Methemoglobinemia

By Ilene B. Anderson, PharmD; and Susan Y. Kim, PharmD

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Hereditary and Acquired Methemoglobinemia (cont.)

Some agents causing Mhgb are direct oxidizers that react directly with hemoglobin to form methemoglobin. Indirect oxidizers reduce oxygen or water to O₂^- or H₂O₂, respectively, which in turn oxidize hemoglobin to methemoglobin. Other agents have to be converted to an oxidizing metabolite. A classic example is aniline, a dye once used extensively in industry. Aniline is metabolized by the cytochrome P-450 system to phenylhydroxylamine, an intermediary that binds with O₂ to form the oxygen free radical, O₂^- , which then produces methemoglobin. Dapsone and benzocaine also are metabolized to oxidizing metabolites. The ongoing redox reaction between the parent compound and the metabolites can result in prolonged, cyclical Mhgb that can persist for days. Dapsone overdose can be further complicated by the concurrent formation of sulfhemoglobinemia,⁷ for which no effective antidotal therapy exists. Nitrates, which are not oxidizers, are converted nonenzymatically to the oxidizing nitrites by bacteria colonizing the gut or burned skin (as with dermal application of silver nitrate). Table 2 is a partial list of some of the most commonly reported causes of acquired Mhgb. 

Table 2—Common Causative Agents in Acquired Methemoglobinemia

Amyl nitrate

Aniline

Arsine

Benzocaine

Chlorates

Chloroquine

Copper

Dapsone

Dimethylsulfoxide

Dinitrotoluene

Isobutyl nitrite

Lidocaine

Methylene blue

Metoclopramide

Naphthalene

Nitric oxide

Nitrobenzene

Nitroethane

Nitroglycerin

Nitroprusside

Phenazopyridine

Phenol

Prilocaine

Procaine

Silver nitrate

Smoke inhalation

Sodium nitrite

Sulfasalazine

Sulfonamide

Infants, as noted above, are especially susceptible to acquired Mhgb, with or without exposure to known oxidizers. There are several possible reasons for this increased susceptibility: (1) fetal hemoglobin is more easily oxidized than those of adults; (2) levels of RBC cytochrome-b₅ reductase in infants is only 50 to 60% of adult levels; and (3) the higher intestinal pH of infants may promote the growth of nitrite-forming bacteria, such as Escherichia coli or Campylobacter jejuni. Mhgb in infants has been associated with ingestion of well water high in nitrates, and, historically, with dermal exposure to aniline ink used on cloth diapers.⁸ Mhgb has been reported in infants with diarrhea-induced dehydration and acidosis, although this is a sporadic observation.^9,10 Some oxidizing chemicals and drugs, including local anesthetics used for epidural analgesia, can cross the placental barrier and cause fetal Mhgb.

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