração. Inflamação significa edema das vias aéreas, excesso de produção de muco presença de células inflamatórias. O músculo que envolve os brônquios torna-se hiperexcitáel e contrai-se a estímulos (broncoconstrição). A manutenção do quadro inflamatório leva a recrutamento celular, lesão epitelial e alterações estruturais precoces. Se não tratada adequadamente as lesões tornam-se irreversíveis (remodelamento). Broncoconstrição Edema Secreção Tosse Recrutamento celular Dano Epitelial Modificações Estruturais Precoces Proliferação Celular Aumento da Matriz Extracelular Cançado, JE 2000

32 SADIO ASMA LEVE Hyperplasia and erosion
Eosinophil and Lymphocyte Infiltration

33 Inflamação das Vias Aéreas na ASMA
O processo inflamatório crônico da asma é composto por infiltrado celular principalmente de eosinófilos, hipertrofia da muscular, hiperplasia da camada glandular, espessamento da membrana basal e descamação epitelial, expondo a submucosa aos antígenos na superfície (hiperresponsividade brônquica). Como mostra a foto o processo leva a destruição crônica da mucosa brônquica, facilitando novas agressões por agentes externos (antígenos), os quais perpetuam este processo inflamatório. Normal Asmático P Jeffery, in: Asthma, Academic Press 1998

34 Etiologia da Asma e da Reatividade Brônquica
Sensibilização Inflamação -HRB Sintomas

35 ASMA Inflamação Sintomas
A asma deve ser entendida como um grande “iceberg”. Os sintomas são apenas as manifestações clínicas do processo inflamatório nas vias aéreas. A inflamação se perpetua na área da submucosa com migração perene de células inflamatórias desta para a mucosa brônquica

36 Ativação celular na asma

37 Classificação Asma persistente grave Asma persistente moderada
Asma intermitente Asma persistente leve Asma persistente moderada Asma persistente grave Após a realização do diagnóstico de gravidade, os pacientes são divididos em dois grandes grupos: - pacientes com asma intermitente - pacientes com asma persistente (leve, moderada ou grave) Para os pacientes com asma persistente está indicado o tratamento de manutenção (de controle, profilático, intercrises) com um medicamento antiinflamatório. É fundamental que o paciente seja orientado a utilizar prolongadamente os medicamentos prescritos para manter a asma sob controle. É importante, também, que o paciente e sua família sejam educados para a correta higiene do ambiente físico, bem como utilização adequda das medicações prescritas. GINA/NIH

38 Mastócitos na Membrana Basal de mucosa brônquica
100 80 60 No. of Mastócitos cel/mm2 40 20 Controles Normais Asmáticos Bronquite eosinofílica

39 Eosinófilos na Membrana Basal de mucosa brônquica
300 100 30 No. of Eosinofilos/mm2 3 1 Controles Normais Asmáticos Bronquite eosinofílica

40 Espessura da membrana basal e lâmina reticularis de mucosa brônquica
25 20 15 Espessura da membrana basal e lâmina reticularis (mm) 10 5 Controles Normais Asmáticos Bronquite eosinofílica

41 Mastócitos no Músculo Liso Brônquico
100.0 30.0 10.0 No. of Mastócitos cel/mm2 3.0 1.0 0.3 0.0 Controles Normais Asmáticos Bronquite eosinofílica

42 Tratamento da Asma Função pulmonar Exacerbações Inflamação Sintomas
Qualidade de vida Inflamação O tratamento ideal é aquele que consegue atingir todos os objetivos propostos, com o mínimo de efeitos colaterais. Os aspectos-chave no tratamentos devem ser: - controle dos sintoamas - prevenção das exacerbações - melhora da função pulmonar - melhora da qualidade de vida dos pacientes. Para atingir esses objetivos a inflamação deve ser tratada.

