Pharmacotherapeutic II PHAR520 PDF

Pharmacotherapeutic II PHAR520 Fouad Sakr, PharmD, MPH, PhD (Course Coordinator) Jihan Safwan, PharmD, MPH Dalal Mourad, PharmD Rebecca Lteif, PharmD Alaa Shamseddine, PharmD Lebanese International University...

Pharmacotherapeutic II PHAR520 Fouad Sakr, PharmD, MPH, PhD (Course Coordinator) Jihan Safwan, PharmD, MPH Dalal Mourad, PharmD Rebecca Lteif, PharmD Alaa Shamseddine, PharmD Lebanese International University School of Pharmacy 1  Chapter 1 Asthma Part 1: Chronic asthma 2 Learning Objectives Learn the epidemiology, pathophysiology and risk factors of asthma Describe common signs and symptoms of an asthma attack Assess patient’s knowledge of asthma and his or her medication Differentiate the stages of asthma Develop a treatment plan for patient with asthma List common asthma triggers Educate patients avoidance techniques and non-pharmacologic treatment Educate a patient on managing his or her asthma using an asthma action plan Learn the treatment of an acute asthma attack 3 Introduction Asthma is a common and potentially serious chronic inflammatory disease of the airways It causes: Respiratory symptoms: Wheezing, Breathlessness, Chest tightness, Coughing Limitation of activity Flare-ups (attacks) Are more frequent and more severe in high risk patients and when asthma is uncontrolled That may require urgent health care and may be fatal Can be effectively treated where most patients can achieve good control 4 Epidemiology Approximately 7% of the US population Most common chronic disease among children in US The prevalence rate is highest in children 5–17 years Gender: boys > girls , women > men Third leading cause of preventable death due to: Inadequate assessment of the severity and therapy Thus the key to prevention of death from asthma is education 5 Etiology Heterogeneous 1. Host factors: Genetic predisposition To atopy To airway hyperresponsiveness Obesity 2. Environmental risk factors Outdoor or indoor allergens Respiratory (viral) infections Occupational sensitizers Tobacco smoke Outdoor/indoor air pollution 3. The “hygiene hypothesis” !? Allowing the allergic immunologic system (TH2- lymphocytes) to develop instead of the one used to fight infections (TH1-lymphocytes) 6 Protective and Risk Factors 7 Pathophysiology Morphologic Changes: -Upper right: Normal bronchus -Upper left section Inflammatory cells infiltrate → producing submucosal edema Epithelial desquamation → fills the airway lumen with cellular debris -Lower section: consequences of chronic inflammation Airway remodeling (altered structure and/or function) Hypertrophy of the basement membrane Mucus production and plugging of the airways Smooth muscle hypertrophy, and hyperplasia Production of Nitric oxide (Amplify the inflammatory process) 8 Pathophysiology 9 Diagnosis Signs and symptoms: More than one type of symptom Volume Wheeze, shortness of breath, cough, chest tightness Normal Wheezing high-pitched, whistling sound when breathing out Symptoms often worse at night or in the early morning FEV1 Asthma Symptoms vary over time and in intensity (after BD) Symptoms occur or worsen in the presence of triggers Presence of eczema, allergic rhinitis, or a FH of asthma or atopic diseases Asthma (before BD) Physical examination Often normal (Wheezing on auscultation) Spirometry: FEV1/FVC is reduced from normal 15-20% from ICS and prn SABA baseline Review response Consider trial of treatment for Skin tests with allergens Diagnostic testing within 1-3 months most likely diagnosis, or refer for further investigations Measurement of specific IgE in serum Treat for ASTHMA Treat for alternative diagnosis 11 Review of Pharmacotherapy CONTROLLER Used to reduce airway inflammation, control sx, ICS MEDICATIONS and reduce future risk of exacerbations and ICS plus LABA decline in lung function RELIEVER Provided to all patients for as-needed relief of SABA MEDICATIONS breakthrough