Tiotropium (Spiriva (TM)): Mechanistical considerations and clinical profile in obstructive lung disease

Inhaled antimuscarinics, often called anticholinergics in clinical medicine , are established as first line bronchodilators in COPD. Tiotropium has bee n developed as a new generation antimuscarinic following ipratropium Tiotro pium is a specific, highly potent antimuscarinic, demonstrating very slow d issociation from muscarinic receptors. Dissociation from M-2-receptors is f aster than from M-3 or M-1, which in functional in vitro studies, appeared as kinetic receptor subtype selectivity of Mf and M1 over Mt. The high pote ncy and slow receptor dissociation found its clinical correlate in signific ant and long lasting bronchodilatation and bronchoprotection in patients wi th COPD and asthma. In asthma, protection against methacholine challenge ex ceeded-the study period of 48 hours. In COPD, bronchodilatation of about 80 % of the plateau was demonstrated after the first dose. Following chronic o nce daily inhalation for 28 days, the improvement in pulmonary function was sustained and there was a further increase in peak effects, but more impor tantly a rising baseline, achieving steady state within 2 weeks. Tiotropium achieves very stable long lasting effects with comparatively low variation of bronchodilatation between peak and trough (the level before the next ad ministration). Stable 24 hour effectiveness profiles the compound as the fi rst once daily bronchodilator. Clinical correlates of kinetic receptor subt ype selective blockade remain to be shown. Plasma levels of tiotropium at t rough are in the low pg/ml range and are unlikely to explain the sustained effectiveness in the airways. Slow dissociation from muscarinic receptors i s likely to be responsible for the long duration of action.