Pharmacotherapy of Asthma - Bronchodilators

Objectives
By the end of the lecture, students should be able to:

Explain the mechanism of action of the various drugs used to dilate the airways

Describe how these agents interact with the autonomic nervous system and each other

List the adverse reactions of each medication

Understand the clinical indication of each medication

Asthma

Chronic inflammatory disease of the airways

Mediated through many inflammatory cells and markers
Causes airway obstruction results in breathlessness, wheezing, cough, chest tightness

Drugs are the mainstay of therapy

Not shown to alter early inhibition of lung growth or late progressive loss of lung function

Drug Therapy

Main treatments:
1- Inhaled Beta-2 Agonists
a. Short acting (SABA) & long acting (LABA)
2- Corticosteroids
a. Inhaled (ICS) & systemic
3- Inhaled anticholinergics

Alternative therapies:
1- Leukotriene modifiers
2- Methylxanthines (theophylline)
3- Omalizumab

Inhaled Beta-2 Agonists

1- Short-acting beta-2 agonists (SABA):
a. Salbutamol
b. Pirbuterol
2- Long-acting beta-2 agonists (LABA):
a. Salmeterol
b. Formoterol

1- Properties of Inhaled Beta-2 Agonists:

Most potent bronchodilating medications

Functional antagonists (reverse bronchoconstriction regardless of cause)
No anti-inflammatory effects
Selective beta-2 agonists are of use, but no role for non-selective agonists
Relatively selective for bronchial tissue when administered via the inhalational route

2- Beta-2 agonist mechanism:

Bind beta-2 receptors in the airway, activating transmembrane G-proteins, which increase cyclic AMP
(cAMP)
cAMP acts through various proteins to decrease unbound calcium

Smooth muscle relaxation, bronchodilation

Stabilize mast cells

3- Classes of Beta-2 agonists:

1- Short-Acting Beta-2 Agonists (SABA)

Treatment of choice for acute, severe asthma
Delivered via metered-dose inhaler (MDI), with or without a spacer, or via nebulizer
Not for regular use:

As needed for asthma exacerbations

Prevention of exercise-induced bronchospasm (EIB)

2- Long-Acting Beta-2 Agonists (LABA)

Longer duration of bronchodilator effect and more beta-2 selective than SABAs

Better control when added to inhaled corticosteroids (ICS) therapy rather than increasing the ICS dose alone
Should only be used in more severe, persistent asthma (continue SABA use as needed)
Should NOT be used as monotherapy (no anti-inflammatory properties)

4- Adverse effects:
Immediate: vasodilation, tachycardia, decreased ventilation/perfusion matching
High doses: hypokalemia, hyperglycemia, tachycardia (not an indication to decrease doses)
Long term use: tolerance primarily decreased duration of bronchodilation (can be overcome by
increasing dose; steroids)
LABA associated with increased risk of asthma-related death

Inhaled Beta-2 Agonists

REFER TO SLIDES TO SEE THE TABLES

Corticosteroids
1- Properties and Mechanism:

Most effective anti-inflammatory agents for asthma

Bind and form complexes with cytoplasmic receptors; complex enters the nucleus and modifies
gene transcription

Increased production of anti-inflammatory mediators and decreased production of proinflammatory cytokines

Corticosteroids: a PICTURE IN SLIDES

2- Corticosteroids effects:

Increase the number of and response to beta receptors

Decrease:
o Inflammatory cell activation, recruitment, and infiltration
o Mucous production, hypersecretion
o Bronchial hyper-reactivity
o Airway edema, exudation

Decrease vascular permeability

3- Corticosteroids ROA:
Administered systemically (oral or parenteral) for treatment of acute asthma exacerbations
Allow for more robust response to SABA
Usually administered as high dose bursts
(1-2 mg/kg/day prednisone for 5 to 10 days)
4- ICS:

ICS preferred agents for long term control

High topical potency in the lung
Low systemic activity (rapidly cleared)
Safe for long-term use

