Chelating Agents

Chelating agents are the drugs or agents used to prevent or reverse the toxic effects of heavy metals on enzymes or accelerate elimination of metals from body.

The term “chelate is derived from the Greek word “ Chele” meaning “Crab’s Claw”. It is used to describe those complexes in which the ligand molecule binds through at least two donor groups so that a ring system is formed. Ligands having potential to form such rings are called chelating agents.

Chelating agent

A flexible molecule with two or more electronegative groups that form stable coordinate bonds with a cationic metal atom.

Metals having Physiological Importance

• Cr
• Cu
• Fe
• Mg
• Mn
• Se
• Zn

Clinically Important Metals

• Au
• Bi
• F
• Ga
• Li
• Pt

Toxic Metals

• Al
• As
• Cd
• Co
• Pb
• Hg
• Hg-CH₃
• Ni

Positively charged metal ion binds with functional groups (OH-SH-NH) of enzymes, proteins, co-enzymes and membranes, inactivate the enzymes.

Classification

• Desferrioxamine      Fe, Al, Ga
• Deferasirox (oral)    Fe
• Deferiprone (oral)    Fe
• Dimercaprol (BAL)    As, Pb, Cu, Au
• Ethylenediaminetetraacetic acid   Pb Pu
• Succimer                As, Pb, Hg
• Penicillamine          Cu, Pb
• Trientine                Cu

Deferoxamine (Desferrioxamine)

Source Streptomyces pilosus

Affinity Fe⁺⁺, Ca⁺⁺, Al⁺⁺⁺

Chelate Fe in hemosiderin & ferritin

But Fe in hemoproteins, cytochromes and microsomes is resistant

Pharmacokinetics

• Oral absorption is poor, as it promotes Fe absorption
• I/M, I/V – S/C preferred in children (in severe toxicity I/V given, while in moderate cases I/M preferred)
• Metabolism –metabolized by plasma enzymes but exact mode is not defined.
• Desferrioxamine metal complex excreted in urine (orange red colour)

The whole bowel irrigation is recommended to flush the un-absorbed iron because activated charcoal does not bind Fe & deferoxamine enhances Fe absorption

Side effects

• Severe hypotension on rapid I/V infusion, so given slowly
• Idiosyncratic reactions (Pruritus, Wheals, rashes, dysuria, abdominal pain, diarrhea, fever, leg cramps)
• Adverse drug reactions on prolonged administration include neurotoxicity
• Acute respiratory distress syndrome

Contraindications

Not given in patients suffering from renal insufficiency and anuria.

Therapeutic uses

1. Iron overload
2. Acute toxicity (oral?)
3. Chronic Poisoning 1g I/V repeat after 2-4 hours maximum 6g

Management of Thalassemia

Repeated blood transfusions cause accumulation of iron, treated by:

1. Admit the Patient
2. 30/40mg/kg S/C abdominal wall
3. DRC (Doses/Urinary excretion)
4. Add ascorbic acid in low doses
5. Repeat for 5 days

Toxicity

• Local reaction at the site of injection
• Neurotoxicity 30% children
• Loss of hearing
• Ocular damage

Deferasirox

• Tridentate ligand binds Fe >> Zn, Cu
• Given orally
• Bioavailability is 70%
• Protein binding is 99%
• Glucuronide conjugation
• Biliary excretion

Uses

• Chronic transfusional iron over load
• Dose 10-20 mg/kg daily
• Iron excretion is predominant fecal

Dimercaprol

Also known as British Anti Lewisite ( BAL)

Used for the first time during the second world war when British Lewisite gas was used for destruction (caused vesicles), thus Dimercaprol was given as antidote. It is given for treatment of arsenic poisoning.

It is oily, colorless fluid having pungent mercaptan like odour.

Mechanism of action

• SH groups has affinity for Lewisite, protect the sulfhydryl-containing enzymes of patient
• Produce a non toxic, stable complex by binding As, Hg, Pb
• Eliminated in urine
• Earlier the drug is given, better is the response

Pharmacokinetics

• Oral absorption is poor
• Deep I/M 10% peanut oil suspension is used (painful), 100mg/ml, as aqueous solution is unstable so mixed with peanut oil
• Peak effect 30-60 minutes. T ½ is 4 hours
• Excreted in urine (at low pH drug/metal complex dissociates nephrotoxicity)
• Use higher doses 2:1 ratio
• Alkaline diuresis for rapid excretion from body.

Toxicity

• Tachycardia, Rise in BP
• Nausea vomiting, burning sensation in throat lips,
• Lacrimation, rhinorrhea, salivation, increase in secretions
• Burning sensation in hand, urinary tract

Used for acute poisoning not for chronic arsenic poisoning as can lead to redistribution of arsenic, which might go to brain.

Edetate Calcium Disodium (EDTA)

• EDTA, Na2 EDTA, Ca Na2 EDTA
• Chelate Di & trivalent metal ions both exogenous and endogeneous e.g. Fe Zn Mn
• Used for acute lead intoxication

Pharmacokinetics

• Oral  absorption is poor
• I/M painful (mix with local anesthetic), Bioavailability is  good, T ½ < one hour, little degradation occurs
• Distribution limited to extra cellular compartment
• Excreted in urine just like inulin clearance (Asses renal functions before drug therapy)
• For preventing life threatening calcium depletion, administered as calcium disodium salt.

Side effects

• Tetany (Slow infusion)
• Renal toxicity, degeneration of renal tubular cells, reversible. urgency, frequency
• Malaise, fatigue, chills, fever
• GIT symptoms –nausea, vomiting, gastric irritation
• Nasal congestion sneezing
• Hypotension ECG changes

Mainly used for chelating lead, but also for zinc and manganese.

Succimer (2,3 – dimercaptosuccinic acid)

• Chemically related to dimercaprol
• Oral absorption
• Selectivity to Pb>>> As, Hg, Cd
• Does not mobilize (Zn, Cu, Fe)
• Excretion in urine, Bile, Enterohepatic circulation
• Drug of choice in children Pb>45µg/dl
• GIT Symptoms

Penicillamine (D – b, b– dimethylcysteine)

• History –in 1953 discovered and isolated from urine of patients on  penicillin treatment, which led to use in Wilson’s disease
• Chelate Cu, Zn, Hg, Pb
• Used mostly for Copper.
• Oral absorption is 40% – 70%
• Drug is stable in vivo-N acetyl penicillamine > stable used for Hg
• Biotransformation: Liver complete
• Excretion in urine, bile

Uses

1. Wilson’s disease
2. Hg Pb poisoning
3. Rheumatoid arthritis –as has effect on immune complex
4. Cystinuria (cystine –penicillamine soluble complex)
5. Biliary cirrhosis
6. Scleroderma

Toxicity

• Allergy to penicillin also leads to allergy to this
• Skin lesions 33% urticaria, maculopaplar  rashes, lupus erythematosis, fever
• Blood aplastic anemia, aggranulocytosis, leukopenia
• Can aggravate myasthenia gravis
• GIT symptoms relieved by Cu supplements