A25: Antidotes in Depth

British anti-Lewisite (BAL) (2,3-dimercaptopropanol; dimercaprol) is a metal chelator used clinically in conjunction with edetate calcium disodium (CaNa₂EDTA) for lead encephalopathy and severe lead toxicity.^23,30 In this, BAL should precede the first dose of CaNa₂EDTA by 4 hours to prevent redistribution of lead to the central nervous system (CNS). BAL has a narrow therapeutic index, BAL must be administered intramuscularly (IM) because it is formulated in peanut oil. Oral succimer is used for patients with less severe lead toxicity. The roles for BAL in arsenic and mercury poisoning have diminished since the development of succimer and the investigational chelator 2,3-dimercaptopropane sulfonate (DMPS). BAL is still indicated when the gastrointestinal tract is compromised.

Investigation into the use of sulfur donors as antidotes was precipitated by the World War II threat of chemical warfare with lewisite (dichloro[2-chlorovinyl]arsine) and mustard gas (dichlorodiethyl sulfide[ClCH₂CH₂]₂S).^1,31,32 Both are vesicants that cause tissue damage when combined with protein sulfhydryl groups (Chap. 132).³⁵ The investigations of Stocken and Thompson at Oxford led to the discovery of the dithiol 2,3-dimercaptopropanol (or BAL) that combines with lewisite to form a stable five-membered ring.^40,42

Chemistry

BAL has a molecular weight of 124.2 Da and a specific gravity of 1.21.³³ It 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 one part BAL to two parts of benzyl benzoate) renders the BAL miscible in peanut oil.³⁶

Mechanism of Action

The sulfhydryl groups of dimercaprol form chelates with certain metals, which are then excreted in the urine. Lead, arsenic, and inorganic mercury salts are the metals most amenable to chelation with BAL.

Pharmacokinetics

There are no recent studies of the pharmacokinetics of BAL. The limited information available was first described in the late 1940s.^1,24 Serum concentrations of BAL peak about 30 minutes after IM administration, and distribution occurs rapidly.^36,39 Within 2 hours after IM administration to rabbits, serum concentrations rapidly fall. Urinary excretion of BAL metabolites, perhaps partially as glucuronic acid conjugates, accounted for nearly 45% of the dose within 6 hours and 81% of the dose within 24 hours.^36,38 Very little is excreted unchanged in the urine.³⁶ BAL is concentrated in the kidney, liver, and small intestine.³⁴ BAL can also be found in the feces, suggesting that enterohepatic circulation exists. Hemodialysis may be useful in removing the BAL–metal chelate in cases of kidney failure.^23,29,41

Animal Studies

The fear of lewisite attack causing skin lesions led researchers to investigate the potential for cutaneous application of BAL.⁴⁰ This was based on the limited water solubility and high lipid solubility of BAL. In a rodent model, low concentrations of topical BAL were very effective both in preventing lewisite-induced toxicity and in reversing toxicity when administered within one hour of skin exposure.^33,35 In rabbits, ophthalmic application of BAL proved effective in preventing corneal destruction if applied within 20 minutes of exposure.²³ Additionally, urinary arsenic concentrations were significantly increased after the application of BAL.³⁵

The effectiveness of both parenteral single-dose and multiple-dose BAL against lewisite and other arsenicals was studied in rabbits. When begun within 2 hours of lewisite exposure, BAL injections of 4 mg/kg every 4 hours led to a 50% survival of exposed rabbits. This dosing regimen was demonstrated to be one-seventh of the maximum tolerated dose of BAL.¹⁷

The most recent animal studies demonstrate that although BAL increases the LD₅₀ (median lethal dose for 50% of test subjects) of sodium arsenite, the therapeutic index of BAL is low and arsenic redistribution to the brain occurs.^4,6,7,20,37 In these same animal models, succimer and DMPS also increased the LD₅₀ but with a better therapeutic index and without causing redistribution to the brain.^3,4

Ophthalmic damage caused by lewisite is partly a result of the liberation of hydrochloric acid, which results in an acid injury causing localized superficial opacity of the cornea and deep penetration of lewisite into the cornea and aqueous humor with resultant rapid necrosis. In an experimental model, a 5% BAL ointment or solution applied within 2 minutes of exposure prevented the development of a significant reaction; application at 30 minutes limited the reaction, but did not prevent permanent damage.²¹

