Clinical Pharmacokinetics

, Volume 34, Issue 6, pp 483–496 | Cite as

Clinical Pharmacokinetics of Neuromuscular Relaxants in Pregnancy

  • Joanne Guay
  • Yvan Grenier
  • France Varin
Review Article Special Populations

Summary

Despite an increased in bodyweight, plasma volume by 45% and blood volume by 35% that might influence the volume of distribution of polar drugs, the apparent volume of distribution at steady state (Vss), volume of distribution (Vd) and the apparent volume of the central compartment (Vc) of atracurium, vecuronium and pancuronium are unchanged during pregnancy. With an elimination that is independent of renal, hepatic and enzymatic functions, the clearance of atracurium is also unchanged. This is corroborated by an unchanged clinical duration of atracurium during pregnancy. The clearance of pancuronium is increased by 27% during caesarean section. This may be explained by the increased glomerular filtration rate reported in pregnant women. The clinical duration of vecuronium in term and postpartum women is twice that reported in nonpregnant women. On the other hand, an increase in the clearance clearance of vecuronium during cesarean sections has been reported.

The umbilical/maternal vein concentration ratio (UV/MV) of nondepolarising neuromuscular relaxants varies from 7 to 26% and clinical doses of these drugs may induce partial residual curarisation in neonates. Fetal concentrations of non-depolarising neuromuscular relaxants are proportional to the maternal dose injected as demonstrated for pancuronium and vecuronium. Increasing UV/MV with longer drug injection to delivery intervals have been demonstrated for drugs with a high molecular weight, such as atracurium, but not for those with a low molecular weight, such as vecuronium, while conflicting results have been reported for pancuronium.

Despite decreased plasma pseudocholinesterases, the clinical duration of succinylcholine 1 mg/kg is unchanged in pregnant women, and only is slightly increased in postpartum women. On the other hand, larger doses of succinylcholine have induced prolonged apnoea and phase II block.

The use of a pretreatment dose of a nondepolarising neuromuscular relaxant to decrease fasciculations and subsequent postoperative muscle pain is not only unnecessary in pregnant women but may be hazardous, since it may produce unexpected significant curarisation with respiratory distress. At clinical doses, transplacental passage of succinylcholine is insufficient to produce curarisation of neonates except in those born to mothers with abnormal plasma pseudocholinesterases.

Magnesium sulfate, used in the treatment of pre-eclampsia, will enhance the blocking effects of nondepolarising neuromuscular relaxants but will have no effects on the characteristics of paralysis of succinylcholine. Histamine type 2 antagonists used to decrease the risk of aspiration during induction of anaesthesia do not influence the blocking properties of neuromuscular relaxants, while metoclopramide prolongs the block of succinylcholine.

