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INTRODUCTION

Organic nitrates (eg, nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate) are widely used as vasodilators for the treatment of ischemic heart disease and heart failure. Organic nitrates such as nitroglycerin also are used in explosives. Bismuth subnitrate, ammonium nitrate, and silver nitrate are used in antidiarrheal drugs, cold packs, and topical burn medications, respectively. Sodium and potassium nitrate and nitrite are used in preserving cured foods and may also occur in high concentrations in some well water and in antifreeze mixtures. Butyl, amyl, ethyl, and isobutyl nitrites often are sold as "room deodorizers" or "liquid incense" and sometimes are inhaled for abuse purposes.

MECHANISM OF TOXICITY

Nitrates and nitrites both cause vasodilation, which can result in hypotension.

  1. Nitrates relax veins at lower doses and arteries at higher doses. Nitrates may be converted into nitrites in the GI tract, especially in infants.

  2. Nitrites are potent oxidizing agents. Oxidation of hemoglobin by nitrites may result in methemoglobinemia, which hinders oxygen-carrying capacity and oxygen delivery. Many organic nitrites (eg, amyl nitrite and butyl nitrite) are volatile and may be inhaled.

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 than is that of adults. Severe methemoglobinemia has occurred in adults when sodium nitrite marketed as a food additive or preservative is applied directly to foods and ingested. Methemoglobinemia induced by nitrite may be more severe and associated with hemolysis in the presence of G6PD deficiency.

  1. Nitrates. The estimated adult lethal oral dose of nitroglycerin is 200–1, 200 mg. Hypotension occurs at low doses, but massive doses of nitroglycerin are usually required to produce methemoglobinemia.

  2. Nitrites. Ingestion of as little as 15 mL of butyl nitrite produced 40% methemoglobinemia in an adult. The estimated adult lethal oral dose of sodium nitrite is 1 g.

CLINICAL PRESENTATION

Headache, skin flushing, and orthostatic hypotension with reflex tachycardia are the most common adverse effects of nitrates and nitrites and occur commonly, even with therapeutic doses of organic nitrates.

  1. Hypotension may aggravate or produce symptoms of cardiac ischemia or cerebrovascular disease and may even cause seizures. However, fatalities from hypotension are rare.

  2. Workers or patients regularly exposed to nitrates may develop tolerance and may develop angina or myocardial infarction owing to rebound coronary vasoconstriction upon sudden withdrawal of the drug. Inhaled nitrites are flammable and their accidental ignition (such as after lighting a cigarette that had been dipped a nitrite solution) has resulted in serious burns.

  3. Methemoglobinemia is most common after nitrite exposure; the skin is cyanotic even at levels low enough for the individual to be otherwise asymptomatic (eg, 15%).

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