Jan Mark Klaas Hyltje Wierda

The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl

The pharmacodynamics and pharmacokinetics of a new non-depolarizing neuromuscular blocking agent, Org 9426, were investigated. Ten patients undergoing elective head and neck surgery and anaesthetized with nitrous oxide, halothane and fentanyl, received a bolus dose of Org 9426 (I mg · kg−1, 3 × ED90). The isometric contractions of the adductor pollids muscle following ulnar nerve stimulation (0.1 Hz and intermittent TOF) were measured. Blood and urine were sampled over 8 and 24 hr, respectively. Concentrations of Org 9426 and its possible metabolites in plasma and urine were determined using HPLC. Pharmacokinelic variables were calculated by iterative linear least square regression analysis. Intubation conditions were excellent one minute after administration at a neuro-muscular block of 88 (13)% (Mean (CV)). Onset time until maximum block, duration until 25% recovery of twitch height, and recovery from 25 until 75% of twitch height were 1.7 (32), 53 (19) and 20 (37) min, respectively. The TOF reached a ratio of 0.7 after 87 (19) min. Half lives were 1.8(33), 19(34), 131 (62) min, respectively, in a three exponential decay; distribution volume at steady-state and plasma clearance were 0.264 (56) L · kg− 1 and 4.0 (21) ml · kg− 1 · min− 1, respectively. Plasma concentration at 25% recover)1 of the twitch height was 1.0 mg · L− 1. Within 24 h, 33 (37)% of Org 9426 was excreted unchanged in the urine. Metabolites were absent both in plasma and urine. We conclude that the difference in potency between Org 9426 and vecuronium is similar to the difference between their effective concentrations. Org 9426 mimics vecuronium in its time-course of action and pharmacokinetic behaviour and produces excellent intubaling conditions one minute following the administration of I mg · kg− 1.RésuméNous avons évalué les profits pharmacocinétique et pharmaco-dynamique d’un nouveau myorelaxanl non-dépolarisant, le Org 9426. Lors d’interventions chirurgicales électives sur le cou on la tele, nous avons injecte 1 mg · kg− 1 (3 × DE90) d’Org 9426 à dix patients anesthésiés avec du protoxyde d’azote, de l’halothane et du fentanyl. Nous mesurions la réponse isométrique de l’adducteur du pouce à la stimulation du nerf cubital (0,1 Hz et train-de-quatre). Nous mesurions aussi les concentrations d’Org 9426 et de ses métabolites par chromatographie en phase liquide dans des échantillons de sang et durine prélevés pendant 8 et 24 h respectivement. Par analyse de regression, nous avons pu tracer le profil pharmacocinétique de l’Org 9426. Une minute après l’injection, les conditions d’intubations étaient excellentes alors que le bloc neuromusculaire était en moyenne de 88%. En moyenne, le temps de latence jusqu’au bloc maximal était de 1,7 min; sa durée jusqu ’ à recupération de 25% de la contraction était de 53 min et l’intervalle de recuperation 25– 75% était de 20 min. Le ratio T4/T1 du train-de-quatre atteint 0,7 après 87 min en moyenne. Les demivies d’élimination d’une courbe tri-e.xponentielle étaient de 1,8, 19 et 131 min alors que le volume de distribution à l’équilibre é’tait de 0,264 L · kg− 1 et la clairance plasmatique itait de 4,0 ml · kg− 1 min− 1. An moment oú la contraction était revenue à 25% du contrôle, la concentration plasmatique de l’Org 9426 était de 1,0 mg · L−1. En 24 heures, on retrouvait inchangé dans l’urine, 33% de la dose d’Org 9426 mats il n’y avail aucun metabolite dans le sang et dans l’urine. La difference de puissance entre l’Org 9426 et le vécuronium s’explique par le rapport de leurs concentrations ejficaces. L’Org 9426 offre un profit pharmacocinetique et d’action temporellement semblable à celui du vécuronium. A raison de 1 mg · kg− 1, il offre d’excellentes conditions pour l’intubation de la trochée une minute après al’injection iv.

