Clinical Pharmacy Chapter 11 Asthma

1. Rowa’ Al-Ramahi Clinical PharmacyChapter 11Asthma

2. The National Asthma Education and Prevention Program (NAEPP) defines asthma as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. In susceptible individuals, inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing. These episodes are usually associated with airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an increase in bronchial hyper-responsiveness (BHR) to a variety of stimuli. DEFINITION

3. CHRONIC ASTHMA • Classic asthma is characterized by episodic dyspnea associated with wheezing, but the clinical presentation of asthma is diverse. Patients may also complain of episodes of dyspnea, chest tightness, coughing (particularly at night), wheezing, or a whistling sound when breathing. Asthma can vary from chronic daily symptoms to only intermittent symptoms. The intervals between symptoms may be days, weeks, months, or years. • Patients can present with mild intermittent symptoms that require no medications or only occasional use of short-acting inhaled β2-agonists to severe chronic asthma symptoms despite receiving multiple medications. CLINICAL PRESENTATION

4. SEVERE ACUTE ASTHMA • Uncontrolled asthma can progress to an acute state where inflammation, airway edema, excessive mucus accumulation, and severe bronchospasm result in profound airway narrowing that is poorly responsive to usual bronchodilator therapy. • Patients may be anxious in acute distress and complain of severe dyspnea, shortness of breath, chest tightness, or burning. They may be able to say only a few words with each breath. Symptoms are unresponsive to usual measures. • Breath sounds may be diminished with very severe obstruction.

5. CHRONIC ASTHMA • The diagnosis of asthma is made primarily by a history and confirmatory spirometry. • The patient may have a family history of allergy or asthma or have symptoms of allergic rhinitis. A history of exercise or cold air precipitating dyspnea or increased symptoms during specific allergen seasons also suggests asthma. • Spirometry demonstrates obstruction (forced expiratory volume in 1 second [FEV1]/forced vital capacity less than 80%) with reversibility after inhaled β2-agonist administration (at least a 12% improvement in FEV1). Failure of pulmonary function to improve acutely does not necessarily rule out asthma. If baseline spirometry is normal, challenge testing with exercise, histamine, or methacholine can be used to elicit BHR. DIAGNOSIS

6. ACUTE SEVERE ASTHMA • Peak expiratory flow (PEF) and FEV1 are less than 50% of normal predicted values. Pulse oximetry reveals decreased arterial oxygen and O2 saturations. The best predictor of outcome is early response to treatment as measured by improvement in FEV1 at 30 minutes after inhaled β2-agonists. • Arterial blood gases may reveal metabolic acidosis and a low PaO2.

7. CHRONIC ASTHMA • The NAEPP provides the following goals for chronic asthma management: • Reducing impairment: (1) prevent chronic and troublesome symptoms (e.g., coughing or breathlessness in the daytime, at night, or after exertion); (2) require infrequent use ( ≤2 days/wk) of inhaled short-acting β2-agonist for quick relief of symptoms (not including prevention of exercise-induced bronchospasm [EIB]); (3) maintain (near-) normal pulmonary function; (4) maintain normal activity levels (including exercise and attendance at work or school); (5) Meet patients’ and families’ expectation of and satisfaction with care. • Reducing risk: (1) prevent recurrent exacerbations and minimize the need for visits or hospitalizations; (2) prevent loss of lung function; for children, prevent reduced lung growth; (3) minimal or no adverse effects of therapy. DESIRED OUTCOME

8. ACUTE SEVERE ASTHMA • The goals of treatment include: (1) correction of significant hypoxemia; (2) rapid reversal of airway obstruction (within minutes); (3) reduction of the likelihood of recurrence of severe airflow obstruction; and (4) development of a written action plan in case of a future exacerbation.

