Chelating agents

Brief description of Chelating agents

1. CHELATING
AGENTS

Dr Kaushik Mukhopadhyay
AIIMS, Kalyani
A

2. Chelating agents are drugs used to
prevent or reverse the toxic effects of a
heavy metal on an enzyme or other
cellular target, or to accelerate the
Chelating agents elimination of the metal from the
body.

~ 0-0
ok =e

Metallic ion Chelating agent Metallic chelate

3. PorE

DOL: 10.5772/intechopen.8251 1

+ M

Pork

sch,
+ a, [Pork
sch,

SAS

SM

PorkE|+4cHy …

Heavy metals -
mechanism

==

Reactions of Heavy metals with
sulphydryl groups of proteins or
enzymes
(A) = Intramolecular bonding;
(B) = Intermolecular bonding;
P = Protein; E = Enzyme; M =
Metal.

4. Heavy metal pollution

Exposure to Human

Metal poisoning

1

Inhibit Induce
I

Chelating therapy
or Combination
therapy with
antioxidant

Oxidative stress

Remove t
metal and reduce

oxidative stress Protein, DNA, Lipid

Impaired cell Abnormal Protein dysfunction,
Restore cell metabolism Disorder of protein/ DNA impairment, &
viability and function metabolism Cancer enzyme Membrane damage

ll
No cell death [Elda] Death

https://doi.org/10.1016/j.jtemb.2019.05.003

5. DJS ANIL,
CIRUSILAIMION G
AGENTS

+ Highly water soluble

+ Resistant to biotransformation

+ Ability to reach sites of metal storage

+ Form nontoxic complexes with heavy metal
+ Retain activity at pH of body fluids

+ Ready excretion of chelate

+ Greater affinity for heavy metal than

endogenous ligand

http://www.authorstream.com/Presentation/drmayur25 1 1-1111072-chelating-agents/

6. Sl 9 © 9 5

8.
9.
10.
ie

Chelating agents and their uses

Drug
Dimercaprol (BAL)

Succimer

Unithiol

Calcium disodium EDTA
DTPA

Dicobalt EDTA
D-penicillamine

Trientine
Desferrioxamine
Deferipirone (oral)
Deferasirox (oral)

Review of Pharmacology — Garg & Gupta

Uses in poisoning of
As, Pb, Hg, Au (contra-indicated in Fe
and Cd poisoning)

Pb, As, Cd, Hg
Hg, As, Pb

Pb, Zn, Cd, Mn, Hg, Fe
Uranium, plutonium
Cyanide

Cu, Wilson disease, Pb, Hg, cystinuria,
scleroderma

Cu
Fe
Fe
Fe

7. SH
Dimercaprol (British Antilewisite - BAL) Hs Non

thei
the body

2:1 complex is more stable

USES

+ Poisoning by As, Hg, Au, Bi, Ni, Sb
+ Adjuvant to Cal. disod. edetate in lead poisoning
+ Adjuvant to penicillamine in Cu poisoning and in Wilson's disease

8. Salt and chelate formation with edetate
(ethylenediaminetetraacetate, EDTA)

I £
HOC, c—oH
“on, ot,
Y ve
N
in
ve zu A
Na—0—0 C—O—Na
Il Il
o o
a 4
B Sa, 0
/ N/ \

los /ox 1
Na—O—C—cH, 0-0 C-0-0—Na
Hy Ha Ha

Katzung 14* Ed.

9. Pharmacokinetics - It is highly ionized,
therefore distributed only extracellularly and
rapidly excreted in urine by glomerular
filtration, poor oral absorption

USE
Lead poisoning,

Zn, Cd, Mn, Cu and some radioactive metals

ADR - proximal tubular necrosis, Acute febrile
reaction, anaphylactoid reaction

10. Penidllamine

CH

|
H,C—C—CH—C

Low |

SH NH, OH

——

It is dimethyl cysteine, obtained
degradation product of penicillin

D-isomer is used therapeutically, L-isomer
is toxic (optic neuritis)

Adequate oral absorption, minimal
metabolism, excretion via urine and faeces

+ Wilson disease
+ Copper/Mercury/Lead poisoning
+ Cystinuria

+ Scleroderma

ADR - Long erm - hematological, renal,

collagen tissue toxicity

11. pie
eferoxamine: Mode of Action

12. Brand Name

Dose (mg/Kg/d)

Iron chelators

Deferoxamine | Deferiprone

Desferal Ferriprox
20 minutes 2-3 hours
SQ, IV infusion PO
20-60 75-100
5-7 days/week 3 times daily
Urine/Stool Urine

Gastro-intestinal
symptoms, Kidney
dysfunction, Hepatitis

Vision, Hearing, Growth,
Local Reactions, Allergy

Deferasirox
Exjade

8-16 hours
PO
20-40
Once daily
Stool

Gastrointestinal
symptoms,
agranulocytosis/
neutropenia, Arthralgia

13. Iron chelators

Iron Chelators

Deferoxamine + Treatment of acute iron intoxication + IV,IM, or SC administration required
+ Treatment of chronic iron overload due to transfusion | + SC administration preferred for chronic iron overload
+ IVuse for cardiovascular collapse or shock
+ IM administration for other acute iron intoxication cases
Deferasirox + Treatment of chronic iron overload due to transfusion | + Orally bioavailable
» Treatment of nontransfusion-dependent iron + Renal failure, hepatic failure, and Gl hemorrhage are concerns
overload + Not recommended over deferoxamine
Deferiprone + Treatment of chronic iron overload due to transfusion | + Orally bioavailable
+ Causes agranulocytosis and neutropenia

+ Not recommended over deferoxamine