Asthma Update PDF

Pharmacology 3 Asthma COPD Inhaled corticosteroids Dr. Lina Tamimi  Background Asthma is characterized clinically by : 1. shortness of breath 2. chest tightness 3. Wheezing 4. often associated with coughing Physiologically occurred by widespread, reversible narrowing...

Pharmacology 3 Asthma COPD Inhaled corticosteroids Dr. Lina Tamimi  Background Asthma is characterized clinically by : 1. shortness of breath 2. chest tightness 3. Wheezing 4. often associated with coughing Physiologically occurred by widespread, reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness to inhaled stimuli Pathologically occurred by lymphocytic, eosinophilic inflammation of the bronchial mucosa.  It is also characterized pathologically by: remodeling of the bronchial mucosa, with thickening of the lamina reticularis beneath the airway epithelium hyperplasia of the cells of all structural elements of the airway wall—vessels, smooth muscle, and secretory glands and goblet cells.  Most common provokers 1. Allergen proteins: from house dust mite, cockroach, animal dander, molds, and pollens. 2. The tendency to produce IgE antibodies is genetically determined. (Runs in families) 3. They are triggered by viral respiratory infection. Most asthma attacks are not triggered by inhalation of allergens.  Most common provokers Some adults with asthma have no evidence of allergic sensitivity to allergens, and even in people with allergic sensitivity, the severity of symptoms correlates poorly with levels of allergen in the atmosphere. 4. non-allergenic stimuli such as distilled water, exercise, cold air, sulfur dioxide, and rapid respiratory maneuvers. distilled water aerosol can stimulate C-fiber afferents and rapidly adapting receptors in the airways due to the low chloride ion concentration  Pathogenesis 1- early-phase allergic reaction 2- Late-phase allergic reaction 1- Early-phase allergic reaction Inhaled allergens cause an early-phase allergic reaction characterized by activation of cells bearing allergen-specific immunoglobulin E (IgE) antibodies. There is rapid activation of airway mast cells and macrophages, which release: pro-inflammatory mediators such as: histamine and eicosanoids that induce contraction of airway smooth muscle, mucus secretion, vasodilation, and exudation of plasma in the airways. Plasma protein leakage induces a thickened, engorged, edematous airway wall and a narrowing of the airway lumen with reduced mucus clearance. 2- Late-phase allergic reaction  A second, more sustained phase of bronchoconstriction, the “late asthmatic response,” 3 to 6 hours after allergen provocation associated with an influx of inflammatory cells into the bronchial mucosa and with an increase in bronchial reactivity that may last for several weeks after a single inhalation of allergen. The mediators responsible for this late response are thought to be cytokines characteristically produced by : TH2 lymphocytes, especially : interleukins 5, 9, and 13  These cytokines are thought to: 1. attract and activate eosinophils 2. stimulate IgE production by B lymphocytes 3. stimulate mucus production by bronchial epithelial cells. Airway smooth muscle: contains non-innervated β2- adrenergic receptors that produce bronchodilation. Trachea and bronchi: contains the non-adrenergic, noncholinergic nervous system in the may amplify inflammation in asthma by releasing nitric oxide. The dual effects of nitric oxide in asthma pathology  Categories In mild asthma: monthly – symptoms occur only occasionally, as on exposure to allergens or certain pollutants, on exercise, or after viral upper respiratory infection. More severe forms of asthma: weekly/daily – are associated with frequent attacks of wheezing dyspnea, especially at night, or with chronic airway narrowing, causing chronic respiratory impairment. Asthmatic bronchospasm might be reversed or prevented Treatment categories 1) Effective treatments for relief of acute bronchoconstriction (“short-term relievers”) – airway obstruction, contraction of smooth muscle is most easily reversed by bronchodilators. 2) Reduction in symptoms and prevention of attacks by controlling the inflammation (“long-term controllers”) – reversal of the edema and cellular infiltration requires sustained treatment with anti-inflammatory agents.  