Respiratory Physiology PDF

Overview of Respiratory Physiology Janel Soucie, Pharm.D. Instructional Associate Professor Orlando Campus Module Overview Respiratory physiology – Respiratory system anatomy – Mechanics of respiration – Control of respiration – Gas exchange and transport Pulmonary fun...

Overview of Respiratory Physiology Janel Soucie, Pharm.D. Instructional Associate Professor Orlando Campus Module Overview Respiratory physiology – Respiratory system anatomy – Mechanics of respiration – Control of respiration – Gas exchange and transport Pulmonary function tests Obstructive lung disease Restrictive lung disease Pulmonary embolism 2 Objectives Review the role and structure of the respiratory system Describe the process of ventilation and perfusion Explain mechanisms of control of respiration Discuss concepts of gas exchange and transport Describe compliance and resistance as it relates to lung function Understand the importance of ventilation and perfusion matching in the process of respiration 3 Respiratory System – Primary Role Principal role of the respiratory system – Uptake of oxygen - make available to tissues for metabolism – Removal of carbon dioxide – byproduct of metabolism Primary function – gas exchange – Ventilation – movement of air in & out of the lungs – Perfusion – flow of blood through the lungs – Diffusion – transfer of gasses between the lungs & the blood 4 Respiratory System Lungs – Conducting airways > - Portion through which participate in gas exchange (The air moves into out larynx trachea, a the bronchi , of the lungs but don't – Respiratory tissues ↳ They Do participate in gas exchange (Bronchiols & Alveoli) Pulmonary vasculature – Pulmonary arteries Deoxygenated > - – Pulmonary veins Oxygenated > - – Bronchial circulation Rib cage Respiratory muscles – Diaphragm – Intercostals – Accessory muscles 5  Respiratory System Left Lobe Two : lobes Right Lobe : Three Lobes Image source: Norris, T. Porth’s Pathophysiology: Concepts of Altered Health States. 11th ed. Philadelphia, PA: Wolters Kluwer; 2025 6 Conducting airways Conduit for air flow Include the nasopharyngeal airways, larynx, tracheobronchial tree Condition inspired air Most conducting airways lined with ciliated pseudostratified columnar epithelium – Mucociliary blanket Airway walls – Cartilage, elastic and collagen fibers, smooth muscle – Composition changes as airways branch 7 Tracheobronchial Tree Subdivision of the conducting airways and respiratory airways 8 Conducting and Respiratory Zones in the Airway 9  Respiratory Airways Site of gas exchange Lobules – smallest functional units of the lung – Respiratory bronchioles – Alveoli – Pulmonary capillaries Alveoli – 300 million in adult lung Type I cells Type II cells Gas exchange Produce surfactant Figure 29.8 & Decreases surface tension Image source: Norris, T. Porth’s Pathophysiology: Concepts of Altered Health States. 11th ed. Philadelphia, PA: Wolters Kluwer; 2025 10 Mechanics of Breathing Inspiration: – Diaphragm contracts – Chest expands – Intrathoracic pressure decreases – Air drawn into lungs Expiration – Diaphragm relaxes – Chest relaxes – Intrathoracic pressure increases – Air flows out 11 Mechanics of Breathing Normal respiratory rate for an adult at rest: 12-20 breaths per minute Movement of the diaphragm and changes in chest volume and pressure during inspiration and expiration. Image source: Norris, T. Porth’s Pathophysiology: Concepts of Altered Health States. 11th ed. Philadelphia, PA: Wolters Kluwer; 2025 12 Respiratory Muscles 13 Respiratory System Compliance Compliance – ease with which something can be stretched / distorted Lung compliance Lung> - inflation – Elastin and collagen fibers in the lung – Surface tension Chest wall compliance – Flexibility of thoracic / chest cage Decreased lung / chest wall compliance increase work of breathing 14 Airway Resistance Volume of airflow depends on – Pressure difference between lungs and atmosphere – Resistance to airflow Airway resistance – impediment to flow that air encounters – Most amount occurs in the medium sized bronchi 15 Principal Site of Airflow Resistance 16 Control of Breathing Respiratory Center - medulla and pons Automatic - controlled by – Chemoreceptors: monitor blood levels of oxygen, carbon dioxide, pH; adjust ventilation as needed – Lung receptors: monitor breathing patterns and lung function Voluntary – singing, blowing, speaking – Initiated by motor and premotor cortex – Suspension of automatic breathing 17 Chemoreceptors Central – Most important for detecting changes in PCO2 – Located near respiratory center in medulla Peripheral – Located in carotid and aortic bodies – Important role is monitoring arterial blood oxygen levels 18 Lung Receptors Stretch – Located in conducting airways – Respond to changes in pressure in airway walls Irritant – Located between airway epithelial cells – Respond to toxic inhalants; lead to airway constriction Juxtacapillary – Located in alveolar walls – Sense lung congestion 19 Ventilation and Gas Exchange Atmospheric pressure Partial pressure – PO2 – PCO2 Diffusion – movement of gasses between lungs and blood Diffusion affected by – Difference in partial pressure across the membrane – Surface area available for diffusion – Thickness of the membrane – Diffusion characteristics of the gas 20 Changes to diffusion Surface area of membrane – Destruction of lung tissue – Removal of lung Thickness of the membrane – Pulmonary edema – Pneumonia Difference in partial pressure – Administering high concentrations of O2 21 Oxygen and Carbon Dioxide Transport Oxygen – Physically dissolved in plasma (1-2%) – Bound to hemoglobin (98-99%) Arterial Blood Gas Ranges Carbon Dioxide Parameter Range pH = acid or base 7.35-7.45 – Dissolved carbon dioxide (10%) PaCO2 - partial pressure of – Attached to hemoglobin (30%) carbon dioxide 35-45 mm Hg HCO3 = bicarbonate 22-26 mEq/L – As bicarbonate (60%) PaO2 = partial pressure of oxygen 80-100 mm Hg Image modified from: Norris, T. Porth’s Pathophysiology: Concepts of Altered Health States. 11th ed. Philadelphia, PA: Wolters Kluwer; 2025 22 Oxygen Transport Oxygen poorly soluble in blood At a normal PaO2 of 100mmHg – 0.3mL dissolved oxygen/100ml plasma Average adult human basal oxygen consumption ~250ml/min Most oxygen transported by hemoglobin – Four oxygen molecules per molecule of hemoglobin – 1g fully saturated hemoglobin ~1.34ml oxygen – 100ml blood containing 15g/dL saturated hemoglobin 20.1ml oxygen 23 Oxygen-hemoglobin Dissociation Curve Oxygen-hemoglobin dissociation curve. pH 7.40, temperature 38 °C. (Data from Severinghaus JW. Blood gas calculator. J Appl Physiol. 1966;21:1108.) Image modified from: Sisson, Thomas H., et al. "Pulmonary Disease." Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e Eds. Gary D. Hammer, and Stephen J. McPhee. McGraw-Hill, 24 2019 Hypoxemia Reduction in arterial blood oxygen levels (PaO2) Can result from – Decreased oxygen in the air – Hypoventilation – Perfusion abnormalities – Impaired diffusion – V/Q mismatch 25 Oxygen Transport Cascade 26 Carbon Dioxide transport * Carbon dioxide is Transported 20 times than more Oxygen soluble – Dissolved carbon dioxide (10%) – Attached to hemoglobin (30%) – As bicarbonate (60%) Acid-Base balance – Amount of dissolved carbon dioxide and amount of bicarbonate in the blood Arterial PCO2 normal range – 35-45 mm Hg Arterial bicarbonate normal range: 22-26 mEq/L 27 Ventilation-Perfusion Matching Ventilation – O2 in, CO2 out – Pulmonary ventilation – total exchange of gasses between atmosphere and lungs – Alveolar ventilation – exchange of gasses between alveoli and external environment Pulmonary perfusion – CO2 in, O2 out Matching of ventilation (V) and perfusion (Q) is needed for optimal respiratory system function Average V/Q ratio: – Alveolar ventilation ~4 L/min – Pulmonary perfusion ~ 5 L/min – Average V/Q ratio = 0.8 28 Ventilation-Perfusion Mismatch High V/Q ratio – ventilation maintained but perfusion decreased Low V/Q ratio – perfusion maintained but ventilation reduced Alveolar dead space (Air gas exchange occurs) is moved but no – Ventilated but not perfused – Example: Pulmonary thromboembolism Physiologic shunt to the left side of the > - Blood moves from the right. circulation w/out being oxygenated – Perfused but not ventilated – Example: Atelectasis 29 Coming up next… Overview of respiratory physiology Pulmonary function tests Obstructive Lung Disease Restrictive Lung Disease Pulmonary Embolism 30 Pulmonary Function Tests Janel Soucie, Pharm.D. Instructional Associate Professor Orlando Campus Module Overview Respiratory physiology Pulmonary function tests (PFTs) – Spirometry – Arterial Blood Gases (ABGs) – Pulse Oximetry – Peak Flow Obstructive lung disease Restrictive lung disease Pulmonary embolism 2 Objectives Define and differentiate between the lung volumes and capacities Describe the different PFTs used to evaluate patients Identify and explain the individual components within different types of PFTs Explain the purpose of each of the PFTs and how they are used Interpret spirometry and ABGs when provided a patient case Educate a patient regarding peak flow monitoring 3 Purpose of Pulmonary Function Tests (PFTs) Assess signs/symptoms of lung disease Evaluate lung disease progression Assess response to therapeutic interventions Screen those at risk of lung disease Monitor for toxic effects of exposures Preoperative risk assessment 4 Lung Volumes and Capacities Lung volumes and capacities. (ERV, expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capacity; IRV, inspiratory reserve volume; RV, residual volume; TLC, total lung capacity; VC, vital capacity; VT, tidal volume) 5  Lung Volumes Tidal volume (VT) – Volume in/ex-haled with each resting breath Inspiratory reserve volume (IRV) – Maximal volume of air inhaled above the tidal volume. Expiratory reserve volume (ERV) – Difference between the resting expiratory level and the maximal expiratory level Residual volume (RV)* Of – volume remaining in the lungs after maximal exhalation 6 * = not determined by spirometry. Lung Capacities & = Not measured spirometry by Vital capacity (VC) – Maximal amount of air that can be exhaled after a maximal inspiration Functional residual capacity (FRC)* D – Volume of air remaining in the lungs at the end of a quiet expiration Inspiratory capacity (IC) – Inspiratory reserve volume plus tidal volume Total lung capacity (TLC)* Of – Volume of air in the lungs after full, maximal inspiration. 7 * = not determined by spirometry. Types of PFTs Spirometry Arterial Blood Gases Pulse Oximetry Peak Flow 8 Spirometry Purpose: measures the rate and volume of airflow Measures – Forced vital capacity (FVC) – total volume able to be forcefully expired after a maximal inspiratory effort – Forced expiratory volume in 1 second (FEV1) – volume exhaled during the first second of the FVC maneuver – FEV1/FVC ratio 9  Spirometry results Sample results: Predicted results based on age, height, sex, and race Also reports percent of predicted Image source: Langan R, Goodbred A, Am Fam Physician. 2020.101(6):362-368 10 Interpreting Spirometry Results Step 1: assess FEV1/FVC ratio – If < lower limit of normal => obstructive Step 2: assess the FVC – If < lower limit of normal => restrictive Step 3: look at total lung capacity (TLC)* – If < lower limit of normal => restrictive Step 4: If obstructive defect, determine reversibility – If FEV1 increases by more than 12% (and more than 200mL in adults) after bronchodilator administration, this suggests acute bronchodilator responsiveness *If full PFTs are available 11 Additional Steps Grade severity of abnormality Bronchoprovocation – If PFTs are normal but asthma diagnosis still suspected – Types include methacholine challenge, mannitol inhalation challenge, exercise testing Compare current/prior PFT results Image source: Langan R, Goodbred A, Am Fam Physician. 2020.101(6):362-368 12.  Spirometry: Case 1 Lower Pre- % of Post- Limit of Broncho- Predicted Broncho- Percent Normal dilator Value dilator Change FVC 2.24 L 2.42 L 83% 2.72 L 12% FEV1 1.86 L 1.52 L 63% 2.05 L 34% FEV1/FVC 73.4% 58.2% 75.3% 29% Step 1: FEV1 Step 2 Step 3: N/A Step 4: FEV1 acute bronchodilator responsiveness Image modified from: Al-Ashkar F, et al. Clev Clin J Med. 2003; 70 (10) 866-881. 13  Spirometry: Case 2 Lower Limit of Patient's % of Normal value Predicted FVC 2.39 L 1.85 L 60% FEV1 1.8 L 1.64 70% FEV1/FVC 67.3% 88.6% Pause the lecture and try working through this case on your own Image modified from: Al-Ashkar F, et al. Clev Clin J Med. 2003; 70 (10) 866-881. 14  Spirometry: Case 2 Lower Limit of Patient's % of Normal value Predicted FVC 2.39 L 1.85 L 60% FEV1 1.8 L 1.64 70% FEV1/FVC 67.3% 88.6% Step 1: FEV1 normal Step 2 Step 3: N/A Step 4: N/A Image modified from: Al-Ashkar F, et al. Clev Clin J Med. 2003; 70 (10) 866-881. 15 Types of PFTs Spirometry Arterial Blood Gases (ABGs) Pulse Oximetry Peak Flow 16 Arterial Blood Gases Purpose: – Determines patient’s acid/base balance – Provides information about patient’s oxygenation – Indicates primary source of a disturbance – Indicates how body is compensating for acid-base disturbance – Assessment of response to interventions 17 ABG Components pH: hydrogen ion (H+) concentration in blood SaO2: percent of oxygen saturated hemoglobin in arterial blood PaO2: partial pressure of O2 in arterial blood PaCO2: partial pressure of CO2 in arterial blood HCO3-: concentration of bicarbonate in blood 18 Acid-Base Disorders; Changes in HCO3- and CO2 Classified as respiratory or metabolic in origin 3 - – 3 - – 3 - 2 – 2 – 2 19 Acid-Base Regulation Lungs: – Ventilation will change to control PaCO2 – Compensation can occur rapidly Kidneys: – Excretion or conservation of H+ and HCO3-, production of new HCO3- – Compensation occurs slower 20 Respiratory Acidosis / Alkalosis Respiratory acidosis – PaCO2 increased; pH decreased – Causes can include COPD, drug overdose, head injury, pneumonia Respiratory alkalosis – PaCO2 decreased; pH increased – Cause is hyperventilation / excessive ventilation anxiety, pain, fever 21 Metabolic Acidosis / Alkalosis Metabolic acidosis – HCO3- decrease; pH decrease – Causes can include lactic acidosis, kidney disease, poisoning, severe diarrhea Metabolic alkalosis – HCO3- increase; pH increase – Causes can include electrolyte imbalances, prolonged vomiting, excess bicarbonate administration 22  Interpretation of ABGs Interpretation of Simple Acid–Base Disorders Acid–Base Primary pH Compensation Disorder Disturbances Acidosis Respiratory Decrease Increase PaCO2 Increase HCO3 Metabolic Decrease Decrease HCO3 Decrease PaCO2 Alkalosis Respiratory Increase Decrease PaCO2 Decrease HCO3 Metabolic Increase Increase HCO3 Increase PaCO2 Image source: Tucker, Anne M., and Tami N. Johnson. "Acid–Base Disorders." DiPiro: Pharmacotherapy A Pathophysiologic Approach, 12e Eds. Joseph T. DiPiro, et al. McGraw Hill, 2021 23 Arterial Blood Gasses - Normal Ranges Measurement Value pH 7.40 (7.35–7.45) PO2 80–100 mm Hg SaO2 95% PCO2 35–45 mm Hg HCO3 22–26 mEq/L Image modified from: Tucker, Anne M., and Tami N. Johnson. "Acid–Base Disorders." DiPiro: Pharmacotherapy A Pathophysiologic Approach, 12e Eds. Joseph T. DiPiro, et al. McGraw Hill, 2021 24 Interpreting ABG Results Step 1: Evaluate pH Step 2: Assess respiratory (PaCO2) and metabolic (HCO3-) components Step 3: Determine which value is Interpreting consistent with pH ABG Results Step 4: Evaluate for evidence of compensation Image modified from: Larkin BG, et al. AORN J. 2015;102(4):343-54 25 Interpreting ABG Results: Example pH 7 35-7 45 Patient values: pH 7.24; PaCO2 38mmHg;.. 