[The respiratory system and safety pharmacology]

Many drugs affect respiration in man. The changes in respiratory function following their administration are due to a direct effect on the respiratory system or are the consequence of a central, metabolic (alteration of the acid-base balance) or vascular effect (pulmonary hypertension). Regulatory documents (CPMP, FDA and MHW drafts) are in agreement in considering the respiratory system as a vital function to explore during safety pharmacology studies. On the basis of these recommendations, the first studies to be performed should be on conscious unrestrained animals, in general the drug being administered as a single dose. The effects on the respiratory function are best studied by plethysmography in the guinea-pig or rat. The measurement of ventilatory parameters--respiratory rate, tidal volume, inspiratory time, expiratory time, peak inspiratory flow, peak exploratory flow and resistance--allow the differentiation between drugs affecting respiratory control and those altering lung mechanical properties. The pulmonary hypertension risk could be evaluated in the dog during haemodynamic studies. Finally, the study of the effects on blood gases should always be carried out in conscious animals, usually in the dog. For drugs belonging to pharmacological classes presenting a high respiratory risk, complementary studies should be considered. The extrapolation from healthy persons to ill patients (especially chronic respiratory insufficiency patients) of the incurred risk is often difficult. For this reason, it is very useful to study the effect of such drugs on the respiratory function of pathological animals.