S Schiere

Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488)

UNLABELLED Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that may become apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic behavior (n = 7) of this metabolite and the pharmacokinetic/pharmacodynamic (PK/PD) relationship of rapacuronium (n = 10) and Org 9488 (n = 7) were investigated in humans. Similar protocols were used for three study groups regarding the anesthetic technique, blood and urine sampling, and pharmacokinetic and PK/PD analyses. The time course of action was measured mechanomyographically using the adductor pollicis muscle. The median clearance of rapacuronium was 7.28 mL x kg(-1) x min(-1) x with an excretion fraction in the urine of 6.2%. The clearance (studied in two groups) of Org 9488 was 1.28 and 1.06 mL x kg(-1) x min(-1) with an excretion fraction in the urine of 51.9% and 53.5%, respectively. The median rate constant of transport between plasma and the biophase of rapacuronium (0.449 min(-1)) is markedly larger than that for Org 9488 (0.105 min(-1)). The modeled concentration in the biophase at 50% effect as a measure of potency is higher for rapacuronium (4.70 microg/mL) than for Org 9488 (1.83 microg/mL). The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium. IMPLICATIONS We investigated the concentration-time-effect relationship of the relaxant rapacuronium and the contribution of its metabolite. Clearance, rate constant of transport between plasma and the biophase, and modeled concentration in the biophase at 50% effect of rapacuronium are consistent with its rapid onset and short to intermediate duration. The lower clearance of the metabolite will gradually prolong the time course of the neuromuscular blockade during maintenance with rapacuronium.

An interstitial compartment is necessary to link the pharmacokinetics and pharmacodynamics of mivacurium.

Background and objective: The time course of action of mivacurium does not correlate with its rapid breakdown by plasma cholinesterase. Pharmacokinetic-pharmacodynamic (PK-PD) modelling was applied to obtain more insight in the concentration-effect relationship. Methods: Fourteen patients between 25 and 55 yr, undergoing non-major surgery, American Society of Anesthesiologists Grade I-II, were included. All patients received thiopentone/fentanyl/isoflurane/oxygen/nitrous oxide anaesthesia. Neuromuscular block was monitored mechanomyographically using single twitch stimulation (0.1 Hz). Mivacurium was administered as a short-term infusion, mean (standard deviation) duration 4.7 (1.0) min and dose 145 (33) μg kg−1. Arterial blood samples were obtained, and plasma was analysed using high performance liquid chromatography. PK-PD modelling was performed using an iterative Bayesian two-stage approach, assuming that the trans-trans and cis-trans isomers are equally potent. Results: A PK-PD model with an effect compartment linked to plasma did not fit to the data satisfactorily. A model using an interstitial space compartment between plasma and effect compartment fitted significantly better. Parameters (mean (percentage coefficient of variation)) of the best fitting model were: kip 0.374 min−1 (46%), kei 0.151 min−1 (36%), EC50 98 μg L−1 (29%) and γ 3.7 (22%). Conclusions: The PK-PD behaviour of mivacurium could be described using a model with an interstitial space compartment interposed between plasma and effect compartment. This model shows that the time course of mivacurium is mainly governed by the concentration decline in this interposed compartment and only indirectly related to the rapid plasma clearance.

Blockade of the mental nerve for lower lip surgery as a safe alternative to general anesthesia in two very old patients

Purpose Regional anesthesia is gaining popularity with anesthesiologists as it offers superb postoperative analgesia. However, as the sole anesthetic technique in high-risk patients in whom general anesthesia is not preferred, some regional anesthetic possibilities may be easily overlooked. By presenting two cases of very old patients with considerable comorbidities, we would like to bring the mental nerve field block under renewed attention as a safe alternative to general anesthesia and to achieve broader application of this simple nerve block. Patients and methods Two very old male patients (84 and 91 years) both presented with an ulcerative lesion at the lower lip for which surgical removal was scheduled. Because of their considerable comorbidities and increased frailty, bilateral blockade of the mental nerve was considered superior to general anesthesia. As an additional advantage for the 84-year-old patient, who had a pneumonectomy in his medical history, the procedure could be safely performed in a beach-chair position to prevent atelectasis and optimize the ventilation/perfusion ratio of the single lung. The mental nerve blockades were performed intraorally in a blind fashion, after eversion of the lip and identifying the lower canine. A 5 mL syringe with a 23-gauge needle attached was passed into the buccal mucosa until it approximated the mental foramen, where 2 mL of lidocaine 2% with adrenaline 1:100.000 was injected. The other side was anesthetized in a similar fashion. Results Both patients underwent the surgical procedure uneventfully under a bilateral mental nerve block and were discharged from the hospital on the same day. Conclusion A mental nerve block is an easy-to-perform regional anesthetic technique for lower lip surgery. This technique might be especially advantageous in the very old, frail patient.

POTENCY AND ONSET OF ACTION OF NEUROMUSCULAR BLOCKING-DRUGS

Dr. Kopman (l), in his reply to Bartkowski et al.‘s study (2), pointed out that the relatively fast onset of rocuronium cannot be satisfactorily explained by the difference in molar potency, expressed as ED,,, compared with the other neuromuscular blockers d-tubocurarine (d-TC), gallamine, pancuronium, vecuronium, and atracurium. We agree with Bartkowski and Witkowski in their response to Kopman (11, that a different stimulation mode and anesthetic technique may be of influence. In the past we repeated the study of Kopman (3) in 18 patients under thiopental/fentanyl anesthesia with a mixture of N,O and OZ. Three groups of six patients each received d-TC, gallamine, and pancuronium, respectively. In contrast to Kopman, who monitored the neuromuscular block with train-of-four (TOF) stimulation, 2 Hz every 20 s, we determined the TOF, 2 Hz every 12 s. We found only a weak relationship between onset and potency (y = -2.6432x + 4.7656; see Figure 1). Since the calculated ED, value for d-TC deviates significantly from the previous findings of Kopman (31, the higher potency of I-TC in our study may be related to its more pronounced intrinsic activity to prejunctional receptors, which is extensively described by Bowman et al. (4,5). Blockade of prejunctional receptors coincides with a more pronounced fade at higher stimulation frequencies, e.g., TOF and tetanic stimulation. This view is supported by several papers. Gibson and Mirakhur (6) demonstrated that d-TC and atracurium produce more fade than vecuronium and pancuronium, especially during onset (TOF 2 H.z every 10 s). Pearce et al (7) showed previously in their experiment that during onset atracurium produced significantly more fade than vecuronium, using TOF stimulation of 2 Hz with a stimulation-free interval of 12 s. With a little more intense TOF stimulation pattern of 4 Hz, Williams et al. (8) showed significant differences between pancuronium and d-TC and also between pancuronium and gallamine. This suggests that compounds with a more pronounced prejunctional affinity will display a higher potency with an increasing stimulation frequency and/or a decreasing stimulation-free interval. Consequently, the high correlation found by Kopman (3) is valid