Pulmonary Pathophysiology I - Obstructive Lung Diseases PDF

Pulmonary Pathophysiology I: Obstructive Lung Diseases JOS H U A M AS TI N , M D S OU T H C OL L E GE S C H OOL OF P H A R M ACY Lecture Objectives Discuss the general anatomy, physiology of the Respiratory System. Discuss the pathophysiologic hallmarks of the following: Chronic Obstructiv...

Pulmonary Pathophysiology I: Obstructive Lung Diseases JOS H U A M AS TI N , M D S OU T H C OL L E GE S C H OOL OF P H A R M ACY Lecture Objectives Discuss the general anatomy, physiology of the Respiratory System. Discuss the pathophysiologic hallmarks of the following: Chronic Obstructive Pulmonary Disease (COPD) Asthma Emphysema Bronchitis (Acute, Chronic) Discuss pharmacologic interventions for COPD, asthma exacerbations. What is the overall role of the respiratory system? Oxygen, Carbon Dioxide Exchange Bicarbonate buffer system, carboxyhemoglobin formation Adjustment of gas levels to offset changes in pH What are the consequences of hypercarbia (increased CO2) as they relate to the blood pH? Production of phonation (sounds) for speech Movement of phlegm (mucus) throughout the respiratory tract – important for combating infections CO2-O2 Exchange in the lungs Hemoglobin Dissociation Curve Conditions which would necessitate the unloading of O2 shift the HDC to the RIGHT (i.e., a higher oxygen partial pressure will be required in order to completely occupy all 4 hemoglobin subunits). Hemoglobin binds oxygen in a WEAKER fashion but more easily RELEASES it to the peripheral tissues. Sepsis Systemic Inflammatory Response Hypoxia Hypotension Hyperthermia Acidosis (Respiratory, Metabolic) Hyperglycemia/DKA  Organization of the pulmonary system The trachea projects inferiorly and separates into right mainstem and left mainstem bronchi. The mainstem bronchi then respectively separate into secondary bronchi. Secondary Bronchi then further separate into tertiary bronchi, which eventually become bronchioles. The bronchioles are concentrated with alveoli, tiny air sacks which are highly vascularized and are involved in gas exchange. Alveoli Alveoli tend to congregate together, and certain alveoli are specialized for certain functions. Type I Alveoli- directly involved in gas exchange Type II Alveoli- involved with secretion of surfactant, which keeps the alveoli open and available for gas exchange. Surfactant lowers surface tension (i.e., the force of fluid within the alveolus which is capable of causing collapse), allowing for the alveolus to remain open and available for gas exchange. Emphysema destroys type II alveoli, resulting in alveolar collapse and inability of the alveolus to participate in gas exchange (irreversible). ARDS (Acute Respiratory Distress Syndrome) discussed later; classically features collapsed alveoli secondary to a loss of surfactant Alveoli, Pulmonary capillaries How does respiration work? The processes of inspiration (lung expansion) and expiration (lung contraction) are driven by pressure and volume. At rest, when no air is moving, the pressure within the alveoli is roughly equal to the pressure outside of the lungs (atmospheric pressure). During inspiration (i.e., the contraction of inspiratory muscles), the thoracic cage expands; this drops the pressure within the lungs. Air travels down the path of least resistance, going from areas of higher pressure to areas of lower pressure. The driving force of air into the lungs rests on the fact that the atmospheric pressure (pressure of the air outside of the lungs) is higher than the pressure within the lungs (intrapleural pressure). As pressure decreases (facilitating the movement of air into the lungs), the volume of the lungs increases since air moves to locations of lower pressure. This is to say, volume and pressure are inversely proportional to one another; as one goes UP, the other goes DOWN. (Boyle’s Law of Partial Pressures!) What other factors are involved in the mechanics of breathing? Surface Tension Lung Compliance Resistance of the Airway Surface tension As mentioned earlier, Type II Alveolar cells are involved in the production of surfactant. Surfactant water, phospholipids, proteins which accumulate onto the surface of the alveolus which is in contact with the blood vessels Without surfactant smaller alveoli (which have larger amounts of pressure and resistance due to their size) would not be able to compete with larger alveoli; this would lead to hypoxia With surfactant surface tension is lowered; in other words, the increased resistance and pressure is overcome, allowing for improved alveolar expansion and, therefore, more alveoli to participate in gas exchange! Lung Compliance Compliance = ability of the chest wall and lungs to expand in response to increased pressures and volumes Higher compliance lungs more easily expand and more powerfully expel air during exhalation Lower compliance lungs are more stiff, resist expansion Compliance is a function of : Elasticity –decreased elasticity (due to a number of