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Extent of beta1- and beta2-receptor occupancy in plasma assesses the antagonist activity of metoprolol, pindolol, and propranolol in the elderly

  • Beta-Blocker Therapy
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Summary

We estimated antagonist activity of metoprolol, pindolol, and propranolol in elderly cardiovascular patients by determining the extent to which the drugs occupied rabbit lung beta1- and rat reticulocyte beta2-adrenoceptors in plasma samples during drug treatment. The randomized, double-blind, crossover study was carried out by administering twice daily 100 mg metoprolol, 5 mg pindolol, and 80 mg propranolol for 7 days to 20 hypertensive subjects with a mean age of about 70 years. A 2-week interval was kept between administration of the different regimens. Receptor occupancy was measured at 1 hour before and 2 hours after administration of the last dose of each regimen by adding rabbit lung beta1- and rat reticulocyte beta2-receptors to plasma samples and by labeling the receptors with a radiolabeled beta-antagonist, (−)-[3H]CGP-12177. The results and conclusions were the following: (a) The extent to which metoprolol, pindolol, and propranolol occupied rabbit lung beta1-and rat reticulocyte beta2-adrenoceptors in plasma samples estimated accurately the intensity of beta-receptor antagonism in the patients who did not tolerate physiological and pharmacological tests measuring the degree of beta1- and beta2-adrenoceptor blockade. (b) The mean beta1- and beta2-receptor occupancy of pindolol and propranolol varied between 76% and 99% during the treatments. The mean beta1-receptor occupancy of the metoprolol regimen varied between 54% and 92%, and its beta2-receptor occupancy varied between 6% and 38%. Thus the antagonist activity of the metoprolol regimen differed significantly from that of the other regimens (ANOVA for repeated measures, p<0.05 and 0.001, for the beta1- and beta2-occupancy, respectively). (c) The extent of beta1- and beta2-receptor occupancy in plasma samples was in conformity with the literature on the intensity, selectivity, and duration of beta-blockade after similar drug doses. (d) The data on the receptor occupancy of beta-blocking drugs in plasma samples appear to be valuable in analyzing their effects, and it may be a method for optimizing drug therapy for aged cardiovascular patients.

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References

  1. Wikstrand J, Berglund G. Antihypertensive treatment with beta-blockers in patients over 65.Br Med J 1982;285:850.

    Google Scholar 

  2. George CF. The rationale of treating high blood pressure in the elderly.Age Ageing 1979;8:110–114.

    PubMed  Google Scholar 

  3. Tregaskis BF, McDevitt DG. Beta-adrenoceptor-blocking drugs in the elderly.J Cardiovasc Pharmacol 1990;16:S25-S28.

    Google Scholar 

  4. Amery A, Hansson L, Gudbrandsson T, Siverstson R, Svensson A. Hypertension in the elderly.Acta Med Scand 1981;210:221–229.

    PubMed  Google Scholar 

  5. Kannel WB, Gordon T. Evaluation of cardiovascular risks in the elderly. The Framingham Study Bull.NY Acad Med 1978:54:573–591.

    Google Scholar 

  6. McDevitt DG. The assessment of beta-adrenoceptor blocking drugs in man.Br J Clin Pharmacol 1977;4:415–425.

    Google Scholar 

  7. McDevitt DG. In vivo studies on the function of cardiac beta-adrenoceptors in man.Eur Heart J 1989;10(Suppl B):22–28.

    Google Scholar 

  8. Koch-Weser J. Metoprolol.N Engl J Med 1979;301:698–703.

    PubMed  Google Scholar 

  9. Frishman WH. Pindolol.N Engl J Med 1983;308:940–944.

    PubMed  Google Scholar 

  10. Shand DG. Propranolol.N Engl J Med 1975;293:280–285.

    PubMed  Google Scholar 

  11. Wellstein A, Palm D, Belz GG, Pitschner HF. Receptor binding characteristics and pharmacokinetic properties as a tool for the prediction on clinical effects of β-blockers.Arzneim Forsch/Drug Res 1985;35:2–6.

    Google Scholar 

  12. Wellstein A, Palm D, Belz G-G, Butzer R, Polsak R, Pett B. Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy.Eur Heart J 1987;8(Suppl M):3–8.

    Google Scholar 

  13. Rochester CL, Gammon DE, Shane E, et al. A radioreceptor assay for propranolol and 4-hydroxypropranolol.Clin Pharmacol Ther 1980;28:32–39.

