Stephania Cormier, PhD scorm1@lsuhsc.edu Respiratory Drugs MedPharm text: Goodman & Gilman Stephania Cormier, PhD scorm1@lsuhsc.edu

Outline Asthma Chronic Bronchitis Emphysema COPD Chronic bronchitis

Asthma 23 million Year 12.4 million “attack” 1.8 million ER visits $21 billion health care costs & meds >5000 deaths

Asthma Normal Lung Asthmatic Lung Inflammation Efficient gas exchange Asthmatic Lung Inflammation Lower airways obstruction: inflammation, constriction, mucus Airway hyperresponsiveness Airway remodeling Chronic and PROGRESSIVE!

Immunopathogenesis of Asthma

Inflammatory cell recruitment Eosinophils Leukocytes macrophages Allergen Mast Cell BRONCHOSPASM Mediators Histamine Leukotrienes Prostaglandins Interleukins Triggers Cold air Exercise Tobacco smoke Other smoke Pollutants Airflow Limitation Inflammatory cell recruitment Eosinophils Leukocytes macrophages Mediators Cytokines Interleukins Leukotrienes Bronchial hyperreactivity INFLAMMATION

COPD >127,000 deaths 12 million 4th leading cause of death Year $26 billion / year >127,000 deaths

Medications Used for Asthma Relief Long-term Control Quick Relief (RESCUE) Corticosteroids - inhaled Corticosteroids – I.V. Cromolyns Short-acting β2-agonists Leukotriene modifiers Methylxanthines Long-acting β2-agonists Anticholinergics Sustained-release methylxanthines Antagonism of IgE Control and prevent asthma symptoms Make airways less sensitive to triggers and prevent inflammation that leads to an acute asthma episode (Immunomodulatory) Taken on a daily basis Provide relief of acute asthma episodes Bronchodilators

β2 Adrenergic Receptor Agonists Inflammatory Cells Vasoactive amines Lipid mediators SMC hyperplasia

β2 Adrenergic Receptor Agonists Relievers: short-acting (SABAs) Adrenaline (epinephrine)….ephedrine (Ma-Huang): α, β1,β2 Stimulates cAMP production Terbutaline, albuterol, pirbuterol, bitolterol, levalbuterol (R- albuterol): β2 > β1 (220- 400 x) Pharmacokinetics Onset: 5 -10 m Effect: 30 m Duration: 4 - 6 h Administration: inhaled, oral (terbutaline:SC) Side Effects: tremor, tachycardia – cardiac β1 receptors. S-albuterol more active at β1

β2 Adrenergic Receptor Agonists Controllers: long-acting (LABAs); selective β2 agonists Formoterol Salmeterol Pharmacokinetics Onset: 15 - 30 m Peak Effect: 22 h Duration: 12 -24 h Administration: inhaled Side Effects: hypotension, hypertension, vascular headaches, tremors. Tolerance over time. Warning: increased chance of serious or fatal asthma

Salmeterol xinafoate (SEREVENT) formoterol (FORADIL)

Methylxanthines MOA Forms Inhibits PDE High levels cAMP SM relaxation Inhibits IgE release of mast cell mediators Competitive antagonist at adenosine (A2) receptors Adenosine Bronchoconstriction Potentiate inflammatory mediator release Forms Theophylline, Caffiene (>) Synthetic: Aminophyline (>theophylline) , Dyphilline, Oxtriphyline

Methylxanthines Use: very limited (CNS stimulants) Administration: Oral, Inhaled, (rectal, IV) Pharmacokinetics: Onset: unknown Effect: 1-2 h Duration: varies Side Effects: nausea, vomiting, anorexia Cardiac effects: sinus tachycardia, extrasystole, palpitations, arrhythmia Kidney: weak diuretic Skeletal Muscle: increase contractions

Anticholinergics 1896: asthma cigarettes Stramonium Atropine, ipratropium, and tiotropium MOA: Competitive antagonists of muscarinic Ach receptors Use: Asthma not responsive to inhaled β2-adrenergic agonists inhaled β agonists are contraindicated (i.e. cardiac ischemia or arrhythmia) Chronic bronchitis/emphysema/COPD Administration: A: IV, I, T:inhalation, T: oral Pharmacokinetics: Onset: 5-15 m Effect: 1-2 h Duration: 4-5 h Side Effects: dryness of mouth and airway, headache. Rarely: tachycardia, dry eyes/blurred vision, urinary retention