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References

  1. 1.
    Cheek TG, Gutsche BB. Maternal physiologic alterations during pregnancy. In: Shnider SM, Levinson G, editors. Anesthesia for obstetrics. 3rd ed. Baltimore: Williams and Wilkins, 1993: 3–17.Google Scholar
  2. 2.
    Reynolds F, Knott C. Pharmacokinetics in pregnancy and placental drug transfer. Oxford Rev Reprod Biol 1989; 11: 389–49.Google Scholar
  3. 3.
    Notarianni LJ. Plasma protein binding of drugs in pregnancy and in neonates. Clin Pharmacokinet 1990; 18: 20–36.PubMedCrossRefGoogle Scholar
  4. 4.
    Knott C, Reynolds F. Therapeutic drug monitoring in pregnancy: rationale and current status. Clin Pharmacokinet 1990; 19 (6): 425–33.PubMedCrossRefGoogle Scholar
  5. 5.
    Guay J, Beaudry B, Lortie L, et al. Pharmacokinetics of atracurium in pregnant women. Clin Drug Invest 1996; 11 (3): 167–73.CrossRefGoogle Scholar
  6. 6.
    Duvaldestin P, Demetriou M, Henzel D, et al. The placental transfer of pancuronium and its pharmacokinetics during cesarean section. Acta Anaesth Scand 1978; 22: 327–33.PubMedCrossRefGoogle Scholar
  7. 7.
    Dailey PA, Fisher DM, Shnider SM, et al. Pharmacokinetics, placental transfer, and neonatal effects of vecuronium and pancuronium administered during cesarean section. Anesthesiology 1984; 60 (6): 569–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Cronelly R, Fisher DM, Miller RD, et al. Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC45) and pancuronium in anesthetized humans. Anesthesiology 1983; 58 (5): 405–8.CrossRefGoogle Scholar
  9. 9.
    Merrett RA, Thompson CW, Webb FW. In vitro degradation of atracurium in human plasma. Br J Anaesth 1983; 55: 61–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Stiller RL, Cook DR, Chakravorti S. In vitro degradation of atracurium in human plasma. Br J Anaesth 1985; 57: 1085–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Ward S, Boheimer N, Weatherley BC, et al. Pharmacokinetics of atracurium and its metabolites in patients with normal renal function, and in patients in renal failure. Br J Anaesth 1987; 59; 697–706.PubMedCrossRefGoogle Scholar
  12. 12.
    Tsui D, Graham GG, Torda TA. The pharmacokinetics of atracurium isomers in vitro and in humans. Anesthesiology 1987; 67: 722–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Fisher DM, Canfell PC, Fahey MR, et al. Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination. Anesthesiology 1986; 65: 6–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Khuenl-Brady KS, Koller J, Mair P, et al. Comparison of vecuronium- and atracurium-induced neuromuscular blockade in postpartum and nonpregnant patients. Anesth Analg 1991; 72: 110–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Agoston S, Vandenbrom RHG, Wierda JMKH. Clinical pharmacokinetics of neuromuscular blocking drugs. Clin Pharmacokinet 1992; 22 (2): 94–115.PubMedCrossRefGoogle Scholar
  16. 16.
    Patel R, Katz R, Martinez V, et al. Effects of mivacurium-induced neuromuscular blockade in the postpartum patients [abstract]. Anesthesiology 1993; 79: A967.Google Scholar
  17. 17.
    Gin T, Derrick JL, Chan MTV, et al. Postpartum patients have slightly prolonged neuromuscular block after mivacurium. Anesth Analg 1998; 86: 82–5.PubMedGoogle Scholar
  18. 18.
    Camp CE, Tessem J, Adenwala J, et al. Vecuronium and prolonged neuromuscular blockade in postpartum patients. Anesthesiology 1987; 67: 1006–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Hawkins JL, Adenwala J, Camp C, et al. The effect of H2-receptor antagonist premedication on the duration of vecuronium-induced neuromuscular blockade in postpartum patients. Anesthesiology 1989; 71 (2): 175–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Hawkins JL, Johnson TD, Kubicek MA, et al. Vecuronium for rapid-sequence intubation for cesarean section. Anesth Analg 1990; 71: 185–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Baraka A, Jabbour S, Tabboush Z, et al. Onset of vecuronium neuromuscular block is more rapid in patients undergoing caesarean section. Can J Anaesth 1992; 39 (2): 135–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Patel R, Moran V, Katz R, et al. The onset and duration of action of rocuronium is not prolonged during the postpartum period [abstract]. Anesthesiology 1996; 85: A826.Google Scholar
