I.V. Bolus Administration of Subconvulsive Doses of Lignocaine to Conscious Sheep: Myocardial Pharmacokinetics

Abstract

Mass balance principles were used to study the myocardial pharmacokinetics of lignocaine in conscious sheep. After i.v. bolus doses of lignocaine 50, 75 or 100 mg, arterial lignocaine concentrations reached a peak in approximately 16 s and these increased linearly with dose. Coronary sinus concentrations reached a peak between 83 and 129 s and the values showed poor relationships with dose. Net myocardial lignocaine uptake lasted for approximately 60 s--this was much shorter than the reported initial distribution half-life of lignocaine. The maximum rate of uptake was proportional to both the dose and the peak arterial lignocaine concentrations. At 15 min, the myocardial lignocaine concentrations were 46 (SD 22)% of their peak values. Pseudo-equilibrium between blood and myocardial lignocaine concentrations was not observed. It is concluded that, despite the myocardium being very well perfused, lignocaine myocardial concentrations were not well represented by blood lignocaine concentrations for at least 15 min. A greater understanding of the determinants of myocardial drug concentrations is required.

Myocardial Pharmacokinetics of Thiopental in Sheep after Short-Term Administration: Relationship to Thiopental-Induced Reductions in Myocardial Contractility

“…In contrast to other drugs we have studied, 21,22 the arterio-venous difference of thiopental across the myocardium after short-term administration was relatively small. This precluded a mass balance approach, but could be indicative of either a slow rate of uptake with a high apparent tissue volume (e.g., membranelimited kinetics) or a rapid rate of uptake with a small apparent tissue volume (e.g., flow-limited kinetics 23 ).…”

“…[2][3][4] An implication of the rapid equilibration between arterial blood and the myocardium discussed above is that, at least in the context of clinical relevance, the effects of thiopental on myocardial contractility closely follow both the arterial and coronary sinus blood concentrations. In contrast, we have previously shown slower equilibration of the basic amines lignocaine 21 and pethidine 22 with the myocardium. For these drugs, their arterial concentrations followed a time course that differed markedly from that of their myocardial and coronary sinus concentrations, and only their concentrations in the myocardium or coronary sinus blood were in equilibrium with their direct myocardial effects.…”

Linear Mixed-Effect Multivariate Adaptive Regression Splines Applied to Nonlinear Pharmacokinetics Data

“…A full description of the data collection and animal preparation is reported in (15) and an analysis of the same data set can be found in (10). Briefly, a series of pharmacokinetics studies were performed in conscious instrumented sheep.…”

The Effect of Hypoxic Hypoxia on the Systemic and Myocardial Pharmacokinetics and Dynamics of Lidocaine in Sheep

“…We have previously studied the myocardial uptake of lidocaine, a local anesthetic and antiarrhythmic, after intravenous bolus administration in a conscious instrumented sheep preparation. It was found that the myocardial concentrations of lidocaine lagged behind those in arterial blood, and the former was better related to the time course of the transient myocardial depression of myocardial contractility caused by lidocaine 7,8. The myocardial uptake of lidocaine was unaffected by tachycardia alone 9.…”