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Cyanide antidote

Sodium nitrite

Sodium nitrite is a methemoglobin-forming agent used as an antidote for acute cyanide poisoning. It works by oxidizing hemoglobin to methemoglobin, which binds cyanide with higher affinity than cytochrome oxidase. The most critical adverse effect is excessive methemoglobinemia leading to tissue hypoxia, making careful dosing essential.

Practice questionsHigh-yield facts
Drug classCyanide antidote (methemoglobin inducer)
MechanismOxidizes hemoglobin to methemoglobin, which binds cyanide ions
Main usesAcute cyanide poisoning (part of cyanide antidote kit)
Key adverse effectExcessive methemoglobinemia causing hypoxia and cardiovascular collapse
6 min readFor medical studentsUpdated 2026-10-14

Mechanism of action

Sodium nitrite acts as a cyanide antidote by inducing the formation of methemoglobin. When administered intravenously, nitrite ions oxidize the ferrous iron (Fe²⁺) in hemoglobin to the ferric state (Fe³⁺), creating methemoglobin. This oxidized form of hemoglobin has a higher affinity for cyanide than cytochrome c oxidase, the primary target of cyanide toxicity in mitochondria.

By competing for cyanide binding, methemoglobin effectively sequesters cyanide ions from cytochrome oxidase, forming cyanomethemoglobin. This allows cellular respiration to resume at the mitochondrial level. The bound cyanide is then gradually released and metabolized by rhodanese (thiosulfate sulfurtransferase) in the liver to thiocyanate, which is renally excreted. Sodium nitrite is typically used in combination with sodium thiosulfate, which provides sulfur donors to accelerate cyanide detoxification.

The therapeutic window is narrow because the goal is to create enough methemoglobin (typically 20-30% of total hemoglobin) to bind circulating cyanide without causing dangerous tissue hypoxia from excessive methemoglobin levels.

High-yield for exams
  • Sodium nitrite treats cyanide poisoning by oxidizing hemoglobin to methemoglobin, which binds cyanide with higher affinity than cytochrome oxidase
  • Target methemoglobin level is 20-30%; levels above 30% cause dangerous tissue hypoxia
  • Contraindicated in smoke inhalation with CO poisoning because it further reduces oxygen-carrying capacity (use hydroxocobalamin instead)
  • Must be followed by sodium thiosulfate to provide sulfur substrate for rhodanese-mediated cyanide conversion to thiocyanate
  • Chocolate-brown blood that does not redden with oxygen is characteristic of methemoglobinemia
  • Major adverse effects: excessive methemoglobinemia, hypotension from vasodilation, and hemolysis in G6PD deficiency
  • Black box warning for life-threatening hypotension and methemoglobin formation; close monitoring required
  • Hydroxocobalamin has largely replaced sodium nitrite as first-line therapy due to superior safety profile
  • Cyanide poisoning triad: altered mental status, lactic acidosis, elevated venous oxygen saturation (cells cannot use oxygen)

Indications

The primary indication for sodium nitrite is acute cyanide poisoning. Cyanide toxicity may result from:

  • Smoke inhalation from fires (combustion of synthetic materials)
  • Industrial exposures (metal processing, electroplating, fumigants)
  • Ingestion of cyanogenic compounds (cassava, apricot pits, amygdalin)
  • Nitroprusside therapy (releases cyanide during metabolism)
  • Acetonitrile exposure (metabolized to cyanide)

Sodium nitrite is part of the older cyanide antidote kit and is administered alongside sodium thiosulfate. Clinical signs suggesting cyanide poisoning include rapid onset of altered mental status, seizures, cardiovascular collapse, lactic acidosis, and a characteristic odor of bitter almonds (though only 40-60% of people can detect this odor due to genetic variation).

In modern practice, hydroxocobalamin has emerged as a preferred first-line antidote in many settings due to its superior safety profile, though sodium nitrite remains an important alternative when hydroxocobalamin is unavailable or in resource-limited settings.

Pharmacokinetics

Sodium nitrite is administered by slow intravenous infusion over 5-20 minutes to minimize hypotension. Following IV administration:

Absorption and distribution: Nitrite distributes rapidly throughout the intravascular and extravascular spaces. Peak methemoglobin levels typically occur within 30-60 minutes after infusion.

Metabolism: Nitrite undergoes reduction to nitric oxide (NO) and is also consumed in the oxidation of hemoglobin. Nitrite reacts with oxyhemoglobin, deoxyhemoglobin, and other blood components.

Elimination: Elimination occurs through multiple pathways including renal excretion, reaction with hemoglobin, and metabolic conversion. The duration of methemoglobinemia depends on the dose and individual metabolic capacity but typically resolves over several hours as methemoglobin reductase (cytochrome b5 reductase) converts methemoglobin back to functional hemoglobin.

Special considerations: Dosing is weight-based and must be adjusted in pediatric patients. Patients with G6PD deficiency, anemia, or other hemoglobinopathies may have altered responses.

Adverse effects

The adverse effects of sodium nitrite are primarily related to methemoglobin formation and vasodilation:

Hematologic

  • Excessive methemoglobinemia: The most serious adverse effect, causing tissue hypoxia when methemoglobin levels exceed 30-40%. Signs include cyanosis, dyspnea, altered mental status, and cardiovascular compromise
  • Hemolysis: Particularly in patients with G6PD deficiency or other red cell enzyme defects

Cardiovascular

  • Hypotension: Results from nitrite-induced vasodilation and decreased oxygen-carrying capacity
  • Tachycardia: Compensatory response to hypotension and reduced oxygen delivery
  • Syncope: From profound hypotension, especially with rapid infusion
  • Cardiovascular collapse: In severe cases or with excessive dosing

Neurologic

  • Headache: Common, related to vasodilation
  • Dizziness and lightheadedness: From hypotension and cerebral hypoxia
  • Seizures: May occur with severe methemoglobinemia

Other effects

  • Nausea and vomiting
  • Dyspnea and tachypnea: From reduced oxygen-carrying capacity
  • Cyanosis: Chocolate-brown discoloration of blood visible in mucous membranes and skin

The risk-benefit calculation in cyanide poisoning often justifies these risks, but careful monitoring of methemoglobin levels and vital signs is essential during and after administration.

Contraindications and warnings

Black box warning

Life-threatening hypotension and methemoglobin formation: Sodium nitrite carries a black box warning for the risks of severe, potentially fatal hypotension and excessive methemoglobin formation. Patients must be closely monitored during and after administration with continuous vital signs monitoring and serial methemoglobin measurements. The balance between therapeutic methemoglobin levels (20-30%) and dangerous levels (>30%) is narrow.

Relative contraindications

  • Smoke inhalation with suspected carbon monoxide poisoning: Dual exposure is common in fires. Inducing methemoglobinemia in a patient with carboxyhemoglobin further reduces oxygen-carrying capacity and may worsen outcome. Hydroxocobalamin is strongly preferred in this setting
  • Severe anemia: Limited hemoglobin reserve makes methemoglobin formation more dangerous
  • G6PD deficiency: Increased risk of hemolysis and inability to reduce methemoglobin efficiently
  • Cardiovascular disease: Hypotension and reduced oxygen delivery pose greater risk

Warnings

Methemoglobin monitoring: Methemoglobin levels should be measured before (if time permits), during, and after administration. Levels above 30% require consideration of methylene blue as a reversal agent.

Dosing errors: Overdosing can be fatal. Weight-based dosing must be calculated carefully, and pediatric doses differ from adult doses on a per-kilogram basis.

Pregnancy category C: Use only when cyanide poisoning is confirmed or strongly suspected, as both the antidote and the poison pose fetal risks. Fetal hemoglobin is more susceptible to oxidation.

Rate of administration: Rapid infusion increases the risk of severe hypotension. Infuse slowly over at least 5 minutes (some protocols recommend up to 20 minutes).

Combination therapy: Sodium nitrite should generally be followed by sodium thiosulfate to provide sulfur substrate for rhodanese-mediated detoxification.

Drug interactions

Significant interactions

Drugs causing methemoglobinemia: Additive effects with other methemoglobin-inducing agents increase the risk of dangerous hypoxia:

  • Local anesthetics (benzocaine, prilocaine, lidocaine)
  • Dapsone
  • Nitrates and nitrites (nitroglycerin, isosorbide)
  • Sulfonamides
  • Phenazopyridine
  • Antimalarials (primaquine, chloroquine)
  • Metoclopramide

Antihypertensive agents: Sodium nitrite potentiates hypotensive effects through vasodilation. Caution with:

  • Nitrates
  • Calcium channel blockers
  • ACE inhibitors and angiotensin receptor blockers
  • Beta-blockers
  • Alpha-blockers

Phosphodiesterase-5 inhibitors: Sildenafil, tadalafil, and vardenafil combined with nitrites can cause severe, potentially fatal hypotension. This interaction is clinically significant even in the emergency setting.

