Pulmonary Pharmacology Notes 2024 PDF

Ellen Tisdale, Ph.D. Dept. of Pharmacology [email protected] PULMONARY PHARMACOLOGY Learning Objectives Students will have a working knowledge of the pathophysiology of asthma and COPD. Students will know the different drug cla...

Ellen Tisdale, Ph.D. Dept. of Pharmacology [email protected] PULMONARY PHARMACOLOGY Learning Objectives Students will have a working knowledge of the pathophysiology of asthma and COPD. Students will know the different drug classes commonly used to treat asthma and COPD. Students will be able to describe the mechanism of action of the different classes of drugs used to treat asthma and COPD and their adverse effects. Students will have a basic understanding of the treatment plan for asthma and COPD. I. What is Asthma? Asthma is a chronic lung disease affecting adults and children: the most common chronic disease among children. Asthma is caused by inflammation and bronchoconstriction of the small airways. Symptoms can include coughing, wheezing, shortness of breath and chest tightness. These symptoms can be mild or severe and can come and go over time. Epidemiologic studies strongly support the concept of a genetic predisposition plus environmental interaction in the development of asthma. A. Pathophysiology – Cellular Mechanism of Asthma (see Figure 1) 1. Early Phase Asthma: Mast cell activation by to re-exposure to allergens and physical stimuli that releases bronchoconstrictor mediators: a. Histamine b. Leukotriene C4 and D4 c. Prostaglandin D2. 2. Late phase asthma (6-9 hours): Mast cells also release leukotrienes and chemokines that recruit additional inflammatory cells including: a. Eosinophils b. Basophils c. Neutrophils d. Lymphocytes The inflammatory process in asthma is mediated through the release of more than 100 inflammatory mediators, including lipid mediators, cytokines, chemokines, and growth factors. The release of these molecules leads to: 1. Contraction of airway smooth muscle (bronchoconstriction) 2. Mucus hypersecretion 3. Plasma exudation and edema 4. Microvascular leakage 5. Activation of sensory nerves. 3. Chronic inflammation leads to structural changes (remodeling) in the airways including : 1. Increase in number (hyperplasia) and size (hypertrophy) of airway smooth muscle cells. 2. Increase in blood vessels (angiogenesis) 3. Increase in mucus secreting cells (goblet cell hyperplasia). Fig. 1. Cellular mechanisms of asthma. Inflammatory cells are recruited and activated in the airways, where they release multiple inflammatory mediators, which can also arise from structural cells. These mediators lead to bronchoconstriction, plasma exudation and edema, vasodilation, mucus hypersecretion, and activation of sensory nerves. Chronic inflammation leads to structural changes, including subepithelial fibrosis (basement membrane thickening), airway smooth muscle hypertrophy and hyperplasia, angiogenesis, and hyperplasia of mucus secreting cells. II. What is Chronic Obstructive Pulmonary Disease (COPD)? COPD refers to a group of diseases that cause breathing-related problems: includes emphysema and chronic bronchitis. COPD is associated with an abnormal inflammatory response of the lungs to noxious particles or gases: primary cause of COPD is cigarette smoking. Chronic inflammation affects the integrity of the airways, causes damage, and promotes destruction of the parenchymal structures: progressive disease, but is treatable. Symptoms include Frequent coughing, wheezing, excess phlegm, mucus, or sputum production, and dyspnea. A. Pathophysiology – Cellular Mechanism of COPD (see Figure 2) COPD involves inflammation of the respiratory tract with a pattern that differs from that of asthma. 1. Cigarette smoke and other irritants activate epithelial cells and macrophages in the lung to release mediators that attract circulating inflammatory cells including: a. Monocytes (which differentiate to macrophages within the lung),  b. Neutrophils c. T lymphocytes (TH1,Tc1, and TH17 cells). 2. Fibrogenic factors released from epithelial cells and macrophages lead to fibrosis of small airways. 