1. ANTIDOTE in Lead Toxicity
Dr Rokhsareh Meamar MD, Ph.D
Associate Professor of Medical Sciences
Department of Medical Toxicology, Isfahan University of Medical sciences

2. Chelation therapy
The indications for and specifics of chelation therapy are determined by patient age, blood-lead concentration, and clinical symptomatology.
Succimer
Calcium disodium Edetate
Dimercaprol
D-pencillamine

3. PRINCIPLES OF CHELATION
Soft metals such as Hg2+, Au+, Cu+, and Ag+ have large atomic radii with a large number of electrons in their outer shell. Accordingly, they form the most stable complexes with sulfur donors and are therefore referred to as sulfur seekers. The chelator or ligand, in this case a sulfur-containing compound such as dimercaprol (BAL), forms a coordinate bond with the metal by donating a pair of free electrons. BAL has two adjacent sulfur groups, thus the term dithiol.
Hard metals, such as Na+, K+, Mg2+, Ca2+, and Al3+, are referred to as oxygen seekers and form the best complexes with hard ligands containing a carboxyl (COO–) group such as calcium disodium edetate (CaNa2EDTA).
Borderline metals, such as Pb2+, Cd2+, Cu2+, As3+, and Zn2+, prefer nitrogen-donating ligands, but will also react with both hard and soft ligands

4. ANTIDOTE: Succimer

5. Succimer
Succimer is the generic name for meso-2,3dimercaptosuccinic acid (DMSA).
Oral DMSA was approved by the US Food and Drug Administration in 1991 as an orphan drug for the treatment of childhood lead poisoning.
It forms water soluble chelates with heavy metals which are subsequently excreted renally.

6. Chemical Properties
Succimer (C4H6O4S2; molecular weight g/ mol) is a white crystalline powder that is soluble in aqueous alkaline solutions, such as 5% sodium bicarbonate.

7. Pharmacodynamics
In addition to increasing excretion of toxic metals, such as lead, mercury, and arsenic, in human and animal studies, succimer has been associated with increases in the urinary excretion of zinc and copper in human trials.

8. Pharmacokinetics
Approximately 20% of orally administered succimer is recovered in the urine as the parent compound or metabolites in human studies.
Bioavailability of approximately 20%.
After absorption, greater than 90% of succimer in the blood is found in the plasma fraction, where it is highly bound (92%–95%) to plasma proteins (mainly albumin) by disulfide linkages.
Peak blood concentrations are reached in approximately 3 h.
Succimer is excreted predominantly in the urine, where 80%–90% appears as mixed disulfides.
The increased urinary excretion of metals such as lead that follows administration of succimer parallels the urinary excretion of the mixed disulfides.

9. PHARMACOKINETICS
The pharmacokinetics of a single oral dose of succimer in humans demonstrates that the half-life is 1.5 times longer in children than in adults, and that the distribution of succimer appears to be greater in poisoned patients than in healthy adults.
Succimer undergoes an enterohepatic circulation facilitated by gastrointestinal (GI) microflora.

10. Lead Poisioning
Animal studies demonstrate the ability of succimer to enhance urinary lead elimination and to reduce blood, brain, liver, and kidney lead concentrations with unclear effects on bone lead concentrations. Interestingly, stopping lead exposure reduced blood lead concentrations by 63% and brain concentrations by 34%, compared to pretreatment concentrations, with the biggest drop in blood lead concentrations over the first 5 days.

11. Lead Poisioning
Under a variety of experimental conditions in animals, succimer prevents the deleterious effect of lead on heme synthesis, blood pressure, and behavior.
Declines in blood lead concentration appear comparable to treatment with a combination of dimercaprol (BAL) for 3 days and 5 days of edetate calcium disodium (CaNa2EDTA).

12. Treatment in adult and children
Oral: 10 mg/kg/dose (or 350 mg/m2/dose) every 8 hours for 5 days, followed by 10 mg/kg/dose (or 350 mg/m2/dose) every 12 hours for 14 days; Maximum: 500 mg/dose.
Repeat courses and extended dosing have been performed in some cases, depending on the patient’s clinical status.
Note: Treatment courses may be repeated, but a 2-week interval between courses is generally recommended because lead reequilibrates between the extravascular storage sites (eg, bone) and the vascular compartment.

