Continuing Education Activity

Ethylenediaminetetraacetic acid (EDTA) is a medication used in the management and treatment of heavy metal toxicity. It is in the chelating class of drugs. This activity outlines and reviews the indications, actions, and contraindications for EDTA as a valuable agent in managing lead toxicity. This activity will highlight the mechanism of action, side effect profile, and other key factors such as dosing, pharmacokinetics, and monitoring pertinent for members of the healthcare team in the use of EDTA.

Objectives:

• Outline the indications for EDTA.
• Identify the most common adverse effects associated with EDTA therapy.
• Explain the importance of monitoring for patients on EDTA therapy, including renal function tests.
• Identify the mechanism of action of EDTA.

Indications

Ethylenediaminetetraacetic acid (EDTA, edetate calcium disodium, calcium disodium versenate) is a chelation agent used for heavy metal toxicity. EDTA, which was first synthesized in the mid-1930s, has non-pharmacologic and pharmacologic purposes. As a pharmacologic agent, EDTA is used as calcium disodium edetate, which prevents it from binding calcium in the body. Another form, edetate disodium, has a markedly improved ability to bind calcium; this form is no longer used for chelation therapy due to the high risk for hypocalcemia. As a non-pharmacologic agent, EDTA is used in many different industries to remove toxic metal ions. It is commonly used in the cosmetic and food industry and has many applications within scientific laboratories.[1]

Lead Poisoning

Currently, EDTA is FDA-approved for the treatment of lead poisoning in adults and children. EDTA has the ability to bind lead tightly and is more effective than other common chelators.

EDTA is also used in a diagnostic test to assess levels of lead present within patients. The lead mobilization test is performed by administering 2 grams of EDTA through the intravenous or intramuscular route. Patients have a positive lead mobilization test if, in the following 24 hours, they excrete more than 6 grams of lead in their urine. The lead mobilization test allows clinicians to have a more accurate total body lead level and further guide treatment with chelation agents.[2]

While not approved by the FDA, EDTA has the ability to bind other heavy metals within the body, including zinc, cadmium, mercury, and iron. Many cases have been reported where EDTA is used to bind other toxic metals, forming a soluble compound that allows excretion through the urine.[3][4]

Coronary Artery Disease/Atherosclerosis

While limited, there have been reports of EDTA being beneficial to reduce coronary artery disease. With the negative effects of heavy metals on the cardiovascular system, EDTA has been proposed as a useful agent against the development of atherosclerosis. Additionally, edetate disodium has a high affinity for calcium within the body. It is thought that chelation therapy might be beneficial by scavenging the calcium present within fatty, atherosclerotic deposits.[5] 

Neurotoxicity

Heavy metals have the ability to produce reactive agents within the body that lead to an inflammatory cascade. The various cytokines and inflammatory agents have negative effects on the nervous system and can lead to neurotoxicity.  Calcium disodium edetate can be useful for the management of certain neurodegenerative disorders. By chelating metal ions, further inflammatory changes are prevented from taking place.[6]

Mechanism of Action

Chelation agents function by forming bonds with various metal ions, including calcium, zinc, lead, etc. After these bonds are formed, a soluble chelate-metal complex is created that can be excreted from the body. In a similar method, EDTA has a complex structure that allows it to bind various metals. The molecular composition of EDTA consists of multiple oxygen molecules, which function to donate electrons and form coordination complexes with metal ions. When calcium disodium edetate binds to metals, the calcium is displaced from the structure. The bonds formed with the metals are extremely strong and prevent further toxic effects from occurring before excretion out of the body.[7]

Pharmacokinetics

Absorption

EDTA is rapidly absorbed through intravenous access and moves into the plasma and interstitial fluids. Oral administration is avoided due to very low (less than 5%) absorption and elevated lead concentrations within the gastrointestinal tract.

Distribution

EDTA is distributed throughout the entire extracellular compartment. Within the blood, the molecule stays within the plasma. It has an ionic form preventing it from entering into cells.

Metabolism/Excretion

After IV administration, calcium EDTA largely goes unmetabolized and is excreted in its administered form through the kidneys. Similarly, the chelate-metal complexes will be quickly excreted in the urine. The half-life is around 20 to 60 minutes. The kidneys can filter out the drug and secrete it into the tubular lumen.[8]

Administration

EDTA is poorly absorbed through the gastrointestinal tract and therefore is administered through intramuscular injection or intravenous infusion.

Due to side effects, chelation therapy is generally not used in adults with lead levels less than 45mcg/dl. However, in cases where patients are symptomatic, chelation is recommended.[9] According to the manufacturer's prescribing information, EDTA is dosed based on body surface area and renal function status.