5- Corticosteroids Adverse Effects

a. ICS Adverse Effects

ICS may carry some risk of systemic adverse effects

Can be reduced by oral rinsing and spitting after the dose

6- Corticosteroids (refer to the schedule in slides)

1) Prednisone (oral)
2) Methylprednisolone (IV, oral)
7- Inhaled Corticosteroids (ICS)
1) Budesonide
2) Fluticasone propionate

Inhaled Anticholinergics
1- Properties:

Competitive inhibitors of muscarinic receptors

Reverse cholinergic-mediated bronchoconstriction

Effective bronchodilators

Not currently FDA labeled for asthma

2- Inhaled Anticholinergics drugs:
a. Ipratropium short acting, non-selective anti-muscarinic

Quaternary amine poor mucosal absorption (little or no systemic effects)

Adjunctive treatment for acute exacerbations

Beneficial when response to SABA is inadequate

b. Tiotropium long acting anti-muscarinic; selective for M1 & M3 receptors

May be as effective as LABA when added to ICS or as an adjunct to ICS + LABA

Inhaled Anticholinergics

Tiotropium in uncontrolled, persistent asthma

Improved FEV1 and decreased risk of acute worsening of asthma when added to ICS + LABA

May be as effective as LABA when added to ICS

Leukotriene Modifiers
1- Classes of Leukotriene:

a. LTRAs montelukast, zafirlukast

i. Block binding of leukotrienes (LT) to LT receptors
b. 5-lipoxygenase inhibitor zileuton
i. Inhibits formation of LT
2- Mechanism:
LTD4 induces bronchoconstriction
Reduce asthma caused by allergens, exercise, cold air, and aspirin
Increase PEF & FEV1
Decrease night awakenings
Decrease SABA use
Orally active, well tolerated

3- Leukotriene Modifiers properties:

Not preferred alternative treatments:

Not as effective as ICS for mild persistent asthma

When added to ICS, not as effective as LABA for moderate persistent asthma

Not as effective as SABA for EIB

Zileuton use limited by elevated liver enzymes and drug interactions
Zafirlukast associated with severe liver failure

Methylxanthines (Theophylline)

Phosphodiesterase (PDE) inhibitor (similar to caffeine)

Increases cAMP/cGMP

Stimulates endogenous catecholamine release

Activates histone deacetylase (involved in steroid-induced reduction of pro-inflammatory genes)

Bronchodilator with anti-inflammatory properties

Functional antagonist

Theophylline

Low therapeutic index requires monitoring of serum drug concentration

Therapeutic range 5 to 15 mcg/mL (28 to 83 mol/L)
Not a preferred alternative:

Less effective than ICS or LABA

No better than LTRAs or cromolyn

Lacks bronchodilator effect in severe exacerbations

Many adverse effects:

Mild to moderate: nausea/vomiting, tachycardia, jitters, insomnia

Severe: tachyarrhythmias, seizure

Omalizumab

Monoclonal antibody against IgE

Prevents IgE binding to mast cells & basophils

Decreased release of inflammatory mediators

Improves outcomes in severe persistent asthma not controlled with ICS/LABA

Allows decreased systemic steroid use

Subcutaneous injection administered every 2 to 4 weeks
Must be given in clinic (risk of anaphylaxis)

Cromolyn

Mast-cell stabilizer:

Inhibits asthmatic response to allergens

Inhibits EIB
Stimulates C-fiber sensory nerves in airways inhibits neuron-mediated bronchoconstriction
Administered via nebulizer 3 to 4 times daily
Well tolerated; may cause cough/wheeze after inhalation
1- Cromolyn properties:

Not as effective as ICS

Similar efficacy to theophylline, LTRAs

Less effective for EIB than SABA, but can be used as adjunct treatment

Summary

Asthma is a chronic inflammatory disease that causes airway obstruction

Medications are the mainstays of therapy
SABA is the most effective treatment for acute exacerbations
ICS are the most effective long-term treatment
Alternative treatments (methylxanthines, leukotriene modifyers, anticholinergics) can be considered as
add-on therapies