Lesson 17 - Pulmonary Disease 2024/25 PDF

Lesson 17 Pulmonary Disease 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. ASTHMA 2. ANTIASTHMATIC DRUGS 3. SEVERE ACUTE ASTHMA 4. ALLERGIC EMERGENCIES 5. COPD 6. SUMMARY 1. ASTHMA Asthma is a chronic disease in which the bronchi...

Lesson 17 Pulmonary Disease 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. ASTHMA 2. ANTIASTHMATIC DRUGS 3. SEVERE ACUTE ASTHMA 4. ALLERGIC EMERGENCIES 5. COPD 6. SUMMARY 1. ASTHMA Asthma is a chronic disease in which the bronchial airways in the lungs become narrowed and swollen, making it difficult to breathe. Common symptoms : shortness of breath, wheeze, chest pain and cough with or without sputum production or haemoptysis. COPD : irreversible It is a heterogeneous disease, typically characterised by: Chronic inflammation of the airways Bronchial hyperreactivity Variable and reversible airflow limitation  1. ASTHMA Heterogeneous disease characterized by chronic airway inflammation and variable remodelling that results in a range of clinical presentations Involves both the large-conducting and the small-conducting airway Most asthma cases follow a variable course, involving viral-induced wheezing and allergen sensitization, that is associated with various underlying mechanisms that can differ between individuals Asthma can spontaneously remit or begin de novo in adulthood 1. ASTHMA PATHOGENESIS The pathogenesis of asthma involves both genetic and environmental factors Activated T cells with a cytokine T helper (Th2) production profile are located in the bronchial mucosa of asthmatics. The activation mechanism of these cells is not yet clear, but allergens represent one possible mechanism.  1. ASTHMA PATHOGENESIS Functions of Released Th2 Cytokines: Attraction of Inflammatory Granulocytes: Th2 cytokines attract other inflammatory granulocytes, especially eosinophils, to the mucosal surface. Damage to Epithelium: IL-5 and GM-CSF participate in the damage to the epithelium, which is the underlying cause of bronchial hyperactivity. IgE Immunoglobulin Synthesis and Reactivity: They promote IgE immunoglobulin synthesis and reactivity in some asthmatics. Stimulation of B Cells and IgE Receptors: IL-4 and IL-13 stimulate B cells to synthesize IgE and mast cells and eosinophils to express receptors for IgE. Eosinophil Adhesion to Endothelium: IL-4 and IL-13 also enhance eosinophil adhesion to the endothelium. 1. ASTHMA PATHOGENESIS APC: dendritic cell that presents the antigen Asthma attack: Eosinophils is characterized by two toxic proteins phases: 1. Immediate phase 2. Late phase cysLTs: cisteinil leucotriens  CHARACTERISTICS OF ASTHMA Reversible airways obstruction. Inflammation of the airways 1. ASTHMA Bronchial hyperreactivity the changes present in chronic CROSS-SECTIONAL REPRESENTATION OF A BRONCHIOLE severe asthma are illustrated  1. ASTHMA Once established, asthma attacks can be triggered by: Viral infection Exercise Atmospheric pollutants 'Aspirin-induced’ asthma (AIA): NSAIDs, especially aspirin, can precipitate asthma in sensitive individuals Inhibition of Cyclooxygenase (COX): Aspirin and NSAIDs inhibit the enzyme cyclooxygenase, which is involved in the production of prostaglandins. Increase in Leukotrienes: The inhibition of COX shifts the metabolic pathway towards lipoxygenase, leading to the production of leukotrienes (LTC4, LTD4, LTE4, cysLTs), which are potent inflammatory mediators and bronchoconstrictors. - bronchial hyperactivity due to increased CysLT receptors This condition is more common in adults and can be particularly severe, often requiring the complete avoidance of aspirin and NSAIDs to prevent asthma attacks.  