Asthma & COPD Management (Part 1) - MA 2025 - PDF

ONGROUND HYBRID In-Class Patient Thursday, 1/16, at 8:30 AM Friday, 1/17, at 8:30 AM Cases (5 points part Cases will be released by Wednesday. of assignment 1 Participate for the whole duration with accurate response rate of >90% (total 10 points)) f...

ONGROUND HYBRID In-Class Patient Thursday, 1/16, at 8:30 AM Friday, 1/17, at 8:30 AM Cases (5 points part Cases will be released by Wednesday. of assignment 1 Participate for the whole duration with accurate response rate of >90% (total 10 points)) for >90% of the questions to receive full credit.  Pharmacology of Asthma and COPD Management Part 1 Maha Abdalla, PharmD, PhD, RPh Associate Professor of Pharmaceutical Sciences Email: [email protected] Office Room#276 Phone: (865)288-5837 *Office Hours: Tuesday & Thursday 9 am - 12 pm or by appointment 2  Big Picture: Asthma **Which Beta Blockers are an option in an angina patient with asthma/COPD/emphysema? Why? **Which Beta Blockers are an option in a HFrEF patient WITH asthma/COPD/emphysema? Asthma - pathogenesis Management: Treatment guidelines : bronchodilators and anti-inflammatory https://ginasthma.org/2024-report/ Part 1: Bronchodilators 1. β2-adrenergic receptor agonists: Non-selective: Epinephrine, isoproterenol – see supplementary information and iMCPI notes. Short-acting (SABA): Albuterol, levalbuterol, terbutaline (Brethine), metaproterenol Long-acting (LABA): Salmeterol (Serevent), formoterol, vilanterol Combination agents: (e.g. Advair, Symbicort, Breo Ellipta, Trelegy Ellipta) 2. Muscarinic Antagonists: Short-acting (SAMA): Ipratropium (Atrovent; Combivent (combination)) Long-acting (LAMA): Tiotropium (Spiriva) 3. Methylxanthines: Theophylline (Theo-Dur; Elixophyllin), aminophylline (Norphyl; Phyllocontin), dyphylline Part 2: Anti-inflammatory agents 1. Corticosteroids: Inhaled (ICS): Fluticasone (Flovent vs. Arnuity), Beclomethasone (Qvar), budesonide (Pulmicort), ciclesonide (Alvesco), flunisolide (Aerobid), mometasone (Asmanex), triamcinolone Combination: budesonide/formoterol (Symbicort), mometasone/formoterol (Dulera), fluticasone/salmeterol (Advair), fluticasone furoate/vilanterol (Breo Ellipta), Systemic CS: Dexamethasone (DexPak), prednisone (Daltasone), methylprednisolone (Medrol), prednisolone 2. Leukotriene antagonists: Montelukast (Singulair), zileuton (Zyflo), zafirlukast (Accolate) 3. IgE antibody: Omalizumab (Xolair) 4. Interleukin Antagonist: Reslizumab (Cinqair), mepolizumab (Nucala), benralizumab (Fasenra), Dupixent (dupilumab) 5. Cromolyns: Cromolyn sodium, neodocromil sodium 3  Add this slide to key “NTK for Life” material – Refer to iMCPI PreFinal Exam Review Study guide for “NTK Common Lists” update it as you go through the curriculum and with any changes in the guidelines. RxPrep Book is an excellent resource. BBs in patients with Which BBs to USE in a patient with asthma/COPD/emphysema HFrEF Which BB to AVOID? WHY? (list them by subgroups based on selectivity and indication) HFrEF AND Bronchospasm conditions (asthma/ COPD/emphysema, etc) 4 Identify the Structure SAR and additional info: See slides 23-24 adjust per our class discussion Which agent(s) is/are a catecholamine: _______ a non-catecholamine _________ Which agent(s) is/are β2 selective:_________ long duration of action and used BID:________ longest duration of action and used once daily:_______ 1 2 Epinephrine Salmeterol 2 2 1 1 Albuterol Vilanterol 5  Combination Agents: (Top 300) **NTK Brand Names listed below Indication (Asthma, **Brand Active ingredients Adverse Unique COPD, or name** effects both) SABA SAMA Combivent Indication **Brand Active ingredients (Asthma, Adverse Unique COPD, or name** effects both) LABA ICS LAMA Fluticasone *Advair Salmeterol Propionate Fluticasone *Breo Ellipta Vilanterol Furoate *Anoro Ellipta Vilanterol Umeclidinium *Trelegy Fluticasone Vilanterol Umeclidinium Ellipta Furoate 6 Different Study Approaches: Common vs Unique – tailor and adjust the table as you see fit. Unique aspects Below are sample examples of what to write in each section. β2-Agonists MOA: Act as an ______ at β2-adrenergic receptors. This leads to ______ SABA Albuterol (ProAir HFA, Proventil HFA, etc.), Drugs/Indication (main role?) Other: Terbutaline (Box warning), metaproterenol all drugs w/n that LABA Asthma or COPD: Salmeterol, formoterol, vilanterol