43 Adrenergic agonist structure
HO CH CH NH Norepinephrine HO OH H H HO Epinephrine CH CH NH HO OH H CH3 Isoproterenol HO CH CH NH HO OH H CH(CH3)3 Salbutamol HOH2C CH CH NH HO OH H C(CH3)2

44 salmeterol O HO CH HO OH

45 Beta2 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 e BIE Por apresentar ação broncodilatadora prolongada este grupo de drogas esta indicado nos pacientes com sintomas noturnos freqüentes. Vários estudos demonstraram que ao invés de dobrar a dose dos corticosteróides nos pacientes que não estão totalmente controlados é melhor manter a mesma dose a associar uma destas drogas. Assim conseguimos um melhor controle da doença com menores efeitos colaterais. Também tem efeito no broncoespasmo induzido por exercício, apesar desta não ser uma indicação para seu uso.

46 Broncodilatadores de longa duração
Beta2 agonistas Xantinas Os broncodilatadores de ação prolongada estão indicados nos pacientes que já estão usando um antiinflamatório e apresentam sintomas persistentes. Existem dois grupos de drogas: as xantinas que são menos potentes broncodilatadores, porém mais baratos e acessíveis e os beta2 de ação prolongada que são mais efetivos e mais caros.

47 FEV1, as percent of Predicted, From two large 12-Week Clinical Trials
First Treatment day 100 90 80 70 60 Hours FEV1 (% of Predicted Salmeterol 42 mcg twice daily (n=178) Salbutamol 180 mcg four times daily (n=176) Placebo (n=181)

48 FEV1, as percent of Predicted, From two large 12-Week Clinical Trials
Last Treatment day (Week 12) 100 90 80 70 60 Salmeterol 42 mcg twice daily (n=152) Albuterol 180 mcg four times daily (n=151) Placebo (n=150) FEV1 (% of Predicted Hours

49 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 Quando opta-se pela utilização de medicamentos por via inalatória é mandatório a utilização dos espaçadores. Para crianças de 5 anos de idade ou menos, uma câmara espaçadora/retentora acoplada a uma máscara facial é recomendada para a administração de corticosteróides inalatórios. Esse método é mais fácil do que o uso isolado do IDM, porém requer ainda coordenação entre a aplicação e a inalação, é volumoso e varia de dispositivo para dispositivo no que se refere à quantidade liberada da medicação.

50 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 Este grupo de drogas broncodilatadoras é menos potente. Pode ser usado no controle dos sintomas noturnos e como poupador dos corticosteróides como alternativa aos antileucotrienos e beta2 de ação prolongada. A biodisponibilidade dessas drogas é bastante variável e o nível sérico é errático. Além disso, a dose terapêutica é próxima da dose tóxica. Os eventos adversos mais freqüêntes são gastrintestinais.

51 Caso Clínico Paciente (sexo masculino) apresenta-se no pronto socorro com crise asmática (broncoconstrição). Paciente é não fumante e não apresenta outras complicações. Qual a dose de teofilina (broncodilatador) a ser infundida por via endovenosa (R0) para alívio dos sintomas deste paciente?

52 Caso Clínico Concentração desejada - 15 mg/mL
Clearance da teofilina - 48 mL/min

53 No estado de equilíbrio (ss)
Q que entra (Qin) = Q que sai (Qout) Infusão intravascular (F=1) Dose = Cl . Css

54 Caso Clínico R0 = Cl . Css R0= 48 mL/min . 15 mg/mL R0= 720 mg/min

55 Caso Clínico O ataque de asma foi aliviado, o médico agora quer manter o paciente com o mesmo nível terapêutico usando medicação por via oral, em intervalos de 8, 12 ou 24h. A biodisponibilidade da teofilina é 1.

56 No estado de equilíbrio (ss)
Quantidade que entra é igual Quantidade que sai

57 Caso Clínico Administração extravascular F. Dose  = Cl . Css
Biodisponibilidade (F) . Dose Intervalo de tempo Cl . Css = F. Dose = Cl . Css

58 Cálculo da dose por via oral
Dose = 720 mg/min .  Dose = 43.2 mg/h .  Se  = 8h, dose = mg 8/8h Se  = 12h, dose = mg 12/12h Se  = 24h, dose = mg 24/24h

59 Administração de Teofilina
40 30 20 10 24/24h Concentração Plasmática de Teofilina (mg/L) 8/8h infusão endovenosa Tempo (h)

60 Caso Clínico Paciente (sexo masculino) apresenta-se no pronto socorro com crise asmática (broncoconstrição). Paciente é não fumante e não apresenta outras complicações. Qual a dose de teofilina (broncodilatador) a ser infundida por via endovenosa (R0) para alívio dos sintomas deste paciente?