Regarding late stage: Increased responsiveness appears to be linked to airway inflammation and because airway inflammation is a feature of late asthmatic responses, this strategy is implemented : 1. by reducing exposure to the allergens that provoke inflammation. 2. prolonged therapy with anti-inflammatory agents, especially inhaled corticosteroids. 1. Drugs that reduce the amount of IgE bound to mast cells (anti- IgE antibody). 2. Prevent mast cell degranulation (cromolyn or nedocromil, sympathomimetic agents, calcium channel blockers). 3. Block the action of the products released (antihistamines and leukotriene receptor antagonists). 4. Inhibit the effect of acetylcholine released from vagal motor nerves (muscarinic antagonists). 5. Directly relax airway smooth muscle (sympathomimetic agents, theophylline).  General management of asthma : Adrenoceptor agonists, or sympathomimetic agents (used as “relievers” or bronchodilators). Inhaled corticosteroids (ICS: used as “controllers” or anti-inflammatory agents). A. Short term relief of bronchoconstriction (bronchodilators)  1- β2-adrenoceptor relax airway smooth muscle stimulants reversal of airway 2-methylxanthine drug constriction. 3-antimuscarinic agents 1- sympathomimetic agents (Beta 2 agonists) MOA They relax airway smooth muscle Sympathomimetic are first-line therapy in acute asthma. reverse asthmatic bronchoconstriction : 1. inhibit release of broncho-constricting mediators from mast cells. 2. They may also inhibit microvascular leakage and increase muco- ciliary transport by increasing ciliary activity. 3. The β agonists stimulate adenylyl cyclase and increase the formation of intracellular cAMP.  SABA: are the drugs of choice for acute episodes of bronchospasm. Their effects last for 4 hrs or less, and they are not effective for prophylaxis. LABA: should be used for prophylaxis, in which their 12-h duration of action is useful. They should not be used for acute episodes because their onset of action is too slow.  epinephrine and isoproterenol increase the rate and force of cardiac contraction (mediated mainly by β 1 receptors), they are reserved for special situations. Isoproterenol is a potent bronchodilator; when inhaled as a microaerosol from a pressurized canister, 80–120 mcg isoproterenol causes maximal bronchodilation within 5 minutes( not used anymore due to high rate death in the 60’s because of arrhythmias)  short-acting β2 agonists (SABA): – Albuterol – Terbutaline – Metaproterenol long-acting β2 agonists (LABA): can improve the response to corticosteroids. Salmeterol Formoterol Indacaterol (currently approved only for COPD) vilanterol  Vasodilation effect True that the vasodilating action of β 2 -agonist treatment may increase perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (PaO2 ). This effect is usually small, however, and may occur with any bronchodilator drug; the significance of such an effect depends on the initial PaO2 of the patient. Administration of supplemental oxygen, routine in treatment of an acute severe attack of asthma, eliminates any concern over this effect.  When epinephrine is used?? α and β 1 as well as β 2 receptor are stimulated , Tachycardia, arrhythmias, and worsening of angina pectoris are troublesome adverse effects. The cardiovascular effects of epinephrine are of value for treating the acute vasodilation and shock as well as the bronchospasm of anaphylaxis, but its use in asthma has been displaced by other, more β 2 -selective agents.  Adverse effects and Toxicity Skeletal muscle tremor is a common adverse β2 effect. Beta2 selectivity is relative. At high clinical dosage, these agents have significant β1 effects. Even when they are given by inhalation, some cardiac effect (tachycardia) is common. Other adverse effects are rare. When the agents are used excessively, arrhythmias and tremor Loss of responsiveness (tolerance, tachyphylaxis) is an unwanted effect of excessive use of the short-acting sympathomimetics. 2-METHYLXANTHINES  The major clinical use of methylxanthines is asthma and COPD. Slow-release theophylline (for control of nocturnal asthma) is the most commonly used methylxanthine. Aminophylline is a salt of theophylline that is sometimes prescribed. Roflumilast: an oral, nonpurine, non-methylxanthines more selective PDE4 inhibitor has been approved for use in COPD.  