Adult Dosing

Lead poisoning (20mcg/dl - 70mcg/dl): 1000 mg/m^2 daily given IV or IM

Lead poisoning (>70mcg/dl): EDTA is combined with dimercaprol; EDTA is administered before dimercaprol

Adults with lead nephropathy: 500 mg/m^2 every 24 hours for 5 days for creatinine levels of 2 to 3 mg/dl; 500 mg/m^2 every 48 hours for 3 doses for creatinine levels of 3 to 4 mg/dl; 500 mg/m^2 weekly for creatinine levels above 4 mg/dl

Pediatric Dosing

In children, patients are commonly given the combination of EDTA and dimercaprol. Chelation therapy is essential in patients with blood lead levels over 45 mcg/dl

Lead poisoning (45 mcg/dl to 70 mcg/dl): 25 mg/kg/day for 5 days [10]

Lead poisoning (>70mcg/dl): IV administration of EDTA at 50 mg/kg/day in six doses

In children with cerebral edema, intravenous administration is avoided due to an increase in intracranial pressure. To avoid this, intramuscular administration is used in these patients

Adverse Effects

There are multiple adverse effects related to the use of EDTA. These side effects are dependent on various factors, including dosage, renal function, and frequency of administration. The most commonly recognized adverse effect is renal toxicity. The toxic effects can manifest as acute tubular necrosis, renal failure, anuria, and proteinuria. Both intramuscular and intravenous routes of administration were shown to increase blood urea nitrogen in more than 25% of patients.[9][10][11]

Additionally, calcium EDTA has a strong affinity for zinc, which can lead to a zinc deficiency. The amount of zinc lost from the body was shown to be negatively correlated with weight. A study assessing the efficacy of calcium disodium edetate found that smaller children were losing a larger proportion of zinc than larger children. The study further reinforced the need to monitor levels of zinc during chelation therapy.[11]

Other side effects include fever, nausea, vomiting, chills, fatigue, arthralgia, hypotension, arrhythmias, acute tubular necrosis, proteinuria, tremors, headache, cheilosis, bone marrow depression, anemia, and hypercalcemia. Pain at the injection site is a common adverse drug reaction of intramuscular administration.[12]

Administration of edetate calcium disodium must be carefully distinguished from the administration of edetate disodium. Edetate disodium is similar in structure to edetate calcium disodium; however, it is not complexed with calcium. This minor difference protects serum levels of calcium and avoids life-threatening hypocalcemia. Cases have been reported where patients who were incorrectly given edetate disodium had seizures and cardiac arrest.[13]

Contraindications

EDTA is contraindicated in patients with renal disease or anuria, as the kidneys eliminate the drug. This may lead to excessive levels of EDTA building up, resulting in further nephrotoxic effects. Additionally, the administration should be avoided in patients with hepatitis. EDTA is classified as a Category B drug and should only be used in pregnant patients if needed. One study showed that EDTA did not produce any teratogenic effects in rats, even at extremely high doses.[14]

Monitoring

Many of the adverse effects of EDTA appear to occur in patients given high doses or with preexisting renal disease. Administration of calcium disodium edetate to patients requires monitoring of renal and hepatic function. These should be monitored before, during, and after administration. If patients become anuric or develop increasing creatinine levels, EDTA should be immediately discontinued. Additional urinalysis may be performed to assess for the presence of hematuria or proteinuria. It is also important to monitor zinc levels as EDTA strongly binds to zinc.[15]

Toxicity

Currently, no antidotes are available for EDTA. In patients who have cerebral edema, increases in intracranial pressure should be treated immediately with osmotic agents. Patients with nephrotoxicity should be given fluids to ensure hydration and be monitored for urine output. Renal function should be continuously monitored even after the development of toxicity. Overall, patients who develop signs or symptoms of toxicity should immediately be discontinued from the drug.

Enhancing Healthcare Team Outcomes

Heavy metal toxicity is a major concern in both adult and pediatric populations. This is of special concern to the pediatric population as lead poisoning can affect cognition and neurodevelopment. Due to the permanent toxic effects of heavy metals, patients must be treated quickly and appropriately. Adequate management by a team of healthcare professionals plays an important role in decreasing overall morbidity and mortality associated with metal toxicity.

Healthcare providers involved in the care of a patient being treated with EDTA should be knowledgeable about the pharmacology and adverse effects of the drug. EDTA has the ability to bind various minerals within the body and should be monitored for any adverse effects. Pharmacists should be mindful of the important difference between edetate disodium and calcium disodium edetate to prevent life-threatening hypocalcemia. Nurses should verify dosing and administration with the pharmacy team and understand the adverse drug reactions mentioned to inform the managing healthcare provider promptly. [Level 5]

Clinicians should be aware of the well-known renal toxicity associated with EDTA. Patients with current renal dysfunction or disease should be monitored carefully or moved to a different chelation agent. Social workers can help the family identify any occupational or home exposure to heavy metals and assist in preventing further exposure. Each member of the interprofessional healthcare team has an important role in treating a patient with EDTA and can significantly reduce the morbidity and mortality associated with heavy metal toxicity.