Current Guidelines forAsthma Treatment Ass. Prof Current Guidelines forAsthma Treatment Ass.Prof.Dr:MUHAMMED WAHEEB AL,OBAIDY Consultant Chest Physician MEDICAL CITY

Mild Intermittent Asthma Symptoms < 2 days/week Symptoms < 2 nights/month PEF or FEV1 > 80% PEF variability < 20% No daily medication needed PRN beta agonists Course of systemic steroids for exacerbations

Mild Persistent Asthma Symptoms > 2 days/wk but < 1x/day > 2 nights/month PEF or FEV1 > 80% PEF variability 20-30% Preferred treatment low dose inhaled corticosteroids Alternatives include cromolyn, leukotriene modifiers, necromodil, or sustained release theophylline

Moderate Persistent Asthma Symptoms daily > 1 night/week PEF or FEV1 > 60% and < 80% PEF variability > 30% Preferred treatment is low to medium dose inhaled corticosteroid and a long acting inhaled beta 2 agonist Alternative includes increasing ICS within moderate dose range, or low to medium dose ICS with either leukotriene modifier or theophylline

Severe Persistent Asthma Continual symptoms Frequent nocturnal attacks PEF or FEV1 < 60% PEF variability > 30% Preferred treatment is high dose inhaled corticosteroid and long acting beta 2 agonists If needed, can add systemic corticosteroids

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

Reasons for Poor Asthma Control Inhaler Technique Compliance Environment Also assess for an alternative diagnosis “All that wheezes is not asthma, and not all asthma wheezes”

Factors Affecting Compliance Education Route of drug administration (inhaled vs. oral) Complexity of drug regimens Side effects of medications Cost

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, levalbuterol ,pirbuterol,metaproterenol, terbutaline, fenoterol 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,

Also B2 agonist : Decrease mast cell mediator release Inhibit neutrophil, eosinophil, and lymphocyte functional responses Increase mucociliary transport Affect vascular tone and edema formation

MDI with Spacer vs. Nebulizer Equivalent bronchodilation can be achieved by giving beta 2 agonist with a spacer/holding chamber or by nebulizer therapy Continuous administration with a nebulizer may be more effective in severely obstructed adults and in those who have difficulty with an MDI plus spacer

Chronic Use of Beta Agonists Arguments against chronic use: Mortality may be increased Control of asthma may worsen Equal or superior efficacy can be achieved with inhaled corticosteroids

Increased Mortality with Chronic Use? A case-control study using linked health insurance databases found: Increased risk of death or near-death from asthma was associated with the regular use of inhaled beta agonists, especially fenoterol Did not appear to be confounded by asthma severity, and there was no relation to non–asthma mortality

Increased Mortality with Chronic Use? However, increased odds ratios were also noted for theophylline and oral corticosteroids

Increased Mortality with Chronic Use? A subsequent analysis demonstrated a relationship between CV death and use of beta agonists taken orally or by nebulizer but not when taken by MDI Risk of CV death was also greater in patients who used theophylline Most of CV deaths in patients with underlying CV disease, including acute coronary insufficiency and congestive cardiomyopathy*

Long Acting Beta Agonist Monotherapy Prolonged treatment with long-acting beta agonists and without inhaled corticosteroids has been associated with increased mortality 28-week placebo-controlled trial assessing the safety of the long-acting beta agonist salmeterol enrolled over 25,000 patients, but was stopped early when interim analysis revealed a significantly increased risk of death in those not taking concomitant inhaled corticosteroids . *"The Pink Sheet" FDC Reports. Chevy Chase, MD. 2003; 65(4):10

Tolerance to Beta Agonists More frequent in chronic use Induced more with oral rather than inhaled preparations Tolerance to long acting beta agonists may or may not occur (conflicting data)

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

Potency of Inhaled Corticosteroids

COMBINATION INHALERS There is no difference in effi cacy in giving inhaled steroid and long-acting β2 agonist in combination or in separate inhalers. Once a patient is on stable therapy, combination inhalers have the advantage of guaranteeing that the long-acting β2 agonist is not taken without inhaled steroid.

In adult patients at step 3 who are poorly controlled, the use of budesonide/formoterol in a single inhaler as rescue medication instead of a short-acting β2 agonist, in addition to its regular use as a controller treatment, has been shown to be an effective treatment option. This management technique has not been investigated with other combination inhalers

Can ICS Cause Osteoporosis? Three year prospective study looked at dose of inhaled triamcinolone and rate of bone loss in premenopausal women with asthma There was a dose-related decline in bone density in the total hip and trochanter No dose-related decline in the femoral neck or spine 􀀻 Titrate the dose of inhaled steroid to the lowest dose at which effective control of asthma is maintained.

COMPARISON OF INHALED STEROIDS BDP and budesonide are approximately equivalent in clinical practice, although there may be variations with different delivery devices. There is limited evidence from two open studies of less than ideal design that budesonide via the turbohaler is more clinically effective

New Inhaled Steroids Mometasone is a new inhaled steroid that appears to provide equal clinical activity to BDP and budesonide at half the dosage. The relative safety of mometasone is not fully established. Ciclesonide is a new inhaled steroid. Evidence from clinical trials suggests that it has less systemic activity and fewer local oropharyngeal side effects than conventional inhaled steroids. The clinical benefit of this is not clear as the exact efficacy to safety ratio compared to other inhaled steroids has not been fully established.

STEROID TABLET-SPARING MEDICATION Immunosuppressants (methotrexate, ciclosporin and oral gold) decrease long term steroid tablet requirements, but all have significant side effects. There is no evidence of persisting beneficial effect after stopping them; and there is marked variability in response

Immunosuppressants (methotrexate, ciclosporin and oral gold) may be given as a three month trial, once other drug treatments have proved unsuccessful. Their risks and benefits should be discussed with the patient and their treatment effects carefully monitored.

Anti-TNF alpha therapy has been investigated in severe asthma but these studies are too small and too short term to allow recommendation of anti-TNF therapy outside the context of a controlled clinical trial

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 5-lipoxygenase 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

Montelukast vs. Beclomethasone Both agents demonstrated similar efficacy with respect to preventing asthma exacerbations in moderate persistent asthma However, beclomethasone was significantly superior to montelukast in its capacity to improve objective measures of lung function as measured by average responses

Cause of Churg-Strauss? Rarely (1 out of 25,000 to 150,000 patient-years of treatment) Churg-Strauss 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

Cromolyn sodium and nedocromil Act as mast cell stabilizers by inhibiting chloride channels (thereby stopping degranulation) Remarkably favorable therapeutic indices Sodium cromoglicate is of some benefit in adults and is effective in children aged 5-12 Nedocromil sodium is also of benefit in adults and children >5

Use of Chromones There is no clear evidence of benefi t with sodium cromoglicate in children aged <5 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 Fc-epsilon-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

Asthma Control During ICS Withdrawl

Omalizumab and ICS Therapy US sites alone US and international sites

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

Exhaled Nitric Oxide

Nitric Oxide Effects in the Lung Regulates vascular and bronchial tone, promoting dilation of both vessels and airway Helps to facilitate the coordinated beating of ciliated epithelial cells Important neurotransmitter for non-adrenergic, non-cholinergic neurons which run in the bronchial wall

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

Immunotherapy

Immunotherapy can be considered in patients with asthma where a clinically signifi cant allergen cannot be avoided. The potential for severe allergic reactions to the therapy must be fully discussed with patients.

Sublingual immunotherapy There has been increasing interest in the use of sublingual immunotherapy, which is associated with far fewer adverse reactions than subcutaneous immunotherapy. Sublingual immunotherapy cannot currently be recommended for the treatment of asthma in routine practice.

DIETARY MANIPULATION

ELECTROLYTES Sodium Increasing dietary sodium has been implicated in the geographical variations in asthma mortality and high sodium intake is associated with increased bronchial hyper-responsiveness

Magnisium Low magnesium intakes have been associated with a higher prevalence of asthma with increasing intake resulting in reduced bronchial hyper-responsiveness and higher lung Function. Magnesium plays a beneficial role in the treatment of asthma through bronchial smooth muscle relaxation, leading to the use of intravenous or inhaled preparations of magnesium sulphate for acute exacerbations of asthma. Studies of oral supplementation are limited and more trials are required.

FISH OILS/LIPIDS In vitro studies suggest that supplementing the diet with omega-3 fatty acids, which are most commonly found in fish oils, might reduce the inflammation associated with asthma. There was insufficient evidence to recommend fish oil supplementation for the treatment of asthma

ANTIOXIDANTS Intervention studies suggest that neither supplementation with vitamin C, vitamin E or selenium is associated with clinical benefits in people with asthma. No intervention studies evaluating the intake of fruit or vegetables and their effects on asthma have been reported.  

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS In adult patients with allergic bronchopulmonary aspergillosis (ABPA), itraconazole may decrease steroid tablet dose and improve asthma control. In adult patients with ABPA, a four month trial of itraconazole should be considered.

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