61 Caso Clínico Concentração desejada - 15 mg/mL
Clearance da teofilina - 48 mL/min Volume de distribuição – 30 L

62 Bôlus e infusão 0 2 3.3 4 6 100 90 75 Percent of Plateau 50 25
From Infusion 75 50 Percent of Plateau 25 From bolus dose Half-lives

63 Bôlus e infusão 400 400 Case B 200-mg Bolus Plus Infusion Case A Infusion Alone 300 300 200 200 Amount of Drug Body (mg) Amount of Drug Body (mg) 100 100 Half-lives Half-lives 400 400 Case C 400-mg Bolus Plus Infusion Case D 100-mg Bolus Plus Infusion 300 300 200 200 Amount of Drug Body (mg) Amount of Drug Body (mg) 100 100 Half-lives Half-lives

64 Ipratropium bromide (Atrovent)

65 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 Os medicamentos que atuam sobre os leucotrienos podem agir de duas formas: 1. Bloqueio da síntese de leucotrieno - inibição da 5-lipoxigenase 2. Bloqueio no local de ação dos leucotrienos - antaganista do receptor de leucotrienos cisteínicos Efeitos dos leucotrienos: liberação de citoquinas, quimiotaxia, broncoconstrição, edema e produção de muco

66 Fosfolípedes de Membrana
Fosfolipase A2 Ácido Aracdônico Ciclooxigenase 5-lipoxigenase Prostaglandina e Tromboxanes Eosinófilo Mastócito Basófilo ATP Ca++ FLAP Leucotrieno A4 LTC4 Sintase LTA Hidrolase Neutrófilo Macrófago Monócito Leucotrieno C4 Leucotrieno E4 Leucotrieno D4 g Glutamil transpeptidase Dipeptidase Leucotrieno B4 Os leucotrienos são produzidos a partir dos fosfolípedes da membrana celular. O ácido aracdônico é metabolizado pela enzima 5-lipoxigenase a leucotrieno E4, que sob ação da LTC4 sintase é transformado em leucotrieno C4 (LTC4). Este transfoma-se em leucotrieno D4 (LTD4) e, a seguir, leucotrieno E4 (LTE4). LTC4, LTD4 e LTE4 são denominados leucotrienos cisteínicos. Os leucotrienos promovem a liberação de citoquinas, quimiotaxia para eosinófilos e neutrófilos, broncoconstrição, edema e aumento da produção de muco.

67 Antileucotrienos Apresentam ação anti-inflamatória
Forma de administração: oral Excelente tolerabilidade Melhor adesão ao tratamento No mercado brasileiro temos disponíveis dois antagonistas do receptor de leucotrienos cisteínicos: montelucaste e zafirlucast. Esses medicamentos são antiinflamatórios efetivos administrados por via oral, o que facilita a adesão ao tratamento. Além disso, possuem excelente tolerabilidade.

68 Zafirlukast (Accolate)

69 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 O zafirlucast é um antagonista do receptor de leucotrienos que deve ser tomado duas vezes ao dia, longe das refeições (uma hora antes ou duas horas depois das refeições). Devido à interação do medicamento com os alimentos pode haver redução da sua biodisponibilidade se esta recomendação não for seguida. Possui boa tlerabilidade, porém deve ser realizada monitoramento do nível de enzimas hepáticas, pois pode elevaá-las. Apresenta interação com aspirina, eritromicina e teofilina. Está indicado para crianças com idade igual ou superior a sete anos de idade.