symptoms and prevention of EIB Low dose BUD/formoterol, or BDP/Formoterol Systemic corticosteroids Anti-inflammatory Patients can use them as needed before exercise BUD/formoterol, or BDP/Formoterol reliever (AIR) or allergen exposure to prevent asthma ICS-salbutamol symptoms and bronchoconstriction Maintenance and Patient uses the same medication inhaler as Only BUD/formoterol, or BDP/Formoterol reliever therapy maintenance and reliever (MART) ADD-ON THERAPIES For patients with severe asthma despite Leukotriene Modifiers (Montelukast, Zafirlukast and optimized treatment with controller Zileuton) medications (high dose of ICS plus a LABA) Anticholinergic (Tiotropium Bromide) Monoclonal Antibodies Anti-IgE: Omalizumab Anti-IL5: Mepolizumab, reslizumab, benralizumab Anti-IL4: Dupilumab Systemic Corticosteroids Others (Azithromycin, theophylline, etc..) 12 Corticosteroids ICS Systemic 13 Inhaled Corticosteroids Most effective anti-inflammatory for Local side effects: asthma Oropharyngeal candidiasis = Thrush Rinse mouth after use First line treatment for asthma Use spacer device with MDI High topical potency, low systemic side Dysphonia effects Local induced myopathy of vocal cords Low, medium or high dose? Low dose ICS provides most of the clinical Systemic Side effects benefit of ICS for most patients with asthma Risk with high doses But ICS responsiveness varies btw patients, so some patients may need medium dose Growth suppression in children ICS Discuss benefits and risks of Tx If their asthma is uncontrolled despite good Check height at least yearly adherence and correct technique May be lower in 1-2 years of Tx High dose ICS (in combination with LABA or separately) is needed by very few patients Is not progressive or cumulative Its long-term use is associated with an Overall effect is small: 1 – 2 cm total increased risk of local and systemic side- effects, which must be balanced against the potential benefits If used, only for a trial of 3–6 months 14  Low, medium and high ICS doses: Children 6-11 years This is NOT a table of equivalence. These are suggested total daily doses for the ‘low’, ‘medium’ and ‘high’ dose treatment options with different ICS. DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; pMDI: pressurized metered dose inhaler (non-CFC); * see product information 15 GINA 2020, Box 3-6B  Low, medium and high ICS doses: Adults/Adolescents This is NOT a table of equivalence. These are suggested total daily doses for the ‘low’, ‘medium’ and ‘high’ dose treatment options with different ICS. DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; pMDI: pressurized metered dose inhaler (non-CFC); * see product information 16 GINA 2020, Box 3-6A Systemic Corticosteroids In chronic asthma Side effects: Short courses of oral systemic CS Short term use → Used to gain control of the disease Sleep disturbance when initiating long-term therapy Increased appetite 1mg/kg/day up to 40-50mg of Reflux prednisolone Mood changes 5 days Hyperglycemia Long-term oral systemic CS Long-term use systemic SE → Used for severe persistent asthma Osteoporosis Last line controller ≤7.5 mg/day prednisone equivalent Cataract 1-3 months Glaucoma If expected ≥3 months Adrenal insufficiency/crisis Provide treatment for prevention of Dermal thinning corticosteroid induced osteoporosis Hypertension Impaired wound healing In acute exacerbations Hypokalemia Short course 17 Beta Agonist LABA SABA 18 β receptor agonists Organ Receptor Sympathomimetic (adrenergic) (NE) (β agonist) Lungs β1 Bronchoconstriction β2 (more dominant) Bronchodilation Metabolic β1 Glycogenolysis (liver/pancreas) β2 Gluconeogenesis,  insulin Non-selective β blockers [Propranolol (Inderal®)] → block β1 and β2 => lead to bronchoconstriction Mild – moderate  in plasma K+ (because Use selective β1 blockers [Bisoprolol (Concor®)] of  insulin drive K+ intracellularly) 19 Short-acting β2 agonist (SABA) SABA Used as a reliever