2. Antiasthmatic drugs 1. BRONCHODILATORS Reverse the bronchospasm of the immediate phase β2-adrenoceptor agonists (mainly used) Theophylline Muscarinic receptor antagonists (M3) 2. ANTI-INFLAMMATORY AGENTS Inhibit or prevent the inflammatory components of both phases Cysteinyl leukotriene receptor antagonists Glucocorticoids Treatment is monitored by measuring forced expiratory volume in 1 second (FEV1) or peak expiratory flow rate and, in acute severe disease, oxygen saturation and arterial blood gases. 2. Antiasthmatic drugs 1. BRONCHODILATORS β2-ADRENOCEPTOR AGONISTS Mechanism of action Bronchodilaton through direct action on the β2 adrenoceptors of smooth muscle Additionally, inhibit mediator release from mast cells and TNF-α release from monocytes, and increase mucus clearance by an action on cilia. β2-adrenoceptor agonists are usually given by inhalation of aerosol, powder or nebulised solution but some products may be given orally or by injection.  2. Antiasthmatic drugs 1. BRONCHODILATORS β2-ADRENOCEPTOR AGONISTS SHORT-ACTING AGENTS (SABA): SALBUTAMOL , TERBUTALINE To prevent or treat wheeze in patients with reversible obstructive airways disease. Given by inhalation the maximum effect occurs within 30 min and the duration of action is 3–5 h Used ‘as needed’ basis to control symptoms. LONGER-ACTING AGENTS (LABA): SALMETEROL , FORMOTEROL To prevent bronchoespasm (e.g. at night or with exercise) In patients requiring long-term bronchodilator therapy. Given by inhalation, and the duration of action is 8–12 h. Administered twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by glucocorticoids 2. Antiasthmatic drugs 1. BRONCHODILATORS β2-ADRENOCEPTOR AGONISTS ADRs: Derived from systemic absorption, the commonest adverse effect is tremor, other unwanted effects include tachycardia and cardiac dysrhythmia (due to a partial involvement of cardiac 1 receptors) Tolerance Rebound effect 2. Antiasthmatic drugs 1. BRONCHODILATORS tee lift METHYLXANTHINES : THEOPHYLLINE, AMYNOPHYLLINE Mechanism of action Bronchodilaton Stimulate the CNS and respiratory stimulation may be beneficial in patients with COPD Anti-inflammatory effect CLINICAL USE OF THEOPHYLLINE In addition to steroids: Asthma does not respond adequately to β2- adrenoceptor agonists. COPD. IV (aminophylline) In acute severe asthma.  2. Antiasthmatic drugs 1. BRONCHODILATORS METHYLXANTHINES ADRs: Insomnia,nervousness,dysrhythmia,seizures… A relatively narrow therapeutic window. Monitoring the concentration of theophylline 2. Antiasthmatic drugs 1. BRONCHODILATORS MUSCARINIC RECEPTOR ANTAGONISTS (M3) Pharmacological effects are bronchodilation and decrease in bronchi secretions IPRATROPIUM (SAMA-not selective muscarinic receptors) Maximum effect occurs approximately 30 min after inhalation and persists only for 3–5 h act on diff M recept TIOTROPIUM (LAMA) 15 2. Antiasthmatic drugs 1. BRONCHODILATORS BRONCHODILATORS MUSCARINIC RECEPTOR ANTAGONISTS (M3) MUSCARINIC RECEPTOR ANTAGONISTS (M3) Clinical Uses ASTHMA/COPD Acute exacerbations as an adjunct to β2-adrenoceptor agonists and steroids (SAMA) COPD Regular daily use (LAMA): TIOTROPIUM. BRONCHOSPASM Precipitated by β2-adrenoceptor (not selective) antagonists (In case of HTA…cardiac pathology..) Use with precaution: Glaucoma, hypertension, urinary retention, cardiovascular pathologies 2. Antiasthmatic drugs 2. ANTI-INFLAMMATORY AGENTS EFFECT IN THE LATER PHASE OF ASTHMA(CHRONIC INFLAMMATION) GLUCOCORTICOIDS Prevent the progression of chronic asthma and are effective in acute severe asthma. Glucocorticoids are sometimes ineffective, even in high doses, for reasons that are incompletely understood. Given by inhalation with a metered-dose or dry powder inhaler