35-45 PaO2 80mmHg; HCO3- PaCOg Step 1: pH indicates acidosis HCOz 22-26 Step 2: PaCO2 is normal; HCO3- is low indicating acidosis Step 3: HCO3- is consistent with pH indicating metabolic cause Step 4: PaCO2 is normal indicating no compensation 26 Interpreting ABG Results: Case 1 Patient values: pH 7.46; PaCO2 32mmHg; PaO2 138mmHg; HCO3- 23mEq/L Pause your lecture and try working through this case on your own 27 Interpreting ABG Results: Case 1 Patient values: pH 7.46; PaCO2 32mmHg; PaO2 138mmHg; HCO3- 23mEq/L Step 1: pH indicates alkalosis Step 2: PaCO2 is alkalotic; HCO3- is normal Step 3: PaCO2 is consistent with pH so respiratory cause Step 4: HCO3- is normal so no compensation 28  Interpreting ABG Results: Case 2 Patient values: pH 7.27; PaCO2 PaO2 93mmHg; HCO3- 41mEq/L Pause the lecture and try working through this case on your own 29  Interpreting ABG Results: Case 2 Patient values: pH 7.27; PaCO2 2 93mmHg; HCO3- 41mEq/L Step 1: pH indicates acidosis Step 2: PaCO2 is acidotic; HCO3- is alkalotic Step 3: PaCO2 is consistent with pH so respiratory cause Step 4: HCO3- is elevated so metabolic compensation 30 Types of PFTs Spirometry Arterial Blood Gases Pulse Oximetry Peak Flow 31 Pulse Oximetry Purpose - measures the oxygen saturation of the blood Probe uses light to measure oxygen saturation Indirect measure Normal / abnormal value varies 32 Pulse Oximetry Indications: – Before, during, and after surgery – Assess efficacy of treatment – Determine affect of increased activity on oxygen saturation – Assess need for/efficacy of mechanical ventilation Factors that may impact accuracy of the reading: – Nail polish, artificial nails – Cold hands, poor circulation – Smoking – Skin pigmentation 33 Types of Pulmonary Function Tests Spirometry Arterial Blood Gases Pulse Oximetry Peak Flow 34 Peak Flow Measures how well air moves out of the lungs Purpose: provides patients and clinicians with objective measure of airflow obstruction Peak flow monitoring in asthma – Establish personal best – Use personal best for comparison of future results – Re-evaluate personal best number annually * Ensure thorough patient education 35 Peak Flow Monitoring in Asthma After asthma diagnosis, may be used short-term or long-term – Short term Assess response to treatment Assist in identification of triggers Monitor recovery after an exacerbation – Long-term for patients that have Difficulty perceiving symptoms History of sudden severe exacerbations Severe asthma Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2024. Available from www.ginaasthma.org 36  Peak Flow Measurements – Asthma Action Plan Image source: https://www.nhlbi.nih.gov/resources/asthma- 37 action-plan-2020 Peak Flow - Considerations Not preferred for diagnostic purposes Devices are not interchangeable – Up to 20% variation between devices Clean according to manufacturers instructions 38 Coming up next…. Overview of respiratory physiology Pulmonary function tests Obstructive Lung Disease Restrictive Lung Disease Pulmonary Embolism 39 Obstructive Lung Disease – Asthma and COPD Janel Soucie, Pharm.D. Instructional Associate Professor Orlando Campus Module Overview Respiratory physiology Pulmonary function tests Obstructive lung disease – Asthma – COPD Restrictive lung disease Pulmonary embolism 2  Objectives Explain pathophysiological mechanisms associated with obstructive lung disease including asthma and COPD Describe risk factors for asthma and COPD Identify common symptoms associated with asthma and COPD Understand the rationale behind treatments used for the management of asthma and COPD 3  Obstructive Lung Disease Increased resistance to expiratory airflow – Difficulty exhaling air from lungs Can result from processes – Within airway lumen Increased secretions – In the airway wall Inflammation bronchoconstriction – In the supporting structures surrounding the airway Destruction of elastin-containing tissues 4 Causes of Obstructive Lung Disease Alpha-1 antitrypsin deficiency Asthma Bronchiectasis COPD Cystic Fibrosis 5 Cystic Fibrosis (CF) Genetic disorder – CFTR gene Thickened, viscous secretions in multiple organ systems Excessive, thick mucus obstructs lungs Chronic lung infections Improved medical management has led to improved survival 6 6 Asthma - Epidemiology About 25 million people with current asthma (7.7%) Over 4.6 million children (6.5%) Over 20 million adults (8%) Prevalence is higher in females Prevalence is higher in Black population Prevalence is higher in lower socioeconomic status Image source: https://www.cdc.gov/asthma/asthmadata.htm 8 https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm  Asthma - Epidemiology Missed days of school / work – 13.8 million missed days of school among children with asthma (2013) – 33.8% of adults with asthma missed days of work (2014) Mortality (2021) – 3,517 people died from asthma – Rate higher in adults than children – Rate higher in Non-Hispanic Blacks Affect on the health system (2020) – Over 94,000 hospital inpatient stays – Over 986,000 emergency department visits www.cdc.gov/asthma 9  Current Asthma Prevalence by State or Territory, 2020 (Adult) 2020 Adult Asthma Data: Prevalence Map Image source: https://www.cdc.gov/asthma/data-visualizations/default.htm Asthma - Etiology Genetic predisposition + environmental interaction Risk factors: – Atopy – genetically determined condition of hypersensitivity to environmental allergens – Exposure to secondhand smoke in infancy and in utero – Allergen exposure – Air pollution in immediate surroundings – Viral respiratory infections – Decreased exposure to common childhood infectious agents – Urbanization 11 Asthma – Severity Impacted by – Genetics – Age of onset – Pollution exposure – Atopy – Environmental triggers – Degree of exposure to triggers – Gastroesophageal Reflux Disease – Viral respiratory tract infections 12  Airway Physiology In lower airways cartilaginous layer is gradually replaced with smooth muscle Diameter of bronchial airways controlled by contraction and relaxation of smooth muscle Autonomic nervous system – Parasympathetic stimulation - bronchoconstriction – Sympathetic stimulation - bronchodilation Inflammatory mediators - bronchoconstriction 13 Asthma – Major Characteristics Variable expiratory airflow limitation – Bronchospasm – Mucus hypersecretion – Edema Bronchial hyper-responsiveness Airway inflammation 14 Pathophysiology of Asthma Exposure to allergen or stimuli Results in inflammatory process – Release of inflammatory mediators Bronchoconstriction, hypersecretion of mucus, edema Narrowed airway -> difficulty breathing 15 Asthma – airway inflammation Airway inflammation – Variety of cells types / mediators including: Mast cells Histamine Cytokines Leukotrienes – Causes inflammation, bronchoconstriction, edema Chronic inflammation -> bronchial hyperresponsiveness, airway remodeling 16 Pathophysiology of Asthma Image source: https://www.epa.gov/asthma/what-asthma 17 Pathophysiology of Asthma 18 Asthma – Defining Features (GINA) “history of respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity” AND “variable expiratory airflow limitation” Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2023. Available from www.ginaasthma.org 19  Asthma – Triggers Triggers Allergens Upper respiratory viral infections Exercise Cold, dry air Air pollution Drugs ( -blockers, aspirin) Emotions / stress / hormonal changes Irritants (strong odors, smoke, etc) Image modified from: Israel, Elliot. "Asthma." Harrison's Principles of Internal Medicine, 21e Eds. Joseph Loscalzo, et al. McGraw Hill, 2022 20  Asthma – symptoms Wheezing – High pitched, whistling sound while breathing – Coughing – Particularly at night and early AM – Airway narrowing, excessive mucus secretion, neural afferent hyperresponsiveness Shortness of breath & chest tightness – Respiratory muscle fatigue, Increased work of breathing * Symptoms vary over time and in intensity * 21 Pulmonary Function Tests - Asthma FEV1 - decreased FEV1/FVC ratio – decreased Peak flow - decreased Reversibility of obstruction after inhaled 2-agonist administration **Normal values do not exclude a diagnosis** 22  Asthma - Treatment Long-term Control Acute Reliever (Rescue) Corticosteroids (usually inhaled) Short- -agonists Long-acting -agonists Short-acting anticholinergic Long-acting anticholinergic ICS + formoterol Leukotriene modifiers ICS + SABA Anti-IgE Long-term treatment goals Risk reduction Anti-IL5 / Anti-IL5R Symptom control Anti-IL4/IL13 23 ICS = inhaled corticosteroid; SABA = Short- -agonist  Asthma - Pharmacotherapy Corticosteroids – most effective anti- inflammatory medications for asthma – Budesonide, mometasone, fluticasone (inhaled) – Oral, IM or IV corticosteroids mostly used for acute exacerbations 2-Agonists- relax bronchial smooth muscle through activation of -2 receptor – Albuterol – (usually inhaled) short acting – Salmeterol, vilanterol – inhaled long acting 24 Asthma – Pharmacotherapy Leukotriene modifiers – interrupt leukotriene pathway (block synthesis or interaction with receptors) – Montelukast, zileuton - oral Anticholinergics – reverse cholinergic- mediated bronchoconstriction through competitive inhibition of muscarinic receptors – Ipratropium – short acting inhaled – Tiotropium – long acting inhaled 25 Asthma – Pharmacotherapy Anti-IgE therapy – inhibits binding of IgE to mast cells and decreases free IgE – Omalizumab - subcutaneous Anti-IL5 / Anti-IL5R therapy – target IL-5 or the IL-5 receptor – Mepolizumab, reslizumab, benralizumab Anti-IL4/IL13 therapy – targets IL-4 receptor – Dupilumab - subcutaneous 26  Asthma Treatment Strategy 12 years old - adults 27 Image source: Global Initiative for Asthma. GINA Pocket Guide for Asthma Management and Prevention for Adults, Adolescents, and Children 6-11 Years – 2023. Available at www.ginaasthma.org 28  COPD - epidemiology Nearly 16 million people in the US affected by COPD Fourth leading cause of death in the US Economic impact in the US (2010) – Annual total national medical costs: ~$32 billion – Absenteeism costs: $3.9 billion – 16.4 million missed days of work Groups more likely to report COPD (2013) – Women – People aged 65 years and older – American Indians/Alaska Natives and multiracial non-Hispanics – Current or former smokers – People with a history of asthma https://www.nhlbi.nih.gov/health-topics/copd 29 https://www.cdc.gov/copd/infographics/copd-costs.html https://www.cdc.gov/copd/basics-about.html COPD Death Rates in the United States Age- - https://www.cdc.gov/copd/data-and-statistics/national-trends.html#data-table-COPD_mortailty_trends.csvhttps://www.cdc.gov/copd/basics-about.html 30 COPD Prevalence in the United States Age-adjusted prevalence of COPD among US adults aged - 2020 31 https://www.cdc.gov/copd/data-and-statistics/state-estimates.html COPD - Risk factors Smoking Long term exposure to lung irritants – Air pollution (outdoor and indoor) – Chemical agents / fumes – Dusts – Secondhand smoke Genetic factors – Alpha-1 antitrypsin deficiency Lung growth and development Asthma 32 COPD – GOLD definition Heterogenous lung condition Characterized by chronic respiratory symptoms Due to abnormalities of the airways and/or alveoli Abnormalities cause persistent, often progressive, airflow obstruction Global Initiative for Chronic Obstructive Lung Disease; Pocket guide to COPD Diagnosis, Management, and Prevention, 2023 available at goldcopd.org 33  COPD - Overview Persistent obstruction of airflow (airflow limitation) Encompasses both emphysema and chronic bronchitis Pathophysiology Inflammation and fibrosis of bronchial wall – Airflow obstruction Hypertrophy of submucosal glands & mucus hypersecretion – Excess mucus Airflow obstruction Loss of elastic lung fibers – Expiratory airflow rate impaired – Airways predisposed to collapse – Air trapping increased Loss of alveolar tissue – Decreased surface area for gas exchange 34 Image source: https://www.nhlbi.nih.gov/health-topics/copd COPD - Emphysema Defining features Loss of lung elasticity – Premature expiratory airway collapse Abnormal, permanent enlargement of the airspaces distal to the terminal bronchioles – Hyperinflation of lungs – Increased total lung capacity (TLC) Destruction of alveolar walls and capillary beds – Decreased surface area for gas exchange – Decreased diffusing capacity 35  COPD – Chronic Bronchitis History of cough and sputum production for at least 3 months/year for 2 consecutive years Airway obstruction of major and small airways Large airways - Hypertrophy of submucosal glands in trachea and bronchi, hypersecretion of mucus Small airways - Increase in goblet cells, excess mucus production, inflammation, bronchiolar wall fibrosis 36 COPD – Symptoms and Physical Findings Symptoms – Chronic cough – Dyspnea – Sputum production Physical findings – Barrel chest – Rapid / shallow breathing – Altered breathing mechanics Pursed lip breathing Use of accessory muscles Image source: https://my.clevelandclinic.org/health/articles/pursed-lip-breathing 37 COPD – Pulmonary Function Tests FEV1 – decreased FEV1/FVC ratio – decreased RV - increased FRC - increased Some patients have features of TLC - increased both asthma and COPD Asthma and COPD may coexist in a single patient 38 Smoking Cessation Most important intervention to slow (or prevent) disease Slows progression of COPD Decreases symptoms Slows rate of decline even after abnormal PFTs *Pharmacist Involvement* 39  COPD - Treatment Bronchodilators – 2-Agonists and Anticholinergics – relax bronchial smooth muscle, reduce air trapping, reduce thoracic hyperinflation, improve exercise tolerance Corticosteroids – smaller role in COPD Treatment goals (stable COPD) Oxygen therapy – for selected patients Reduce symptoms Reduce future risk of exacerbations 40  Stable COPD Initial Pharmacological Treatment Algorithm - GOLD LABA: long- 2-agonists LAMA: Long-acting muscarinic antagonists ICS: inhaled corticosteroids 41 Image source: Global Initiative for Chronic Obstructive Lung Disease; Pocket guide to COPD diagnosis Management and Prevention, 2023 available at goldcopd.org COPD – Treatment Considerations COPD is often a progressive condition Individualized treatment – Symptoms, side effects, access, cost, patient preference, other factors Progression of disease possible increase in number of medications Patient education and reinforcement 42 Coming up next…. Overview of respiratory physiology Pulmonary function tests Obstructive Lung Disease Restrictive Lung Disease Pulmonary Embolism 43 Restrictive Lung Disease and Pulmonary Embolism Janel Soucie, Pharm.D. Instructional Associate Professor Orlando Campus Module Overview Respiratory physiology Pulmonary function tests Obstructive lung disease Restrictive lung disease Pulmonary embolism 2 Objectives Understand the definition of restrictive lung disease and mechanisms by which it can occur Explain causes for and contributing factors to restrictive lung disease Identify medications which can cause Drug Induced Interstitial Lung Disease Discuss the pathophysiological processes in venous thromboembolism (VTE) Recognize the risk factors for and signs and symptoms of pulmonary embolism (PE) Describe options for the treatment and prevention of PE/deep vein thrombosis 3 Restrictive Lung Disease Inability to get sufficient air into the lungs and maintain normal lung volumes Reduces all subdivisions of lung volumes No reduction of airflow Normal airway resistance 4 Restrictive Lung Disease Increased elastic recoil of the lung parenchyma Respiratory muscle weakness – Decreased ability to inflate and deflate the lungs Mechanical restrictions – Mechanical compression / something limits expansion 5 Restrictive Lung Disease - PFTs FEV1 – decreased (or normal) FVC - decreased FEV1/FVC normal (or increased) Decreased TLC spirometry > - by A can't be measured Decreased lung volumes 6  Restrictive Lung Disease - Causes Causes of Restrictive Lung Disease Interstitial lung diseases Miscellaneous causes Pleural diseases Space occuping Idiopathic pulmonary fibrosis Obesity Pleural effusion > - mass Sarcoidosis Pregnancy Fibrothorax Collagen vascular disease Ascites Pneumothorax Pneumoconiosis Paralyzed diaphragm Chest wall diseases outward Elateral Drug-induced lung disease Lung resection Kyphoscoliosis - curvature of the spine Infiltrative lung diseases Ankylosing spondylitis Granulomatosis Neuromuscular disease Tumor Image modified from: Carreon, Megan L., et al. "Evaluation of Respiratory Function." DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition Eds. Joseph T. DiPiro, et al. McGraw Hill, 2023, https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=267239492. 