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MODULE 1: PHARMACOTHERAPY OF Two principal conditions include: RESPIRATORY DISEASES ​ Chronic bronchitis: chronic or recurrent M1.1:CHRONIC OBSTRUCTIVE PULMONARY excess m...

MODULE 1: PHARMACOTHERAPY OF Two principal conditions include: RESPIRATORY DISEASES ​ Chronic bronchitis: chronic or recurrent M1.1:CHRONIC OBSTRUCTIVE PULMONARY excess mucus secretion with cough that occurs DISEASE on most days for at least 3 months of the year for at least 2 consecutive years. Chronic obstructive pulmonary disease (COPD) is ​ Emphysema: abnormal, permanent a disease state characterized by airflow limitation that enlargement of the airspaces distal to the terminal bronchioles, accompanied by is not fully reversible. The airflow limitation is usually destruction of their walls, without fibrosis. both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases (GOLD, 2009). COPD is a general term that covers a variety of other disease labels including chronic obstructive airways disease (COAD), chronic obstructive lung disease (COLD), chronic bronchitis and emphysema. COPD has been defined (National Institute for Health and Clinical Excellence, 2010) as: ​ Airway obstruction with a reduced FEV1/FVC Pathophysiology of COPD ratio of less than 0.7. ​ If FEV1 is more than or equal 80% of predicted normal, a diagnosis of COPD should only be Chronic inflammatory changes lead to destructive made in the presence of respiratory symptoms, changes and chronic airflow limitation. The most for example breathlessness or cough. common cause is exposure to tobacco smoke. Inhalation of noxious particles and gases activates neutrophils, macrophages, and CD8+ lymphocytes, which release chemical mediators, including tumor necrosis factor-α, interleukin-8, and leukotriene B4. Inflammatory cells and mediators lead to widespread destructive changes in airways, pulmonary vasculature, and lung parenchyma. Oxidative stress and imbalance between aggressive and protective defense systems in the lungs (proteases and antiproteases) may also occur. Oxidants generated by cigarette smoke react with and damage proteins and lipids, contributing to tissue damage. Oxidants also promote inflammation and exacerbate protease–antiprotease imbalance by inhibiting antiprotease activity. The protective antiprotease α1-antitrypsin (AAT) inhibits protease enzymes, including neutrophil elastase. In presence of unopposed AAT activity, elastase attacks elastin, a major component of alveolar walls. Hereditary AAT deficiency increases risk for premature emphysema. In emphysema from cigarette smoking, imbalance is associated with Initial symptoms include chronic cough and sputum increased protease activity or reduced antiprotease production; patients may have symptoms for several activity. years before dyspnea develops. Inflammatory exudate in airways leads to increased Physical examination is normal in most patients in number and size of goblet cells and mucus glands. milder stages. When airflow limitation becomes Mucus secretion increases and ciliary motility is severe, patients may have cyanosis of mucosal impaired. There is thickening of the smooth muscle membranes, development of a “barrel chest” due to and connective tissue in airways. Chronic inflammation hyperinflation of the lungs, increased resting leads to scarring and fibrosis. Diffuse airway narrowing respiratory rate, shallow breathing, pursing of lips occurs and is more prominent in small peripheral during expiration, and use of accessory respiratory airways. muscles. Smoking-related COPD usually results in centrilobular Patients experiencing COPD exacerbation may have emphysema that primarily affects respiratory worsening dyspnea, increased sputum volume, or bronchioles. Panlobular emphysema is seen in AAT increased sputum purulence. Other features of deficiency and extends to the alveolar ducts and sacs. exacerbation include chest tightness, increased need for bronchodilators, malaise, fatigue, and decreased Vascular changes include thickening of pulmonary exercise tolerance. vessels that may lead to endothelial dysfunction of pulmonary arteries. Later, structural changes increase The table below summarizes the common risk factors pulmonary pressures, especially during exercise. In for COPD: severe COPD, secondary pulmonary hypertension leads to right-sided heart failure (cor pulmonale). Clinical Presentation and Risk Factors Tobacco smoking is the most important and dominant risk factor in the development of COPD but other noxious particles also contribute, such as occupational exposure to chemical fumes, irritants, dust and gases. Tobacco exposure is quantified in ‘pack-years’: Diagnosis The physician may perform the following additional investigations for the diagnosis of COPD: A diagnosis