Preliminary investigations of the clinical pharmacology of three short-acting non-depolarizing neuromuscular blocking agents, Org 9453, Org 9489 and Org 9487

Three muscle relaxants, Org 9453, Org 9489 and Org 9487, short-acting in animals, were investigated to establish their profiles in humans. Potency, time course of action, and pharmacokinetic behaviour were studied in 90 healthy patients during fentanyl/halothane/N2O anaesthesia. Neuromuscular Junction was monitored mechanomyographically. Plasma and urine concentrations (three patients per compound) were measured by HPLC, and these data were analyzed by iterative linear least square regression analysis. The ED90 values for Org 9453, Org 9489 and Org 9487 were 1.4, 0.45 and 1.15 mg · kg−1 respectively. The onset times of Org 9453 (1.5 mg · kg−1,1.1 × ED90), Org 9489 (0.9 mg · kg−1, 2 × ED90) and Org 9487 (1.5 mg · kg−1, 1.3 × ED90) were 1.2, 1.6 and 1.5 min, and the durations until 25% twitch recovery were 8.6, 22.0 and 8.9 min, respectively. Clearances of these doses were 6.9, 5.8, and 11.1 ml · kg−1 · min−1, and mean residence times 26, 79, and 41 min, respectively. Mean renal excretion (parent compound and metabolites) within 24 hr amounted to 5, 11.3 and 12.2% respectively. No side effects other than a moderate short-lasting decrease of blood pressure and a concomittant increase in heart rate were noted. It is concluded that Org 9453 and Org 9487 are short-acting muscle relaxants in humans.RésuméTrois myorelaxants à courte durée d’action chez l’animal, l’Org 9453, l’Org 9489 et l’Org 9487 sont étudiés pour déterminer leurs caractéristiques chez l’homme. La puissance, le décours temporel de leur activité et leur comportement pharmacologique sont étudiés chez 90 adultes bien portants pendant une anesthésie constituée de fentanyl/halothane/protoxyde d’azote. La fonction neuromusculaire est monitorisée par électromyographie. Les concentrations urinaires et plasmatiques (trois patients par produit) sont thrées par chromatographie en phase liquide et ces données analysées par régression linéaire itérative multiple. Les valeurs de l’ED90 pour l’Org 9453, l’Org 9489 et l’Org 9487 sont de 1,4, 0.45 et 1,15 mg · kg−1 respectivement. Le début d’action de l’Org 9453 (1,5 mg · kg−1, 1,1 × ED90), l’Org 9489 (0,9 mg · kg−1, 2 × ED90) et l’Org 9487 (1,5 mg · kg−1, 1,3 × ED90 sont de 1,2, 1,6 et 1,5 min respectivement. A ces doses, la clairance est de 6,9, 5,8 et 11,1 ml · kg−1 respectivement et les temps de séjour moyen 26, 79 et 41 min, respectivement. En-deça de 24 h, l’excrétion rénale moyenne (produit et métabolites) se situe à 5, 11,3 et 12,2% respectivement. On ne note pas d’effets secondaires à l’exception d’une baisse modérée transitoire de la pression artérielle accompagnée d’une augmentation de la fréquence cardiaque. En conclusion, l’Org 9453 et l’Org 9487 sont des myorelaxants à courte durée d’action.

Clinical Pharmacokinetics of Neuromuscular Blocking Drugs

SummaryNeuromuscular blocking agents provide muscle relaxation for a great variety of surgical procedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharmacological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures.In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium, rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.

