European Journal of Clinical Pharmacology

, Volume 46, Issue 5, pp 399–404

Esmolol, an ultrashort-acting, selective β1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic properties

  • C. Volz-Zang
  • B. Eckrich
  • P. Jahn
  • B. Schneidrowski
  • B. Schulte
  • D. Palm
Originals

Abstract

The effects of esmolol at different rates of infusion (100, 250 and 500 μg·kg−1 BW·min−1) were compared with β-adrenoceptor occupancy (β1 and β2, estimated by a subtype selective radioreceptor assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 μg·kg−1 BW·min−1 there was a maximal β1-receptor occupancy of 84.7% while β2-receptor occupancy was below the detection limit; confirming the β1 selectivity of esmolol. Exercise-induced increases in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC50 values of rate of infusion for the reduction in heart rate and systolic blood pressure during exercise were 113 and 134 μg·kg−1 BW · min−1, respectively. Additionally, heart rate and systolic blood pressure were reduced moderately at rest. Because of the short elimination half-life of esmolol caused by the rapid hydrolysis to its acid metabolite, 45 min after end of infusion high plasma concentrations of the metabolite (maximally 80 μg·ml−1) but no esmolol were detectable. Since no in vivo effects have been observed, despite the presence of high plasma concentrations of the metabolite, the metabolite did not participate in the observed effects up to an infusion rate of esmolol of 500 μg·kg−1 BW·min−1. The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a good correlation (r=0.97). Since the cardiovascular effects, determined before and 45 min after termination of infusion of esmolol were similar, it can be concluded that the observed effects on heart rate and systolic blood pressure are exclusively mediated by esmolol.

