PHARMACODYNAMIC MODELING OF VECURONIUM-INDUCED TWITCH DEPRESSION - RAPID PLASMA-EFFECT SITE EQUILIBRATION EXPLAINS FASTER ONSET AT RESISTANT LARYNGEAL MUSCLES THAN AT THE ADDUCTOR POLLICIS

Background: After bolus doses of nondepolarizing muscle relaxants, the adductor pollicis recovers from paralysis more slowly than the diaphr agm and the laryngeal adductors, suggesting that the adductor pollicis is more sensitive than the respiratory muscles to effects of those dr ugs, In contrast, during onset, the respiratory muscles are paralyzed more rapidly than the adductor pollicis, suggesting that the respirato ry muscles are more sensitive than the adductor pollicis. To reconcile these apparently conflicting findings, me determined vecuronium's pha rmacokinetics and its pharmacodynamics at both the adductor pollicis a nd the laryngeal adductors. Methods: Six volunteers were studied on tw o occasions during anesthesia with propofol, Mechanical responses to t rain-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors, Vecuronium (15-60 mu g/kg) was given and art erial plasma samples were obtained from 0.5-60 min. Vecuronium doses d iffered by twofold on the two occasions, A pharmacokinetic model accou nting for the presence and potency of vecuronium's 3-desacetyl metabol ite and a sigmoid e-max pharmacodynamic model were fit to the resultin g plasma concentration and effect (adductor pollicis and laryngeal add uctors) data to determine relative sensitivities and rates of equilibr ation between plasma and effect site concentrations. Results: The stea dy-state plasma concentration depressing laryngeal adductor twitch ten sion by 50% was approximately 1.5 times larger than that for the adduc tor pollicis, The equilibration rate constant between plasma and laryn geal adductor concentrations mas about 1.5 faster than that between pl asma and adductor pollicis concentrations. The Hill factor (gamma) tha t describes the steepness of the laryngeal adductor concentration-effe ct relation was approximately 0.6 times that of the adductor pollicis. Conclusions: More rapid equilibration between plasma and laryngeal ad ductor vecuronium concentrations explains why onset is more rapid at t he laryngeal adductors than at the adductor pollicis, During recovery, both rapid equilibration and lesser sensitivity of the laryngeal addu ctors contribute to earlier recovery.