70 Montelukast Sodium (Singulair)

71 Effect of Singulair on FEV1
Placebo Singulair 15 10 5 Mean percent change from Baseline Weeks in treatment Washout

72 Effect of Singulair on FEV1
Placebo Beclometasone Singulair 15 10 5 Mean percent change from Baseline Washout Weeks in treatment

73  Placebo  Montelukast
Effect of Montelukast FEV1 14 12 10 8 % Change fro Baseline 6 4 2 -2 Weeks in treatment Placebo washout A  Placebo  Montelukast

74  Placebo  Montelukast
Effect of Montelukast Beta-Agonist Use 10 % Change from Baseline -10 -20 -30 Placebo washout Weeks in treatment B  Placebo  Montelukast

75 AM Peak Flow (L/minute)
Effect of Montelukast AM Peak Flow (L/minute) 30 20 Change from Baseline 10 -10 Placebo washout Weeks in treatment C  Placebo  Montelukast

76 Daytime Symptom (Score)
Effect of Montelukast Daytime Symptom (Score) 0.0 -0.1 % Change from Baseline -0.2 -0.3 -0.4 -0.5 Placebo washout Weeks in treatment D  Placebo  Montelukast

77 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 Os antagonistas do receptor de leucotrienos estão indicados em monoterapia para o tratamento de controle de pacientes com asma persistente leve a moderada. Nos pacientes com asma grave, que requerem doses altas de corticosteróides inalatório e oral, os antileucotrienos podem ser prescritos como terapia adicional objetivando reduzir a dose do corticosteróide. Em pacientes com doenças atópicas associadas à asma, como rinite alérgica e urticária, os antileucotrienos são uma opção. Broncoconstrição induzida pelo exercício está presente em 70% a 80% dos pacientes com asma. Os antileucotrienos demonstraram eficácia superior ao salmeterol nos pacientes com asma e BIE, sem desenvolvimento de tolerância. Os leucotrienos parecem desempenhar papel-chave na asma induzida por aspirina e, portanto, os antileucotrienos são droga de escolha nessa condição.

78 Montelucaste (Singulair®)
Posologia: 2 a 5 anos mg - 1 comp ao deitar 6 a 14 anos - 5 mg - 1comp ao deitar > 15 anos mg - 1 comp ao deitar (Não tem interação com alimentos) Efeitos colaterais: semelhantes ao placebo Interação medicamentosa:  concentração de fenobarbital O montelucaste está indicado para o tratamento de controle da asma em crianças com idade igual ou superio a 2 anos. É o único medicamento que pode ser administrado uma vez ao dia, preferencialmente à noite. Não apesenta interação com alimentos. Possui excelente tolerabilidade, com índice de eventos adversos semelhante ao placebo. Não há necessidade de monitoramento das enzimas hepáticas.

79 FEV1 in patients (HBR) FEV1 (% FALL) Dose (mmol) 60 50 40 30 20 10
METHACHOLINE HISTAMINE ASTHMA FEV1 (% FALL) Severe Moderate Mild Slight COPD Normal Dose (mmol)

80 Steroid treatment FEV1 (% FALL) Histamine Dose (mmol) 60 50 40 30 20
10 4 months (3.0) Initial (2.0) FEV1 (% FALL) 6 months (2.6) Severe Moderate Mild Slight 7 months (3.0) Histamine Dose (mmol)

81 Efeito do omalizumab (300mg s.c. de 30/30d) in asmáticos
200 100 Median free IgE (ng/mL) Day 1 post-dose Days not to scale Day 0 = screening (n = 93)

82 Características dos pacientes
Adults and adolescents (protocol 008) Adults and adolescents (protocol 009) Children (protocol 010) Omalizumab Placebo Omalizumab Placebo Omalizumab Placebo Number treated 268 257 274 272 225 109 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) 6 (1-12) Mean serum total IgE (IU/ml) 172 186 223 206 348 323 Mean (range) FEV1 (% predicted) 68 (30-112) 68 (32-111) 70 (30-112) 70 (22-109) 84 (49-129) 85 (43-116) Mean (range) BDP dose (mg/day) 679 ( ) 676 ( ) 769 ( ) 772 ( ) 338 ( ) 318 ( ) Severe asthma (%) 22 21 22 22 9 6

