Therapeutics II: Chronic Asthma (Fall Semester 2024-2025) PDF

Therapeutics II Fall Semester, 2024/2025 Respiratory Disorders Chronic Asthma Professor Wesam Ammari PhD in Clinical Pharmacy, University of Bradford, UK Pharmacy - Faculty of Health Sciences American University of Madaba (AUM)...

Therapeutics II Fall Semester, 2024/2025 Respiratory Disorders Chronic Asthma Professor Wesam Ammari PhD in Clinical Pharmacy, University of Bradford, UK Pharmacy - Faculty of Health Sciences American University of Madaba (AUM) 1  Chronic Asthma “A chronic inflammatory disorder of the airways in susceptible individuals. The inflammatory symptoms are usually associated with a widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli”. Airflow obstruction is often reversible, either spontaneously or with treatment”. 2  Pathophysiology of Asthma Asthma is primarily classified into two types; atopic (allergic) and non-atopic asthma. Atopic asthma: - The immune response at the surface of the involved airways is regulated in a way that it recognizes certain environmental stimuli (allergens); thus initiating multicellular inflammatory processes. 3 - These environmental irritants may include cigarette smoke, dust, air pollution, pollens and fungal spores. - Dendritic cells distributed in the epithelial lining of the airways uptake (internalize) the inhaled allergens; consequently acting as antigen- presenting cells to the T-lymphocytes (Th2-Type cells). - This allergen internalization is promoted and enhanced by the immunoglobulin E (IgE) bound to the surface of the dendritic cells. 4 5  Once the antigen peptide is presented to the T- cells. Sensitization of the immune response is initiated. under the influence of the chemokines, T-cells (Th2- Type) proliferate at the site of antigen presentation on the airways’ surface and start producing a wide range of cytokines. 6  Attract secondary effector cells (eosinophils, basophiles and macrophages) to the inflammation site and activate them to secrete their inflammatory mediators 7 IgE binding to their receptors on mast cells surface → initiates the EAR through their main mediators: - leukotriene (LT)D4, - tryptase - prostaglandin (PG)D2, - heparin - histamine, - cytokines inflammatory features bronchoconstriction, increase in microvascular permeability and thus cellular infiltration, fibrogenesis and smooth muscle remodelling (airway thickening) 8 The inflammatory processes of asthma impair mucociliary transport and increase the size and number of the goblet cells. ↑ mucus secretion & viscosity 9 10  In more severe asthma conditions, the Th1- Type T lymphocytes are also involved in the inflammation process causing tissue damaging through the secretion of the tumor necrosis factor (TNF)-α and interferon (INF)-γ. Mast cells have also a major role in both: 1. The early asthmatic reaction (EAR) (immediate and lasts 30-60 min). 2. The late asthmatic reaction (LAR) starting 4-6 hours later. 11 Eosinophil leukocytes contribute to the inflammatory responses through their various mediators Tissue remodelling by the production of the transforming growth factor (TGF)-ß1. 12  Non-atopic Asthma: - underlying pathophysiology is not very clear yet. - Features are related to Non-IgE dependent provocation caused by: 1. Occupational chemicals. 2. Viral and bacterial infections. 3. Exercise-induced bronchoconstriction 13 Atopic asthma is more life-threatening than non-atopic asthma. A) True B) False 14  Clinical Presentation Patients may complain of episodes of: - dyspnea, - chest tightness, - coughing, - wheezing (whistling sound when breathing). Symptoms tend to be worse at night or early morning. 16  Asthma can vary from chronic daily symptoms to only intermittent symptoms. Severity classification is determined by: - Lung function test, - Symptoms’ frequency, - Night time awakenings, - Interference with normal activity prior to therapy. 17  Lung Function Test Lung function evaluation is important to confirm or exclude the diagnosis of many respiratory diseases as well as to assess/follow up on any related medical intervention. A spirometer → gives many outcome measures that are compared to normal predicted values based on the subject’s age, sex, race and height. 18 19 20  Spirometric parameters Peak expiratory flow (PEF) (litre/minute): - The subject is asked to inhale to their total lung capacity (TLC) and then to breathe out as hard and fast as possible to the residual volume (RV). - The PEF is normally used to monitor respiratory diseases (especially asthma) once the diagnosis has been made. 21 22  Spirometric Parameters Forced Vital Capacity (FVC) (litres): The volume of air exhaled during a forced expiratory manoeuvre starting from a maximal inspiration. Forced Expiratory Volume in one second (FEV1) (litres): The volume of air expelled during the first second of a FVC manoeuvre. It is very important as it is reproducible and correlates well with lung function and disease prognosis. 