7 Interstitial Lung Disease (ILD) Over 180 different disorders Occupational & environmental ILDs – Pneumoconiosis – inhalation of inorganic dusts and particulate matter – Hypersensitivity pneumonitis – inhalation of organic dusts and associated antigens Sarcoidosis – granulomas, inflammation in alveoli Idiopathic pulmonary fibrosis Drug-induced interstitial lung diseases 8 Interstitial Lung Disease Accumulation of inflammatory & immune cells Diffuse lung fibrosis Increased lung elastic recoil Decreased lung compliance Decreased lung volumes Impaired oxygen diffusion Impaired gas exchange 9 ILD – Signs/Symptoms Dyspnea SOB > - Tachypnea Prespiration > - rate ↓ Tidal Wave Non-productive cough Clubbing of fingers and toes Eventual cyanosis 10 Interstitial Lung Disease - Treatment Goals of therapy – Remove offending agent – Suppress inflammatory response – Prevent or slow progression of disease – Provide supportive care Treatment varies depending on type of ILD Drug therapy may include – Corticosteroids – Immunosuppressants – Anti-fibrotic therapies Supplemental O2 Lung transplantation 11 Idiopathic Pulmonary Fibrosis (IPF) Uncommon disorder 18/100,000 people in the US Most often presents between the ages of 50 and 70 No known cause present Major risk factors – Tobacco smoke exposure, occupational / environmental exposures, chronic viral infections, genetic factors Mean survival 2.5 to 5 years from diagnosis 12 IPF – Treatment Supportive care – Supplemental Oxygen – Pulmonary Rehabilitation – Vaccinations Medications – slow progression, possible mortality benefit – Pirfenidone – Nintedanib Clinical trials Lung transplant 13 Drug-Induced Interstitial Lung Disease (DIILD) Exact frequency of drug induced respiratory diseases unknown Large number of drugs associated with DIILD Risk factors may include age, dose, concomitant drugs Mechanism not fully understood Parenteral and oral route most common 14  Drugs Associated with Drug- Induced ILDs Chemotherapeutic agents – Bleomycin, cyclophosphamide, methotrexate Antimicrobial agents – Amphotericin B, nitrofurantoin Biologic agents – traztuzumab, alemtuzumab, cetuximab Cardiovascular agents – amiodarone, statins, flecainide Others – Gold salts, phenytoin, carbamazepine 15 Drug-Induced Interstitial Lung Disease - Treatment Withdrawal of medication Supportive care – Oxygen Appropriate immunizations Corticosteroids (in some cases) 16 Obesity and Lung Function Fat deposition in the chest wall, abdomen, and upper airway reduces lung volumes Reduction in respiratory system compliance FRC, ERV decreased TLC, VC decreased Obesity increases risk of obstructive sleep apnea, asthma, DVT/pulmonary embolism 17 Pulmonary Embolism 18 Pulmonary Embolism (PE) Blood borne substance lodges in a pulmonary artery branch Obstructs blood flow Causes – Thrombus – Air – Fat – Amniotic fluid 19 DVT/PE - Epidemiology Up to 900,000 may be affected by DVT/PE annually in the US 60,000 – 100,000 deaths due to VTE – 10-30% die within one month of diagnosis – First symptom is sudden death in ~25% of individuals with a PE About 33% with DVT/PE will have recurrence within 10 years https://www.cdc.gov/ncbddd/dvt/data.html 20 Venous Thromboembolism Venous Thromboembolism (VTE) – Deep vein thrombosis (DVT) and pulmonary embolism (PE) Clot forms in venous circulatory system Embolus travels to lung Obstruction of blood flow V/Q mismatch 21 Venous Circulation >95% of pulmonary thromboemboli come from thrombi that occur in lower extremity deep veins Upper extremity DVTs much less common 22 Hemostasis Overview of hemostasis Hemostasis – process of blood clot formation at the site of vessel injury Dont e – Maintains integrity of the circulatory system after vessel damage memorize Disruption in process -> abnormal bleeding or thrombosis Hemostatic clots -> localized to blood vessel wall, no significant impairment of blood flow Pathologic clots -> blood flow impairment and vessel occlusion 23 Pulmonary Embolism – Respiratory Effects (and beyond) ventilation & impaired gas exchange Possible pulmonary infarction Decreased PaO2, Decreased PaCO2 Decreased oxygen delivery to vital organs Circulatory collapse and death Image source: https://www.cdc.gov/ncbddd/dvt/facts.html 24 Pulmonary Embolism – Signs and Symptoms Shortness of breath Chest pain Tachypnea Tachycardia Possible symptoms of DVT – Leg swelling, pain, warmth, redness 25 Risk Factors – Virchow’s triad Blood Stasis Vascular Injury Hypercoagulability 26  Venous Thromboembolism – Risk Factors Older Age History of VTE Blood stasis Surgery Acute medical Illness requiring hospitalization Paralysis Immobility Obesity Image modified from Witt, Daniel M., et al. "Venous Thromboembolism." DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition Eds. Joseph T. DiPiro, et al. McGraw Hill, 2023, https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=268553772. 27  Venous Thromboembolism – Risk Factors Vascular Injury Major orthopedic surgery Trauma Indwelling venous catheters Hypercoagulability Malignancy Pregnancy / Postpartum Medications (estrogens, selective estrogen receptor modulators, others) Inherited coagulation disorders (Factor V Leiden, Protein C and S deficiencies, antithrombin III deficiency) Image modified from Witt, Daniel M., et al. "Venous Thromboembolism." DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition Eds. Joseph T. DiPiro, et al. McGraw Hill, 2023, https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=268553772. 28 Pulmonary Embolism - Diagnosis Computed tomography pulmonary angiography (CTPA) Ventilation / Perfusion scan (V/Q scan) D-Dimer Compression ultrasound - DVT Image Source: Cardiothoracic Imaging, Elsayes KM, Oldham SA. Introduction to Diagnostic Radiology; 2015. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=1562&sectionid= 95876454&jumpsectionid=95876588 29 Goals of treatment Prevent clot progression Prevent pulmonary embolism (from DVT) Reduce risk of recurrent VTE Prevent complications: – Post-thrombotic syndrome – Chronic thromboembolic pulmonary hypertension Prevent death 30 Pulmonary Embolism - Treatment Mainstay of VTE treatment - Anticoagulation Unfractionated Heparin (UFH) – Typically given IV Low Molecular Weight Heparins (LMWH) > - Do not require lab monitoring of their anticoagulant activity – Enoxaparin, dalteparin Anticoagulant – – Subcutaneous prevents or delays Fondaparinux blood coagulation – Subcutaneous 31 Pulmonary Embolism - Treatment Mainstay of VTE treatment - Anticoagulation Oral Anticoagulants: Warfarin Requires > - testing lab called INR Direct oral anticoagulants – Dabigatran, rivaroxaban, apixaban, edoxaban *Pharmacist involvement* 32 Pulmonary Embolism - Treatment Alternative treatments – Thrombolytic agents Alteplase – Embolectomy Thrombolytic – dissolves existing clots 33 Pulmonary Embolism - Prevention Prophylaxis in appropriate situations – Some surgical populations – Acutely ill hospitalized medical patients at increased risk of thrombosis – Long distance travelers at increased risk of VTE Options for VTE prevention – Early / frequent ambulation – Graduated Compression Stockings – Intermittent Pneumatic Compression – Medications Image Source: https://www.uptodate.com/contents/image?imageKey=PULM%2F102817&topicKey=PULM%2F1346&source=outline_link&search=vte%20prophylaxis&selectedTitle=1~150 34 Thank you for your attention! 