top of page
Drug-Induced Methaemoglobinaemia


19 Oct 2022

Source: Drug-Induced Methaemoglobinaemia | SpringerLink

In normal erythrocytes, small quantities of methaemoglobin are formed constantly and are continuously reduced, almost entirely by the reduced nicotine adenine dinucleotide (NADH) diaphorase system, rather than the reduced nicotine adenine dinucleotide phosphate (NADPH) diaphorase system.

Methaemoglobinaemias are usually the result of xenobiotics, either those that may directly oxidise haemoglobin or those that require metabolic activation to an oxidising species. The most clinically relevant direct methaemoglobin formers include local anaesthetics (such as benzocaine and, to a much lesser extent, prilocaine) as well as amyl nitrite and isobutyl nitrite, which have become drugs of abuse. Indirect, or metabolically activated, methaemoglobin formation by dapsone and primaquine may cause adverse reactions.

The clinical consequences of methaemoglobinaemia are related to the blood level of methaemoglobin; dyspnoea, nausea and tachycardia occur at methaemoglobin levels of ≤30%, while lethargy, stupor and deteriorating consciousness occur as methaemoglobin levels approach 55%. Higher levels may cause cardiac arrhythmias, circulatory failure and neurological depression, while levels of 70% are usually fatal.

Cyanosis accompanied by a lack of responsiveness to 100% oxygen indicates a diagnosis of methaemoglobinaemia, which should be confirmed using a CO-oximeter. Pulse oximeters do not detect methaemoglobin and may give a misleading impression of patient oxygenation.

Methaemoglobinaemia is treated with intravenous methylene blue (methyl-thioninium chloride; 1 to 2 mg/kg of a 1% solution). If the patient does not respond, perhaps because of glucose-6-phosphate dehydrogenase (G6PD) deficiency or continued presence of toxin, admission to an intensive care unit and exchange transfusion may be required.

Dapsone-mediated chronic methaemoglobin formation can be reduced by co-administration of cimetidine to aid patient tolerance.

Increasing knowledge and awareness of drug-mediated acute methaemoglobinaemia among physicians should lead to prompt diagnosis and treatment of this potentially life-threatening condition.


  1. Misra HP, Fridovitch I. The generation of Superoxide radical during the autoxidation of hemoglobin. J Biol Chem 1972; 247: 6960–2 PubMed CAS Google Scholar

  2. Mansouri A, Lurie AA. Methemoglobinaemia. Am J Hematol 1993; 42: 7–12 Article PubMed CAS Google Scholar

  3. Bunn HF, Forget BG. Hemoglobin: molecular, genetic and clinical aspects. Philadelphia: WB Saunders, 1986: 634–62 Google Scholar

  4. Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaine-induced methaemoglobinaemia: report of a severe reaction and review of the literature. Ann Pharmacother 1994; 28(5): 643–9 PubMed CAS Google Scholar

  5. Lindstrom TR, Ho C, Pisciotta AV. Nuclear magnetic resonance studies of haemoglobin. M Milwaukee Nat New Biol 1972; 237: 263–5 CAS Google Scholar

  6. Wilson G, Borthwick T, Lamb R. Toxic methaemoglobinaemia. J Tenn Med Assoc 1989; 82: 581–3 PubMed CAS Google Scholar

  7. Jaffe ER. Methaemoglobinaemia in the differential diagnosis of cyanosis. Hosp Pract 1985; 20: 92–110 CAS Google Scholar

  8. Winterhalter KH, Di Iorio EE, Beetlestone JG, et al. The electronic structure of haem in haemoglobin Zurich β63-His-Arg. J Mol Biol 1972; 70: 665–74 Article PubMed CAS Google Scholar

  9. Coleman MD, Ogg MS, Holmes JL, et al. Studies on the differential sensitivity between diabetic and non-diabetic human erythrocytes to monoacetyl dapsone hydroxylamine-mediated methaemoglobin formation in vitro. Env Toxicol Pharmacol 1996; 1: 97–102 Article CAS Google Scholar