9. NONPHARMACOLOGIC THERAPY • Patient education and the teaching of self-management skills should be the cornerstone of the treatment program. • The NAEPP advocates use of PEF monitoring only for patients with severe persistent asthma who have difficulty perceiving airway obstruction. • Avoidance of known allergenic triggers can improve symptoms, reduce medication use, and decrease BHR. Environmental triggers (e.g., animals) should be avoided in sensitive patients, and those who smoke should be encouraged to stop. • Patients with acute severe asthma should receive supplemental oxygen therapy to maintain arterial oxygen saturation above 90% (above 95% in pregnant women and patients with heart disease). Significant dehydration should be corrected; urine specific gravity may help guide therapy in young children, in whom assessment of hydration status may be difficult. TREATMENT

10. β2-Agonists • The short-acting β2-agonists are the most effective bronchodilators available. β2-Adrenergic receptor stimulation activates adenyl cyclase, which produces an increase in intracellular cyclic adenosine monophosphate. This results in smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation. • Aerosol administration enhances bronchoselectivity and provides a more rapid response and greater protection against provocations that induce bronchospasm (e.g., exercise, allergen challenges) than does systemic administration. • Albuterol and other inhaled short-acting selective β2-agonists are indicated for treatment of intermittent episodes of bronchospasm and are the first treatment of choice for acute severe asthma and EIB. Regular treatment (four times daily) does not improve symptom control over as-needed use. PHARMACOTHERAPY

11. Formoterol and salmeterol are inhaled long-acting β2-agonists indicated as adjunctive long-term control for patients with symptoms who are already on low to medium doses of inhaled corticosteroids prior to advancing to medium- or high-dose inhaled corticosteroids. Short-acting β2–agonists should be continued for acute exacerbations. Long-acting agents are ineffective for acute severe asthma because it can take up to 20 minutes for onset and 1-4 hours for maximum bronchodilation after inhalation. • In acute severe asthma, continuous nebulization of short-acting β2–agonists (e.g., albuterol) is recommended for patients having an unsatisfactory response after three doses (every 20 minutes) of aerosolized β2-agonists and potentially for patients presenting initially with PEF or FEV1 values <30% of predicted normal. Short acting agents provide complete protection for at least 2 hours after inhalation; long-acting agents provide significant protection for 8 to 12 hours initially, but the duration decreases with chronic regular use. • In nocturnal asthma, long-acting inhaled β2-agonists are preferred over oral sustained-release β2-agonists or sustained-release theophylline.

12. Corticosteroids • Corticosteroids increase the number of β2-adrenergic receptors and improve receptor responsiveness to β2-adrenergic stimulation, thereby reducing mucus production and hyper secretion, reducing BHR, and reducing airway edema and exudation. • Inhaled corticosteroids are the preferred long-term control therapy for persistent asthma in all patients because of their potency and consistent effectiveness; they are also the only therapy shown to reduce the risk of death from asthma. Most patients with moderate disease can be controlled with twice-daily dosing; some products have once-daily dosing indications. Patients with more severe disease require multiple daily dosing. Because the inflammatory response of asthma inhibits steroid receptor binding, patients should be started on higher and more frequent doses and then tapered down once control has been achieved. The response to inhaled corticosteroids is delayed; symptoms improve in most patients within the first 1 to 2 weeks and reach maximum improvement in 4 to 8 weeks. Maximum improvement in FEV1 and PEF rates may require 3 to 6 weeks.

13. Systemic toxicity of inhaled corticosteroids is minimal with low to moderate inhaled doses, but the risk of systemic effects increases with high doses. Local adverse effects include dose-dependent oropharyngeal candidiasis and dysphonia, which can be reduced by the use of a spacer device. The ability of spacer devices to enhance lung delivery is inconsistent and should not be relied on. • Systemic corticosteroids are indicated in all patients with acute severe asthma not responding completely to initial inhaled β2- agonist administration (every 20 minutes for three to four doses). Prednisone is administered orally in two divided doses for 3 to 10 days. Because short-term (1 to 2 weeks), high-dose systemic steroids do not produce serious toxicities, the ideal method is to use a short burst and then maintain the patient on appropriate long-term control therapy with inhaled corticosteroids. • In patients who require chronic systemic corticosteroids for asthma control, the lowest possible dose should be used. Toxicities may be decreased by alternate-day therapy or high-dose inhaled corticosteroids.

