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Mediator Modifiers

Asthma is essentially an inflammatory disorder of the airways, in which allergic stimuli often trigger IgE-mediated mast cell release of mediators of inflammation. Airway reactivity can be triggered by such nonspecific stimuli as cold air or dust. Allergic inflammation of the airway is a product of an immune response, and the T-lymphocyte plays a central role in attracting mast cells and eosinophils, which in turn release mediators that attract other cells and damage epithelial cells.

The clinical result of asthma is a chronic persistent inflammation of the airway, coupled with occasional acute episodes of wheezing and airway obstruction caused by bronchostriction, mucosal swelling and mucus secretion. There are drugs available to inhibit the mediators of inflammation, including: cromolyn sodium, nedocromil sodium, zafirlukast, and zileuton. These agents, sometimes referred to as mediator modifiers, are prophylactic and are intended to assist the management of chronic asthma, not to relieve acute airway obstruction or provide bronchodilation in an acute asthma attack. Patients who show an improvement in bronchospastic symptoms with steroids may benefit from mediator modifier

Cromolyn sodium (Disodium Cromoglycate) is considered an antiasthmatic, antiallergic, and mast cell stabilizer. Cromolyn is available as a dry powder inhaler, a nebulizer solution, and an MDI.It does not block cholinergic, muscarinic receptors, and has no intrinsic bronchodilating capability. Pretreatment with inhaled cromolyn sodium results in inhibition of mast cell degranulation, thereby blocking release of the chemical mediators of inflammation. While the dosage varies at the discretion of the physician, the usual adult dose of cromolyn is 20 mg TID or QID.

Nedocromil sodium (Tilade) is another prophylactic drug used in the management of mild to moderate asthma. It exerts its antiinflammatory and antiasthmatic effect by inhibiting the activation and activity of multiple inflammatory cells, including mast cells, eosinophils, airway epithelial cells, and sensory neurons. Available as an MDI with 1.75 mg per actuation, the recommended dosage for maintenance therapy in asthma is two inhalations 4 times a day.

Zafirlukast (Accolate) is a relatively new (approved for use in U.S. in 1996) prophylactic agent that acts on a portion of the inflammatory process as a leukotriene receptor antagonist, preventing the inflammaory response of airway contractility, vascular permeability, and mucus secretion caused by certain leukotrienes.

While its been in use a relatively short period of time, Zafirlukast gives evidence of being effective in preventing bronchoconstriction and other asthmatic airway responses, against LTD₄-induced constriction, allergen, exercise, and cold air challenge. Side effects have included headache, respiratory infection, nausea, diarrhea, generalized and abdominal pain.

Zileuton (Zyflo) also new (approved in 1997), inhibits the 5-lipoxygenase enzyme which would otherwize catalyze the formation of leukotrienes from arachidonic acid. It is indicated for the prophylaxis and chronic treatment of asthma in patients over 12 years of age, and has been effective in attenuating the asthma response to allergen challenge, cold air, and aspirin challenges. It is available in a 600 mg tablet form, with dosage being recommended at one tablet 4 times daily.

There are at least four classes of drugs which provide antiinflammatory activity within the arachidonic acid cascade, and which are being investigated for possible use in assisting the treatment of asthma (some only have code names at this time):

Cysteinyl LT antagonists

5-lipoxygenase inhibitors

FLAP binding inhibitors

LTB₄ antagonists

Inhibitors of 5-lipoxygenase either inhibit the enzyme directly or bind to a membrane protein called FLAP. FLAP then combines with 5-lipoxygenase to inhibit leukotriene synthesis. Zileuton is an agent that directly inhibits 5-lipoxygenase. While there are still questions regarding the usefullness of blocking the synthesis or activity of a single family of mediators such as leukotrienes, there has been a high efficacy in clinical trials of these drugs that supports the thesis that these may prove useful in the future.