Chelation Therapy

Chelation Therapy

1. Definition, principle & the ideal chelator

• Chelating agents are drugs that complex (sequester) metallic ions by forming ring structures within their molecule — Greek chele = crab; the agent grips the metal like a crab's claw. They are used principally in heavy-metal poisonings (KDT 8e Ch.68, p.964).
• A chelate is a stable, non-toxic, water-soluble, readily-excreted complex between the agent and a toxic metal; only agents forming such complexes are clinically valuable (KDT 8e Ch.68, p.964).
• Ligand = a functional group capable of forming a coordinate (dative) covalent bond — both shared electrons donated by the ligand. Biologically relevant donor atoms are O, N or S, present in hydroxyl, carboxyl, keto, sulfhydryl (–SH), disulfide, amino and phosphate groups (KDT 8e Ch.68, p.964).
• A useful agent carries two or more reactive ligand groups that hold the metal from at least two sides, generating a ring; the ring is most stable when it is 5- to 7-membered (KDT 8e Ch.68, p.964). G&G frames the same point as chelators forming "typically five- or six-membered rings" (G&G 14e Ch.76, p.1521).
• Mechanism of metal toxicity that chelation reverses: heavy metals exert toxicity by combining with and inactivating functional ligand groups of enzymes or other critical biomolecules; chelating agents compete with these body ligands for the metal, mobilise it and promote excretion (KDT 8e Ch.68, p.964).
• Properties of the ideal chelator (the examinable "criteria" list — KDT 8e Ch.68 p.964 + G&G 14e Ch.76 p.1521):
  • Higher affinity for the toxic metal than for Ca²⁺ (and Zn²⁺), because physiological Ca²⁺/Zn²⁺ are abundant and would otherwise be stripped (KDT 8e Ch.68, p.964; G&G 14e Ch.76, p.1521).
  • Higher affinity than the body ligands the metal is bound to, so it can actually pull the metal off enzymes (KDT 8e Ch.68, p.964).
  • Body distribution matching that of the metal to be chelated — the agent must reach the metal's storage compartment (KDT 8e Ch.68, p.964; G&G: "reach sites of metal storage", p.1521).
  • Water-soluble, resistant to biotransformation, and the metal–chelator complex itself readily excreted (KDT 8e Ch.68, p.964; G&G 14e Ch.76, p.1521).
  • Complex should be stable and non-toxic (G&G 14e Ch.76, p.1521).
• Time-dependence of efficacy (key clinical principle): efficacy in promoting metal excretion and reversing toxicity declines rapidly as the interval between metal entry and chelator administration lengthens — "earlier the treatment, the better" (KDT 8e Ch.68, p.964; G&G echoes that dimercaprol "is most beneficial when given very soon after exposure" because it prevents, rather than reverses, sulfhydryl-enzyme inhibition, p.1522).
• Acute vs chronic exposure (a recurring G&G caution): in acute high-dose metal exposure chelation reduces toxicity, but following chronic exposure chelation shows no clinical benefit beyond cessation of exposure and may do more harm than good (it can redistribute metal and increase neurotoxicity); chelation is recommended only for acute poisonings (G&G 14e Ch.76, p.1521).

Agents covered (the working list)

• Dimercaprol (BAL) · Dimercaptosuccinic acid / Succimer (DMSA) · DMPS (unithiol) · Disodium edetate (Na₂EDTA) · Calcium disodium edetate (CaNa₂EDTA) · Penicillamine (and Trientine) · Desferrioxamine (deferoxamine) · Deferiprone · Deferasirox (KDT 8e Ch.68, p.964; G&G 14e Ch.76, pp.1521–24). Prussian blue (insoluble ferric hexacyanoferrate) is the gut-lumen antidote for radioactive caesium and thallium and is covered under Recent Advances.