- Tx: Albuterol ± Ipratropium. And a short burst of oral steroids, usually 40-60mg Prednisone 3-10 days o Continue supplemental oxygen, SABA via nebulizer or MDI. Monitor vital signs

- Discharge: Upon discharge, all patients should be on an ICS, educated on triggers, and review inhaler technique o If not previous prescribe ICS à Initiate ICS o If previously prescribed ICS à Step up therapy for 2 or more weeks!

- Adjuvant Therapy: o IV Magnesium Sulfate: Moderate bronchodilator, promotes smooth muscle relaxation and CNS

depression. AE: Hypotension o Heliox: Mixture of Helium and Oxygen, helps clear obstructive symptoms

(10/30) Wilken Lecture: Chronic Obstructive Pulmonary Disease Chronic Obstructive Pulmonary Disorder (COPD) “Airflow limitation that is not fully reversible”

- Epidemiology: Affects 5% of US, it is the 3rd leading cause of death and 2nd leading cause of disability - Risk Factors of COPD

o Modifiable: Tobacco Smoke, occupational dusts, indoor/outdoor air pollution o Non-modifiable: Asthma (13x more likely), Underdeveloped lungs, infection, genetic predisposition

§ Infection: Hx of Tuberculosis, Bronchitis, Pneumonia can all increase the risk of COPD § Genetic: a1-Antitrypsin Deficiency (AAT) – Can be diagnosed by a quick blood test

- Phenotype: Chronically obstructed, as proven by Spirometry o Emphysema: characterized by destruction and enlargement of the lung alveoli (Dx: CT Scan of lungs) o Chronic Bronchitis: chronic cough and phlegm o Small Airways Disease: Bronchioles are narrowed. This is also known as Fibrosis

- Sx: Chronic Cough, Progressive Shortness of breath, Sputum Production, Dyspnea - Dx: Asthma and COPD are over-diagnosed because they are not properly evaluated. Spirometry is essential

o Inflammatory Markers: Neutrophils (major) and Eosinophils § Eosinophils are more common in Asthma

o Physical Changes: Fibrosis (small airways), Alveolar Wall Destruction, Mucus Hypersecretion o Spirometry Evaluation: Provides GOLD Grade Scores based on lung function.

§ FEV1/FVC < 70% = OBSTRUCTED! à COPD - Assessing COPD Patients: Reassess COPD patients at each visit

o (1) Spirometry to diagnose severity and airflow limitation (GOLD Grade) o (2) Determine Exacerbation (flare-up) risk

§ # of exacerbations in past 12 months § # of COPD-related hospitalizations past 12 months

o (3) Use COPD Assessment Test (CAT) Scale (8 item list, 0-40) § If CAT ³ 10, à Then these are high level symptoms

COPD Health Priorities: Stop smoking, get vaccinates, and move them legs - Goals: Reduce the associated risks and reduce the symptoms - Smoking Cessation

o Lung Health Study: Landmark trial that demonstrated the importance of getting people to quit smoking. Cessation leads to 18% reduction in all cause mortality. It is the only long-term intervention to affect long-term decline in FEV1, it slows the progression of COPD and helps decrease the risk of pneumonia

o Tx: There are nicotine and non-nicotine therapies § Nicotine Replacement Therapy (NRT): Patches, gum, nasal spray, inhaler, lozenges § Non-Nicotine: Bupropion, Varenicline (Chantix)

- Immunizations: o Influenza: Highly recommended, it greatly reduces the risk of serious illness and death. Given annually

intramuscularly October-March o Pneumovax-23 (Pneumococcal Polysaccharide Vaccine): All smokers should receive this vaccine

§ Smokers have 5x higher risk of pneumonia. Provides protection against 85% invasive strains § 65yo+ à Get Prevnar13 then 12 months later get Pneumovax23 § 65yo

- Pulmonary Rehab: Exercise and Strength training, Education, Adequate Nutrition

o Encourage patients to go out and meet people. Helps with exercise and depression, hell yea

COPD Tx Options - Short-Acting Bronchodilators: Treats Exacerbations and Reduces Sx Includes SABA and SAMA

o Short-Acting b2-Agonist (SABA): Albuterol, Levalbuterol o Short-Acting Muscarinic Antagonists (SAMA): Ipratropium MDI (Atrovent) and Nebulizing Solution

§ The efferent vagus nerve as sympathetic and parasympathetic fibers, synapses on smooth muscle, has M2 and M3 receptors for G-protein signal transduction pathways

• M2: Cardio – If you hit this one – systemic side effects (Albuterol giving tachycardia) • M3: Pulmonary- Congrats you found the right one

§ Ipratropium is non-selective, poking M2 and M3, blocking ACh and NE release • Hitting M3: Helps open the airway. The efficacy is relative to the bronchiole diameter

§ AE: Dry mouth, urinary retention, tachycardia, increased cardiovascular events • If you have bad aim and spray the face – anticholinergic effect à blurry vision

o Combination Therapy: Combivent, Duoneb (Both are Albuterol + Ipratropium) § Combo improves FEV1 better than either agent alone – and it improves adherence

