Medical Pharmacology Topics   

Asthma

Asthma is a pulmonary disease characterized by reversible airway obstruction, airway inflammation and hyper-responsiveness. The hyper-responsiveness determines the severity of the disease, and is assessed by histamine bronchoprovocation. Patients are also evaluated by measuring airway obstruction or hypoxemia in conjunction with the overall clinical situation (?).

Asthma cases occur throughout a spectrum of severity. Mild, intermitent asthma is managed using b-agonisnts as needed. Mild, persistent cases are treated with cromolyn, nedocromil, 5-LO antagonists, LTRAs and inhaled steroids. Moderate-persistent cases are treated with salmeterol, thophyline and oral steroids. Severe asthma is treated with high doses of inhaled steroids, systemic steroids, salmeterol and theophilline.

Anti-Inflamatory Agents

The antinflamatory agents used to treat asthma can be classified as mast cell stabilizers, 5-lipoxygenase inhibitors, leukotriene receptor antagonists and glucocorticoids.

Nedocromil and cromolyn are mast cell stabilizers that inhibit the release of inflamatory mediators like leukotrienes, prostaglandings and histamine. They act via the cromolyn binding protein (CBP), which controls a membrane Ca gating mechanism. Cromolyn and nedocromil also inhibit Ca mobilization from intracellular stores.

Nedocromil and cromoly are preventative agents that decrease lung eosinophil and mast cells and inhibit IgE production in B-cells. This leads to reduction of airway reactivity, reducing the effects of specific and non-specific stimuli and inhibiting both immediate and late bronchospasm. They are effective treatment if the airway is exposed to chronic stimuli, although the response may lag at least 2 weeks. Cromolyn and nedocromil are used as metered-dose inhaler (MDI) or nebulizer and are free of systemic adverse effects, although local irritation may aggravate airway bronchoconstriction during flare. Minor adverse effects include bad taste, cough and pharyngitis.

Leukotrienes cause bronchoconstriction, mucus secretion and edema at lower levels than other inflamatory mediators. They are produced from arachidonic acid by 5-lipoxygenase (5-LO). Two types drugs for the treatment of asthma target the leukotrienes: 5-LO inhibitors, like zileuton, and leukotriene receptor antagonists (LTRA) like zafirlukast, montelukast and pranlukast. LTRAs also reduce the symptoms of allergic rhinitis by blocking nasal constriction, edema, vasopermeability and mucus hypersecretion.

An important drug interaction regarding leukotriene inhibitors and antagonists is the use of non-steroidal antinflammatory drugs. Especifically, when COX antagonists like aspirin are used, more arachidonic acid is available for the 5-LO pathway.

As discussed earlier, glucocorticoids at higher than physiological concentrations inhibit the inflamatory response. By inhibiting the release of inflamatory mediators (histamne and leucotrienes) they reduce airway reactivity and inhibit late bronchodilation, diminishing edema formation, decreasing inflamatory cell infiltrtion and reducing mucus production. Agent used include beclomethasone, triamcinolone, flunisolide, budesonide and flucticasone.

Chronic use of systemic glucocorticoids leads to Cushing's syndrome. Inhaled therapy is effective and less toxic than systemic regimes. In either case, important factors to consider are dose, duration of therapy, and administration technique (ex. rinse mouth immediately after inhalatin. Some adverse effect of inhaled steroid therapy are oral candidiasis, adrenal suppression, dysphonia, posterior subcapsular cataracts and bone turnover.

A new antinflamatory agent not yet available for clinical use is the anti IgE recombinant humanized monoclonal antibody olizumab/E25. It binds the Fc domain of IgE, preventing its binding to the IgE receptor of mast cells. Olizumab/E25 reduces serum free IgE concentration, thus reducing airway responsiveness and inflammation and reducing both the early and late airway response. It has a half-life of 1-4 weeks by the parenteral route.

Bronchodilators

Non-specific catecholamines like ephedrine, epinephrine and isoproterenol can be used as bronchodilators. Synthetic agents that are more specific to b2-agonism include metaproterenol and albuterol. Salmeterol has a longer duration of action than other b2-adrenergic agonists, probbly due to strong binding to a site outside the receptor. A b-receptor polymorphism present in 15% of the population increases the effectiveness of b2-adrenergic agonists (reduction of the dose may be needed).

In addition to the b2-adrenergic agonists, theophilline is an important bronchodilator in the maintenance treatment of asthma and recurrent apnea.It is a phosphodiesterase inhibitor, therefore its action as bronchodilator and inhibitor of mediator release is due to inhibition of PDE3 and PDE4. Its duration of action is longer than b2-agonists, making it more effective to relieve nocturnal asthma.

Theophilline is a second-line agent because of its narrow therapeutic index. Its inhibition of PDE3 makes it a cariac stimulant. It is also an inhibitor of adenosine A2b (?), induces catecholamine secretion form the adrenal medulla, is a systemic and coronary vasodilator and a cerebral vasoconstrictor, stimulates gastric acid secretion, increases duafragm contraction and act as a weak diuretic. By being an adenosine antagonist, it is a CNS stimulant and increases respiratory drive.

Theohilline is metabolized by CYP1A2, which is inhibited by several other drugs (ex. inhibitor erythromycing, ex. inducer phenobarbital). CYP1A2 is also nduced by smoking and inhibited by fever, cor pulmonale, and cirrhosis.

Muscarinic M3 and M2 receptors seem to mediate bronchoconstriction through cGMP generation. Ipratropium bromide is an acetylcholine receptor antagonist used as a bronchoilator. Ipratropium is a quaternary ammonium. Therefore after inhalation its poor systemic absorption limits its effects to the lungs. It does not affect mcucillary clearance. It is indicated s an adjunt to other bronchodilators in the treatment of asthma, chronic bronchitis and emphisema. Anticholinergic brochodilators have a more gradual onset and longer duration of action thn b2-agonists.

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