Pharmacokinetics and pharmacodynamics of beta 2-agonists (in the light of fenoterol)

As an example of beta 2-agonists fenoterol was used in this study on 27 patients with chronic obstructive airways diseases (COAD). After refraining from any kind of bronchodilator during 12 h the patients were given the drug in a crossover design in three groups. Using aerosol inhalation, intravenous route and nasal instillation we measured the response of airway resistance, intrathoracic gas volume and fenoterol plasma concentrations. The plethysmographic measurement of airways resistance (Rt) and intrathoracic gas volume showed comparable results of bronchodilation (at different dosages) for each of the routes. Even the onset of action was nearly the same with all the different routes. The amount of bronchodilatation was in the range of 59% of the initial Rt values. The duration of bronchodilatation was much longer after metered dose inhalers (MDI) inhalation ( > 4 h) than after intravenous routes. The duration after nasal administration was in between. The infusion maintains its effect only as long as the infusion is given. The bronchodilation response induced by fenoterol reaches the same values with different routes of administration and depends on the amount of decrease of airway obstruction. The highest plasma concentrations were reached with the intravenous boluses. Immediately after injection the concentration decreased rapidly. The maximum plasma concentrations after MDI were around 20% of that after the intravenous route for the same bronchodilatation. The heart rate is a function of the plasma concentration. At low concentrations such as after aerosol inhalation of 200 micrograms the influence on the heart rate is not significant. After aerosol inhalation the effect at the receptor can be calculated to be > 7 times stronger than seen from any plasma concentration after intravenous administration. It is assumed that there are structures near the beta 2-bronchodilator receptor which are responsible for the long-lasting effect that is observed only after aerosol inhalation. These depot structures cannot be reached from the plasma in concentrations needed under in vivo conditions. Loss of these structures shortens the duration of the bronchodilator effect. In respect to effect/side effect relationship, more frequent administration of smaller doses may be the best method for administering beta 2-agonists as aerosols in patients with COAD. For many patients with severe forms of this disease, individual optimal dosage with MDI has to be defined following repeated measurements of the airway obstruction so as to achieve the best possible bronchodilatation.