14. Methylxanthines • Theophylline appears to produce bronchodilation by inhibiting phosphodiesterases, which may also result in antiinflammatory and other nonbronchodilator activity. Methylxanthines are ineffective by aerosol and must be taken systemically (orally or IV). Sustained-release theophylline is the preferred oral preparation, whereas its complex with ethylenediamine (aminophylline) is the preferred parenteral product due to increased solubility. IV theophylline is also available. • Theophylline is eliminated primarily by metabolism via hepatic cytochrome P450 (primarily CYP1A2 and CYP3A4) with 10% or less excreted unchanged in the kidney. The hepatic cytochrome P450 enzymes are susceptible to induction and inhibition by various environmental factors and drugs. Clinically significant reductions in clearance can result from cotherapy with cimetidine, erythromycin, clarithromycin, allopurinol, propranolol, ciprofloxacin, interferon, ticlopidine, zileuton, and other drugs. Some substances that enhance clearance include rifampin, carbamazepine, phenobarbital, phenytoin, charcoal-broiled meat, and cigarette smoking.

15. Because of large interpatient variability in theophylline clearance, routine monitoring of serum theophylline concentrations is essential. A steady-state range of 5 to 15 mcg/mL is effective and safe for most patients. • Sustained-release oral preparations are favored for outpatient therapy, but each product has different release characteristics and some products are susceptible to altered absorption from food or gastric pH changes. Preparations unaffected by food that can be administered a minimum of every 12 hours are preferable. • Adverse effects include nausea, vomiting, tachycardia, jitteriness, and difficulty sleeping; more severe toxicities include cardiac tachyarrhythmias and seizures. • Sustained-release theophylline is less effective than inhaled corticosteroids and no more effective than oral sustained-release β2-agonists, cromolyn, or leukotriene antagonists. • The addition of theophylline to optimal inhaled corticosteroids is similar to doubling the dose of the inhaled corticosteroid and is less effective overall than the long-acting β2-agonists as adjunctive therapy.

16. Anticholinergics • Ipratropium bromide and tiotropium bromide are competitive inhibitors of muscarinic receptors; they produce bronchodilation only in cholinergic mediated bronchoconstriction. Anticholinergics are effective bronchodilators but are not as potent as β2-agonists. They attenuate, but do not block, allergen- or exercise-induced asthma in a dose-dependent fashion. The time to reach maximum bronchodilation from aerosolized ipratropium is longer than from aerosolized short-acting β2-agonists (30 to 60 minutes vs. 5 to 10 minutes). This is of little clinical consequence because some bronchodilation is seen within 30 seconds and 50% of maximum response occurs within 3 minutes. Ipratropium bromide has a duration of action of 4 to 8 hours; tiotropium bromide has a duration of 24 hours. • Inhaled ipratropium bromide is only indicated as adjunctive therapy in severe acute asthma not completely responsive to β2-agonists alone because it does not improve outcomes in chronic asthma. Tiotropium bromide has not been studied in asthma.

17. Mast Cell Stabilizers • Cromolyn sodium and nedocromil sodium have beneficial effects that are believed to result from stabilization of mast cell membranes. They inhibit the response to allergen challenge as well as EIB but do not cause bronchodilation. These agents are effective only by inhalation and are available as metered dose inhalers; cromolyn also comes as a nebulizer solution. Both drugs are remarkably nontoxic. Cough and wheezing have been reported after inhalation of each agent, and bad taste and headache after nedocromil. • They are indicated for the prophylaxis of mild persistent asthma in children and adults regardless of etiology. Their effectiveness is comparable to theophylline or leukotriene antagonists for persistent asthma. Neither agent is as effective as inhaled corticosteroids for controlling persistent asthma. Neither is as effective as the inhaled β2- agonists for preventing EIB, but they can be used in conjunction for patients not responding completely to inhaled β2-agonists. • Most patients experience improvement in 1 to 2 weeks, but it may take longer to achieve maximum benefit.

18. Leukotriene Modifiers • Zafirlukast and montelukast are oral leukotriene receptor antagonists that reduce the proinflammatory (increased microvascular permeability and airway edema) and bronchoconstriction effects of leukotriene D4. In adults and children with persistent asthma, they improve pulmonary function tests, decrease nocturnal awakenings and β2-agonist use, and improve asthma symptoms. However, they are less effective in asthma than low-dose inhaled corticosteroids. They are not used to treat acute exacerbations and must be taken on a regular basis, even during symptom-free periods.

