Atopy and Antiallergic Therapy

Atopy denotesa hereditary predisposition for IgE-mediated allergic reactions. Clinical pictures include allergic rhinoconjunctivitis (“hay fever”), bronchial asthma, atopic dermatitis (neurodermatitis, atopic eczema) and urticaria.Evidently,differentiationofT-helper (TH) lymphocytes toward the TH2 phenotype is the common denominator. Therapeutic interventions are aimed at different levels to influence pathophysiological events (A).

1. Specific immune therapy (“hyposensitization”) with intracutaneous antigen injections is intended to shift TH cells in the direction of TH1.

2.Inactivation of IgE can be achieved by means of the monoclonal antibody, omalizumab. This is directed against the Fc portion of IgE and prevents its binding to mast cells.

3.Stabilization of mast cells. Cromolyn prevents IgE-mediated release of mast cell mediators, although only after chronic treatment. It is applied locally to conjunctiva, nasal mucosa, the bronchial tree (inhalation), and intestinal mucosa (absorption is almost nil with oral intake). Indications: prophylaxis of hay-fever, allergic asthma, and food allergies. Nedocromil acts similarly.

4.Blockade of histamine receptors. Allergic reactions are predominantly mediated by H1 receptors. H1-antihistaminics (p.118) are mostly used orally. Their therapeutic effect is often disappointing. Indications: allergic rhinitis (hay fever).

5.Blockade of leukotriene receptors. Montelukast is an antagonist at receptors for (cysteinyl) leukotriene. Leukotrienes evoke intense bronchoconstriction and promote allergic inflammation of the bronchial mucosa. Montelukast is used for oral prophylaxis of bronchial asthma. It is effective in analgesiainduced asthma (pp. 200, 340) and exerciseinduced bronchospasm.

6.Functional antagonists of mediators of allergy.

aα-Sympathomimetics, such as naphazoline, oxymetazoline, and tetrahydrozoline, are applied topically to the conjunctival and nasal mucosa to produce local vasoconstriction. Their use should be short-

term at most.

bEpinephrine, given i.v., is the most important drug in the management of anaphylactic shock: it constricts blood vessels,

reduces capillary permeability, and dilates bronchi.

cβ2-Sympathomimetics, such as terbutaline, fenoterol, and albuterol, are employed in bronchial asthma, mostly by inhalation, and parenterally in emergencies. Even after inhalation, effective amounts can reach the systemic circulation and cause side effects (e. g., palpitations, tremulousness, restlessness, hypokalemia). The duration of action of both salmeterol and formoterol, given by inhalation, is 12 hours. These long-acting β2-mimetics are included in the treatment of severe asthma. Given at nighttime, they can prevent attacks that preferentially occur in the early morning hours.

dTheophylline belongs to the methylxanthines. Its effects are attributed to both inhibition of phosphodiesterase (cAMP increase, p. 66) and antagonism at adenosine receptors. In bronchial asthma, theophylline can be given orally for prophylaxis or parenterally to control the attack. Manifestations of overdosage include ton-

ic-clonic seizures and cardiac arrhythmias (blood level monitoring).

eGlucocorticoids (p.244) have significant antiallergic activity and probably interfere with different stages of the allergic response. Indications: hay fever, bronchial asthma (preferably local application of analogues with high presystemic elimination, e.g., beclomethasone dipropionate, budesonide, flunisolide, fluticasone propionate); and anaphylactic shock (i.v. in high dosage)—a probably nongenomic action of immediate onset.

Bronchial Asthma

Definition. A recurrent, episodic shortness of breath caused by bronchoconstriction arising from airway inflammation and hyperreactivity.

Pathophysiology. One of the main pathogenetic factors is an allergic inflammation of the bronchial mucosa. For instance, leukotrienes that are formed during an IgE-medi- ated immune response (p. 72) exert a chemotactic effect on inflammatory cells. As the inflammation develops, bronchi become globally hyperreactive to spasmogenic stimuli. Thus, stimuli other than the original antigen(s) can act as triggers (A); e. g., breathing of cold air is an important trigger in exerciseinduced asthma. Cyclooxygenase inhibitors (p. 200) exemplify drugs acting as asthma triggers.

Management. Avoidance of asthma triggers is an important prophylactic measure, though not always feasible. Drugs that inhibit allergic inflammatory mechanisms or reduce bronchial hyperreactivity (glucocorticoids, “mast-cell stabilizers,” and leukotriene antagonists) attack crucial pathogenetic links. Bronchodilation is achieved by inhalation of β2-sympathomimetics (with high presystemic elimination) or, in the case of chronic obstructive lung disease, the anticholinergic, tiotropium (long-acting; single daily dose).

The step scheme (B) illustrates successive levels of pharmacotherapeutic management at increasing degrees of disease severity.

Step 1. Medications of first choice for the acute attack are short-acting, aerosolized β2- sympathomimetics, e.g., salbutamol or fenoterol. Their action occurs within minutes after inhalation and lasts for 4–6 hours.

Step 2. If β2-mimetics have to be used more frequently than once a week, more severe disease is present. At this stage, management includes anti-inflammatory drugs, preferably an inhalable glucocorticoid

(p. 246). Inhalational treatment with glucocorticoids must be administered regularly, improvement being evident only after several weeks. With proper inhalational use of glucocorticoids undergoing high presystemic elimination, concern about systemic adverse effects (“cortisone fear”) is unwarranted. Possible local adverse effects are oropharyngeal candidiasis and dysphonia. To minimize the risk of candidiasis, drug administration should occur before morning or evening meals. Alternatively, a “mast-cell stabilizer” (p.118) given by inhalation may prove adequately successful. Oral administration of timed-release theophylline (p. 338) is considered a further alternative, particularly so since the effect of theophylline is thought to possess an additional in- flammation-inhibiting component, apart from bronchodilation. The margin of safety is narrow (cardiac or CNS stimulation; plasma level controls!). A leukotriene antagonist (montelukast, p. 338) may also merit consideration.

Anti-inflammatory therapy is the more successful the less use is made of asneeded β2-mimetic medication.

Step 3. Continuous bronchodilator treatment is added to the low-dose glucocorticoid regimen. Preference is given to local use of a long-acting inhalable β2-mimetic (salmeterol or formoterol; p.338). If this proves insuf cient, the glucocorticoid dose is increased. Instead of a long-acting β2-mimetic, oral administration of timed-release theophylline, of a controlled release β2-agonist, or of a leukotriene antagonist would be possible.

Step 4. The dose of inhalable glucocorticoid is increased further. When this proves unsatisfactory, the active principles shown in (B) can be added on, including systemic administration of a glucocorticoid.