Corticosteroids MOA: gene regulation Administration Anti-inflammatory Immunosuppression Administration Inhaled: beclomethasone, triamcinolone, fluticasone, budesonide, flunisolide, mometasone Side Effects: Oropharyngeal candidiasis, dysphonia oral (most potent): dexamethasone, prednisone Side Effects: mood disturbances, increased appetite, impaired glucose control in diabetics, and candidiasis Long-term use: bone resorption Inhaled Prednisone

Corticosteroids Pharmacokinetics (inhaled): Warning: compliance poor! Onset: unknown Effect: unknown Duration: 24 h Warning: compliance poor!

Cromolyns: Mast Cell Stabilizers Cromolyn, nedocromil MOA: Alter fxn of delayed Cl- channels (inhibiting their activation) Blocks release of inflammatory mediators: mast, eosinophil, basophil, lymphocyte Use: prophylactic therapy for mild-moderate allergic asthma Allergic rhinitis (C) Administration: Inhalation Pharmacokinetics: Effect: wks Side Effects: C: safest of all increased coughing, wheezing Age matters: Cromolyn: children, adolescents Nedocromil: ≥12 yoa

Leukotriene Modifiers Strategies Leukotriene-Synthesis Inhibitors Zileuton Leukotriene Receptor Antagonists Montelukast, zafirlukast Use: “responder” mild chronic asthma allergic rhinitis Administration: Inhalation (, oral (M,Z) Pharmacokinetics: Onset: 3-6 h Effect: 4 h Duration: 24h Side Effects: Churg-Strauss syndrome … happens in the unLUcKiest

Drug Interactions Montelukast (Singulair) Zafirlukast (Accolate) MOA Phenobarbital Rifampin MOA Increased metabolism Result Decreased montelukast levels Zafirlukast (Accolate) Drugs Aspirin: Zafir Erythromycin: Zafir Tolbutamide, phenytoin, carbamazepine: levels Warfarin: levels Zileuton (Zyflo) Drugs: levels Propranolol Theophylline Warfarin

Antagonism of IgE Anti-IgE: omalizumab 95% humanized High cost >$10K/yr Use: moderate-to-severe persistent asthma Administration: SC Pharmacokinetics: Pk Plasma: 7-8d Duration: 26 d Side Effects: injection- site reaction, infections, anaphylaxis, cancer

Drug Delivery Metered Dose Inhaler Nebulizers Injection Dry Powder Inhaler

MDI 21% lung

Monotherapy

Combi-therapies Budesonide + formeterol fumerate Refer to each component Moderate-severe uncontrolled asthma Fluticasone proprionate + salmeterol xinofate

Potential New Therapies for Asthma Vaccines (DNA vaccine; Mycobacterium, CpG) Desensitization (allergen-specific immunotherapy including recombinant gene-manipulated antigens and peptides) Cytokine modulators (gene, protein) Anti IL-4, IL-5, IL-13 IL-12 IL-10 Selective phosphodiesterase inhibitors Selective tryptase inhibitors Potassium channel activators Adhesion molecule inhibitors Gene therapy Targeting susceptibility genes Targeting polymorphism of receptors for drugs Others

