Background and objective This study involved an investigation into the pharmacokinetic and pharmacodynamic behavior of esmolol in the presence of dobutamine in healthy subjects of European ancestry. Methods We conducted a single-center, prospective randomized study of 16 healthy subjects with each receiving an infusion of dobutamine sufficient to increase heart rate (HR) by 30 beats per minute (bpm) followed by a 60-minute infusion of 50 µg/kg/min esmolol. Pharmacokinetics, HR, and blood pressure were evaluated for 180 minutes. Results In the presence of dobutamine, esmolol elimination was substantially faster than without dobutamine, Esmolol infusion reduced dobutamine-induced elevation of HR reversibly whereas the dobutamine-induced systolic blood pressure (SBP) reduction did not recover after the termination of the esmolol infusion. No serious adverse events (AEs) were observed. Conclusions The accelerated elimination of esmolol was likely due to higher cleavage through tissue esterases induced by dobutamine-induced increased tissue passage cycles per time unit. The HR effect was characteristic of a beta-blocker, whereas the blood pressure effect was likely due to a mechanism other than direct beta-blockade. HR remained elevated after the infusion of esmolol and dobutamine, most likely due to persistent blood pressure reduction.

Biostatistics Advanced Drug Development Services s r o Brno CZE

Drug Safety AOP Orphan Pharmaceuticals AG VIenna AUT

Operational Business Development AOP Orphan Pharmaceuticals AG Vienna AUT

Pharmacology Center for Pharmacology and Analysis s r o Plzeň CZE

Pharmacology MRN Medical Research Network Vienna AUT

Research and Development AOP Orphan Pharmaceuticals AG Vienna AUT

Zobrazit více v PubMed

Beta 1-adrenoceptor subtype selective antagonism of esmolol and its major metabolite in vitro and in man. Investigations using tricresylphosphate as red blood cell carboxylesterase inhibitor. Jahn P, Eckrich B, Schneidrowski B, Volz-Zang C, Schulte B, Mutschler E, Palm D. https://europepmc.org/article/med/7612051. Arzneim-Forsch/Drug Res. 1995;45:536–541. PubMed

The negative inotropic effect of esmolol on isolated cardiac muscle. Arlock P, Wohlfart B, Sjöberg T, Steen S. Scand Cardiovasc J. 2005;39:250–254. PubMed

Esmolol inhibits Na+ current in rat ventricular myocytes. Deng CY, Lin SG, Zhang WC, et al. Methods Find Exp Clin Pharmacol. 2006;28:697–702. PubMed

Esmolol cardioplegia: the cellular mechanism of diastolic arrest. Fallouh HB, Bardswell SC, McLatchie LM, Shattock MJ, Chambers DJ, Kentish JC. Cardiovasc Res. 2010;87:552–560. PubMed

Direct effects of esmolol and landiolol on cardiac function, coronary vasoactivity, and ventricular electrophysiology in guinea-pig hearts. Shibata S, Okamoto Y, Endo S, Ono K. J Pharmacol Sci. 2012;118:255–265. PubMed

Comparison of the β-adrenergic receptor antagonists landiolol and esmolol: receptor selectivity, partial agonism, and pharmacochaperoning actions. Nasrollahi-Shirazi S, Sucic S, Yang Q, Freissmuth M, Nanoff C. J Pharmacol Exp Ther. 2016;359:73–81. PubMed

The safety and effectiveness of esmolol in the perioperative period in patients undergoing abdominal aortic surgery. Harwood TN, Butterworth J, Prielipp RC, Royster RL, Hansen K, Plonk G, Dean R. J Cardiothorac Vasc Anesth. 1999;13:555–561. PubMed

Pharmacokinetics and pharmacodynamics of low-, intermediate-, and high-dose landiolol and esmolol during long-term infusion in healthy whites. Krumpl G, Ulč I, Trebs M, Kadlecová P, Hodisch J, Maurer G, Husch B. J Cardiovasc Pharmacol. 2018;71:137–146. PubMed

Esmolol: a review of its use in the short-term treatment of tachyarrhythmias and the short-term control of tachycardia and hypertension. Garnock-Jones KP. Drugs. 2012;72:109–132. PubMed

Esmolol. A review of its therapeutic efficacy and pharmacokinetic characteristics. Wiest D. Clin Pharmacokinet. 1995;28:190–202. PubMed

Kinetics of esmolol, an ultra-short-acting beta blocker, and of its major metabolite. Sum CY, Yacobi A, Kartzinel R, Stampfli H, Davis CS, Lai CM. Clin Pharmacol Ther. 1983;34:427–434. PubMed

Postoperative prophylactic administration of beta-adrenergic blockers in patients at risk for myocardial ischemia. Urban MK, Markowitz SM, Gordon MA, Urquhart BL, Kligfield P. Anesth Analg. 2000;90:1257–1261. PubMed