    PubMed  Google Scholar 

  14. Brodde O-E, Kuhlhoff F, Arroyo J, Prywarra A. No evidence for temperature-dependent changes in the pharmacological specificity of β1- and β2-adrenoceptors in rabbit lung membranes.Naunyn Schmiedebergs Arch Pharmacol 1983;322:20–28.

    PubMed  Google Scholar 

  15. Pauwels PJ, Gommeren W, Van Lommen G, Janssen PAJ, Leysen JE. The receptor binding profile of the new antihypertensive agent Nebivolol and its stereoisomers compared with various β-adrenergic blockers.Mol Pharmacol 1988;34:843–851.

    PubMed  Google Scholar 

  16. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent.J Biol Chem 1951;193:265–275.

    PubMed  Google Scholar 

  17. Kaiser G, Wiemer G, Kremer G, Dietz J, Palm D. Identification and quantification of beta-adrenoceptor sites in red blood cells from rats.Naunyn Schmiedeberg's Arch Pharmacol 1978;305:41–50.

    Google Scholar 

  18. Wellstein A, Palm D, Wiemer G, Schäfer-Korting M, Mutschler E. Simple and reliable radioreceptor assay for beta-adrenoreceptor antagonists and active metabolites in native human plasma.Eur J Clin Pharmacol 1984;27:545–553.

    PubMed  Google Scholar 

  19. Kaila T. A sensitive radioligand binding assay for timolol.J Pharm Sci 1991;80:296–299.

    PubMed  Google Scholar 

  20. Staehelin M, Simons P, Jaeggi K, Wigger N. CGP-12177: A hydrophilic beta-adrenergic receptor radioligand reveals high affinity binding of agonists to intact cells.J Biol Chem 1983;258:3496–3502.

    PubMed  Google Scholar 

  21. Scatchard G. The attractions of proteins for small molecules and ions.Ann NY Acad Sci 1949;51:660–672.

    Google Scholar 

  22. O'Donnell SR, Wanstall JC. Evidence that ICI 118,551 is a potent highly selective beta-2 adrenoceptor antagonist and can be used to characterize beta-adrenoceptor populations in tissues.Life Sci 1980;27:671–677.

    PubMed  Google Scholar 

  23. Munson PJ, Rodbard D. LIGAND: A versatile computerized approach for characterization of ligand-binding systems.Anal Biochem 1980;107:220–239.

    PubMed  Google Scholar 

  24. McPherson GA. Analysis of radioligand binding experiments. A collection of micro computer programs for the IBM PC.J Pharmacol Methods 1985;14:213–228.

    PubMed  Google Scholar 

  25. Wellstein A, Palm D, Pitcshner HF, Belz GG. Receptor-binding of propranolol is the missing link between plasma concentration kinetics and the effect-time course in man.Eur J Clin Pharmacol 1985;29:131–147.

    PubMed  Google Scholar 

  26. Williams LT, Lefkowitz RJ. Theory of ligand-receptor interactions. In:Radioligand Binding Studies in Adrenergic Pharmacology. New York: Raven Press, 1978:27–41.

    Google Scholar 

  27. Juberg EN, Minneman KP, Abel PW. β1- and β2-receptor binding and functional response in right and left atria of the rat heart.Naunyn Schmiedeberg's Arch Pharmacol 1985;330:193–198.

    Google Scholar 

  28. Brown EM, Fedak SA, Woodard CJ, Aurbach GD, Rodbard D. Beta adrenergic receptor interactions. Direct comparison of receptor interaction and biological activity.J Biol Chem 1976;251:1239–1246.

    PubMed  Google Scholar 

  29. Kaila T, Karhuvaara S, Huupponen R, Iisalo E. The analysis of plasma kinetics and β-receptor binding and -blocking activity of timolol following its small intravenous dose.Int J Clin Pharmacol Ther Tox 1993;31:351–354.

    Google Scholar 

  30. Walle UK, Walle T, Bai SA, Olanoff LS. Stereoselective binding of propranolol to human alpha-1-acid glycoproteins and albumin:Clin Pharmacol Ther 1983;34:718–723.

    PubMed  Google Scholar 

  31. Fitzgerald JD, O'Donnell SR. Pharmacology of 4-OH-propranolol, a metabolite of propranolol.Br J Pharmacol 1971;43:222–235.

    PubMed  Google Scholar 

  32. Von Bahr CD, Hermansson J, Tawara K. Plasma levels of (+) and (−) propranolol and 4-hydroxypropranolol after administration of racemic (±)-propranolol in man.Br J Clin Pharmacol 1982;14:79–82.

