CHELATING AGENTS

Dr Bikash Meher MBBS,MD

Contents

Introduction

Classification of chelating agents

Uses

Adverse effects

Introduction 80 metals in periodic table

They have corrosive & astringent properties

Act as a protoplasmic poison by inhibiting essential enzymes

Exert toxic effects by combining with and inactivating

functional groups of enzyme like SH,NH2,OH

Heavy metal poisoning is not uncommon Commonly implicated metals

Lead

Mercury

Arsenic

Cadmium

Chelation (Chele- Claw) Process of an equilibrium reaction between a metal ion and

a complexing agent that produce a stable, nonionized, non

toxic & water soluble complexes which can be eliminated easily.

Chelating agents Agents having ability to form complexes with heavy metal and

prevent or reverse the binding of metallic cation to ligands of the

body

Ideal Chelating Agents More affinity for metals than endogenous ligand

High solubility in water

Resistance to biotransformation

Form non toxic complexes with toxic metal

Accelerate mobilization and/or removal of the metals

Cheap and easy to administer

Easy excretion of chelating complex

Classification of Chelating Agents1. Dimercaprol( BAL),Succimer(DMSA),DMPS

2. D-Penicillamine & N-acetylpenicillamine

3. EDTA derivatives

4. Desferrioxamine,Deferiprone,Defrasirox

5. Trientene

Dimercaprol(BAL) (2-3 DIMERCAPTOPROPANOL)

Synthesized by Stocken and Thompson during world war II

Developed as antidote to lewisite( arsenical war gas)

BAL-British anti lewisite

Oily, Pungent smelling, Viscous liquid

M.O.A Form poorly dissociable complex with metal ions

Protect the SH enzymes

Prevent inhibition of enzyme

Reactivates the inhibiting enzymes( amount and duration)

P/K Can’t be given orally

Given by deep IM injection

Short t1/2,Peak plasma level in 1/2hrs -1 hr( IM)

Metabolized in 6hrs and excreted as glucuronide

Uses Poisoning by As,Hg,Pb(AML)

Dose 5mg/kg stat, followed by 2-3 mg/kg every 4-8hrs for

2 days and then twice daily for 10 days

As an adjuvant to edetate in Lead poisoning

As an adjuvant to penicillamine in Wilson’s disease

C/I Hepatic disease

Iron and cadmium poisoning

A/E Injection is painful and Chances of sterile abscess

Allergic reaction

Nausea, vomiting, headache

Lacrimation,Conjuctivitis,Blepharospasm

Sialorrhoea,paresthesia,muscle pain

Hemolysis in G-6PD deficiency

Anginal pain, Tachycardia, Hypertension

DMSA(2,3 Dimercaptosuccinic acid or Succimer) Synthesized 1940’s by British chemist L.N. Owen

Water soluble analogue of dimercaprol

P/K Orally administered

Absorption rapid but variable

Rapid and extensive hepatic metabolism

90% cysteine disulfides, 10% unchanged

Uses Lead poisoning

As, Cd, , Hg

Side Effects GI - nausea, anorexia, vomiting, diarrhea

Weakness, dizziness, rash

Transient elevation of hepatic transaminase enzymes

Unithiol(DMPS) Dimercaptopropane sulphonate

Water soluble analogue

Used orally and IV

Used in severe acute poisoning with As and Hg

A/E

Skin reaction

D-Penicillamine D-β ,β dimethyl cysteine

Degradation product of penicillin

D-isomer –More potent

P/K Well absorbed orally

Absorption is inhibited by foods, Fe, antacids

Peak plasma conc. In 1-3hr

Metabolized in liver

Uses1.For Cu, Hg, Pb poisoning

2.Wilson’s disease( Hepato lenticular degeneration)

Dose 1-2gm/day in four divided odses

3.Other uses

Rheumatoid arthritis( DMARD)

Cystinuria

Primary biliary cirrhosis and scleroderma

A/E

General toxicities Headache, rash, fever,lymphadenopathy, dysguesia

Hematological toxicities

Aplastic anemia, agranulocytosis, thrombocytopenia

Autoimmune syndrome

Good pasture's Syndrome, Myasthenia Gravis

Others

Drug fever, polyarthritis, exfoliative dermatitis

Trientene Cupriuretic agent

Useful in wilson’s disease

Less potent but safer then d-penicillamine

A/E

Anemia

Dose 2gm in adult in 2-4 divided doses

Desferioxamine Obtained from streptomyces pilocus

Chelator of iron

Removes iron from hemosiderin and ferritin but not from

hemoglobin and cytochrome

M.O.A Bind ferric iron to form ferrioxamine ( stable , water soluble)

P/K Poorly absorbed after oral administration ,Used parenterally

Metabolized by enzyme present in plasma

Uses Acute Iron toxicity

10-15mg/kg/hr constant infusion

50mg/kg IM

For chronic iron intoxication

( 0.5 to 1gm/day, IM)

For chelation of aluminum in dialysis patient

A/E Allergic reactions(pruritus, wheal, rash)

Dysuria, abdominal discomfort, diarrhea

Cataract, neurotoxicity

Pulmonary syndrome

C.I Renal disease

Pregnant women

Deferiprone Orally effective but less effective then desferrioxamine

Use In patient in whom desferioxamine is C .I , unacceptable or

not tolerated.

A/E Anorexia,Vomiting,Joint pain, Blood dyscrasia

Dose 50-100mg/kg daily in 2-4 divided doses

Defrasirox Orally effective

Use Use when desferrioxamine is C I

Iron over load

A/E GI ulceration

Fanconi like syndrome

Dose 20-30mg/kg

EDTA(Ethylene Diamine Tetra Acetic acid) EDTA,Calcium EDTA,Edetate calcium disodium

Chelates divalent or trivalent metals

Chelates extracellular metal ions more than intracellular

ions

P/K Not absorbed orally

Doesn’t cross BBB

IM injection-Painful

T/U Lead poisoning

Acute poisoning

Slow iv , 40mg /kg in two divided doses /day for 5days

Fe,Zn,Cu,Mn, Cd, poisoning

Porphyria

Not useful for Hg poisoning

S/E Thromboplebitis

Nausea, diarrhea

Oliguric renal failure

Febrile reaction, myalgia, rhino rhea

Lacrimation,dermatitis

Hypocalcaemic tetany(rapid IV infusion)

Dicobalt EDTA Used in cyanide poisoning

Diagnosis must be correct

Cobalt toxicity

Chelating agent Use in poisoningCa Na EDTA LeadDesferioxamine Iron,AluminiumDeferiprone IronDicobalt EDTA CyanideDimercarpol(BAL) Arsenic,Mercury,Lead,Cu,AuSuccimer Cu,Hg,PbD-Penicillamine Cu

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