Asthma Rx 2023 (1) PDF

Asthma Jennifer Hofmann, MS, PA-C Pharmacology Objectives a. Describe the basic pathophysiology of asthma b. Summarize the classification of asthma and discuss the primary guidelines for treatment c. Discuss the goals of asthma pharmacotherapy. d. Distinguish medications indicated for immediate re...

Asthma Jennifer Hofmann, MS, PA-C Pharmacology Objectives a. Describe the basic pathophysiology of asthma b. Summarize the classification of asthma and discuss the primary guidelines for treatment c. Discuss the goals of asthma pharmacotherapy. d. Distinguish medications indicated for immediate relief from those indicated for long-term control and maintenance. e. Describe the various inhalation devices and explain/ education patients how to use them. Objectives a. Explain the mechanism of action, clinical use, routes of administration and adverse effects of the following medications: i. Short and long-acting beta-adrenergic agonists ii. Corticosteroids iii.Ipratropium and long acting anticholinergics iv.Leukotriene antagonists/modifiers v. Theophylline vi.Mast cell stabilizers vii.Roflumilast viii.Omalizumab ix.Biologic agents for asthma b. Describe the anti-inflammatory actions, indications, adverse effects and toxicities of corticosteroids. c. Discuss the types of steroids used as therapeutic agents for severe asthma and other inflammatory disorders. d. Explain the consequences of withdrawal of corticosteroids and chronic use of supraphysiologic doses of steroids. e. Discuss the basic mechanism of action, adverse effects, and clinical uses of antitussive agents. Asthma - background • Atopy – genetic susceptibility to produce IgE directed toward common environmental allergens • IgE causes mast cells and lymphocytes to become activated and sensitized when challenged by allergens  release inflammatory mediators – Eosinophils are activated, CD4+ cells, basophils, neutrophils and macrophages Pathophysiology of Asthma • Airflow obstruction with edema, bronchoconstriction, hypersecretion and INFLAMMATION • Acute inflammation  provoked by unknown or known factors such as viral infection, allergens and irritants Early and late responses of acute inflammation in asthma • Early phase – – Release of histamine and leukotrienes from mast cells cause bronchoconstriction and airway edema – Lasts 1 hour • Late phase – Cytokines released by inflammatory cells attract and recruit (eosinophils, basophils, neutrophils) and contribute to airway obstruction and inflammation – 4-8 hrs Asthma- Background info • Chronic inflammation – Eosinophils, T cells, mast cells, macrophages, epithelial cells, fibroblasts and smooth muscle cells – Clinical result is chronic airway hyperreactivity • Remodeling of airways with fibrotic tissue, increased smooth muscle leading to bronchospasm, and excessive mucus production caused by hypertrophy and hyperplasia of goblet cells – Loss of lung function if inflammatory process is not controlled with corticosteroids Asthma- background • Parasympathetic (vagal) provides normal resting airway tone – Maximum bronchoconstriction via vagal stimulation occurs in small bronchi not bronchioles • Catecholamines e.g. epinephrine cause bronchodilation via activation of Beta-2 receptors on bronchial smooth muscle  Treatment of asthma- aerosol delivery devices • Site specific to enhance therapeutic ratio • Devices – – – – Nebulizers (jet, ultrasonic) Metered dose inhalers (MDIs) Dry powder inhalers (DPIs) Soft mist inhalers (SMIIs) • Must deposit in lungs so particle size is important – Larger than 10mcg  oropharynx – Smaller than 0.5 are exhaled so ideal size is 0.55mcg Nebulizers • Jet nebulizers produce an aerosol from liquid in a cup connected to compressed O2- need to have flow rates > 6L/Minute for efficient delivery – Get most in first few minutes – May need to add saline and tap sides to get all drug • Ultrasonic