23  Spirometric Parameters PEF, FEV1 and FVC can be read off the spirometric plots; however, modern spirometry instruments automatically provide these parameters along with the normal predicted values for the subject. → plot Spirometric parameters can be used to confirm the disease diagnosis, severity level classification and follow up/prognosis. 24 25  Diagnosis of Asthma Diagnosis is primarily made by the clinical history of recurrent symptoms: (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). ▪ Diagnosis is confirmed by spirometry. 26 Spirometry demonstrates obstruction → FEV1/FVC ratio less than 80% with reversibility after inhaled β2-agonist administration (at least a 12% improvement in FEV1). If baseline spirometry is normal, challenge testing with exercise, histamine, or methacholine can be used to elicit BHR. Severity classification of asthma (GINA) → 27 28 Management of Chronic Asthma Desired Outcome/Goals: Reducing impairment: (1) Prevent or ↓ chronic and troublesome symptoms. (2) ↓ the need for frequent use (≤2 days/wk) of inhaled short-acting β2-agonist for quick relief of symptoms. (3) Maintain (near-) normal pulmonary function. (4) Maintain normal activity levels (including exercise and attendance at work or school) 29  Reducing risk: (1) prevent recurrent exacerbations and minimize the need for ER visits or hospitalizations. (2) prevent loss of lung function; for children prevent reduced lung growth. (3) minimal or no adverse effects of therapy. 30  Non-Pharmacological Rx Patient education and teaching of self- management skills: - Counselling/training on correct inhaler technique. - Avoidance of known allergenic triggers: (can improve symptoms, reduce medication use, and decrease BHR). 31 Pharmacotherapy: Bronchodilators 1) β2-Agonists: 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. 32  Depending on their onset and duration of action:- 1. Short-acting ß2-agonists (SABA), e.g. salbutamol (albuterol), terbutaline and fenoterol, are used as rescue (reliever) bronchodilators on “as- and when-needed” administration basis. 33  Lec 3: Asthma Albuterol and other inhaled short-acting selective β2-agonists are indicated for treatment of intermittent symptoms of bronchospasm. SABA provide complete protection for at least 2 hours after inhalation (~ 4 hours). Regular treatment (four times daily) does not improve symptom control over as-needed use. 34 2. Long-acting ß2-agonists (LABA), e.g. Formoterol and salmeterol (LABA): indicated as adjunctive long-term control for patients with symptoms who are already on inhaled corticosteroids. LABA are ineffective for acute asthma symptoms because it can take up to 20 minutes for onset. However, Formoterol has been shown to have both short and long acting effects. 35 LABA provide significant protection for 8 to 12 hours initially (allows twice a day administration). 36  2) Anticholinergics Ipratropium bromide and oxitropium bromide (S.A.) are competitive inhibitors of muscarinic receptors; they produce bronchodilation only in cholinergic-mediated bronchoconstriction. A.C. attenuate, but do not block, allergen- or exercise-induced asthma in a dose-dependent fashion. 37  Anticholinergics are effective bronchodilators but are not as potent as β2-agonists. → 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). Ipratropium & oxitrop. have a duration of action of 4 to 8 hours. Tiotropium bromide. 38  3) Methylxanthines E.g.: Theophylline Act mainly as bronchodilators: by inhibiting phosphodiesterases. This also results in some extra anti-inflammatory benefit through: - ↓ mast cell mediator release. - ↓ eosinophil basic protein release. - ↓ T-lymphocyte proliferation & cytokine release. - ↓ plasma exudation. 39  Theophyllines are administered orally (SR) or parentally (IV). Elimination: - Hepatic metabolism (90%): primarily CYP1A2 and CYP3A4. - Renal excretion (10% unchanged). Clinically significant reductions in clearance can result from cotherapy (e.g. cimetidine, erythromycin, clarithromycin, allopurinol, etc.). Other drugs can enhance clearance (e.g. rifampin, carbamazepine, phenobarbital, etc) 40 Due to high inter-patient variability in theophylline clearance → routine monitoring of serum theophylline concentrations is essential for safe and effective use (TI: 5 to 15 mcg/mL). Adverse effects include nausea, vomiting, tachycardia, nervousness and difficulty sleeping. More severe toxicities include cardiac tachy- arrhythmias and seizures. 