on as needed basis Albuterol (salbutamol) The use of: Levalbuterol > 1 canister per month indicates poor asthma control Pirbuterol ≥ 2 canisters per months associated with risk Bitolterol of severe asthma attacks Side effects Stimulate β2-adrenergic receptors → Cardiac arrhythmias/Tachycardia Smooth muscle relaxation (bronchodilation) Skeletal muscle tremor Most effective bronchodilator Headache and irritability Hyperglycemia Fast onset of action (5 mins) Hypokalemia Short duration of action (4 hours) Hypotension Indication Chronic use of β2 agonist can lead to Treatment of intermittent episodes of tolerance bronchospasm Solved by  dose of SABA Treatment of choice in acute exacerbations 20 and in EIB Long Acting Beta Agonists (LABA) Bronchial smooth muscle relaxation LABA approved for use in asthma (Step 3) Bronchodilation for more than 12 hrs Salmeterol Formoterol Use and efficacy: Vilanterol (ultra LABA) available in Long term prevention of symptoms combination with fluticasone Indicated for use in combination with ICS LABA monotherapy increased risk of severe exacerbations Similar S.E as SABA Black box warning Never stop LABA abruptly: rebound bronchoconstriction Never use LABA monotherapy Also used for EIB Response reduction in EIB 21  ICS Combination Medications for Asthma Doses Available (μg) Formulation Inhaler Device Inhalations/day Therapeutic Use ICS/LABA Fluticasone 100/50 propionate/ DPI 250/50 1 inhalation x 2 Maintenance Salmeterol 500/50 Fluticasone 50/25 pMDI 2 inhalations x 2 propionate/ 125/25 Maintenance (Suspension) Salmeterol 250/25 80/4.5 Budesonide/ Maintenance and DPI 160/4.5 1-2 inhalations x 2 Formoterol Relief 320/9.0 Budesonide/ pMDI 100/6 Maintenance and 2 inhalations x 2 Formoterol (Suspension) 200/6 Relief Beclomethasone/ pMDI Maintenance and 100/6 1-2 inhalations x 2 Formoterol (Solution) Relief Mometasone / 100/5 pMDI 2 inhalations x 2 Maintenance Formoterol 200/5 Fluticasone furoate / DPI 184/22 1 inhalation qd Maintenance Vilanterol 22 Leukotriene Modifiers Montelukast Pranlukast Zafirlukast Zileuton 23 Leukotriene modifiers The 5-lipoxygenase (5-LO) pathway of arachidonic acid (AA) and inhibitors. FLAP: 5-lipoxygenase activating protein, 5-HPETE: 5- Hydroperoxyeicosatetraenoic acid, DC: dendritic cell, Inh: Inhibition 24 Leukotriene modifiers Use: Major advantages: Prevent release of inflammatory Effective orally mediators Administered once or twice a day Improve FEV1 and PEF Contribute to patient adherence and  nocturnal awakenings and Improve satisfaction with therapy symptoms Disadvantages: Less effective than low doses of ICSs Indication: Unpredictable response Alternative to ICS in mild asthma Side effects: Appropriate for patients Nausea, headache, flu-like symptoms Unable or unwilling to use ICS Risk of Churg-Strauss Syndrome (type Those who experience Intolerable SE of vasculitis disease) from ICS Concomitant allergic rhinitis Administered in the evening 25  Leukotriene modifiers Montelukast Montelukast Before prescribing montelukast, consider B vs. R Used in children and adults Patients should be counselled about the risk of neuropsychiatric events DF: 10 mg tab, 4 &5 mg chewable tab, 4 mg granules/ packet Dose: ≥ 15 years: 10 mg po qd 6-14yrs = 5 mg Chewable 2-5yrs = 4 mg Chewable 12m-5yrs = 4 mg Granules Granules 4mg/packet: directly into mouth or Zafirlukast mixed with applesauce, carrot, baby formula.. Elevation of liver enzymes Administer within 15 mins of opening the packet Monitor LFTs and signs and symptoms of live March 2020: FDA boxed warning of the risk toxicity of serious of neuropsychiatric events Limited case reports of reversible hepatitis and includes: hyperbilirubinemia Suicidality in adults and adolescents Nightmares and behavioural problems in children Zileuton Limited clinical use because of hepatotoxicity 26 Anticholinergic Tiotropium Bromide 27 Tiotropium Bromide MOA: Long acting muscarinic antagonist Competitively block the effects of Ach on M1 and M3 receptors → bronchodilation Indication: Steps 4 and 5 Add-on controller medication by mist inhaler in patients ≥6 years with history of exacerbations Efficacy Modestly improves lung function and reduces exacerbations Side effects: Dry mouth, dyspepsia, abdominal pain, vomiting, constipation, GERD, stomatitis, tachycardia, angina pectoris, headache, dizziness, rash, pharyngitis, insomnia, depression, cataract. 