medical conditions) decreased expansion of the lung decreased compliance RESTRICTIVE lung diseases (e.g., fibrosis, chemical pneumonitis) Surface tension- higher surface tensions  decreased alveolar expansion decreased compliance Airway resistance The size of the airways determines the resistance (driving force for pushing air through the respiratory tract to the alveoli). Larger diameter = less resistance = facilitated movement of air Smaller diameter = higher resistance = more difficult to move air Asthma, COPD decreased airway diameters lead to increased airway resistance, which is usually due to acute or chronic alveolar collapse. Obstructive Lung Diseases, Foreign Body Obstructions  feature increased resistance via bronchoconstriction, narrowing of airways Neurological Control of breathing Two primary centers in the brain responsible for control of respiration: Pons Medulla In the Pons (Pneumotaxic Center): Certain populations of cells send projections to the medulla, aiding in the maintaining adequate rhythmicity of breathing In the Medulla (Apneustic Center): Also involved in maintaining rhythmicity, but also receives neuronal input from peripheral baroreceptors (which detect pressure) and chemoreceptors (which detect CO2 and oxygen levels) and modulates respiratory muscle contractility in response to changing pressures and/or CO2 levels. “Holding your breath” won’t kill you because your medulla is able to override your cerebrum when your CO2 levels dramatically rise! Brainstem strokes can result in autonomic instability which can alter or destroy the rhythmicity of breathing, as well as the body’s ability to adapt to rising CO2 levels. Questions??? Diseases of the Respiratory Tract Diseases of the Upper Airways Obstructive Lung Diseases Restrictive Lung Diseases Vasculitis (not addressed today) V/Q Mismatch (ventilation-perfusion) Infection (Bacterial, Viral, Fungal) – addressed in the infectious diseases lectures! Toxin-Mediated (Inhaled, smoked) Trauma (Pneumothorax, Pneumomediastinum) Drug-Induced (Nitrofurantoin, Amiodarone) Chronic Hypoxia, resulting in pulmonary hypertension and right-sided heart failure (cor pulmonale) “Obstructive Versus Restrictive” Lung Disease “Restrictive” Disease  Reduced Expansion of the lung tissue due to low compliance (increased stiffness, decreased elasticity); “parenchymal” problem (problems which directly affect parts of the lung not involved in gas exchange such as connective tissue) Pneumothorax, Conditions which cause pulmonary fibrosis, pulmonary effusions “Obstructive” Disease Increase in airway resistance from the trachea, larger bronchi to the smaller bronchioles and alveoli; “airway problem” (problems with either the airways or the alveoli themselves) Asthma, COPD, Emphysema, Bronchiectasis Obstructive Lung Diseases The most common obstructive lung diseases are: Asthma COPD/Emphysema Bronchiectasis These conditions are due to increased airflow obstruction from the larger airways (trachea, larger bronchi) to the smaller airways (terminal bronchioles, alveoli). Increased airflow obstruction decreased ability to expel carbon dioxide Clinical Signs/Symptoms: Wheezing Cough productive of sputum Cyanosis (blue hue of face and body secondary to hypoxia) Chest tightness Over time chronic hypoxia leads to increased pulmonary vasoconstriction pulmonary hypertension Chronic Hypoxia pulmonary vasoconstriction, which leads to increased right ventricular strain right sided heart failure (cor pulmonale) REMEMBER…. Hypoxia causes VASODILATION outside of the lungs! Cor Pulmonale, Echocardiogram https://www.youtube.com/watch?v=zaYxtKYthDk Asthma Chronic hyper-reactive airway disease which is characterized by acute flares secondary to certain exposures Allergic Asthma (pet dander, fur, ragweed, hay, many more) Occupational Asthma (Paints, farm chemicals, fixatives, pesticides, strongly pungent cleaning agents) Social exposures (perfumes, colognes, body odor) Tobacco exposure Environmental Exposures (cold air) Exercise (Exercise-induced asthma) Infectious Causes (Rhinovirus, RSV in kids; self-limited viruses in adults) History of cardiopulmonary disease (specifically COPD, but also heart failure) GERD/Peptic Ulcer Disease Epidemiology: Approximately 8.3% of the American population (~30,000,000 people) have asthma!  