S. Agoston

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.

The fate of pancuronium bromide in man.

The fate of pancuronium bromide has been investigated in 20 anaesthetized patients, seven undergoing cholecystectomy with choledochostomy (Group I), seven undergoing cholecystectomy only (Group II) and six undergoing pelvic operations (Group III). A fluorimetric method was used to determine pancuronium bromide and its bis‐quaternary derivatives in blood, urine and bile. After a single intravenous injection of 6 mg pancuronium bromide, disappearance of the drug from the plasma proceeded in three phases with half‐lives of < 5 min, 7‐13 min and 108–147 min, respectively. Renal elimination is suggested as the major excretory pathway in man, but biliary excretion is also significant. Thirty hours after injection, the total recovery of unchanged pancuronium and its metabolite was approximately 37–44% in the urine (Groups I, II, III) and 11% in the bile (Group I). Only one metabolite (3‐hydroxy derivative) of pancuronium bromide, accounting in total for about 15% of the administered dose, was identified in urine and 5% in bile by thin‐layer chromatography. Renal and hepatic elimination varied widely between patients.

DISPOSITION AND URINARY-EXCRETION OF VECURONIUM BROMIDE IN ANESTHETIZED PATIENTS WITH NORMAL RENAL-FUNCTION OR RENAL-FAILURE

The effect and plasma concentrations of vecuronium bromide were measured in normal patients after an intravenous dose of 50, 100, or 150 μg/kg and in patients with renal failure after 50 or 100 μg/kg. Urinary excretion of vecuronium was studied in normal patients after the 150 μg/kg dose. Pharmacokinetic parameters of patients with or without renal failure were similar. No metabolites of vecuronium were found in the plasma. Twenty percent of vecuronium was excreted unchanged in the urine; 5% as the 3-hydroxy derivative. No other metabolites of vecuronium were found in the urine. Increasing doses of vecuronium shortened the onset, but prolonged the duration of action and the recovery rate, to a similar extent in Patients with or without renal failure. It was concluded that the disposition of vecuronium was best described by a three compartment model. Both the disposition and the effect of vecuronium are only marginally disturbed by renal failure.

COMPARATIVE PHARMACOKINETICS AND DYNAMICS OF VECURONIUM AND PANCURONIUM IN ANESTHETIZED PATIENTS

Plasma concentrations and the degree of neuromuscular blockade after a 2-min infusion of 0.1 mg/kg of vecuronium bromide or pancuronium bromide (equipotent doses) were studied in 12 gynecologic patients. The plasma concentrations of both drugs declined in a triphasic manner. The difference between the intercepts and rate constants of the two drugs was not significant. Vecuronium was removed faster from the plasma than pancuronium; this was reflected in a significantly larger plasma clearance rate for vecuronium (4 ml·min−1·kg−1 vs 1.1 ml·min−1 for pancuronium). The effective plasma concentrations at 50% recovery of the twitch height were 0.11 ± 0.02 (vecuronium) and 0.2 ± 0.03 μg/ml (pancuronium). The disposition kinetics were adequately described by a three-compartment model. An effect compartment was added to the model to correlate the neuromuscular effects and plasma concentrations of both drugs. The ratio between concentrations of vecuronium and pancuronizim in the effect compartment at 50% twitch height was 0.83. In spite of its greater potency, vecuronium has a shorter duration of action than pancuronium.

FLUORIMETRIC AND CHROMATOGRAPHIC DETERMINATION OF PANCURONIUM BROMIDE AND ITS METABOLITES IN BIOLOGICAL-MATERIALS

Abstract A relatively simple method for quantitative determination of the neuromuscular blocking agent pancuronium bromide and its metabolites in body fluids is described. Complex formation of the bisquaternary ammonium steroids with the fluorescent dye rose-bengal is followed by extraction of the complexes in an organic phase which is read in a filter fluorimeter (excitation = 546 nm; emission = 570 nm). Up to 0.02 μg/ml plasma can be detected. The authentic compound and the 3-hydroxy, 17-hydroxy and 3, 17-dihydroxy derivatives are identified by thin-layer chromatography of the various rose-bengal complexes. A semiquantitative estimation of the four agents can be obtained by spraying with iodoplatinate and visual comparison with the reference compounds.