class or subclass (main role?) COPD Only: Indacaterol, olodaterol Common AE Common AEs/Precautions/ Serious AE/ Boxed warning Precautions Boxed Warning BB agents ______ Explain the interaction. How to avoid it in a patient with HF and COPD Common: DDI/CI QT prolonging agents _____ Unique aspects what differentiates each drug from the other in that class or subclass (e.g. place in therapy, indication, structure, MOA, PK (longest and shortest (OOA, DOA, and/or half-life), metabolism), adverse effects, DDIs, CI, monitoring parameters, patient counseling, etc) Unique aspects Unique Terbutaline Once daily dosing Indication COPD ONLY agents are: __________ Combination 7 Different Study Approaches: Common vs Unique – tailor and adjust the table as you see fit. Unique aspects Below are sample examples of what to write in each section. Muscarinic Antagonists MOA: _______ M3 receptors. This leads to________________ SAMA Ipratropium Drugs/Indication all drugs w/n that Tiotropium class or subclass LAMA COPD Only: Aclidinium, Umeclidinium, Glycopyrrolate (inhaled formulation) Common Common AE AEs/Precautions/ Serious AE/ Boxed warning Precautions Boxed Warning DDI/CI etc. Unique aspects what differentiates each drug from the other in that class or subclass (e.g. place in therapy, indication, structure, MOA, PK (longest and shortest (OOA, DOA, and/or half-life), metabolism), adverse effects, DDIs, CI, monitoring parameters, patient counseling, etc) Unique aspects Glycopyrrolate Combination: Unique +Formoterol Once daily dosing Combination: test yourself on agents listed in each combo (MOA, AEs, unique counseling, etc) Umeclidinium + vilanterol (Anoro Ellipta) + vilanterol + fluticasone Furoate (Trelegy Ellipta) Indication COPD ONLY agents are: __________ 8 Different Study Approaches: Common vs Unique – tailor and adjust the table as you see fit. Unique aspects Below are sample examples of what to write in each section. Inhaled (ICS) General MOA/Purpose: Drugs Fluticasone (Furoate vs Propionate), all drugs w/n that class Beclomethasone, budesonide, mometasone or subclass Other: ciclesonide, flunisolide, triamcinolone Common Common AE AEs/Precautions/ Serious AE/ Boxed warning Precautions Boxed Warning DDI/CI etc. Unique aspects what differentiates each drug from the other in that class or subclass (e.g. place in therapy, indication, structure, MOA, PK (longest and shortest (OOA, DOA, and/or half-life), metabolism), adverse effects, DDIs, CI, monitoring parameters, patient counseling, etc) Unique aspects Unique Furoate: agents/unique aspects Fluticasone Propionate: agents/unique aspects Mometasone 9  Big Picture: Asthma & COPD Parts 1-3: other agents Drugs per class (separate Unique ( MOA, adverse effects, DDI, pertinent PK, Class Indication by subclass) CI, place in therapy, boxed warning, etc.) Theophylline, Methylxanthines aminophylline Leukotriene Montelukast Antagonists Leukotriene Synthesis Inhibitor Zileuton (5-LOX): Selective LT Montelukast (Singulair), receptor Zafirlukast Inhibitors: IgE antibody Omalizumab (Xolair) Interleukin Antagonist IL-5 Antagonist Reslizumab, Mepolizumab Benralizumab - IL-5 Receptor Antagonist Other: Dupilumab - Inhibitor of Il-4 and IL13 signaling PDE4 inhibitor: Roflumilast Cromolyns 10  Overall Lecture Objectives: Asthma & COPD 1. Describe the underlying pathophysiology of asthma / COPD 1. Explain the biosynthesis of leukotrienes and their role in asthma 2. Describe the biosynthesis and metabolism for corticosteroids 2. For each drug class: β2-adrenergic receptor agonists (SABA and LABA), muscarinic antagonists (SAMA and LAMA), methylxanthines, corticosteroids, and leukotriene antagonists, interleukin Antagonists, etc. 1. Using the information below, be able to explain the “why” and “how” a drug is effective, adverse events that may occur, and possible drug interactions. 1. Drugs in the class, key structural differences, mechanism of action, Pharmacokinetic aspects (t1/2, metabolism, etc.), side /adverse effects, contraindications, and mechanisms of drug interactions and outcomes of such interactions 2. List the drug combinations most commonly used and describe why these drug combinations are more effective than either of the compounds alone 3. Application of concepts using patient cases 11  Asthma Asthma is a chronic inflammatory airway/lung disease characterized by recurring episodes of wheezing, shortness of breath (SOB), coughing, and chest tightness. Affects approximately 25 million people in the U.S.A Asthma-related deaths: Asthma is one of the leading causes of preventable death Per the CDC, approx. 