83 Effect of omalizumab on ICS treatment
Adults and adolescents (protocol 009) Adults and adolescents (protocol 008) Children (protocol 010) Omalizumab Placebo Omalizumab Placebo Omalizumab Placebo Number treated 268 257 274 272 225 109 Corticosteroid-stable phase (%) with >  1 exacerbation 14.6 23.3 12.8 30.5 15.6 22.9 P=0.009 P<0.001 P=0.095 Corticosteroid-withdrawal phase (%) with > 1 exacerbation 21.3 32.3 15.7 29.8 18.2 38.5 P=0.004 P<0.001 P<0.001 Median %  reduction in BDP dose 75 50 83 50 100 67 P<0.001 P<0.001 P=0.001

84 Eur Respir J Jan;3(1):27-32. Department of Lung Medicine, Region Hospital of Trondheim, Norway. Comparison between theophylline and an adenosine non-blocking xanthine in acute asthma. Vilsvik JS, Persson CG, Amundsen T, Brenna E, Naustdal T, Syvertsen U, Storstein L, Kallen AG, Eriksson G, Holte S. Enprofylline, a drug without adenosine antagonism and theophylline, a potent adenosine antagonist, were compared, double-blind, randomized, in acute asthma (n = 33). The drugs were given intravenously as loading over 10 min followed by maintenance infusion for 24 h. Mean final plasma levels were very high with enprofylline (14 mg.l), and larger than calculated with theophylline (16 mg.l). Seven patients had maximum levels of enprofylline ranging between 16 and 42 mg.l. Extreme plasma levels of enprofylline were not associated with any theophylline-like central nervous system excitatory effects related to seizure-inducing ability. Some irregularities in the heart rhythm did not raise clinical problems and no significant difference between enprofylline and theophylline was recorded. At 1 h patients on enprofylline (mean plasma level: 5.7 mg.l) and theophylline (12.2 mg.l) had improved their peak expiratory flow rates by 31% and 15% (p less than 0.05), respectively. The improvement in lung function after 24 hours did not differ between treatments suggesting that the high levels of enprofylline were supramaximal for its anti-asthma effects in this situation. In conclusion, with enprofylline it is demonstrated that an adenosine non-blocking xanthine derivative may lack CNS-excitatory effects, but be more potent than theophylline in the treatment of acute asthma.

85 Br J Clin Pharmacol. 2004 Jul;58(1):34-9.
Asthma & Allergy Research Group, Department of Clinical Pharmacology, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK. Single and short-term dosing effects of levocetirizine on adenosine monophosphate bronchoprovocation in atopic asthma. Lee DK, Gray RD, Wilson AM, Robb FM, Soutar PC, Lipworth BJ. AIMS: Adenosine monophosphate (AMP) acts indirectly via primed airway mast cells to induce bronchial hyper-responsiveness, which in turn correlates with eosinophilic asthmatic inflammation and atopic disease expression. We evaluated single and short-term dosing effects of a modern histamine H1-receptor antagonist, levocetirizine, given at the usual clinically recommended dose, on the primary outcome of AMP bronchoprovocation. METHODS: Fifteen atopic asthmatics were randomized in double-blind, cross-over fashion to receive for 1 week either levocetirizine 5 mg or placebo. There was a 1-week washout period prior to each randomized treatment. The provocative concentration of AMP producing a 20% fall in FEV1 (PC20) was measured after each washout at baseline and at 4-6 h following the first and last doses of each randomized treatment. RESULTS: Baseline mean +/- SEM values after washout prior to each randomized treatment comparing levocetirizine vs placebo were not significantly different for prechallenge FEV1 (% predicted) 83 +/- 4 vs 82 +/- 4, or AMP PC20 (mg ml(-1)) 45 +/- 24 vs 45 +/- 22, respectively. Airway calibre as prechallenge FEV1 for levocetirizine vs placebo was not significantly different following the first dose 86 +/- 4 vs 82 +/- 4, or the last dose 85 +/- 4 vs 83 +/- 4, respectively. There were significant improvements (P < 0.05) in AMP PC20 comparing levocetirizine vs placebo following the first dose 123 +/- 73 vs 48 +/- 24, a 1.4 doubling dilution difference (95% CI 0.8, 1.9), and the last dose 127 +/- 74 vs 53 +/- 29, a 1.2 doubling dilution difference (95% CI 0.5, 2.0). AMP PC20 was also improved (P < 0.05) by the first and last doses of levocetirizine but not placebo, vs respective baseline values, with there being no difference in the degree of protection between first and last doses. CONCLUSIONS: Single and short-term dosing with levocetirizine conferred similar improvements in bronchial hyper-responsiveness to AMP challenge, which was unrelated to prechallenge airway calibre. Further studies are indicated to evaluate the longer-term effects of levocetirizine on asthma exacerbations.