Asthma Pathophysiology: Acute asthma attack: Exposure to a stimulus known to cause attacks/bronchospasms release of histamine, immunoglobulin E (IgE, an antibody which mediates allergy/anaphylaxis), which further upregulates mast cell-mediated release of histamine bronchoconstriction Other cytokines such as leukotrienes, interleukins, attract mast cells, eosinophils, and basophils to areas of bronchial hyperrreactivity inflammatory damage to the bronchial walls, promoting airway edema, increased mucus production The cough reflex, which is promoted by the vagus nerve, induces the release of acetylcholine into the lungs promotes further bronchoconstriction With a severe attack accessory muscle fatigue, which can result in severe respiratory distress requires higher level intervention Chronically: Due to repetitious inflammatory stress from asthma attacks, airway remodeling occurs. Bronchial wall hypertrophy, resulting in constant airway hyperreactivity Asthma, Pathophysiology Molecular Mechanisms of Asthma Antigen Presentation antigen is initially presented to naïve T cells (CD4, CD8 T cells), which release cytokines/chemokines which promote B cell proliferation and immunoglobulin class switching from IgM IgE. This response becomes hyper-exaggerated. BONUS: Which subpopulation of T cells will be involved with this process? Sensitization As a result of hyper-exaggeration to a particular antigen, B cells begin to “mass produce” antigen-specific IgE, which becomes incorporated onto the cell surfaces of mast cells and basophils Degranulation upon re-exposure + binding to an antigen, mast cells and basophils release their granular contents (histamine, prostaglandins, leukotrienes), resulting in airway edema, bronchoconstriction, inflammation Mucus Production airway edema + chemotaxis of immune cells promotes increased mucus release and impaired muco-ciliary escalator activity increased risk of concomitant Asthma Diagnosis of asthma: Pulmonary Function Testing (PFT’s), measuring the FEV1/FVC ratio. FEV1 Forced Expiratory volume in one second FVC  Forced vital capacity (the amount of air which can be expelled from the lungs with the deepest breath possible) Because asthma is an obstructive disease, the FEV1/FVC ratio will be low. Bronchodilator Testing- First, measure the FEV1/FVC ratio; then give a bronchodilator. If there is a significant improvement in FEV1 diagnosis of asthma is consolidated! Laboratory assays hypereosinophilia, increased IgE levels Asthma Medical management of asthma rests upon rescue medications (for acute asthma attacks) and maintenance medications (for prevention of asthma attacks and airway remodeling). Rescue medications used in the case of acute asthma exacerbation/attack Short-Acting Beta Agonists (SABA’s)--> antagonize the effects of histamine, acetylcholine in the bronchial smooth muscle promote bronchodilation Albuterol is most commonly used; many standards of care also suggest utilizing inhaled corticosteroids with albuterol! If albuterol alone is ineffective OR if acute asthma attack is severe consider an anticholinergic such as ipratropium Intravenous beta-2 agonist therapy ONLY USED IN SEVERE, REFRACTORY CASES OF ASTHMA! Maintenance therapy for asthma is tailored based on: 1) Frequency of symptoms, and 2)severity of symptoms: Maintenance Medications: Long-acting bronchodilators +/- Inhaled corticosteroids (budesonide, fluticasone, beclomethasone) Beta-2 agonists salmeterol, formoterol Anticholinergics Ipratropium, Tiotropium 5-LOX (lipoxygenase) inhibitor Zileuton (by inhibiting 5-LOX, no leuktotrienes are produced) Theophylline no longer used significantly for asthma management; cGMP PDE inhibitor, BUT has no anti-inflammatory effects and only mild bronchodilatory properties. QUESTIONS??? Chronic Obstructive Pulmonary Disease (COPD) “Hybrid” disease of chronic bronchitis (inflammation of the bronchioles), emphysema (irreversible damage to the alveoli), and hyper-reactive airway disease similar to asthma Epidemiology: Highly affects those around age 40-45; third leading cause of death among older Americans, HIGHLY PREVALENT in the smoking population. 90% of adults with COPD are smokers; the remaining 10% consist of patients with: Alpha-1 antitrypsin deficiency (congenital absence of alpha-1 antitrypsin, an enzyme involved in inhibition of neutrophils neutrophilic destruction of alveoli) HIV with resultant Pneumocystis Jirovecii pneumonia Chronic Obstructive Pulmonary Disease (COPD) Pathophysiology: Chronic airway hyperreactivity similar to asthma in terms of pathophysiology Chronic bronchitis, which leads to large-scale mucus production Emphysema (irreversible alveolar destruction), resulting in compromised gas exchange in multiple zones of the lung Compromised gas exchange chronic hypoxia pulmonary artery hypertension due to prolonged vasoconstriction right sided heart strain which can lead to cor pulmonale (isolated right-sided heart failure) Pathophysiology of COPD Similar to asthma increased mucus secretion + ciliary dysfunction = impaired mucociliary escalator function increased risk of developing bacterial pneumonia Emphysema loss of viable alveoli which normally participate in gas exchange; largely due to the presence of increased oxidative/inflammatory damage to alveolar walls, resulting in expansion of alveoli without the ability to expel carbon dioxide; results in air trapping and decreased oxygen transit into the blood Chronic Obstructive Pulmonary Disease (COPD) Clinical Findings: Cough which is productive of large amounts of sputum (usually light- brown, thick, usually around a cupful) Wheezing, chest tightness Diagnosis: PFT’s (as with asthma), indicative of a low FEV1/FVC ratio (usually