10 people die from asthma each day Mortality (2021) Child 18 yo: 3,372 Economic Burden: More than $56 billion in medical cost each year https://www.cdc.gov/asthma/most_recent_national_asthma_data.htm 12 Primer Asthma Triggers Risk Factors Allergens Endogenous Factors mold, pollen, dust mites, or pet dander Genetic predisposition Upper respiratory tract viral infections Atopy Airway hyper-responsiveness Exercise and hyperventilation Gender Cold air or sudden changes in temperature Ethnicity? Environmental Factors Drugs Indoor allergens β blockers, aspirin, NSAIDs Outdoor allergens If aspirin is required, a patient may undergo aspirin desensitization Occupational sensitizers Stress Passive smoking Irritants Respiratory infections cigarette smoke, air pollution, chemicals, dust, aerosol sprays, paint Obesity? fumes, gases such as sulfur dioxide Early viral infections? (harmful gas emitted by power plants, diesel engines, etc.) 13 Primer Asthma Pathogenesis Definition: hyper-responsiveness to stimuli that produce reversible bronchospasms resulting in airway obstruction and airway inflammation Biphasic asthma response: Biphasic reduction in pulmonary function The immediate response: early, acute phase reaction Mast cells and basophils undergo degranulation to release histamine, prostaglandin, and leukotrienes. These mediators cause SM contraction and bronchoconstriction (symptoms: shortness of breath, wheezing, and coughing) The late phase reaction occurs several hours after the initial reaction Infiltration of the airway by eosinophils and other cytokine-secreting leukocytes, This causes excessive and persistent inflammation and lead to structural changes that result in airway remodeling. Outcome: Acute Delayed Bronchoconstriction bronchosconstriction bronchosconstriction Mucus hyper-secretion Remodeling of lung tissue Sub-epithelial fibrosis, epithelial shedding, airway smooth muscle hypertrophy and hyperplasia, angiogenesis 14 Primer Mediators and Bronchial Obstruction see supplementary section for more information Asthma Inflammation Tissue remodeling Hyper-responsiveness of the airways Untreated or not appropriately managed (medication misuse), the airways in an asthmatic patient becomes: Chronically inflamed Thickened and narrowed via persistent tissue remodeling Hyper-responsive to triggers or stimuli Over-constriction (severe bronchoconstriction) 15  Pharmacological Management of Asthma Asthma Inflammation Tissue remodeling Hyper-responsiveness Anti-inflammatory Bronchodilators Bronchodilators Inhaled corticosteroid (rescue/reversal) (maintenance/prevention) Inhaled cromolyn Na Inhaled nedocromil Na Examples: Examples: Oral corticosteroids Inhaled short-acting Inhaled long-acting β2- Oral leukotriene β2-adrenergic agonists adrenergic agonists antagonists (SABA) (LABA) Anti-IgE-specific immunotherapy Inhaled long acting Anti-IL-5 specific muscarinic antagonists immunotherapy (LAMA) 16  GINA 2019 landmark changes in asthma management GINA: 2018 Global strategy for asthma GINA: 2019 Global strategy for asthma management and prevention management and prevention https://ginasthma.org/wp-content/uploads/2019/04/GINA-2019-main-Pocket-Guide-wms.pdf ginasthma.org/2018-gina-report-global- strategy-for-asthma-management-and- For safety, GINA no longer recommends SABA-only treatment for Step 1 prevention/ GINA now recommends that all adults and adolescents with asthma should receive symptom-driven or regular low dose ICS-containing controller treatment, to reduce the risk of serious exacerbations NAEPP: 2007 National Asthma Education Prevention Program Guidelines for the Diagnosis and Management of Asthma (EPR-3). National Heart, Lung and Blood Institute. www.nhlbi.nih.gov/health-topics/guidelines- for-diagnosis-management-of-asthma 17 NAEPP: 2020 focused update to the Asthma Management Guidelines - National Asthma Education and Prevention Program GINA 2024 https://ginasthma.org/2024-report/ GINA 2020, Box 3-4A https://www.nhlbi.nih.gov/health-topics/all-publications-and- resources/2020-focused-updates-asthma-management-guidelines © Global