  10. Park CM, Nagel RL. Sulfhemoglobinemia: clinical and molecular aspects. N Engl J Med 1984; 310: 1579–84 Article PubMed CAS Google Scholar

  11. Smith RP. Toxic responses of the blood. In: Klaasen CD, Amdur MO, Doull J, editors. Casarett and Doull’s toxicology. New York: MacMillan, 1986: 223–45 Google Scholar

  12. Jaffe ER, Hultquist DE. Cytochrome b5 reductase deficiency and enzymopenic hereditary methemoglobinaemia. In: Scriver CR, Beaudel AL, Sly WS, et al., editors. The metabolic basis for hereditary disease. New York: McGraw-Hill, 1989: 2267–80 Google Scholar

  13. Posthumus MD, van Berkel W. Cytochrome b 5 reductase deficiency and uncommon cause of cyanosis. Neth J Med 1994; 44: 136–40 PubMed CAS Google Scholar

  14. Yubisui T, Miyata T, Iwanaga S, et al. NADPH-flavin reductase in human erythrocytes and the reduction of methaemoglobin through flavin by the enzyme. Biochem Biophys Res Commun 1977; 76: 174–82 Article PubMed CAS Google Scholar

  15. Curry S. Methemoglobinemia. Ann Emerg Med 1982; 11: 214–21 Article PubMed CAS Google Scholar

  16. Scott EM, Griffith IV. The enzymic defect of hereditary methemoglobinemia: diaphorase. Biochem Biophys Acta 1959; 34: 584–6 Article PubMed CAS Google Scholar

  17. Tanishima K, Tanimoto K, Tomoda A, et al. Hereditary methaemoglobinaemia due to cytochrome B5-reductase deficiency in blood-cells without associated neurologic and mental disorders. Blood 1985; 66(6): 1288–91 PubMed CAS Google Scholar

  18. Hegesh E, Hegesh J, Kraftory A. Congenital methemoglobinemia with a deficiency of cytochrome b 5. N Engl J Med 1986; 314: 757–61 Article PubMed CAS Google Scholar

  19. Kaplan JC, Chirouze M. Therapy of recessive congenital methemoglobinemia by oral riboflavine. Lancet 1987; II: 1043–4 Google Scholar

  20. Lo SC-L, Agar NS. NADH-methemoglobin reductase activity in the newborn and adult mammals. Experientia 1986; 42: 1264–5 Article PubMed CAS Google Scholar

  21. Knotek Z, Schmidt P. Pathogenesis, incidence and possibilities of preventing alimentary nitrate methemoglobinemia in infants. Pediatrics 1964; 34: 78–83 PubMed CAS Google Scholar

  22. Hjelt K, Lund JT, Scherling B, et al. Methaemoglobinaemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995; 84 365–70 Article PubMed CAS Google Scholar

  23. Feig SA. Methemoglobinemia. In: Nathan DG, Oski FA, editors. Hematology of infancy and childhood. Philadelphia: WB Saunders, 1981: 654–86 Google Scholar

  24. Blakynty R, Harding JJ, Glycation (non-enzymatic glycosylation) inactivates glutathione reductase. Biochem J 1992; 288: 303–7 Google Scholar

  25. Costagliola C. Oxidative state of glutathione in red blood cells and plasma of diabetic patients: in vivo and in vitro study. Clin Physiol Biochem 1990; 8: 204–10 PubMed CAS Google Scholar

  26. DeGowin RL, Bennet Eppes R, Powell RD. The haemolytic effects of diphenylsulphone (DDS) in normal subjects and in those with glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ 1966; 35: 165–79 PubMed CAS Google Scholar

  27. Beutler E, Baluda MC. Methemoglobin reduction-studies of the interaction between red cell populations and of the role of methylene blue. Blood 1963; 22: 323–33 PubMed CAS Google Scholar

  28. Bhutani A, Bhutani MS, Patel R. Methaemoglobinaemia in a patient undergoing gastrointestinal endoscopy. Ann Pharmacother 1992; 26(10): 1239–40 PubMed CAS Google Scholar

