Heavy metal antagonists

1. Dr Bikash Meher
MBBS,MD

2. Contents
Introduction
Classification of chelating agents
Uses
Adverse effects

3. 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

4. Heavy metal poisoning is not uncommon
 Commonly implicated metals
 Lead
 Mercury
 Arsenic
 Cadmium

5. 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

6. 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

7. Classification of Chelating Agents
1. Dimercaprol( BAL),Succimer(DMSA),DMPS
2. D-Penicillamine & N-acetylpenicillamine
3. EDTA derivatives
4. Desferrioxamine,Deferiprone,Defrasirox
5. Trientene

8. 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

9. 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

10. 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

11. 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

12. 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

13. Uses
 Lead poisoning
 As, Cd, , Hg
Side Effects
 GI - nausea, anorexia, vomiting, diarrhea
 Weakness, dizziness, rash
 Transient elevation of hepatic transaminase enzymes

14. Unithiol(DMPS)
 Dimercaptopropane sulphonate
 Water soluble analogue
 Used orally and IV
 Used in severe acute poisoning with As and Hg
A/E
 Skin reaction

15. 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

16. Uses
1.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

17. 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

18. 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

19. 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

20. 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

21. A/E
 Allergic reactions(pruritus, wheal, rash)
 Dysuria, abdominal discomfort, diarrhea
 Cataract, neurotoxicity
 Pulmonary syndrome
C.I
 Renal disease
 Pregnant women

22. 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

23. Defrasirox
 Orally effective
Use
 Use when desferrioxamine is C I
 Iron over load
A/E
 GI ulceration
 Fanconi like syndrome
 Dose 20-30mg/kg

24. 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

25. 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

26. S/E
 Thromboplebitis
 Nausea, diarrhea
 Oliguric renal failure
 Febrile reaction, myalgia, rhino rhea
 Lacrimation,dermatitis
 Hypocalcaemic tetany(rapid IV infusion)

27. Dicobalt EDTA
 Used in cyanide poisoning
 Diagnosis must be correct
 Cobalt toxicity

28. Chelating agent Use in poisoning
Ca Na EDTA Lead
Desferioxamine Iron,Aluminium
Deferiprone Iron
Dicobalt EDTA Cyanide
Dimercarpol(BAL) Arsenic,Mercury,Lead,Cu,Au
Succimer Cu,Hg,Pb
D-Penicillamine Cu

29. Thank You