of COPD should be considered in any patient who has symptoms of cough, wheeze, regular sputum production or exertional dyspnoea and/or a history of exposure to COPD risk factors. Spirometry is then used to confirm the diagnosis. There is no single diagnostic test for COPD. Lung function tests are used to assist in diagnosis. Aspirometer is used to measure lung volumes and flow rates. The main measurement made is the forced expiratory volume in the first second exhalation (FEV1). Other tests can be performed, such as: ​ Vital capacity (VC): the volume of air inhaled Treatment and exhaled during maximal ventilation; ​ Forced vital capacity (FVC): the volume of air Goals of Treatment: Prevent or minimize disease inhaled and exhaled during a forced maximal progression, relieve symptoms, improve exercise expiration after full inspiration; tolerance, improve health status, prevent and treat ​ Residual volume (RV): the volume of air left in exacerbations, prevent and treat complications, and the lungs after a maximal exhalation. reduce morbidity and mortality. Airflow obstruction is defined as: NONPHARMACOLOGIC THERAPY ​ FEV1 less than 80% of that predicted for the ​ Smoking cessation is the only intervention patient , and proven to affect long-term decline in FEV1 and ​ FEV1/FVC less than 0.7. slow COPD progression. ​ Pulmonary rehabilitation programs include The table below summarizes the assessment of exercise training, breathing exercises, optimal severity of airflow obstruction (adapted from NICE, medical treatment, psychosocial support, and 2010; GOLD, 2009): health education. ​ Administer vaccinations as appropriate (eg, pneumococcal vaccine, annual influenza vaccine). PHARMACOLOGIC THERAPY The newest version of the GOLD COPD strategy takes into account research from 2018 and 2019, explains the use of blood eosinophil counts as a biomarker for the efficacy of inhaled corticosteroids, and includes new algorithms for management cycle and follow-up Treat patients with intermittent symptoms and low risk pharmacological treatment. for exacerbations (Group A) with short-acting inhaled bronchodilators as needed. When symptoms become This updated GOLD 2020 summary provides more persistent (Group B), initiate long-acting inhaled evidence-based advice on the prevention, diagnosis, bronchodilators. For patients at high risk for and management of COPD in primary care. exacerbations (Groups C and D), consider inhaled corticosteroids. ​ Short-acting inhaled bronchodilators (β2-agonists or anticholinergics) are initial therapy for patients with intermittent symptoms; they relieve symptoms and increase exercise tolerance. ​ Long-acting inhaled bronchodilators (β2-agonists [LABA] or anticholinergics) are recommended for moderate to severe COPD when symptoms occur on a regular basis or when short-acting agents provide inadequate relief. They relieve symptoms, reduce exacerbation frequency, and improve quality of On the other hand, NICE Guidelines, 2010 also life and health status. provides a stepwise approach to pharmacological Sympathomimetics treatment of COPD. ​ β2-Selective sympathomimetics cause relaxation of bronchial smooth muscle and bronchodilation and may also improve mucociliary clearance. Administration via metered-dose inhaler (MDI) or dry-powder inhaler (DPI) is at least as effective as nebulization therapy and is usually favored because of cost and convenience. ​ Albuterol, levalbuterol, bitolterol, pirbuterol, and terbutaline are preferred short-acting agents because they have greater β2 selectivity and longer durations of action than other short-acting agents (isoproterenol, Pharmacotherapy of COPD metaproterenol, isoetharine). ​ Salmeterol, formoterol, and arformoterol An approach to initial pharmacotherapy of stable are LABAs that are dosed every 12 hours on a COPD based on combined assessment of airflow scheduled basis and provide bronchodilation limitation, symptom severity, and risk of exacerbations. throughout the dosing interval. Indacaterol is  an ultra-long-acting agent that requires only mcg) once daily using the HandiHaler, a once-daily dosing. In addition to providing single-load, dry-powder, breath actuated greater convenience for patients with device. Because it acts locally, tiotropium is persistent symptoms, LABAs produce superior well tolerated; the most common complaint is outcomes in terms of lung function, symptom dry mouth. Other anticholinergic effects have relief, reductions in exacerbation frequency, also been reported. and quality of life when compared with ​ Aclidinium bromide is a long-acting agent short-acting β2-agonists. These agents are not administered twice daily using the Press Air recommended for acute relief of symptoms. DPI multi-dose device. Anticholinergics Corticosteroids ​ When given by