Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

Chele-claw- chelating agents usually contain polargroups such as –SH or –OH which can bind a metal ionas endogenous ligands bind to metal ion and formstable non-toxic water soluble complexes

Relative affinity of chelator to heavy metalDistribution of chelator in bodyCapacity to mobilize the complexHalf life of heavy metalTime after exposure

Heavy metals combines withone or more reactive groups (Ligands)

Oxygen (-OH, -COO, -OPO)Nitrogen (-NH2, -NH)

Sulphur (-SH, -S-S)

Hamper physiological functionEnzyme inhibition, Oxidative stress

Chelating agents useful as drugs are:Dimercaprol (BAL)Dimercaptosuccinic acid (DMSA)Dimercaptopropane sulfonic acid (DMPS)Disodium edetateCalcium disodium edetatePencillamineDesferrioxamineDeferiprone

DrugEDTA ----------------Dimercaprol ---------------Succimer ---------------Penicillamine -------------Trientine -------------Deferrioxamine -----------Deferiprone -----------

Used againstLeadArsenic, copper, mer.Lead, arsenic, mercuryCopper, mercury, leadCopperIronIron

It was synthesized during the world war II by Britishersas an antidote to arsenic war gas lewisiteOily, pungent smelling, viscous fluidIt is administered i.m in oil (arachis oil)-SH ligands of dimercaprol compete with –SH groups ofenzymes for heavy metalDimercaprol –metal complex is stable and excreted inurine( urine should be kept alkaline to preventdissociation)

Uses:For the treatment of arsenic and mercury poisoningAs adjuvant to Cal. disod. Edetate in lead poisoningAs an adjuvant to pencillamine in copper poisoningand in Wilson’s diseaseContraindicated in iron and cadmium poisoningAs BAL-Fe-complex is toxic

Adverse effects:Frequent, dose related, but generally not damagingRise in BP, tachycardia, tingling and burning sensations,inflammation of mucous membranes, sweating,cramps, headache and anxietyDose 5mg/kg followed by 2-3mg/kg 4hr/2days

2,3 Dimercapro Succinic acidDimercaprol analogueWater soluble, less toxic and orally effectiveSpecific for the treatment of lead intoxication andneeds no combination with edetate calcium disodiumEffective in allevating acute toxicity and preventingdistribution of orally administered mercury

Side effects are nausea, anorexia, raised serum aminotransferases and loose motionsDose-10mg/kg 8hrly/5days

Dimercaptopropane sulfonic AcidDimercaprol analogueWater soluble, less toxicCan be administered orally as well as IVUsed for severe acute poisoning by mercury and arsenicAlso effective in the treatment of lead poisoningDose-3-5mg/kg 4hrly by i.v in 20minAdverse effects are low, except for mild self-limitedurticaria, IV infusion may cause hypotension

Ethylene Diamine tetra acetic acid disodium calcium saltIt is a disodium salt of EDTAEDTA is a potent chelator for Ca+ and produces lifethreatening tetany.Causes tetany on i.v. injection (but not on slow infusion)Can be used for emergency control of hypercalcaemia(rare) 50mg/kg i.v. over 2-4hours

Ethylene Diamine tetra acetic acid disodium calcium saltIt is a disodium salt of EDTAPotent chelator of many divalent(lead, zinc, cadmium,manganese and mercury). In this exchange process, its owncalcium is displaced from the moleculeCalcium chelator of Na2 EDTAHas a high affinity for leadMost important use is lead poisoningPoorly absorbed from GI –given i.m or i.v.i.m is very painful –i.v. preferredNot metabolizedExcreted by glomerular filtration and tubular secretion

DTPA-Diethylene Triamine Penta Acetic AcidIs useful in removing radioactive uranium andplutoniumAdverse reactions:Does not produce tetany –relatively safeNephrotoxicity-Kidney damage with proximal tubularnecrosis –but dose relatedAn acute febrile reaction with chills, body ache,malaise, tiredness occurs in some individualsDose- 50-75mg/kg /day i.v

Dimethylcysteine is a water soluble degradationproduct of penicillinD –isomer is used-relatively non toxic compared to l –isomer (optic neuritis) is used in copper poisiiningEasily absorbed from GITLittle metabolized, excreted in urine and faecesIt has strong copper chelating property and was usedin 1956 for Wilson’s diseaseIt selectively chelates Cu, Hg, Pb and Zn

Wilson’s disease (hepatolenticular degeneration)Copper/ mercury (alternate to BAL & DMSA) poisoningAdjuvant to cal. disod. Edetate in lead poisoning butDMSA is preferredCystinuria and cystine stones-it complexes with cystineand prevents precipitation in the urinary tractScleroderma –benefits by increasing the solublecollagenIt was used as a disease modifying drug in rheumatoidarthritis, but now replaced by safer drugs

Triethyl tetramine dihydrochlorideLess toxic alternative to pencillamineAlso effective orally1gm BD on empty stomach

Adverse effectIron deficiency

Short term administration –does not cause muchproblem (cutaneous reactions)Long term use –produces pronounced toxicity

hypersensitivityDermatological, renal,Hematological-leukopenia, aplastic anemiaand collagen tissue toxicitiesDose-0.5-1g daily in divided doses

Ferrioxamine derivative devoid of ironObtained from actinomyceteHigh affinity for Fe3+

1gm is capable of chelating 85mg of elemental ironUnique property that it can remove iron from ferritin,haemosiderin and to some extent from transferrin but notfrom hemoglobin or cytochromeLow affinity for calciumLittle of orally administered desferrioxamine is absorbedParenterally –partly metabolized, rapidly excreted in urine

Uses:Acute iron poisoning: mostly in children, importantand life savingTransfusion siderosis-blood transfusion to patients ofthalassemiaWith hemodialysis in treatment of aluminium toxicityin renal failure

Adverse effects:Hypotensive shock due to histamine releaseAbdominal pain, muscle cramps, fever and diarrhoeaDose- i.v ,10-15mg/kg/hr infusion

Orally active iron chelatorUsed in transfusion siderosisSomewhat less effective, alternate to injecteddesferrioxamineSide effects and cost of treatment are reducedAlso indicated in iron poisoning (less effective thandesferrioxamine) and iron load in liver cirrhosis

Side effects are:Anorexia, vomiting, altered taste, joint pain, reversibleneutropenia, rarely agranulocytosisLong term safety is not yet knownDose-50-100mg/kg

Oral iron chelatorFor chronic iron overload- beta thalassemiaHigh affinity for iron, less affinity for zinc, copperIron deferasirox chelator complex is secreted throughbile and excreted in faeces

DEXRAZOXANE-used to protect iron against cardiotoxicdrugs—anthrocyclines-doxorubicin, daunorubicin

Primary goals of chelation therapy:To reduce metal retentionTo decrease morbidity and mortalityTo prevent complications

Administer less toxic chelator when possibleUnsolved issues:Chelation of cadmium, chromium, platinum…Chelation therapy in infants, children and during pregnancyCombined chelation therapy

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