Influence of Aging on the Pharmacokinetics and Pharmacodynamics of Doxacurium

Abstract

Doxacurium (30 ig/kg) pharmacokinetics and pharmacodynamics were evaluated in nine elderly (age range, 70 to 83 years) and nine young (age range, 19 to 39 years) patients under nitrous oxideisoflurane anesthesia. The force of contraction of the adductor pollicis was monitored and plasma samples were collected for an 8-hour period. In the elderly group, doxacurium elimination half-life was prolonged (119.7 versus 75.9 minutes) and plasma clearance was significantly reduced (1.75 versus 2.54 ml/min/kg) without any change in volume of distribution. Onset (12.9 versus 8.9 minutes) and recovery times (113.4 versus 48.1 minutes) were longer in the elderly group. The equilibrium rate constant to the effect compartment (lc.) was decreased in the elderly (0.039 versus 0.051 min -1), whereas the effect compartment concentration at 50% block was similar in both groups (44.7 versus 54.1 ng/ml). An agerelated reduction in muscle blood flow may be responsible for the decrease in keo. The pharmacokinetic changes observed in the elderly are consistent with a decreased function in the organs of elimination.Differences in response to drugs between young and elderly patients have been frequently documented. Decreased cardiac output, renal and hepatic blood flow, glomerular filtration rate, and hepatic function attributable to aging may modify the pharmacokinetics of drugs. [1][2][3][4][5] For neuromuscular-blocking agents, the most common features are an increased onset time, a prolonged effect, and a decreased elimination of the drug in the elderly. Such changes have been observed for pancuronium,6'7 atracurium,8 vecuronium," alcuronium,11 tubocurarine, and metocurine.12 Recently the pharmacokinetics and pharmacodynamics of doxacurium, a new long acting nondepolarizing blocker, were shown to be unchanged in elderly patients.13'14 Though the disposition of doxacurium in humans has not been fully characterized, preliminary studies indicate that it would be excreted by way of both urinary and biliary pathways .13'15-16 Therefore a decreased

Evaluating the 10X Uncertainty Factor for Children and Elderly with Data-Derived Values for Neuromuscular Blocking Agents

“…The action of rocuronium is also prolonged in the elderly because of decreased elimination of the drug. Doxacurium kinetic changes observed in the elderly are also consistent with a decreased function in the organs of elimination (Gariepy et al 1993).…”

“…Because children were not sensitive compared with adults, the ratio between the groups was 1.0. Doxacurium (30 µg/kg) pharmacokinetics and pharmacodynamic were evaluated in nine elderly (74 + 1 y) and nine young patients (27 + 3 years) under nitrous oxide- isoflurane anesthesia (Gariepy et al 1993) (Table 9). The force of contraction of the adductor pollicis was monitored and plasma samples were collected for an 8-h period.…”

Efficacy, Safety, and Pharmacokinetics of Sugammadex for the Reversal of Rocuronium-induced Neuromuscular Blockade in Elderly Patients

“…prolonged compared with younger individuals; this potentially reflects a reduced blood flow to the muscles in elderly patients 23 or an increased volume of distribution, although the latter has not been reported for either rocuronium 7 or for other NMBAs. 6 An alternative phenomenon, perhaps occurring simultaneously with altered blood flow, would be possible changes in receptor biologic features (e.g., ligand affinity and kinetics), potentially resulting in a slower release of the NMBA from the receptor, delayed recovery of the receptor, or possibly altered receptor expression at the neuromuscular junction. 24,25 Further research is required in this area, but it may be that a combination of factors ultimately contributes to the somewhat slower recovery to a TOF ratio of 0.9 seen in elderly patients compared with younger adults.…”

“…1 For example, several neuromuscular blocking agents (NMBAs), including pancuronium, vecuronium, rocuronium, and doxacurium, all display an increased onset time in elderly patients, possibly as the result of a less dynamic circulation in elderly persons and, thus, an increased transfer time to the effector site. [5][6][7] Furthermore, rocuronium has an increased duration of action in elderly patients [7][8][9] as the result of decreased elimination of the drug, 7 which may be due to the decreased total body water and decreased liver mass that often accompany aging. The selective relaxant binding agent sugammadex, a modified ␥ cyclodextrin, was designed specifically to encapsulate the steroidal NMBAs rocuronium and vecuronium to result in rapid reversal of neuromuscular blockade.…”

Postoperative Cognitive Dysfunction in Older Patients With a History of Alcohol Abuse

“…22,23 Age-related physiologic changes give rise to a decreased efficiency in the mobilization of homeostatic mechanisms 24 and the elimination of drugs. 25 Older persons are consumers of medications that produce cognitive deficits, such as antihypertensive agents, digitalis, antiparkinsonian drugs, antidepressants, and corticosteroids. 26,27 We compared cognitive function in four groups: alcoholic and nonalcoholic patients undergoing surgery with general anesthesia as well as age-, education-, and sexmatched alcoholic and nonalcoholic nonsurgical controls.…”