Adverse effects and Toxicity gastrointestinal distress tremor insomnia. Overdose: Severe nausea and vomiting, hypotension, cardiac arrhythmias, and seizures. Very large overdoses (eg, in suicide attempts) are potentially lethal because of arrhythmias and seizures. Beta blockers are useful in reversing severe cardiovascular toxicity from theophylline. 3- MUSCARINIC ANTAGONISTS  1- Atropine and other naturally occurring belladonna alkaloids were used for many years in the treatment of asthma but have been replaced by: 2- ipratropium, a quaternary antimuscarinic agent designed for aerosol use 3-Tiotropium and 4- aclidinium are longer-acting analogs approved for use in COPD.  useful in one third to two thirds of asthmatic patients β2 agonists are effective in almost all. For acute bronchospasm, therefore, the β agonists are usually preferred. in COPD, which is often associated with acute episodes of bronchospasm, the antimuscarinic agents may be more effective and less toxic than β agonists. WHY? Because these agents are delivered directly to the airway and are minimally absorbed, systemic effects are small. When given in excessive dosage, minor atropine-like toxic effects may occur. In contrast to the β2 agonists, muscarinic antagonists do not cause tremor or arrhythmias. Contraindications The anti-muscarinic agents should be used cautiously in infants because of the danger of hyperthermia. The drugs are relatively contraindicated in persons with glaucoma, especially the closed angle form, and in men with prostatic hyperplasia. B. Long term relief Inflammation  effectively Long-term control is achieved with an anti-inflammatory agent such as an inhaled corticosteroid. Less effectively with: 1. a leukotriene pathway antagonist 2. an inhibitor of mast cell degranulation, such as cromolyn or nedocromil. 3. humanized monoclonal antibody, omalizumab, which specifically targeted the IgE antibody responsible for allergic sensitization 1- Mast cells stabilizers  Rarely used prophylaxis of asthma cromolyn also used for ophthalmic nasopharyngeal, and gastrointestinal allergy. 2- Leukotriene antagonists  Montelukast, zafirlukast:  antagonists at LTD4 receptors Prophylaxis of asthma……… Oral Duration: 12–24 h Minimal TOXICITIES  Zileuton: Inhibitor of lipoxygenase reduces synthesis of leukotrienes. Prophylaxis of asthma, Oral. Duration: 12 h Elevation of liver enzymes 3- Anti IgE Antibodies Omalizumab: Binds IgE antibodies on mast cells reduces reaction to inhaled antigen. Prophylaxis of severe, refractory asthma Parenteral : administered as several courses of injections. Extremely expensive. long-term toxicity not yet well documented. 4- Corticosteroids:  They do not relax airway smooth muscle directly 1. reduce bronchial reactivity 2. reduce the frequency of asthma exacerbations if taken regularly.  All the corticosteroids are potentially beneficial in severe asthma. However, because of their toxicity 1- systemic (oral) corticosteroids (usually prednisone) are used chronically only when other therapies are unsuccessful. 2- local inhaled aerosol administration of surface-active corticosteroids (eg, beclomethasone, budesonide, dexamethasone, flunisolide fluticasone, mometasone) is relatively safe. Inhaled corticosteroids (ICS) have become common first-line therapy for individuals with moderate to severe asthma.  MOA 1- reduce the synthesis of arachidonic acid by phospholipase A2 2- inhibit the expression of COX-2, the inducible form of cyclooxygenase. 3- Accordingly, the concentrations of prostaglandins and leukotrienes are reduced. It has also been suggested that the glucocorticoid corticosteroids increase the responsiveness of β adrenoceptors in the airway and they probably act by other mechanisms as well. Inhaled glucocorticoids  Inhaled glucocorticoids are now considered appropriate (even for children) in most cases of: early use may prevent the moderate asthma severity not fully responsive to aerosol β2 agonists. It is believed that such progressive inflammatory changes characteristic of long-standing asthma. This is a shift from the earlier belief that steroids should be used only in severe refractory asthma. In such cases of severe asthma, patients are usually hospitalized and stabilized on : 1- daily systemic prednisone 2- then switched to inhaled or alternate-day oral therapy before discharge.  