PHARMACOTHERAPY - I PHCY 310 University of Nizwa College of Pharmacy and Nursing School of Pharmacy PHARMACOTHERAPY - I PHCY 310 Lecture -7 Respiratory Disorders “Chronic Obstructive Pulmonary Disease” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outcome Upon completion of this lecture the students will be able to Explain the etiology of chronic bronchitis and emphysema, Describe the pathophysiology and diagnosis using spirometry, and the pharmacological treatment for COPD, Individualize the therapeutic plan for COPD patients with comorbid disease conditions.

Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation that is not fully reversible. The two major forms of COPD are chronic bronchitis and emphysema. Chronic bronchitis is a recurrent cough with sputum production into bronchial tree, on most days for at least 3 months of the year, over 2 consecutive years. Chronic bronchitis

Emphysema is a permanent enlargement of airspaces distal to the terminal bronchioles with loss of normal architecture accompanied by destruction of their walls, but without obvious fibrosis. Emphysema

Etiology Disease is more common in men than women. Passive smoking, environmental factors such as pollution, occupational exposures, serious or recurrent pulmonary infections during childhood are involved. A deficiency of α1-antitrypsin (or α–proteinase inhibitor), an elastase inhibitor, is the genetic basis for alveolar wall destruction in the inherited form of emphysema (<1% patients occur in earlier age). Occupational exposures include inhalation of dust from grains, coal, and other minerals, as well as fumes from adhesives and welding materials.

STRUCTURAL CHANGES IN ALVEOLI An overall increase in respiratory rate is common. Wheezes may be heard during attacks of airway obstruction in both chronic bronchitis and emphysema. An increase in anteroposterior diameter of the chest and classic ‘‘barrel chest’’ may occur in both diseases.

Some patients may develop cor-pulmonale and right-sided congestive heart failure; the term ‘‘blue bloater’’ has been used to describe this presentation. Hypoxemia and respiratory acidosis are common findings. The other common presentation is a patient with largely emphysematous changes. These patients are termed ‘‘pink puffers’’ because alveolar ventilation is maintained until the terminal stages of the disease.

Signs and symptoms: Chronic cough, sputum production, and dyspnea on exertion. As COPD progresses, dyspnea at rest develops and signs of hypoxemia may include cyanosis and tachycardia. Laboratory Tests: 1. Hematocrit may be elevated and may exceed 55% (polycythemia). 2. Increased arterial carbon dioxide tension (PaCO2) and decreased arterial oxygen tension (PaO2). Long standing COPD will cause enlargement of Right heart leading to failure. This is called Cor-pulmonale.

Spirometry Gold standard, performed according to ATS criteria. Obstruction to air outflow present when FEV1/ FVC ratio is less than 70%. Spirometry provides the best information on degree of airway obstruction and also is useful to assess the efficacy of drug therapy. Procedure Patient exhales as rapidly and forcefully as possible for a minimum of 6 seconds through a device that measures airflow. Bronchodilator reversibility testing should be performed at least initially to establish a baseline. A short-acting bronchodilator (e.g., albuterol) is administered and spirometry is repeated in 15 to 30 minutes. COPD is typically characterized by less than a 12% improvement in FEV1 after the bronchodilator administration, or less than 200 mL in patients with very low lung volumes.

International guidelines available for COPD from Smoking history is quantified into pack-years by multiplying the number of packs per day smoked times the number of years smoked. The pack-year smoking history provides insight into the general level of risk for COPD and other smoking-related diseases. International guidelines available for COPD from American Thoracic Society (ATS) European Respiratory Society (ERS) National Heart Lung and Blood Institute (NHLBI) and the World Health Organization (WHO) ‘‘Global Initiative for Chronic Obstructive Pulmonary Diseases’’ (GOLD) guidelines.

