PLASMA PROTEIN BINDING DECREASES RECURONIUM POTENCY AFTER BOLUS ADMINISTRATION

Abstract

S400 INTRODUCTION: The contribution of plasma protein binding to the pharmacokinetics and pharmacodynamics of non-depolarizing muscle relaxants has not been quantified and is generally thought to be small [1,2]. Human alpha -1-acid glycoprotein (AAG) was used to increase the plasma protein binding after bolus administrations of rocuronium (ROC) in a rat model. By comparing muscular blockade before and after the addition of AAG we may be able to estimate the effect of protein binding to the potency of ROC. METHODS: After IACUC approval, 3 male Sprague-Dawley rats (wt. 275-300g) were anesthetized with ketamine and xylazine given IP with follow-up boluses given as needed. The jugular vein and carotid artery were cannulated for drug administration and arterial pressure monitoring. Mean arterial pressure was maintained between 70-90 mm Hg with small boluses of NSS. A tracheostomy was performed and the rats were mechanically ventilated. Rectal temperature waws, aomtaomed at 36.5-37.5[degree sign]C. The left triceps surae muscles were exposed, the distal tendon severed and attached to a Grass transducer. The resting tension was adjusted to 10g. The sciatic nerve was dissected in the popliteal fossa and supramaximally stimulated with 0.2 msec square wave at a frequency of 0.1Hz. The muscle was stimulated for 10-15 min (until the twitch height was constant) then ROC 1.0mg in 0.5cc NSS was given as a bolus to prime the jugular cannula and as a loading dose. A bolus amount was then chosen (0.5-0.7mg) to produce a greater than 80% block. The bolus was then accurately reproduced and repeated 4-7 times at a fixed time interval (10.0-13.3 min) allowing the muscle response to return to a stable twitch height. For preparations 1 and 2 the intensity of the block was determined for each bolus using the minimum twitch tension obtained compared to twitch tension prior to the bolus. For preparation 3 the intensity of the block was determined by the time required to 95% recovery of twitch tension (there was no detectable twitch during part of the measurement). Human AAG (99% pure; Sigma Chem. Co.) 100 mg in 0.3cc was given through the carotid artery cannula a few minutes before the last ROC bolus was given in each of the preparations and flushed with an additional 0.3cc NSS. A control bolus of 0.6cc NSS was given during one of the prior ROC boluses during the experiment. RESULTS: Addition of AAG results in a 10-30% decrease in ROC potency (see Table I and Table II). Identical ROC boluses, given at a fixed time intervals, produced reproducible block intensities without evidence of drug accumulation. The rat preparations served as their own control. Hemodilution was ruled out by appropriate controls.Table I: %BLOCKTable II: TIME IN MIN TO 95% RECOVERYDISCUSSION: The 10-30% decrease in ROC potency is a result of increased plasma binding by AAG. The muscle response (i.e. twitch height) is a function of the ROC concentration in the effect compartment which is in equilibrium with unbound ROC in the plasma. We calculate that a 100mg bolus of AAG in a 300g rat increases the native AAG concentration approx. 10 fold. From other in-vitro plasma binding experiments a similar increase in AAG afforded a [similar]50% reduction in unbound ROC plasma concentration. We expect most neuromuscular blocking agents to be similar to ROC and show an inverse relationship between plasma protein binding and potency.