inhalation, anticholinergics ​ Corticosteroids reduce capillary permeability to produce bronchodilation by competitively decrease mucus, inhibit release of proteolytic inhibiting cholinergic receptors in bronchial enzymes from leukocytes, and inhibit smooth muscle. prostaglandins. ​ Ipratropium bromide is the primary ​ Appropriate situations for corticosteroids in short-acting anticholinergic agent used for COPD include (1) short-term systemic use for COPD. It has a slower onset of action than acute exacerbations and (2) inhalation therapy short-acting β2-agonists (15–20 min vs 5 min for chronic stable COPD. Chronic systemic for albuterol). It may be less suitable for corticosteroids should be avoided in COPD as-needed use, but it is often prescribed in this management because of questionable benefits manner. Ipratropium has a more prolonged and high risk of toxicity. effect than short-acting β2-agonists. Its peak ​ Inhaled corticosteroid therapy may be effect occurs in 1.5 to 2 hours, and its duration beneficial in patients with severe COPD at high is 4 to 6 hours. The recommended dose via risk of exacerbation (Groups C and D) who are MDI is two puffs four times daily with upward not controlled with inhaled bronchodilators. titration often to 24 puffs/day. It is also ​ Side effects of inhaled corticosteroids are mild available as a solution for nebulization. The and include hoarseness, sore throat, oral most frequent patient complaints are dry candidiasis, and skin bruising. Severe side mouth, nausea, and, occasionally, metallic effects such as adrenal suppression, taste. Because it is poorly absorbed osteoporosis, and cataract formation occur systemically, anticholinergic side effects are less frequently than with systemic uncommon (eg, blurred vision, urinary corticosteroids, but clinicians should monitor retention, nausea, and tachycardia). patients receiving high-dose chronic inhaled ​ Tiotropium bromide is a long-acting agent therapy. that protects against cholinergic ​ Combination of inhaled corticosteroids and bronchoconstriction for more than 24 hours. Its long-acting bronchodilators (fluticasone plus onset of effect is within 30 minutes, with a peak salmeterol or budesonide plus formoterol) is effect in 3 hours. The recommended dose is associated with greater improvements in FEV1, inhalation of the contents of one capsule (18 health status, and exacerbation frequency than  either agent alone. Availability of combination Goals of Treatment: The goals are to 1) prevent inhalers makes administration of both drugs hospitalization or reduce length of hospital stay, 2) convenient and decreases the total number of prevent acute respiratory failure and death, 3) resolve inhalations needed daily. symptoms, and 4) return to baseline clinical status and quality of life. Methylxanthines Bronchodilators ​ Theophylline and aminophylline produce bronchodilation by inhibiting ​ Dose and frequency of bronchodilators are phosphodiesterase and other mechanisms. increased during acute exacerbations to ​ Chronic theophylline use in COPD improves provide symptomatic relief. Short-acting lung function, including vital capacity and β2-agonists are preferred because of rapid FEV1. Subjectively, theophylline reduces onset of action. Anticholinergic agents may be dyspnea, increases exercise tolerance, and added if symptoms persist despite increased improves respiratory drive. doses of β2-agonists. ​ Methylxanthines have a very limited role in ​ Bronchodilators may be administered via MDIs COPD therapy because of drug interactions or nebulization with equal efficacy. Nebulization and interpatient variability in dosage may be considered for patients with severe requirements. Theophylline may be considered dyspnea who are unable to hold their breath in patients intolerant of or unable to use after actuation of an MDI. inhaled bronchodilators. It may also be added ​ Theophylline should generally be avoided due to the regimen of patients not achieving to lack of evidence documenting benefit. It may optimal response to inhaled bronchodilators. be considered for patients not responding to other therapies. Phosphodiesterase Inhibitors Corticosteroids ​ Roflumilast is a phosphodiesterase 4 (PDE4) indicated to reduce risk of exacerbations in ​ Patients with acute COPD exacerbations may patients with severe COPD associated with receive a short course of IV or oral chronic bronchitis and a history of corticosteroids. Although optimal dose and exacerbations. duration are unknown, prednisone 40 mg orally daily (or equivalent) for 10 to 14 days can be Pharmacotherapy of COPD Acute effective for most patients. Exacerbations ​ If treatment is continued for longer than 2 weeks, employ a tapering oral schedule Patients with COPD suffer acute worsenings of the because of hypothalamic-pituitary-adrenal