  29. Frayling IM, Addison GM, Chattergee K. Methaemoglobinaemia in children treated with prilocaine-lignocaine cream. BMJ 1990; 301: 153–4 Article PubMed CAS Google Scholar

  30. Tarburton JP, Metcalf WK. The kinetic differences between sodium nitrite, amyl nitrite and nitroglycerin oxidation of hemoglobin. Histol Histopathol 1986; 1: 213–7 PubMed CAS Google Scholar

  31. Bradberry SM, Whittington RM, Parry DA, et al. Fatal methemoglobinemia due to inhalation of isobutyl nitrite. J Toxicol Clin Toxicol 1994; 32(2): 179–84 Article PubMed CAS Google Scholar

  32. Machabert R, Testud F, Descotes J. Methaemoglobinaemia due to nitrite inhalation: a case report. Hum Exp Toxicol 1994; 13(5): 313–4 Article PubMed CAS Google Scholar

  33. Johnson WS, Hall AH, Rumack BH. Cyanide poisoning successfully treated without ‘therapeutic methaemoglobin levels’. Am J Emerg Med 1989; 7(4): 437–40 Article PubMed CAS Google Scholar

  34. Bruning-Fann CS, Kaneene JB. The effects of nitrate, nitrite and N-nitroso compounds on human health. Vet Hum Toxicol 1993; 35(6): 521–38 PubMed CAS Google Scholar

  35. Dusdieker LB, Getchell JP, Liarakos TM, et al. Nitrate in baby foods-adding to the nitrate mosaic. Arch Pediatr Adolesc Med 1994; 148(5): 490–4 Article PubMed CAS Google Scholar

  36. Kaplan A, Smith C, Promnitz, et al. Methaemoglobinaemia due to accidental sodium nitrite poisoning. S Afr Med J 1990; 77: 300–1 PubMed CAS Google Scholar

  37. Ellis Y, Hiss Y, Shenkman L. Fatal methemoglobinemia caused by inadvertent contamination of a laxative solution with sodium nitrite. Isr J Med Sci 1992; 28(5): 289–91 PubMed CAS Google Scholar

  38. Ternberg JL, Luce E. Methaemoglobinaemia: a complication of the silver nitrate treatment of burns. Paediatric Surg 1968; 63: 328–30 Google Scholar

  39. Adatia I, Lillehei C, Arnold JH. Inhaled nitric oxide in the treatment of post-operative graft dysfunction after lung transplantation. Ann Thorac Surg 1994; 57(5): 1311–8 Article PubMed CAS Google Scholar

  40. Shah N, Jacob T, Exler R. Inhaled nitric oxide in congenital diaphragmatic hernia. J Pediatr Surg 1994; 29(8): 1010–5 Article PubMed CAS Google Scholar

  41. Rossaint R, Gerlach H, Schmidt-Ruhnke H. Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest 1995; 107(4): 1107–15 Article PubMed CAS Google Scholar

  42. Williams RS, Mickell JJ, Young ES. Methaemoglobin levels during prolonged combined nitroglycerin and sodium nitroprusside infusions in infants after cardiac surgery. J Cardiothorac Anesth 1994; 8(6): 658–62 Article CAS Google Scholar

  43. Norambuena E, Videla LA, Lissi EA. Interaction of nitrobenzoates with haemoglobin in red blood cells and a haemolysate. Hum Exp Toxicol 1994; 13: 345–51 Article PubMed CAS Google Scholar

  44. Hornfeldt CS, Rabe WH. Nitroethane poisoning from an artificial fingernail remover. J Toxicol Clin Toxicol 1994; 32(3): 321–4 Article PubMed CAS Google Scholar

  45. Schimelman MA, Soler JM, Muller HA. Methemoglobinemia: nitrobenzene ingestion. J Amer Coll Emerg Phys 1994; 7(11): 406–8 Article Google Scholar

  46. Dinneen SF, Mohr DN, Fairbanks VF. Methemoglobinemia from topically applied anesthetic spray. Mayo Clin Proc 1994; 69(9): 886–8 PubMed CAS Google Scholar

