Pharmacology of chelators Domina Petric, MD

Chelators Chelators or chelating agents are drugs used to prevent or reverse the toxic effects of a heavy metal on an enzyme or other cellular target. They are also used to accelerate the elimination of the metal from the body. Chelators form a complex with the heavy metal and make metal unavailable for toxic interactions with functional groups of enzymes, coenzymes, cellular nucleophiles and membranes.

Chelators Chelators contain one or more coordinating atoms (oxygen, sulfur, nitrogen). That atom donates a pair of electrons to a cationic metal ion to form one or more coordinate-covalent bonds. The complex may be referred to as monodentate, bidentate or polydentate. The longer the half-life of a metal in a particular organ, the less effectively it will be removed by chelation. Chelators should be administered very soon after an acute metal exposure to maximise their therapeutical value.

Dimercaprol Oily, colorless liquid with a strong mercaptan-like odor. It is dispensed in 10% solution in peanut oil. It must be administered by intramuscular injection. Im. injection is often painful.

Dimercaprol It can increase the rate of excretion of arsenic and lead. Indications: treatment of acute poisoning by arsenic and inorganic mercury treatment of severe lead poisoning when used in conjunction with edetate calcium disodium (EDTA)

Dimercaprol Intramuscularly administered dimercaprol is readily absorbed, metabolized and excreted by the kidney within 4-8 hours. Side effects: hypertension, tachycardia, nausea, vomiting, lacrimation, salivation, fever and pain at the injection site.

Dimercaprol It can cause thrombocytopenia, increased prothrombin time and hematoma on the injection site. It is not advocated for treatment of chronic arsenic and mercury poisoning. It is contraindicated in elementary or organic mercury poisoning.

Succimer Water-soluble analog of dimercaprol. It increases urinary lead excretion and decreases blood lead concentration. It may also decrease the mercury content of the kidney. It is absorbed rapidly after oral administration with peak blood levels at 3 hours.

Dose is 10 mg/kg orally three times a day. Succimer It is indicated for the treatment of children with blood lead concentrations greater than 45 mcg/dL, but also in adults. Dose is 10 mg/kg orally three times a day.

Succimer It induces mild increase in urinary excretion of zinc and copper. Side effects: anorexia, nausea, vomiting, diarrhea (10%) rashes (5%) reversible increase in liver aminotransferases (6-10%) mild to moderate neutropenia

EDTA is administered by intravenous infusion. EDTA mobilizes lead from soft tissues, increases urinary lead excretion and decreases blood lead concentration.

EDTA It is indicated for the chelation of lead. It may also be usefull in poisoning by zinc, manganese and certain heavy radionuclides. EDTA is relatively contraindicated in anuric patients.

EDTA Prevention of EDTA toxicity: maintenance of adequate urine flow avoidance of excessive doses limitation of a treatment course to 5 or fewer consecutive days

Analogs of EDTA The calcium and zinc disodium salts of DTPA, pentetate are used for decorporation of transuranic, rare earth and transition metal radioisotopes. Analogs of EDTA are indicated for treatment of contamination with plutonium, americium and curium.

Unithiol It can be administered orally and intravenously. Bioavailability by the oral route is approximately 50% with peak blood levels occurring in 3,7 hours. The elimination half-time of total unithiol is 20 hours.

Unithiol Intravenous unithiol is indicated as initial treatment of severe acute poisoning by inorganic mercury or arsenic. Aqueous preparations of unithiol can be administered at a dosage of 3-5 mg/kg every 4 hours by slow intravenous infusion over 20 minutes.

Unithiol After patient´s cardiovascular and gastrointestinal stabilisation, it may be possible to change to oral administration of 4-8 mg/kg every 6-8 hours.

Unithiol Side effects: self-limited dermatologic reactions like drug exanthemas and urticaria erythema multiforme Stevens-Johnson syndrome Unithiol should be infused slowly over an interval of 15-20 minutes because rapid iv. infusion may cause vasodilatation and hypotension.

Penicillamine White, crystalline, water-soluble derivative of penicillin. D-penicillamine is less toxic than the L-isomer. It is readily absorbed from the gut and is resistant to metabolic degradation.

Penicillamine Indications: treatment of poisoning with copper prevention of copper accumulation like in Wilson´s disease (hepatolenticular degeneration) intoxication with lead and mercury (less common)

Penicillamine Adverse effects: hypersensitivity reactions like rash, pruritus and drug fever nephrotoxicity with proteinuria renal insufficiency with protracted use pancytopenia pyridoxine deficiency

Deferoxamine It is the parenteral chelator (preferably intravenously) of choice for iron poisoning. Deferoxamine plus hemodialysis may also be useful in the treatment of aluminium toxicity in renal failure. Rapid iv. administration may result in hypotension.

Deferoxamine adverse effects Adverse idiosyncratic responses: flushing, abdominal discomfort and rash. Pulmonary complications (acute respiratory distress syndrome) in patients undergoing infusions lasting more than 24 hours. Neurotoxicity and increased susceptibility to infections like Yersinia enterocolitica after long-term therapy of iron overload conditions (thalassemia major).

Deferasirox It is indicated for oral treatment of iron overload caused by blood transfusions (in patients with thalassemia and myelodysplastic syndrome). Adverse effects: mild to moderate gastrointestinal disturbances (<15%) and skin rash (5%).

Prussian blue It is indicated for the treatment of contamination with radioactive cesium and intoxication with thallium salts.

Katzung, Masters, Trevor. Basic and clinical pharmacology. Literature Katzung, Masters, Trevor. Basic and clinical pharmacology.