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.

4-AMINOPYRIDINE KINETICS

Nine healthy subjects (7 men; 2 women) received single 20‐mg IV injections of 4‐aminopyridine (4‐AP). Six of the subjects received the same dose in the form of enteric‐coated tablets and four the same dose in uncoated tablets; treatments were at least 2 wk apart. Blood, saliva, and urine were assayed for 4‐AP using a high‐performance liquid chromatography. Kinetic analysis of serum concentrations after intravenous dosing resulted in the best fitting of a triexponential model in five and a biexponential model in four subjects. The apparent volume of distribution (V) was 2.6 ± 0.9 (mean ± SD) l/kg−1, the terminal half‐life (t½) 3.6 ± 0.9 hr, and the total serum clearance 0.61 ± 0.14 lhr−1kg−1. Saliva concentrations were higher than those in serum after 5 min, with a mean correlation coefficient of 0.989 (n = 5). The t½ and V calculated from serum and saliva concentrations were of the same order. The total urinary excretion of unchanged 4‐AP was 90.6 ± 7.8% after intravenous doses and 88.5 ± 4.8% after oral doses of enteric‐coated tablets. The bioavailability of the enteric‐coated tablets calculated from the area under the serum concentration curve (95 ± 29%) did not differ from that calculated from urinary excretion (98 ± 8%). Protein binding of 4‐AP was found to be negligible. Biotransformation is unlikely.

4-AMINOPYRIDINE POTENTIATES NEOSTIGMINE AND PYRIDOSTIGMINE IN MAN

To elucidate the interaction of 4-aminopyridine with neostigmine and pyridostigmine, the authors studied 57 anesthetized surgical patients using a technique of constant infusion of pancuronium to quantitate antagonist activity. 4-Aminopyridine, 0.15 or 0.35 mg/kg, produced no antagonism, while 0.5 mg/kg produced a mean 24 ± 6 per cent (peak) antagonism. The dose that produced 50 per cent antagonism (EDsn) of neostigmine alone was 22 μg/kg; with 0.35 mg/kg 4-aminopyridine, it was 7 μg/kg. The ED50 of pyridostigmine alone was 110 μg/kg; with 0.35 mg/kg 4-aminopyridine, it was 27 μg/kg. 4-Aminopyridine prolonged the onset times of both neostigmine and pyridostigmine, but prolonged the duration of action of neostigmine only. At a given level of antagonism of pancuronium, adding 4-aminopyridine 0.35 mg/kg, to neostigmine and to pyridostigmine decreased the amounts of atropine needed to prevent a change in heart rate by 68 and 70 per cent, respectively. The authors conclude that 4-aminopyridine potentiates antagonism of a pancuronium-induced neuromuscular blockade by neostigmine or pyridostigmine. Also, less atropine is needed to prevent cardiac muscarinic stimulation when 4-aminopyridine is used with either neostigmine or pyridostigmine.

Dose-response relationship and time course of action of Org 9426. A new muscle relaxant of intermediate duration evaluated under various anaesthetic techniques.

The dose‐response relationship of Org 9426, its time course of action and the reversibility of the residual block by neostigmine have been investigated in 100 patients undergoing various anaesthetic techniques. The dose‐response was measured immediately following induction of anaesthesia. Doses of Org 9426, required for 50% and 90% depression of the twitch height, were 202 and 328 μg.kg−1, respectively. The clinical duration of the maintenance doses, 150 μg.kg−1, ranged from 9.5 to 13.4 min and from 12.8 to 18.9 min for the first and fifth maintenance doses, respectively. Spontaneous recovery indices (25%‐75%) were between 9.5 and 16.7 min; neostigmine methylsulphate administered at 25% recovery of the twitch height promptly reversed the residual block. No side effects were observed. The extent of the influence of the anaesthetic on the time course of Org 9426 appears to be fractional considering the variation of the time course within the separate groups.

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.