86 Cochrane Database Syst Rev. 2003;(3):CD003535
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.

87 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.

88 Cochrane Database Syst Rev. 2002;(1):CD001279
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.

89 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.

90 Cochrane Database Syst Rev. 2003;(3):CD002863
Cochrane Database Syst Rev. 2003;(3):CD   Division of Internal Medicine and Specialized Women's Health, University of British Columbia, Children's and Women's Health Centre of British Columbia, 4500 Oak Street, Suite 1U59, Vancouver, British Columbia, Canada, V6H 3N1. Oral beta-blockers for mild to moderate hypertension during pregnancy. Magee LA, Duley L. BACKGROUND: Antihypertensives, such as beta-blockers, are used for pregnancy hypertension in the belief these will improve outcome for mother and baby. OBJECTIVES: To assess whether oral beta-blockers are better than placebo, or no beta-blocker, and have advantages over other antihypertensives, for women with mild to moderate pregnancy hypertension. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (May 2002), MEDLINE (1966 to May 2002), bibliographies of retrieved papers and personal files. SELECTION CRITERIA: Trials comparing beta-blockers with placebo or no therapy, or other antihypertensives, for women with mild to moderate pregnancy hypertension. DATA COLLECTION AND ANALYSIS: We extracted the data independently and were not blinded to trial characteristics or outcomes. Whenever possible, we contacted authors for missing data. MAIN RESULTS: Twenty-nine trials (approximately 2500 women) are included. Thirteen trials (1480 women) compared beta-blockers with placebo/no beta blocker. Oral beta-blockers decrease the risk of severe hypertension (relative risk (RR) 0.37, 95% confidence interval (CI) 0.26 to 0.53; 11 trials, N = 1128 women) and the need for additional antihypertensives (RR 0.44, 95% CI 0.31 to 0.62; 7 trials, N = 856 women). There are insufficient data for conclusions about the effect on perinatal mortality or preterm birth. Beta-blockers seem to be associated with an increase in small-for-gestational-age (SGA) infants (RR 1.36, 95% CI 1.02 to 1.82; 12 trials; N = 1346 women). Maternal hospital admission may be decreased, neonatal bradycardia increased and respiratory distress syndrome decreased, but these outcomes are reported in only a small proportion of trials. In 13 trials (854 women), beta-blockers were compared with methyldopa. Beta-blockers appear to be no more effective and probably equally as safe. Single small trials have compared beta-blockers with hydralazine, nicardipine or isradipine. It is unusual for women to change drugs due to side effects. REVIEWER'S CONCLUSIONS: Improvement in control of maternal blood pressure with use of beta-blockers would be worthwhile only if it were reflected in substantive benefits for mother and/or baby, and none have been clearly demonstrated. The effect of beta-blockers on perinatal outcome is uncertain; the worrying trend to an increase in SGA infants is partly dependent on one small outlying trial. Large randomised trials are needed to determine whether antihypertensive therapy in general (rather than beta-blocker therapy specifically) results in greater benefit than risk, for treatment of mild-moderate pregnancy hypertension. If so, then it would be appropriate to consider which antihypertensive is best, and beta-blockers should be evaluated.



93 Cough Suppressants (Antitussive Agents)
Netter’s Illustrated Pharmacology – fig 7-24

94 The role of GLP-1 in glucose homeostasis.

95 The chemical structure of sitagliptin phospate.


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