Induced Methemoglobinemia

FIGURE 16.1 Metabolism of acetanilide. The major route of metabolism is via hydroxylation to form 4-hydroxyacetanilide (acetaminophen). Less than 1% is deacety-lated to form anilme. 

Drugs and other xenobiotics that cause methemoglobinemia react either stoichiometrically or in a cyclic fashion to convert heme iron from the ferrous to the ferric state. A partial list of these compounds 

TABLE 16.1 Partial List of Compounds Producing Methemoglobinemia S 

Silver nitrate Sulfamethoxazole Dapsone Primaquine Benzocaine Prilocaine Metoclopramide 

FIGURE 16.3 Chemical structures of chloramphenicol and thiamphenicol. Thiamphenicol, in which the nitroso group of chloramphenicol is replaced by a methylsulfone group, retains antibiotic activity, but does not cause the aplastic anemia that is a major concern with chloramphenicol therapy. 

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Burgess, B.A., T.P.Pastoor, and G.L.Kennedy, Jr. 1984. Aniline induced methemoglobinemia and hemolysis as a function of exposure concentration and duration. Toxicologist 4 64. 

The subjects were primarily healthy young males. Because no susceptible populations were identified (angina patients are not considered at additional risk and the absorbed dose at these concentrations is far below that inducing methemoglobinemia), an intraspecies uncertainty factor (UF) of 3 was used. The intraspecies UF of 3 is supported by the steep dose-response curve for the induction of headaches namely, a 2-fold difference in the threshold concentra-... 

Intraspecies 3—no unusually susceptible populations were identified. Because the time and concentration values were based on a threshold, these concentrations were adjusted by an uncertainty factor of 3 to account for differences in human sensitivity. More severe headaches are often experienced by heart patients medicated with nitroglycerin for angina and these concentrations are far below those inducing methemoglobinemia in infants. ... 

Dinitrobenzene is an intermediate employed in chemical syntheses of a large number of compounds used in the dye, explosives and plastics industry. The compound is known to induce methemoglobinemia and to cause testicular toxicity with the Sertoli cell being the major target. Nitro reduction was observed in erythrocytes, in rat Sertoli-germ cell cocultures and in rat testicular subcellular fractions, and it was shown that 3-nitrosonitrobenzene was formed that was considerably more toxic. Testicular toxicity was enhanced when the intracellular thiol levels were reduced by pretreatment with diethylmaleate. In turn, pretreatment with cysteamine or ascorbate reduced the toxicity of 1,3-dinitrobenzene and 3-nitrosonitrobenzene. 

E. Heymann, K. Kirsch, H. Buech, W. Buzello, Inhibition of Phenacetin- and Acetani-hde-Induced Methemoglobinemia in the Rat by the Carboxylesterase Inhibitor Bis(/>-ni-trophenylphosphate) , Biochem. Pharmacol. 1969, 18, 801-811. 

The development of intravascular hemolysis and anemia due to aniline-induced methemoglobinemia has been postulated, but neither is observed often in industrial practice, despite careful and prolonged study of numerous cases. Occasional deaths from asphyxiation caused by severe aniline intoxication are said to occur. The existence of chronic aniline poisoning is controversial, but some investigators have suggested that continuous exposure to small doses of aniline may produce anemia, loss of energy, digestive disturbance, and headache. ... 

Kearney TE et al Chemically induced methemoglobinemia from aniline poisoning. West J Med 140 282-286, 1984... 

Ingestion of the salt or its solution can cause nausea, vomiting, diarrhea, and renal injury. Also, it can induce methemoglobinemia. 

Treatment Conventional antidote kit consists of nitrites to induce methemoglobinemia (which binds cyanide) and thiosulfate (which hastens conversion of cyanide to less toxic thiocyanate) a newer antidote kit (Cyanokit) consists of concentrated hydroxocobalamin, which directly converts cyanide into cyanocobalamin... 