28 Monoclonal Antibodies anti-IgE IL-5 inhibitors IL-4 inhibitor 29  Anti-IgE: Omalizumab Omalizumab Pharmacological Humanized monoclonal anti-Ig E antibody Class 95% human and 5% mouse IgE sequences Lower risk of an immune and anaphylactic response MOA Binds to Ig-E antibody → prevent binding of IgE to mast cells → ↓release of inflammatory mediators Indication In Step 5: Add-on therapy to Mod/High dose ICS + LABA Adults and children ≥6 yrs. Who have a positive skin test or whose symptoms inadequately controlled with ICS Dose 150-375 mg q 2-4 weeks SC Side effects Pain and injection site reaction, Viral infection, URTI, headache, sinusitis, pharyngitis Risk of anaphylaxis (0.1% ) FDA warning and BBW: patients should remain in the physician’s office for a reasonable period of time past the injection because 70% of reactions occur within 2 hours 30 IL-5 antagonists: Mepolizumab, Reslizumab, Benralizumab Mepolizumab Reslizumab Benralizumab MOA Inhibit IL-5 signaling →reduces the production and survival of eosinophils Benralizumab is an IL-5 receptor antagonist leading to apoptosis of eosinophils Indication In Step 4-5 Add-on option for those with severe eosinophilic asthma (with blood eosinophil count ≥ 300 cells/μL) and frequent exacerbations uncontrolled on Step 4 treatment (ICS/LABA) Patients aged ≥6 yrs Patients aged ≥18 yrs Patients aged ≥12 yrs Dose SC q 4 weeks 3 mg/kg IV q4wk infused 30mg SC q 4 weeks *3 then q 6-11 yo: 40 mg over 20-50 minutes 8 weeks ≥12 yo: 100 mg Side effects Headache and reactions Oropharyngeal pain Headache and reactions at at injection site Increase creatine injection site phosphokinase (CK), Myalgia Anaphylactic reactions 31 IL-4 inhibitor: Dupilumab Dupilumab MOA Interleukin-4 receptor alpha antagonist blocking both IL-4 and IL-13 signaling Indication Add-on treatment in Step 5 in patients ≥ 12 years with: An eosinophilic phenotype (blood eosinophils ≥300/μl, or FeNO ≥25 ppb) or with oral corticosteroid dependent severe asthma Concomitant moderate/severe atopic dermatitis Dose 200mg or 300mg by SC injection every 2 weeks Side Oropharyngeal pain, injection site reactions and transient blood effects eosinophilia 32 Others 33 Others Mast cells stabilizers Add-on azithromycin (three times a Nedocromil and cromolyn week) Weak anti-inflammatory effect and low For adult patients with persistent asthma efficacy despite moderate-high dose ICS and LABA Favorable safety profile Risk of ototoxicity and cardiac arrythmia Most common S.E: cough and wheeze, At baseline: Consider ECG for long QT, headache, unpleasant taste (nedocromil) sputum for atypical mycobacteria, risk of Their inhalers require burdensome daily increasing antimicrobial resistance washing to avoid blockage. Treatment for at least 6 months is Limited role in treatment of asthma suggested Sustained-release theophylline Allergen-specific immunotherapy Weak efficacy in asthma Treatment option where allergy plays a Alternative to LABA in combination with ICS prominent role (Step 3 and 4) (Step 3-4) Most common allergen included house dust Not recommended in children 70% predicted used Adults with rhinitis and asthma who are allergic to house dust mite41  Step 4 – two or more controllers + as-needed inhaled reliever Preferred Medium dose ICS/formoterol (MART) (mentioned in Box 3.7) Adults option Refer for expert advice Children 6- Medium dose ICS/LABA 11 years Low dose ICS-formoterol Other Adults Medium-high dose ICS/LABA with as-needed SABA