Bronchial asthma
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This presentation was used for lecture for B. Pharm 3rd year students (MMCTH)
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Bronchial asthma
- 1. Bronchial Asthma: Pharmacotherapy Dr. Pravin Prasad MBBS, MD Clinical Pharmacology Assistant Professor, Department of Clinical Pharmacology Maharajgunj Medical Campus Maharajgunj, Kathmandu 2 June 2020 (20 Jestha 2077), Monday
- 2. By The Of This Discussion B. Pharm 3rd Year Students Will Be Able To: Understand the term Bronchial Asthma (BA) List the risk factors and explain the pathophysiology for BA Enumerate the therapeutic objectives in BA and classify the response of patients based on the objectives List the modalities for management of BA Explain the pharmacological management of BA Outline the stepwise approach for the management of chronic asthma List the drugs used in management of acute severe asthma 2
- 3. Introduction Asthma is a chronic inflammatory disorder of the airways, in which many cells and cellular elements play a role. Associated with airway hyper-responsiveness with recurrent symptoms Accompanied by variable airflow obstruction that is often reversible either spontaneously or with treatment. 3
- 4. 4 Risk Factors for Bronchial Asthma Endogenous Factors Genetic predisposition Atopy Airway Hyperresponsiveness Gender Ethnicity Obesity Early viral infactions Environmental Factors Allergens (Indoor, outdoor, air) Occupational sensitizers Smoking (Active, Passive) Respiratory infections Diet Dampness and mould exposure Acetaminophen 4
- 5. Triggers of Bronchial Asthma Allergens Upper respiratory tract viral infections Exercise and hyperventilation Cold air Sulfur dioxide and irritant gases Drugs (beta blockers, aspirin) Stress Irritants (Household sprays, paint, fumes) 5
- 6. Pathophysiology: Bronchial Asthma Allergenic Exposure Activation of allergen specific IgE in the surface of the cell Release of inflammatory mediations Contraction of airway smooth muscle, mucus secretion and mucus plugging Microvascular Leakage Exudation of plasma proteins Plasma protein leakage induce a thickened, engorged, edematous airway wall Narrowing of airway and reduced mucus clearance Airway inflammation Bronchial responsiveness Airway remodelling (structural changes) 6
- 7. 7 Bronchial Asthma: Mediators of Pathophysiological changes Mediators Histamine Leukotrienes Prostanoids PAF Kinins Adenosine Endothelins Nitric oxide Cytokines Chemokines Growth factors
- 8. Clinical Presentation Symptoms: Characteristic symptoms of asthma are wheezing, dyspnea, and coughing, which are variable, both spontaneously and with therapy. increased ventilation and use of accessory muscles of ventilation May show variations thorough the day (diurnal variation) Increased thick tenacious mucus production that is difficult to expectorate. Signs: Hyperinflated lungs Noisy breathing (inspiratory as well as expiratory ronchi) https://youtu.be/T4qNgi4Vrvo 8
- 9. Bronchial Asthma: Diagnosis Usually clinical Objective diagnosis necessary for monitoring response to treatment Lung function Tests Reduced Forced Expiratory Volume at 1 second (FEV1), FEV1/FVC ratio Reduced Peak Expiratory Flowrate (PEF) Reversible with drugs Chest X-ray Hyperinflated Lungs Skin Tests To identify culprit allergen 9
- 10. Therapeutic Objectives and responses Characteristics Controlled (all of the following) Partly controlled Uncontrolled Daytime symptoms None (=< 2/week) > 2/week Three or more features of the partly controlledLimitation of activities None Any Nocturnal symptoms/ awakenings None Any Need for reliever/ rescue treatment None (=< 2/week) > 2/week Lung Function (PEF or FEV1) Normal < 80% predicted or personal best if known For acute asthma: Termination of attack of asthma 10
- 11. 11 Treatment options General information and advice Non-pharmacological therapy Pharmacological Therapy Referral 11 • Identify and avoid allergens • Reduce adverse environment, house mites/cockroaches • Smoking cessation
- 12. 12 Treatment options General information and advice Non-pharmacological therapy Pharmacological Therapy Referral 12 • Hypnosis, acupuncture, chiropraxis, breathing control, yoga, and speleotherapy • Bronchial thermoplasty • Humidified oxygen therapy • HeliCox (Helium: Oxgen = 60:40) • Immunotherapy (not recommended)
- 13. 13 Treatment options General information and advice Non-pharmacological therapy Pharmacological Therapy Referral 13 Relievers Bronchodilators Controllers Anti-inflammatory Anti-allergic Vaccines
- 14. Drugs used in Bronchial Asthma (Relievers) Bronchodilators β2 agonists: Short acting (SABA): Albuterol, terbutaline Long acting (LABA): salmeterol, formeterol, indacaterol, olodaterol, vilanterol Anticholinergics (LAMA): Ipratropium bromide, Tiotropium bromide Methyl Xanthines: Theophylline, Aminophylline, Doxophylline 14