  23. 23.
    Piihringer FK, Sparr HJ, Mitterschiffthaler G, et al. Extended duration of action of rocuronium in postpartum patients. Anesth Analg 1997; 84: 352–4.Google Scholar
  24. 24.
    Bencini AF, Scaf AHJ, Sohn YJ, et al. Hepatobiliary disposition of vecuronium bromide in man. Br J Anaesth 1986; 58: 988–95.PubMedCrossRefGoogle Scholar
  25. 25.
    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
  26. 26.
    Dam M, Christiansen J, Munck O, et al. Antiepileptic drugs: metabolism in pregnancy. Clin Pharmacokinet 1979; 4: 53–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Cameron M, Donati F, Varin F. In vitro plasma protein binding of neuromuscular blocking agents in different subpopulations of patients. Anesth Analg 1995; 81: 1019–25.PubMedGoogle Scholar
  28. 28.
    Wood M, Wood AJJ. Changes in plasma drug binding and α-1-acid glycoprotein in mother and newborn infant. Clin Pharmacol Ther 1981; 29 (4): 522–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Abouleish E, Abboud T, Lechevalier T, et al. Rocuronium (Org 9426) for caesarean section. Br J Anaesth 1994; 73: 336–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Magorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine and vecuronium for rapid-sequence induction of anesthesia in adult patients. Anesthesiology 1993; 79: 913–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Pacifi GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet 1995; 28 (3): 235–69.CrossRefGoogle Scholar
  32. 32.
    Flynn PJ, Frank M, Hughes R. Use of atracurium in caesarean section. Br J Anaesth 1984; 56: 599–605.PubMedCrossRefGoogle Scholar
  33. 33.
    Shearer ES, Fahy LT, O’sullivan EP, et al. Transplacental distribution of atracurium, laudanosine and monoquaternary alcohol during elective caesarean section. Br J Anaesth 1991; 66: 551–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Perreault C, Guay J, Gaudreault P, et al. Residual curarization of the neonate after caesarean section. Can J Anaesth 1991; 38 (5): 587–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Bertrand JC, Duvaldestin P, Henzel D, et al. Quantitative assessment of placental transfer of fazadinium in obstetric anaesthesia. Acta Anaesth Scand 1980; 24: 135–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Demetriou M, Depoix JP, Diakite B, et al. Placental transfer of Org NC 45 in women undergoing caesarean section. Br J Anaesth 1982; 54: 643–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Booth PN, Watson MJ, McLeod K. Pancuronium and the placental barrier. Anaesthesia 1977; 32: 320–3.PubMedCrossRefGoogle Scholar
  38. 38.
    Abouleish E, Wingard LB, de la Vega S, et al. Pancuronium in caesarean section and its placental transfer. Br J Anaesth 1980; 52: 531–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee C, Kwan WF, Chen BJ, et al. Neuromuscular blocking effect and placental gradient of pipecuronium bromide in elective caesarean section. Proceedings of the National Science Council, ROC: part B. Life Sci 1992; 16(3): 119–24.Google Scholar
  40. 40.
    Duvaldestin P, Henzel D. Binding of tubocurarine, fazadinium, pancuronium and ORG NC 45 to serum proteins in normal man and in patients with cirrhosis. Br J Anaesth 1982; 54: 513–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Wood M, Stone WJ, Wood AJJ. Plasma binding of pancuronium: effects of age, sex and disease. Anesth Analg 1983; 62: 29–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Fisher DM, Canfell PC, Spellman MJ, et al. Pharmacokinetics and pharmacodynamics of atracurium in infants and children. Anesthesiology 1990; 73: 33–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Amiel-Tison C, Barrier G, Shnider SM, et al. A new neurologic and adaptive capacity scoring system for evaluating obstetric medications in full-term newborns. Anesthesiology 1982; 56: 340–50.PubMedCrossRefGoogle Scholar