The full effect on bronchial hyper-responsiveness being attained only after weeks or months of therapy. Oral glucocorticoids: reserved for patients with severe asthma Several inhaler formulations combined inhaled corticosteroids (ICS) are combined together with long-acting β2-adrenoceptor agonists (LABA) and/or long-acting muscarinic antagonists (triple therapy in COPD) 2. Antiasthmatic drugs 2. ANTI-INFLAMMATORY AGENTS GLUCOCORTICOIDS BECLOMETASONE (inhaled) PREDNISOLONE (oral) severe HYDROCORTISONE (iv) for acute attacks severe BUDESONIDE (inhaled) FLUTICASONE (inhaled) MOMETASONE (inhaled) CICLESONIDE (inhaled) Mechanism of action: Anti-inflammatory (reduction of bronchial hyperreactivity) by decreased formation of cytokines, particularly those generated by Th2 lymphocytes, decreased activation of eosinophils and other inflammatory cells. Not bronchodilator effect, only anti-inflammatory effect 2. Antiasthmatic drugs 2.ANTI-INFLAMMATORY AGENTS GLUCOCORTICOIDS ADRs: Oropharyngeal candidiasis: sore throat and croaky voice. (due to the suppression of the immune response) Regular high doses of inhaled glucocorticoids: adrenal suppression Less likely with fluticasone, mometasone and ciclesonide. 2. Antiasthmatic drugs CLINICAL USE OF GLUCOCORTICOIDS IN ASTHMA Patients who require regular bronchodilators should also be prescribed glucocorticoid treatment (e.g. with low-dose inhaled beclometasone) More severely affected patients are treated with higher doses of inhaled corticosteroids in combination with LABA Patients with acute exacerbations of asthma may require intravenous hydrocortisone followed by a course of oral prednisolone. Prolonged treatment with oral prednisolone, in addition to inhaled bronchodilators and steroids, is needed by a few severely asthmatic patients. 21 2. Antiasthmatic drugs 2. ANTI-INFLAMMATORY AGENTS CYSTEINYL LEUKOTRIENE RECEPTOR ANTAGONISTS singulair MONTELUKAST, ZAFIRLUKAST Mechanism of action: act on leukotriene receptors CysLT1 and CysLT2 expressed in respiratory mucosa and infiltrating inflammatory cell Decrease acute reactions to aspirin in sensitive patients, Inhibit exercise-induced asthma Clinical Uses: Add-on therapy to inhaled corticosteroids and long-acting β 2 agonists Generally well tolerated! 2. Antiasthmatic drugs Others zumab = humanized monoglonal ab lumab = non humanized BIOLOGIC THERAPY Anti-IgE: OMALIZUMAB is a recombinant DNA-derived humanized monoclonal antibody that selectively binds human immunoglobulin E (IgE). IL-5 antagonists: MEPOLIZUMAB or reslizumab are monoclonal antibodies that inhibit IL-5 signalling result in reduced production and survival of eosinophils that mediate the allergic inflammatory process in patients with asthma. IL-4/IL-13 antagonist: DUPILUMAB binds to the alpha subunit of the IL-4 receptor which is shared by the IL-4 and IL-13 receptor complexes. And supresses type 2 inflammation biomarkers Thymic stromal lymphoprotein (TSLP) antagonist: TEZEPELUMAB, TSLP is a cytokine derived from epithelial cells that acts as mediator between the immune system and structural cells of the airway. Drugs to treat respiratory pathology STEP 1 Short-acting bronchodilator alone. SABA (beta agonist) SAMA (M antagonist) If patients need this more than once a day STEP 2 A regular inhaled corticosteroid (ICS) should be added If the asthma remains uncontrolled STEP 3 Add a long-acting bronchodilator LABA LAMA Minimises the need for increased doses of inhaled corticosteroid. Remain symptomatic and/or the dose of inhaled corticosteroid increased to the maximum recommended STEP 4 Theophylline OR leukotriene antagonists, such as montelukast, also exert a corticosteroid- sparing effect, but this is less reliable. STEP 5 Is addition of a regular oral corticosteroid (e.g. prednisolone). Consider biologic treatment 25 3. Severe acute asthma (status asthmaticus) A medical emergency requiring hospitalisation. Treatment includes: Oxygen Inhalation of NEBULISED SALBUTAMOL IV HYDROCORTISONE Course of ORAL PREDNISOLONE. Additional measures occasionally Nebulised Ipratropium (SAMA) IV Salbutamol Aminophylline, and antibiotics (if bacterial infection is present). Monitoring by measurement of PEFR or FEV1, arterial blood gases and oxygen saturation.  