- Long-Acting Bronchodilators: Reduce Risks and Reduce Sx Includes LABA and LAMA o Between LABA and LAMA, most experts would prefer LAMA, though there are exceptions (BPH) o Long-Acting b2-Agonists (LABA): Salmeterol, Formoterol, Arfomoterol, Indacaterol, Olodaterol

§ SMART Trial: Cannot use LABA as monotherapy, this is true for asthma BUT NOT COPD § Salmeterol (Serevent): Most common. § Olodaterol (Striverdi) and Indacaterol (Arcapta): ULTRA-long acting, dose only once daily! § AE: QT interval prolongation, Hypokalemia, Tremors, Tachycardia

• Black Box Warning: Increased risk of asthma-related deaths § Efficacy: Reduce risk, Reduce Sx

o Long-Acting Muscarinic Antagonists (LAMA): Tiotropium, Aclidinium, Umeclidinium, Glycopyrrolate § UPLIFT Trial: Tiotropium does not slow down the rate of decline in FEV1, but it does decrease

the number of exacerbations and is associated with a reduction in cardiac AE § Tiotropium is the GOLD Standard. Glycopyrrolate is making a comeback, its pretty nice § AE: Dry mouth, blurred vision, constipation § Efficacy: Reduce risk, Reduce Sx § ContraX: Narrow-angle glaucoma, Prostatic hyperplasia, bladder-neck obstruction, poor renal

o Combination Therapy: These bad boys are all just starting to come out: Anoro, Stiolto, Utibron, Bevespi - Monotherapy Inhaled Corticosteroids (ICS): Fluticasone, Budesonide

o TORCH Trial: Landmark, multinational COPD study § à DO NOT USE ICS ALONE IN COPD – Increased mortality risk AND risk of pneumonia § à Combination ICS+LABA did not reach clinical significance in mortality reduction § à Combination ICS+LABA did show significance in exacerbation reduction

o Pneumonia Risk Factors: Current smoker, prior exacerbations or pneumonia, BMI

§ à Again failed to prove clinical significance in mortality or exacerbation risk with ICS+LABA § à Again showed ICS+LABA increases risk of pneumonia § à Verified that LABA+LAMA is preferred prior to adding on ICS to therapy

o Drugs: Budesonide/Formoterol (Symbicort): 2 inhalations BID § Fluticasone Propionate/Salmeterol (Advair): 1 inhalation BID (Diskus and HFA) § Fluticasone Furoate/Vilanterol (Breo): 1 inhalation daily

o Indication: Asthma+COPD, Eosinophil Count of CBC >150, Repeated Exacerbations or 1 hospitalization o MoA: Addition of corticosteroid upregulates b2 receptor

- Triple Therapy: LAMA+LABA+ICS - Recently Approved: Fluticasone+Umeclindium+Vilanterol (Ellipta) o Indication: Approved for patients on multiple inhalers for severe category D individuals o Efficacy: Improved FEV1 (compared to ICS+LABA), Improve QoL, 35% reduction of moderate/severe

exacerbations!. Reduces risk, reduces symptoms - PDE4 Inhibitors: Oral medication: Roflumilast (Daliresp)

o Indication: Add-on therapy for severe (Group D) COPD, frequent exacerbation+ chronic cough+ sputum § Not indicated for individuals with Emphysema**

o MoA: Anti-inflammatory action through inhibition/blocking of neutrophil, CD8+, and macrophage PDE o Dosing: 500mcg PO Qdaily o AE: 14% discontinuation rate, likely due to the D (11%), N (5%), HA (4.6%) and CYP3A4 ADRs!

§ Caution: Potent medication, must monitor patients with: Cancer, depression, Immunosuppression, and latent infections (may activate TB)

o ContraX: Moderate to severe hepatic impairment (Child-Pugh Class B or C) [Monitor LFTs] - Macrolides: Azithromycin –When you have no idea what else to do and would be satisfied by minor improvement

o Indication: Qualify- (1) Severe COPD w/ many exacerbations, (2) Adherent to meds, (3) Don’t smoke o MoA: Antibacterial and anti-inflammatory properties “inhibit” IL-1, IL-6, IL-8, TNFa to reduce mucus

and sputum production, impair neutrophil migration into the interstitial space, inhibit ROS production, and inhibit breakdown of neutrophils. S P E C U L A T E D

o Unreferenced 1 year study: People developed hearing loss and bacterial resistance. (Monitor them) o Efficacy: Umm…. ‘reduce’… risk of….e…exa….. exacerbations?

- ICS Withdrawal (as a treatment): o WISDOM Trial: Huuuge study examining ICS withdrawal in Gold Grade 3-4 COPD pt w/ exacerbations

§ Why do this? ICS has AE, pneumonia, osteoporosis… and we know the inflammation relevant to COPD is neutrophil driven (largely), so how about we quit the ICS and improve their lives?