or as-needed options ICS/SABA (mentioned in Box 3.7) Not Add-on tiotropium By mist inhaler for patients aged ≥6 years mentioned with a history of exacerbations in Box 3.7 but can be Add SLIT For patients with allergic rhinitis and if used FEV1>70% of predicted Children 6- Add tiotropium (mentioned in Box 3.10) 11 years Add LTRA if not trialed before(mentioned in Box 3.10) 42 As-needed ICS-formoterol – maximum daily dose? Low dose budesonide-formoterol prescribed in: Maintenance and reliever therapy (Steps 3–5), or as-needed only (Steps 1–2) or within an asthma action plan The maximum recommended daily dose is 72 mcg formoterol (12 inhalations of budesonide-formoterol Turbuhaler 200/6 mcg) Such high usage was rarely seen in step 1 and 2 (average use was 3-4 doses per week) Low dose beclomethasone-formoterol Prescribed in: Maintenance and reliever therapy (Steps 3–5), or within an asthma action plan The maximum recommended daily dose is 48 mcg formoterol (8 inhalations of beclometasone-formoterol pMDI100/6 mcg) 43  Step 5 – higher level care and/or add-on treatment – Severe Asthma ICS/LABA (high dose) Complete resistance to ICS is rare Optimize therapy High dose maintenance ICS- Consider therapeutic trial of higher dose (3-6 months) formoterol Tiotropium Reduces exacerbations History of Add-on treatments without exacerbations phenotyping Age ≥6 years Omalizumab (anti-IgE) Severe Sputum-guided (≥6 years old) allergic treatment to reduce asthma exacerbations and/or Preferred option: steroid dose Referral for specialist Mepolizumab (≥6 yo) or Severe investigation and Phenotype-guided reslizumab (≥8yo) (anti-IL5), or eosinophilic consideration of add- treatment benralizumab(≥12 yo)(anti-IL5R) asthma on treatment or dupilumab 9(≥6 yo) (anti-IL4R) or Tezepelumab (anti-TSLP) (≥12yo) Severe asthma 3 times per week after specialist referral for adults patients with persistent Add Azithromycin symptomatic asthma Add-on low dose oral CS ≤7.5mg/day prednisone Monitor for and manage side-effects, (last line) equivalent including osteoporosis Non-pharmacological Consider bronchial thermoplasty for selected patients interventions Comprehensive adherence-promoting program 44  45 © Global Initiative for Asthma, www.ginasthma.org  Treating to Control Symptoms and Minimize Risk Establish a patient-doctor partnership Manage asthma in a continuous cycle: Assess asthma NSE A Adjust treatment SP O SS RE ESS Review the response REVIEW Teach and reinforce essential skills Inhaler skills NT AD JU Adherence ST TREATM E Guided self-management education Highly effective in improving asthma outcomes Reduced hospitalizations, ED visits, symptoms, night waking, time off work, improved lung function and QOL 3 essential components: Written asthma action plan Self-monitoring Regular medical review 46 Treating to Control Symptoms and Minimize Risk ONSE SP RE AS SES W REVIE S T DJ N A UST M E TREAT 47 Assess Asthma Symptom control & risk factors Inhaler technique & adherence Patient preference 48 Assessment of Asthma Control A. Symptom control Level of asthma symptom control Well- Partly Uncontrolled In the past 4 weeks, has the patient had: controlled controlled Daytime asthma symptoms more than twice a week? Yes❑ No❑ Any night waking due to asthma? Yes❑ No❑ 1-2 of 3-4 of None of these SABA reliever for symptoms* more Yes❑ No❑ these these than twice a week? Any activity limitation due to asthma? Yes❑ No❑ *Based on SABA (as-needed ICS-formoterol reliever not included); excludes reliever taken before exercise Assess Asthma severity: After patient has been on controller treatment for several months Categories of asthma severity Mild asthma: well-controlled with Steps 1 or 2 Moderate asthma: well-controlled with Step 3 Severe asthma: requires Step 4/5 or remains uncontrolled despite this treatment 49 Assessment of Asthma Control Assess RF for poor outcomes, including low lung function: B. Risk factors for poor asthma