nebulizer vibrates liquid above transducer but produces large particles – Less commonly used Nebulizer Metered Dose Inhaler • Most used, convenient • Drug in pressurized canister with metering valve; when actuator is pressed it releases a metered dose of drug and propellant • Must be shaken (primed also) and pressed when patient is INHALING • Optimal use delivers 10-40% of propelled dose – More for newer devices Spacers and MDIs • SPACER = Hollow chambered tube that allows more evaporation of propellant prior to inhalation better delivery – Best for pts. with poor coordination DPIs • DPIs are breath-actuated devices that deliver micronized drug particles • Drug delivered via inspiration / inhalation of air over a punctured capsule, blister, or reservoir DPIs DPIs • Several asthma medicines are now delivered in a dry powder inhaler. – Since the medicines are dry powder, they must be delivered in a special inhaler. – When you inhale fast enough the medicine is released. • The basic technique for using a dry powdered medication is: 1. Exhale 2. Put mouthpiece in your mouth 3. Breathe in Quickly https://www.nationaljewish.org/ conditions/medications/inhaledmedication-asthma-inhalercopd-inhaler/instructionalvideos Soft Mist Inhalers • Large than MDI, no propellant, twist lower half to prime and compress button to release dose • The SMI aerosol has a high fine particle fraction, a low velocity, and more sustained duration than a pMDI • SMI technology achieves a two-to-three fold higher pulmonary deposition than a pMDI • Used for COPD inhalers Goals of asthma treatment § Few asthma symptoms § No sleep disturbance § No exercise limitation Symptom control (e.g. ACT, ACQ) § Maintain normal lung function § Prevent flare-ups (exacerbations) § Prevent asthma deaths § Minimize medication side-effects (including OCS) Risk reduction § The patient’s goals may be different § Symptom control and risk may be discordant § Patients with few symptoms can still have severe exacerbations ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; OCS: oral corticosteroids © Global In GINA 2023 Box 3-2 © Global Initi Terminology n Reliever § n n For symptom relief, or before exercise or allergen exposure Controller § Function: targets both domains of asthma control (symptom control and future risk) § Mostly used for ICS-containing treatment Maintenance treatment § Frequency: regularly scheduled, e.g. twice daily ICS: inhaled corticosteroid; SABA: short-acting beta2-agonist GINA 2023 Box 3-4 © Global Initiative for Asthma, www.ginasthma.org Terminology n Anti-Inflammatory Reliever = AIR § e.g. ICS-formoterol, ICS-SABA § Provides rapid symptom relief, plus a small dose of ICS § Reduces the risk of exacerbations, compared with using a SABA reliever Regimens with ICS-formoterol anti-inflammatory reliever n As-needed-only ICS-formoterol = AIR-only § n Maintenance And Reliever Therapy with ICS-formoterol = MART § n The patient takes low-dose ICS-formoterol whenever needed for symptom relief A low dose of ICS-formoterol is used as the patient’s maintenance treatment, plus whenever needed for symptom relief ICS-formoterol can also be used before exercise or allergen exposure ICS: inhaled corticosteroid: SABA: short-acting beta2-agonist; MART is sometimes also called SMART © Global Initiative for Asthma, www.ginasthma.org GINA 2023 – Adults and adolescents Track 1 Maintenance and reliever therapy (MART) with ICS-formoterol As-needed-only ICS-formoterol (‘AIR-only’) *An anti-inflammatory reliever (AIR) Box 3-12 (2/4) Track 1 © Global Initiative for Asthma, www.ginasthma.org *Anti-inflammatory reliever (AIR) Box 3-12 © Global Initiative for Asthma, www.ginasthma.org Broad Overview of Classes of Medications • Beta-2 agonists – SABAs – LABAs • Glucocorticosteroids – Inhaled (ICS) – Systemic • Leukotriene blockers • Mast cell stabilizers • Methylxanthines (e.g. Theophylline) • Biologic