13. COMBINED CHELATION THERAPY
Succimer can be combined with CaNa2EDTA to take advantage of the ability of succimer to remove lead from soft tissues, including the brain, while capitalizing on the ability of CaNa2EDTA to mobilize lead from bone.
Although the addition of succimer to CaNa2EDTA prevented the redistribution of lead to the brain caused by CaNa2EDTA alone, the combination also increased urinary excretion of zinc, calcium, and iron.

14. Administration
If unable to swallow whole, capsule may be separated and contents sprinkled on a small amount of soft food, or the contents placed on a spoon and administered followed by fruit drink (cap 100mg, 200mg).
The ability to coadminister iron (if needed), without any adverse events. The timing of administration of the iron should be separate from administration of the succimer.
It is not contraindicated in glucose-6-phosphate dehydrogenase-deficient individuals

15. ADVERSE EFFECTS AND SAFETY ISSUES
Succimer is generally well tolerated, with few serious adverse events reported.
Common adverse effects are gastrointestinal in nature, including nausea, vomiting, flatus, diarrhea, and a metallic taste in 10–20% of patients.
Mild elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are reported.
Rarely, chills, fever, urticaria, rash, transient neutropenia, and eosinophilia are reported.
Cardiovascular: Cardiac arrhythmia (adults: 2%)

16. Concerns related to adverse effects
Hematologic effects: Mild-to-moderate neutropenia has been reported; evaluate CBC with differential at baseline, weekly during treatment, and immediately upon the development of any sign of infection. The manufacturer recommends withholding treatment for ANC <1200/mm3; treatment may be cautiously resumed when ANC returns to baseline or >1500/mm3.
Hepatic effects: Transient elevations in serum transaminases have been reported. Evaluate serum transaminases at baseline and weekly during treatment; more frequent monitoring may be required in patients with a history of liver disease. The drug should be stopped if there is an increase in ALT or AST ≥ 10 times above the upper limit of the reference range.
Hypersensitivity reactions: Monitor for the development of allergic or other mucocutaneous reactions. A reversible mucocutaneous vesicular eruption of the oral mucosa, external urethral meatus, or perianal area has been reported (rarely).

17. Disease-related concerns
Encephalopathy: Succimer does not cross blood-brain barrier and should not be used to treat encephalopathy associated with lead toxicity.
Lead poisoning: Investigate, identify, and remove sources of lead exposure prior to treatment; do not permit patients to re-enter the contaminated environment until lead abatement has been completed.
Succimer is not used to prevent lead poisoning. A rebound rise in serum lead levels may occur after treatment as lead is released from storage sites into blood. The severity of rebound may guide the frequency of future monitoring and the need for additional chelation therapy.
Renal impairment: Use with caution in patients with renal impairment. Succimer is dialyzable; however, the lead chelates are not.

18. Other warnings/precautions
Hydration: Adequate hydration should be maintained during therapy. .

19. ANTIDOTE: Calcium disodium Edetate

20. Edetate calcium disodium
In 1952, investigators reported the first use of the calcium disodium salt of ethylenediaminetetraacetate (calcium edetate) in the treatment of lead intoxication in children and adults.
Edetate calcium disodium (CaNa2EDTA) belongs to the family of polyaminocarboxylic acids. Although it is capable of chelating many metals, its current use is almost exclusively in the management of lead poisoning. When CaNa2EDTA chelates lead, the calcium is displaced by lead, forming a stable-ring compound.

21. PHARMACOKINETICS
CaNa2EDTA has a small volume of distribution (0.05–0.23 L/kg) that approximates the extracellular fluid compartment. It penetrates erythrocytes poorly, and less than 5% gains access to the spinal fluid.
The half-life is about 20–60 minutes and renal elimination approximates the glomerular filtration rate.
As a result, 50% of a given dose of CaNa2EDTA is excreted in the urine in 1 hour and more than 95% is excreted in 24 hours. Following CaNa2EDTA administration, urinary lead excretion is increased 20–50-fold, in the form of a stable, soluble compound.

22. CaNa2EDTA and lead poisoning
In animals, although CaNa2EDTA decreases tissue lead stores, it may transiently increase brain lead concentrations.
This phenomenon may explain why some human case reports demonstrate worsening lead encephalopathy when CaNa2EDTA is used without antecedent initiation of dimercaprol (BAL) therapy.
In humans, CaNa2EDTA reduces blood lead concentrations, enhances renal excretion of lead, and reverses the effects of lead on hemoglobin synthesis. No rigorous clinical studies have ever been performed to evaluate whether CaNa2EDTA is capable of reversing the neurobehavioral effects of lead.

23. Pharmacodynamics
Calcium edetate forms complexes not only with lead but also with zinc, an essential trace metal. During the course of calcium edetate treatment, serum zinc levels may decline to approximately 60–70% of pretreatment values, and urinary zinc excretion may increase approximately 5-to20-fold.
These indices of zinc status return to normal within a few days of cessation of calcium edetate treatment; their clinical significance is uncertain.

24. DOSING AND ADMINISTRATION
The dose of CaNa2EDTA is determined by the patient’s body surface area or weight, the severity of the poisoning and renal function. .
Concurrent dimercaprol and CaNa2EDTA therapies are administered for 5 days.
A blood lead concentration should be measured 1 hour after the CaNa2EDTA infusion is discontinued to avoid falsely elevated blood lead concentration determinations.

25. Adult Treatment Use with dimercaprol (BAL) x5 days
IV: mg/m2 , 50-75mg/kg/day infused over 24 hours, OR infused over 8-12 hours
IM: 250 mg/m2/dose q4hr `

26. Lead nephropathy Scr 2 to 3 mg/dL: 500 mg/m2 every 24 hours for 5 days
Scr 3 to 4 mg/dL: 500 mg/m2 every 48 hours for 3 doses
Scr >4 mg/dL: 500 mg/m2 once weekly

27. Lead poisoning in pediatrics
CaNa2EDTA is used as a single chelator for asymptomatic patients with blood lead 45 to 69 mcg/dL, especially those who cannot tolerate or have contraindications to succimer treatment,
It is also be used in combination with dimercaprol for patients with lead encephalopathy.

28. Lead poisoning in pediatrics
If the child is not encephalopathic, not vomiting, and blood lead level has decreased below 70 mcg/dL, CaNa2EDTA may be changed to succimer.
Succimer is replacing CaNa2EDTA as the chelator of choice in lead-poisoned children without encephalopathy.

29. COMBINATION THERAPY WITH SUCCIMER
The combination of CaNa2EDTA with succimer appears more potent than either individual drug in promoting urine and fecal lead excretion, and in decreasing blood and liver lead concentrations. However, this approach may increase nephrotoxicity and zinc depletion.

30. Intravenous Administration
For IM or IV use; IV is generally preferred, because of the pain of IM administration, however, the IM route is preferred when cerebral edema is present.
IV infusion: Administer the daily dose as a diluted solution over 8 to 12 hours or continuously over 24 hours.
Continuous intravenous infusion is the preferred route of calcium edetate administration(more efficacy and lower toxicity). The drug should be diluted to a concentration of 2–4 mg/mL in normal saline or 5% dextrose.

31. Other route of Administration
For IM injection: Daily dose should be divided into 2 to 3 equal doses spaced 8 to 12 hours apart. Procaine hydrochloride or lidocaine may be added to minimize pain at injection site. Administer by deep IM injection. Mixing 1 mL of a 1% procaine solution for each mL of chelator (0.5%). When used in conjunction with dimercaprol, inject into a separate site.
Oral administration is not recommended because it may increase absorption of lead that may be present in the intestinal tract

32. Repeat Of treatment
Depending upon the blood lead level, additional courses may be necessary; at least 2 to 4 days should elapse before repeat treatment is initiated.
The oliguria developed 1–2 days after chelation was discontinued and lasted 2–4days. Elevations in serum creatinine (3.9–8.4 mg/dL) normalized after 11–22 days.

33. AVAILABILITY
Edetate calcium disodium EDTA is available as calcium disodium Versenate in 5 mL ampules containing 200 mg of CaNa2EDTA per milliliter (1 g per ampule).

34. : Concerns related to adverse effects
Arrhythmias: Monitor for arrhythmias and ECG changes during IV therapy
Nephrotoxicity: Edetate CALCIUM disodium is potentially nephrotoxic. Renal tubular acidosis and fatal nephrosis may occur, especially with high doses; do not exceed the recommended daily dose. If anuria, increasing proteinuria, or hematuria occurs during therapy, discontinue use. Minimize nephrotoxicity by providing adequate hydration, establishment of good urine output, avoidance of excessive doses, and limit continuous administration to ≤5 days.

35. ADVERSE EFFECTS AND SAFETY ISSUES
When CaNa2EDTA is given to patients with lead poisoning, renal toxicity results from the release of lead in the kidneys during excretion.
Nephrotoxicity may be minimized by limiting the total daily dose of CaNa2EDTA to 1 g in children or 2 g in adults, although doses may need to be higher to treat lead encephalopathy.

36. ADVERSE EFFECTS AND SAFETY ISSUES
Because the administration of disodium EDTA (Na2EDTA) can lead to life threatening hypocalcemia, CaNa2EDTA has become the preparation of choice and hypocalcemia is no longer a clinical concern.
Other adverse effects of CaNa2EDTA, most of which are uncommon, include malaise, fatigue, thirst, chills, fever, myalgia, dermatitis, headache, anorexia, sneezing, nasal congestion, lacrimation, glycosuria, anemia, transient hypotension, increased prothrombin time, and inverted T waves. Mild increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (usually reversible) and decreases in alkaline phosphatase are frequently reported.
Depletion of endogenous metals, particularly zinc, iron, and manganese, can result from chronic therapy.

37. ANTIDOTE: Dimercaprol

38. Dimercaprol
Dimercaprol is the generic term for2,3-dimercaptopropanol. Because British investigators developed dimercaprol during World War II as an antidote to the war gas lewisite, it also came to be known as the British anti-lewisite or BAL.

39. Chemistry
BAL is an oily liquid with only 6% weight/volume water solubility, 5% weight/volume peanut oil solubility, and a disagreeable odor.
Aqueous solutions are easily oxidized and therefore unstable. Peanut oil stabilizes BAL and benzyl benzoate (in the ratio of 1 part BAL to 2 parts of benzyl benzoate) renders the BAL miscible with peanut oil.

40. Pharmakokinetic
Dimercaprol increases elimination of lead, copper, an essential trace mineral. In human studies, dimercaprol injection results in a transient increase in blood pressure and heart rate, but it otherwise has no clinically significant pharmacodynamic impact on cardiovascular, hepatic function.

41. Pharmakokinetic
Following IM administration, blood concentrations of BAL peak in about 30 minutes, distribution occurs quickly, and blood concentrations begin to fall within 2 hours.
BAL is concentrated in the kidney, liver, and small intestine. BAL can also be found in the feces, strongly implying that enterohepatic circulation exists.
Hemodialysis may be useful in removing the BAL–metal chelate in cases of renal failure

42. USE FOR LEAD POISONING
BAL may be used in combination with CaNa2EDTA to treat patients with severe lead poisoning. In all other cases, succimer has become the chelator of choice.
When administering BAL in patients with lead encephalopathy, it is essential to administer the BAL first, followed 4 hours later by CaNa2EDTA concomitantly with the second dose of BAL. This regimen prevents the CaNa2EDTA from redistributing lead into the brain. Dimercaprol against of CaNa2EDTA, which does cross the blood-brain barrier.