Treatment of cyanide poisoning includes rapid administration of activated charcoal (although charcoal binds cyanide poorly, it can reduce absorption) and general supportive care. The conventional antidote kit available in the USA includes two forms of nitrite (amyl nitrite and sodium nitrite) and sodium thiosulfate. The nitrites induce methemoglobinemia, which binds to free CI T creating the less toxic cyanomethemoglobin thiosulfate is a cofactor in the enzymatic conversion of CN to the much less toxic thiocyanate (SCINT). Recently, the FDA approved a concentrated form of hydroxocobalamin, which is now available as the Cyanokit (EMD Pharmaceuticals, Durham, North Carolina). Hydroxocobalamin (one form of vitamin B12) combines rapidly with CN to form cyanocobalamin (another form of vitamin B12). 

Kwok, S., Fischer, J.L. and Rogers, J.D. (2008) Benzocaine and lidocaine induced methemoglobinemia after bronchoscopy a case report. J. Med. Case Rep., 2, 16. 

Figure 2. Influence of diet on the time course of nitrobenzene-induced methemoglobinemia. Each point represents X SE of at least three determinations. Astericks and daggers represent a significant difference from AIN-76A and AIN-76A containing 5% pectin groups, respectively (p < 0.05).

Figure 3. Influence of diet on the dose-resonse relationship of nitrobenzene-induced methemoglobinemia. Each point...

No studies were located regarding interactions of 2-nitrophenol or 4-nitrophenol with other chemicals in vitro or regarding interactions of 2-nitrophenol with other chemicals in vivo. However, it was reported that, in ethanol-treated rats, 4-nitrophenol is rapidly metabolized to 4-nitrocatechol, which competes with 4-nitrophenol for the formation of sulfate and glucuronide conjugates (Reinke and Moyer 1985). This prevention of the conjugation of 4-nitrophenol may lead to the formation of amino derivatives, which can then induce methemoglobinemia. 

Acute-Duration Exposure. No data were located indicating specific organs or systems as targets for 2-nitrophenol or 4-nitrophenol in humans by any route of exposure. However, amino and nitro aromatic compounds in general have been known to induce methemoglobinemia in humans (Beard and Noe 1981). The data in experimental animals were insufficient to derive oral and inhalation MRLs. 

Nitrate/nitrite-induced methemoglobinemia is an important event that generates free radicals (Kohn et al., 2002). It is well known that nitrate/nitrite could enhance... 

McGrath PD, Moloney JF, Riker RR. Benzocaine-induced methemoglobinemia complicating transesophageal echocardiography a case report. Echocardiography 1998 15(4) 389-92. 

Malhotra S, Kolda M, Nanda NC. Local anesthetic-induced methemoglobinemia during transesophageal echocardiography. Echocardiography 1998 15(2) 165-8. 

Ho RT, Nanevicz T, Yee R, Figueredo VM. Benzocaine-induced methemoglobinemia—two case reports related to transesophageal echocardiography premedication. Cardiovasc Drugs Ther 1998 12(3) 311-12. 

Slaughter MS, Gordon PJ, Roberts JC, Pappas PS. An unusual case of hypoxia from benzocaine-induced methemoglobinemia. Ann Thorac Surg 1999 67(6) 1776-8. 

Gregory PJ, Matsuda K. Cetacaine spray-induced methemoglobinemia after transesophageal echocardiography. Ann Pharmacother 2000 34(9) 1077. 

Nguyen ST, Cabrales RE, Bashour CA, Rosenberger TE Jr, Michener JA, Yared JP, Starr NJ. Benzocaine-induced methemoglobinemia. Anesth Analg 2000 90(2) 369-71. 

Gupta PM, Lala DS, Arsura EL. Benzocaine-induced methemoglobinemia. South Med J 2000 93(l) 83-6. 

Wurdeman RL, Mohiuddin SM, Holmberg MJ, Shalaby A. Benzocaine-induced methemoglobinemia during an outpatient procedure. Pharmacotherapy 2000 20(6) 735-8. 

Singh RK, Kambe JC, Andrews LK, Russell JC. Benzocaine-induced methemoglobinemia accompanying adult respiratory distress syndrome and sepsis syndrome case report. J Trauma 2001 50(6) 1153-7. 

TrUlo RA Jr, Aukburg S. Dapsone-induced methemoglobinemia and pulse oximetry. Anesthesiology 1992 77(3) 594-6. 

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