4. Allergic emergencies Anaphylaxis and angio-oedema are emergencies involving acute airways obstruction ADRENALINE is potentially life-saving. By means of activation of β2 adrenoreceptors IM or occasionally IV Patients at risk of acute anaphylaxis: may self-administer IM adrenaline using a spring-loaded syringe. OXYGEN, antihistamine treatment (CHLORPHENAMINE) and glucocorticoids, are also indicated.  5. Chronic obstructive pulmonary disease (COPD) COPD is the third leading cause of death worldwide, causing 3.23 million deaths in 2019. Cigarette smoking is the main cause Air pollution may contribute to the etiology Clinical features Initiate with attacks of morning cough during the winter, and progresses to chronic cough with intermittent exacerbations, often initiated by an upper respiratory infection Progressive breathlessness Pulmonary hypertension is a late complication, causing symptoms of heart failure ( cor pulmonale ). Exacerbations may be complicated by respiratory failure requiring hospitalisation and intensive care.  5. Chronic obstructive pulmonary disease (COPD) Pathogenesis Fibrosis of small airways, resulting in obstruction, and/or destruction of alveoli and of elastin fibres in the lung parenchyma. The latter features are hallmarks of emphysema Emphysema causes respiratory failure, because it destroys the alveoli, impairing gas transfer. There is chronic inflammation (bronchitis), predominantly in small airways and lung parenchyma, characterised by increased numbers of macrophages, neutrophils and T lymphocytes. 5. Chronic obstructive pulmonary disease (COPD) Differential Diagnosis vs. Asthma Asthma COPD elder Onset age young/adult virus, allergies pollutants, smoking Trigger Associated pathologies rinitis, conjuntivitis, dermatitis NO Genetic yes Inflammatory cells eosinophils neutrophils Obstruction reversibility si no Response to glucocorticoids reduces inflammation Not Always  5. Chronic obstructive pulmonary disease (COPD) PRINCIPLES OF TREATMENT STOP SMOKING slows the progress of COPD. Patients should be IMMUNIZED against influenza and Pneumococcus, because superimposed infections with these organisms are potentially lethal. Initial treatment: long-acting bronchodilator, either LAMA, (LABA) or their combination more in asthma normally but rule For patients with high blood eosinophil counts (>300 cells per μL): ICS combined with LABA (LABA-ICS) is considered. In follow-up management, dual (LAMA-LABA and LABA-ICS) and triple combinations (LAMA-LABA-ICS) depending on symptoms: dyspnoea and frequency of exacerbations Advanced COPD: LONG-TERM OXYGEN THERAPY administered at home  5. Chronic obstructive pulmonary disease (COPD) ACUTE EXACERBATIONS INHALED O2 IN A CONCENTRATION Blood gases and tissue oxygen saturation are monitored. BROAD-SPECTRUM ANTIBIOTICS with activity against Haemophilus influenzae ( CEFUROXIME), are used if there is evidence of infection. INHALED BRONCHODILATORS INHALED STEROIDS improve the quality of life. A systemically ACTIVE GLUCOCORTICOID (IV HYDROCORTISONE OR ORAL PREDNISOLONE) is also administered routinely, although efficacy is modest. 6. SUMMARY 6. SUMMARY