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Pharmacokinetics of diuretics and methylxanthines in the neonate

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Summary

The elimination of diuretics and methylxanthines is considerably slower in the neonate than in the adult. Dose guidelines, especially during long term maintenance, must be adjusted to account for this slower drug elimination. Pharmacokinetic studies and the requisite pharmacologic evaluation on diuretics such as hydrochlorothiazide, spironolactone, ethacrynic acid and others should be done. Furosemide undergoes biotransformation in the newborn producing an acid metabolite and a glucuronide conjugate. Methylxanthines are effective in the treatment of neonatal apnea. Plasma elimination of theophylline is exceedingly slow, more so with caffeine. Decreased elimination is partly explained by decreased oxidative biotransformation. Caffeine is excreted in the urine of the newborn mainly unchanged (85%) in contrast to the adult where caffeine is a minor portion of urinary excretion (2%). Theophylline is methylated to caffeine and may possibly exert additive pharmacologic effects.

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References

  1. Aranda JV, Cohen S, Neims AG (1976) Drug utilization in a newborn intensive care unit. J Pediatr 89: 315–317

    Google Scholar 

  2. Aranda JV, Turmen T (1979) Methylxanthines in apnea of prematurity. Clin Perinatol6: 87–108

    Google Scholar 

  3. Calesnick B, Christensen JA, Richter M (1966) Absorption and excretion of furosemide-S35 in human subjects. Proc Soc Exp Biol Med 123: 17–22

    Google Scholar 

  4. Beermann B, Dalén E, Lindström B, Rosen A (1975) On the fate of furosemide in man. Eur J Clin Pharmacol 9: 57–61

    Google Scholar 

  5. Hook JB, Williamson HE (1965) Influence of probenecid and alterations in acid-base balance of the saluretic activity of furosemide. J Pharmacol Exp Ther 149: 404–408

    Google Scholar 

  6. Cutler RE, Forrey AW, Christopher TG, Kimpel EM (1974) Pharmacokinetics of furosemide in normal subjects and functionally anephric patients. Clin Pharmacol Ther 15: 588–596

    Google Scholar 

  7. Lindström B, Molander M (1974) Gas chromatographic determination of furosemide in plasma using an extractive alkylation technique and an electron capture detector. J Chromatogr 101: 219–221

    Google Scholar 

  8. Beermann B, Dalén E, Lindström B (1977) Elimination of furosemide in healthy subjects and in those with renal failure. Clin Pharmacol Ther 22: 70–78

    Google Scholar 

  9. Branch RA, Roberts CJC, Homeida M, Levine D (1977) Determinants of response to furosemide in normal subjects. Br J Clin Pharmacol 4: 121–127

    Google Scholar 

  10. Andreasen F, Mikkelsen E (1977) Distribution, elimination and effect of furosemide in normal subjects and in patients with heart failure. Eur J Clin Pharmacol 12: 15–22

    Google Scholar 

  11. Aranda JV, Perez J, Sitar DS, Collinge J, Portuguez-Malavasi A, Duffy B, Dupont C (1978) Pharmacokinetic disposition and protein binding of furosemide in newborn infants. J Pediatr 93: 507–511

    Google Scholar 

  12. Peterson RG, Rumack BH, Brooks JG (1978) Furosemide pharmacokinetics in the premature newborn. Pediatr Res 12: 407

    Google Scholar 

  13. Aranda JV, Perez J, Sitar DS (1980) Altered pharmacokinetic disposition of furosemide with multiple dosing. (Unpublished observation)

  14. Edelmann CM, Spitzer A (1969) The maturing kidney. J Pediatr 75: 509–519

    Google Scholar 

  15. Loggie JMH, Kleinman LI, Van Maanen EF (1975) Renal function and diuretic therapy in infants and children, part I. J Pediatr 86: 485–496

    Google Scholar 

  16. Huang CM, Atkinson AJ, Levin M, Levin NM, Quintanilla A (1974) Pharmacokinetics of furosemide in advanced renal failure. Clin Pharmacol Ther 16: 659–666

    Google Scholar 

  17. Aranda JV, Sitar DS, Collinge J, Shaw D (1980) Metabolism of furosemide in the newborn infant. (Manuscript in preparation)

  18. Häussler von A, Hajdú P (1964) Untersuchungen mit dem Salidiureticum 4-Chlor-N-(furylmethyl)-5-sulfamyl-anthranilsäure. Arzneim Forsch 14: 710–713

    Google Scholar 

  19. Häussler von A, Wicha H (1965) Untersuchungen mit dem Salidiureticum 4-Chlor-N-(furylmethyl)-5-sulfamyl-anthranilsäure. Arzneim Forsch 15: 81–83

    Google Scholar 

  20. Andreasen F, Hansen HE, Mikkelsen E (1978) Pharmacokinetics of furosemide in anephric patients and in normal subjects. Eur J Clin Pharmacol 13: 41–48

    Google Scholar 

  21. Ross BS, Pollak AP, Oh W (1978) The pharmacologic effects of furosemide therapy in the low birth weight infant. J Pediatr 92: 149–152

    Google Scholar 

  22. Woo WCR, Dupont C, Collinge J, Aranda JV (1978) Effects of furosemide in the newborn. Clin Pharm Ther 23: 266–271

    Google Scholar 

  23. Shankaran S, Poland RL (1977) The displacement of bilirubin from albumin by furosemide. J Pediatr 90: 642–646

    Google Scholar 

  24. Duchin K, Hutcheon D (1974) Renal pharmacology of bumetanide. A new sulfamoylmetanilic acid diuretic. J Clin Pharmacol 14: 396

    Google Scholar 

  25. Østergaard EH, Magnussen MP, Nielsen CK, Eilertsen E, Frey H-H (1972) Pharmacological properties of 3-n-butylamino-4-phenoxy-5-sulphamylbenzoic acid (bumetanide), a new potent diuretic. Arzneim Forsch 22: 66–72

    Google Scholar 

  26. Wennberg RP, Rasmussen LF, Ahlfors CE (1977) Displacement of bilirubin from human albumin by three diuretics. J Pediatr 90: 647–650

    Google Scholar 

  27. Prandota J, Pruitt AW (1974) Effect of albumin and drug concentration on the binding of furosemide. Pediatr Res 8: 365

    Google Scholar 

  28. Davies DL, Lant AF, Millard NR, Smith AJ, Ward JW, Wilson GM (1974) Renal action, therapeutic use, and pharmacokinetics of the diuretic bumetanide. Clin Pharmacol Ther 15: 141–155

    Google Scholar 

  29. Turmen T, Thom P, Louridas T, Aranda JV (1980) Protein binding and bilirubin displacement properties of bumetanide and furosemide. Pediatr Res 14: 288

    Google Scholar 

  30. Aranda JV, Gorman W, Bernsteinsson H, Gunn T (1977) Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr 90: 467–472

    Google Scholar 

  31. Gunn TR, Metrakos K, Riley P, Willis D, Aranda JV (1979) Sequelae of caffeine treatment in preterm infants with apnea. J Pediatr 94: 106–109

    Google Scholar 

  32. Davi MJ, Sankaran K, Simons KJ, Simons FER, Seshia MM, Rigatto H (1978) Physiologic changes induced by theophylline in the treatment of apnea in preterm infants. J Pediatr 92: 91–95

    Google Scholar 

  33. Aranda JV, Sitar DS, Parsons WD, Loughnan PM, Neims AH (1976) Pharmacokinetic aspects of theophylline in premature newborns. N Engl J Med 295: 413–416

    Google Scholar 

  34. Neese AL, Soyka LF (1977) Development of a radioimmunoassay for theophylline: application to studies in premature infants. Clin Pharmacol Ther 21: 633–641

    Google Scholar 

  35. Latini R, Assael BM, Bonati M, Caccamo ML, Gerna M, Mandelli M, Marini A, Sereni F, Tognoni G (1978) Kinetics and efficacy of theophylline in the treatment of apnea in the premature newborn. Eur J Clin Pharmacol 13: 203–207

    Google Scholar 

  36. Giacoia G, Jusko WJ, Menke J, Koup JR (1976) Theophylline pharmacokinetics in premature infants with apnea. J Pediatr 89: 829–832

    Google Scholar 

  37. Cottancin G, Baltassat P, Bory C, Challamel MJ, Frederich A (1977) Pharmacocinetique de la theophylline chez le nouveau né de petit poid de naissance. Pediatrie 32: 677–684

    Google Scholar 

  38. Brazier JL, Renaud H, Ribon B, Faucon G, Sassard G (1978) Evolution du taux plasmatique des xanthines dans le traitement de l'apnee du premature. Thérapie 33: 341–355