THE RELAXOMETER - A COMPLETE AND COMPREHENSIVE COMPUTER-CONTROLLED NEUROMUSCULAR-TRANSMISSION MEASUREMENT SYSTEM DEVELOPED FOR CLINICAL RESEARCH ON MUSCLE-RELAXANTS

The Relaxometer is a computer-controlled system developed for reliable clinical experimental measurements on neuromuscular block. This system is based on an adapted personal computer (Atari 1040 ST) with a monochrome monitor (Atari SM 124), and a microcomputer-driven slave unit (stimulator). There are several stimulation patterns available: single twitch at 0.1 and 1 Hz, single train-of-four, continuous train-of-four every 12 seconds, and tetanic stimulation at 50 Hz for 5 seconds followed by posttetanic count. The system is equipped with a temperature module for continuous monitoring of the skin/muscle temperature and a rechargeable battery to allow uninterrupted measurements if the apparatus is disconnected from the line power. All acquired data, computer-calculated parameters (onset time, duration time, recovery index, train-of-four ratio, tetanic fade, and posttetanic count), and the mechanomyogram are presented on screen continuously, are stored on floppy disk, and can be printed in a well-organized format.

Pharmacokinetics and Neuromuscular Blocking Effects of Atracurium Besylate and Two of Its Metabolites in Patients with Normal and Impaired Renal Function

SummaryThe pharmacokinetics of atracurium, laudanosine and the quaternary alcohol were studied in patients with normal and impaired renal function following intravenous administration of atracurium. Anaesthesia consisted of thiopental, fentanyl, halothane and nitrous oxide in oxygen. Plasma and urine concentrations of the parent compound and its degradation products were measured by high performance liquid chromatography. Renal failure was defined as a creatinine clearance of less than 5 ml/min; it caused no significant differences in the pharmacokinetics of atracurium but did result in a different pharmacokinetic profile of laudanosine, with a 3-fold increase in the mean (± SD) terminal half-life (176 ± 84 and 516 ± 262 minutes for patients with normal and impaired renal function, respectively). Moreover, the half-life of the quaternary alcohol increased from 27.1 ± 8.3 minutes in patients with normal renal function to 42.5 ± 8.3 minutes in those with impaired renal function (mean ± SD). Renal elimination of unchanged atracurium accounted for 11% of the administered dose and at least 27% of the total degradation of atracurium occurred via ester hydrolysis.The neuromuscular function was monitored by measuring the twitch tension of the adductor pollicis muscle elicited by stimulation of the ulnar nerve at 0.1Hz. The total duration of neuromuscular blockade (51.8 ± 11.5 minutes) and the recovery index (9.6 ± 2.0 minutes) are shortened in patients with impaired renal function, compared with those with normal renal function (64.1 ± 7.2 and 16.7 ± 4.1 minutes, respectively), indicating that sensitivity to the neuromuscular blocking action of atracurium may be altered by renal failure.

Comparison of vecuronium with ORG 9487 and their interaction

PurposeTo compare the pharmacodynamic behaviour of vecuronium with that of ORG 9487. we measured the time-course of action of equipotent doses of ORG 9487 and vecuronium and investigated their mutual interaction when given in succession.MethodsSixty ASA I–II patients were anaesthetized with thiopentone, fentanyl halothane and nitrous oxide and assigned randomly to four groups. Each patient received an initial dose (ID) of either vecuronium (V) or ORG 9487 (O) followed by maintenance doses (MDn) of either V or O (ID/MD: O/O, V/O, O/V, and V/V). The time course of action was measured mechanomyographically, determining the duration until 25% recovery of the single twitch (DUR25).ResultsThe onset time of an ID of ORG 9487 was shorter than that of an ID of vecuronium (96vs 203 sec. P < 0.001). The DUR25 of the ID of ORG 9487 was less than half that of vecuronium (10.7 ± 2.8 vs 28.8 ± 6.1 min, P< 0.001). The DUR25 of MD1 and MD2 of ORG 9487 were shorter than those of vecuronium (O/O: 7.3 ± 2.8 and 8.5 ± 2.4 mm. V/O: 12.7 ± 3.3 and 11.5 ± 3.5 min,vs O/V. 16.4 ± 4.5 and 20.6 ± 4.7 min: V/V: 18.8 ± 3.0 and 20.1 ± 3.8 min, respectively, P < 0.05). An ID of vecuronium prolonged the DUR25 of MD1 and MD2 of ORG 9487 (P < 0.05)ConclusionORG 9487 is a muscle relaxant with a shorter duration of action than vecuronium. Maintenance doses of ORG 9487 are also shorter acting than roughly equipotent maintenance doses of vecuronium, irrespective of which relaxant is given initially.RésuméObjectifDans le but de comparer le comportement pharmacodynamique du vécur onium avec celui de l’ORG 9487, nous avons mesuré le décours temporel de l’activité de deux doses équipotentes d’ORG 9487 et de vécuronium et étudié leur interaction mutuelle lorsqu’ils sont administrés successivement.MéthodesSoixante patients ASA I et II anesthésiés au thiopental, fentanyl, halothane et protoxyde d’azote ont été répartis aléatoirement en quatre groupes. Chaque patient recevait une dose initiale (DI) de vécuronium (V) ou d’ORG 9487 (O) suíví par des doses d’entretien (DE) de V ou de O (DI/DE: O/O, V/O, O/V et V/V. Le décours temporel de l’activité était mesuré par mécanomyographie en déterminant l’intervalle de récupération de 25% du twitch (DUR25)RésultatsLe début d’action d’une Dl d’ORG 9487 était plus court qu’une DI de vécuronium (96vs 203 s, P < 0.001). La DUR25 de la Dl d’ORG 9487 était la moitié de celle du vecuronium (10.7 ± 2,8vs 28.8 ± 6.1 min, P < 0.001). La DUR25 de la DE et de la DE2 de l’ORG 9487 était plus courte que celle du vécuronium (respectivement. O/O: 7.3 ± 2.8 et 8.5 ± 2.4 min; V/O: 12.7 ± 3.3 et 11.5 ± 3.5 min vs O/V: 16.4 ± 4.5 et 20.6 ± 4.7 min, V/V, 18.8 ± 3.0 et 20.1 ± 3.8 min. P < 0.05) Une DI de vécuronium prolongeait la DUR25 de la DE1 et de la DE2 de l’ORG 9487 (P < 0.05).ConclusionLe myorelaxant ORG 948/ possède une durée d’action plus courte que le vécuronium. Les doses d’entretien de l’ORG 9487 ont une durée d’action plus courte que des doses à peu presque équipotentes de vécuronium quel que soit le myorelaxant initial administré.

Pharmacodynamic behaviour of vecuronium in primary hyperparathyroidism.

