Class chelating agents 1
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This document discusses chelating agents used to treat heavy metal poisoning. It describes how chelating agents work by binding to metal ions through groups like -SH or -OH, forming stable water-soluble complexes that can be excreted. Several chelating drugs are mentioned, including dimercaprol, DMSA, DMPS, EDTA, penicillamine, desferrioxamine, and deferiprone. Their uses in treating various heavy metal toxicities like lead, arsenic, mercury, copper, and iron poisoning are outlined. Side effects of the drugs and dosing information is also provided. The goals of chelation therapy to reduce metal retention and prevent complications of toxicity are noted in conclusion.
Class chelating agents 1
- 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.
- 2. Chele-claw- chelating agents usually contain polar groups such as –SH or –OH which can bind a metal ion as endogenous ligands bind to metal ion and form stable non-toxic water soluble complexes Relative affinity of chelator to heavy metal Distribution of chelator in body Capacity to mobilize the complex Half life of heavy metal Time after exposure
- 3. Heavy metals combines with one or more reactive groups (Ligands) Oxygen (-OH, -COO, -OPO) Nitrogen (-NH2, -NH) Sulphur (-SH, -S-S) Hamper physiological function Enzyme inhibition, Oxidative stress
- 4. Chelating agents useful as drugs are: Dimercaprol (BAL) Dimercaptosuccinic acid (DMSA) Dimercaptopropane sulfonic acid (DMPS) Disodium edetate Calcium disodium edetate Pencillamine Desferrioxamine Deferiprone
- 5. Drug EDTA, DMSA ---------- Dimercaprol --------------- Succimer (DMSA) DMPS -------- Penicillamine, ------------- Trientine Desferrioxamine ----------- Deferiprone ----------- Used against Lead Arsenic, copper, mercury Lead, arsenic, mercury Copper, mercury, lead Copper Iron Iron
- 6. It was synthesized during the world war II by Britishers as an antidote to arsenic war gas lewisite Oily, pungent smelling, viscous fluid It is administered i.m in oil (arachis oil) -SH ligands of dimercaprol compete with –SH groups of enzymes for heavy metal Dimercaprol –metal complex is stable and excreted in urine( urine should be kept alkaline to prevent dissociation)
- 7. Uses: For the treatment of arsenic and mercury poisoning As adjuvant to Cal. disod. Edetate in lead poisoning As an adjuvant to pencillamine in copper poisoning and in Wilson’s disease Contraindicated in iron and cadmium poisoning As BAL-Fe-complex is toxic
- 8. Adverse effects: Frequent, dose related, but generally not damaging Rise in BP, tachycardia, tingling and burning sensations, inflammation of mucous membranes, sweating, cramps, headache and anxiety Dose 5mg/kg followed by 2-3mg/kg 4hr/2days
- 9. 2,3 Dimercapro Succinic acid Dimercaprol analogue Water soluble, less toxic and orally effective Specific for the treatment of lead intoxication and needs no combination with edetate calcium disodium Effective in allevating acute toxicity and preventing distribution of orally administered mercury Side effects are nausea, anorexia, raised serum amino transferases and loose motions Dose-10mg/kg 8hrly/5days
- 10. Dimercaptopropane sulfonic Acid Dimercaprol analogue Water soluble, less toxic Can be administered orally as well as IV Used for severe acute poisoning by mercury and arsenic Also effective in the treatment of lead poisoning Dose-3-5mg/kg 4hrly by i.v in 20min Adverse effects are low, except for mild self-limited urticaria, IV infusion may cause hypotension
- 11. Ethylene Diamine tetra acetic acid disodium calcium salt It is a disodium salt of EDTA EDTA is a potent chelator for Ca+ and produces life threatening 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
- 12. Ethylene Diamine tetra acetic acid disodium calcium salt It is a disodium salt of EDTA Potent chelator of many divalent(lead, zinc, cadmium, manganese and mercury). In this exchange process, its own calcium is displaced from the molecule Calcium chelator of Na2 EDTA Has a high affinity for lead Most important use is lead poisoning Poorly absorbed from GI –given i.m or i.v. i.m is very painful –i.v. preferred Not metabolized Excreted by glomerular filtration and tubular secretion
- 13. DTPA-Diethylene Triamine Penta Acetic Acid Is useful in removing radioactive uranium and plutonium Adverse reactions: Does not produce tetany –relatively safe Nephrotoxicity-Kidney damage with proximal tubular necrosis –but dose related An acute febrile reaction with chills, body ache, malaise, tiredness occurs in some individuals Dose- 50-75mg/kg /day i.v
- 14. Dimethylcysteine is a water soluble degradation product of penicillin D –isomer is used-relatively non toxic compared to l – isomer (optic neuritis) is used in copper poisiining Easily absorbed from GIT Little metabolized, excreted in urine and faeces It has strong copper chelating property and was used in 1956 for Wilson’s disease It selectively chelates Cu, Hg, Pb and Zn
- 15. Wilson’s disease (hepatolenticular degeneration) Copper/ mercury (alternate to BAL & DMSA) poisoning Adjuvant to cal. disod. Edetate in lead poisoning but DMSA is preferred Cystinuria and cystine stones-it complexes with cystine and prevents precipitation in the urinary tract Scleroderma –benefits by increasing the soluble collagen It was used as a disease modifying drug in rheumatoid arthritis, but now replaced by safer drugs
- 16. Short term administration –does not cause much problem (cutaneous reactions) Long term use –produces pronounced toxicity hypersensitivity Dermatological, renal, Hematological-leukopenia, aplastic anemia and collagen tissue toxicities Dose-0.5-1g daily in divided doses
- 17. Triethyl tetramine dihydrochloride Less toxic alternative to pencillamine in copper poisoning Also effective orally 1gm BD on empty stomach Adverse effect Iron deficiency
- 18. Ferrioxamine derivative devoid of iron Obtained from actinomycete High affinity for Fe3+ 1gm is capable of chelating 85mg of elemental iron Unique property that it can remove iron from ferritin, haemosiderin and to some extent from transferrin but not from hemoglobin or cytochrome Low affinity for calcium Little of orally administered desferrioxamine is absorbed Parenterally –partly metabolized, rapidly excreted in urine
- 19. Uses: Acute iron poisoning: mostly in children, important and life saving Transfusion siderosis-blood transfusion to patients of thalassemia With hemodialysis in treatment of aluminium toxicity in renal failure Adverse effects: Hypotensive shock due to histamine release Abdominal pain, muscle cramps, fever and diarrhoea Dose- i.v ,10-15mg/kg/hr infusion
- 20. Orally active iron chelator Used in transfusion siderosis Somewhat less effective, alternate to injected desferrioxamine Side effects and cost of treatment are reduced Also indicated in iron poisoning (less effective than desferrioxamine) and iron load in liver cirrhosis
- 21. Side effects are: Anorexia, vomiting, altered taste, joint pain, reversible neutropenia, rarely agranulocytosis Long term safety is not yet known Dose-50-100mg/kg
- 22. Oral iron chelator For chronic iron overload- beta thalassemia High affinity for iron, less affinity for zinc, copper Iron deferasirox chelator complex is secreted through bile and excreted in faeces DEXRAZOXANE-used to protect against cardiotoxic drugs—anthracyclines-doxorubicin, daunorubicin
- 23. Primary goals of chelation therapy: To reduce metal retention To decrease morbidity and mortality To prevent complications Administer less toxic chelator when possible Unsolved issues: Chelation of cadmium, chromium, platinum… Chelation therapy in infants, children and during pregnancy Combined chelation therapy