Oxygen therapy: Concurrent high-flow oxygen is essential to maximize oxygen delivery despite reduced oxygen-carrying capacity from methemoglobinemia.

There is no interaction with hydroxocobalamin, and the two antidotes can be used sequentially if needed, though this is rarely necessary.

Clinical pearls

  • Classic triad of cyanide poisoning: Altered mental status, lactic acidosis, and elevated venous oxygen saturation (cells cannot extract oxygen). However, do not delay treatment waiting for laboratory confirmation in high-suspicion cases.
  • Hydroxocobalamin vs sodium nitrite: Hydroxocobalamin is now preferred as first-line therapy in most developed countries because it does not reduce oxygen-carrying capacity, can be given more rapidly, and is safer in smoke inhalation with possible CO poisoning. Sodium nitrite remains important when hydroxocobalamin is unavailable.
  • Methemoglobin target: Aim for 20-30% methemoglobin in cyanide poisoning. This provides enough methemoglobin to bind cyanide while maintaining adequate oxygen delivery. Levels above 30% risk symptomatic hypoxia.
  • Chocolate-brown blood: A classic exam finding. Blood with high methemoglobin content appears chocolate-brown and does not change color when exposed to oxygen, unlike deoxyhemoglobin which turns red.
  • Co-oximetry required: Standard pulse oximetry cannot distinguish between oxyhemoglobin, methemoglobin, and carboxyhemoglobin. Co-oximetry on arterial blood is required for accurate assessment.
  • Methylene blue reversal: If excessive methemoglobinemia occurs (>30% or symptomatic), methylene blue can be administered to reduce methemoglobin back to hemoglobin. However, this may theoretically release bound cyanide, so it should only be used if methemoglobinemia is life-threatening.
  • Pediatric dosing difference: Children require lower per-kilogram doses than adults due to higher baseline hemoglobin and different distribution volumes. Dosing follows specific pediatric protocols.
  • Cyanide antidote kit: The traditional kit contains amyl nitrite (inhaled), sodium nitrite (IV), and sodium thiosulfate (IV). Amyl nitrite is used only as a temporizing measure if IV access is delayed.
  • Thiosulfate is essential: Always follow sodium nitrite with sodium thiosulfate. Thiosulfate provides sulfur substrate for rhodanese, which converts cyanide to thiocyanate. Nitrite alone only sequesters cyanide temporarily.
  • G6PD patients: Avoid sodium nitrite if possible in patients with known G6PD deficiency. They have impaired methemoglobin reduction and increased hemolysis risk. Hydroxocobalamin is strongly preferred.
Mnemonic

Cyanide antidote kit components (old): ABC = Amyl nitrite (inhaled), Break ampule, then Sodium nitrite (IV Creates methemoglobin), then Sodium thiosulfate (Completes detoxification)

Practice questions

1. A 45-year-old man is brought to the emergency department after being rescued from a house fire. He has altered mental status, tachypnea, and an elevated lactate of 12 mmol/L. Arterial blood gas shows elevated venous oxygen saturation. The physician considers administering sodium nitrite as part of cyanide antidote therapy. Which of the following is the most important reason to avoid sodium nitrite in this patient?

Answer: B. Smoke inhalation from fires commonly causes both cyanide and carbon monoxide poisoning. Sodium nitrite induces methemoglobinemia, further reducing oxygen-carrying capacity in a patient who already has carboxyhemoglobin. This combination can be fatal. Hydroxocobalamin is the preferred antidote in fire victims because it does not impair oxygen transport. The elevated lactate and venous oxygen saturation suggest cyanide toxicity (cells cannot utilize oxygen), but CO co-exposure makes sodium nitrite dangerous.

2. A 32-year-old industrial worker is treated with intravenous sodium nitrite for suspected cyanide poisoning after a chemical spill. Thirty minutes after administration, his blood has a chocolate-brown appearance and does not redden when exposed to air. His oxygen saturation by pulse oximetry is 85% despite high-flow oxygen. Co-oximetry reveals methemoglobin level of 35%. Which of the following is the most appropriate next step?