43. Treatment with dimercaprol
Dimercaprol is administered as a deep intramuscular injection at a dose of 75 mg/m2 (or 3 to 5 mg/kg) every four hours for 5 days. The first dose of dimercaprol should precede the first dose of CaNa2EDTA by 4 hours.
Pretreatment with Diphenhydramine (eg, 1 mg/kg IV or orally every six hours as needed, maximum single dose 50 mg) is recommended to prevent the adverse effects of dimercaprol that are related to histamine release.
Encephalopathic patients are treated for five days; other patients with symptomatic lead toxicity are treated for three to five days depending upon their degree of symptomatology.
A daily urine flow of 300 to 350 mL/m2 or 0.5 mL/kg per hour should be maintained. Intravenous fluids may be necessary to maintain urine output because nausea and vomiting are one of the major side effects of  Dimercaprol

44. Administration
Administer all injections by deep IM injection. Rotate injection sites. When used in the treatment of lead poisoning, administer in a separate site from edetate CALCIUM disodium.
Not recommended for IV administration
Dimercaprol inunctions have been used as an experimental topical treatment for vesicant burns to the skin and eye induced by lewisite. A 5% solution prepared by diluting the 10% ampules in vegetable oil should be applied immediately to the exposed surface of the eye, conjunctivae, and skin. Systemic effects should be treated parenterally.

45. AVAILABILITY
BAL is available in 3-mL ampules containing 100 mg/mL of BAL, 200 mg/ mL of benzyl benzoate, and 700 mg/mL of peanut oil. This drug should only be administered by deep IM injection.

46. ADVERSE EFFECTS AND SAFETY ISSUES
At these higher doses, reported symptoms include, in decreasing order of frequency, nausea, vomiting; headache; burning sensation of lips, mouth, throat, and eyes; lacrimation; rhinorrhea; salivation; muscle aches; burning and tingling of extremities; tooth pain; diaphoresis; chest pain; anxiety; and agitation.
Elevations in systolic and diastolic blood pressure and tachycardia commonly occurred and correlated with increasing doses. Thirty percent of children given BAL may develop a fever that can persist throughout the therapeutic period. Compared to adults, children are prone to tachycardia rather than blood pressure elevation after dimercaprol injections.

47. ADVERSE EFFECTS related to nephrotoxicity
Because dissociation of the BAL–metal chelate will occur in an acid urine, the urine of patients receiving BAL should be alkalinized with hypertonic sodium bicarbonate to a pH of 7.5–8.0 to prevent renal liberation of the metal.
Iron therapy should be discontinued during dimercaprol therapy because the combination of iron and dimercaprol increases nephrotoxicity.

48. ADVERSE EFFECTS
BAL should be used with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as it may cause hemolysis.
Because BAL is formulated in peanut oil, the patient should be questioned regarding any known peanut allergy.
Unintentional IV infusion of BAL could theoretically produce fat embolism, lipoid pneumonia, chylothorax, and associated hypoxia.

49. Lead Poisoning Initial 4 mg/kg (75-83 mg/m2) IM
Repeat dose at least 4 hours later (but not until adequate urine flow established), THEN
4 mg/kg (75-83 mg/m2) + EDTA 250mg/ m2 IM q4hr x3-5 days
If blood lead concentration rebounds to >45 mcg/dL within 5-7 days, may repeat course of treatment (usually just EDTA without dimercaprol)

50. ANTIDOTE: D-penicillamine

51. D-penicillamine
D-penicillamine is another oral chelating agent. It was developed originally to reduce serum copper concentration in patients with Wilson's disease.
American Academy of Pediatrics (AAP) guidelines for the treatment of lead toxicity describe D-pencillamine as a third-line agent, indicated only when unacceptable reactions have occurred to succimer or CaNa2EDTA, and continued therapy is required.
Given the potential for significant adverse events (including leukopenia, thrombocytopenia, hematuria, abnormal liver function, urticaria, angioedema, Stevens-Johnson syndrome, and nephritic syndrome), use of this agent is not generally recommended.