outcomes Assess risk factors at diagnosis and periodically Measure FEV1 at start of treatment, after 3 to 6 months of treatment to record the patient’s personal best, then periodically for ongoing risk assessment At least every 1-2 years for most adults More frequently in higher risk patients More frequently in children based on severity and clinical course ASSESS PATIENT’S RISKS FOR: Exacerbations Fixed airflow limitation Medication side-effects 50 Assessment of Risk Factors for Poor Asthma Outcomes Risk factors for exacerbations include: Uncontrolled asthma symptoms Additional risk factors, even if the patient has few symptoms: High SABA use (≥ 3 canisters/year) Having ≥1 exacerbation in last 12 months Low FEV1; especially if 15% of baseline Lasts up to 3 hours after exercise Caused by an acute depletion of mast cell mediators Characteristics Exacerbated with cold, dry air Treadmill or bicycle exercise diagnostic of asthma Acute management: SABA agent of choice Prevention of EIB: Exercise 3 hrs: Formoterol 15 min, Salmeterol 30 min before PEFR: peak expiratory flow rate 63 Nocturnal Asthma Worsening of asthma during sleep Nadir at 3-4 am Factors contributing to nocturnal asthma: High levels of epinephrine Low levels of cortisol Allergies and improper environmental control Gastroesophageal reflux Obstructive sleep apnea Sinusitis A sign of inadequately treated persistent asthma Same management of long term therapy persistent asthma 64 Primary prevention of asthma The development and persistence of asthma are driven by gene- environment interactions For children, a ‘window of opportunity’ exists in utero and in early life, but intervention studies are limited For intervention strategies including allergen avoidance Strategies directed at a single allergen have not been effective Multifaceted strategies may be effective, but the essential components have not been identified Current recommendations are Avoid exposure to tobacco smoke in pregnancy and early life Encourage vaginal delivery Advise breast-feeding for its general health benefits Where possible, avoid use of paracetamol (acetaminophen) and broad-spectrum antibiotics in the first year of life 65 GINA 2017, Box 7-1 CASE # 1 A 12 yo (wt: 35kg, ht:140cm) presenting with respiratory sxs suggestive of asthma (chronic cough, worse at night variable in severity, wheezing when breathing out and upon auscultation). After further evaluation and lung function studies a diagnosis of asthma was confirmed (FEV1/FVC= 0.8, Normal FEV1/FVC 85% → reduced FEV1/FVC) Over the past 3 weeks, the pt is reporting daytime sxs on a daily basis and 1 night time awakening per week. Today his measured PEF is 69% of predicted (Low lung function) Explain in details how you would manage this patient by using the assess/adjust/review method. Include medications and doses for different scenarios (Step Up/Step Down) 66 CASE # 2 AF is a 25-year-old lady who presents to her physician complaining of cough and dyspnea. She’s been waking up 2 times per week due to her asthma symptoms. AF has no known drug allergies. She has eczema, and a FH of asthma. Spirometry is done showing FEV1/FVC of 75%. 1. What factors would help diagnose her asthma? 2. What’s the preferred initial controller / reliever? 3. 3 weeks later, AF calls her physician because her symptoms haven’t improved yet, what should her physician recommend in this case? 4. 4 months later, she returns to a follow up visit, and reports that her day symptoms are rare (2 times per week) and she’s not waking up at night due to symptoms, she’d been using her reliever (SABA) daily before doing her physical activity and around 2 other times per week. Assess AF’s symptom control and asthma severity 5. Considering treatment to control sxs and minimize risk, what is the next step? 67 Chill!! Please solve this word search and recall chronic asthma ☺ 68  Thank you… Next: Management of acute asthma attacks 69