agents – IgE – Others Medications for asthmaBeta2 agonists (inhaled) Short acting (fast relief) SABA – Names (generic) • Albuterol • Levalbuterol Pharmacology • Route: inhaled (MPD or Neb) • Immediate onset for acute bronchospasm < 5 minutes • 4-8 hours of bronchodilation B2 agonists are most effective bronchodilator available Long acting LABAs Names • Formoterol = fast-acting longlasting beta agonist (LABA), formoterol**preferred • Salmeterol • Vilanterol is ultra long acting an approved for use in patients with asthma. (24-hour duration) • Pharmacology – Inhaled – Onset 20 minutes so NOT for ACUTE attacks Class: Beta agonists – clinical aspects • Inhaled short acting (SABA) – – – – Intermittent episodes of bronchospasm (PRN use!) Acute bronchospasm DOES NOT improve control of asthma Can give via MDI or nebulizer • Inhaled long-acting beta agonists (LABA) – Formoterol plus Low dose ICS is preferred as a reliever and controller med – Long term control for patients with persistent asthma who are already on low or medium dose inhaled corticosteroids (preferred maintenance drugs) • Not used without anti-inflammatory meds ! – Good for nighttime symptoms – LABELING RE: RISKS associated with long-acting beta agonists Formoterol plus low dose inhaled corticosteroid (ICS) are preferred for both relief and control of asthma symptoms Class: LABAs- Warning • SMART Study and Practical Implications of LABAs • 7-month PB controlled observational study looking at salmeterol, vs PB + usual care in several thousand asthma pts. • Outcome – In salmeterol group slightly increased RR of respiratory-related death or respiratory-related lifethreatening experience – Implications: • FDA warning re: long-acting beta agonists with label changes LABA Warnings – NO monotherapy Other Beta Agonists • Name: Terbutaline – in emergencies only (parenteral) • Name: Isoproterenol (non selective)- not used – http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf • Names: Epinephrine (beta and alpha agonist) subcutaneously works quickly but has many systemic effects – – – – BP Heart rate Arrhythmias Rebound Class: Beta- 2 agonists: Adverse Effects • • • • • Heart rate Tremor Nervousness Hypokalemia Tolerance – Chronic use may lead to downregulation and decreased affinity for Beta receptors – Increased use signifies poor control – May reduce duration of bronchodilatory effects – Can be counteracted by administering steroids Class: Corticosteroids • Most effective anti-inflammatory agents for asthma (used as controller/maintenance daily) • Route: Inhaled is preferred method of delivery (ICS) • MOA: – Improves responsiveness to beta2 agonists – Delayed response in acute asthma (4-12 hours for systemic and longer for inhaled) – ICS improve in 1-2 weeks – Improvement of lung function (FEV1 and PEFs) by 36 weeks Class: Inhaled corticosteroids (ICS) • Preferred for daily maintenance therapy • Low, medium and high dose regimens depending on severity of asthma – Dosed BID sometimes once daily (mcg/ puff) – Names of some ICS • • • • • • • Budesonide is only ICS available for nebulization Beclomethasone Fluticasone propionate fluticasone furoate Mometasone Triamcinolone acetonide Ciclesonide Class: ICS- Adverse Effects • Oral candidiasis aka thrush(rinse and expectorate) • Dysphonia (hoarseness) • Reflex cough or bronchospasm • Other – Bone metabolism/ osteoporosis – Suppression of HPA function (higher doses and more with fluticasone) – Ocular effects – Altered glucose metabolism (at high ICS doses) – Linear growth suppression in children ** How to prescribe low-dose ICS-formoterol in GINA Track 1 Example: budesonide-formoterol 200/6 mcg [160/4.5 delivered dose] n Steps 1–2: take 1 inhalation whenever needed for symptoms n Step 3: take 1 inhalation twice a day (or once a day) PLUS 1 inhalation whenever needed for symptoms n Steps 4–5: take 2 inhalations twice a day PLUS 