Chelating Agents

CHELATING AGENTS

These are drugs which complex metallic ions, forming ring structures within their molecule (Greek Chele = Crab; the compound holds the metal like a crab’s claw). They are primarily used in heavy metal poisonings.

Those compounds which form stable, nontoxic and easily excreted complexes with toxic metals are valuable in poisonings. The useful agents contain two or more reactive groups (ligands) which can hold the metal from at least two sides so that a ring is formed. When the ring is 5–7 membered, it is most stable.

Ligand is a functional group capable of forming coordinate bond, i.e. a covalent bond in which both the shared electrons are donated by the ligand—generally O, N, or S atoms in hydroxyl, carboxyl, keto, sulfhydryl, disulfide, amino or phosphate groups.

Heavy metals exert their toxic effects by combining with and inactivating functional groups (ligands) of enzymes or other critical biomolecules. Chelating agents compete with body ligands for the heavy metal. They differ in their affinity for different metals. Clinically useful agents should have a higher affinity for the toxic metal than for calcium, because Ca2+ is readily available in plasma and extracellular fluid. They should also have higher affinity than the body ligands for the toxic metal. Moreover, to be effective in metal poisoning, their distribution in the body should correspond to that of the metal to be chelated, and they should be water soluble.

Efficacy of all chelating agents in promoting excretion of the toxic metal and in reversing toxic manifestations declines rapidly as the interval between entry of the metal in the body and the administration of the chelator increases.

Chelating agents useful as drugs are:

Dimercaprol (BAL)

Calcium disodium DTPA

Dimercaptosuccinic Penicillamineacid (Succimer)

Desferrioxamine

Disodium edetate

Deferiprone

Calcium disodium edetate

Dimercaprol (British anti-lewisite; BAL)

It is an oily, pungent smelling, viscous liquid, developed during World War II by Britishers as an antidote to the arsenical war gas lewisite. The two SH groups of dimercaprol bind those metals which produce their toxicity by interacting with sulfhydryl containing enzymes in the body, i.e. As, Hg, Au, Bi, Ni, Sb, Cu. The complex of 2 molecules of dimercaprol with one metal ion is more stable than 1:1 complex. It is, therefore, desirable to maintain excess of dimercaprol in plasma to allow formation of 2 : 1 complex. The dimercaprol-metal complex spontaneously dissociates releasing the metal at a slow rate; also dimercaprol is partly oxidized in the body: further emphasizing the necessity to have excess dimercaprol available. But due to dose dependent toxicity of dimercaprol, large amounts should not be given at a time.

Uses

Poisoning by As, Hg, Au, Bi, Ni, Sb: it is administered i.m., 5 mg/kg stat, followed by 2–3 mg/kg every 4–8 hours for 2 days, then once or twice a day for 10 days. It is partly oxidized and glucuronide conjugated, but mainly excreted as such in 4–6 hours. Earlier the treatment is instituted, the better it is. Because the dimercaprol-metal complex dissociates faster in acidic urine and the released metal can damage the kidney, urine is alkalinized during dimercaprol therapy.

As an adjuvant to Cal. disod. edetate in lead poisoning.

As an adjuvant to penicillamine in Cu poisoning and in Wilson’s disease—300 mg/day i.m. for 10 days every second month.

BAL INJ 100 mg/2 ml (in arachis oil) inj.

It is contraindicated in iron and cadmium poisoning, because the dimercaprolFe and dimercaprolCd complex is itself toxic.

Adverse effects

These are frequent, dose related and distressing, but generally not damaging. Rise in BP, tachycardia, vomiting, tingling and burning sensations, inflammation of mucous membranes, sweating, cramps, headache and anxiety.

Antihistaminics given 30 min before dimercaprol injection, reduce the intensity of adverse effects.

Dimercaptosuccinic acid (Succimer)

It is similar to dimercaprol in chelating properties, water soluble, less toxic and orally effective. Its efficacy has been demonstrated in As, Hg and Pb poisoning. It has been marketed in USA and some other countries, but not in India for the treatment of lead intoxication. Side effects are nausea, anorexia and loose motions.

Disodium edetate (Na₂EDTA)

It is the disodium salt of ethylene diamine tetraacetic acid (EDTA). It is a potent chelator of calcium—causes tetany on i.v. injection. When a slow infusion is given, tetany does not occur, because calcium is withdrawn from bones. It can be used for emergency control of hypercalcaemia: 50 mg/kg i.v. infusion over 2–4 hours, but bisphosphonates are preferred.

Calcium disodium edetate (Ca Na₂ EDTA)

It is the calcium chelate of Na₂ EDTA. Because this chelating agent has higher affinity for metals like Pb, Zn, Cd, Mn, Cu and some radioactive metals, it can remove them from the body by exchanging with Ca held by it. It is highly ionized, therefore distributed only extracellularly and rapidly excreted in urine by glomerular filtration (t½ < 1 hour) carrying the toxic metal along. It is not metabolized. Because of its ionic nature, Ca Na₂ EDTA is not absorbed from the g.i.t.—must be given parenterally. Since i.m. injection is painful, preferred route is i.v. It does not enter brain or CSF. Thus, it can remove toxic metals only from accessible sites.

