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Pharmacodynamic modelling of the drug-induced downregulation of a β2-adrenoceptor mediated response and lack of restoration of receptor function after a single high dose of prednisone

  • Pharmacodynamics
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Abstract

Changes in β2-adrenoceptor function by chronic dosing of β2-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 β2-adrenoceptor agonist terbutaline. Hypokalaemia was used as the specific β2-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.

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References

  • Aarons RD, Nies AS, Gerber JG, Molinoff PB (1983) Dercreased beta adrenergic receptor density on human lymphocytes after chronic treatment with agonists. J Pharmacol Exp Ther 224:1–6

    Google Scholar 

  • Akaike H (1976) An information criterion. Math Sci 14:5–9

    Google Scholar 

  • Bartter F, Fourman P (1962) The different effects of aldosterone-like steroids on urinary excretion of potassium and acid. Metab Clin Exp 11:6–20

    Google Scholar 

  • Bengtsson B, Fagerstrom P-O (1982) Extrapulmonary effects of terbutaline during prolonged administration. Clin Pharmacol Ther 31:726–732

    Google Scholar 

  • Bernardi M, DePalma R, Trevisani F, Capani F, Santini C, Baraldini M, Gasbarrini G (1985) Serum potassium circadian rythm. Relationship with aldosterone. Horm Metabol Res 17:69

    Google Scholar 

  • Bia MJ, DeFronzo RA (1981) Extrarenal potassium homeostasis. Am J Physiol 240:F257-F268

    Google Scholar 

  • Braat MCP, Jonkers RE, Van Boxtel CJ (1992) Quantification of metoprolol beta2-adrenoceptor antagonism in asthmatic patients by pharmackinetic-pharmacodynamic modelling. Pulm Pharmacol 5:31–38

    Google Scholar 

  • Brodde O-E, Brinkman M, Schemuth R, O'Hara N, Daul A (1985) Terbutaline-induced desensitization of human lymphocyte β2-arenoceptors. Accelerated restoration of β-adrenoceptor responsiveness by prednisone and ketotifen. J Clin Invest 76:1096–1101

    Google Scholar 

  • Brodde OE (1991) Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev 43:203–242

    Google Scholar 

  • Brown MJ, Brown DC, MB Murphy (1983) Hypokalemia from beta-2-receptor stimulation by circulating epinephrine. N Engl J Med 309:1414–1419

    Google Scholar 

  • Clausen T, Flatman JA (1980) Beta 2 adrenoceptors mediate the stimulating effect of adrenaline on active electrogenic Na-K transport in rat soleus muscle. Br J Pharmacol 68:749–755

    Google Scholar 

  • Davies AO, Lefkowitz RJ (1984) Regulation of beta adrenergic receptors by steroid hormones. Ann Rev Physiol 46:119–130

    Google Scholar 

  • Ellul-Micallef R, Fenech FP (1975) Effect of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness. Lancet II:1269–1271

    Google Scholar 

  • Farfel Z, Iaina A, Eliahou HE (1978) Presence of insulin-reninaldosterone-potassium interrelationship in normal subjects, disrupted in chronic hemodialysis patients. J Clin Endocrinol Metab 49:9–17

    Google Scholar 

  • Fauci AS, Dale DC (1974) The effect of in vivo hydrocortisone on subpopulations of human lymphocytes. J Clin Invest 53:240–246

    Google Scholar 

  • Fuseau E, Sheiner LB (1984) Simultaneous modeling of pharmacokinetics and pharmacodynamics with a non-parametric pharmacodynamic model. Clin Pharmacol Ther 35:733–741

    Google Scholar 

  • Georgopoulos D, Wong D, Anthonisen NR (1990) Tolerance to β2-agonists in patients with chronic obstructive pulmonary disease. Chest 97:280–284

    Google Scholar 

  • Gibaldi M, Perrier D (1975) Pharmacokinetics. Dekker I, New York

    Google Scholar 

  • Goldstein A, Aronow L, Kalman SM (1974) Principles of drug action, the basis of pharmacology (2nd ed). Wiley, New York, pp 96–104