    Google Scholar 

  39. Boutroy MJ, Vert P, Royer RJ, Monin P, Royer-Morrot MJ (1979) Caffeine, a metabolite of theophylline during the treatment of apnea in the premature infant. J Pediatr 94: 996–998

    Google Scholar 

  40. Hilligoss DM, Jusko WJ, Koup JR, Giacoia G (1980) Factors affecting theophylline pharmacokinetics in premature infants with apnea. Dev Pharmacol Ther 1: 6–15

    Google Scholar 

  41. Simons FER, Friesen FR, Simons KJ (1980) Theophylline toxicity in term infants. Am J Dis Child 134: 39–41

    Google Scholar 

  42. Aranda JV, Cook CE, Gorman W, Collinge JM, Loughnan PM, Outerbridge EW, Aldridge A, Neims AH (1979) Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. J Pediatr 94: 663–668

    Google Scholar 

  43. Gorodischer R, Karplus M, Worszowski D, Bark H, Moses SW, Gordon C (1977) Caffeine pharmacokinetics in the neonate: Human and animal studies. Pediatr Res 11: 1013

    Google Scholar 

  44. Parsons W, Aranda JV, Neims AH (1976) Elimination of caffeine in the newborn. Pediatr Res 10: 333

    Google Scholar 

  45. Ogilvie RI (1978) Clinical pharmacokinetics of theophylline. Clin Pharmacokinet 3: 267–293

    Google Scholar 

  46. Aranda JV, Collinge JM, Zinman R, Watters G (1979) Maturation of caffeine elimination in infancy. Arch Dis Child 54: 946–949

    Google Scholar 

  47. Lagercrantz H, Rane A, Tunell R (1980) Plasma concentration-effect relationship of theophylline in treatment of apnea in preterm infants. Eur J Clin Pharmacol 18: 65–68

    Google Scholar 

  48. Turmen T, Zinman R, Aranda JV (1978) Relationship of dose and plasma concentrations of caffeine and ventilation in neonatal apnea. Clin Res 26: 838A

  49. Zwillich CW, Sutton FD Jr, Neff TA, Cohn WM, Matthay RA, Weinberger MM (1975) Theophylline-induced seizures in adults. Correlation with serum concentrations. Ann Intern Med 82: 784–787

    Google Scholar 

  50. Aldridge A, Aranda JV, Neims AH (1979) Caffeine metabolism in the newborn. Clin Pharmacol Ther 25: 447–453

    Google Scholar 

  51. Horning MG, Butler CM, Nowlin J, Hill RM (1975) Drug metabolism in the human neonate. Life Sci 16: 651–672

    Google Scholar 

  52. Sved S, Hossie RD, McGilveray IJ (1976) The human metabolism of caffeine to theophylline. Res Commun Chem Pathol Pharmacol 13: 185–192

    Google Scholar 

  53. Midha KK, Sved S, Hossie RD, McGilveray IJ (1977) High performance liquid chromatographic and mass spectrometric identification of dimethylxanthine metabolites of caffeine in human plasma. Biomed Mass Spectrom 4: 172–177

    Google Scholar 

  54. Cornish HH, Christman AA (1957) A study of the metabolism of theobromine, theophylline and caffeine in man. J Biol Chem 228: 315–323

    Google Scholar 

  55. Jenne JW, Nagasawa HT, Thompson RD (1976) Relationship of urinary metabolites of theophylline to serum theophylline levels. Clin Pharmacol Ther 19: 375–381

    Google Scholar 

  56. Bonati M, Latini R, Marre G, Assael BM, Parini R (1980) Theophylline metabolism in the premature neonate. Pediatr Res 14: 176

    Google Scholar 

  57. Bory C, Baltassat P, Porthault M, Bethenod M, Frederich A, Aranda JV (1979) Metabolism of theophylline to caffeine in the premature newborn infant. J Pediatr 94: 988–993

    Google Scholar 

  58. Bada HS, Khanna NN, Somani SM, Tin AA (1979) Interconversion of theophylline and caffeine in newborn infants. J Pediatr 94: 993–995

    Google Scholar 

  59. Aranda JV, Louridas AT, Vitullo BB, Thom P, Aldridge A, Haber R (1979) Metabolism of theophylline to caffeine in human fetal liver. Science 206: 1319–1321

    Google Scholar 

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Aranda, J.V., Turmen, T. & Sasyniuk, B.I. Pharmacokinetics of diuretics and methylxanthines in the neonate. Eur J Clin Pharmacol 18, 55–63 (1980). https://doi.org/10.1007/BF00561479

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