Initiative for Asthma, www.ginasthma.org  Bronchodilators 1. β2-adrenergic receptor Agonists: Non-selective: Epinephrine, isoproterenol - see supplementary information Short-acting (SABA): Albuterol (Proventil; Ventolin; ProAir HFA ), levalbuterol, Terbutaline (Brethine), metaproterenol Long-acting (LABA): Salmeterol Formoterol Vilanterol Combination agents (e.g. Advair, Symbicort, Breo Ellipta, Trelegy Ellipta) 2. Muscarinic Antagonists: Ipratropium (Atrovent) Tiotropium (Spiriva) 3. Methylxanthines: Theophylline (Theo-Dur; Elixophyllin) Aminophylline (Norphyl; Phyllocontin) Dyphylline 19  Bronchodilators Reverse & Prevent Airway Hyper-responsiveness Figure 1. G-protein-coupled-receptor (GPCR)-mediated β2- Agonists M3-Antagonists signaling in the pulmonary artery smooth muscle cell (PASMC). GPCR activation promotes the exchange of the G-protein-bound GDP for GTP, thereby inducing a conformational change and dissociation of Ga from the Gbg and thus initiating downstream signaling. The Gbg subunits can directly activate phosphatidylinositol 3- kinase (PI3K) and phospholipase Cb (PLCb). PLCb, activation (by Gbg and Ga q) promotes the hydrolysis of β2AR M3 R phosphatidylinositol 4,5-bisphosphate and yields the intracellular messengers 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate. DAG remains membrane- bound and promotes the translocation of protein kinase C from the cytoplasm to the membrane and its subsequent activation. Ga12/13-dependent pathways (guanine nucleotide exchange factors for Rho activate the small G protein RhoA followed by Rho kinase) and Gai-dependent pathways (inhibition of adenylyl cyclase decreases cyclic AMP accumulation) lead to PASMC vasoconstriction and proliferation. In contrast Ga s stimulates the production of cyclic AMP via activation of adenylyl cyclase, which in turn decreases PASMC proliferation and enhances vasodilation. Reference: Murray F, Yuan J, and Insel PA. Receptor- Mediated Signal Transduction and Cell Signaling. Textbook of Pulmonary Vascular Disease. Chapter 14. 2011, pp 245-260 http://pvri.info/content/receptor- mediated-signal-transduction-and-cell-signaling- 0#.VMqIDkfF-So 20  β2 Adrenergic Receptor Agonists *Class Effect “Sympathomimetic” Agents: SABA and LABA Differ in formulation (oral, MDI, powder inhalations, nebulizer solution) Differ in potency accounted for in delivered “puff” *MOA in bronchial smooth muscle cell (SMC) 1. ↑ intracellular cAMP → ↓ Ca2+ → ↑ SM relaxation 2. Inhibition of inflammatory mediators and cytokine release from basophils, neutrophils, and mast cells Increased cAMP leads to decreased degranulation of mast cells 3. Indirectly ↑opening and conductance of K+ channels on the SM → membrane hyperpolarization *Outcome: Bronchodilation (relaxation) → o improve FEV1 (Forced Expiratory Volume) and PEF (Peak Expiratory Flow) ***Boxed Warning*** *Monotherapy with LABA agents increase the risk of asthma-related deaths. o The use of LABA inhalation powder without a concomitant long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. 21  β2 Adrenergic Receptor Agonists – *Class Effect Adverse effects: Common: Neuro: skeletal mm tremor, nervousness, weakness, headache. *CV: hypertension, palpitations, (β2 receptors also found in heart; β1 more predominant, affected at high doses) Resp: upper respiratory infection, rhinitis, cough GI: nausea, throat irritation, pharyngitis Endo: hypO (kalemia, magnesemia),– acute response to high doses *Tachyphylaxis (tolerance): prolonged treatment → loss of response (esp. with LABA) Serious: *CV: A. Fib, MI, QT prolongation, tachyarrhythmias Endo: hypERglycemia, diabetic ketoacidosis *Precautions – Pt Counseling Paradoxical bronchospasm, acute asthmatic crisis, and death Contributing factors: Excessive use or exposure to higher than recommended doses, new canister, unfamiliar with how to use new inhaler, failure to report exacerbations, uncontrolled comorbidities, etc. *DDI/CI (esp with LABA) **Pharmacological antagonism: β blockers (with either LABA or SABA) **QT prolongation o PK: Potent CYP 3A4 inhibitors (fluconazole, ketoconazole, clarithromycin, erythromycin) o PD: additive effect on QT interval (clozapine, citalopram, fluconazole, ketoconazole, levofloxacin, antiarrhythmic agents (class III, IA etc) Hypertensive crisis: in combination with MAOI, tricyclic antidepressants 22 β2 