Electrophysiologic actions of high plasma concentrations of propranolol in human subjects

Abstract

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel

“…For example, in the report by Priori et al the specific β-blocker was known in 69% of cases and this was either propranolol or nadolol 40. As we have demonstrated in this study, propranolol may offer specific advantages in treating certain SCN5A mutations because of apparent local anesthetic-like properties of the drug 18,19. By contrast, we recently determined that nadolol has no activity against sodium channels (Wang, D.W., unpublished observations).…”

“…Propranolol is a widely used β-adrenergic receptor antagonist, but early studies indicated that this drug also exhibits anti-arrhythmic (“membrane stabilizing”) properties at high serum concentrations possibly from effects on voltage-gated sodium channels 18,19 Figure 7A. illustrates that both WT and G1631D channels are blocked by 3µM propranolol during repetitive stimulation (1Hz).…”

Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment

“…High concentrations of propranolol were required to significantly inhibit cell proliferation, with IC 50 values ranging from 100 μM to >250 μM across the panel of cell lines. Early pharmacokinetics studies revealed that clinically relevant concentrations of propranolol are in the low μM range [35, 36], thus suggesting that propranolol alone is not likely to inhibit cell proliferation in vivo . The sensitivity to propranolol was cell type specific but did not depend on the tissue of origin, since all 4 cell lines of breast tissue origin displayed different levels of sensitivity.…”

QT-Interval prolonging drugs: Mechanisms and clinical relevance of their arrhythmogenic hazards

“…Vaughan Williams [236] described APD prolongation in the rabbit myocardium, but subsequent studies both confirmed and failed to reproduce this effect [54]. Except for sotalol, there is no conclusive effect on ventricular repolarization of beta-blocking agents that may result in antiarrhythmic or proarrhythmic effects.…”