Drug Interactions between clonidine / ketorolac / ropivacaine and prilocaine

MONITOR CLOSELY: Prilocaine can cause dose-related methemoglobin formation via its ortho-toluidine metabolite. Coadministration with other oxidizing agents that can also induce methemoglobinemia including other local anesthetics (e.g., benzocaine, lidocaine), antimalarials (e.g., chloroquine, primaquine, quinine, tafenoquine), nitrates and nitrites, sulfonamides, aminosalicylic acid, dapsone, dimethyl sulfoxide, flutamide, metoclopramide, nitrofurantoin, phenazopyridine, phenobarbital, phenytoin, and rasburicase may increase the risk. Additional risk factors include very young age, anemia, cardiac/pulmonary disease, peripheral vascular disease, liver cirrhosis, shock, sepsis, acidosis, and genetic predisposition (e.g., NADH cytochrome-b5 reductase deficiency; glucose-6-phosphate dehydrogenase deficiency; hemoglobin M). The development of methemoglobinemia due to prilocaine is usually dose-related and asymptomatic in normal patients receiving recommended doses, but symptoms may occur at any dose in susceptible individuals. Neonates and infants are particularly susceptible due to a lower activity of the enzyme that reduces methemoglobin to hemoglobin. Neonatal methemoglobinemia has been reported after paracervical or pudendal block in the obstetric patient. The repeated administration of prilocaine, even in relatively small doses, can lead to clinically overt methemoglobinemia (cyanosis). Prilocaine is therefore not recommended for continuous techniques of regional anesthesia.

MANAGEMENT: Prilocaine should be used with caution in the presence of other methemoglobin-inducing drugs. Patients should be closely monitored to ensure adequate perfusion and oxygenation during treatment with prilocaine. Methemoglobin levels should be monitored and oxygen administered whenever possible. Signs and symptoms of methemoglobinemia may be delayed some hours after drug exposure. Patients or their caregivers should be advised to seek medical attention if they notice signs and symptoms of methemoglobinemia such as slate-grey cyanosis in buccal mucous membranes, lips, and nail beds; nausea; headache; dizziness; lightheadedness; lethargy; fatigue; dyspnea; tachypnea; tachycardia; palpitation; anxiety; and confusion. In severe cases, patients may progress to central nervous system depression, stupor, seizures, acidosis, cardiac arrhythmias, syncope, shock, coma, and death. Methemoglobinemia should be considered if central cyanosis is unresponsive to oxygen. Calculated oxygen saturation and pulse oximetry are generally not accurate in the setting of methemoglobinemia. The diagnosis can be confirmed by an elevated methemoglobin level of at least 10% using co-oximetry. Methemoglobin concentrations greater than 10% of total hemoglobin will typically cause cyanosis, and levels over 70% are frequently fatal. However, symptom severity is not always related to methemoglobin levels. Experts suggest that treatment of methemoglobinemia varies from supplemental oxygen and symptom support to the administration of methylene blue, depending on severity of symptoms and/or the presence of G6PD deficiency. Institutional guidelines and/or individual product labeling should be consulted for further guidance.