Asthma presentation and management
- 1. PHARMACOLOGY OF ASTHMA AND ADVANCES IN ITS MANAGEMENT A SEMINAR PRESENTED BY JOSEPH, OYEPATA SIMEON (Ph.D)
- 2. INTRODUCTION Asthma is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction and bronchospasm. Asthma is thought to be caused by a combination of genetic and environmental factors. Its diagnosis is usually based on the pattern of symptoms, response to therapy over time and spirometry.
- 3. Figure 1: shows the location of the lungs and airways in the body
- 4. Asthma is one of the major noncommunicable diseases. WHO 235–300 million people globally are diagnose with asthma, and it caused 250,000 deaths (WHO, 2013).
- 5. Causes of asthma Asthma is caused by a combination of complex and incompletely understood environmental and genetic interactions. Causes include Environmental Genetic Drug use Hygiene hypothesis Medical conditions Exercise-induced Occupational
- 6. Asthma Pathophysiology Most patients do experience 2 clear phases of the asthmatic response when exposed to a particular trigger, the “early” phase and the “late” phase. The “early” phase of the asthma response usually occurs 10-30 minutes following exposure to an asthma trigger and involves the release of inflammatory mediators from IgE-coated mast cells throughout the respiratory passages These mediators induce bronchospasm and increase permeability of the airways to antigen Abnormal activation of the parasympathetic nervous system also seems to occur during the early phase of the asthmatic response. Activation of vagal nerves in the airway constricts bronchial smooth muscle and increases secretions from mucous-producing cells
- 7. Neutrophils, attracted by chemotaxis to the area of inflamed airway, leave the more permeable blood vessel and enter the respiratory tissues Neurophils are joined by other inflammatory immune cells such as basophils, and eosinophils that escalate the inflammatory response by releasing their own inflammatory mediators T-lymphocytes may also play an important role in the asthmatic response since a particular subset of T-lymphocytes (TH2) responds to environmental allergens by releasing cytokines that are involved in the formation of IgE-producing plasma cells. This heightened period of inflammation constitutes the “late” phase of asthma response and can last for hours to days
- 8. The heightened airway inflammation that occurs during the late phase of asthma leads to marked airway edema, impaired mucociliary function, and further impaired movement of airflow. If severe or prolonged, the inflammation associated with asthma can damage respiratory epithelium and lead to a pathologic remodeling of the airways.
- 9. Figure 2: Components of the early phase of asthma.
- 10. Figure 3: Components of the late phase of asthma.
- 11. Diagnosis A diagnosis of asthma should be suspected if there is a history of recurrent wheezing, coughing or difficulty breathing and these symptoms occur or worsen due to exercise, viral infections, allergens or air pollution. Spirometry is then used to confirm the diagnosis. In children under the age of six the diagnosis is more difficult as they are too young for spirometry
- 12. Classification Clinical classification (≥ 12 years old) Severity Symptom frequency Night time symptoms %FEV1 of predicted FEV1 Variability SABA use Intermittent ≤2/week ≤2/month ≥80% <20% ≤2 days/week Mild persistent >2/week 3–4/month ≥80% 20–30% >2 days/week Moderate Daily >1/week 60–80% >30% daily Severe persistent Continuously Frequent (7×/week) <60% >30% ≥twice/day
- 13. Severity of an acute exacerbation Near-fatal High PaCO2 and/or requiring mechanical ventilation Life-threatening (any one of) Clinical signs Measure ments Altered level of consciousness Peak flow < 33% Exhaustion Oxygen saturation < 92% Arrhythmia PaO2 < 8 kPa Low blood pressure "Normal" PaCO2 Cyanosis Silent chest Poor respiratory effort Acute severe (any one of) Peak flow 33–50% Respiratory rate ≥ 25 breaths per minute Heart rate ≥ 110 beats per minute Unable to complete sentences in one breath Moderate Worsening symptoms Peak flow 50–80% best or predicted No features of acute severe asthma
- 14. Differential diagnosis Chronic obstructive pulmonary disease can coexist with asthma and can occur as a complication of chronic asthma COPD can be differentiated by increased airway neutrophils, abnormally increased wall thickness, and increased smooth muscle in the bronchi.
- 15. Prevention limiting smoke exposure both in utero and after delivery, breastfeeding, and increased exposure to day care or large families but none are well supported enough to be recommended. Early pet exposure may be useful Reducing or eliminating compounds known to sensitive people from the work place may be effective. It is not clear if annual influenza vaccinations effects the risk of exacerbations. Immunization; however, is recommended by the World Health Organization. Smoking bans are effective in decreasing exacerbations of asthma
- 16. Management While there is no cure for asthma, symptoms can typically be improved The most effective treatment for asthma is identifying triggers, such as cigarette smoke, pets, or aspirin, and eliminating exposure to them. If trigger avoidance is insufficient, the use of medication is recommended Specific medications for asthma are broadly classified into fast-acting and long-acting categories.