Human Studies

Experiments in human volunteers who were given minute amounts of arsenic demonstrated that BAL increased urinary arsenic concentration by approximately 40%, with maximum excretion occurring 2 to 4 hours after BAL administration.⁴⁴ BAL was subsequently used in the treatment of arsenical dermatitis resulting from organic arsenicals used to treat syphilis. When applied to affected skin, topical BAL produced erythema, pruritus, and dysesthesias, but it had no adverse effects on unaffected skin. IM BAL produced both subjective and objective improvement, limited the duration of the arsenical dermatitis, and increased urinary arsenic elimination.^13,27,28

In a study of 227 patients with inorganic arsenic poisoning, maximal efficacy and minimal toxicity were achieved when 3 mg/kg of BAL was administered IM every 4 hours for 48 hours and then twice daily for 7 to 10 days. This regimen resulted in complete recovery in six of seven patients with severe arsenic-induced encephalopathy and demonstrated the importance of administering BAL as soon as possible after the exposure. Of 33 patients with severe arsenic-induced encephalopathy, 18 of 24 (75%) treated within 6 hours survived, versus only four of nine (44%) treated after a delay of at least 72 hours.¹⁶ Furthermore, the effectiveness of BAL was also demonstrated in three patients who were treated successfully after mistakenly receiving 10 to 20 times the therapeutic dose of oxophenarsine hydrochloride (Mapharsen). A fourth patient, treated with inadequate doses of BAL, died.¹⁶ These cases support the effectiveness of BAL in treating arsenic-induced agranulocytosis, encephalopathy, dermatitis, and probably arsenical fever.¹⁵

When BAL first became more widely available, 42 children were treated following arsenic ingestions, and their results were compared with a historical group of 111 untreated children who had also ingested arsenic.⁴⁵ The percentage of children exhibiting symptoms on presentation were similar between groups (46%), but in the group of children treated with BAL there were fewer deaths (zero versus three), a shorter average hospital stay (1.6 versus 4.2 days), and fewer cases of persistent symptoms at 12 hours (0% versus 29.3%).

Because mercury also reacts with sulfhydryl groups, animal studies were performed to assess the affinity and ability of thiols to competitively chelate inorganic mercury and prevent toxicity. As in the case of arsenic, the dithiol BAL was more effective than the monothiol 1-thiosorbitol in preventing mercury-induced death and uremia.¹⁹ The clinical efficacy of BAL in treating inorganic mercury poisoning was substantiated in patients who ingested mercuric chloride.^25,26 Thirty-eight patients ingesting more than 1 g of mercuric chloride who were treated with BAL within 4 hours of exposure were compared with historical controls.²⁵ There were no deaths in the 38 patients treated with BAL as compared to 27 deaths in the 86 untreated patients. Death typically resulted from hemorrhagic gastritis and kidney failure.²⁵ BAL is particularly useful for patients who have ingested a mercuric salt, as the associated gastrointestinal toxicity of the mercuric salt limits the potential of an orally administered antidote such as succimer.⁴³

Animal models demonstrate that when BAL is administered following poisoning from elemental mercury vapor or exposure to short-chain organic mercury compounds, brain concentrations of mercury may increase.^9,12 As a result BAL therapy is not recommended in these circumstances.^2,5,23 (Chap. 98).

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 treating patients with lead encephalopathy, it is essential to administer the BAL first, followed 4 hours later by CaNa₂EDTA with a second dose of BAL. This regimen prevents the CaNa₂EDTA from redistributing lead into the brain.^14,15 Providing two different chelators also reduces the blood lead concentration significantly faster than either one alone, and maintains a better molar ratio of chelator to lead.¹⁴ Once the mobilization of lead has begun, it is important to provide uninterrupted therapy to prevent redistribution of lead to the brain (Chap. 96).¹⁴

BAL has an LD₅₀ in mice via intraperitoneal administration of 90 to 180 mg/kg, which is significantly lower than that of CaNa₂EDTA at 4000 to 6000 mg/kg, succimer at 2480 mg/kg, and DMPS at 1100 to 1400 mg/kg.²