  44. 44.
    Guay J, Gaudreault P, Boulanger A, et al. Lidocaine hydrochloride and lidocaine hydrocarbonate: transplacental passage and neonatal effects. Acta Anesthesiol Scand 1992; 36: 722–7.CrossRefGoogle Scholar
  45. 45.
    Seeds JW, Corke BC, Spielman FJ. Prevention of fetal movement during invasive procedures with pancuronuim bromide. Am J Obstet Gynecol 1986; 155: 818–9.PubMedGoogle Scholar
  46. 46.
    Leveque C, Murat I, Toubas F, et al. Fetal neuromuscular blockade with vecuronium bromide: studies during intravascular intrauterine transfusion in isoimmunized pregnancies. Anesthesiology 1992; 76: 642–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Jago RH. Arthrogryposis following treatment of maternal tetanus with muscle relaxants. Arch Dis Child 1970; 45: 277–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Hawkins JL, Koonin LM, Palmer SK, et al. Anesthesia-related deaths during obstetric delivery in the United States, 1979–1990. Anesthesiology 1997; 86: 277–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Wright PM, Caldwell JE, Miller RD. Onset and duration of rocuronium and succinylcholine at the adductor pollicis and laryngeal adductor muscles in anesthetized humans. Anesthesiology 1995; 81 (5): 1110–5.CrossRefGoogle Scholar
  50. 50.
    Baraka A, Haroun S, Bassili M, et al. Response of the newborn to succinylcholine injection in homozygotic atypical mothers. Anesthesiology 1975; 43: 115–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Carnie JC, Street MK, Kumar B. Emergency intubation of the trachea facilitated by suxamethonium. Br J Anaesth 1986; 58: 498–501.PubMedCrossRefGoogle Scholar
  52. 52.
    Peek AW. Relative importance of the enzymatic hydrolysis of suxamethonium in plasma and tissues: studies in rhesus monkeys. Br J Pharmacol 1971; 45: 64–70.CrossRefGoogle Scholar
  53. 53.
    Savarese JJ, Miller RD, Lien CA, et al. Pharmacology of muscle relaxants and their antagonists. In: Miller RD, editor. Anesthesia. 4th ed. New York: Churchill Livingstone, 1994: 417–88.Google Scholar
  54. 54.
    Zeller EA, Burkhauser H, Wattenwyl HV, et al. Geschlechtsfunktion und Serum-Cholinesterase des Menschen, 3. Mitteilung über Beziehhungen zwischen Sexualhormonen und Fermenten. Helvetica Chim Acta 1941; 24: 962–8.CrossRefGoogle Scholar
  55. 55.
    Shnider SM. Serum cholinesterase activity during pregnancy, labor and puerperium. Anesthesiology 1965; 26: 335–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Evans RT, Wroe JM. Plasma cholinesterase changes during pregnancy. Anaesthesia 1980; 35: 651–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Ravindran RS, Cummins DF, Pantazis KL, et al. Unusual aspects of low levels of pseudocholinesterase in a pregnant patient. Anesth Analg 1982; 61: 953–5.PubMedGoogle Scholar
  58. 58.
    Friedman MM, Lapan B. Variations of enzyme activities during normal pregnancy. Am J Obstet Gynecol 1950; 60: 1343–7.Google Scholar
  59. 59.
    Pritchard JA. Plasma cholinesterase activity in normal pregnancy and eclamptogenic toxemias. Am J Obstet Gynecol 1955; 70: 1083–6.PubMedGoogle Scholar
  60. 60.
    Tourtelotte WW, Odell LD. Plasma acetylcholinesterase activity. Am J Obstet Gynecol 1950; 60: 1343–7.Google Scholar
  61. 61.
    Blitt CD, Petty WC, Alberternst EE, et al. Correlation of plasma cholinesterase activity and duration of action of succinylcholine during pregnancy. Anesth Analg 1977; 56: 78–83.PubMedCrossRefGoogle Scholar
  62. 62.
    Leighton BL, Cheek TG, Gross JB, et al. Succinylcholine pharmacodynamics in peripartum patients. Anesthesiology 1986; 64: 202–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Hoshi K, Hashimoto Y, Matsukawa S. Pharmacokinetics of succinylcholine in man. Tohoku J Exp Med 1993; 170: 245–50.PubMedCrossRefGoogle Scholar
  64. 64.
    Wildsmith JAW. Serum pseudocholinesterase, pregnancy and suxamethonium. Anaesthesia 1972; 27: 90–1.PubMedCrossRefGoogle Scholar
  65. 65.
