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Suneel Kumar MD
Definition of Asthma
National Asthma Education and Prevention Program (NAEPP) defined as:
Airway obstruction that is reversible (but not completely so in some subjects), either spontaneously or with treatment Airway inflammation Increased airway responsiveness to a variety of stimuli
Symptoms
Cough Wheezing Chest tightness Shortness of breath
Update in Asthma
Current guidelines for treatment of asthma Beta agonist use Inhaled corticosteroids Leukotriene modifiers Chromones Anti-IgE therapy Use of exhaled nitric oxide in monitoring asthma Asthma during pregnancy
Goals of Therapy
Minimal or no chronic symptoms day or night Minimal or no exacerbations No limitations on activities; no school/work missed Maintain (near) normal pulmonary function Minimal use of short-acting inhaled beta 2 agonist Minimal or no adverse effects from medications
Stepwise Approach
Review treatment every 1 to 6 months, and gradually step down treatment If asthma controlled not maintained, then a step up in treatment may be warranted
Beta 2 Agonists
Beta 2 Agonists
Most potent and rapidly acting bronchodilators currently available for clinical use Given in different forms:
short acting = isoproterenol intermediate acting = albuterol, metaproterenol, pirbuterol, levalbuterol, terbutaline (IV only), fenoterol [not available in the US] long acting = salmeterol, formoterol
Mechanism of Action
Beta 2 agonists interact with beta 2 receptors on the surface of a variety of cells that may play a role in asthma pathogenesis Beta agonists have the potential to relax bronchial smooth muscle, decrease mast cell mediator release, inhibit neutrophil, eosinophil, and lymphocyte functional responses, increase mucociliary transport, and affect vascular tone and edema formation
Corticosteroids
Glucocorticoids
Most potent antiinflammatory agents available for the treatment of asthma More effective than beta agonists, theophylline, and cromolyn sodium in reducing airway hyperresponsiveness during maintenance therapy
Glucocorticoid Mechanisms
Alleviating airway inflammation Reducing collagen and tenascin deposition, two features associated with airway remodeling Inhibit the synthesis of almost all known cytokines Alteration of the number and availability of circulating leukocytes Reduction in vascular permeability Inhibition of mediator synthesis and release
Steroids and Long Acting Beta Agonists Results in greater improvements in lung function and symptom control than monotherapy with escalating doses of inhaled glucocorticoid Act synergistically to activate transcription factors, decrease smooth muscle proliferation, and impair eosinophil adhesion
Leukotriene Modifiers
Leukotriene Modification 5-lipoxygenase pathway is a series of biochemical reactions that result in the transformation of arachidonic acid into leukotrienes Produced by eosinophils and mast cells when appropriately activated
Leukotriene Modifiers
Zafirlukast (Accolate) and montelukast (Singulair) are inhibitors of the action of LTD4 at its receptor Zileuton (Zyflo) is an inhibitor of 5lipoxygenase All are oral
Leukotriene Modifiers
Superior effect when compared to placebo in the treatment of patients with mild to moderate asthma Associated with both a significant decrease in the need for rescue beta agonist therapy and improved asthma symptoms, especially at night Similar in magnitude to those achieved with inhaled steroids given at recommended doses
Cause of Churg-Strauss?