35 Lecture 2.5 Cancer Statistics Fan Zhang Ph.D. Assistant Professor, Department of Pharmaceutics Member: UF Cancer Center Lecture Overview Lecture2.5 Cancer Statistics Lecture2.6 Cell Growth and Dysregulation Lecture2.7 Tumor Characteristics Lecture2.8 Cancer Metastasis Lecture2.9 Cancer Diagnosis and Treatment Lecture2.10 Lung Cancer 2 Lecture 2.5 Cancer Statistics Objectives Understand the basic terminology of cancer statistics; Describe the current cancer status and future trend; Interpret data, chart, figures related to cancer statistics 3 Cancer: Incidence and Mortality New Cancer Cases, 2024 New Cancer Death, 2024 in the United States in the United States Lung & Breast Bronchus Other Other Incidence (rate): Number of new Colon& Prostate rectum cases of a specific type/site (per 100,000) in a specific population in a Lung & Pancreas Bronchus particular year. Colon Breast US: ~2.0 million new rectum cases in 2024. (1.6 million in 2016) Number of deaths: 611,720 (2024) Mortality (rate): Number of cancer related Cause of death rank: 2 death in a year (per 100,000). 18.1 million cancer survivors (as of US: ~611,720 total cancer death in 2024 2022) (~600,00 in 2016) Source: https://www.cancer.org/; https://seer.cancer.gov/statfacts/html/common.html; 4 https://www.cdc.gov/nchs/fastats/cancer.htm#print; Cancer Incidence: Male vs. Female 5 Cancer Survival Trend 6 Source: CA Cancer J Clin. 2022;1–32 Cancer Survival Trend Five-year survival rate: the percentage of people who are alive five years after being diagnosed with cancer. 7 Cancer Survival Trend From 2018-2022, 16/19 most common cancers in men and 16/21 most common cancers in women showed statistically significant decreases in death rates. 8 Source: https://seer.cancer.gov/statfacts/html/common.html;  Study Guide 1. Which type of cancers has the highest incidence in men and women in the US, respectively? Graphs Adapted from Center for Disease Control, “An Update on Cancer in the United States” 2. Which type of cancer is responsible for the most deaths in the US (it is also the deadliest type of cancer for both man and women)? 9 https://www.cdc.gov/cancer/dcpc/research/update-on-cancer-deaths/index.htm Lecture 2.6 Cell Growth Regulation and Dysregulation Fan Zhang Ph.D. Assistant Professor, Department of Pharmaceutics Member: UF Cancer Center Objectives Describe key features of cell cycle regulation in a normal cell Know the major cancer risk factors (Genetic, Biological, Physical and Chemical) and describe how they contribute to tumor formation 2 Cancer: uncontrolled proliferation of transformed self cells in the body Initiators Promoters Benign Tumor (Genetic, Biological, Normal Tumor Chemical, Physical) cell in cell in original original tissue Transformation Promotion tissue Malignant Tumor cells Tumor in secondary (Cancer) Metastasis tissues Loss of Functions Screening for hereditary cancers ? Diagnosis Intervention 3  Cell Proliferation : Cell Cycle Regulation G2 Checkpoint: M Checkpoint: 1. DNA integrity All sister chromatids 2. Complete DNA correctly attached to Nuclear & replication Cytoplasmic spindle microtubules division Pause and wait for completion If Not G1 Checkpoint: - Cell size large enough - Enough energy & nutrients - Damage-free DNA - Arrest DNA - Mitotic signal (growth factors) - Complete DNA Protein Replication Replication synthesis If Not - Repair damage Wait for favorable growth conditions If irreparable: apoptosis 4 Cyclin & CDK: Key Cell Cycle Regulators Cyclins: are synthesized only in specific phase in response to mitogenic stimuli CDKs (Cyclin-dependent kinase): are inactive and present at constant levels in a cell. Cyclin:CDK dimer renders CDK active Active CDK then phosphorylates target proteins to control cell cycle entry and progression. Cyclin:CDK complexes drive cell cycle progression. 5 Cell Growth and Differentiation: Tumor Formation Stem cells 6 Overview: Turning a normal cell into a tumor cell Initiators Promoters Benign Tumor (Genetic, Biological, Normal Tumor Chemical, Physical) cell in cell in original original tissue Transformation Promotion tissue Malignant Tumor cells Tumor in secondary (Cancer) Metastasis tissues Loss of Functions Screening for hereditary cancers ? Diagnosis Intervention 7 Genetic Risk Factors Proto-Oncogenes: Normal genes, when mutated, become * Gain of oncogenes that promote abnormal growth and - function mutation tumor formation Tumor Suppressor Genes: Genes involved in preventing cells with damaged DNA from proliferating. Loss-of-function > - * Loss of function mutation for tumor mutation or deletion of the genes result in suppressor gene abnormal cell growth and tumor formation. 8  Proto-oncogene: RAS First isolated from a rat sarcoma caused by a virus. Encodes a small G protein that drives downstream signaling pathways used by growth factors to initiate cell growth and differentiation. RAS becomes activated following growth factor binding to its receptor under normal conditions. Certain Mutations in RAS gene render RAS protein constitutively active (always in “On” state). Cell continue to grow in the absence of growth factors. Normal ras (not oncogenic) vs mutated ras (oncogenic) Mutated RAS genes are found in 30% of human tumors and highly prevalent in pancreatic (90%), colorectal (50%), and lung cancers (40%) and certain leukemias (30%). Anti-RAS inhibitors are still being actively developed as potential anti- cancer drugs. 9 Tumor Suppressor Gene: Rb – Part I Rb: Retinoblastoma protein In A Normal Cell -- Rb regulates cell cycle transition from G1 to S phase in response to mitogenic stimuli (growth factors) via its association with E2F. -- Rb is a cytosolic protein and is in a hypophosphorylated state. -- Hypophosphorylated Rb remains bound to transcription factor E2F. -- In response to growth factors, Cyclin D ( & E) synthesis is increased; Cyclin:CDK complex is formed; CDK becomes active and starts phosphorylate Rb. -- Hyperphosphorylated Rb dissociates from E2F, allowing free E2F to enter the nucleus and acts as a transcription factor. initiated transcriptional activity -- E2F initiated transcriptional activity is required for transition For for transition from G1 to S phase. from G1 to S phase. Tumor Suppressor Gene: Rb – Part 2 In a cell with DNA damage ATP ADP -- Damaged DNA is detected by ATM dimer. -- DNA-bound ATM dimer self phosphorylates becomes active kinase. -- ATM phosphorylates p53 which is bound to MDM2, leading to release of p53. -- p53 initiated transcriptional activity leads to the production of protein p21. -- p21 inhibits the kinase activity of cyclin:CDK complex Cell cycle arrest -- Rb phosphorylation is inhibited No transition from G1 to S -- The cell with damaged DNA will not transition from G1 to S so cell cycle is This mechanism prevents a cell with damaged DNA from dividing and (survival) arrested unless damage is later repaired. Tumor Suppressor Gene: Rb – Part 3 Rb and Cancer Rb is a tumor suppressor gene because its normal function is to prevent cells with damaged DNA from dividing, hence preventing tumor formation. Rb gene mutation (loss of function) or gene deletion will result in a loss of DNA damage-sensitive control over transcription factor E2F, allowing cells with DNA damage to continue to divide. In addition, growth factor-controlled E2F release is also lost so cell growth no longer depends on growth factors. Rb mutations or gene deletions have also been frequently detected in retinoblastoma and cancers of bladder, breast, lung and bone, as well as leukemia, and melanomas. 