Stephania Cormier, PhD [email protected]. Outline Asthma Chronic Bronchitis Emphysema COPD ...
-
Upload
debra-whitehead -
Category
Documents
-
view
227 -
download
0
Transcript of Stephania Cormier, PhD [email protected]. Outline Asthma Chronic Bronchitis Emphysema COPD ...
Outline Asthma Chronic Bronchitis Emphysema COPD
Chronic bronchitis Emphysema
Asthma
23 million Year
12.4 million “attack” 1.8 million ER visits $21 billion health care
costs & meds >5000 deaths
Asthma Normal Lung Efficient gas exchange
Asthmatic Lung Inflammation Lower airways
obstruction: inflammation, constriction, mucus
Airway hyperresponsiveness
Airway remodeling Chronic and
PROGRESSIVE!
Immunopathogenesis of Asthma
Allergen
Mast Cell
Mediators• Histamine• Leukotrienes• Prostaglandins• Interleukins
Inflammatory cell recruitment• Eosinophils• Leukocytes• macrophages
Mediators• Cytokines
• Interleukins• Leukotrienes
INFLAMMATION
BRONCHOSPASM
Bronchial hyperreactivity
Triggers• Cold air• Exercise• Tobacco smoke• Other smoke• Pollutants
Airflow Limitatio
n
COPD 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
• Provide relief of acute asthma episodes• Bronchodilators
• 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
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 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
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): 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) 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
Dry Powder Inhaler
Nebulizers
Injection
MDI
21% LUNG
Monotherapy
Combi-therapies Budesonide + formeterol fumerate
Refer to each component Moderate-severe uncontrolled asthma
Fluticasone proprionate + salmeterol xinofate Refer to each component Moderate-severe uncontrolled asthma
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
Staging COPD - GOLD
Gq-coupled receptor signaling in airway smooth muscle
Billington et al. Respiratory Research 2003, 4:2