Rarely (1 out of 25,000 to 150,000 patient-years of treatment) ChurgStrauss vasculitis has been seen in patients started on leukotriene modifiers who were on systemic steroids It is unlikely that this is a direct effect of leukotriene inhibition in these patients, and is more probably due to preexisting CSS unmasked as a result of steroid withdrawal
Chromones
Chromones
Cromolyn sodium and nedocromil Act as mast cell stabilizers by inhibiting chloride channels (thereby stopping degranulation) Remarkably favorable therapeutic indices
Use of Chromones
Children and young adults with mild to moderate asthma requiring an antiinflammatory agent Patients with a strong allergic component to their asthma Patients with exercise-induced bronchospasm Patients who require an antiinflammatory agent but for whom ICS are contraindicated or undesirable
Anti-IgE Therapy
Anti-IgE Therapy
Most asthmatic patients have elevated circulating IgE concentrations when levels are adjusted for age IgE is produced by B lymphocytes
Anti-IgE Therapy
Recombinant humanized antibody omalizumab (Xolair) binds IgE with high affinity Developed for the treatment of allergic diseases Binds to the C-epsilon-3 domain of circulating IgE but does not bind to Fcepsilon-RI, and therefore does not activate mast cells or basophils Specific to IgE; does not bind to IgG or IgA
Omalizumab
SQ injection every 2 to 4 weeks Dose determined by levels of serum IgE Considered as an add-on therapy to reduce or discontinue treatment with oral corticosteroids May also be indicated in patients who have severe allergic symptoms of asthma and rhinitis and who have very high circulating levels of IgE
Omalizumab
Circulating IgE-omalizumab complexes are small No evidence of immune complex formation Elimination half-life is 1 to 4 weeks Aerosolized omalizumab (10 mg) is ineffective in protecting against allergen challenge and has no effect on circulating IgE
Omalizumab
Necessary to obtain almost complete disappearance of circulating IgE in order to achieve clinical efficacy Dose of 150 to 375 mcg every 2 to 4 weeks Peak serum concentration is reached in 7 to 8 days Should be treated for a minimum of 12 weeks Cost is $10,000 to $12,000 per year Well tolerated
Isoforms of NOS
NO Formation
nNOS and eNOS are usually constitutively active and produce low amounts of NO iNOS has the capacity to generate large quantities of NO when transcriptionally upregulated by the inflammatory cytokines TNF alpha, IL-1 beta, and IFN-gamma
FENO in Asthma
Red = normals Blue = asthmatics
FENO
Asthmatics have higher FENO than do similar non-asthmatic subjects The magnitude of FENO in increased in proportion to bronchial wall inflammation, induced-sputum eosinophils, and airway hyperresponsiveness
FENO
Increased FENO levels are associated with deterioration in asthma control FENO is reduced in a dose-dependent manner with antiinflammatory treatment Prospective randomized single-blind placebo controlled trial showed tha following FENO levels can significantly decrease the dose of ICS without a significant change in rate of asthma exacerbations, use of oral steroids, or in level of airway inflammation*
*Smith et al, NEJM May 2005; 352(21):2163-73
Beta 2 Agonists
Beta agonists are safe More experience with older medications Also used as tocolytic agents
Theophylline
Methylxanthines, especially theophylline and aminophylline, are considered safe Clinical use is limited Decreased protein binding during pregancy; should use levels 8 to 12 g/mL Fetal serum levels same as maternal Decreased drug clearance during the third trimester Can inhibit uterine contraction
Inhaled Anticholinergics
Safe, especially ipatropium No adverse development in fetus
Corticosteroids
Small risk during pregnacy, and should be withheld unless indicated Three potential areas of concern have been raised: congenital malformations, primarily cleft palate; low birth weight; and neonatal adrenal insufficiency No data in humans to show increased risk of cleft palate in humans Palatial closure in 12th week
Corticosteroids
Some studies show a slight decrease in birth weight with systemic steroids Slight increased risk of prematurity in studies, but may be related to severity of asthma rather than use of steroids
Inhaled Corticosteroids
ICS, especially beclomethasone, triamcinolone, and budesonide, have been studied The only randomized, controlled trial assessed 105 asthma exacerbations in 84 pregnant women who were managed with or without inhaled beclomethasone Associated with a decreased rate of readmission for asthma (12 vs 33%), and no adverse events or outcomes were noted*
*Wendel et al,Am J Obstet Gynecol 1996 Jul;175(1):150-4
Inhaled Corticosteroids
Registry-based cohort study of 2,014 Swedish women who used inhaled budesonide during early pregnancy Rate of congenital malformations was no different from that of the general population (3.8 vs 3.5%)* Based largely upon these findings, budesonide is currently the only inhaled corticosteroid with a pregnancy category B rating
Chromones
Animal data and experience in 296 human pregnancies have not demonstrated an increase in fetal malformations or other adverse effects with cromolyn sodium Human data are not available for nedocromil, although preclinical animal studies suggest that this drug is also safe
Leukotriene Modifiers
Animal data on zafirlukast have shown no teratogenicity at oral doses up to 160 times the maximum human daily oral dose on a mg/m2 basis No teratogenicity has been observed with montelukast given to rats or rabbits at doses greater than 300 times the maximum human daily oral dose on a mg/m2 basis Adequate studies in pregnant human women have not been performed
Conclusion
Horse hospitals