3. Release of proteases results in alveolar wall destruction (emphysema) and mucus hypersecretion (chronic bronchitis). Fig. 2. Cellular mechanisms in COPD. Cigarette smoke and other irritants activate epithelial cells and macrophages in the lung to release mediators that attract circulating inflammatory cells, including monocytes (which differentiate to macrophages within the lung), neutrophils, and T lymphocytes. Fibrogenic factors released from epithelial cells and macrophages lead to fibrosis of small airways. Release of proteases results in alveolar wall destruction (emphysema) and mucus hypersecretion (chronic bronchitis). Table 1. Features of Inflammation in COPD compared to Asthma Note: You should have a general understanding of the pathophysiological mechanisms of asthma and COPD to better understand the role of the various classes of medications used to treat and manage asthma/COPD symptoms and exacerbations. This information will not be tested on the exam. III. Routes of Drug Delivery to the Lungs A. Inhaled Route The major advantage of inhalation is the delivery of drug to the airways in doses that are effective with a much lower risk of systemic side effects. This is particularly important with the use of inhaled corticosteroids, which largely avoids systemic side effects. In addition, inhaled bronchodilators have a more rapid onset of action with a direct effect on airways. Of the total drug delivered, only 10% to 20% enters the lower airways with a conventional pressurized metered dose inhaler. Drugs are absorbed from the airway lumen and have direct effects on target cells of the airway. Drugs may also be absorbed into the bronchial circulation and then distributed to more peripheral airways. B. Oral Route The oral dose is much higher than the inhaled dose required to achieve the same effect (typically by a ratio of about 20:1), so that systemic side effects are more common. C. Parenteral Route The intravenous route should be reserved for delivery of drugs in the severely ill patient who is unable to absorb drugs from the gastrointestinal (GI) tract. Side effects are generally frequent due to the high plasma concentrations. Fig. 3. Schematic representation of the deposition of inhaled drugs. Inhalation therapy deposits drugs directly, but not exclusively, in the lungs. Distribution between lungs and oropharynx depends mostly on the particle size and the efficiency of the delivery method. Most material will be swallowed and absorbed, entering systemic circulation after undergoing the first pass effect in the liver. Some drug will also be absorbed into the systemic circulation from the lungs. IV. Drug Classes Used to Treat Asthma and COPD / COPD Note: You should have a general understanding of the mechanism of action of the various classes of medications used to treat and manage asthma/COPD symptoms and exacerbations. You will not be tested on the individual drugs. I. Bronchodilators Bronchodilators may directly relax airway smooth muscle or may cause bronchodilation indirectly by blocking the effects of bronchoconstrictor mediators or neurotransmitters. Three main classes of bronchodilators in current clinical use: A. β2 Adrenergic agonists (sympathomimetics) B. Muscarinic receptor antagonists C. Methylxanthine (Theophylline) A. β2 Adrenergic Agonists a. Mechanism of Action (See Figure 4) Activation of the b-2 adrenergic receptor by b2-agonist initiates a transmembrane signal cascade, which involves the heterotrimeric G protein, Gs, and the effector, adenylyl cyclase. Adenylyl cyclase then increases intracellular cAMP via the hydrolysis of ATP. The elevated cAMP concentration serves to activate cAMP-dependent protein kinase A (PKA). PKA can phosphorylate intracellular substrates, which modulate various effects within the cell. In airway smooth muscle, PKA acts to phosphorylate Gq-coupled receptors leading to a cascade of intracellular signals, which reduces intracellular Ca2+. The change in Ca2+ results in the inhibition of myosin light chain phosphorylation, subsequently preventing airway smooth muscle contraction (increase bronchodilation). Fig. 4. Molecular actions of β2 agonists to induce relaxation of airway smooth muscle cells. b. Clinical Use of β2 Adrenergic Agonists b-2 adrenergic receptor agonists are first-line drugs for treatment of bronchial asthma and COPD. Onset of action and duration determines the classification of b-2 agonists: Short-acting b2-agonists (SABAs): shortest half-life Long-acting b2-agonists (LABAs) Ultra-long-acting b2-agonists (ultra-LABAs). The different properties between these classes occur through modifications of the molecular structure of the drugs. SABAs are the first-line medications for acute treatment in asthma symptoms and exacerbations. They are also commonly used in conjunction with LABAs, inhaled corticosteroids, or long-acting muscarinic antagonists in treatment for COPD. LABAs are generally added as second-line treatment in asthma that has failed symptomatic relief with SABAs and ICS. However, there is current controversy on using LABA as monotherapy versus dual therapy with inhaled corticosteroids. Table 2. Common Clinically Used b2-Agonist Short Acting b2 Agonist (SABA) Long Acting b2 Agonist (LABA) Albuterol Salmeterol Levalbuterol Formoterol Metaproterenol Indacaterol Pirbuterol Terbutaline B. Muscarinic Antagonists a. Mechanism of Action (See Figure 5) As competitive antagonists of endogenous acetylcholine at muscarinic receptors, these agents inhibit the M3-Gq-PLC-IP3-Ca2+ pathway. The resulting decrease in intracellular calcium promotes bronchodilation and reduced mucous secretion from glandular cells.  