- 15. Drugs used in Bronchial Asthma (Controllers) Anti-inflammatory Corticosteroids: Inhaled (ICS): Budesonide Systemic: Prednisone, Hydrocortisone Anti-leukotrienes: Montelukast, Zafirlukast Mast Cell stabilizers: Cromolyn sodium, nedocromil sodium Anti-allergic Anti-IgE: Omalizumab Anti-IL 5: mepolizumab, reslizumab; benralizumab (receptor blocker) 15
- 16. Beta agonists Most effective bronchodilator Relaxes airway smooth-muscle cells of all airways Reversing and preventing contraction of airway smooth-muscle cells by all known bronchoconstrictors Additional non-bronchodilator effects also seen Usually given by inhalation SABA: rapid onset of action (3-6 hrs) In high doses by nebulizer or via a metered-dose inhaler (MDI) with a spacer. LABA: slow sustained action (12 hrs or more) Improve asthma control and reduce exacerbations when added to ICS, which allows asthma to be managed with lower doses of corticosteroids. 16
- 17. Anticholinergics Muscarinic receptor antagonists prevent cholinergic nerve-induced bronchoconstriction and mucus secretion. They are less effective than β2-agonists in asthma therapy LAMA: additional bronchodilator in patients with asthma that is not controlled by maximal doses of ICS-LABA combinations, and improve lung function and further reduce exacerbations High doses of short-acting anticholinergics for termination of attack As an add on to β2 agonist 17
- 18. Methyl Xanthines (Phosphodiesterase inhibitors) Inexpensive bronchodilator Effect seen due to inhibition of phosphodiesterases in airway smooth- muscle cells, which increases cyclic AMP Accompanied with significant side effects at therapeutic doses (narrow therapeutic index) Possibility of anti-inflammatory effects at lower doses By switching off activated inflammatory genes May reduce corticosteroid insensitivity in severe asthma Given orally as slow release tablets as an add-on therapy Slow i.v. infusion in acute exacerbations refractory to SABA 18
- 19. Inhaled Corticosteroids Most effective controller, instituted at early stages of diseases Acts by switching off the transcription of multiple activated genes that encode inflammatory proteins such as cytokines, chemokines, adhesion molecules, and inflammatory enzymes Additional activation of anti-inflammatory genes Usually given twice daily as first line therapy for persistent asthma Rapidly improve the symptoms of asthma, and lung function improves over several days. Early treatment with ICS appears to prevent irreversible changes in airway function that occur with chronic asthma. 19
- 20. Systemic Corticosteroids Can be give intravenously ororally in severe asthma Oral prednisolone 35-40 mg once daily for 5-10 days Tapering not required at the end of therapy Systemic side effects seen Consider steroid-sparing therapies (SST) None of SSTs have any long-term benefit and each is associated with a relatively high risk of side effects 20
- 21. Antileukotrienes Block cys-LT1-receptors and provide modest clinical benefit in asthma Less effective than ICS or LABA Useful as an add-on therapy They are given orally once or twice daily and are well tolerated 21
- 22. Mast cell stabilizers Cromolyn sodium and nedocromil sodium Appear to inhibit mast cell and sensory nerve activation Relatively little benefit in the long-term control of asthma Very safe and were popular in the treatment of childhood asthma 22
- 23. Anti-allergics Anti-IgE Omalizumab Blocking antibody that neutralizes circulating IgE Reduces the number of exacerbations Very expensive and is only suitable for highly selected patients Patient should be given a 3- to 4-month trial of therapy to show objective benefit Anti-IL-5 Mepolizumab, Reslizumab, Benralizumab Markedly reduce blood and tissue eosinophils Reduce exacerbations in patients who have persistently increased sputum eosinophils despite maximal ICS therapy 23
- 24. Vaccines Recommended to prevent infection, which may precipitate an exacerbation e.g: influenza vaccine 24
- 25. Management of Chronic Asthma 25
- 26. Management of Acute Severe Asthma Oxygen. High concentrations (humidified if possible) should be administered to maintain the oxygen saturation above 92% in adults. High doses of inhaled bronchodilators SABA via nebulizer or multiple dose MDI Short acting anticholinergics Systemic corticosteroids Reduces the inflammatory response and hasten the resolution of an exacerbation. Orally or parenterally Others: Intravenous magnesium, intravenous aminophylline, mechanical ventilation 26
Editor's Notes
- The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night and in the early morning.