This study evaluated the potency and time course of action of vecuronium in patients with primary hyperparathyroidism (HPT) and marked hypercalcaemia during nitrous oxide-opioid anaesthesia. Twenty ASA physical status I and II patients were studied by measuring the force of contraction of the adductor pollicis in response to stimulation of the ulnar nerve: ten control patients and ten patients with HPT and ionized calcium concentration over 2.80 mEq · L−1. After induction of anaesthesia with thiopentone and maintenance with N2O/O2 and fentanyl, vecuronium was administered to determine cumulative doseresponse curves. When maximum block had been obtained, twitch height was maintained at 10% of baseline value over 20 min by adjusting the infusion rate of a syringe-pump containing vecuronium and vecuronium plasma concentration (EC90ss) was determined. During spontaneous recovery, after termination of infusion, the recovery index, the time from 25 to 75% recovery, was measured. The dose to produce 90% block was greater in the HPT than in control group: 69 (24) vs 54 (18) μg · kg−1 (P < 0.02). The calculated ED50 was also greater in HPT: 42 (4) vs 31 (5) μg · kg−1 in controls (P < 0.001). (Values are given as mean and coefficient of variation). The slope of the dose-response curve, the dose necessary to maintain 90% block, and the EC90ss did not differ. The RI25–75 was slower in the HPT group although the difference did not reach statistical significance. It is concluded that hyperparathyroidism with hypercalcaemia increases vecuronium requirement; only during the onset of neuromuscular blockade.RésuméCette étude évalue la puissance et le décours temporel, pendant une anesthésie au protoxyde d’azote-morphinique, du vécuronium chez des patients souffrant d’hyperparathyroïdie primaire (HPT) avec hypercalcémie importante. Vingt patients ASA I et II sont étudiés par la mesure de la force de contraction de l’adducteur du pouce en réponse à une stimulation du nerf cubital: dix patients servent de contrôles à dix patients souffrant d’HPT et dont le concentration de calcium ionisé dépasse 2,80 mEq · L−1. Après induction au thiopentone et entretien au N2O/O2 avec fentanyl, on administre du vécuronium pour déterminer les courbes cumulatives doses-effets. Après l’obtention d’un bloc maximal, la hauteur du twitch est maintenu à 10% au-dessus de la ligne de base pendant plus de 20 min en ajustant la vitesse de perfusion d’un pousse-seringue contenant du vécuronium; on détermine à ce moment la concentration plasmatique de vécuronium (ED90ss). Pendant la récupération spontanée, après l’arrêt de la perfusion, l’index de récupération, la durée requise pour une récupération de 25 à 75% est mesuré. La dose requise pour produire un bloc à 90% est plus élevée dans l’HPT que dans le groupe contrôle: 69 (24) vs 54 (18) μg · kg−1 (P < 0,02). L’ED50 calculée est aussi plus élevée dans l’HPT: 42 (4) vs 31 (5) μg · kg−1 dans le groupe contrôle (P < 0,001). (Les valeurs reproduites sont la moyenne et le coefficient de variation). La pente de la courbe dose-effet, la dose nécessaire au maintien du bloc à 90% et l’EC90ss sont identiques. Le RI25–75 est plus lent dans le groupe HPT mais sans différence statistique. En conclusion, l’hyperparathyroïdie associée à une hypercalcémie importante n’augmente les besoins en vécuronium que pendant l’installation du bloc neuromusculaire.

The isolated heart-lung preparation in the cat an in situ model to study the role of the lungs in the disposition of drugs

In the search for drugs with an extreme short time course of action, compounds should be developed that are rapidly distributed to and temporarily stored in well-perfused organs. Since the lungs receive the complete cardiac output and have the ability to temporarily store drugs, we have developed an in situ, isolated lung preparation in the cat to study the contribution of the lungs to the disposition of drugs. The cats own heart perfuses the lung in situ with autologous blood. The circulation between the left ventricle and the right atrium is short-circuited via an aorta-caval shunt. The right forelimb is added to study pharmacodynamics simultaneously (only for muscle relaxants). Validation of the model for 180 min of perfusion showed complete isolation of the organs without major biochemical changes or edema and a stable muscle response. In pilot experiments with two structurally related muscle relaxants, initial muscle relaxation was followed by spontaneous recovery of neuromuscular function and a gradually decreasing plasma concentration, indicating partial disposition by the lungs. This was confirmed by direct concentration measurements in the lung. The present model may provide a powerful experimental tool to elucidate the role of the lungs in the disposition of drugs.

Female Rats are More Sensitive to the Neuromuscular Blocking Action of Rocuronium than Male Rats

Potency (1), being the result of pharmacokinetics and pharmacodynamics, and sensitivity (intrinsic potency) (2), which is based solely on pharmacodynamics, have been reported to differ for NMBAs between male and female patients. Although gender has been reported to have a clear impact on pharmacokinetics of several drugs (3), pharmacokinetic data on NMBAs are inconsistent with respect to the influence of gender on the neuromuscular blocking response. We investigated the influence of gender on the sensitivity of rocuronium in rats under pseudo steady state conditions, i.e. stable block under unchanged infusion rates for over 15 min.