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Asthma is characterized by:

Increased responsiveness of the bronchi Contraction of airway smooth muscle

The most easily reversed pathology

Mucosal thickening Viscid plugs of mucus

Many cells and mediators are involved in

asthma and lead to several effects on the

airways.

Prevent mast cell degranulation Anti-IgE antibody

Block the action of the products released Cromolyn, Nedocromil

Inhibit acetylcholine released from vagus nerve Muscarinic antagonists

Relax smooth muscle Sympathomimetics, Methylxanthines

Sympathomimetic Agents

Along with corticosteroids, are the most widely used drugs for asthma.

They relax smooth muscle and inhibit release of bronchoconstricting substances from mast cells.

They also inhibit microvascular leakage, increase ciliary activity and increase cAMP.

They cause tachycardia and tremor as side effects.

Adrenoceptor agonists are best delivered by inhalation for greatest effect and least systemic toxicity.

Even in best conditions, 80-90% of the aerosol is deposited in the mouth or pharynx.

Effectiveness can be increased by holding the breath in inspiration.

Side effects include tremor and nervousness. Short acting 2 selective drugs:

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Albuterol (salbutamol) Terbutaline Metaproterenol Pirbuterol

Bronchodilation is maximal within 15-30 min. and persists for 3-4 hr.

All can be diluted in saline for administration from a nebulizer.

Long-acting 2 selective agonists: Salmeterol Formoterol

Their duration of action is 12 hr. They are usually used with other drugs (eg:

inhaled corticosteroids) Methylxanthines

Methylxanthines: Theophylline (tea) Theobromine (cocoa) Caffeine (coffee)

Theophylline is most selective in its smooth muscle effects.

Caffeine has the most marked CNS effects. Theophylline is not an ideal drug, but has a low

cost. Aminophylline is an injectable derivative of

theophylline. They Inhibit phosphodiesterase (PDE) and

increase cAMP. Adenosine causes airway contraction and

histamine release. Theophylline derivatives also nay inhibit

adenosine receptors. Theophylline also improves contractility and

reverses fatigue of the diaphragm in patients with COPD.

So theophylline can diminish dyspnea even in patients with irreversible airflow obstruction.

Rate of metabolism: Children > adults > neonates and young infants

Cigarette smoking induces metabolizing enzymes. Theophylline has a narrow therapeutic window. Improvement in lung function is seen at 5-20

mg/L. Vomiting, abdominal discomfort, headache, and

anxiety occur at 15 mg/L in some, and at >20 mg/L in all patients.

Higher levels (> 40 mg/L) causes seizures or arrhythmias.

These may NOT be preceded by GI or neurologic warning symptoms.

Methylxanthines stimulate secretion of both gastric acid and digestive enzymes.

Even decaffeinated coffee has a potent stimulant effect on GI secretion.

Methylxanthines decrease blood viscosity and may improve blood flow.

For this reason pentoxifylline is used in the treatment of intermittent claudication.

Caffeine causes mild arousal with increased alertness and deferral of fatigue.

Very high doses cause convulsions and even death.

Caffeine has positive chronotropic and inotropic effects on the heart.

In very sensitive individuals, consumption of a few cups of coffee may result in arrhythmias.

Amount (gram) Caffeine (mg)

Coffee

Brewed, regular

Instant

Espresso

14222714222757

4018030120120

Tea

Brewed, leaf or bag

Instant

Iced

227

227

340

80

50

70

Soft Drinks

Pepsi, Diet Pepsi 340 38

9/24/2014 empperezmd2014 25

Caffeine Amount In Drinks

Antimuscarinic Agents

Involvement of parasympathetic system in respiratory diseases varies among individuals.

Antimuscarinic agents are used: Instead of inhaled -agonists in

asthmatics In addition to inhaled -agonists in

asthmatics In COPD patients

Ipratropium is a polar drug used for asthma. Tiotropium is used for COPD.

Corticosteroids Their most important action is inhibition of

airway mucosal inflammation. Inhalational therapy minimizes their adverse

effects. Inhalational drugs include:

Beclomethasone Budesonide Fluticasone Triamcinolone

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They do not relax airway smooth muscle directly. To prevent adrenal insufficiency they are used in

the morning. If nocturnal asthma happens they have to be

given in the afternoon. Oropharyngeal candidiasis may occur which can

be managed by gargling water and spit after each dose.

Hoarseness happens by their effect on vocal cords.

Chronic use of inhaled corticosteroids reduces bronchial reactivity.

Corticosteroids are not curative, asthma returns after stopping them even if they have been taken for > 2 years.

Cromolyn & nedocromil

They effectively inhibit both antigen and exercise induced asthma.

Alter the function of delayed chloride channels in the cell membrane, inhibiting cellular activation.

They inhibit cough and mast cell (but not basophil) degranulation in the lung.

Are only of value when taken prophylactically. Young patients with extrinsic asthma are most

likely to respond. A 4 weeks trial determines whether a patient will

respond. Cromolyn solution is also useful for allergic

rhinoconjunctivitis. Because the drugs are so poorly absorbed,

adverse effects are minor and are.

Leukotriene Pathway Inhibitors

LTC4 & LTD4 exert many effects known to occur in asthma

There are two treatment strategy: Inhibition of lipoxygenase and

leukotriene synthesis Zileuton

Antagonizing leukotriene D4 receptor

Zafirlukast, montelukast

They are weaker than inhaled corticosteroids, but reduce the frequency of exacerbations

One advantage is that they are taken orally; children comply poorly with inhaled therapies.

Montelukast is approved for children as young as 6 years of age.

5-10% of asthmatics are exquisitely sensitive to aspirin and other NSAIDs.

It is thought to result from inhibition of cyclooxygenase.

LT antagonists are useful for preventing this problem.

Anti-IgE Antibodies

Omalizumab inhibits the binding of IgE to mast cells but does not activate IgE already bound.

It also inhibits IgE synthesis by B lymphocytes. The murine antibody has been humanized and it

does not cause sensitization. Omalizumab's effect is reduction of both the

severity of asthma and corticosteroid dosage. Patients most likely to respond are those with the

greatest need: Patients with a history of repeated

exacerbations A high requirement for corticosteroid

treatment Poor pulmonary function

Omalizumab treatment reduced exacerbations requiring hospitalization by 88%.

These benefits justify the high cost of this treatment in severe disease.

Treatment strategy

All asthmatics should be instructed for severe, attacks:

To take up to four puffs of albuterol every 20 minutes over 1 hour.

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If they do not note clear improvement after the first four puffs, refer to emergency department.

Children exposed to allergens (pets) may be protected from asthma in later stages of life.

Mild asthma Inhaled beta receptor agonist (Albuterol)

on an "as-needed" basis In these cases inhaled corticosteroid is added:

Asthma attacks more than twice a week Nocturnal symptoms more than twice a

month FEV1 less than 80% predicted

Cromolyn or LT antagonist may be used alternatively, but inhalational steroids are superior.

If FEV1 is