- Acts as functional antagonists additional non-bronchodilator effects that may be clinically useful, including inhibition of mast cell mediator release, reduction in plasma exudation, and inhibition of sensory nerve activation β2-Agonists are usually given by inhalation to reduce side effects. SABA, such as albuterol and terbutaline, have a duration of action of 3–6 h. They have a rapid onset of bronchodilatation and are, therefore, used as needed for symptom relief (relievers). Increased use of SABA indicates that asthma is not controlled. They are also useful in preventing EIA if taken prior to exercise. SABA are used in high doses by nebulizer or via a metered-dose inhaler (MDI) with a spacer. Long-acting β2-agonists (LABA) include salmeterol and formoterol, both of which have a duration of action over 12 h and are given twice daily by inhalation; and indacaterol, olodaterol, and vilanterol, which are given once daily. LABA have replaced the regular use of SABA, but LABA should not be given in the absence of ICS therapy as they do not control the underlying inflammation. They do, however, improve asthma control and reduce exacerbations when added to ICS, which allows asthma to be managed with lower doses of corticosteroids. This observation has led to the widespread use of fixed combination inhalers that contain a corticosteroid and a LABA, which have proved to be highly effective in the control of asthma and prevention of exacerbations.
- They are less effective than β2-agonists in asthma therapy as they inhibit only the cholinergic reflex component of bronchoconstriction, whereas β2-agonists prevent all bronchoconstrictor mechanisms. Long-acting muscarinic antagonists (LAMA), including tiotropium bromide or glycopyrronium bromide, may be used as an additional bronchodilator in patients with asthma that is not controlled by maximal doses of ICS-LABA combinations, and improve lung function and further reduce exacerbations.
- This effect involves several mechanisms, including inhibition of the transcription factors NF-κB, but an important mechanism is recruitment of HDAC2 to the inflammatory gene complex, which reverses the histone acetylation associated with increased gene transcription. Corticosteroids also activate anti-inflammatory genes such as mitogen-activated protein (MAP) kinase phosphatase-1, and increase the expression of β2-receptors. They are effective in preventing asthma symptoms, such as EIA and nocturnal exacerbations, but also prevent severe exacerbations. ICS reduce AHR, but maximal improvement may take several months of therapy
- Corticosteroids are used intravenously (hydrocortisone or methylprednisolone) for the treatment of acute severe asthma, although several studies now show that OCS are as effective and easier to administer. A course of OCS (usually prednisone or prednisolone 30–45 mg once daily for 5–10 days) is used to treat acute exacerbations of asthma; no tapering of the dose is needed. Approximately 1% of asthma patients may require maintenance treatment with OCS; the lowest dose necessary to maintain control needs to be determined. Systemic side effects, including truncal obesity, bruising, osteoporosis, diabetes, hypertension, gastric ulceration, proximal myopathy, depression, and cataracts, may be a major problem, and steroid-sparing therapies may be considered if side effects are a significant problem. If patients require maintenance treatment with OCS, it is important to monitor bone density so that preventive treatment with bisphosphonates or estrogen in postmenopausal women may be initiated if bone density is low. Intramuscular triamcinolone acetonide is a depot preparation that is occasionally used in noncompliant patients, but proximal myopathy is a major problem with this therapy.