12 Tumor Suppressor Gene: p53 – Part 1 P53 protein: Guardian of the Genome Coordinating cellular response to DNA damage; Coordinating cellular response to stress Determining the fate of a cell under stress or with DNA damage 13 Tumor Suppressor Gene: p53 – Part 2 14 Tumor Suppressor Gene: p53 – Part 3 P53 protein and Cancer Mutated P53 genes (loss-of-function mutations) are found in >50% of human tumors Li-Fraumeni syndrome: a very rare autosomal dominant disorder (500 families worldwide); individuals who inherit one copy of mutated P53 develop multiple types of cancer at a young age, including breast cancer, osteosarcoma and soft tissue sarcoma, brain tumors and leukemia. 15 Viral Risk Factor: Human Papillomavirus (HPV):Part 1 ~120 types of HPV (a DNA virus), ~40 types are sexually transmitted. Repeated infections by high-risk HPV such HPV-16 and HPV-18 cause a variety of cancers including cervical cancer. 60-70% attributed to HPV 16/18. HPV-associated cancers (genital and oral): ~20,000 cases in women and ~12,000 cases in men each year in the US. 12,000 cervical cancer with 4,000 mortality each year. Diagnosis: PAP smear to screen for cervical intraepithelial neoplasia (CIN). Benign CIN may progress to CIS and then to squamous cell carcinoma (over 3-40 yrs). Repeated HPV infections promote the transformation. Prevention: HPV vaccines: protect against cervical and other genital cancers and genital warts (Gardasil, HPV-6, 11, 16, 18). 16 HPV– Part 2: E7 protein HPV Following infection of a host cell, HPV produces a number of early and late stage proteins. HPV protein E7 is a ‘jailbreaker’ The infected cell therefore moves HPV protein E7 forward along cell cycle and divides ”steals” Rb from in the absence of growth factor and E2F to free up E2F. even if its DNA is damaged Transcription to allow cell enter S phase 17 HPV– Part 3: E6 protein P53 : HPV protein E6 forms a complex with Regulate G1/S cell E6- associated protein (E6AP) cycle with Rb; E6:E6AP heterodimer (active ubiquitin Promote DNA ligase) targets p53 for ubiquitination damage repair and proteosomal degradation. Promote cell death HPV protein E6 kills the gatekeeper p53 Without p53, an infected cell with DNA damage or under stress will moves forward along cell cycle and divides, hence promoting tumor formation 18  Cancer Risk Factors: Radiation UV and ionizing radiation (x ray and gamma ray) can induce DNA damage. Examples of DNA Damage Caused by Radiant Energy If not properly repaired, cells with damaged can continue to divide resulting in tumor formation. This is especially true when proper control mechanisms are not functional such as in the case of Rb and p53 mutation, as well as HPV infection. 19 Cancer Risk Factors: Carcinogens Chemical carcinogens form covalent adducts with DNA. If not removed by repairing systems, miscoding of gene sequences occur, leading to loss of function. Some agents such as alkylating agents are directly reactive. Some agents are not directly active and undergo cytochrome P450- mediated biotransformation to generate an active metabolite. – Aflatoxin B1, a fungal toxin found in contaminated food such as peanuts and corn; – Benzo(a)pyrene, a polycyclic aromatic hydrocarbons found in smoked meat and tobacco smoke. Metabolites of both bind to bases and intercalate into DNA, leading to the formation of an inactive proteins; Similar to radiation-induced mutations, if not properly repaired, cells with damaged can continue to divide resulting in tumor formation. 20 Study Guide 1. How does a CDK become an active protein kinase to drive cell cycle forward? 2. What happens to cell proliferation when proto-oncogene RAS becomes an oncogene? 3. How do p53 and Rb work together to prevent a cell with DNA damage from moving forward in cell cycle to proliferate and produce daughter cells? 4. How does the HPV virus “double whammy” instigate its “jailbreaking” and “gatekeeper killing” acts to promote cancer formation? 21 Lecture 2.7 Tumor Characteristics Fan Zhang Ph.D. Assistant Professor, Department of Pharmaceutics Member: UF Cancer Center Objectives Know the major difference between benign and malignant tumors Describe key features of cancer cell characteristics compared to a normal cell 2 Overview: Turning a normal cell into a tumor cell Initiators Promoters Benign Tumor (Genetic, Biological, Normal Tumor Chemical, Physical) cell in cell in original original tissue Transformation Promotion tissue Malignant Tumor cells in Tumor secondary (Cancer) Metastasis tissues Loss of Functions Screening for hereditary cancers ? Diagnosis Intervention 3 Cell Growth and Differentiation: Tumor Formation Stem cells 4 Tumor vs. Cancer Benign Tumor Slow and limited overgrowth, Cells well differentiated and resemble cells in tissue of origin, Does not invade surrounding tissues, Localized growth Malignant tumor (Cancer): Rapid and uncontrollable growth, Cells much less differentiated or very different from cells in tissue of origin (more like their progenitor cells), Invades surrounding tissues, Metastasizes to distal organs to form metastases 5 Tumor Types 6 Begin to Malignant ‘Transformation’ Benign tumor turning malignant Started as benign tumors; can progress to malignant tumors. “Mucinous cystadenoma”, a form of benign cystic tumors of the pancreas, if left untreated by surgery, often evolves into malignant invasive pancreatic cancer. Pre-malignant tumor: Having high tendency to become malignant tumors. “Colon polyp”---50% of people over age 60 have ≥ 1 polyp. Polyps have a higher chance of becoming cancerous. Risk doubles with family history of colon cancer. “Actinic keratosis” --- very common in fair skinned individuals; UV damaged skins may develop into squamous cell carcinomas. 7  Impact of tumors on normal functions Benign Tumor Generally not life threatening. Exception: brain tumors such glioma; Pressure on tissues, blood vessels and nerves: interfering with normal functions; Affect normal functions of the tissues: e.g. prolactinoma of the pituitary gland causes overproduction of prolactin. Malignant tumor (Cancer): Life threatening; Invade surrounding tissues, cause tissue damage and affects the normal function of the organ of origin; Compressing blood vessels and outgrowing blood supply causing ischemia and tissue injury; Secreting pro-inflammatory and toxic substances causing inflammation and tissue damage; Metastasize to distal organ(s) to induce additional and more extensive damage. 8  Cancer Cell Characteristics---1 Morphologic/histologic: Abnormal size/shape of cells and/or nuclei; abnormal number of chromosomes; More cells in mitosis in tumors than in normal tissues -> Highly Proliferative; Poorly differentiated; little resemblance to cells in the fully differentiated cells in the “host” tissue; more like embryonic cells; Histologic grading based on degree of differentiation and number of proliferating cells. 9  Cancer Cell Characteristics---2 Functional: 1. Genetic abnormality: chromosome abnormalities (number and structure), point mutations, addition, deletion; 2. Alterations in growth factor dependence: Proliferation without the presence of growth factors (e.g., breast epithelial cells and estrogen); Autocrine production of growth factors; Inappropriate activation of proliferation pathway due to altered growth factor receptors and/or signaling pathways 10  Cancer Cell Characteristics---3 Functional: 3. Altered cell-cell and cell-environment interactions: Change in surface expression of receptors/proteins that mediate normal cell-cell and cell-environment interactions; Loss of normal cell-cell contact inhibition -- continue to grow; In tumor mass, reduced ability to adhere to sister cells in a tissue -- surface tumor cells easier to dislodge to promote metastasis; Ability to survive without contact with matrix or other cells; As a “free” tumor cells, increased ability to adhere to matrix proteins, endothelium, and/or platelets --- enhance ability to invade and metastasize 11 Cancer Cell Characteristics---4 4. Increased life span: Normal cells undergo shortening of telomere at the end of chromosome during each division. Once the telomere shortens to a threshold length, cells can no longer divide. Tumor cells have high levels of telomerase that add a TTAGGG sequence to telomere to keep its length after each division, hence making tumor cells immortal. 