Chelating agents

This presentation was used for lecture class in MBBS first year

1. Chelating Agents Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Lecturer, Lumbini Medical College & TH 12 December, 2018 (26 Mangsir , 2075), Wednesday

2. Questions from last class… What are the information included in National List of Essential Medicines of Nepal (5 th Edition)? Define Rational use of drugs. What do you mean by P-drug? What are the steps of selecting a P-drug?

3. By the end of the class, MBBS I st year students will be able to: Define chelating agents Identify the characteristics of clinically useful chelators List clinically important chelating agents Discuss the pharmacology of chelating agents

4. Introduction Chelating agents are drugs that complex metallic ions Forms stable, non toxic and easily excreted complexes Important in heavy metal poisonings Metals with relative high densities, atomic weights or atomic numbers Heavy metals: combines and inactivates enzymes and other critical biomolecules

5. Introduction Clinically useful agents should: Have a higher affinity for the toxic metals than for calcium Have a higher affinity for toxic metals than body ligands have for the toxic metal Have distribution that corresponds to the distribution of metal to be chelated Be water soluble Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+

6. Chelating agents Includes: Dimercaprol (British antilewisite) Dimercaptosuccinic acid ( Succimer ) Disodium edetate (Na 2 EDTA) Calcium disodium edetate (Ca Na 2 EDTA) Penicillamine Desferrioxamine , Deferiprone, Deferasirox

7. Dimercaprol (British antilewisite, BAL) Developed during World War II by Britishers Antidote to arsenical war gas lewisite Excess of BAL needs to be maintained in the body Two molecules of BAL and one metal ion more stable Spontaneously dissociates releasing the metal at slower rate BAL gets partly oxidised

8. Dimercaprol (British antilewisite, BAL) Uses: Poisoning: Arsenic, Mercury, Gold, Bismuth, Nickel, Antimony Alkalinisation of urine essential Adjuvant: Lead, Copper poisoning Adverse Effects: Dose dependent Rise in BP, tachycardia, inflammation of mucous membrane, vomiting Antihistamines prior to BAL Contraindication: Iron, cadmium poisoning

9. Calcium Disodium EDTA (Ca Na 2 EDTA) Calcium chelate of disodium ethylene diamine tetracetic acid Tetany caused by Na 2 EDTA is not seen Exchanges Ca 2+ for lead, zinc, cadmium, manganese, copper, radioactive metals Highly ionised: Must be given parenterally, distributed extracellularly, rapidly excreted in urine Not metabolised

10. Calcium Disodium EDTA (Ca Na 2 EDTA) Uses: Lead poisoning Iron, zinc, copper, manganese, radioactive metal poisoning Adverse effects: Kidney damage with proximal tubular necrosis Maintain high urine flow Acute febrile illness Anaphylactoid reactions Not to be used in mercury poisoning

11. Penicillamine Degradation product of penicillin Strong copper chelating property Chelates copper, mercury, lead, zinc d-isomer: therapeutically important l-isomer: optic neuritis Given orally, little metabolised, excreted in urine and faeces

12. Penicillamine Uses: Wilson’s disease Poisoning: Copper: drug of choice Mercury: alternative Chronic lead: adjuvant to CaNa 2 EDTA Cystinurina and cysteine stones Sceloderma

13. Penicillamine Adverse effects: Short term administration: Well tolerated Cutaneous reaction, itching, febrile episodes Long term administration: Dermatological, renal, haematological and collagen tissue toxicities

14. Desferrioxamine Iron removed from ferrioxamine chemically Very high affinity for iron 1gm desferrioxamine can chelate 85 mg of elemental iron Excreted in urine Removes loosely bound iron, iron from haemosiderin , ferritin Low affinity for calcium

15. Desferrioxamine Uses: Acute iron poisoning Transfusion siderosis Adverse effects: Histamine release Changes in lens and retina Problem: Oral administration- little absorbed Parenteral administration required Partly metabolised, rapidly excreted in urine

16. Other iron chelators Deferiprone: Orally active Less effective than desferrioxamine Use: Transfusion siderosis Hepatic cirrhosis Deferasirox : Oral iron chelator Low affinity for Copper, zinc Deferasirox -iron complex excreted in bile Side effect: G.I. ulceration, haemorrhages

17. Conclusion Chelating agents form stable, non toxic and easily excretable complexes with metals Chelating agents must be selective for the metal to be chelated, and with higher affinity than other endogenous ligands Each chelator has specific chelating actions

18. Next class… Tomorrow (9-10 am) Topics: Clinical Trials Any queries? Thank you!