- Cysteinyl-leukotrienes are potent bronchoconstrictors; they cause microvascular leakage and increase eosinophilic inflammation through the activation of cys-LT1-receptors. These inflammatory mediators are produced predominantly by mast cells and, to a lesser extent, eosinophils in asthma. Antileukotrienes, such as montelukast and zafirlukast, block cys-LT1-receptors and provide modest clinical benefit in asthma. They are less effective than ICS in controlling asthma and have less effect on airway inflammation, but are useful as an add-on therapy in some patients not controlled with low doses of ICS, although less effective than a LABA. They are given orally once or twice daily and are well tolerated. Some patients show a better response than others to antileukotrienes, but this has not been convincingly linked to any genomic differences in the leukotriene pathway.
- Cromolyn sodium and nedocromil sodium are asthma controller drugs that appear to inhibit mast cell and sensory nerve activation and are, therefore, effective in blocking trigger-induced asthma such as EIA and allergen- and sulfur dioxide-induced symptoms. Cromones have relatively little benefit in the long-term control of asthma due to their short duration of action (at least four times daily by inhalation). They are very safe and were popular in the treatment of childhood asthma, although now low doses of ICS are preferred as they are far more effective and have a proven safety profile.
- Anti-IgE Omalizumab is a blocking antibody that neutralizes circulating IgE without binding to cell-bound IgE and, thus, inhibits IgE-mediated reactions. This treatment has been shown to reduce the number of exacerbations in patients with severe asthma and may improve asthma control. However, the treatment is very expensive and is only suitable for highly selected patients who are not controlled on maximal doses of inhaler therapy and have a circulating IgE within a specified range. Patients should be given a 3- to 4-month trial of therapy to show objective benefit. Omalizumab is usually given as a subcutaneous injection every 2–4 weeks and appears not to have significant side effects, although anaphylaxis is very occasionally seen. Anti-IL-5 Antibodies that block IL-5 (mepolizumab, reslizumab) or its receptor (benralizumab) markedly reduce blood and tissue eosinophils and reduce exacerbations in patients who have persistently increased sputum eosinophils despite maximal ICS therapy.
- Step-down therapy Once asthma control is established, the dose of inhaled (or oral) corticosteroid should be titrated to the lowest dose at which effective control of asthma is maintained. Decreasing the dose of ICS by around 25–50% every 3 months is a reasonable strategy for most patients.
- Mild to moderatae exacerbations: short term oral corticosteroids, do not taper before stopping if used for less than 3 weeks Oxygen. High concentrations (humidified if possible) should be administered to maintain the oxygen saturation above 92% in adults. The presence of a high PaCO2 should not be taken as an indication to reduce oxygen concentration, but as a warning sign of a severe or life-threatening attack. Failure to achieve appropriate oxygenation is an indication for assisted ventilation. High doses of inhaled bronchodilators. Short-acting β2-agonists are the agent of choice. In hospital, they are most conveniently given via a nebuliser driven by oxygen, but delivery of multiple doses of salbutamol via a metered-dose inhaler through a spacer device provides equivalent bronchodilatation and can be used in primary care. Ipratropium bromide provides further bronchodilator therapy and should be added to salbutamol in acute severe or life-threatening attacks. Systemic corticosteroids. These reduce the inflammatory response and hasten the resolution of an exacerbation. They should be administered to all patients with an acute severe attack. They can usually be administered orally as prednisolone, but intravenous hydrocortisone may be used in patients who are vomiting or unable to swallow. If patients fail to improve, a number of further options may be considered. Intravenous magnesium may provide additional bronchodilatation in patients whose presenting PEF is below 30% predicted. Some patients appear to benefit from the use of intravenous aminophylline but cardiac monitoring is recommended.