chelating agent - drdhriti
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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
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