Key words

Esmolol β1-Adrenoceptor antagonist tricresylphosphate pharmacokinetics effect kinetics 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Benfield P, Sorkin EM (1987) Esmolol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 33: 392–412Google Scholar
  2. 2.
    Viray R, Turlapaty P, Laddu A (1988) Esmolol: a short-acting titratable beta-blocker in acute moycardial ischemia. Int J Clin Pharmacol Ther Toxicol 26: 153–161Google Scholar
  3. 3.
    Lowenthal DT, Porter RS, Saris SD, Bies CM, Slegowski MB, Staudacher A (1985) Clinical pharmacology, pharmacodynamics and interactions with esmolol. Am J Cardiol 56: 14F-18FGoogle Scholar
  4. 4.
    Gorczynski RJ (1985) Basic pharmacology of esmolol. Am J Cardiol 56: 3F–13FGoogle Scholar
  5. 5.
    Erhardt PW, Woo CM, Gorczynski RJ (1982) Ultra-short acting beta-adrenergic blocking agents: Aryloxypropanol-amines containing esters in the nitrogen substituent. J Med Chem 25: 1402–1407Google Scholar
  6. 6.
    Erhardt PW, Woo CM, Anderson WG (1982) Ultra-short acting beta-adrenergic blocking agents. 2. (Aryloxy)propanolamines containing esters on the aryl function. J Med Chem 25: 1408–1412Google Scholar
  7. 7.
    Sum CY, Yacobi A, Kartzinel R, Stampfli H, Davis CS, Lai CM (1983) Kinetics of esmolol, an ultra-short-acting beta blocker, and of its major metabolite. Clin Pharmacol Ther 34: 427–434Google Scholar
  8. 8.
    Flaherty JF, Wong B, La Follette G, Warnock DG, Hulse JD, Gambertoglio JG (1989) Pharmacokinetics of esmolol and ASL-8123 in renal failure. Clin Pharmacol Ther 45: 321–327Google Scholar
  9. 9.
    Shaffer JE, Quon CY, Gorczynski RJ (1988) Beta-adrenoceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol. J Cardiovasc Pharmacol 11: 187–192Google Scholar
  10. 10.
    Turlapaty P, Laddu A, Murthy VS, Singh B, Lee R (1987) Esmolol: a titratable short-acting intravenous beta blocker for acute critical care settings. Am Heart J 114: 866–885Google Scholar
  11. 11.
    Iskandrian AS, Hakki A, Laddu A (1985) Effects of esmolol on cardiac function: evaluation by noninvasive techniques. Am J Cardiol 56: 27F-32FGoogle Scholar
  12. 12.
    Koner RA, Kirshenbaum J, Lange R, Antman EM, Braunwald E (1985) Experimental and clinical observations on the efficacy of esmolol in myocardial ischemia. Am J Cardiol 56: 40F–48FGoogle Scholar
  13. 13.
    Greenspan AM, Spielman SR, Horowitz LN, Senior S, Steck J, Laddu A (1985) Electrophysiology of esmolol. Am J Cardiol 56: 19F-24FGoogle Scholar
  14. 14.
    Reves JG, Flezzani P (1985) Perioperative use of esmolol. Am J Cardiol 56: 57F-62FGoogle Scholar
  15. 15.
    Morganroth J, Horowitz LN, Anderson J, Turlapaty P, Esmolol Research Group (1985) Comparative efficacy and tolerance of esmolol to propranolol for control of supraventricular tachyarrhythmia. Am J Cardiol 56: 33F-39FGoogle Scholar
  16. 16.
    Ellenbogen KA, McCarthy EA, Pritchett ELC (1987) Effects of bolus injection of esmolol in healthy, exercising subjects. Clin Pharmacol Ther 41: 455–459Google Scholar
  17. 17.
    Covinsky JO (1987) Esmolol: a novel cardioselective, titratable, intravenous beta-blocker with ultrashort half-life. Drug Intell Clin Pharm 21: 316–321Google Scholar
  18. 18.
    Zaroslinski J, Borgman RJ, O'Donnell JP (1982) Ultra-short acting beta-blockers: a proposal for the treatment of the critically ill patient. Life Sci 31: 899–907Google Scholar
  19. 19.
    Jahn P, Volz-Zang C, Eckrich B, Schneidrowski B, Schulte B, Palm D (1992) Cardiovascular effects of esmolol in man — influence of rate of infusion, plasma concentration and occupancy of β1-adrenoceptors. Naunyn Schmiedeberg's Arch Pharmacol 345 [Suppl]: R9Google Scholar
  20. 20.
    Wellstein A, Palm D, Belz GG, Pitschner HF (1985) Receptor binding of propranolol is the missing link between plasma concentration kinetics and effect time course in man. Eur J Clin Pharmacol 29: 131–147Google Scholar
  21. 21.
    Achari R, Drissel D, Hulse JD (1986) Liquid-chromatographic analysis for esmolol and its major metabolite in urine. Clin Chem 32: 374–376Google Scholar
  22. 22.
    Wellstein A (1989) Radioreceptor assay of β-blockers. In: Marco V (Ed) Determination of beta-blockers in biological materials. Elsevier Amsterdam, pp 264–278Google Scholar
  23. 23.
    Wellstein A, Palm D, Belz GG (1986) Affinity and selectivity of β-adrenoceptor antagonists in vitro. J Cardiovasc Pharmacol 8 [Suppl 11]: S36–40Google Scholar
  24. 24.
    Wellstein A, Belz GG, Palm D (1988) Beta adrenoceptor subtype binding activity in plasma and beta blockade by propranolol and beta-1-selective bisoprolol in humans. Evaluation with Schild plots. J Pharmacol Exp Ther 241: 328–337Google Scholar
  25. 25.
    Lowenthal DT, Porter S, Achari R, Turlapaty P, Laddu AR, Matier WL (1987) Esmolol-digoxin drug interaction. J Clin Pharmacol 27: 561–566Google Scholar
  26. 26.
    Reilly CS, Wood M, Koshakji RP, Wood AJJ (1985) Ultrashortacting beta-blockade: a comparison with conventional beta-blockade. Clin Pharmacol Ther 38: 579–585Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • C. Volz-Zang
    • 1
  • B. Eckrich
    • 1
  • P. Jahn
    • 1
  • B. Schneidrowski
    • 1
  • B. Schulte
    • 2
  • D. Palm
    • 1
  1. 1.Zentrum der PharmakologieKlinikum der Johann-Wolfgang-Goethe-UniversitätFrankfurtGermany
  2. 2.Kerckhoff-Klinik der Max-Planck-GesellschaftBad NauheimGermany
  3. 3.Zentrum der PharmakologieKlinikum der Johann-Wolfgang-Goethe-UniversitätFrankfurtGermany

Personalised recommendations