  47. Guertler AT, Lagutchik MS, Martin DG. Topical anesthetic-induced methemoglobinemia in sheep: a comparison of benzocaine and lidocaine. Fundam Appl Toxicol 1992; 18: 294–8 Article PubMed CAS Google Scholar

  48. Jensen CB, Jollow DJ. The role of N-hydroxyphenetidine in phenacetin-induced hemolytic anemia. Toxicol App Pharmacol 1991; 111(1): 1–12 Article CAS Google Scholar

  49. Morais M da S, Augusto O. Peroxidation of the antimalarial drug primaquine: characterisation of a benzidine-like metabolite with methaemoglobin forming capacity. Xenobiotica 1993; 23(2): 133–9 Article CAS Google Scholar

  50. Zone JJ. Dermatitis Herpetiformis. Curr Probl Dermatol 1991; 3: 4–42 Article Google Scholar

  51. Coleman MD. Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance. Br J Dermatol 1993; 129: 507–13 Article PubMed CAS Google Scholar

  52. Kiese M, Reinwein D, Waller HD. Kinetik der Hamiglobinbildung. IV Mitteilung. Die Hamiglobinbildung durch Phenylhydroxylamin und Nitrosobenzol in roten Zellen in vitro. Naun Schmied Arch Exp Pathol Pharmakol 1950; 210: 393–8 CAS Google Scholar

  53. Coleman MD, Rhodes LA, Scott AK, et al. The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients. Brit J Clin Pharmacol 1992; 34: 244–9 Article CAS Google Scholar

  54. Cribb AE, Spielberg SP. Sulfamethoxazole is metabolised to the hydroxylamine in humans. Clin Pharmacol Ther 1992; 51: 522–6 Article PubMed CAS Google Scholar

  55. Pirmohamed M, Coleman MD, Galvani D, et al. Lack of interaction between sulphasalazine and cimetidine in patients with rheumatoid arthritis. Br J Rheumatol 1993; 32: 222–6 Article PubMed CAS Google Scholar

  56. Brown TD, O’Rourke TJ, Kuhn JG, et al. Phase I trial of sulofenur (LY186641) given orally on a daily × 21 schedule. Anticancer Drugs 1994; 5(2): 151–9 Article PubMed CAS Google Scholar

  57. Ehlhardt WJ, Woodland JM, Worzalla JF. Comparison of metabolism and toxicity to the structure of the anticancer agent sulofenur and related sulphonyl ureas. Chem Res Toxicol 1992; 5(5): 667–73 Article PubMed CAS Google Scholar

  58. Heilmair R, Karreth S, Lenk W. The metabolism of 4-aminobiphenyl in the rat II. Reaction of 4-hydroxy-4-aminobiphenyl with rat blood in vitro. Xenobiotica 1991; 21: 805–15 Article PubMed CAS Google Scholar

  59. Schott AM, Vial T, Gozzo I. Flutamide-induced methaemoglobinaemia. DICP 1991 June; 25(6): 600–1 PubMed CAS Google Scholar

  60. Conroy JM, Baker JD, Martin WJ. Acquired methaemoglobinaemia from multiple oxidants. South Med J 1993; 86: 1156–9 Article PubMed CAS Google Scholar

  61. Kearns GL, Fiser DH. Metoclopramide-induced methaemoglobinaemia. Pediatrics 1988 Sep; 82(3): 364–6 PubMed CAS Google Scholar

  62. Blisard KS, Mieyal JJ. Characterisation of the aniline hydroxylase activity of red cells. J Biol Chem 1979; 254: 5104–10 PubMed CAS Google Scholar

  63. Van Veldhuizen PJ, Wyatt A. Metoclopramide-induced sulfhemoglobinemia. Am J Gastroenterol 1995; 90(6): 1010–11 PubMed Google Scholar

  64. Halvorsen SM, Dull WL. Phenazopyridine-induced sulfhemoglobinemia: inadvertent rechallenge. Am J Med 1991; 91(3): 315–7 Article PubMed CAS Google Scholar

