Asthma

W e sa m R Kadhum

Introduction
Asthma is a chronic (long-term) lung disease that inflames and narrows the airways. Asthma causes recurring periods of wheezing, chest tightness, shortness of breath, and coughing. The coughing often occurs at night or early in the morning. Asthma affects people of all ages, but it most often starts in childhood. In the United States, more than 22 million people are known to have

 The airways are tubes that carry air into and out of the lungs. People who have asthma have inflamed airways. This makes the airways swollen and very sensitive. They tend to react strongly to certain substances that are breathed in. When the airways react, the muscles around them tighten. This causes the airways to narrow, and less air flows to the lungs.

 The swelling also can worsen, making the airways even narrower. Cells in the airways may make more mucus than normal. Mucus is a sticky, thick liquid that can further narrow your airways. This chain reaction can result in asthma symptoms. Symptoms can happen each time the airways are irritated.

 Airflow obstruction in asthma is due to bronchoconstrictio n that results from contraction of bronchial smooth muscle, inflammation of the bronchial wall, and increased mucous secretion. The symptoms of asthma may be effectively treated by several drugs, but no agent provides a

 Asthma is a chronic disease with an underlying inflammatory pathophysiology that, if untreated, may incur airway remodeling, resulting in increased severity and incidence of exacerbations and/or death.

Pathogenesis of Asthma
In the classic immunologic model, asthma is a disease mediated by reaginic (IgE) antibodies bound to mast cells in the airway mucosa. On reexposureto an antigen, antigen-antibody interaction on the surface of the mast cells triggers both the release of mediators stored in the cells' granules and the synthesis and release of other mediators.

 The agents responsible for the early reactionimmediate bronchoconstrictioninclude histamine, tryptase and other neutral proteases, leukotrienes C4 and D4, and prostaglandins.

 These agents diffuse throughout the airway wall and cause muscle contraction and vascular leakage. Other mediators are responsible for the more sustained bronchoconstriction, cellular infiltration of the airway mucosa, and mucus hypersecretion of the late asthmatic reaction that occurs 28 hours later. These mediators are thought to be cytokines characteristically produced by TH2 lymphocytes, especially GMCSF and interleukins 4, 5, 9, and 13, which attract and activate eosinophils and stimulate IgE production by B

 It is not clear whether lymphocytes or mast cells in the airway mucosa are the primary source of the cytokines and other mediators responsible for the late inflammatory response, but it is now thought that the benefits of corticosteroid therapy may result from their inhibition of cytokine production in the airways.

FEV1 = forced expiratory volume in one second.

 Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. On reexposure to allergen, antigenantibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene C4, A4, B4 and platelet-activating factor (PAF). These agents provoke contraction of airway smooth muscle, causing the immediate fall in FEV1.

 Reexposure to allergen also causes the synthesis and release of a variety of cytokines: interleukins 4 and 5, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. These cytokines in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor (PAF). These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the late

Asthma classification and management

Mechanisms of response to inhaled irritants

The airway is represented microscopically by a cross-section of the wall with branching vagal sensory endings lying adjacent to the lumen. Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia.

 (ACh), which binds to muscarinic receptors on airway smooth muscle. Inhaled materials may provoke bronchoconstriction by several possible mechanisms. First, they may trigger the release of chemical mediators from mast cells. Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release

First-Line Drugs Used to Treat Asthma

Asthma is an inflammatory disease of the airways characterized by episodes of acute bronchoconstriction causing shortness of breath, cough, chest tightness, wheezing, and rapid respiration. These acute symptoms may resolve spontaneously, with nonpharmacologic relaxation exercises, or with use of quick relief medications, such as a short-acting 2-adrenergic agonist. Unlike chronic bronchitis, cystic fibrosis, or bronchiectasis, asthma is usually not a progressive disease; that is, it does not inevitably lead to crippled airways.

Goals of therapy

a.

Reducing impairment:
1.Prevent chronic and troublesome symptoms. 2.Require infrequent use (2 days a week) of inhaled short-acting 2 agonist for quick relief of symptoms. 3.Maintain (near) normal pulmonary function. 4.Maintain normal activity levels (including exercise and other physical activity and attendance at work or school). 5.Meet patients' and family expectations of and satisfaction with asthma care.

b. Reducing risk:
1.Prevent recurrent exacerbations of asthma, and minimize the need for emergency department visits or hospitalizations. 2.Prevent progressive loss of lung function; for children, prevent reduced lung growth. 3.Provide optimal pharmacotherapy with minimal

Adrenergic agonists
1.Quick relief: Most clinically useful 2 agonists have a rapid onset of action (5 to 30 minutes) and provide relief for 4 to 6 hours.

They are used for symptomatic treatment of bronchospasm, providing quick relief of acute bronchoconstriction. 2 Agonists have no anti-inflammatory effects, and they should never be used as the sole therapeutic agents for patients with persistent asthma.