Uses

Lead Poisoning

This is the most important indication for CaNa₂EDTA; 1 gm is diluted to 200–ml in saline or glucose solution and infused i.v. over 1 hour twice daily for 3–5 days. The urinary excretion of Pb is promptly increased, but declines quickly as the metal is removed from accessible sites (primarily bone). A second course of CaNa₂EDTA may be repeated after 5–7 days, allowing time for Pb to redistribute to extracellular sites.

It is also useful in Fe, Zn, Cu, Mn and radioactive metal, but not Hg poisoning, because Hg is more firmly bound to body constituents and is localized in areas not accessible to CaNa₂ EDTA.

Adverse Effects CaNa₂ EDTA does not produce tetany and is relatively safe.

Kidney damage with proximal tubular necrosis is the most important problem. This is roughly dose-related and may be due to the toxic metal partly dissociating in the tubule. It can be minimized by maintaining high urine flow.

An acute febrile reaction with chills, body-ache, malaise, tiredness occurs in some individuals. Anaphylactoid reaction with fall in BP and congestion of eyes and nose is also reported.

Calcium disodium DTPA

Diethylene triamine penta acetic acid (DTPA, Pentetic acid) is a congener of EDTA. It has higher affinity for many heavy metals than EDTA. Its calcium chelate has been used in metal poisonings (especially radioactive metals like urenium, plulonium) which do not respond to CaNa₂EDTA. However, because of its limited distribution in the body, results are not impressive.

Penicillamine

It is dimethyl cysteine, obtained as a degradation product of penicillin. It was found to have strong copper chelating property and was used in 1956 for Wilson’s disease. It selectively chelates Cu, Hg, Pb and Zn. The disomer is used therapeutically, because the lisomer and the recemate produce optic neuritis and are more toxic. It is adequately absorbed after oral administration, little metabolized in the body and excreted in urine and faeces. When given to patients with heavy metal toxicity, excretion of the metal is enhanced.

Uses

Wilson’s disease (Hepatolenticular degeneration): This is due to genetic deficiency of ceruloplasmin, a protein which normally binds and disposes off Cu from the body. In its absence, plasma concentration of free Cu is high which gets deposited in liver, substantia nigra, basal ganglia of brain, and causes local degeneration. Life long therapy is needed to prevent progression of the disease.

Dose: 0.5–1 g daily in divided doses 1 hour before or 2 hour after meals to avoid chelation of dietary metals. ARTAMIN, CILAMIN 250 mg cap, ARTIN 150, 250 mg cap.

Pot. sulfide 20–40 mg may be given with each meal to decrease the absorption of dietary copper.

Copper/mercury poisoning: 1–1.5 g/day is given for a few days. It is the drug of choice for Cu poisoning and alternative drug to dimercaprol/ succimer for Hg poisoning.

Chronic lead poisoning: It may be used as an adjuvant to CaNa₂EDTA, but succimer is preferred.

Cystinuria and cystine stones: It promotes the excretion of cysteine and prevents its precipitation in the urinary tract, because penicillaminecysteine complex is more soluble than dicysteine (cystine).

Scleroderma: Penicillamine benefits by increasing soluble collagen.

It was used as a disease modifying drug in rheumatoid arthritis, but has been replaced now by safer drugs .

Adverse Effects

Short-term administration (as metal chelator) of penicillamine does not cause much problem. Various cutaneous reactions, itching and febrile episodes may occur. However, long-term use produces pronounced toxicity. Dermatological, renal, haematological and collagen tissue toxicities are prominent.

Desferrioxamine

Ferrioxamine is a long chain iron containing complex obtained from an actinomycete. Chemical removal of iron from it yields desferrioxamine which has very high affinity for iron: 1g is capable of chelating 85 mg of elemental iron. The straight chain desferrioxamine molecule winds round ferric iron and forms a stable nontoxic complex which is excreted in urine. It removes loosely bound iron as well as that from haemosiderin and ferritin, but not from haemoglobin or cytochrome. Another desirable property is its low affinity for calcium.

Little of orally administered desferrioxamine is absorbed. Parenterally administered desferrioxamine is partly metabolized and rapidly excreted in urine.

Uses

Acute iron poisoning: mostly in children. This is the most important indication—may be life saving .

Transfusion siderosis: occurs in thalassemia patients who receive repeated blood transfusion. Desferrioxamine 0.5–1 g/day i.m. helps to excrete the chronic iron overload; may also be infused i.v. concurrently with blood transfusion—2 g per unit of blood.

Adverse effects

Desferrioxamine can cause histamine release → fall in BP, flushing, itching, urticaria, rashes. A variety of allergic reactions are reported. Changes in lens and retina can occur on repeated use.

Other side effects are abdominal pain, loose motions, muscle cramps, fever and dysuria.

DESFERAL 0.5 g/vial inj.

Deferiprone

It is an orally active iron chelator which has simplified the treatment of transfusion siderosis in thalassemia patients. Excessive haemolysis occurs in these patients, and they have to be given repeated blood transfusions. An iron chelator has to be used to clear the resulting iron overload. Oral deferiprone is a somewhat less effective alternative to injected desferrioxamine. Side effects and cost of treatment are reduced. Deferiprone has also been indicated for acute iron poisoning (less effective than desferrioxamine) and for iron load in liver cirrhosis.

Dose: 50–100 mg/kg daily in 2–4 divided doses.

KELFER 250, 500 mg caps.

Side Effects are anorexia, vomiting, altered taste, joint pain, reversible neutropenia, rarely agranulocytosis. However, long-term safety is not yet known.