PHARMACOKINETIC OPTIMIZATION OF ASTHMA-TREATMENT

Asthma is generally managed with bronchodilator therapy and/or anti-in flammatory drugs. Guidelines now advocate selection of drugs and pharm aceutical formulations (long-acting vs short-acting, inhaled vs system ic) on the basis of disease severity. Theophylline has a narrow therap eutic margin. Clearance is highly variable and plasma concentrations s hould be monitored to avoid the occurrence of plasma concentration-rel ated adverse effects. The rate of absorption of theophylline differs d epending on the sustained release formulation administered. Some produ cts do not provide sufficient plasma drug concentrations for therapeut ic efficacy over a 12-hour period, particularly in patients with high clearance rates (e.g. children and patients who smoke). Administration of drugs via inhalation offers several advantages over systemic route s of administration (e.g. adverse effects are decreased). Inhalation i s now advocated as first-line therapy. Aerosol medications available f or the treatment of asthma are Pa-agonists (including the newer long-a cting agents such as salmeterol), corticosteroids, anticholinergic dru gs, sodium cromoglycate (cromolyn sodium) and nedocromil. To reach the airways, aerosolised particles should be 1 to 5 mu m in diameter. Par ticles of this size can be produced by nebuliser for continuous admini stration or by metered-dose inhaler and drug powder inhaler for unit d ose medication. For efficient use of the metered-dose inhaler, slow in halation and actuation must be coordinated. However, efficacy and conv enience can be improved when spacer devices are used. Furthermore, spa cer devices lessen the oropharyngeal adverse effects of inhaled cortic osteroids. Dry powder inhalers are more easily used by children and el derly patients than metered-dose inhalers. Regardless of the device us ed, a maximum of 10% of the inhaled dose reaches the airways. The rest of the dose is swallowed and absorbed through the gastrointestinal tr act. Most inhaled drugs have low oral bioavailability, either because of a high first-pass metabolism (beta(2)-agonists and glucocorticoids) or because of lack of absorption (sodium cromoglycate). Sulphation of beta(2)- agonists occurs in the wall of the gastrointestinal tract an d extensive metabolism of inhaled corticosteroids occurs in the liver. Low bioavailability of the swallowed fraction contributes to reduced adverse effects.