Fig. 5. Mechanism Action of Anti-Muscarinic Drugs. b. Clinical Use of Muscarinic Antagonists Two classes of anti-muscarinic drugs: short-acting or long acting. In asthma, anti-muscarinic drugs are less effective than β2 agonist. Antimuscarinic drugs have additive effect when combined with β2 agonists LAMAs are used as an additional bronchodilator in asthmatic patients not controlled on LABA. In COPD, anticholinergic drugs as effective or superior to β2 agonists. Inhibitory effect on vagal tone in the narrowed airways of patients with COPD. Antimuscarinic drugs reduce air trapping and improve exercise tolerance in patients with COPD. Fig. 6. Anticholinergic drugs inhibit vagally mediated airway tone, thereby producing bronchodilation. This effect is small in normal airways but is greater in airways of patients with COPD, which are structurally narrowed and have higher resistance to airflow. C. Methylxanthines Methylxanthines are a purine-derived group of pharmacologic agents that have clinical use because of their bronchodilation and stimulatory effects. Theophylline is the major methylxanthine in clinical use. a. Mechanism of Action (See Figure 7) Several molecular mechanisms of action have been proposed: 1. Theophylline is a nonselective phosphodiesterase (PDE) inhibitor. PDE3 inhibition and the concomitant elevation of cellular cAMP and cyclic GMP contribute to bronchodilation. 2. Theophylline antagonizes adenosine receptors. Adenosine causes bronchoconstriction in airways from asthmatic patients by releasing histamine and LTs. 3. Theophylline increases Interleukin IL 10 release. IL10 has a broad spectrum of ant- inflammatory effects, and its secretion is reduced in asthma and COPD. Fig. 7. Theophylline has several mechanisms of action: Inhibit PDE3, Adenosine receptor antagonist, and increase IL-1o release. b. Clinical Use of Theophylline Theophylline is used in the management of mild persistent asthma. Theophylline is inexpensive and may be the only affordable addon treatment when the costs of medication are limiting. Theophylline is still used as a bronchodilator in COPD, but inhaled antimuscarinics and β2 agonists are preferred. Theophylline added to these inhaled bronchodilators in patients with more severe disease and can give additional clinical improvement. V. Anti-Inflammatory Agents 1. Corticosteroids a. Mechanism of Action (See Figure 8) Corticosteroids activate and suppress many genes relevant to their action in asthma and COPD. Corticosteroids enter target cells and bind to the glucocorticoid receptor in the cytoplasm. The steroid glucocorticoid receptor complex moves into the nucleus, where it binds to specific sequences on the upstream regulatory elements of certain target genes increasing the transcription of several anti-inflammatory genes and suppressing transcription of many inflammatory genes. Fig. 8 Mechanism of Anti-Inflammatory Action of Corticosteroids. Fig. 9. Effect of corticosteroids on inflammatory and structural cells in the airways. b. Clinical Use of Corticosteroids Inhaled corticosteroids (ICSs) are first-line therapy for persistent asthma. ICSs are less effective in treatment of COPD: used only in patients with severe disease. Intravenous steroids are indicated in acute asthma if lung function is less than 30% predicted and in patients who show no significant improvement with β2 agonist: Hydrocortisone is the steroid of choice because it has the most rapid onset. Prednisone and prednisolone are the most used oral steroids. Oral corticosteroids are used to treat acute exacerbations of COPD, but the effect is small. ICS Systemic Beclomethasone Hydrocortisone Fluticasone Prednisone Budesonide Prednisolone Ciclesonide Methylprednisolone Flunisolide 2. Anti-leukotrienes a. Mechanism of Action (See Figure 10) Leukotriene pathway inhibitors consist of both inhibitors of 5’-lipoxygenase and leukotriene receptor antagonists: The leukotriene receptor antagonists are highly selective and bind with high affinity to the cysteinyl leukotriene receptor for leukotrienes D4 and E4 to block receptor activation. The enzyme 5-lipoxygenase (5-LO) is necessary for the biosynthesis of leukotrienes. Inhibitors of 5-LO prevent the formation of four types of leukotrienes, LTB4, LTC4, LTD4 and LTE4.  Fig. 10. The metabolic pathway by which leukotrienes are formed by leukocytes in response to stimulation by inflammatory conditions. Zileuton is a selective inhibitor of 5- lipoxygenase (LOX), an early step in the synthesis of leukotrienes. Montelukast and zafirlukast are leukotriene receptor antagonists. b. Clinical Use of Anti-leukotrienes The Leukotriene receptor antagonists are used in the management of asthma; not rescue medications. These drugs can be administered orally and are relatively well tolerated. but they are less effective than inhaled corticosteroids and are less effective than LABAs as add on treatments for asthma. 