    Weissman DB, Ehrenwerth J. Prolonged neuromuscular blockade in a parturient associated with succinylcholine. Anesth Analg 1983; 62: 444–6.PubMedGoogle Scholar
  66. 66.
    Donati F, Bevan DR. Succinylcholine in obstetrics [letter]. Anesth Analg 1983; 62: 1051–2.PubMedCrossRefGoogle Scholar
  67. 67.
    Cherala S, Eddie D, Halpern M, et al. Priming with vecuronium in obstetrics [letter]. Anaesthesia 1987; 42: 1021.PubMedCrossRefGoogle Scholar
  68. 68.
    Crawford JS. Suxamethonium muscle pains and pregnancy. Br J Anaesth 1971; 43: 677–80.PubMedCrossRefGoogle Scholar
  69. 69.
    Datta S, Crocker JS, Alper MH. Muscle pain following administration of suxamethonium to pregnant and non-pregnant patients undergoing laparoscopic tubal ligation. Br J Anaesth 1977; 49: 625–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Thind GS, Bryson THL. Single dose suxamethonium and muscle pain in pregnancy. Br J Anaesth 1983; 55: 743–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Cook WP, Schultetus RR, Caton D. A comparison of d-tubocurarine pretreatment and no pretreatment in obstetric patients. Anesth Analg 1987; 66: 756–60.PubMedCrossRefGoogle Scholar
  72. 72.
    Felton DJC, Goddard BA. The effect of suxamethonium chloride on uterine activity. Lancet 1966; I (442): 852–4.CrossRefGoogle Scholar
  73. 73.
    Luppa JB, Smith GA, Colella JJ, et al. Succinylcholine effect on human myometrical activity. Obst Gyn 1971; 37: 591–5.Google Scholar
  74. 74.
    Healy TEJ. Suxamethonium and intra-uterine pressure. Br J Anaesth 1971; 43: 1156–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Kvisselgaard N, Moya F. Investigation of placental thresholds to succinylcholine. Anesthesiology 1961; 22: 7–10.PubMedCrossRefGoogle Scholar
  76. 76.
    Owens WD, Zeitlin GL. Hypoventilation in a newborn following administration of succinylcholine to the mother: a case report. Anesth Analg 1975; 54: 38–40.PubMedCrossRefGoogle Scholar
  77. 77.
    Hoefnagel D, Harris A, Kim TH. Transient respiratory depression of the newborn. Am J Dis Child 1979; 133: 825–6.PubMedGoogle Scholar
  78. 78.
    Dupuis JY, Martin R, Tetrault JP. Atracurium and vecuronium interaction with gentamycin and tobramycin. Can J Anaesth 1989; 36 (4): 407–11.PubMedCrossRefGoogle Scholar
  79. 79.
    Giesecke Jr AH, Morris RE, Dalton MD, et al. Of magnesium, muscle relaxants, toxemic parturients, and cats. Anesth Analg 1968; 47 (6): 689–95.PubMedCrossRefGoogle Scholar
  80. 80.
    Ahn EK, Bai SJ, Cho BJ, et al. The infusion rate of mivacurium and its spontaneous neuromuscular recovery in magnesium treated participants. Anesth Analg 1998; 86: 523–6.PubMedGoogle Scholar
  81. 81.
    Baraka A, Yazigi A. Neuromuscular interaction of magnesium with succinylcholine-vecuronium sequence in the eclamptic parturient. Anesthesiology 1987; 67: 806–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Gaiser RR, Seem EH. Use of rocuronium in a pregnant patient with an open eye injury, receiving magnesium medication, for preterm labour. Br J Anaesth 1996; 77: 669–71.PubMedCrossRefGoogle Scholar
  83. 83.
    Salib Y, Donati F. Potentiation of pancuronium and vecuronium neuromuscular blockade by intravenous salbutamol. Can J Anaesth 1993; 40 (1): 50–3.PubMedCrossRefGoogle Scholar
  84. 84.
    James MFM, Cork RC, Dennett JE. Succinylcholine pretreatment with magnesium sulfate. Anesth Analg 1986; 65: 373–6.PubMedGoogle Scholar
  85. 85.
    Bogod DG. The effect of H2 antagonists on duration of action of suxamethonium in the parturient. Anaesthesia 1989; 44: 591–3.PubMedCrossRefGoogle Scholar
  86. 86.
    Turner DR, Kao YJ, Bivona C. Neuromuscular block by suxamethonium following treatment with histamine type 2 antagonists or metoclopramide. Br J Anaesth 1989; 63: 348–50.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Joanne Guay
    • 1
  • Yvan Grenier
    • 1
  • France Varin
    • 2
  1. 1.Department of AnaesthesiologyHôpital Maisonneuve-RosemontMontréalCanada
  2. 2.Faculty of PharmacyUniversity of MontrealMontrealCanada

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