Agonists SARs N Substitution Phenylethanolamines R2 Substitution R3 Substitution 2  Adrenergic AGONISTS Adapted from iMCPI General points: Effect: enhance/augment NE-mediated adrenergic response such as ______________ (to varying degrees) Serious Adverse effects: Cardiac dysrhythmias General MOA: Direct acting agents act as an AGONIST at _______________ Receptors (degree of effect and AE is impacted by affinity for α & β receptors). Effect: enhance/augment adrenergic response such as ______________(to varying degrees) Direct Acting α1 Phenylephrine – Indication, MOA, AE vs α2 Clonidine – Indication, MOA/Effect, AE α&β Epinephrine (mimics endogenous)– Indication, MOA, PK, Structure (Catecholamine) β Isoproterenol – Indication, MOA β2 Asthma/COPD: agents, MOA, which one is a long-acting Beta2-Agonist? 24 Identify the Structure SAR and additional info: See slides 23-24 adjust per our class discussion Which agent(s) is/are a catecholamine: _______ a non-catecholamine _________ Which agent(s) is/are β2 selective:_________ long duration of action and used BID:________ longest duration of action and used once daily:_______ Epinephrine Salmeterol Albuterol Vilanterol 25 SABA *Albuterol *Short Acting β2-selective agonist (SABA) Epinephrine Prototypical SABA Indication: asthma, EIB, prophylaxis Effect: rapid relief of dyspnea associated with bronchoconstriction Formulation: MDI, oral, nebulized solution 2 1 Structure and stereochemistry: 1. Salicyl alcohol analog Albuterol 2. N t-butyl substituent Resistant to COMT &slow MAO metabolism Chiral βcarbon - Albuterol is a racemic form R- isomer; Levalbuterol is 4-fold more potent PK OOA: 5 – 15 mins, DOA: 4-8 hrs t1/2 = ~5 hrs Levalbuterol MDI: Metered dose inhaler; EIB: exercise-induced asthma 26 SABA Terbutaline Short Acting β2-selective agonist Indication: treatment and prophylaxis of asthma or bronchospasm associated with bronchitis and emphysema, off-label: Intrauterine fetal distress Formulation: Tablet (Brethine), SubQ (generic is available in both forms) Structure and stereochemistry: 2 1. Resorcinol analog of isoproterenol 1 2. t-butyl o Resistant to COMT & ↓MAO metabolism o 3-fold greater potency than metaproterenol PK o OOA~ 5-30 mins ; DOA ~ 3-4 hrs o t1/2 ~ 3 hrs (oral), 3-14 h (SQ) ***BOXED WARNING Terbutaline sulfate has not been approved and should not be used for prolonged tocolysis (beyond 48 to 72 hours). In particular, terbutaline sulfate should not be used for maintenance tocolysis in the outpatient or home setting. Serious adverse reactions, including death, have been reported after administration of terbutaline sulfate to pregnant women. In the mother, these adverse reactions include increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema and myocardial ischemia. Increased fetal heart rate and neonatal hypoglycemia may occur as a result of maternal administration. 27 SABA Metaproterenol Short Acting β2-selective Agonist Formulation: syrup (generic) 1 Structure and stereochemistry: 1. Resorcinol Resistant to COMT metabolism Sulfate formulation  quarternary amine Chiral β -carbon o *Least potent of all β2-selective agonist PK o OOA~ 5-30 mins ; DOA ~ 2-6 hrs 28 LABA *Salmeterol *Long Acting β2-selective agonist (LABA) Indication: Asthma, COPD, EIB, nocturnal asthma Formulation: inhalation disk Combination with ICS - Fluticasone Propionate (Advair) 2 1 Structure and stereochemistry: 1. Salicyl alcohol analog 2. N-phenyl butoxy hexyl substituent Higher potency and direct selectivity for β2-R o ~ 50X more selective for β2-R than albuterol Resistant to COMT & MAO metabolism PK OOA~ 15-30 mins (relatively slow); Long DOA (> 12 hrs) Peak bronchodilation: 1-2 hrs High protein binding (96%) Metabolism: hydroxylation via CYP 3A4 29 LABA *Formoterol *Long Acting β2-selective agonist (LABA) - BID Indication: Asthma, COPD Symbicort (Formoterol/Budesonide) PK OOA~ 5-10 mins; Long DOA (> 12 hrs) ; Peak bronchodilation ~ 30 mins Protein binding (31%-64%) *Metabolism: glucuronidation & O-demethylation via CYP2D6, 2C19,2C9, 2A6 t1/2 ~ 10 hrs (capsule), 7 hrs (solution) 2 1 *Vilanterol *Ultra-Long Acting β2-selective agonist (LABA) – once daily Vilanterol Indication: Asthma, COPD *Breo Ellipta (Vilanterol/Fluticasone Furoate) *Trelegy Ellipta (Vilanterol/Fluticasone Furoate/Umeclidinium) COPD only: *Anoro Ellipta (Vilanterol/ Umeclidinium) PK OOA~ 