1 inhalation whenever needed for symptoms n As-needed doses of ICS-formoterol can also be taken before exercise (Lazarinis et al, Thorax 2014) or before allergen exposure (Duong et al, JACI 2007) See following slides for medications, doses, and maximum number of inhalations in any day for GINA Track 1 © Global Initiative for Asthma, www.ginasthma.org Class: Systemic Corticosteroids • Indications: – Nearly all patients with a significant asthma exacerbation (e.g., PEF <80 percent of personal best or predicted after initial inhaled beta-agonist) • Clinical: – A short course of glucocorticoids (eg, equivalent of prednisone 40 to 60 mg/day for five to seven days) – Low incidence of AE with short bursts – LONG TERM THERAPY HAS SIGNIFICANT AE (refer to GC lecture) Class: Systemic Corticosteroids • Clinical: Short burst therapy of systemic steroids (names: prednisone or methylprednisolone) may start with IV or po QID for 48 hours then reduce to 1-2 times/day and continue until patient achieves 70- 80% of PEF personal best or symptoms subside Class: Leukotriene Modifiers • Cysteinyl leukotriene (LT)receptor antagonists * • MOA: – Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor (see notes) • Name: – Montelukast – Singulair (most common) oral once daily • Indications: Used for maintenance of persistent asthma in addition/ alterative to ICS • Route of administration /pharmacology – Orally effective with few adverse effects – Liver metabolism and excreted in bile (feces) • Class: Leukotriene Modifiers • Clinical info: – Improve PFTS – Decrease nocturnal symptoms and B2 agonist use – Improve symptoms also in exercise and allergic rhinitis – Not as effective as ICS overall and variable events from patient to patient • AE/ warnings; – Well-tolerated – Boxed warning for Serious neuropsychiatric (NP) events and increased suicidality Class: long-acting muscarinicantagonist (LAMA) • Names: – Tiotropium (inhaled once daily) or – Triple agent dry powder inhaler, fluticasone furoate-umeclidinium-vilanterol (FF/UM/VI; once daily) • Role: – Add on maintenance therapy for adults with one or more asthma exacerbations in the past year despite use of a GC-LABA inhaler Class – Mast cell stabilizers • Names: Cromolyn Na and nedocromil • MOA; Mast cell stabilization (details in notes) • Route: MDIs and cromolyn available as a nebulizer solution – Short duration of action • AE: – nontoxic ! • Clinical applications: – Similar efficacy to LT antagonists – Trial 1- 3 mths to determine efficacy – Used as alternative to or in addition to ICS for mild to moderate persistent asthma Class: Methylxanthine Name: Theophylline • Class: methylxanthine • Name: Theophylline • MOA: – inhibits Phosphodiesterase enzyme – Other anti-inflammatory effects Name: Theophylline • Pharmacology: – Liver metabolism – Short half lives so give sustained release preps – 1–9-year-olds have highest clearance and require higher/kg dosing • : Narrow therapeutic window – Serum concentration 5-15MCG/ML – Monitor pts with serum levels • (esp if acute attack in ER) Name: Theophylline – drug interactions and AE/ toxicity • Many drug interactions – Cigarettes and alcohol (increase clearance of theophylline) – Phenytoin and barbiturates – Erythromycin and cimetidine • Adverse effects (> 20mcg/mL) – – – – – HA Palpitations and tachycardia Severe agitation Emesis Seizures Topic: Biologics for Asthma Class: Anti- IgE Therapy • Biologic for moderate to severe asthma with poor ICS control • Name: Omalizumab (Xolair) • • MOA: Anti IgE Monoclonal antibody (notes) Route: Subcutaneous injection dose based in IgE levels and weight (kg) – admin. Q 2-4 weeks • Indications: – – – Add on maintenance med for Adults and children > 6 yrs with moderate to severe asthma poorly controlled by ICS IgE levels Allergic sensitization demonstrated by positive skin testing or in vitro testing for allergenspecific IgE to an