41 Pharmacotherapy of Chronic Asthma: Inhaled Corticosteroids Advantages: - ↓ mucus production and hypersecretion. - ↓ BHR. - ↓ airway edema and exudation. - Increase the β2-adrenergic receptors’ responsiveness to β2-adrenergic stimulation 43 44 Inhaled corticosteroids are the recommended long-term preventer therapy for persistent asthma in all patients. Most patients with moderate disease can be controlled with twice-daily dosing. Asthmatics should be started on higher and more frequent doses than the daily maintenance doses and then stepped down once control has been achieved. (inflammatory response of asthma inhibits steroid receptor binding). 45 The response to inhaled corticosteroids is delayed: → symptoms improve within the first 1 to 2 weeks. → maximum improvement (including lung function) in 4 to 8 weeks. 46  Systemic toxicity of inhaled corticosteroids is minimal with low to moderate inhaled doses. The risk of systemic effects increases with high doses → Local AE: oropharyngeal candidiasis and dysphonia. Systemic (oral) corticosteroids are indicated in all patients with severe asthma not responding completely to initial inhaled combination Rx. (1-2 weeks to ↓ toxicities) (e.g. Hydrocortisone, prednisone, methylprednisolone) 47 Pharmacotherapy of Chronic Asthma: Mast Cell Stabilizers E.g.: Cromolyn sodium, and nedocromil sodium. Cause stabilization of mast cell membranes → inhibit the response to allergen challenge. Do not cause bronchodilation. Both agents are effective only by inhalation (available as MDIs). 48 Cromolyn and nedocromil are less effective than ICS and inhaled LABA → add-on therapy. A.E. (mild): - Cough and wheezing have been reported (both). - Nedocromil: bad taste and headache. 49  Pharmacotherapy of Chronic Asthma: Leukotriene Modifiers A) Oral leukotriene receptor antagonists E.g : Zafirlukast and montelukast. They: - reduce the proinflammatory (increased microvascular permeability and airway edema) and bronchoconstriction effects of leukotriene D4. - improve pulmonary function tests. - decrease nocturnal awakenings. 50 Dosing: Zafirlukast: Adults: 20 mg twice daily, taken at least 1 hour before or 2 hours after meals. children (5-11 years): 10 mg twice daily. Montelukast Adults:10 mg once daily, taken in the evening without regard to food. Children (6-14 years): one 5-mg chewable tablet daily in the evening. 51  Zileuton: - An inhibitor of leukotriene synthesis. - The dose of zileuton tablets is 600 mg four times daily with meals and at bedtime. Use of zileuton is limited due to: - Potential for elevated hepatic enzymes (especially in the first 3 months) - Inhibition of the metabolism of some drugs metabolized by CYP3A4 (e.g., theophylline, warfarin) 52 Pharmacotherapy of Chronic Asthma: Omalizumab An anti-IgE antibody. Only indicated for patients who have difficult to treat, severe allergic asthma with high serum IgE that is inadequately controlled with the combination of high-dose inhaled corticosteroids and LABA. Doses range from 150 to 375 mg (SC) at either 2- or 4-week intervals. Disadv: anaphylaxis (0.1%), cost. 53 Pharmacotherapy of Chronic Asthma: Mepolizumab U.S. FDA approval: 04/11/2015. A humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology. → Reduces the levels of blood eosinophils. Only indicated for patients (≥ 12 yrs) who have severe recurrent asthma attacks (exacerbations) - as add-on option. Given SC every 4-weeks. 54 Pharmacotherapy of Chronic Asthma: Reslizumab U.S. FDA approval: 23/03/2016. A humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology. → Reduces the levels of blood eosinophils. Only indicated for patients (≥18 yrs) who have severe recurrent asthma attacks (exacerbations) - as add-on option. Given IV infusion every 4-weeks. 55  Goals of asthma treatment § Few asthma symptoms § No sleep disturbance Symptom control (e.g. ACT, ACQ) § No exercise limitation § Maintain normal lung function § Prevent flare-ups (exacerbations) Risk reduction § Prevent asthma deaths § Minimize medication side-effects (including OCS) § The patient’s goals may be different § Symptom control and risk may be discordant § Patients with few symptoms can still have severe exacerbations ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; OCS: oral corticosteroids © Global Initiative for Asthma, www.ginasthma.org 57 *Anti-inflammatory reliever (AIR) Box 3-12 © Global Initiative for Asthma, www.ginasthma.org  GINA 2023 – Adults and adolescents Track 2 *An anti-inflammatory reliever (Steps 3–5) Box 3-12 (3/4) Track 2 © Global Initiative for Asthma, www.ginasthma.org Evaluation of Therapeutic Outcomes Control of asthma is the ultimate goal ( reducing both impairment and risk). Assessment include: - symptoms. - night-time awakenings. - interference with normal activities & QoL. - pulmonary function. -, - exacerbations. - adherence to treatment & related AE. 62 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. All patients on inhaled drugs should have their inhalation technique evaluated monthly initially and then every 3 to 6 months. Validated instruments (ACT & ACQ) are recommended (poor vs. well controlled asthma). 63