CHELATING AGENTS

CHELATING AGENTSIntroduction Heavy metals acts as general protoplasmic poison and impairs the cell functionHave ability to form complexes with important biological radicals like sulfhydryl hydroxyl, carboxyl, aminoacid, imidazoleChelating agentThese are the drugs used to prevent heavy metal poisoningChelationThe process y which these organic compounds combine with the metals to form relatively stable non ionised ring complexes ( Chele claw)Mechanism of actionDrug + Metallic ionsNon toxic, water soluble complexEliminated by the kidneyChelating agentsThese compounds are usually flexible organic molecules which can incorporate metal ions in to their molecular structure by means of chemical groups called ligandsChele crabs clawLigare to bindChelating agentsHave two or more electronegative groups that form stable coordinate covalent bonds with the cationic metal atomChelator metal complex is stable biologically inert and excreted in urineThus appropriate chelating agent can be effectively used in cases of heavy metal poisoningUseful chelating agentsChelating agents useful as drugs areDimercaprol ( BAL)Dimercapto succinic acid (DMSA)Dimercapto propane sulfonic acid ( DMPS)Disodium edetateCalcium disodium edetatePenicillamineDesferrioxamineDeferiprone Classification Drug Used againstEDTALeadDimercaprolArsenic mercury copperSuccimerLead arsenic mercuryPenicillamineCopper mercury leadTrientineCopperDeferrioxamineIronDeferiproneIron Dimercaprol ( BAL)It was synthesized during world war II by Britishers as an antidote to arsenic war gas lewisiteOily, pungent smelling viscous fluidIt is administered IM in oil ( arachis oil)-SH ligands of mercaprol compete with SH gorups of enzymes for heavy metalDimercaprol metal complex is stable and excreted in urineDimercaprolUsesTreatment of arsenic and mercury poisoningAs adjuvant to cal.dosodium.edetate in lead poisoningAs an adjuvant to penicillamine in copper poisoning and in wilsons diseaseContraindicated in iron and cadmium poisoningDimercaprolAdverse effectsFrequent, dose related, but generally not damagingRise in BP, tachycardia, tingling and burning sensations, inflammation of mucous mmebranes, sweating, cramps, headache and anxietyDose5mg/kg 2-3 mg/kg hrly / 2daysDMSA ( Succimer )Dimercaprol analogueWater soluble, less toxic and orally effectiveMarketed in USA and some other countries, not in INDIA for the treatment of lead intoxicationSide effectsNausea, anorexa and diarrheaDose 10mg/kg 8hrly for 5 daysSuccimerCOOHICHSHICHSHICOOHDMPS ( Unithiol )Dimercaprol 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 poison ingDose3-5mg/kg 4hrly IV in 20 minAdverse effectsLow except for mild self limited urticariaDisodium Edetate ( Na2 EDTA)It is a disodium salt of EDTAPotent chelator of calciumCauses tetany on IV injection ( But not on slow infusion)Can be used for emergency control of hypercalcemia (rare) 50mg/kg IV over 2-4hrsCalcium disodium edetae ( Ca2 Na2 EDTA)Calcium chelator of Na2 EDTAHas a high affinity for leadMost important use is lead poisoningPoorly absorbed from GI given IM or IVIM is very painful IV preferredNot metabolizedExcreted by glomerular filtration and tubular secretionCa Na2 EDTAAdverse reactionsDoes not produce tetany relatively safeKidney damage with proximal tubular necrosis but dose relatedAn acute febrile reaction with chills, bodyache, malaise, tiredness occurs in some individualsDose50-75 mg/kg/day IVPenicillamineDimethylcysteineWater soluble degradation product of penicillinD-isomer is used relatively non toxic compared to I-isomer (Optic neuritis)Easily absorbed from GITLittle metabolized, excreted in urine and faecesIt has strong copper chelating property and was useful in 1956 for Wilsons diseaseIt selectively chelates Cu, Hg, Pb, ZnPenicillamineUsesWilsons disease ( Hepatolenticular degenration)Copper / mercury ( Alternate to BAL & DMSA) poisoningAdjuvant to cal. disod.EDTA in lead poisoning but DMSA is preferredCystinuria and cystine stonesScleroderma benefits by increasing the soluble collagenIt was used as a disease modifying drug in rheumatoid arthritis but now replaced by safer drugsPenicillamineAdverse effectsShort term administration does not cause much problem ( cutaneous reactions)Long term use produces pronounced toxicityDermatological, renal, hematological and collagen tissue toxicitiesDose0.5-1 g daily in divided dosesTrientine ( triethylene tetramine)Chelates copper and is used in Wilsons diseaseMay be less toxic than penicillamineHowever in animal studies it has been found to be teratogenicDesferrioxamineFerrioxamine obtained from actinomycete, long chain iron containing complexChemical removal of iron from it yields desferrioxamine1 gm is capable of chelating 85 mg of elemental ironLow affinity for calciumLittle of orally administered desferrioxamine is absorbedParenterally partly metabolized, rapidly excreted in urineDesferrioxamine UsesAcute iron poisoning mostly in children, important & life savingTransfusion siderosisAdverse effectsHypotensive shock due to histamine releaseAbdominal pain, muscle cramps, fever and dysuriaDose : IV 10-15 mg/kg/hr infusionDeferiproneOrally activeUsed in transfusion siderosisSomewhat less effective, alternate to injected desferrioxamineSide effects and cost of treatment are reducedAlso indicated in iron poiosning ( less effective than desferrioxamine) and iron load in liver cirrhosisDeferiproneSide effectsAnorexia, vomitinh, altered taste, joint pain, reversible neutropenia, rarely agranulocytosisLong term safety is not yet knownDose50-100mg/kgConclusions Primary goals of chelation therapyTo reduce metal retentionTo decrease morbidity and mortalityTo prevent complicationsMany efficient chelators exist todayAdminister less toxic chelator when possibleUnsolved issuesChelation of cadmium, chromium, platinumChelation therapy in infants, children and during pregnancyCombined chelation therapy ( Chelators,vitamins, minerals)