Chelating AgentsDr. D. K. BrahmaDepartment of PharmacologyNEIGRIHMS, Shillong

What are they ???• These 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 exretable complexes

with toxic metals▫ Contains 2 or more reactive groups (ligand) such that

can hold metal from two sides▫ 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.

Chelating Agents - MOA• Heavy metals exert their toxic effects by

combining with and inactivating functional groups (ligands) of enzymes and important biomolecules - sulfhydril, hydroxyl, carboxyl etc. leading to inactivation

• Chelating agents compete with body ligands for the heavy metal – also differ in affinity for different metals

• 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

Ideal chelating agent1. Ideal chelating agents have higher affinity for

toxic metals than for body Ca++ (readily available in plasma and ECF)

2. Should also have higher affinity for toxic metals than body ligands

3. 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

Chelating Agent - Classification1. Dimercaprol (British antilewisite) or BAL

– As, Au, Bi, Ni, Sb and Hg poisoning2. Dimercaptosuccinic acid (succimer) - Pb3. Calcium disodium edetate (EDTA) – lead

poisoning4. Disodium edetate5. Penicillamine – Cu, Pb, Hg, Zn6. Desferrioxamine – Iron overload7. Deferiprone - Iron

BAL or Dimercaprol:• World War-II as anti-Lewisite • Oily , pungent smelling, viscous liquid, water

insolublePharmacological actions:

▫ heavy metals like As, Hg, Au, Bi, Ni, Sb 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

▫ 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

BAL – contd.• Uses:

1. 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 3rd day

2. As adjuvant to Cal. disod. edetate in Lead Poisoning

3. As adjuvant to Penicillamine in Cu poisoning

• 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

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• 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

• 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.

Calcium disodium edetate (CaNa2EDTA)• 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

• 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• Uses:

• Lead Poisoning – 1 gm is diluted in 200-300 ml of NS infused over 1 hr twice daily – 2nd 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; 2. febrile reactions – chills, body ache, malaise, tiredness etc. 3. Anaphylactoid reactions

Desferrioxamine (Acute Iron Poisoning)• Ferrioxamine – an Iron containing compound –

actinomycetes▫ Chemical removal of Iron – desferrioxamine▫ 1gm = 85 mg of elemental iron

• 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

• Uses: SC or IV (0.5 gm/vial )1.Acute Iron Poisoning2.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

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

• 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.

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.

Important

•Short Questions on – BAL, Penicillamine, Calcium edetate and Deferiprone – all are important

•Acute Iron Poisoning management - Desferrioxamine

Thank you - -

All the Best