§ à Loss of Lung function (FEV1) went down MORE in the Withdrawal group L Pharmacotherapy Model: Doctors are at the mercy of what is covered by their patient’s insurance

- Selection base: Patient response, convenience to the patient, cost to the patient - Perform trials: ideally (bit of a fantasy) we want a 1-2 week course before evaluating efficacy (likely 1-2 months) - Monitoring: Scheduled query frequency

o Every time: ASK THEM HELLA, smoking status, sx, adherence, efficacy, AE o Quarterly: COPD Assessment Test (CAT) o Annually: Lung Function Test

- Critical Components: Smoking cessation is the most important, Muscarinic Antags are the mainstay COPD tx - Education: COPD is a chronic, gradual, debilitating disease state that is preventable

Acute COPD Exacerbation – Managed in ambulatory or hospital settings - Definition: When a patient experiences two to four exacerbations annually.

o Rates: 10% of those hospitalized will die, 50% will revisit the hospital within 6 months

- Sx: SoB, Thick yellow sputum, wheezing, chest tightness, fever - Cx: Viral is the most common, usually grandkids à grandparents

o Air pollution, bacterial, and potentially just unknown - Before treating, must rule out: Pneumonia (X-Ray), CHF, Pneumothorax

(hole in lungs), Pleural effusion, pulmonary embolism, arrhythmia - Tx:

o Home Management: Intensify bronchodilator (albuterol, ipratropium), add oral corticosteroids ,consider antibiotics, refer to the hospital if experiencing worsening signs or sx

o Steroid Burst: Prednisone 40mg Qdaily x5days (reduces relapse rates and improves spirometry) § It is best to minimize the burst of prednisone, due to the AE

§ AE: HPA Suppression, Osteoporosis, fractures, sodium and water retention, hypokalemia o Consider Antibiotics: Reserved for pt with: 3 cardinal sx –OR- patient requires mechanical ventilation

§ Requires Sx: (1) Increased dyspnea, (2) Increased sputum, (3) Increased sputum purulence § Efficacy: Studies show it lowers morality, hospitalization, and mechanical ventilation rates

o Supplemental Oxygen: These patients are losing their ability to breath. Chronic compensation to elevated CO2 may result in difficulty to treat – do not supply hypoxemic patients O2 too quickly – it may suppress their breathing

o LTOT: Helps decrease pulmonary artery pressure, reversing secondary polycythemia § Indication: PaO2 < 55mmHg, or SaO2 < 88%. § Dosing: 2L/min, 18-24 hours a day, with a goal of PaO2 > 60mmHg or SaO2 > 90% § Efficacy: Prolongs survival and improves exercise tolerance and QOL! Improves memory

(11/3) Orjala Lecture: Medicinal Chemistry of Immunomodulatory Medications Immunosuppressant use: Transplant rejection prophylaxis and the treatment of autoimmune disorders

- Before the transplant: Induction therapy: Help block T cell activation to avoid rejection of the graft - And throughout the life of the transplanted organ: requires incessant use - Problem: These drugs have narrow therapeutic indexes, as well has significant individual variability

Timeline - The first successful Kidney transplant was in 1954 by Joseph Murray

on identical twins (Nobel Prize) - Late 50s-60s: Steroids and Azathioprine recognized as effective

immunosuppressants - Cyclosporine changed transplant surgery from research to a life-saving

treatment option in 1980s Molecular Targets

- Signal 1: TCR Stimulation o Native: Stimulation results in calcineurin activation, thereby dephosphorylates/activates NFAT-P, and

NFAT acts as a transcription factor (TF) and binds to the IL-2 gene promoter inducing IL-2 production and IL-2 related activities (proliferation of T Cells + other immune activation)

o Drug Therapy: Calcineurin inhibitors – Cyclosporine (CSA) and Tacrolimus (TAC) aka FK506 - Signal 2: Co-stimulatory Signaling

o Native: Costimulation is necessary to optimize T cell IL-2 gene transcription, in fact, without it, TCR signaling will simply result in T cell anergy. Thus, Co-stimulation is require for full activation and inhibition of apoptosis

o Drug Therapy: Selective Co-stimulation blocker – Belatacept - Signal 3: IL-2 Receptor Signaling

o Native: IL-2 binds to the IL-2 receptor of the T cell, producing a cascade of second messenger signals that ultimately result in cell cycle modulation

o Drug Therapy: IL-2 Receptor Antibodies – Sirolimus § Cell Cycle Inhibitors (Cytostatic): Mycophenolic Mofetil, Azathioprine

TRIAL Parameters SIGNIFICANCE/Results SMART* LABA vs Placebo Asthma: Do not use LABA alone AUSTRI LABA+ICS vs ICS Asthma: LABA+ICS ³ ICS SNS LABA vs SABA Asthma: LABA < SABA if w/o ICS TORCH* LABA vs ICS vs Placebo COPD: Do not use ICS alone (pneumoniaÝ) SUMMIT LABA vs ICS vs LABA+ICS vs Placebo COPD: LABA+LAMA > LABA+ICS UPLIFT Tiotropium and FEV1 studies COPD: Tiotropium reduced exacerbations and

cardiac events, but doesn’t slow FEV1 WISDOM Withdraw ICS in GOLD grade 3-4 COPD: FEV1 goes down with ICS withdraw REDUCED (JAMA 2013) Short-burst roids in acute exacerbation COPD: Higher dose roids unnecessary