Less than 1% of 700 IM injections resulted in minor reactions, such as pain at the injection site, among patients who received 2.5 mg/kg of BAL every 4 to 6 hours for 4 doses.¹³ When doses of 4 mg/kg and 5 mg/kg were given, the incidence of adverse effects rose to 14% and 65%, respectively.¹⁶ At these higher doses, the following symptoms were reported 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.²⁷ These effects were maximal within 10 to 30 minutes of exposure and usually subsided within 30 to 50 minutes.¹⁶ Elevations in systolic and diastolic blood pressure and tachycardia commonly occurred and correlated with increasing doses.^23,30 Thirty percent of children given BAL may develop a fever that can persist throughout the therapeutic period.²³ In addition, in children, a transient reduction in the percentage of polymorphonuclear leukocytes may also occur.²³ Doses above 5 mg/kg should not be administered because of the high risk of adverse reactions. Doses above 25 mg/kg can be expected to produce a hypertensive encephalopathy with convulsions and coma.⁴⁵

BAL is not very effective in the presence of arsenic-induced hepatotoxicity.²⁸ Moreover, in rats, preexistent hepatotoxicity was exacerbated when BAL was used for treatment of arsenic poisoning. Therefore, unless the hepatotoxicity is considered to be arsenic induced, hepatic dysfunction is a contraindication to BAL use.³⁵ BAL should not be used for patients poisoned by methylmercury because animal studies demonstrate a redistribution of mercury to the brain.^5,23

Because dissociation of the BAL–metal chelate will occur in acidic urine, the urine of patients receiving BAL should be alkalinized with hypertonic sodium bicarbonate to a pH of 7.5 to 8.0 to prevent kidney liberation of the metal.²³ BAL should be used with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as it may cause hemolysis²²; a risk-to-benefit analysis must be made because G6PD-deficiency syndromes are variably expressed. In addition, chelators are relatively nonspecific and may bind metals other than those desired, thus causing deficiency of an essential metal. For example, BAL given to mice increased copper elimination to three times normal.¹¹ BAL is formulated in peanut oil; therefore, the patient should be questioned regarding any known peanut allergy and a risk-benefit analysis undertaken. Limited evidence suggests that iron supplements should not be given to patients who are receiving BAL because the BAL–iron complex appears to cause severe vomiting and decreases metal chelation.^14,15,18

Unintentional intravenous (IV) infusion of BAL could theoretically produce fat embolism (peanut oil), lipoid pneumonia, chylothorax, and associated hypoxia.³⁸

Pregnancy and Lactation

Dimercaprol is pregnancy category C.⁸ There have not been any animal studies evaluating the effects of BAL on reproduction. It is not known whether BAL is harmful to a fetus or is capable of affecting reproduction capability.⁸ There are no data in human poisoning in pregnancy, and BAL should only be administered to a pregnant woman if clearly indicated.⁸

No data address whether BAL or its chelates are excreted in human breast milk.

No clinical trial has been performed to identify the appropriate dose of BAL. The dosing for BAL is expressed in both mg/m² and mg/kg. BAL should be administered only by deep IM injection. The dose of BAL for lead encephalopathy is 75 mg/m² IM every 4 hours for 5 days in children.^14,15 As noted earlier, the first dose of BAL should precede the first dose of CaNa₂EDTA by 4 hours. Thereafter, IV CaNa₂EDTA, in a dose of 1500 mg/m²/d (up to a maximum of 2–3 g) as a continuous infusion, or divided into two to four doses, should be administered. These daily doses are equimolar. For adults, the dose of BAL is 4 mg/kg every 4 hours.⁸

The dose of BAL for severe inorganic arsenic poisoning has not been established. One regimen suggests the use of 3 mg/kg IM every 4 hours for 48 hours and then twice daily for 7 to 10 days.¹⁶ Another regimen uses 3 to 5 mg/kg IM every 4 to 6 hours on the first day and then tapers the dose and frequency, depending on the patient’s symptomatology. A third regimen reduces the number of injections by day 2 and terminates therapy within 5 to 7 days⁴⁵ (Table A25–1).

The dose of BAL for patients exposed to inorganic mercury salts is 5 mg/kg IM initially, followed by 2.5 mg/kg every 12 to 24 hours until the patient appears clinically improved, up to a total of 10 days.⁸

As noted above, the urine should be kept alkaline to avoid dissociation of the BAL–metal chelate.^10,23

Commercially available BAL is a yellow, viscous liquid with a sulfur odor. It 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.⁸ BAL is for deep IM use only.

• BAL is a metal chelator used clinically in conjunction with CaNa₂EDTA for lead encephalopathy and severe lead toxicity.^23,30

• In this instance, BAL should precede the first dose of CaNa₂EDTA by 4 hours.

• The roles of BAL in arsenic and mercury poisonings are being supplanted by oral succimer and the investigational chelator DMPS, which is indicated unless the gastrointestinal tract is compromised.

References