Step-wise Approach to Asthma Therapy Review of treatment — Adolescents and adults with asthma are usually seen by their healthcare provider every one to six months to evaluate symptom severity and frequency and response to treatment. If control has been adequate for at least three months, the medication dose may be decreased. If control is not adequate, the medication schedule, delivery technique, and trigger avoidance will be reviewed and the medication dose may be increased. CATEGORIES OF ASTHMA SYMPTOMS — The medications used to treat asthma vary according to a person's age, the severity of asthma, and the level of symptom control. The asthma treatment plan must be reviewed and adjusted on a regular basis. If symptoms are well controlled, medication can often be reduced. As symptoms worsen, medication should be increased. Intermittent asthma — People with intermittent asthma are defined as those who have the following characteristics: Symptoms of asthma occur two or fewer times per week Asthma does not interfere with daily activities Nighttime symptoms awaken the person two or fewer nights per month Oral steroid treatment (eg, prednisone) is needed no more than once per year to treat increased asthma symptoms A person whose asthma is triggered only by vigorous exercise (exercise-induced bronchoconstriction) might fit into this category, even if he or she exercises more than twice per week. (See "Patient information: Exercise-induced asthma"). Persistent asthma — People with persistent asthma have symptoms regularly. There may be days when activities are limited due to symptoms, and the person may be awakened from sleep. Lung function is usually normal between episodes but becomes abnormal during an asthma attack. Based on symptom frequency and severity of asthma flares, the clinician will determine whether a person's persistent asthma is mild, moderate, or severe. Treatment plans will vary based upon the severity of the person's asthma as well as their level of symptom control (show figure 3). The symptoms that are used to determine a person's asthma severity include the number of days per week that the person has one or more of the following: Symptoms such as cough, wheeze, and shortness of breath Nighttime symptoms that awaken the person Uses a bronchodilator (reliever medication) Symptoms that affect the person's ability to participate in normal activities The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs. If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up. Zileuton is a less desirable alternative due to limited studies as adjunctive therapy and the need to monitor liver function. Theophylline requires monitoring of serum concentration levels. In step 6, before oral systemic corticosteroids are introduced, a trial of high-dose ICS + LABA + either LTRA, theophylline, or zileuton may be considered, although this approach has not been studied in clinical trials. Step 1, 2, and 3 preferred therapies are based on Evidence A; step 3 alternative therapy is based on Evidence A for LTRA, Evidence B for theophylline, and Evidence D for zileuton. Step 4 preferred therapy is based on Evidence B, and alternative therapy is based on Evidence B for LTRA and theophylline and Evidence D for zileuton. Step 5 preferred therapy is based on Evidence B. Step 6 preferred therapy is based on (EPR-2 1997) and Evidence B for omalizumab. Immunotherapy for steps 2-4 is based on Evidence B for house-dust mites, animal danders, and pollens; evidence is weak or lacking for molds and cockroaches. Evidence is strongest for immunotherapy with single allergens. The role of allergy in asthma is greater in children than in adults. Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur. Alphabetical order is used when more than one treatment option is listed within either preferred or alternative therapy. EIB: exercise-induced bronchospasm; ICS: inhaled corticosteroid; LABA: long-acting inhaled beta2-agonist; LTRA: leukotriene receptor antagonist; SABA: inhaled short-acting beta2-agonist. Reproduced from: National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma. NIH Publication no. 08-4051, 2007.

Staging COPD - GOLD The primary care provider must have timely access to pulmonary function testing for all symptomatic patients as part of the initial workup for COPD. Testing should include a bronchodilatory challenge. If the results of this challenge indicate that the obstructive disease is completely reversible, a diagnosis of asthma should be favored over one of COPD. If the obstruction is only partially reversible, a diagnosis of COPD should be considered. The degree of reversibility, even if only partial, may indicate a positive prognosis if the patient can reduce risk factors. Stage 0 Early in COPD, patients have classic signs and symptoms (cough, sputum production, shortness of breath) but normal results on pulmonary function tests. Thus, the absence of measurable airway obstruction is designated stage 0, and the patient is said to be at risk. Stage I Mild COPD manifests with chronic cough and sputum production. Patients have some shortness of breath but may not be aware that their pulmonary function is measurably decreased. FEV1/FVC is less than 70% of predicted normal values. FEV1 may equal or exceed 80% of predicted values. Stage II Moderate COPD is characterized by chronic cough and sputum production, and shortness of breath may limit exertion. Patients may present with only shortness of breath. The FEV1/FVC is less than 70% of predicted (as in stage I), but the FEV1 is at least 50% of predicted. Stage III Severe COPD involves progressive airway limitation, and clinical signs and symptoms worsen. The FEV1 falls below 50%—but not below 30%—of predicted. Clinically, the patient has more exacerbations with continuing problems of cough and sputum production. This progression markedly impairs quality of life. Stage IV In very severe COPD, the FEV1 is less than 30% of predicted or patients are in a chronic state of respiratory failure even if the FEV1 is greater than 30% of predicted. Hypercapnia and hypoxia are present, and supplemental oxygen therapy may be required to maintain an O2 saturation higher than 90%. Severe, recurrent exacerbations markedly affect quality of life and threaten survival.  

Gq-coupled receptor signaling in airway smooth muscle Billington et al. Respiratory Research 2003, 4:2