Advertisement

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

  • J. Mark K. H. Wierda
  • Ursula W. Kleef
  • Ludwina M. Lambalk
  • Wybe D. Kloppenburg
  • Sandor Agoston
Reports of Investigation

Abstract

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.

Key words

neuromuscular relaxants: Org 9426 pharmacokinetics: distribution, metabolism, urinary excretion pharmacology: dynamic-kinetic relationship 

Résumé

Nous 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.

References

  1. 1.
    Wierda JMKH, de Wit APM, Kuizenga K, Agoston S. Clinical observations on the neuromuscular blocking action of Org 9426, a new steroidal non-depolarizing agent. Br J Anaesth 1990; 64: 521–3.PubMedCrossRefGoogle Scholar
  2. 2.
    Muir AW, Houston J, Green KL, Marshall RJ, Bowman WC, Marshall IG. Effects of a new neuromuscular blocking agent (Org 9426) in anaesthetized cats and pigs and in isolated nerve-muscle preparations. Br J Anaesth 1990: 63: 400–10.CrossRefGoogle Scholar
  3. 3.
    Marshall RJ, Muir AW, Booij L,Crul J, Marshall IG. The cardiovascular effects of four new non-depolarising neuromuscular blocking drugs in rats, cats, dogs, pigs and monkeys. Abstracts of the 9th World Congress of Anaes-thesiologists 1988; Vol II: AO534.Google Scholar
  4. 4.
    Cason B, Baker DG, Hickey RF, Miller RD, Agoston S. Cardiovascular and neuromuscular effects of three steroidal neuromuscular blocking drugs in dogs (Org 9616, Org 9426, Org 9991). Anesth Analg 1990; 70: 382–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Khuenl-Brady K, Castagnoli KP, Canfell PC, Caldwell JE, Agoston S, Miller RD. The neuromuscular blocking effects and pharmacokinetics of Org 9426 and Org 9616 in the cat. Anesthesiology 1990; 72: 669–74.PubMedCrossRefGoogle Scholar
  6. 6.
    Krieg N, Mazur L, Booij LHDJ, Crul FJ. Intubation conditions and reversibility of a new non-depolarizing neuromuscular blocking agent, Org NC 45. Acta Anaesthesiol Scand 1980; 24: 423–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Paanakker JE, Thio JMSL, van den Wildeberg HM, Kaspersen FM. Assay of vecuronium in plasma using solid phase extraction, high performance liquid chromatography and post-column ion-pair extraction with fluorimetric detection. J Chromatogr 1987; 421: 327–35.PubMedCrossRefGoogle Scholar
  8. 8.
    Scaf AHJ. Pharmacokinetic analyses with RUGFIT: an interactive pharmacokinetic computer program. Biopharm Drug Dispos 1988; 9: 415–46.PubMedCrossRefGoogle Scholar
  9. 9.
    Krieg N. Pharmacodynamische untersuchungen mit vecuronium. Anaeslhesist 1985; 34: 340–5.Google Scholar
  10. 10.
    Agoston S, Salt P, Newton D, Bencini A, Boomsma P, Erdmoim W. The neuromuscular blocking action of Org NC 45, a new pancuronium derivative, in anaesthetized patients. A pilot study. Br J Anaesth 1980; 52: 53S-9S.PubMedCrossRefGoogle Scholar
  11. 11.
    Bencini AF, Scaf AHJ, Sohn YJ et al. Disposition and urinary excretion of vecuronium bromide in anesthetized patients with normal renal function or renal failure. Anesth Analg 1986; 65: 245–51.PubMedCrossRefGoogle Scholar
  12. 12.
    Sohn YJ, Bencini AF, Scaf AHJ, Kersten UW, Agoston S. Comparative pharmacokinetics and dynamics of vecuronium and pancuronium in anesthetized patients. Anesth Analg 1986; 65: 233–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bencini AF, Scaf AHJ, Sohn YJ, Kersten-Kleef UW, Agoston S. Hepatobiliary disposition of vecuronium bromide in man. Br J Anaesth 1986; 58: 988–95.PubMedCrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists 1991

Authors and Affiliations

  • J. Mark K. H. Wierda
    • 1
  • Ursula W. Kleef
    • 1
  • Ludwina M. Lambalk
    • 1
  • Wybe D. Kloppenburg
    • 1
  • Sandor Agoston
    • 1
  1. 1.Research Group for Experimental Anesthesiology and Clinical PharmacologyUniversity of GroningenThe Netherlands

Personalised recommendations