Respiratory Drugs

Stephania Cormier, PhD

scorm1@lsuhsc.edu

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