allergen that is present year-round ( Name: Omalizumab (Xolair) Adverse Effects • Adverse effects – Pain at injection – HA – URI – Rarely anaphylaxis • Monitor first 3 doses in office • Can self administer after 3 doses monitored in ofifice Class: Biologics Anti I-L therapies for Eosinophilic Asthma • Name: Mepolizumab= – MOA: monoclonal antibody to IL-5 – Indications reduces exacerbations in patients with severe asthma who have blood eosinophil counts of 150/microL or greater – Route (subcutaneous) • Name: Reslizumab – MOA: Reslizumab, a monoclonal anti-IL-5 antibody, – Indication: add-on, maintenance therapy of severe asthma in patients who are age 18 or older and have an eosinophilic phenotype – Route: (IV infusion every 4 weeks) • Name: : Benralizumab, – MOA: Interleukin-5 Receptor Antagonist, Monoclonal Antibody Inidcation: (add therapy for severe eosinophilic asthma) – Route: Subcutaneous Class: Biologics Anti-IL-4 • Name: Dupilumab • MOA: – Blocks effects of IL-4 reduces exacerbations, improves lung function, decrease need for oral GC • Route: – subcutaneous every other week • Role: – add for moderate-to-severe, eosinophilic asthma • AE: – injection site reactions – Eye symptoms (red eyes, blepharitis, dry eyes) – Treat underlying helminthic infections Class: Biologics for Severe Asthma • Name – Tezepelumab (Tezspire) • MOA – monoclonal antibody binds to epithelial cytokine human thymic stromal lymphopoietin (TSLP) blocking interaction with its receptors leading to many anti-inflammatory effects • Role: – Add-on maintenance treatment of severe asthma in adult and pediatric patients ≥12 years of age. • Pharm: – SUBQ: 210 mg once every 4 weeks • AE: – sore throat (pharyngitis) • joint pain (arthralgia) • back pain – Rare –hypersensitivity reactions Patients with parasitic especially helminthic infections should NOT use Biologics that affect eosinophils ! *Anti-inflammatory reliever (AIR) Box 3-12 © Global Initiative for Asthma, www.ginasthma.org Classifying and Managing Asthma • Severity – Impairment • Symptom frequency • Nighttime awakening • Use of SABA for control of sxs/week • Interference w/ normal activities • Lung function (FEV1 and FEV1/FVC – Risk of exacerbations requiring oral steroids • Control of asthma – How well asthma is controlled based on risk and impairment category – Determines changes in therapy (step up or down) • Well controlled • Not well controlled • Very poorly controlled Achieving Control in Newly Diagnosed Patients • Assess severity of asthma • Select tx that corresponds to asthma severity • F/U in 2-6 weeks and if not well-controlled, reassess and advance to next step • After tx is selected make additional therapeutic changes based on level of control (well, not well, poor) Step1 - Mild Intermittent Asthma • Dx: Infrequent asthma symptoms (eg, <2 times/week) • Tx: Low-dose ICS with rapid onset LABA (eg, budesonide-formoterol combination MDI 160 mcg-4.5 mcg/inhalation or DPI 200 mcg-6 mcg/inhalation) 1 inhalation, as needed (preferred) Step2 – Mild Persistent • Dx: Asthma symptoms or need for reliever inhaler ≥2 times/week • Tx: Low-dose ICS-formoterol as needed (preferred) – Or alternatively – Low-dose ICS daily and SABA as needed Step 3 Moderate Persistent Dx: Troublesome asthma symptoms most days, nocturnal awakening due to asthma ≥1 time/month, risk factors for exacerbations Tx: Low-dose ICS-formoterol as maintenance and reliever therapy (i.e., budesonide-formoterol) (preferred) or – Low-dose ICS-LABA combination daily and SABA as needed Treatment: Step 4 or 5 Severe Persistent Asthma • Dx: Severely uncontrolled asthma with ≥3 of the following: – daytime asthma symptoms >2 times/week; – nocturnal awakening due to asthma; – reliever needed for symptoms >2 times/week, or – activity limitation due to asthma • Tx: Step 4: – Medium-dose ICS-formoterol as maintenance and reliever therapy (preferred) – • or – Medium dose ICS-LABA daily and SABA as needed Tx: Step 5: – Medium-dose ICS-formoterol as maintenance and reliever therapy plus LAMA daily (preferred) – or – Medium-dose ICS-LABA plus LAMA daily and SABA as needed – Assess asthma phenotype and evaluate for possible addition of asthma biologics Topic: Severe Asthma • Definition (Clin Med) – Treatment with guidelines suggested medications for GINA steps 4-5 asthma (high dose inhaled glucocorticoid* and long-acting beta agonist [LABA] or leukotriene modifier/theophylline) for the previous year – Treatment with systemic glucocorticoid for ≥50% of the year • Refer to asthma specialist • Asthma phenotype characterization may guide therapy – – – – Biomarkers for T2 /eosinophilic asthma Child onset allergic Adult onset Hypereosinophilic Topic: Acute Exacerbation of Asthma- Therapy • NOTE: ALL asthma patients should have readily available immediate relief inhaler (SABA or ICS- formoterol) Asthma and Risk Factors for Death • Risk factors for death due to asthma – – – – – – – – – History of sudden and severe asthma attacks Prior intubation Prior ICU admission Recent ED visits Two or more hospitalizations within past year Use of 2 or more canisters of beta2 agonists /month Psychiatric, illicit drug use Other medical Comorbities Current or recent withdrawal from SYSTEMIC Corticosteroids Topic Home Management of Mild to Moderate Exacerbations • Mild to moderate exacerbations may be managed at home (initially at least) • Treatment – SABA Beta2 agonists short acting 2-4 puffs or nebulizer every 20 minutes X 3 and assess peak flow and clinical status or – GC (budesonide)-formoterol for acute symptom relief is one to two inhalations (4.5 mcg formoterol per inhalation). Reassess – Good  no wheezing, or tachypnea and peak flow 80% or better continue B2 agonists q 4 hours for 48 hours  call MD/PA – Intermediate  wheezing and dyspnea with PEF 50-79% continue beta agonist but call PA/MD THAT DAY for appointment and further instructions and add oral steroid burst – Poor response  to ED ASAP and add oral burst steroid Asthma Action Plan • http://www.lung.org/lungdisease/asthma/taking-control-ofasthma/AsthmaActionPlan-JUL2008-highres.pdf • http://www.nhlbi.nih.gov/files/docs/public/lu ng/SoYouHaveAsthma_PRINT-reducedfilesize.pdf ED and Acute Asthma Meds • Refer to Clin Med Courses • Intermediate and poor response to SABA requires – ED management with possible admission depending on response to initial treatment – Inhaled beta agonist and anticholinergic (ipratropium) via nebulizer • Albuterol neb soln 2.5-5mg q 20 minutes X 3 then q 1-4 hrs prn or 10-15mg/hour continuously • Ipratropium Br 0.5mg every 30minutes X 3 then q 2-4 hrs prn – – – – – Systemic corticosteroid po or IV Oxygen inhaled IV Magnesium Sulfate Monitor FEV1 or PEF, O2 saturation and pulse Severe respiratory distress unresponsive to meds may require intubation and mechanical ventilation Topic: Asthma Admission • Refer to clinical medicine lectures • Incomplete or poor response to initial ED treatments • Admit to floor or if impending respiratory failure  ICU – Continue oxygen, inhaled SABA, IV then po steroids – Monitor • Vitals, SaO2, FEV1 or PEF • Discharge instructions with close follow and patient education regarding need for better control and close follow up Review • Assess asthma control. Watch for patients with frequent or early refill requests for rescue inhalers (albuterol, etc). – Use the "rule of two." Reassess controller meds if patients have asthma symptoms or need a rescue inhaler more than twice a week...or if patients ≥ 5 years wake at night with symptoms more than twice a month. – Evaluate technique and adherence. Have patients show you HOW they use each of their inhalers...and correct technique BEFORE making a change in meds. References • https://ginasthma.org/2023-gina-mainreport/ • Dr. Covino’s Clinical Medicine Lecture