5’- Lipoxygenase Inhibitors Leukotriene Receptor Antagonists Zileuton Montelukast Zafirlukast Pranlukast (not available in US) 3. Monoclonal Antibody Immune-Modulating Drugs a. Mechanism of Action Anti-IgE (Omalizumab) (see Figure 11) Omalizumab is a humanized monoclonal antibody that blocks the binding of IgE to: 1. High affinity IgE receptors (FcεR1) on mast cells and prevents their activation by allergens. 2. Low affinity IgE receptors (FcεRII, CD23) on other inflammatory cells, including T and B lymphocytes, macrophages, and possibly eosinophils, to inhibit chronic inflammation. Omalizumab also reduces levels of circulating IgE.  Fig. 11. Immunoglobulin E plays a central role in allergic diseases. IgE activates high affinity receptors (FcεRI) on mast cells as well as low affinity receptors (FcεRII, CD23) on other inflammatory cells. Omalizumab prevents these interactions and the resulting inflammation. b. Clinical Use of Omalizumab Used for the treatment of patients with severe allergic asthma. Reduces the requirement for oral corticosteroids and inhaled corticosteroids and markedly reduces asthma exacerbations. Because of its high cost, this treatment is generally used only in patients with very severe allergic asthma who are poorly controlled. a. Mechanism of Action Anti-IL-5 (see Figure 12) Anti–IL5 and anti–IL5 receptor (IL5Rα) blocking antibodies inhibit eosinophilic inflammation in asthmatic patients. Three antibodies are approved for use in severe eosinophilic (type 2 immunity) asthma: 1. The anti–IL5 antibodies Mepolizumab and Reslizumab block circulating IL5. 2. Benralizumab blocks IL5Rα.  Fig. 12. Anti–IL5 therapies. IL5 released predominantly from TH2 and ILC2 lymphocytes, stimulates eosinophilic inflammation. IL5 action can be inhibited by the antibodies Mepolizumab and Reslizumab. The IL5 receptor (IL5Rα) can be blocked and rendered unresponsive to IL5 by the antibody Benrlizumab. b. Clinical Use of Anti-IL5 Monoclonal Antibodies These therapies all reduce exacerbations by 50% in severe asthma patients. They also reduce the maintenance dose of oral corticosteroids by at least 50%, permitting many steroid dependent asthmatics to come off steroid treatments completely. Anti–IL5 treatments have not been effective in reducing exacerbations in COPD patients, even when there is an increase in blood eosinophils 4. Degranulation Inhibitor a. Cromolyn: Mechanism of Action (see Figure 13) Cromolyn inhibits mast cell degranulation and therefore the release of inflammatory mediators: histamine and leukotrienes.  Fig. 13. Mechanism of Action of Cromolyn. Cromolyn blocks mast cell degranulation. B. Clinical Use of Cromolyn Cromolyn has no bronchodilator action but can prevent bronchoconstriction The drug is very insoluble: large doses result in minimal systemic blood levels and only local effects. Cromolyn sodium is used for prophylaxis of mild to moderate bronchial asthma. IV. Tables Drug Summary Table DRUG THERAPEUTIC USE Short-Acting B2 Agonists (SABA) Inhaled bronchodilators for symptom relief and acute exacerbation: asthma, COPD Albuterol Asthma, COPD, and exercise-induced bronchospasm Levalbuterol Metaproterenol Pirbuterol Terbutaline Long-Acting B2 Agonists (LABA) Add on therapy to ICSs in asthma; can be used alone in COPD Salmeterol Maintenance for COPD Formoterol Asthma as add-on to ICS Maintenance and treatment severe COPD Indacaterol Anticholinergics Muscarinic receptor antagonists inhaled as bronchodilators Short-Acting (SAMA) Ipratropium bromide Long-Acting (LAMA) Asthmatic patients not controlled on maximal doses of LABA, effective for COPD Tiotropium bromide Glycopyrrolate bromide Umeclidinium bromide LABA-LAMA Combination Inhalers Maintenance treatment for COPD Glycopyrrolate/indacaterol Umeclidinium/vilanterol Tiotropium/olodaterol Inhaled Corticosteroids Maintenance for asthma (First-line therapy chronic asthma) Beclomethasone dipropionate (BDP) Fluticasone propionate Budesonide Ciclesonide ICS/LABA Combination Inhalers Maintenance treatment in asthma and COPD Fluticasone/Salmetereol Budesonide/formoterol Systemic Corticosteroids Short course or oral maintenance for asthma (and COPD) Prednisone Prednisolone Hydrocortisone Antileukotrienes Asthma maintenance Montelukast Zileuton Methylxanthines Add on maintenance treatment of severe asthma and COPD Theophylline Immunomodulators Patients with demonstrated eosinophilia Omalizumab Severe uncontrolled allergic asthma Reslizumab Severe eosinic inflammation in asthma Benralizumab Severe eosinic inflammation in asthma Degranulation Inhibitor Cromolyn Prophylaxis