Chelating Agents

DR. B.K. Mishra DEPTT. OF PHARMACOLOGY,H.I.D.S.G-NOIDA

Chelation It is the binding or complexation of a bi-or multidentate ligands. These ligands, which are often organic compounds, are called chelants,chelators, chelating agents, or sequestering agents Chelating agents Greek-chele=crab; The compound holds the metal like a crabs claw. These are the drugs used to prevent or reverse the toxic effect of a heavy metal on an enzyme or other cellular targets, or to accelerate the elimination of the metal from the body. Primarily used in heavy metal poisoning.

Chelating Agents
Properties of chelating agents: Flexible molecules with two or more electro negative groups that form stable co-ordinate covalent bonds with a cationic metal atom. The chelator-metal complexes formed are excreted by the body. Efficiency of the chelator is partly determined by the no. of legands groups on the molecule available for metal binding. Greater the no.of ligand groups, the more stable the metal chelator complex Depending of the no of metal ligands bonds, the complex may be referred as mono, bi-or poly dentate.

 The chelating ligand groups include functional groups as OH, -SH, and NH; which can donate electrons for co-ordination with the metals. Some chelating agent may enhance the excretion of essential cation such as zinc or copper ex. Ca EDTA used for lead intoxication. Some chelating not only enhance that metals excretion but also redistribute some of the metals to other vital organs Ex. Dimercaprol The capacity of chelating agent to prevent or reduce the adverse effect of toxic metals appears to be greatest when they are administered very soon after an acute exposure.

Chelation Therapy It is the use of chelating agent to detoxify poisonous metal agents such as mercury, arsenic and lead by converting them to a chemically inert form that can be excreted without further interaction with the body. Also used as a scientifically unsupported treatment for autism.

Chelating agents useful as drug are: Dimercaprol (BAL) Calcium disodium DTPA Dimercapto-succinic acid (Succimer) Disodium Edetate Penicillamine Desferrioxamine Deferiprone

(1). Dimercaprol (BAL) Chemically K/a 2,3- Dimercapto- propanol Oily, Colourless liquid with strong mercaptan like odour, Aq. Solu of dimercaprol are unstable and oxidize readily, hence it is dispensed in 10% solution in peanut oil. Must be administered by I/M injection hence painful. 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. . Due to dose dependent toxicity of dimercaprol, large amount should not be given at time.

Use: poisoning by As, Hg, Au, Bi, Ni, Sb,.

Dose:- I/M 5mg/Kg stat, followed by 2-3mg/kg every 4-8 hours for 2days, than once or twice a day for 10 days. Precaution:- Because 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 calcium disodium edetate in lead poisoning As an adjuvant to penicillamine in Cu poisoning & in wilsons disease

Dose:- 300mg/day I/M for 10 days every 2nd month.

Contra- indicated :- in Iron & cadmium poisoning . Adverse effects frequent & dose related. Rise in B.P, tachycardia, vomiting, tingling& burning sensations, sweating, cramps, headache& anxiety. How to reduce the intensity of adverse effects. Give Antihistaminic 30 minutes before dimercaprol injection Caution:- Not advocated for treatment of chronic poisoning by Hg &As

II. Succimer : K/a Dimercapto-succinic acid DMSA Water soluble analog of dimercaprol Absorbed rapidly;peak blood levels occur at approx. 3 hr. Elimination half life 2-4 hrs. Use:- approved for the treatment of children with blood lead conc. greater than 45 mcg/dl but it is also commonly used in adults. Also used in the treatment of arsenic& mercury poisoning Dose:- 10mg/kg orally TDS. Adverse effects:- GIT Disturbances as anorexia, nausea, vomiting , diarrhea are most common.

III. Edetate Calcium Disodium: Also k/a Ethylene-di-amine tetraacetic acid(EDTA) Efficient chelator of many divalent & trivalent metals in vitro such as- Pb, Zn, Cd, Mn, Cu , and some radio active metal. It is not absorbed from G.I.T.- must be given parenterally. Since I/M injection is painful, hence preferred route is I/V. Does not enters brain or c.s.f.,thus it can remove toxic metals only from accessible sites

Uses: Lead poisoning- most imp. indication.

Dose:- 1 gm is diluted to 200-300 ml in saline or glucose solution and infused I/V over 1 hour, twice daily for 3-5 days. 2nd course may be repeated after 5-7 days
Also useful in Fe, Zn, Cu, Mn, & radioactive metal but not Hg. Also used in root canal treatment as a way to irrigate the canal

Caution :- To prevent potentially like threatening depletion of calcium, the drug should only be administered as the calcium di-sodium salt. Adverse effects: Kidney damage with proximal tubular neurosis is the most imp problem. Anaphylactoid reaction with fall in BP,& congestion of eye& nose is also reported.

IV. Disodium edetate (Na2 EDTA)

Dose:- 50mg/kg ;I/V infusion over 2-4 hours.

V. Pencillamine dimethyl cysteine, obtained as a degradation production of penicillin. Selectively chelates Cu, Hg, Pb and Zn. D- isomer is used therapeutically . Use:
Wilson disease

Life long therapy is needed to prevent progression of the disease. Dose:- 0.5-1g daily in divided doses 1 hour before or 2 hour after need Pot. Sulfide 20-40 mg may be given with each meal to decrease the absorption of dietary copper.

 2. Cu/Hg poisoning 1-1.5g/day is given for few days It is drug of choice for Cu poisoning and alternative drug to dimercaprol for Hg poisoning. 3. can be uses as an adjuvant to CaNa2 EDTA in chronic lead poisoning. 4. promotes the excretion of cysteine& prevents its precipitation in the urinary tract. Adverse effects:- Rash, proteinuria, anorexia, nausea, loss of taste sensation.

VI. Desferrioxamine: Ferrioxamine is a long chain iron containing complex obtained from an actinomycetes. chemical remoxal of iron from it yields desferrioxamine which has very high affinity for iron. 1 g is capable of chelating 85 mg of elemental iron. Parenterally administered desferrioxamine is partly metabolized and rapidly excreted in urine.

Uses: Acute iron poisoning mostly in children Dose: I/M 0.5mg-1g (50mg/kg) repeated 4-12 hourly as required or I/V (if shock +nt ) 10-15 mg/kg hour; max 75mg/kg in a day till serum iron falls below 300 mcg/dl. Transfusion siderosis- occurs in thalassemia patients who receive repeated blood transfusion. Dose:- desferrioxamine 0.5-1g /day ;I/M help to excrete the chronic iron overloads.
May also be infused I/V Concurrently with Blood transfusion -2g per unit of blood.

Adverse effects: It can cause histamine release fall in Bp,flushing,itching,urticaria;abdominal pain,loose motion,fever

6.Deferiprone: Recently introduced orally active iron chelator. Has simplified the treatment of transfusion siderosis in thalassemia patients. Excessive haemolysis occurs in these patients, and they have to be given repeated blood transfusion. An iron chelator has to be used to clear the resulting iron overload. Indicated for acute iron poisoning -Iron load in liver cirrhosis

 S/E Anorexia Vomiting Altered taste Joint Pain Reversible Neutropenia