52. Treatment
Adult:
1-1.5 g qDay PO or divided BID-TID x1-6 months. Max dos/day 1500mg
Usually given with mg/day pyridoxine
Take on empty stomach; last dose given at least 3 hr after evening meal
Pediatrics
Considered 3rd-line therapy
20-40 mg/kg/day PO divided q8hr

53. Overview of Treatment

54. Treatment
Clinicians suggest that adults with severe lead poisoning successfully treated with infusion CaNa2EDTA and dimercaprol and,
Mild to moderate poisoning successfully treated with succimer.

55. Adults Treatment Encephalopathy:
BAL 75 mg/m2 IM every 4 h for 5 d and CaNa2EDTA 1500 mg/m2/da Continuous infusion or 2–4 divided IV doses for 5 d (start 4 h after BAL).
Symptoms suggestive of encephalopathy or >100:
BAL 50–75 mg/m2 every 4 h for 3–5 d CaNa2EDTA 1000–1500 mg/m2/da Continuous infusion or 2–4 divided IV doses for 5 d (start 4 h after BAL)
Mild symptoms or 70–100
Succimer 350 mg/m2 tid for 5 d, then bid for 14 d
Asymptomatic and <70
Usually not indicated Remove from exposure

56. Treatment in Pediatrics
For the treatment of high blood lead levels in children, chelation therapy
Recommended with blood lead levels >45 mcg/dL
Children with blood lead levels >70 mcg/dL or symptomatic lead poisoning should be treated with parenteral agents

57. Pediatric treatment Encephalopathy: Symptomatic or > 69 :
BAL 75 mg/m2 IM every 4 h for 5 d and CaNa2EDTA 1500 mg/m2/da Continuous infusion or 2–4 divided IV doses for 5 d (start 4 h after BAL).
Symptomatic or > 69 :
BAL 50–75 mg/m2 every 4 h for 3–5 d CaNa2EDTA 1000–1500 mg/m2/da Continuous infusion or 2–4 divided IV doses for 5 d (start 4 h after BAL)
Asymptomatic: 45–69 :
Succimer 350 mg/m2 tid for 5d, then bid for 14 d, or CaNa2EDTA, 1000 mg/m2/d Continuous infusion or 2–4 divided IV for 5 d(or rarely, D-penicillamine)
20–44:
Routine chelation not indicated If succimer used, same regimen
<20:
Chelation not indicated Attempt exposure reduction

58. Pregnancy Implications
Adverse events were observed in animal reproduction studies.
Lead poisoning: Lead is known to cross the placenta in amounts related to maternal plasma levels. Prenatal lead exposure may be associated with adverse events such as spontaneous abortion, preterm delivery, decreased birth weight, and impaired neurodevelopment.
Some adverse outcomes may occur with maternal blood lead levels <10 mcg/dL. In addition, pregnant women exposed to lead may have an increased risk of gestational hypertension.
Consider chelation therapy in pregnant women with confirmed blood lead levels ≥45 mcg/dL (pregnant women with blood lead levels ≥70 mcg/dL should be considered for chelation regardless of trimester)

59. Pregnancy Risk Factor
Succimer and Dimercaprol is rated pregnancy category C by the US Food and Drug Administration
CaNa2EDTA is rated pregnancy category B by the US Food and Drug Administration
D-pencillamineis rated pregnancy category D by the US Food and Drug Administration

60. Pregnancy Risk Factor
Calcium edetate was teratogenic when administered to pregnant rats. This teratogenicity may have been a consequence of zinc depletion, because the administration of a zinc chelate of EDTA was not teratogenic, 25 mg zinc sulfate orally during chelation and for one additional week.

61. Breast-Feeding Considerations
It is not known if succimer is excreted in breast milk. When used for the treatment of lead poisoning, the amount of lead in breast milk may range from 0.6% to 3% of the maternal serum concentration.
Women with confirmed blood lead levels ≥40 mcg/dL should not initiate breastfeeding; pumping and discarding breast milk is recommended until blood lead levels are <40 mcg/dL, at which point breastfeeding may resume.
Calcium supplementation may reduce the amount of lead in breast milk.

62. Thank you for your Attention