Chelating agents

Chelating agents

1. Chelating agents

2. Chelating agents are the compounds mainly used in heavy metal poisoning Combines (complex) with metallic ions, forming ring structures within their molecule ( Chele – crab) Form stable, non toxic and easily excretable complexes with toxic metals Contains 2 or more reactive groups (ligand) such that can hold metal from two sides

3. Ligand: is a functional group capable of forming coordinate bond in which both the shared electrons are donated by ligand – mostly O, N or S atom in hydroxyl, carboxyl, keto , sulhydryl , disulfide, amino or phosphate groups.

4. MOA Heavy metals exert their toxic effects by combining with and inactivating functional groups (ligands) of enzymes and important biomolecules - sulfhydryl, hydroxyl, carboxyl etc. leading to inactivation Chelating agents compete with body ligands for the heavy metal – also differ in affinity for different metals

5. Chelating agents have high affinity for such metals and combine with them to form non toxic and water soluble complexes for elimination Possesses: – ve charged groups to attract + ve charged toxic metals

6. Ideal chelating agent Ideal chelating agents have higher affinity for toxic metals than for body Ca++ (readily available in plasma and ECF) Should also have higher affinity for toxic metals than body ligands Ideally should be water soluble and distribution should correspond to that of the metal intended to Interval of administration between exposure to metals and chelating agents should be less

7. Classification Drug EDTA ---------------- Dimercaprol --------------- Succimer --------------- Penicillamine ------------- Trientine ------------- Deferrioxamine ----------- Deferiprone ----------- Used against Lead Arsenic,copper,mer. Lead,arsenic,mercury Copper,mercury,lead Copper Iron Iron

8. BAL or Dimercaprol: World War-II as anti-Lewisite Oily , pungent smelling, viscous liquid, water insoluble Pharmacological actions: heavy metals like As, Hg, Au, Ni and Cu etc. attacks (-SH), an important component of CoA and prevents formation of acetyl CoA leading to disaster - BAL binds with these metals and protects CoA

9. 1:1 Vs 2:1 Complex (more stability) – excess amount is required Metal-BAL complex dissociates quickly releases metal slowly – BAL partly metabolized in the body BAL is oxidized in the body Alkalinazation of urine is required – in acid urine complex dissociates faster However dose dependent toxicity – no large dose at time

10. BAL – contd. Uses: Poisoning by As, Hg, Au, Bi, Ni and Sb etc. Dose: Given I/M in 10% solution in oil - Available as 2 ml ampoules (50 mg/ml) Given deep IM 5 mg/kg stat every 4 Hrly for 2 days followed by increase in interval after 3 rd day As adjuvant to Cal. disod . edetate in Lead Poisoning As adjuvant to Penicillamine in Cu poisoning

11. ADRs: Unpleasant nausea, vomiting, burning sensation of mouth, inflammation of mucous membranes, sweating, cramps and lacrimation etc. Contraindicated in hepatic damage and Cd and Fe poisoning

12. Penicillamine Degraded product of Penicillin (beta dimethylcysteine ) Prepared by alkaline hydrolysis of benzyl penicillin – d- penicillamine Strong Cu chelating property - useful in Cu poisoning MOA is same as others – selective chelating of Cu, Hg, Pb and Zn Absorbed orally - available as 250 mg capsules, metabolized in liver and excreted in urine

13. Uses: Wilson`s disease: hepatolenticular degeneration due to genetic deficiency of ceruplasmin (Cu deposition in body) – life long therapy (0.5-1 gm daily) Cu and Hg (alternative) Poisoning Chronic Pb poisoning (adjuvant to edetate) Cystinuria and cystine stones Scleroderma: benefits by increasing soluble collagen

14. ADRs: Cutaneous dermatological reactions General: headache, sore throat, fever, rash, loss of taste, neuritis Blood: leucopenia, thrombocytopeenia , aplastic anaemia etc. Renal: nephrotic syndrome, haematuria Autoimmune: Myaesthenia like syndrome, diabetes, SLE etc.

15. Disodium edetate (Na 2 EDTA) It is a disodium salt of EDTA Potent chelator of calcium 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

16. Calcium disodium edetate (CaNa 2 EDTA) Calcium chelate of Na2EDTA is used clinically instead of Na2EDTA – ethylene diamine tetracetic acid High affinity for Pb , Zn, Cd, Mn , Cu and some radioactive metals

17. MOA: Removes the metals by exchanging with Ca ++ Highly ionized – not absorbed orally and that ’ s why acts extracellularly – rapidly excreted via kidney Given IV as not absorbed in gut – IM is painful No CSF penetration

18. Uses: Lead Poisoning – 1 gm is diluted in 200-300 ml of NS infused over 1 hr twice daily – 2 nd course repeated after 1 week Fe, Zn, Cu and Mn poisoning – but not in Hg poisoning ADRs: 1. Kidney damage – toxic metal dissociate in tubule – should enhance urine flow; febrile reactions – chills, body ache, malaise, tiredness etc. Anaphylactoid reactions

19. Desferrioxamine (Acute Iron Poisoning) Ferrioxamine – an Iron containing compound – actinomycetes Chemical removal of Iron – desferrioxamine 1gm = 85 mg of elemental iron

20. MOA: Desferrioxamine binds with ferric Iron – stable non-toxic compound Also removes Iron (loosely bound) from haemosiderin and ferritin, but not Hb and Cyt . Low Ca ++ affinity

21. Uses: SC or IV (0.5 gm/vial ) Acute Iron Poisoning Transfusion siderosis : –– 0.5-1 gm/day SC or with Blood transfusion 2 gm /unit of blood ADRs: Histamine release – fall in BP and alleric reactions

22. Acute Iron Poisoning Common in infants and children – 10 to 20 mg iron tablets or equivalent (above 60 mg/kg) Symptoms: Vomiting, abdominal pain, haematemesis , diarrhoea, lethargy, cyanosis, dehydration, acidosis, shock, convulsion and death Pathology: haemorrhage & inflammation in gut, hepatic necrosis and brain damage

23. Aim of treatment: To induce vomiting or gastric lavage with sodibicarb , egg yolk or milk - orally to complex Iron Desferrioxamine : To bind the iron already present 50 mg/kg IM/SC every 4-12 Hrly till serum levels of Iron falls below 200mcg/dl Or IV 10-15 mg/kg/ hr till serum Iron falls below 200 mcg/dl Supportive therapy with fluid and correction of acidosis etc.

24. Deferiprone Orally active Iron chelator Given in transfusion siderosis in thalassemia patients Also used in iron poisoning but less effective than desferrioxamine Dose: 50 to 100 mg/kg in daily in 4 divided doses ADRs: Joint pain, anorexia, vomiting and agranulocytosis etc.