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Pulmonary Disease and Drug Kinetics

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Summary

A number of examples of altered drug disposition in patients with respiratory disease have been reported. These reports have been analysed in terms of absorption, distribution and elimination. The changes have been examined mechanistically in light of the pathophysiology of respiratory disease and the known influence of these physiological parameters on drug disposition. Our analysis has included in vivo and in vitro data from laboratory animals in addition to appropriate data from humans.

Acute hypoxaemia appears to decrease intrinsic hepatic clearance while chronic hypoxia appears to increase intrinsic clearance. The free fraction of some bases is decreased in plasma taken from patients with chronic hypoxaemia and this change can interact with changes in intrinsic metabolic activity. Blood gas disturbances also can affect drug disposition by decreasing hepatic and renal perfusion.

Cor pulmonale has not been linked to altered drug disposition, except in the case of theophylline. However, this pathophysiological condition may be equivalent to congestive cardiac failure through diminished hepatic and renal perfusion.

The marked reduction (approximately 50%) in theophylline clearance documented in some asthmatic patients may reflect protein binding changes, a paradoxical response of metabolic pathways to hypoxaemia, or other as yet unidentified processes.

It is apparent that respiratory disease significantly changes drug disposition through a number of interacting mechanisms. These have not been adequately studied to provide a basis for clinical dosage adjustment, however, general principles are emerging: Drugs showing flow-dependent hepatic clearance (e.g. lignocaine/lidocaine, pethidine/meperidine, propoxyphene) and those drugs showing predominant renal clearance (aminoglycosides, digoxin) should be used with caution. Theophylline doses must be reduced on an empirical basis, as the mechanisms causing reduced clearance cannot be convincingly explained in terms of the pathophysiology of respiratory disease.

The lungs must be added to the existing list of organs (liver, kidney, heart) whose dysfunction significantly affects drug disposition.

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Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Amherst, New York, USA

    P. du Souich,  A. J. McLean, D. Lalka, S. Erill & M. Gibaldi

  2. Clinical Pharmacokinetics Laboratory, Buffalo General Hospital, Buffalo, New York, USA

    P. du Souich,  A. J. McLean, D. Lalka, S. Erill & M. Gibaldi

  3. Departmento de Farmacologia, Facultad de Medicina, Bilbao, Spain

    P. du Souich,  A. J. McLean, D. Lalka, S. Erill & M. Gibaldi

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  1. P. du Souich
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  2. A. J. McLean
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du Souich, P., McLean, A.J., Lalka, D. et al. Pulmonary Disease and Drug Kinetics. Clin Pharmacokinet 3, 257–266 (1978). https://doi.org/10.2165/00003088-197803040-00001

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