19. Zafirlukast and montelukast are generally well tolerated. Rare elevations in serum aminotransferase concentrations and clinical hepatitis have been reported. An idiosyncratic syndrome similar to the Churg-Strauss syndrome, with marked circulating eosinophilia, heart failure, and associated eosinophilic vasculitis, has been reported in a small number of patients; a direct causal association has not been established. Zileuton is an inhibitor of leukotriene synthesis. Use of zileuton is limited due to the potential for elevated hepatic enzymes (especially in the first 3 months of therapy), and inhibition of the metabolism of some drugs metabolized by CYP3A4 (e.g., theophylline, warfarin). Serum alanine aminotransferase should be monitored before treatment and then periodically thereafter.

20. Combination Controller Therapy • The addition of a second long-term control medication to inhaled corticosteroid therapy is one recommended treatment option in moderate to severe persistent asthma. • Single-inhaler combination products containing fluticasone propionate and salmeterol (Advair) or budesonide and formoterol (Symbicort) are currently available. The inhalers contain varied doses of the inhaled corticosteroid with a fixed dose of the long-acting β2-agonist. The addition of a long-acting β2-agonist allows a 50% reduction in inhaled corticosteroid dosage in most patients with persistent asthma. Combination therapy is more effective than higher-dose inhaled corticosteroids alone in reducing asthma exacerbations in patients with persistent asthma. • Leukotriene receptor antagonists also are successful as additive therapy in patients inadequately controlled on inhaled corticosteroids alone and as corticosteroid-sparing therapy. However, the magnitude of these benefits is less than that reported with the addition of long-acting β2-agonists.

21. Omalizumab • Omalizumabis an anti-IgE antibody approved for the treatment of allergic asthma not well controlled by oral or inhaled corticosteroids. The dosage is determined by the patient’s baseline total serum IgE (international units/mL) and body weight (kg). Doses range from 150 to 375 mg given subcutaneously at either 2- or 4-week intervals. • Because of its high cost, it is only indicated as step 5 or 6 care for patients who have allergies and severe persistent asthma that is inadequately controlled with the combination of high-dose inhaled corticosteroids and long-acting β2-agonists. • Because it is associated with a 0.1% incidence of anaphylaxis, patients should remain in the physician’s office for a reasonable period after the injection because 70% of reactions occur within 2 hours. Some reactions have occurred up to 24 hours after injection.

22. CHRONIC ASTHMA • Regular follow-up is essential (at 1- to 6-month intervals, depending on control). • Components of the assessment of control include symptoms, nighttime awakenings, interference with normal activities, pulmonary function, quality of life, exacerbations, adherence, treatment-related adverse effects, and satisfaction with care. The categories of well controlled, not well controlled, and very poorly controlled are recommended. Validated questionnaires can be administered regularly, such as the Asthma Therapy Assessment Questionnaire, Asthma Control Questionnaire, and Asthma Control Test. • Spirometric tests are recommended at initial assessment, after treatment is initiated, and then every 1 to 2 years. Peak flow monitoring is recommended in moderate to severe persistent asthma. • Patients should also be asked about exercise tolerance. • All patients on inhaled drugs should have their inhalation technique evaluated monthly initially and then every 3 to 6 months. EVALUATION OF THERAPEUTIC OUTCOMES

23. After initiation of antiinflammatory therapy or an increase in dosage, most patients should begin experiencing a decrease in symptoms within 1 to 2 weeks and achieve maximum symptomatic improvement within 4 to 8 weeks. Improvement in baseline FEV1 or PEF should follow a similar time frame, but a decrease in BHR as measured by morning PEF, PEF variability, and exercise tolerance may take longer and improve over 1 to 3 months. ACUTE SEVERE ASTHMA • Patients at risk for acute severe exacerbations should monitor morning peak flows at home. • Lung function, either spirometry or peak flows, should be monitored 5 to 10 minutes after each treatment. • Oxygen saturations can be easily monitored continuously with pulse oximetry. For young children and adults, pulse oximetry, lung auscultation, and observation for supraclavicular retractions is useful. • Most patients respond with the first hour of initial inhaled β-agonists. Patients not achieving an initial response should be monitored every 0.5 to 1 hour.