- 17. Classification of drugs used in asthma
- 18. Specific β2 agonists Figure 4: Cellular actions of β2 agonists and theophylline.
- 19. Specific β2 agonists Specific β2 agonists exert their beneficial effects through relaxation of bronchial smooth muscle. These agents bind to G-protein-linked cell surface receptors in the airways. Activation of β2 receptors leads to the activation of adenylate cyclase and subsequent generation of cyclic AMP (cAMP). Increased levels of cAMP in turn activate protein kinase A which induces calcium extrusion and sequestration and thus smooth muscle relaxation.
- 20. Adverse effects of short term use of specific β2 agonists are relatively minor and infrequent due to their high specificity and topical delivery. Beta-2 adrenergic receptors in bronchial smooth muscle seem to be somewhat resistant to desensitization, while those on mast cells and lymphocytes appear more susceptible to this phenomenon. The potential for adverse effects is greater when these agents are used orally and may include muscle tremors and cramps, cardiac effects and metabolic changes.
- 21. Corticosteroids Corticosteroids exert multiple antiinflammatory actions including inhibition of inflammatory cytokine release and reduced activity of inflammatory immune cells. E.g. of corticosteroid are Fluticasone propionate and beclomethasone. Several inhibitor proteins such as annexins and lipocortins are generated in response to corticosteroid receptor binding, which appear to inhibit the release of the arachidonic acid substrate from membrane lipids.
- 22. Corticosteroids also interact with specific receptors in tissues to regulate expression of corticosteroid-responsive genes. Side effects of oral corticosteroid uses may include endocrine suppression, increased risk of infections, osteoporosis, osteonecrosis, cataract formation, fluid and electrolyte imbalances and impaired growth and development in children
- 23. Steroid resistance 5-10% of patients with severe asthma respond poorly to a maximal dose of steroids. A type of lymphocytes called natural helper (NH) cells has been identified to plays a critical role in corticosteroid resistance T lymphocytes and NH cells in the asthmatic lung produce proteins named interleukin (IL)-5 and IL-13 that are responsible for severe airway inflammation.
- 24. However, in severe asthma patients, another protein called interleukin-33 (IL-33) produced in the airways strongly activates NH cells to produce IL-5 and IL-13, leading to severe airway inflammation. Research shows that NH resistance to steroids is induced by the protein thymic stromal lymphopoietin (TSLP), present in the airways of severe asthma patients The drug, Pimozide, an approved anti-psychotic drug, was found to restore the effects of steroids on NH cells.
- 25. Theophylline There are several proposed mechanisms for the beneficial effect of theophylline in asthma. The first involves its ability to inhibit cyclic nucleotide phosphodiesterases which in turn inhibits the degradation of cyclic AMP and cyclic GMP (Figure4). Increased levels of these second messengers in turn lead to bronchodilation (similar to β2 agonists) as well as decreased release of inflammatory mediators from mast cells. A second proposed mechanism action of theophylline in asthma centers on its ability to antagonize adenosine receptors in the airways.
- 26. At high doses they can cause marked CNS stimulation, tremors, and even convulsions. The cardiovascular effects of methylxanthines are also significant and may include tachycardia, increased cardiac output and, of greatest concern with high blood levels, cardiac arrhythmia and sudden death
- 27. Anticholinergic Anticholinergic agents exert a bronchodilator effect through blockade of muscarinic receptors in the airways. Blocking cholinergic activity likewise blocks the increase in mucous secretion that occurs in response to vagal activation. Anticholinergic bronchodilators can also be used if a person cannot tolerate a SABA. The major limiting factor to the use of atropine was its potential for CNS penetration and cardiac effects E.g. ipratropium bromide
- 28. Cromolyn sodium and derivative Cromolyn sodium is a mast cell stabilizer. The mechanism of action for these agents remains incompletely understood. It is likely they exert multiple effects including inhibition of mast cell release, altered parasympathetic response, altered leukocyte function, and suppression of leukocyte chemotaxis. The major use of these agents is to prevent asthma attacks in patients with mild to moderate asthma. Nedocromil is generally more effective at relieving asthma symptoms than cromolyn and may reduce the amount of inhaled steroids used in certain asthmatic patients.
- 29. Leukotriene antagonist Role of leukotrienes in asthma.