5. Acquired ability to invade surrounding tissues: Produce and secrete enzymes to digest matrix proteins; Produce factors to cause changes in the arrangement of cytoskeletal proteins and cell shape for mobility and migration; 6. Different surface antigen profiles: Tumor cells may express tumor associated antigens (TAAs) that are different from neighboring cells in the tissue. They may serve as markers for tumors. May also risk being recognized and destroyed by host immune cells. (Presenting surface antigens only found on immature cells =tumor cells) 12 Cancer Cell Characteristics---5 7. Ability to induce angiogenesis (formation of new blood vessels): Solid tumors < 1-2 mm3 in size are not vascularized. Once a tumor reaches the size of 2 mm3, O2 and nutrients can not reach the cells in the center of the tumor mass. Hypoxia in the center triggers angiogenesis by activating HIFs (hypoxia inducing factors) which in turn induces the expression of genes for angiogenesis factors such as VEGFs that stimulate endothelial cell proliferation and migration to form new vasculatures. 13 Study Guide 1. How does a benign tumor differ from a malignant tumor (i.e., cancer)? 2. What are the seven function characteristics of cancer cells? 14 Lecture 2.8 Cancer Metastasis Fan Zhang Ph.D. Assistant Professor, Department of Pharmaceutics Member: UF Cancer Center Overview: Turning a normal cell into a tumor cell Initiators Promoters Benign Tumor (Genetic, Biological, Normal Tumor Chemical, Physical) cell in cell in original original Tumor tissue Transformation Promotion tissue Malignant cells in Tumor secondary (Cancer) Metastasis tissues Loss of Functions Screening for hereditary cancers ? Diagnosis Intervention 2 Objectives Know the main routes of cancer metastasis Describe the major steps of the metastasis process and the key features of each step 3 Cancer Metastasis: Overview Metastasis is a complex and multi- stage process ~ 85% of cancer-related mortality is a result of metastasis; Cancers spread through the blood or lymphatic systems; Cancer Metastasis: Intravasation Detachment from primary tumor mass though rearranging surface adhesion molecule (CAM) pattern to reduce cell-cell contact. Adhesion to basement membrane through increased surface expression of certain CAMs for basement membrane proteins. Locally degrade basement membrane proteins through the secretion of proteinases. Tumor cells secrete factors to induce retraction of endothelial cell lining and actively move through the gap to gain access to the blood stream 5  Cancer Metastasis: Survival in the blood stream and Arrest Most of the cancer cells that enter the blood stream will be eliminated by body’s immune cells Survival through evasion: Cancer cells can induce platelet aggregation to form a thrombus to evade immune surveillance. Arrest: Thrombosis also allows cancer cells to work against the flow of the blood stream to “settle down” and spread over endothelium ensuring a full stop for extravasation. 6 Cancer Metastasis: Extravasation Cancer cells induce endothelial cell retraction, produce proteases to digest subendothelial matrix (SEM) proteins, and migrate into the sub- endothelial space. Cancer cells establish a new core of tumor cells and induce angiogenesis to form new blood vessels to supply oxygen and nutrients for the expanding secondary tumor (metastasis). Angiogenesis is driven by various soluble factors (cytokines and growth factors) secreted by tumor cells. 7 Cancer Metastasis: Site Preference? Potential factors influencing site(s) of metastasis Route of travel: Lymphatic or vasculature drainage Local environment suitability: availability of specific growth factors, cytokines that facilitate secondary tumor growth Common site(s) of metastasis of primary solid cancers Lung cancer: brain and bones Colon cancer: liver Prostate cancer: bones Breast cancer: bones, lungs, liver, brain 8 Cancer Metastasis: Site Preference? Identification of a metastatic tumor Histological: Resemblance to the cells in the tissue of origin Immunological: antigenic profile More advanced genome > - testing Timeline Metastatic cancers may be detected before or after the discovery of primary tumor Occasionally, a metastatic cancer is detected and primary tumor can not be found. 9 Study Guide 1. Which circulating system(s) cancer cells may utilize to metastasize to distal organs? 2. What are the three steps of cancer metastasis? 3. What is the process of establishing new blood vessels by metastatic cancer cells called? 10 Lecture 2.9 Cancer Diagnosis and Treatment Fan Zhang Ph.D. Assistant Professor, Department of Pharmaceutics Member: UF Cancer Center Overview: Turning a normal cell into a tumor cell Initiators Promoters Benign Tumor (Genetic, Biological, Normal Tumor Chemical, Physical) cell in cell in original original tissue Transformation Promotion tissue Malignant Tumor cells Tumor in secondary (Cancer) Metastasis tissues Loss of Functions Screening for hereditary cancers ? Diagnosis Intervention 2 Objectives Describe how tumor is graded and how cancer is staged Know the principle of chemotherapeutic drugs and immunotherapies 3 Diagnosis Imaging: presence, size Example: mammograms; PET; MRI… Cytologic and histologic: Tumor grading Examples: Pap smear Genetic: Mutations Examples: PCR, DNA arrays; Single Cell Sequencing 4  Tumor Grading To determine morphological abnormality compared to normal tissue； To predict how quickly a tumor will grow and how likely it will spread； 1. Histologic Grade: degree of morphological resemblance to normal cells in the same tissue 2. Nuclear Grade: size/shape of nuclei, and percent of cells in mitosis Grade X: Undetermined Grade I: Closely resemble well differentiated normal cells; slow growth, least aggressive Grade II: Moderately differentiated Grade III: Poorly differentiated, tend to grow rapidly and spread Grade IV: Closest to progenitor cells (undifferentiated), rapid growth and high tendency to spread 5 Cancer Staging To determine the overall severity of cancer To provide intervention guidelines Factors to be considered: Tumor grade Size and number Presence in regional lymph nodes Presence in distal organs/tissues 6 TNM system Cancer Staging System - I T---The extent of the primary tumor TX: Can not be evaluated T0: No evidence of primary tumor Tis/Cis: Tumor in situ/Carcinoma is situ---Cancerous cells found, no sign of invasion into surrounding tissue, maybe preinvasive cancer T1-T4: increasing size and extent of invasion of the primary tumor 7 TNM system Cancer Staging System - II N---Presence in regional lymph Nodes NX: Can not be evaluated. N0: No evidence of tumor in regional lymph nodes N1-N3: Presence of tumor in regional lymph nodes M---Presence of metastases in distal organs/tissues MX: Can not be evaluated M0: No evidence of distance metastases M1: Distance metastases detected 8 TNM system Cancer Staging System - III Stage 0-----------Carcinoma In Situ (CIS) Stage I, II, III----Tumor size (primary) , tumor grade (primary), has spread to neighboring lymph nodes and/or organ Stage IV---------Has spread to distal organ(s) Not all tumors are staged using the same scales. Example: T3N0M0 is stage II for bladder cancer, but is stage III for colon cancer. Not all types of tumors use the TNM staging system.  Brain/spinal cord tumor--Staged based on cell type and grade  Most blood/bone marrow cancers (leukemia)--No clear cut staging  Lymphoma--Ann Arbor staging system 9 Intervention Standard of Care Surgery Radiation Drugs-------------Pharmacist a. Anti-proliferative agents (Chemo) b. Targeted Therapy c. Cancer Immunotherapy 10 Chemo Drugs: Examples Alkylating agents (cisplatin): form covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups of proteins and nucleic acids. Anti-metabolites