Dosing Beclomethasone (400 mcg/d): An average daily dose of 4 puffs/BID is equivalent to oral prednisone: about 10–15 mg/d for the control of asthma, with far fewer systemic effects  side effects 1- Deposition of inhaled drug droplets in the pharynx causes: changes in oropharyngeal flora that result in candidiasis. How to prevent it??? can be reduced by having patients gargle water and spit after each inhaled treatment. 2- Hoarseness can also result from a direct local effect of inhaled corticosteroids on the vocal cords. 3- These agents are remarkably free of other short term complications in adults but may increase the risks of osteoporosis and cataracts over the long term. 4- In children, inhaled corticosteroid therapy has been shown to slow the rate of growth by about 1 cm over the first year of treatment, but not the rate of growth thereafter, so that the effect on adult height is minimal.  Toxicity The major systemic toxicities of the glucocorticoids are much more likely to occur when systemic treatment is required for more than 2 weeks, as in severe refractory asthma. Regular use of inhaled steroids does cause mild growth retardation in children.  Urgent treatment using CS Is often begun with an: oral dose of 30–60 mg prednisone per day or an intravenous dose of 1 mg/kg methylprednisolone every 6–12 hours the daily dose is decreased after airway obstruction has improved. In most patients, systemic corticosteroid therapy can be discontinued in 7–10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels. it is customary to administer corticosteroids early in the morning: due to side effects such as adrenal suppression For prevention of nocturnal asthma, however, oral or inhaled corticosteroids are most effective when given in the late afternoon.  Side effects of systemic CS Adrenal suppression. Growth inhibition. Muscle wasting. Osteoporosis. Salt retention. Glucose intolerance. Behavioral changes. Moon face. Clinical uses of CS COPD  COPD is now the third most common cause of death in the United States. COPD resembles asthma in that it is also characterized by airflow limitation, although the obstruction of COPD is not fully reversible with treatment. COPD, believed to reflect an abnormal inflammatory response of the lung to: noxious particles or gases, especially to cigarette smoke. Compared to asthma……………COPD: 1. occurs in older patients 2. is associated with neutrophilic rather than eosinophilic inflammation 3. is poorly responsive even to high-dose ICS therapy 4. is associated with progressive, loss of pulmonary function over time, especially with continued cigarette smoking.  Despite these differences, the approaches to treatment are similar 1- For relief of acute symptoms: inhalation of a short-acting β agonist (e.g. Albuterol) an anticholinergic drug (e.g. Ipratropium bromide) or of the two in combination is usually effective. 2- persistent symptoms of exertional dyspnea and limitation of activities: For patients with, regular use of : a long-acting bronchodilator, whether an LABA or a long-acting anticholinergic, or the two together, is indicated. Tiotropium Aclidinium 3- Theophylline: may have a particular place in the treatment of COPD, as it may improve contractile function of the diaphragm, thus improving ventilatory capacity. Remember: Beta blocker remove its toxicity 4- roflumilast : The non-methylxanthine, a selective phosphodiesterase inhibitor that improves pulmonary function and reduces exacerbation frequency, is now approved as a treatment for COPD. 5- ICS: less in treatment of COPD than of asthma because ???? 1. its lower efficacy for this condition 2. its use being associated with heightened risk of bacterial pneumonia. Recommended use: only for patients with: 1. severe airflow obstruction 2. history of prior exacerbations: episodes of worsening of symptoms, leading to substantial morbidity and mortality  history of prior exacerbations: For patients with a history of two or more exacerbations: 1. daily treatment with an ICS is appropriate 2. daily treatment with azithromycin: immunomodulatory and anti‐inflammatory effects a recent large study showed significant reduction in exacerbation frequency