Methemoglobinemia with nitrates

Explain the occurrence of methemoglobinemia with nitrate therapy. 

Nitrate accumulation may occur in plants growing on soil fertilized with nitrate under moisture-deficient conditions. In the stomachs of ruminant animals, nitrate (NOj) ingested with plant material is reduced to nitrite (N02). The nitrite product enters the bloodstream and oxidizes the iron(II) in hemoglobin to iron(III). The condition that results is methemoglobinemia, which was discussed in Section 15.3 in connection with aniline poisoning. 

SAFETY PROFILE Moderately toxic by ingestion and inhalation causing a fall in blood pressure that may result in weakness, headache, and dizziness. Chronic exposure may produce methemoglobinemia with cyanosis. A powerful explosive sensitive to shock or heat. Upon decomposition it emits toxic fumes of NOx. See also NITRATES and EXPLOSIVES, HIGH. 

The authors assumed that displacement of lidocaine from protein binding by bupivacaine, in combination with metabolic acidosis and treatment with nitrates, had caused methemoglobinemia. 

Methemoglobinemia is a rare occurrence with nitrate therapy and is characterized by cyanosis, and nausea/vomiting, progressing to shock and coma. This rare adverse effect is usually associated with high doses/overdoses of nitrate products, but can also be seen at normal therapeutic doses. 

A case series of methemoglobinemia with respiratory distress, cyanosis, and tachycardia, was reported in four infants, 7 to 9 months old, that had been fed purees of fennel (part and dose used not specified). High nitrate levels in the products administered were believed to be responsible for the methemoglobinemia (Murone et al. 2005). 

As noted under Mechanisms of Toxicity (Section 4.2), nitrate and nitrite esters are vasodilators with resulting hypotension (Nickerson 1975). Therapeutic doses of nitroglycerin for relief of angina are associated with headaches of vascular origin. Both PGDN and the structurally related ethylene glycol dinitrate produce headaches in humans and methemoglobinemia and hypotension in rats (Andersen and Mehl 1979). 

Anesthetized dogs given 50-250mg/kg intravenously immediately showed hypotension, arrest of gut activity, respiratory paralysis, hyperpnea, and moderate methemoglobinemia. Because death was produced with methe-moglobin levels of only 4%, -propyl nitrate intoxication may be caused in part by a direct action on vascular smooth muscle. (It has been noted that the oral toxicity of -propyl nitrate is very low compared with intravenously administered doses, in which mg/kg doses were lethal versus g/kg orally. )... 

The gut bacteria may also reduce nitrates to nitrites, which can cause methemoglobinemia or may react with secondary amines in the acidic environment of the gut, giving rise to carcinogenic nitrosamines. 

DOT CLASSIFICATION 6.1 Label Poison SAFETY PROFILE Poison by ingestion, intravenous, and intraperitoneal routes. Moderately toxic by intramuscular route. Mutation data reported. Acute symptoms of exposure are headache, nausea, vomiting, weakness and stupor, cyanosis and methemoglobinemia. Chronic exposure can cause liver damage. Experimental reproductive effects. Combustible when exposed to heat or flame. See NITRATES for explosion and disaster hazards. To fight fire, use water spray or mist, foam, dry chemical, CO2. Vigorous reaction with sulfuric acid above 200°C. Reaction with sodium hydroxide at 130°C under pressure may produce the explosive sodium-4-nitrophenoxide. When heated to decomposition it emits toxic fumes of NOx. See also m-NITROANILINE, o-NITROANILINE, NITRO COMPOUNDS OF AROMATIC HYDROCARBONS, and ANILINE DYES. 

Fatal methemoglobinemia occurred in a 3-year-old Caucasian girl who had burns involving 82% of the body surface and had been treated by painting the burns with silver nitrate solution (33). By the fourth... 

II. Toxic dose. In the quantities found in food, nitrates and nitrites are generally not toxic however, infants may develop methemoglobinemia after ingestion of sausages or well water because they readily convert nitrate to nitrite and because their hemoglobin Is more susceptible to oxidation compared with that of adults. 

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