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

2. Outline
Asthma
Chronic Bronchitis
Emphysema
COPD
Chronic bronchitis

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

4. 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!

5. Immunopathogenesis of Asthma

6. 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

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

8. 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

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

10. 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 ( x)
Pharmacokinetics
Onset: m
Effect: 30 m
Duration: h
Administration: inhaled, oral (terbutaline:SC)
Side Effects: tremor, tachycardia – cardiac β1 receptors.
S-albuterol more active at β1

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

12. Salmeterol xinafoate (SEREVENT)
formoterol (FORADIL)

13. 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

14. 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

15. 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: 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

16. 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

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

18. 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

19. 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

20. 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

21. 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

22. Drug Delivery Metered Dose Inhaler Nebulizers Injection
Dry Powder Inhaler

23. MDI
21% lung

24. Monotherapy

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

26. 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

27. 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 ) 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 , 2007.

28. 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.  

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