    PubMed  Google Scholar 

  33. Brodde O-E, Daul A, Wellstein A, Palm D, Michel MC, Beckeringh JJ. Differentiation of beta-1 and beta-2 adrenoceptor-mediated effects in humans.Am J Physiol 1988;254:H199-H206.

    PubMed  Google Scholar 

  34. Lucker P, Moore G, Wieselgren I, Olofsson B, Bergstrand R. Pharmacokinetic and pharmacodynamic comparison of metoprolol CR/ZOK once daily and with conventional tablets once daily and divided doses.J Clin Pharmacol 1990;30:S17-S27.

    PubMed  Google Scholar 

  35. Benfield P, Clissold SP, Brogden RN, Metoprolol: An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in hypertension, ischemic heart disease and related cardiovascular disorders.Drugs 1986;31:376–429.

    PubMed  Google Scholar 

  36. Kaila T, Iisalo E. Selectivity of acebutolol, atenolol and metoprolol in healthy volunteers estimated by the extent the drugs occupy β2-receptors in the circulating plasma.J Clin Pharm 1993;33(10).

  37. Kendall M, Akhlagli S, Hughhes B, Lewis H. Is metoprolol CR/ZOK more selective than conventional metoprolol and atenolol?J Clin Pharmacol 1990;30:S98-S102.

    PubMed  Google Scholar 

  38. Lennard MS, Tucker GT, Silas JH, Freestone S, Ramsay LE, Woods HF. Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquine-metabolizers.Clin Pharmacol Ther 1983;34:732–737.

    PubMed  Google Scholar 

  39. Regårdh C-G, Landahl S, Larsson M, et al. Pharmacokinetics of metoprolol and its metabolite alpha-OH-metoprolol in healthy, nonsmoking, elderly individuals.Eur J Clin Pharmacol 1983;24:221–226.

    PubMed  Google Scholar 

  40. Regårdh C-G. Summary of session I.J Clin Pharmacol 1990;30:S55-S56.

    Google Scholar 

  41. Aellig WH. Clinical pharmacology of pindolol.Am Heart J 1982;104:346–356.

    PubMed  Google Scholar 

  42. Gretzer I, Alvan G, Duner H, Garle M, Sjöquist F. Beta-blocking effects of pindolol in young and elderly hypertensive patients.Eur J Clin Pharmacol 1986;31:415–418.

    PubMed  Google Scholar 

  43. Routledge PA, Shand DG. Clinical pharmacokinetics of propranolol.Clin Pharmacokinet 1979;4:73–90.

    PubMed  Google Scholar 

  44. Cruickshank JM, Prichard BNC. Kinetics of individual beta-blockers. Lipophilic, liver-metabolized beta-blockers. Propranolol. In: Cruickshank JM, Prichard BNC, eds.Beta-Blockers in Clinical Practice. London: Churchill Livingstone, 1988:214–223.

    Google Scholar 

  45. Wood AJJ, Feely J. Pharmacokinetic drug interactions with propranolol.Clin Pharmacokinet 1983;8:253–262.

    PubMed  Google Scholar 

  46. Lemaire M, Tillement JP. The binding characteristics of some adrenergic beta-receptor antagonists to human serum proteins.Biochem Pharmacol 1982;31:359–365.

    PubMed  Google Scholar 

  47. Hawksworth GM, Betts T, Crowe A, et al. Diazepam/beta-adrenoceptor antagonist interactions.Br J Clin Pharmacol 1984;17(Suppl 1):69S-76S.

    PubMed  Google Scholar 

  48. Kaila T, Marttila R. Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.Br J Clin Pharmacol 1993;35:507–515.

    PubMed  Google Scholar 

  49. Brodde O-E, Zerkowski H-R, Borst HG, Maier W, Michel MC. Drug- and disease-induced changes of human cardiac β1- and β2-adrenoceptors.Eur Heart J 1989;10(Suppl B):38–44.

    Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520, Turku, Finland

    Timo Kaila MD & Esko Iisalo

  2. Department of Medicine, Turku City Hospital, Turku, Finland

    Aapo Lehtonen & Heikki Saarimaa

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  1. Timo Kaila MD
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Kaila, T., Iisalo, E., Lehtonen, A. et al. Extent of beta1- and beta2-receptor occupancy in plasma assesses the antagonist activity of metoprolol, pindolol, and propranolol in the elderly. Cardiovasc Drug Ther 7, 839–849 (1993). https://doi.org/10.1007/BF00877714

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