From the Guidelines
Medications that can cause methemoglobinemia include local anesthetics (benzocaine, lidocaine, prilocaine), antibiotics (dapsone, trimethoprim-sulfamethoxazole), nitrates/nitrites (nitroglycerin, sodium nitroprusside), antimalarials (chloroquine, primaquine), and others like metoclopramide, phenazopyridine, and rasburicase, as well as cyclophosphamide, flutamide, and certain industrial products like aniline dyes and nitrates 1. These medications oxidize the iron in hemoglobin from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state, creating methemoglobin which cannot carry oxygen effectively.
Risk Factors and Symptoms
Risk factors include high medication doses, genetic predisposition, and underlying conditions like G6PD deficiency. Symptoms range from cyanosis and headache to severe cases with confusion, respiratory distress, and even death.
Treatment
Treatment involves discontinuing the offending medication and, in severe cases, administering methylene blue (1-2 mg/kg IV over 5 minutes) 1. Patients with known risk factors should avoid these medications when possible, and healthcare providers should monitor for symptoms when these medications must be used. According to the most recent guidelines, methylene blue is recommended for the treatment of methemoglobinemia 1. It is essential to note that exchange transfusion and hyperbaric oxygen therapy may be considered in cases where methemoglobinemia is not responsive to methylene blue 1. However, N-acetylcysteine and ascorbic acid are not recommended as treatments for methemoglobinemia 1. Some key medications to avoid in patients at risk of methemoglobinemia include:
- Local anesthetics: benzocaine, lidocaine, prilocaine, and articaine
- Antibiotics: dapsone, trimethoprim-sulfamethoxazole, and sulfonamides
- Nitrates/nitrites: nitroglycerin, sodium nitroprusside, and nitrates salt
- Antimalarials: chloroquine and primaquine
- Others: metoclopramide, phenazopyridine, rasburicase, cyclophosphamide, and flutamide 1.
From the FDA Drug Label
Examples of Drugs Associated with Methemoglobinemia: Class Examples Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine Antineoplastic Agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides Antimalarials chloroquine, primaquine Anticonvulsants phenobarbital, phenytoin, sodium valproate Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine
The following drugs can cause methemoglobinemia:
- Nitrates/Nitrites: nitric oxide, nitroglycerin, nitroprusside, nitrous oxide
- Local anesthetics: articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine
- Antineoplastic Agents: cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase
- Antibiotics: dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides
- Antimalarials: chloroquine, primaquine
- Anticonvulsants: phenobarbital, phenytoin, sodium valproate
- Other drugs: acetaminophen, metoclopramide, quinine, sulfasalazine 2
From the Research
Medications that Cause Methemoglobinemia
The following medications have been reported to cause methemoglobinemia:
- Benzocaine 3, 4, 5: a widely used topical oropharyngeal anesthetic
- Lidocaine 4, 6, 7: a local anesthetic that can cause methemoglobinemia, especially when used in combination with prilocaine
- Prilocaine 6, 7: a local anesthetic that can cause methemoglobinemia, especially when used in combination with lidocaine
- Dapsone 4: an antibiotic that can cause methemoglobinemia due to its oxidizing properties
- Sulfonamides 4: a class of antibiotics that can cause methemoglobinemia due to their oxidizing properties
- Cocaine-derived anesthetics 4: can cause methemoglobinemia due to their oxidizing properties
Mechanism of Methemoglobinemia
Methemoglobinemia can occur through various mechanisms, including:
- Oxidizing reactions to certain medications, such as benzocaine and lidocaine 4
- Metabolic activation of certain medications, such as prilocaine and lidocaine, by human carboxylesterase-, CYP2E1-, and CYP3A4-mediated metabolism 6
Treatment of Methemoglobinemia
Treatment of methemoglobinemia typically involves: