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

Life Sci. 1999;64(6-7):457-64. doi: 10.1016/s0024-3205(98)00588-8.

Abstract

Inhaled antimuscarinics, often called anticholinergics in clinical medicine, are established as first line bronchodilators in COPD. Tiotropium has been developed as a new generation antimuscarinic following ipratropium. Tiotropium is a specific, highly potent antimuscarinic, demonstrating very slow dissociation from muscarinic receptors. Dissociation from M2-receptors is faster than from M3 or M1, which in functional in vitro studies, appeared as kinetic receptor subtype selectivity of M3 and M1 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long lasting bronchodilatation and bronchoprotection in patients with COPD and asthma. In asthma, protection against methacholine challenge exceeded the study period of 48 hours. In COPD, bronchodilatation of about 80% of the plateau was demonstrated after the first dose. Following chronic once daily inhalation for 28 days, the improvement in pulmonary function was sustained and there was a further increase in peak effects, but more importantly 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 administration). Stable 24 hour effectiveness profiles the compound as the first once daily bronchodilator. Clinical correlates of kinetic receptor subtype selective blockade remain to be shown. Plasma levels of tiotropium at trough are in the low pg/ml range and are unlikely to explain the sustained effectiveness in the airways. Slow dissociation from muscarinic receptors is likely to be responsible for the long duration of action.

Publication types

  • Review

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Asthma / metabolism
  • Binding Sites
  • Bronchodilator Agents / metabolism
  • Bronchodilator Agents / pharmacology
  • Bronchodilator Agents / therapeutic use*
  • Cell Membrane / metabolism
  • Clinical Trials as Topic
  • Dose-Response Relationship, Drug
  • Humans
  • Lung Diseases, Obstructive / drug therapy*
  • Lung Diseases, Obstructive / metabolism
  • Muscarinic Agonists / metabolism
  • Muscarinic Agonists / pharmacology
  • Muscarinic Antagonists / metabolism
  • Muscarinic Antagonists / pharmacology
  • Muscarinic Antagonists / therapeutic use*
  • Receptors, Muscarinic / metabolism
  • Scopolamine Derivatives / blood
  • Scopolamine Derivatives / metabolism
  • Scopolamine Derivatives / pharmacology
  • Scopolamine Derivatives / therapeutic use*
  • Tiotropium Bromide

Substances

  • Bronchodilator Agents
  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Receptors, Muscarinic
  • Scopolamine Derivatives
  • Tiotropium Bromide