- 30. Leukotriene antagonist The first class of asthma drugs to be targeted to a specific component of the asthmatic response were the leukotriene pathway inhibitors leukotriene was found to play a key role in a number of inflammatory processes including those associated with the asthmatic response Studies have shown LTD4 to be nearly 100 times more potent than histamine in causing bronchoconstriction. Two strategies have been employed to block the actions of the leukotrienes in the airways. The first involves direct inhibition of the enzyme 5-lipoxygenase, which is responsible for the synthesis of leukotrienes e.g Zeleuton. The second involves direct blockade of leukotriene receptors in the airways (E.g. zafirlukast and montelukast).
- 31. Adverse effects for the leukotriene receptor antagonists are low. A small percentage of patients taking these agents have developed a systemic vasculitis that is similar to Chrug-Strauss syndrome. Leukotriene receptor antagonists may be used in addition to inhaled corticosteroids, typically also in conjunction with a LABA
- 32. Monoclonal antibodies (Omalizumab) Figure 6: Actions of omalizumab in asthma.
- 33. Another approach to the treatment of asthma involves the targeting of IgE, the main immunoglobulin involved in the binding and degranulation of mast cells. Omalizumab is designed to bind the Fc receptor on IgE, the same receptor that IgE uses to bind to mast cell FC epsilon receptor I (FCεRI) (Figure (Figure6).6). Thus omalizumab is essentially an antibody against an antibody. Omalizumab binds free IgE with high affinity but does not interact with any IgE that is already bound to mast cells and thus will not induce mast cell degranulation even if IgE is already present on mast cells. The adverse effects of omalizumab reported in controlled trials up to this point have been relatively minor and include mainly injection site reactions. Less than 1% of patients receiving omalizumab developed antibodies against the drug
- 34. others Oxygen to alleviate hypoxia if saturations fall below 92%. Magnesium sulfate intravenous treatment increases bronchodilation when used in addition to other treatment in severe acute asthma attacks. Heliox, a mixture of helium and oxygen, may also be considered in severe unresponsive cases.
- 35. Alternative medicine Evidence is insufficient to support the usage of Vitamin C. There is tentative support for its use in exercise induced brochospasm. Acupuncture is not recommended for the treatment as there is insufficient evidence to support its use. Manual therapies, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, have insufficient evidence to support their use in treating asthma. Air ionisers show no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.
- 36. For those with severe persistent asthma not controlled by inhaled corticosteroids and LABAs, bronchial thermoplasty may be an option It involves the delivery of controlled thermal energy to the airway wall during a series of bronchoscopies. While it may increase exacerbation frequency in the first few months it appears to decrease the subsequent rate Effects beyond one year are unknown. Evidence suggests that sublingual immunotherapy in those with both allergic rhinitis and asthma improve outcomes.
- 37. New drug development for Asthma Pharmacotherapy. One key component of chronic asthma that needs to be addressed with new therapies is the prevention or reversal of airway remodeling. The development of so called synthetic “soft” steroids has been an active area of research (Belvisi and Hele 2003). These synthetic steroids may take the form of inactive ester prodrugs that are converted to their active form in the airways. One such agent, ciclesonide (Alvesco) received preliminary FDA approval in 2003 and is still undergoing extensive clinical testing. Early results indicate that systemic bioavailability of this agent was negligible and that it did not suppress cortisol secretion
- 38. Novel bronchodilator compounds such as vasoactive intestinal peptide (VIP), atrial natriuretic peptide (ANP), and prostaglandin E analogs are undergoing investigation. Despites some promising success, the main draw of using peptides as therapeutic agents, their instability, still needs to be overcome. activation of adenosine receptor subtype A2A has inhibitory effects on leukocyte activity and agonists of this specific receptor are under investigation as well. Cytokines such as interleukins (IL) and tumor necrosis factor alpha (TNF- α) have been the subject of intensive recent investigation in a number of inflammatory human conditions such as inflammatory bowel disease and rheumatoid arthritis
- 39. Antagonism of 2 related cytokines, IL-4 and IL-13, have shown more promising effects on asthma in early trials Chemotactic cytokine called “chemokines” are also substances of interest in asthma. Through interaction with cell surface chemokine receptors (CCR), these substances (eg, eotaxin) mobilize a number of immune cells such as eosinophils and lymphocytes that are involved in the allergic asthmatic response. A number of potent and highly specific small molecule CCR antagonists are under development (eg, SB-328437 from Glaxo-SmithKline and RO116-9132/238 from Roche). Several of these (eg, GSK 766994) have entered early clinical trials.
- 40. CONCLUSION Given the wealth of new therapeutic targets currently under investigation, the next decade holds great promise (s) for the development of new and effective asthma drugs, particularly in the area of preventing the detrimental long-term effects of airway remodeling.
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