Pathogenesis The most common aetiology is exposure to environmental tobacco smoke, but other chronic inhalational exposures can also lead to COPD. Inhalation of noxious particles and gases stimulates the activation of neutrophils, macrophages, and CD8+ lymphocytes, which release a variety of chemical mediators, including tumor necrosis factor- α (TNF- α), interleukin-8 (IL-8), and leukotriene B4 (LT-B4). These inflammatory cells and mediators lead to widespread destructive changes in the airways, pulmonary vasculature, and lung parenchyma. Inflammation results in chronic or recurrent excessive mucus secretion.

Treatment of COPD exacerbations: Acute exacerbations are often precipitated by infection and lead to respiratory failure with hypoxemia and retention of CO2. Desired outcome: 1. Prevent or reduce hospital stay. 2. Prevent acute respiratory failure and death. 3. Return to baseline health status before exacerbation. Nonpharmacologic therapy: Oxygen therapy to reverse hypoxemia. - IV hydration to reverse dehydration. - Chest physiotherapy to mobilize respiratory secretions. - Mechanical ventilation in patients with moderate to severe dyspnea, acidosis (pH between 7.25 and 7.35), hypercapnia (PaCO2 between 45 and 60 mm Hg [6–8 kPa]); and respiratory rate between 25 and 35 breaths per minute.

Pharmacologic therapy: 1. Doxapram infusion: (1-4mg/min.) to stimulate respiratory centres in medulla to improve ventilation and ↓ CO2 retention. 2. Bronchodilators: High dose SABA is preferred due to its rapid onset (with or without anticholinergic). It could be given by MDI or nebulizer. Theophylline could be used if no response to other therapies. 3. Corticosteroids: A short course of IV or oral corticosteroids can be used to reduce duration of hospitalization, but the optimal dose and duration is not known (e.g. 30 mg prednisolone every morning, for 7-14 days).

4. Anticholinergics When given by inhalation, anticholinergic agents produce bronchodilation by competitively inhibiting cholinergic receptors in bronchial smooth muscle. Ipratropium bromide has a slower onset of action than short-acting β2- agonists (15 to 20 minutes vs. 5 minutes for albuterol). Because it is poorly absorbed systemically, anticholinergic side effects are uncommon (e.g., blurred vision, urinary retention, nausea, and tachycardia). Tiotropium bromide is a long-acting agent that protects against cholinergic bronchoconstriction for more than 24 hours. Combination of both short- and long-acting β2-agonists with ipratropium provide added symptomatic relief and improvements in pulmonary function.

5. Methylxanthines Theophylline and aminophylline may produce bronchodilation by inhibition of phosphodiesterase inhibition of calcium ion influx into smooth muscle. Nonpulmonary effects that may contribute to better functional capacity include improved cardiac function and decreased pulmonary artery pressure. A methylxanthine may also be added to the regimen of patients who have not achieved an optimal clinical response to an inhaled anticholinergic and β2-agonist. Therapy can be initiated at 200 mg twice daily and titrated upward every 3 to 5 days to the target dose; most patients require daily doses of 400 to 900 mg. Theophylline is a drug of narrow therapeutic Index hence the therapeutic range of 8 to 15 mcg/mL is often targeted, especially in elderly patients, to minimize the chances of toxicity.

6. Antimicrobial therapy: Exacerbations of COPD typically have an infectious etiology, either viral or bacterial. During an exacerbation, there are increased symptoms, increased mucus production, and worsening of gas exchange and airflow obstruction. Spirometry may not be markedly decreased because airflow limitation is fixed and does not change substantially. Empirical antibiotic therapy should be started if at least two of the following three symptoms: dyspnea, increased sputum volume, and increased sputum purulence. Most common organisms include Moroxella Catarrhalis, Streptococcus Pneumonia, and Haemophilus Influenza.

Write the general instructions for use of Dry Powder Inhalers (DPI). Questions to Answer Differentiate the clinical presentations and pathogenesis of Asthma and COPD. Write the factors to be considered when selecting an inhalation device. What are the strategies for assisting patients in smoking cessation: “The 5A’s”. Write the general instructions for use of Dry Powder Inhalers (DPI).