A27: Antidotes in Depth

INTRODUCTION

Edetate calcium disodium (CaNa₂EDTA) is a chelator that is primarily used for the management of severe lead poisoning (blood lead concentrations >70 mg/dL) in conjunction with dimercaprol (British anti-Lewisite {BAL}). Edetate calcium disodium has been replaced by succimer (2,3-dimercaptosuccinic acid) for the treatment of patients with lead concentrations between 45 and 70 µg/dL. Recently, in a clinical trial with much criticism, disodium EDTA (Na₂EDTA) (not approved by the US Food and Drug Administration {FDA} and extemporaneously compounded) was demonstrated to produce some reduction in adverse cardiovascular outcomes in patients with a history of myocardial infarction.^3,21,32,38 This preparation is not to be used for lead chelation due to the potential for life-threatening hypocalcemia.

HISTORY

Ehylenediaminetetraacetic acid (EDTA) was first discovered and synthesized in the 1930s. In the late 1940s, it was approved by the FDA as a food additive. Work on using CaNa₂EDTA for lead toxicity began in the 1950s. At the same time, investigation into the uses of EDTA for the reversal of cardiovascular disease began.

The CaNa₂EDTA mobilization test was once widely recommended as a diagnostic aid for assessing the potential benefits of chelation therapy.^35,36 Currently, it can only be considered obsolete.^14,18,21 Criticisms of the test include difficulties with administration of the antidote, unreliability as a predictor of total-body lead burden, expense, and the risk of worsening toxicity through redistribution of lead to either the kidney or the brain.¹⁸

PHARMACOLOGY

Chemistry

Edetate calcium disodium is an ionic, water-soluble compound with a molecular weight of 374.27 (anhydrous) and a formula of C₁₀H₁₂CaNa₂O₈.

Mechanism of Action

Edetate calcium disodium belongs to the family of polyaminocarboxylic acids. Although it is capable of chelating many metals, its current use is almost exclusively in the management of lead poisoning. The term chelate has its origin in the Greek word chele, which means “claw,” implying an ability to tightly grasp the metal.⁴⁸ Implicit in chelation is the formation of a ring-structured complex. When CaNa₂EDTA chelates lead, the calcium is displaced and the lead takes its place, forming a stable ring compound.³⁰ Bone is the primary source of lead chelated by CaNa₂EDTA. Blood lead concentration drops due to urinary elimination; however, once chelation is stopped, redistribution to soft tissues, including the brain, and then, ultimately, the return of lead to bone occurs.¹¹ Zinc is also capable of displacing calcium and forming a stable chelate, whereas copper and mercury are not.¹¹

PHARMACOKINETICS AND PHARMACODYNAMICS

Edetate calcium disodium is a highly polar drug with a small volume of distribution (Vd) due to ...