    Google Scholar 

  • Harden TK (1983) Agonist-induced desensitization of the β-adrenergic receptor-linked adenylate cyclase. Pharmacol Rev 35:5–32

    Google Scholar 

  • Haynes BF, Fauci AS (1978) The differential effect of in vivo hydrocortisone on the kinetics of subpopulations of human peripheral blood thymus-derived lymphocytes. J Clin Invest 61:703–707

    Google Scholar 

  • Holford NHG (1984) Drug concentration, binding, and effect in vivo. Pharm Res 3:102–105

    Google Scholar 

  • Holford NHG, Sheiner LB (1981) Understanding the dose effect relationship: clinical applications of pharmacokinetic-dynamic models. Clin Pharmacokinet 6:429–453

    Google Scholar 

  • Holgate ST, Baldwin CJ, Tattersfield AE (1977) β-Adrenergic agonist resistance in normal human airways. Lancet II:375–377

    Google Scholar 

  • Hui KPP, Conolly ME, Tashkin DP (1982) Reversal of lymphocyte β-adrenoceptor desensitization by glucocorticoids. Clin Pharmacol Ther 32:566–571

    Google Scholar 

  • Jenne JW, Chick TW, Strickland RD, Wall FJ (1977) Subsensitivity of beta responses during therapy with a long-acting beta-2 preparation. J Allergy Clin Immunol 59:383–390

    Google Scholar 

  • Jonkers RE, Van Boxtel CJ, Oosterhuis B (1987) Beta-2-adrenoceptor mediated hypokalemia and its abolishment by oxprenolol. Clin Pharmacol Ther 42:627–633

    Google Scholar 

  • Jonkers RE, Van Boxtel CJ, Koopmans RP, Oosterhuis B (1989) A non steady state agonist antagonist interaction model using plasma potassium concentrations to quantify the beta 2 selectivity of beta blockers. J Pharmacol Exp Ther 249:297–302

    Google Scholar 

  • Jonkers RE, Koopmans RP, Portier EJG, van Boxtel CJ (1991) Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers. J Pharmacol Exp Ther 256:959–966

    Google Scholar 

  • Knight RP, Kornfeld DS, Glaser G, Bondy P (1955) Effects of intravenous hydrocortisone on electrolytes of serum and urine in man. J Clin Endocrinol 15:176–118

    Google Scholar 

  • Leferink JG, Van den Berg W, Wagemaker-Engels J, Kreukniet J, Maas RAA (1982) Pharmacokinetics of terbutaline, a beta 2 sympathicomimetic, in healthy volunteers and asthmatic patients. Arzneim Forsch 32:159–164

    Google Scholar 

  • Leferink JG (1979) Terbutaline. Analytical, clinical pharmacological and toxicological aspects. Thesis, Utrecht

  • Levitzki A (1984) Receptor occupancy and “spare” receptors. In “Receptors: A quantitative approach”. Benjamin/Cummings, Menlo Park, CA, pp. 91–101

    Google Scholar 

  • Maisel AS, Fowler P, Rearden A, Motulsky HJ, Michel MC (1989) A new method for isolation of human lymphocyte subsets reveals differential regulation of β-adrenergic receptors by terbutaline treatment. Clin Pharmacol Ther 46:429–439

    Google Scholar 

  • Martinsson A, Larsson K, Hjemdahl P (1987) Studies in vivo and in vitro of terbutaline-induced β-adrenoceptor desensitization in healthy subjects. Clin Sci 72:47–54

    Google Scholar 

  • Metzler CM, Elfring GL, McEvan AJ (1974) The users manual for NONLIN and associated programs, research biostatistics. Upjohn, Kalamazoo, MI

    Google Scholar 

  • Morris HG, Sherman NA, Silvers WS, Mills D, Shepperdson FT (1983) Timed effects of an oral adrenergic bronchodilator on pulmonary function and measurements of plasma and leukocyte cyclic AMP: divergence in duration of drug action and development of tolerance. J Allergy Clin Immunol 71:266–276

    Google Scholar 

  • Nelson HS, Dudley R, Doner HC, Posey WC (1977) Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am Rev Resp Dis 116:871–878

    Google Scholar 

  • Nelson HS (1982) Beta adrenergic agonists. Chest 82 (suppl):33S–38S

    Google Scholar 

  • Oosterhuis B, Ten Berge IJM, Schellekens PTA, Van Boxtel CJ (1987) Concentration-dependent effects of prednisolone on lymphocyte subsets and mixed lymphocyte culture in humans. J Pharmacol Exp Ther 243:716–722

    Google Scholar 

  • Oosterhuis B, Braat MCP, Roos CM, Wemer J, Van Boxtel CJ (1986) Pharmacokinetic-dynamic modeling of terbutaline bronchodilation in asthma. Clin Pharmcol Ther 40:469–475

    Google Scholar 

  • Repsher LH, Anderson JA, Bush RK, Falliers CJ, Kass I, Kemp JP, Reed C, Siegel S, Webb DR (1984) Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol. Chest 85:34–38

    Google Scholar 

  • Samuelson WM, Davies AO (1984) Hydrocortisone-induced reversal of beta-adrenergic receptor uncoupling. Am Rev Resp Dis 130:1023–1026

    Google Scholar 

  • Smith SR, Kendall MJ (1986) Downgrading of biochemical and cardiovascular responses to an intravenous infusion of terbutaline following chronic treatment with oral terbutaline. Int J Clin Pharmacol Ther Toxicol 24:1–3

    Google Scholar 

  • Solomon R, Dubey A (1989) Diurnal variation in serum potassium (K). Clin Pharmacol Ther 45:155

    Google Scholar 

  • Stiles GL, Caron MG, Lefkowitz RJ (1984) β-Adrenergic receptors: Biochemical mechanisms of physiological regulation. Physiol Rev 64:661–743

    Google Scholar 

  • Struthers AD, Reid JL, Whitesmith R, Rodger JC (1983) Effect of intravenous epinephrine on electrocardiogram, blood pressure and serum potassium. Br Heart J 49:90–93

    Google Scholar 

  • Tashkin DP, Conolly ME, Deutsch RI, Hui KKP, Littner M, Scarpace P, Abrass I (1982) Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects. Am Rev Resp Dis 125:185–193

    Google Scholar 

  • Van den Berg W, Leferink JG, Fokkens JK, Kreukniet J, Maes RAA, Bruynzeel PLB (1982) Clinical implications of drug-induced desensitization of the beta receptor after continuous oral use of terbutaline. J Allergy Clin Immunol 69:410–417

    Google Scholar 

  • Whyte KF, Addis GJ, Whitesmith R, Reid JL (1987) The mechanism of salbutamol-induced hypokalemia. Br J Clin Pharmacol 23:65–71

    Google Scholar 

  • Yu DT, Clements PT, Paulus HE, Peter JB, Levy J, Barnett EV (1974) Human lymphocyte subpopulations. Effect of corticosteroids. J Clin Invest 53:565–571

    Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Pulmonology, F3n, Academic Medical Center, University of Amsterdam, P.O. Box 22700, NL-1100 DE, Amsterdam

    R. E. Jonkers & M. C. P. Braat

  2. Department of Clincal Pharmacology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, NL-1100 DE, Amsterdam, The Netherlands

    R. P. Koopmans & C. J. van Boxtel

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  1. R. E. Jonkers
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  2. M. C. P. Braat
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  3. R. P. Koopmans
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  4. C. J. van Boxtel
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Jonkers, R.E., Braat, M.C.P., Koopmans, R.P. et al. Pharmacodynamic modelling of the drug-induced downregulation of a β2-adrenoceptor mediated response and lack of restoration of receptor function after a single high dose of prednisone. Eur J Clin Pharmacol 49, 37–44 (1995). https://doi.org/10.1007/BF00192356

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  • DOI: https://doi.org/10.1007/BF00192356

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