Use of an ultra short-acting beta-blocker in patients with acute myocardial ischemia. Kirshenbaum JM, Kloner RA, Antman EM, Braunwald E. Circulation. 1985;72:873–880. PubMed

Randomized study of early intravenous esmolol versus oral beta-blockers in preventing post-CABG atrial fibrillation in high risk patients identified by signal-averaged ECG: results of a pilot study. Balcetyte-Harris N, Tamis JE, Homel P, Menchavez E, Steinberg JS. Ann Noninvasive Electrocardiol. 2002;7:86–91. PubMed PMC

Randomized control of sympathetic drive with continuous intravenous esmolol in patients with acute ST-segment elevation myocardial infarction: the BEtA-Blocker Therapy in Acute Myocardial Infarction (BEAT-AMI) trial. Er F, Dahlem KM, Nia AM, et al. JACC Cardiovasc Interv. 2016;9:231–240. PubMed

Bolus application of landiolol and esmolol: comparison of the pharmacokinetic and pharmacodynamic profiles in a healthy Caucasian group. Krumpl G, Ulc I, Trebs M, Kadlecová P, Hodisch J. Eur J Clin Pharmacol. 2017;73:417–428. PubMed

Esmolol, an ultrashort-acting, selective beta 1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic properties. Volz-Zang C, Eckrich B, Jahn P, Schneidrowski B, Schulte B, Palm D. Eur J Clin Pharmacol. 1994;46:399–404. PubMed

Biochemical properties of blood esmolol esterase. Quon CY, Stampfli HF. https://dmd.aspetjournals.org/content/13/4/420.long. Drug Metab Dispos. 1985;13:420–424. PubMed

Influence of temperature on in vitro metabolism of esmolol. Melendez JA, Stone JG, Delphin E, Quon CY. J Cardiothorac Anesth. 1990;4:704–706. PubMed

Effect of hypothermia and sampling site on blood esmolol concentrations. Jacobs JR, Croughwell ND, Goodman DK, White WD, Reves JG. J Clin Pharmacol. 1993;33:360–365. PubMed

Stress echocardiography expert consensus statement: European Association of Echocardiography (EAE) (a registered branch of the ESC) Sicari R, Nihoyannopoulos P, Evangelista A, et al. Eur J Echocardiogr. 2008;9:415–437. PubMed

Pharmacodynamic and pharmacokinetic behavior of landiolol during dobutamine challenge in healthy adults. Krumpl G, Ulč I, Trebs M, Kadlecová P, Hodisch J. BMC Pharmacol Toxicol. 2020;21:82. PubMed PMC

Pharmacodynamic and -kinetic behavior of low-, intermediate-, and high-dose landiolol during long-term infusion in whites. Krumpl G, Ulč I, Trebs M, Kadlecová P, Hodisch J, Maurer G, Husch B. J Cardiovasc Pharmacol. 2017;70:42–51. PubMed

The pharmacokinetics of esmolol in pediatric subjects with supraventricular arrhythmias. Adamson PC, Rhodes LA, Saul JP, et al. Pediatr Cardiol. 2006;27:420–427. PubMed

Esmolol: a titratable short-acting intravenous beta blocker for acute critical care settings. Turlapaty P, Laddu A, Murthy VS, Singh B, Lee R. Am Heart J. 1987;114:866–885. PubMed

Studies on the metabolic fate of ultra short acting β1 blocker ONO-1101 (3): metabolism and protein binding. Tsunekawa K, Imakawa H, Yamamoto K, Shibakawa K, Hiraku S. Yakobutsu Dotai (Drug Metab Pharmacokin) 1997;12:31–41.

Are all effects of esmolol equally rapid in onset? Ornstein E, Young WL, Ostapkovich N, Matteo RS, Diaz J. Anesth Analg. 1995;81:297–300. PubMed

A novel ultra short acting beta-blocker, landiolol supress the central sympathetic nerve activity directory and exerts a more potent negative chronotropic effect and less effect on blood pressure than esmolol. Iizuka T, Kakinuma T, Hamada Y, Isshiki A. https://journals.lww.com/ejanaesthesiology/Fulltext/2004/06002/A_novel_ultra_short_acting_beta_blocker,_landiolol.466.aspx Eur J Anesthesiol. 2004;21:128.

Deliberate hypotension in patients with intracranial arteriovenous malformations: esmolol compared with isoflurane and sodium nitroprusside. Ornstein E, Young WL, Ostapkovich N, Matteo RS, Diaz J. Anesth Analg. 1991;72:639–644. PubMed

Coronary vasospasm after dobutamine stress echocardiogram triggered by esmolol. Manasrah N, Naik R, Al Sbihi AF, Afonso LC. Cureus. 2020;12:0. PubMed PMC