Pharmacodynamic modelling of the drug-induced downregulation of a beta 2-adrenoceptor mediated response and lack of restoration of receptor function after a single high dose of prednisone.
Changes in beta 2-adrenoceptor function by chronic dosing of beta 2-mimetics and the possible influence of a single dose of prednisone have been studied as changes over time in the concentration-effect relationship of the beta 2-adrenoceptor agonist terbutaline. Hypokalaemia was used as the specific beta 2-adrenoceptor mediated effect. 8 healthy volunteers were given subcutaneous terbutaline 0.01 mg.kg-1 BW on 3 occasions over a 10-day experimental protocol: 1 Control experiment on Day 1; 2 After 7 days of oral terbutaline 5 mg t.i.d. (Day 8); and 3 After 8 days on oral terbutaline and 12 h after prednisone 100 mg orally (Day 10). The time course of the terbutaline concentrations and hypokalaemia was related using a pharmacokinetic-pharmacodynamic model. A sigmoid and a threshold Emax model were used to relate drug concentrations to effects. The oral terbutaline treatment caused a 35% increase in the distribution volume of SC terbutaline. After one week on oral terbutaline the concentration-effect relationship was shifted to the right and was steeper, with a higher EC50 of terbutaline and higher values for the apparent threshold concentration. These observations are compatible with a decrease in receptor numbers after 7 days of terbutaline in a system characterised by the presence of spare receptors. The data after prednisone pretreatment showed an apparent decline in the baseline plasma potassium concentrations that could be included in the Emax model. There was no change in the concentration-effect relationship 12 hours after prednisone.
Jonkers
R E
RE
Department of Pulmonology, F3n, Academic Medical Center, University of Amsterdam.
Braat
M C
MC
Koopmans
R P
RP
van Boxtel
C J
CJ
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000328:Adult; D015536:Down-Regulation; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007008:Hypokalemia / Q000378:metabolism*; D008297:Male; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000378:metabolism; D013726:Terbutaline / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D005938:Glucocorticoids; D018343:Receptors, Adrenergic, beta-2; D013726:Terbutaline; D011241:Prednisone