Answer: B. Methemoglobin level of 35% is excessive and causing symptomatic hypoxia (target is 20-30%). Methylene blue reduces methemoglobin back to hemoglobin via NADPH-methemoglobin reductase and is indicated for symptomatic methemoglobinemia or levels >30%. The chocolate-brown blood that does not redden with oxygen is pathognomonic for methemoglobinemia. While there is theoretical concern about releasing bound cyanide, the immediate threat is tissue hypoxia from excessive methemoglobin. More sodium nitrite would worsen the problem, and observation is inappropriate at this dangerous level.

3. A 28-year-old woman with known G6PD deficiency ingests cassava root containing cyanogenic glycosides and develops acute cyanide poisoning. She presents with altered mental status, lactic acidosis, and seizures. The emergency physician plans antidote therapy. Which of the following antidotes is most appropriate for this patient?

Answer: B. Hydroxocobalamin is the antidote of choice in patients with G6PD deficiency because it does not cause methemoglobinemia or hemolysis. Sodium nitrite is relatively contraindicated in G6PD deficiency due to increased risk of hemolysis and impaired methemoglobin reduction. Methylene blue alone does not treat cyanide poisoning and would also cause hemolysis in G6PD deficiency. Amyl nitrite produces methemoglobin like sodium nitrite. N-acetylcysteine treats acetaminophen toxicity, not cyanide. Hydroxocobalamin binds cyanide directly without affecting red blood cells.

Frequently asked questions

How does sodium nitrite work as a cyanide antidote?

Sodium nitrite oxidizes hemoglobin to methemoglobin, which binds cyanide ions with higher affinity than cytochrome c oxidase. This sequesters cyanide away from mitochondria, allowing cellular respiration to resume. The bound cyanide is then gradually released and metabolized by rhodanese to thiocyanate for renal excretion. Sodium nitrite is given with sodium thiosulfate, which provides sulfur substrate to accelerate this detoxification process.

What are the side effects of sodium nitrite?

The main adverse effect is excessive methemoglobinemia causing tissue hypoxia, which presents with cyanosis, dyspnea, and cardiovascular compromise. Sodium nitrite also causes hypotension from vasodilation, leading to tachycardia, dizziness, and potential syncope. Other effects include headache, nausea, and hemolysis, particularly in patients with G6PD deficiency. The chocolate-brown discoloration of blood is a visible sign of methemoglobinemia.

Why is sodium nitrite dangerous in smoke inhalation victims?

Smoke inhalation often causes both cyanide and carbon monoxide poisoning simultaneously. Inducing methemoglobinemia in a patient who already has carboxyhemoglobin from CO exposure further reduces oxygen-carrying capacity and worsens tissue hypoxia. This combination can be fatal. Hydroxocobalamin is strongly preferred in fire victims because it treats cyanide toxicity without reducing oxygen-carrying capacity.

What is the difference between sodium nitrite and hydroxocobalamin for cyanide poisoning?

Sodium nitrite works by creating methemoglobin to bind cyanide, but this reduces oxygen-carrying capacity. Hydroxocobalamin directly binds cyanide without affecting oxygen transport. Hydroxocobalamin is now preferred because it is safer (no methemoglobinemia or hypotension), works in CO co-poisoning, can be given rapidly, and has fewer contraindications. Sodium nitrite remains useful when hydroxocobalamin is unavailable but requires careful monitoring and slower administration.

Can methylene blue reverse sodium nitrite toxicity?

Yes, methylene blue can reduce excessive methemoglobin back to functional hemoglobin by activating NADPH-methemoglobin reductase. However, it should only be used if methemoglobinemia exceeds 30% or causes severe symptoms, because reducing methemoglobin may release bound cyanide back into circulation. Methylene blue is contraindicated in G6PD deficiency as it can precipitate hemolysis. Co-oximetry monitoring is essential to guide this decision.

Conditions it is used for

Cyanide poisoningAcute cyanide toxicitySmoke inhalation with cyanide exposure
HydroxocobalaminSodium thiosulfateMethylene blueAmyl nitriteDimercaprolPralidoximeFomepizoleDeferoxamine

Sources and further reading

DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: V03AB08

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.