10-20 mins; **Long DOA (~24 hrs) ; Peak bronchodilation ~ 30 mins Protein binding: 94%; Bioavailability: 2-27% *Metabolism: CYP 3A4 , t1/2 ~ 11-24 hrs 30  Bronchodilators 1. β2-adrenergic receptor Agonists: Non-selective: Epinephrine, isoproterenol - see supplementary information Short-acting (SABA): Albuterol (Proventil; Ventolin; ProAir HFA ), levalbuterol, Terbutaline (Brethine), metaproterenol Long-acting (LABA): Salmeterol Formoterol Vilanterol Combination agents (e.g. Advair, Symbicort, Breo Ellipta, Trelegy Ellipta) 2. Muscarinic Antagonists: Ipratropium (Atrovent) Tiotropium (Spiriva) 3. Methylxanthines: Theophylline (Theo-Dur; Elixophyllin) Aminophylline (Norphyl; Phyllocontin) Dyphylline 31  Muscarinic Antagonists Agents: SAMA: Ipratropium (Atrovent) in combination with albuterol (Combivent) LAMA: Tiotropium (Spiriva); **Indication: Asthma, COPD Ipratropium: asthma (mod-severe) exacerbation Tiotropium: asthma – maintenance management Quarternary (+) amine Decreases systemic absorption *MOA: Inhibit M3 (Gαq) receptors in bronchial smooth muscle ↓ PLC activation and ↓ intracellular calcium Outcome: Bronchodilation *Adverse effects: *Common: xerostomia (dry mouth), bronchitis, abnormal taste (bitter), dry nasal mucosa, sinusitis *Serious: MI, anaphylaxis (hypersensitivity reaction), severe bronchospasm, death 32  Muscarinic Antagonists SAMA -Ipratropium (Atrovent) Analog of atropine Pharmacokinetics OOA ~ 15 mins *DOA ~ 4-6 hrs Protein binding: 0-9% Metabolism via ester hydrolysis *t1/2 = 2 hrs LAMA - Tiotropium (Spiriva) Analog of scopolamine More selectivity for M1 & M3 receptors High affinity and slow dissociation from M3 receptor OOA~ 15 mins *DOA ~ 24 hrs Protein binding: 72% *Metabolism: CYP 3A4 and 2D6 -DDIs *t1/2 = 5 days *Adverse effects: anticholinergic effects: urinary retention, paradoxical bronchospasm, angle-closure glaucoma, bowel obstruction 33  Bronchodilators 1. β2-adrenergic receptor Agonists: Non-selective: Epinephrine, isoproterenol - see supplementary information Short-acting (SABA): Albuterol (Proventil; Ventolin; ProAir HFA ), levalbuterol, Terbutaline (Brethine), metaproterenol Long-acting (LABA): Salmeterol Formoterol Vilanterol Combination agents (e.g. Advair, Symbicort, Breo Ellipta, Trelegy Ellipta) 2. Muscarinic Antagonists: Ipratropium (Atrovent) Tiotropium (Spiriva) 3. Methylxanthines: Theophylline (Theo-Dur; Elixophyllin) Aminophylline (Norphyl; Phyllocontin) Dyphylline 34  Methylxanthines Theobromine and caffeine (natural products found in coffee, tea, chocolate,) Drugs: Theophylline, aminophylline (a more soluble, inactive ester of theophylline) *MOA *Inhibit PDE (esp PDE4) → ↑ cAMP → bronchodilation Other effects: Anti-inflammatory: inhibit the release of inflammatory mediators from mast cells Reduces bronchial exudates CNS: cortical alertness / arousal *CV: increases the force and rate of heart contraction *Direct (+) inotropic and (+) chronotropic effects *Toxicity/Adverse effects *Narrow therapeutic index Common: N/V, headache, insomnia, tremor, irritability, restlessness *Serious: A.Fib, tachyarrhythmia, steven-johnson-syndrome, intra-cranial hemorrhage, seizure, death Signs of toxicity: Tachycardia, severe restlessness, agitation, and emesis, seizure Rapid administration of theophylline or aminophylline can result in sudden death 35  Theophylline Indication: Asthma, COPD Formulation: Oral: Theophylline: Oral tablet, elixir, Theophylline capsule, solution IV: Aminophylline PK: Peak~1-2 hrs, DOA ~ 5-16 hrs Protein binding: 40% Aminophylline *Hepatic metabolism: CYP3A4, 1A2, 2E1, 3A3 *DDI – risk of Theophylline toxicity: Metabolism and/or Elimination mediated: CYP 3A4 inhibition: Cimetidine, clarithromycin, erythromycin, ketoconazole, CYP 1A2 inhibition: Cipro, zileuton, zafirlukast, deferasirox Elimination: Levofloxacin, Ciprofloxacin, zileuton Salt forms of theophylline Careful calculations when switching from base to salt Aminophylline; ethylenediamine salt form Oxitriphylline; choline salt form Dyphylline A non-salt xanthine derivative of theophylline Decreased bronchodilator effects Reduced side effects compared to Theophylline 36  Top 200 Drugs Short-Acting Beta Agonist (SABA) Combination inhalers Albuterol (ProAir HFA, Proventil HFA, LABA/ICS/LAMA Ventolin HFA) Vilanterol/Fluticasone Furoate/Umeclidinium (Trelegy Ellipta) Short-Acting