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 diaphragm and the laryngeal adductors, suggesting that the adductor pollicis is more sensitive than the respiratory muscles to effects of those drugs. In contrast, during onset, the respiratory muscles are paralyzed more rapidly than the adductor pollicis, suggesting that the respiratory muscles are more sensitive than the adductor pollicis. To reconcile these apparently conflicting findings, we determined vecuronium's pharmacokinetics and its pharmacodynamics at both the adductor pollicis and the laryngeal adductors.


METHODS
Six volunteers were studied on two occasions during anesthesia with propofol. Mechanical responses to train-of-four stimulation were measured at the adductor pollicis and at the laryngeal adductors. Vecuronium (15-60 micrograms/kg) was given and arterial plasma samples were obtained from 0.5-60 min. Vecuronium doses differed by twofold on the two occasions. A pharmacokinetic model accounting for the presence and potency of vecuronium's 3-desacetyl metabolite and a sigmoid e-max pharmacodynamic model were fit to the resulting plasma concentration and effect (adductor pollicis and laryngeal adductors) data to determine relative sensitivities and rates of equilibration between plasma and effect site concentrations.


RESULTS
The steady-state plasma concentration depressing laryngeal adductor twitch tension by 50% was approximately 1.5 times larger than that for the adductor pollicis. The equilibration rate constant between plasma and laryngeal adductor concentrations was about 1.5 faster than that between plasma and adductor pollicis concentrations. The Hill factor (gamma) that describes the steepness of the laryngeal adductor concentration-effect relation was approximately 0.6 times that of the adductor pollicis.


CONCLUSIONS
More rapid equilibration between plasma and laryngeal adductor vecuronium concentrations explains why onset is more rapid at the laryngeal adductors than at the adductor pollicis. During recovery, both rapid equilibration and lesser sensitivity of the laryngeal adductors contribute to earlier recovery.
Fisher
D M
DM
Department of Anesthesia, University of California, San Francisco 94143-0648, USA. fisher@zachary.ucsf.edu
Szenohradszky
J
J
Wright
P M
PM
Lau
M
M
Brown
R
R
Sharma
M
M
D000328:Adult; D001665:Binding Sites; D003864:Depression, Chemical; D004351:Drug Resistance; D006801:Humans; D007821:Laryngeal Muscles / Q000187:drug effects* / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D003473:Neuromuscular Nondepolarizing Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004856:Postural Balance; D014673:Vecuronium Bromide / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D003473:Neuromuscular Nondepolarizing Agents; D014673:Vecuronium Bromide