 Monotherapy with short-acting 2 agonists may be appropriate only for patients identified as having mild intermittent asthma, such as exercise-induced asthma.

direct-acting 2-selective The agonists, such as pirbuterol, terbutaline, and albuterol , offer the advantage of providing maximally attainable bronchodilation with little of the

2.Long-term control: Salmeterol, xinafoate and formoterol are long-acting 2 agonists bronchodilators. Salmeterol and formoterol have a long duration of action, providing bronchodilation for at least 12 hours. Both salmeterol and formoterol have slower onsets of action and should not be used for quick relief of an acute asthma attack.

 long-acting 2 agonists should be prescribed for routine administration. Whereas inhaled corticosteroids remain the long-term control drugs of choice in asthma, long-acting 2 agonists are considered to be useful adjunctive therapy for attaining asthma control. Appropriate inhaler technique with long-acting 2 agonists is critical to the success of therapy, may differ from the patient's other inhalers (metered-dose inhaler versus dry

 Adverse effects of the long-acting 2 agonists are similar to quickrelief 2 agonists such as tachycardia, hyperglycemia, hypokalemia, and hypomagnesemia, insomnia, anxiety, and tremor occur in some patients.

Theophylline
Theophylline is a bronchodilator that relieves airflow obstruction in chronic asthma and decreases its symptoms. Theophylline is well absorbed by the gastrointestinal tract, and several sustained-release preparations are available. Previously the mainstay of asthma therapy, theophylline has been largely replaced with 2 agonists and corticosteroids due to a narrow therapeutic window, high side-effect profile, and potential for drug interactions. Overdose may cause seizures or potentially fatal arrhythmias. Theophylline is metabolized in the liver, is a

Corticosteroids
Inhaled corticosteroids (ICS) are the drugs of first choice in patients with any degree of persistent asthma (mild, moderate, or severe). Severe persistent asthma may require the addition of a short course of oral glucocorticoid treatment. No other medications are as effective as ICS in the long-term control of asthma in children and adults. If appropriately prescribed and used, ICS therapy may reduce or eliminate the need for oral glucocorticoids in patients with severe asthma.

Route of administration
1. Inhalation: The development of ICS has markedly reduced the need for systemic corticosteroid treatment to achieve asthma control. Appropriate inhalation technique is critical to the success of therapy. Patients should be instructed to SLOWLY and DEEPLY inhale upon activation of these inhalers to avoid impaction of the medication onto the laryngeal mucosa rather than the bronchial smooth muscle. 2. Oral/systemic: Patients with severe exacerbation of asthma (status asthmaticus) may require intravenous administration. Once the patient has

3. Spacers: A spacer is a large-volume chamber attached to a metered-dose inhaler. Spacers decrease the deposition of drug in the mouth caused by improper inhaler technique

 Spacers improve delivery of inhaled glucocorticoids and are advised for virtually all patients, especially children less than 5 years old and elderly patients who may have difficulty coordinating actuation with inhalation. Patients should be counseled about regular washing and/or rinsing of spacers to reduce the risk of bacterial, mold, or mildew growth

Mechanism of action
Corticosteroids act on the immune system by blocking the production of substances that trigger allergic and inflammatory actions, such as prostaglandins (Explain how ??). However, they also impede the function of white blood cells which destroy foreign bodies and help keep the immune system functioning properly. The interference with white blood cell function yields a side effect of increased susceptibility to infection.

Adverse effects

Alternativ e Drugs Used to Treat Asthma

Leukotriene Pathway Inhibitors

Two approaches to interrupting the leukotriene pathway have been pursued: 1. inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis. 2. inhibition of the binding of leukotriene D4 to its receptor on target tissues, thereby preventing its action. Efficacy in blocking airway responses to exercise and to antigen challenge has been shown for drugs in both categories: zileuton, a 5-lipoxygenase inhibitor. zafirlukast and montelukast, LTD4receptor antagonists.

M e ch a n ism o f a ctio n

Adverse effects:
Elevations in serum hepatic enzymes have occurred with all three agents, requiring periodic monitoring and discontinuation when enzymes exceed three to five times the upper limit of normal. Although rare, eosinophilic vasculitis (Churg-Strauss syndrome) has been reported with all agents, particularly when the dose of concurrent glucocorticoids is reduced. Other effects include headache and dyspepsia. Both zafirlukast and zileuton are inhibitors

Cromolyn and nedocromil

Cromolyn and nedocromil are effective prophylactic antiinflammatory agents. However, they are not useful in managing an acute asthma attack, because they are not direct bronchodilators. Because it is poorly absorbed, only minor adverse effects are associated with it.

 Pretreatment with cromolyn blocks allergenand exercise-induced bronchoconstriction. Cromolyn is also useful in reducing the symptoms of allergic rhinitis. Toxic reactions are mild and include a bitter taste and irritation of the pharynx and larynx. Neither cromolyn nor nedocromil should replace ICS or quickrelief 2 agonists as the mainstay of asthma therapy.

Cholinergic antagonists
Anticholinergic agents are generally less effective than 2-adrenergic agonists. They block the vagally mediated contraction of airway smooth muscle and mucus secretion. Inhaled ipratropium a quaternary derivative of atropine, is useful in patients who are unable to tolerate adrenergic agonists. Ipratropium is slow in onset and nearly free of side effects.

Omalizumab
Omalizumab is a recombinant DNA derived monoclonal antibody that selectively binds to human immunoglobulin E (IgE). This leads to decreased binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils. Reduction in surface-bound IgE limits the degree of release of mediators of the allergic response. Omalizumab may be particularly useful for treatment of moderate to severe allergic asthma in patients who are poorly controlled with conventional therapy. Due to the high cost of the drug (approximately $600 for a 150-mg vial), limitations on dosage, and available

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