axis disease, referred to as acute exacerbations. These suppression. exacerbations can be spontaneous but are often precipitated by infection and lead to respiratory failure Antimicrobial Therapy with hypoxaemia and retention of carbon dioxide. ​ Antibiotics are of most benefit and should be initiated if at least two of the following three  symptoms are present: 1) increased dyspnea, activity (levofloxacin). If IV therapy is required, 2) increased sputum volume, and 3) increased a β-lactamase-resistant penicillin with sputum purulence. Utility of sputum Gram stain antipseudomonal activity or a third- or and culture is questionable because some fourth-generation cephalosporin with patients have chronic bacterial colonization of antipseudomonal activity should be used. the bronchial tree between exacerbations. M1.2: ASTHMA ​ Selection of empiric antimicrobial therapy should be based on the most likely organisms: Asthma is a chronic inflammatory disorder of the Haemophilus influenzae, Moraxella catarrhalis, airways causing airflow obstruction and recurrent Streptococcus pneumoniae, and Haemophilus episodes of wheezing, breathlessness, chest parainfluenzae. tightness, and coughing. Asthma means ‘laboured ​ Initiate therapy within 24 hours of symptoms to breathing’ in Greek and was first described 3000 years prevent unnecessary hospitalization and ago. It is a broad term used to refer to a disorder of the generally continue for at least 7 to 10 days. respiratory system that leads to episodic difficulty in Five-day courses with some agents may breathing. The national UK guidelines (BTS/SIGN, produce comparable efficacy. 2009) define asthma as ‘a chronic inflammatory ​ In uncomplicated exacerbations, disorder of the airways which occurs in susceptible recommended therapy includes a macrolide individuals; inflammatory symptoms are usually (azithromycin or clarithromycin), second- or associated with widespread but variable airflow third-generation cephalosporin, or obstruction and an increase in airway response to a doxycycline. Avoid variety of stimuli. Obstruction is often reversible either trimethoprim–sulfamethoxazole because of spontaneously or with treatment’. increasing pneumococcal resistance. Amoxicillin and first-generation cephalosporins Clinical Presentation are not recommended because of β-lactamase susceptibility. Erythromycin is not CHRONIC ASTHMA recommended because of insufficient activity against H. influenzae. ​ Symptoms include episodes of dyspnea, chest ​ In complicated exacerbations where tightness, coughing (particularly at night), drug-resistant pneumococci, β-lactamase wheezing, or a whistling sound when producing H. influenzae and M. catarrhalis, breathing. These often occur with exercise but and some enteric gram-negative organisms may occur spontaneously or in association with may be present, recommended therapy known allergens. includes amoxicillin/clavulanate or a ​ Signs include expiratory wheezing on fluoroquinolone with enhanced auscultation; dry, hacking cough; and atopy pneumococcal activity (levofloxacin, (eg, allergic rhinitis or eczema). gemifloxacin, or moxifloxacin). ​ Asthma can vary from chronic daily symptoms ​ In complicated exacerbations with risk of to only intermittent symptoms. Intervals Pseudomonas aeruginosa, recommended between symptoms may be days, weeks, therapy includes a fluoroquinolone with months, or years. enhanced pneumococcal and P. aeruginosa  ​ Severity is determined by lung function, as exposure to rhinovirus during the first 3 years of life symptoms, nighttime awakenings, and (Holgate et al., 2010). ‘Intrinsic asthma’ develops in interference with normal activity prior to adulthood, with symptoms triggered by non-allergenic therapy. Patients can present with mild factors such as a viral infection, irritants which cause intermittent symptoms that require no epithelial damage and mucosal inflammation, medications or only occasional short-acting emotional upset which mediates excess inhaled β2-agonists to severe chronic parasympathetic input or exercise which causes water symptoms despite multiple medications. and heat loss from the airways, triggering mediator release from mast cells. In practice, patients often ACUTE SEVERE ASTHMA have features of both types of asthma and the classification is unhelpful and oversimplifies the ​ Uncontrolled asthma can progress to an acute pathogenesis of asthma. state in which inflammation, airway edema, mucus accumulation, and severe The illustration below provides a summary of the bronchospasm result in profound airway postulated cellular mechanism involved in airway narrowing that is poorly responsive to inflammation during asthma: bronchodilator therapy. ​ Patients may be anxious in acute distress and complain of severe dyspnea, shortness