CHAPTER 20 SUMMARY

ASTHMA
- Characterized clinically by recurrent bouts of shortness of breath, chest tightness
and wheezing, often associated with coughing.
- Reversible narrowing of bronchial airways and a marked increase in bronchial
responsiveness to inhaled stimuli.
- Lymphocytic. Eosinophil inflammation of the bronchial mucosa,
- With thickening of the lamina reticularis beneath the airway epithelium

Mild Asthma
- Symptoms occur only occasionally, as on exposure to allergens or certain pollutants,
on exercise, or after viral upper respiratory infection.

Severe forms of Asthma
- Associated with frequent attacks of wheezing dyspnea, especially at night
- Chronic airway narrowing

Causes of airway narrowing in acute asthmatic attacks
- Contraction of airway smooth muscle
- Inspissation of viscid mucus plugs in the airway lumen
- Thickening of bronchial mucosa from edema
- Cellular infiltration
- Hyperplasia of secretory, vascular and smooth muscle cells
- Reversal of the edema and cellular infiltration requires sustained treatment with
anti-inflammatory agents

Beta-adrenoceptor stimulants
- Agents that relax airway smooth muscle
- For short term relief, most effectively achieved by these agents
- Salmeterol and Formoterol; effective in improving asthma control when added to
inhaled corticosteroid treatment

Theophylline and Antimuscarinic agents
- Sometimes used for reversal of airway constriction
- Theophylline- regarded as bronchodilator, inhibits some lymphocyte functions and
modestly reduces airway mucosal inflammation; enhance anti-inflammatory action
of inhaled corticosteroid

Anti-inflammatory agent (such as an inhaled corticosteroid)
- Long term control is most effectively achieved; long term controllers
- Produce the modest immediate bronchodilation

Leukotriene Pathway Antagonist/ Inhibitor of mast cell degranulation (Cromolyn and
Nedocromil)
- Can also achieve long term control, although less effective than anti-inflammatory
agent

Omalizumab (Humanized Monoclonal Antibody)
- Targeted IgE, the antibody responsible for allergic sensitization

Allergens
- Foreign materials that provoke IgE production
- Most common are proteins from house dust mite, cockroach, animal danders, molds
and pollens

IgE antibodies
- Bind to mast cells in the airway mucosa
- Histamine, tryptase, leukotrienes C4 and D4 and prostaglandin D2, trigger the
muscle contraction and vascular leakage responsible for acute bronchoconstriction
(early asthmatic response)

Cytokines
- Produced by TH2 lymphocytes, especially interleukins 5,9 and 13
- Late asthmatic response- associated with an influx of inflammatory cells into the
bronchial mucosa and with an increase in bronchial reactivity
- Increase in bronchial reactivity that may last for several weeks after a single
inhalation of allergen
- Attract and activate eosinophils
- Stimulate IgE production by B lymphocytes
- Stimulate mucus production by bronchial epithelial cells

Notes:
- Allergen model does not reproduce all the features of asthma.
- Most asthma are triggered by viral respiratory
- Bronchospasm can be provoked by nonallergenic stimuli such as distilled water,
exercise, cold air, sulfur dioxide and rapid respiratory maneuvers
- (Read more about the mechanism)

BASIC PHARMACOLOGY OF AGENTS USED IN THE TREATMENT OF ASTHMA
Adrenoceptor agonists or sympathomimetic agents and inhaled corticosteroids
- Most commonly used for the management of asthma

I. Sympathomimetic Agents
- Adrenoceptor agonists
- Relax airway smooth muscle and inhibit release of bronchoconstricting mediators
from mast cells
- Also inhibit microvascular leakage and increase mucociliary transport by increasing
ciliary activity
- Stimulate adenylyl cyclase and increase the formation of intracellular cAMP
- Causes Tachycardia and skeletal muscle tremoras side effects
- Epinephrine, ephedrine, isoproterenol and albuterol
- Epinephrine and isoproterenol increase the rate and force of cardiac contraction

1. Epinephrine
- Is an effective, rapidly acting bronchodilator (SQ 0.4 mL of 1:1000 solution, inhaled
320mcg)
- Maximal bronchodilation is achieved 15 minutes after inhalation
- Adverse effects: Tachycardia, arrhythmias and worsening of angina pectoris
- Stimulates alpha and beta 1&2 receptors
- Cardiovascular effects of epinephrine are of value in treating the acute vasodilation
and shock as well as the bronchospasm of anaphylaxis
- Its use in asthma has been displaced by other more B2 selective agents

2. Ephedrine
- Has a longer duration than epinephrine
- More pronounced central effects, much lower potency
- Now used infrequently in treating asthma

3. Isoproterenol
- Potent bronchodilator
- Causes maximal bronchodilation within 5 minutes after inhalation (80-120 mcg)
- Has a 60 to 90 minute duration of action
- Was attributed to cardiac arrhythmias resulting from the use of high doses of
inhaled isoproterenol in US
- Now rarely used for asthma

II. Beta2- Selective Drugs
- Most widely used sympathomimetics for the treatment of bronchoconstriction of
asth,a at present
- Have larger substitution on the amino group and in the position of the hydroxyl
groups on the aromatic ring
- Effective after inhaled or oral administration
- Have a long duration of action
- Mixture of R and S isomers
- R- isomer= activates the beta agonist receptor; levalbuterol (R isomer of albuterol)
- S-isomer=may promote inflammation;

Albuterol, terbutaline, metaproterenol and pirbuterol
- Are available as metered-dose inhalers
- Cause bronchodilation equivalent to that produced by isoproterenol
- Maximal bronchodilation is 15-30 minutes and persists for 3-4 hours
- All can be dilutes in saline for administration from a hand-held nebulizer
- Particle size: Nebulizer>metered- dose inhaler, so former is given at higher doses
- Nebulized therapy should be reserved for patients unable to use metered-dose
inhaler

Albuterol and terbutaline
- Also available in tablet form
- 1 tab 2-3x a day is usual regimen
- Principal adverse effects: skeletal muscle tremor, nervousness and occasional
weakness
- Adverse effect maybe reduced by starting patient on half-strength tablets for first 2
weeks of therapy
- Oral administration rarely prescribed

Terbutaline
- Only drug available for SC (0.25 mg)
- SC route indications similar to those for SC epinephrine- severe asthma requiring
emergency treatment when aerosolized therapy is ineffective or unavailable
- Has longer duration of action; can accumulate

New generation of long acting beta2-selective agonists:
- Salmaterol (a partial agonist)
- Formoterol (a full agonist)
- Both potent selective beta 2 agonists
- Long duration of action as a result of high lipid solubility (12 or more hours)
-