  65. Savic M, Siriski-Sasic J, Djulizibaric D. Discomforts and laboratory findings in workers exposed to sulfur dioxide. Int Arch Occup Environ Health 1987; 59(5): 513–8 Article PubMed CAS Google Scholar

  66. Darling RC, Roughton FJW. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol 1942; 137: 56–68 CAS Google Scholar

  67. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome — a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med 1990; 323: 776–82 Article PubMed CAS Google Scholar

  68. Banzato CEM, Magna LA. In vitro effect of dapsone on NADH-methaemoglobin reductase. Int J Lepr 1991; 59: 486–7 CAS Google Scholar

  69. Smith RP, Olson MV. Drug-induced methaemoglobinemia. Semin Hematol 1973; 10: 253–68 PubMed CAS Google Scholar

  70. Winthrobe MM, Lee GR, Boggs DR, et al., editors. Clinical hematology. 8th ed. Philadelphia: Lea and Febiger, 1981: 97–100 Google Scholar

  71. Cline MS. Curing the ‘nitrate blues’. Postgrad Med 1994; 96(3): 124–6 PubMed CAS Google Scholar

  72. Henretig FM, Gribetz B, Kearney T, et al. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol 1988; 26: 293–301 PubMed CAS Google Scholar

  73. Severinghaus JW. Nomenclature of oxygen saturation. Adv Exp Med Biol 1994; 345: 921–3 Article PubMed CAS Google Scholar

  74. Barker SJ, Temper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anaesthesiol 1989 70: 112–7 Article CAS Google Scholar

  75. Reynolds K, Palayiwa E, Moyle JT. The effect of dyshaemoglobins on pulse oximetry: Part 1, theoretical approach, and Part 2, experimental results using an in vitro system. J Clin Monit 1993; 9(2): 81–90 Article PubMed CAS Google Scholar

  76. Olsen ML, McEvoy GK. Methemoglobinemia induced by topical anesthetics. Am J Hosp Pharm 1981; 38: 89–93 Google Scholar

  77. Goluboff N, Wheaton R. Methylene blue induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. J Pediatr 1961; 58: 86–9 Article PubMed CAS Google Scholar

  78. Foxworth JW, Roberts JA, Mahmoud SF. Acquired methemoglobinemia: a case report. Mo Med 1987; 84: 187–9 PubMed CAS Google Scholar

  79. Moon RE, Camparesi EM. Respiratory Monitoring. In Anesthesia, 3rd ed. Ronald D. Miller, ed. New York: Churchill Livingston, 1990: 1140 Vol 1 Google Scholar

  80. Hall AH, Kulig KW, Rumack BH. Drug- and chemical-induced methemoglobinemia: clinical features and management. Med Toxicol 1986; 1: 253–60 PubMed CAS Google Scholar

  81. Prussick R, Ali MAM, Rosenthal D, et al. The protective effect of vitamin E on the hemolysis associated with dapsone treatment in patients with dermatitis herpetiformis. Arch Dermatol 1992; 128: 210–3 Article PubMed CAS Google Scholar

  82. Kelly JW, Scott J, Sandland M, et al. Vitamin E and dapsone-induced hemolysis. Arch Dermatol 1984; 120: 1582–4 Article PubMed CAS Google Scholar

  83. Rhodes LE, Tingle MD, Park BK, et al. Cimetidine improves the therapeutic/toxic ratio of dapsone in patients on chronic dapsone therapy. Br J Derm 1995; 132: 257–62 Article CAS Google Scholar

  84. Szeremeta W, Dohar JE. Dapsone-induced methemoglobinemia: an anesthetic risk. Int J Pediatr Otorhinolaryngol 1995; 33: 75–80 Article PubMed CAS Google Scholar

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Biological Sciences, Aston University, Birmingham, B4 7ET, England Michael D. Coleman

  2. Department of Intensive Care, Royal Liverpool University Teaching Hospital, Liverpool, England Nicholas A. Coleman

Corresponding author

Correspondence to Michael D. Coleman.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Coleman, M.D., Coleman, N.A. Drug-Induced Methaemoglobinaemia. Drug-Safety 14, 394–405 (1996).

Download citation

bottom of page