Muscarinic Antagonist (SAMA) SABA/SAMA Ipratropium (Atrovent) Albuterol/Ipratropium (Combivent) Long-Acting Muscarinic Antagonist (LAMA) LABA/ ICS Tiotropium (Spiriva, Spiriva Handihaler) Vilanterol/Fluticasone Furoate (Breo Ellipta) Inhaled Corticosteroids Salmeterol/Fluticasone Propionate (Advair Beclomethasone (Qvar) Diskus) Budesonide (Pulmicort) Formoterol/Budesonide (Symbicort) Fluticasone (Arnuity, Flovent) Leukotriene Receptor Antagonist Montelukast (Singulair) 37 Supplementary Information 38  Cellular Events in Asthma Inflammatory cell recruitment Release of inflammatory mediators Bronchoconstriction Vasodilation Mucus hypersecretion Plasma exudation / edema Nerve activation 39 Goodman & Gilman; 12th edition; F36-1  Asthma Pathogenesis: Cellular Events Exposure to inhaled allergens, such as pollen, dust mites, mold, or animal dander can initiate an acute immune response in allergen-sensitive individuals that leads to airway inflammation.. Persistent inflammation leads to allergen-induced asthma.. The asthmatic response is two phases. The early and late phase asthmatic responses are initiated by the recognition and processing of allergens by dendritic cells which drive naïve T cells to differentiate into T helper type 2 cells (Th2). Th2 lineage commitment is established by STAT6-dependent expression of GATA-3 which induces the expression of Th2 cytokines, including IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF (Induction phase; dark blue arrows). Together these cytokines direct the inflammatory response to allergens (light blue arrows). The hallmark Th2 cytokine, IL-4 promotes clonal expansion and, along with IL-13 and specific co-stimulatory molecules, induces B cells to produce allergen-specific IgE antibodies. IgE antibodies bind to the Fce RI high affinity receptors found on mast cells, basophils, neutrophils, and eosinophils. Upon allergen re-exposure, allergen binding to the IgE-Fce RI complexes on mast cells and basophils leads to receptor cross-linking which triggers the release of mediators that cause immediate hypersensitivity (Early phase asthmatic reaction; green arrow). Several hours later the late phase asthmatic reaction occurs. During this phase, Th2- and mast cell-derived cytokines stimulate eosinophil activation and leukocyte recruitment to the sites of allergen exposure (red arrow). The release of pro-inflammatory molecules at these sites by eosinophils, infiltrating basophils, neutrophils, and Th2 cells plays a critical role in promoting chronic inflammation and airway remodeling. 40 http://www.rndsystems.com/resources/images/6114.pdf 41 Slide title 42  Asthma Biological Targets for Pharmacological Treatment o Beta-adrenergic receptors o Muscarinic receptors o cAMP o Leukotrienes o IgE – mast cells o Inflammation 43  β2-adrenergic receptor activation Tissue distribution o Pulmonary (respiratory) smooth muscle o Uterine smooth muscle o Vascular smooth muscle Physiological effects o Smooth muscle relaxation Increase intracellular cAMP levels  MLCK-PO4 Bronchial dilation 44 45 Catecholamines 46 Biosynthesis of Epinephrine 47 Metabolism of Epinephrine & β-agonists 48 Phenyl ring substituents Formoterol 49  β2 Agonists Organize the following structures from shortest to longest duration of action (DOA). Explain why? A B C D 50 51 β2-adrenergic Agonists 52  Methylxanthines - metabolism Metabolic pathways C-8 oxidation N-demethylation Xanthine oxidase Safe for patients with gout 53 Muscarinic Antagonist Binding 54 Muscarinic Antagonists Atropine 55 Reminders 56  Adapted from “Intro to iMCPI” 5 Tips on Learning and Understanding Topics for Long-Term Success Improving patient outcomes is your number 1 priority 1. Be able to adapt – Pharmacy profession is constantly changing and constantly moving Observe and monitor changes in your performance You notice that you now struggle answering questions (homework, worksheets, class discussions, exams, etc.) despite using the same style of studying that worked in this course and/or in previous courses (in undergrad, pharmacy etc.) Be willing to learn, identify the root cause, and adjust you approach accordingly Once you observe that there is an issue, address it – the sooner the better. Meet with the faculty, bring your notes, discuss how you approached their material, identify the root cause, identify how to improve your study approach Constantly re-evaluate and adapt Do NOT get complacent. Each course brings new challenges, being able to adapt is a key skill to have. Avoid procrastination 2. Time management is essential Studying for iMCP3 should not overshadow other courses. If you devote all your time to iMCP3 and your academic performance in another class –regardless of its credit hour- is below passing, it will negatively impact your progression through the program. 