ENHANCED HISTAMINE H I RECEPTOR BLOCKADE WITH CHLORPHENIRAMINE IN THE ASTHMATIC TRACHEO-BRONCHIAL TREE: FURTHER EVIDENCE FOR INCREASED DRUG DELIVERY IN ASTHMA

We have measured the competitive antagonistic effect of chlorpheniramine in bronchi of 8 normal and 12 asthmatic subjects. Classical pharmacological theory states that the degree of competitive antagonism depends only upon 1) antagonist concentration at the receptor, and 2) receptor affinity. Delivery and affinity also influence agonist responsiveness, but measurement of bronchial antagonism allows study of these factors in isolation. Bronchial responsiveness to histamine was measured as the dose required to produce a 35% fall in specific conductance (sGaw), called PD35• On different days, 2 measurements of control PD35 were made on each subject. Measurements of PD35 were also repeated after inhalation of 1.45 mg chlorpheniramine and intravenous injection of 0.17 mg/kg chlorpheniramine. Antagonist effect of chlorpheniramine was measured as Dose Ratio-l (DR-I), where DR= PD35 after chlorpheniramine/control PD35• Geometric mean of DR -1 with inhaled chlorpheniramine in asthmatic subjects (5.8) was 6.8 times that of normal subjects (0.86) (p= 0.002), and DR-l with intravenous chlorpheniramine in asthmatic subjects (4.4) was 2.75 times that of normal subjects (1.6) (p=0.005). There were significant negative correlations between PD35 and DR-I, whether chlorpheniramine was administered by inhalation (r= -0.87, p<O.OO 1) or intravenously (r= -0.62, p<0.005). There was also a significant correlation between DR-1 obtained by two routes of administration (r= 0.77, p<0.001). Taken with our previous study showing enhanced antagonism with atropine at bronchial muscarinic receptors in asthma, I these results suggest that drug delivery by inhaled and parenteral routes may be increased in asthmatic bronchi.