of breath, chest tightness, or burning. They may be able to say only a few words with each breath. Symptoms are unresponsive to usual measures (short-acting inhaled β-agonists). ​ Signs include expiratory and inspiratory wheezing on auscultation; dry, hacking cough; tachypnea; tachycardia; pallor or cyanosis; and hyperinflated chest with intercostal and supraclavicular retractions. Breath sounds may be diminished with severe obstruction. Mast cell components are released as a result of an IgE antibody-mediated reaction on the surface of the Pathophysiology of Asthma cell. Histamine and other mediators of inflammation are released from mast cells, for example, Asthma can be classified according to the underlying leukotrienes, prostaglandins, bradykinin, adenosine pattern of airway inflammation with the presence or and prostaglandin-generating factor of anaphylaxis, as absence of eosinophils in the airways (eosinophilic vs. well as various chemotactic agents that attract non- eosinophilic). Traditionally patients are described eosinophils and neutrophils. as having ‘extrinsic asthma’ when an allergen is thought to be the cause of their asthma. This is more Macrophages release prostaglandins, thromboxane common in children with a history of atopy, where and platelet-activating factor (PAF). PAF appears to triggers, such as dust mite, cause IgE production. sustain bronchial hyperreactivity and cause respiratory Other environmental factors are also important, such capillaries to leak plasma, which increases mucosal oedema. PAF also facilitates the accumulation of This ratio is a useful and highly reproducible eosinophils within the airways, a characteristic measure of the capabilities of the lungs. pathological feature of asthma. Normal individuals can exhale at least 70% of their total capacity in 1s. In obstructive lung Eosinophils release various inflammatory mediators disorders, such as asthma, the FEV1 is usually such as leukotriene C4 (LTC4) and PAF. Epithelial decreased, the FVC normal or slightly reduced damage results and thick viscous mucus is produced and the FEV1/FVC ratio decreased, usually that causes further deterioration in lung function. 3–5 days). Patients with this 1 to 2 hours before anticipated exposure to the condition use more spray more often with less offending allergen. Adverse anticholinergic response. Abrupt cessation is an effective such as dry mouth, difficulty in voiding urine, treatment, but rebound congestion may last for constipation, and cardiovascular effects may several days or weeks. Other adverse effects occur. of topical decongestants are burning, stinging, ​ The table below summarizes the relative sneezing, and dryness of the nasal mucosa. adverse effect profiles of different ​ Systemic decongestants: Pseudoephedrine antihistamines: and phenylephrine. Nasal Corticosteroids ​ Intranasal corticosteroids relieve sneezing, rhinorrhea, pruritus, and nasal congestion with minimal side effects. They reduce inflammation by blocking mediator release, suppressing neutrophil chemotaxis, causing mild vasoconstriction, and inhibiting mast cell–mediated, late-phase reactions. ​ These agents are an excellent choice for persistent rhinitis and can be useful in seasonal rhinitis, especially if begun in advance of symptoms. Some authorities recommend nasal steroids as initial therapy over antihistamines because of their high degree of efficacy when used properly along with allergen avoidance. Other Miscellaneous Agents ​ Cromolyn sodium (Nasalcrom), a mast cell stabilizer, is available as a nonprescription nasal spray for symptomatic prevention and treatment of allergic rhinitis. It prevents antigen-triggered mast cell degranulation and release of mediators, including histamine. The most common side effect is local irritation (sneezing and nasal stinging). ​ Ipratropium bromide (Atrovent) nasal spray is an anticholinergic agent useful in persistent allergic rhinitis. It exhibits antisecretory properties when applied locally and provides symptomatic relief of rhinorrhea. ​ Montelukast (Singulair) is a leukotriene receptor antagonist approved for treatment of persistent allergic rhinitis in children as young as 6 months and for seasonal allergic rhinitis in children as young as 2 years. It is effective alone or in combination with an antihistamine. ​ Immunotherapy is the slow, gradual process of injecting increasing doses of antigens responsible for eliciting allergic symptoms into a patient with the intent of inducing tolerance to the allergen when natural exposure occurs. Beneficial effects of immunotherapy may result from induction of IgG-blocking antibodies, reduction in specific IgE (long-term), reduced recruitment of effector cells, altered T-cell cytokine balance, T-cell anergy, and alteration of regulatory T cells.