3. Keep your study guides (electronic copy is preferred) Remember, as you go through the program, the curriculum builds on what you learn previously. Keep your study guides and tables, and add to them as you move through the curriculum For example, when you take Pharmacotherapy in P2 year, instead of having to re-learn all the pharmacology parameters of antibiotics or heart failure meds all over again (drug class, MOA, AEs, CI, DDIs, special consideration, boxed warning, etc), you just have brush up on your notes from iMCP and that will give you time to focus on learning the new parameters specific to pharmacotherapy and the appropriate use of medications to optimize patient care: (assessment, plan, evidence-based and guideline-driven recommendations, dosing regimen, dose adjustments, monitoring parameters, follow-up plan, patient counseling, etc.). 57  Adapted from “Intro to iMCPI” 5 Tips on Learning and Understanding Topics for Long-Term Success 4. Having a diverse toolkit of study resources to help you understand concepts helps increase your chances for success Learning antibiotics and oncology can be challenging because it requires diverse knowledge base and to be well- versed in various: physiology and pathophysiology concepts, diseases, drugs within and across drug classes and their unique facts and places in therapy, patient- and drug- specific factors, and the many exceptions to some “rules” 5. Rewrite the material in a way that you understand it and make your own study guides/tables/graphics Explain what you learn in class and explain the “how” and “why” of concepts to a family member or friend in a way that is accurate, and they understand it. Ultimately, you will be working with patients, who have different levels of education and different backgrounds - effective communication is essential. Don’t simply memorize slides. Remember each Faculty has their own teaching style, it’s up to you to rewrite the material in a way that you understand it (see item 3 in previous slide). Memorization is not the same as knowledge. Memorization may only help in the short term. Take the time to think out relationships in order to truly understand concepts. If a concept doesn’t make sense, try to research the answer using available resources, and do not hesitate to contact the Faculty who taught that concept. It’s best to contact the respective Faculty via email first to schedule an appointment, this will ensure that they set adequate time to discuss these points with you and fully address your concerns. 58  Adapted from “Intro to iMCPI” Resources 1. Canvas iMCP3 – Study Resources and Videos/Illustrations (duration range: approx. 1 – 8 min) 2. Online via South College Library: http://library.south.edu/ 1. SOP: http://library.south.edu/c.php?g=843137 1. Guidelines, AccessPharmacy, Micromedex, Lexicomp 2. For literature search: PubMed, Discover search (SC library) 3. Textbooks: Required Recommended RxPrep Course Basic & Clinical Foye’s Principles of Goodman & Pharmacogenomics: An Review of Organic Book for NAPLEX Pharmacology, 15th Medicinal Gilman’s Introduction and Functional Licensure Exam Ed. (2021) Chemistry, 8th Pharmacological Clinical Perspective Groups: Preparation by Katzung BG. Ed. (2019) Basis of (2013) by Joseph S. Introduction to Note: in P1/P2 year- Available on by Roche VF Therapeutics, 13th Bertino Jr, et al. Medicinal you may buy a used AccessPharmacy et al. Ed. (2018) by Available on Organic book released after Brunton LL, Lazo AccessPharmacy Chemistry, 5th 2020. In P3 year: you’ll JS, and Parker KL. Ed. (2012) have the latest released Available on by Lemke TL. book and online AccessPharmacy package. 59  Adapted from “Intro to iMCPI” Resources - Top Medications Top 300 Medications document available on Canvas iMCPI Course AccessPharmacy https://accesspharmacy.mhmedical.com/ Multimedia Study Tools Flashcards Review Questions 60