Pharmacology

Pharmacology. Chemically, British anti-Lewisite is 2,3-dimercaptopropanol. It is a viscous, oily liquid with the offensive odor of mercaptans. It is moderately soluble in water but highly soluble in vegetable oils. British anti-Lewisite is a dithiol compound highly reactive with arsenic and other heavy metal compounds. It has a higher affinity for these compounds than body lipids (20; 31). Because British anti-Lewisite is unstable and susceptible to oxidation, there are storage difficulties as a ready-to-use preparation (02).

British anti-Lewisite is administered intramuscularly. More than 50% of those receiving British anti-Lewisite suffer side effects, most of which are not serious and abate with discontinuation of treatment.

Pharmacodynamics. British anti-Lewisite contains two sulfhydryl groups that react to form a stable, generally nontoxic chelate with heavy metals, particularly arsenic, mercury, lead, and tin. The combined compound prevents the metal from reacting with sulfhydryl groups in physiological proteins and thereby renders them inert until they are excreted.

Pharmacokinetics. British anti-Lewisite is most effective when injected soon after exposure, because it more effectively prevents inhibition of sulfhydryl enzymes than reactivation of them (05). Peak blood levels occur within 30 to 60 minutes of intramuscular injection. Highest concentration is in the liver and kidneys. Animal data suggest that 40% to 60% is excreted in urine within 6 to 24 hours. Half-life is short – excretion by 4 hours.

Indications

FDA-approved uses of British anti-Lewisite are for treatment of mild and severe arsenic toxicity, mild and severe gold toxicity, mild and severe lead poisoning (when used concomitantly with EDTA injection), and acute mercury toxicity. Chelating treatment should be started as quickly as possible, as efficacy declines rapidly as the time interval between metal poisoning and treatment increases (16).

Mückter and colleagues, in 1997, published an intriguing article titled, “Are we ready to replace dimercaprol (BAL) as an arsenic antidote?” (21). The authors concluded that whereas two hydrophilic British anti-Lewisite derivatives (2,3,dimercaptopropane-1-sulphonate sodium [DMPS] and meso-2-3-dimercaptosuccinic acid [DMSA]) are less toxic than British anti-Lewisite and approved in several countries, in time-critical situations British anti-Lewisite may be more effective than these two compounds in restoring cellular function.

A 2004 report described the use of British anti-Lewisite in acute lead poisoning in a 4-year-old boy following ingestion of a lead-containing toy medallion. The child was treated with British anti-Lewisite and EDTA, which rapidly reduced his blood lead levels from 123 µg/dL to 57 µg/dL. He was then switched to other chelators to reduce his blood lead level still further (29). A report described using British anti-Lewisite for intentional arsenic trioxide ingestion and for intentional mercuric chloride ingestion (35). In the first case, British anti-Lewisite (5 mg/kg) was given every 6 hours for 48 hours by deep intramuscular injection. After the first dose the patient complained of a burning sensation in the lips, throat, and mouth; lacrimation; rhinorrhea; sweating; and nausea. After a dose adjustment to 3 mg/kg every 6 hours and later to every 12 hours, there were no further adverse effects. The second patient was treated by 3 mg/k British anti-Lewisite every 4 hours for 5 days. The patient developed a rash that was thought to be related to a peanut allergy and not directly to British anti-Lewisite. Both of these patients purchased their metal powders on the internet. It was concluded that the knowledge of aggressive decontamination, presumably using British anti-Lewisite, is essential. British anti-Lewisite is still being successfully used in patients with lead poisoning. Vossoughinia and colleagues treated a 19-year-old woman with severe abdominal pain, icterus, and anemia (32). The patient did not respond to oral chelators, so parenteral dimercaprol and calcium ethylenediaminetetraacetic acid (EDTA) was given. The patient responded dramatically after 5 days of treatment.

British anti-Lewisite is also a third-line alternative in the treatment of Wilson disease in patients intolerant to penicillamine and trientine. British anti-Lewisite has been reported effective in controlling unilateral rubral tremors in patients with Wilson disease refractory to 1-year therapy with penicillamine and anti-tremor medications. The tremors decreased considerably after adding dimercaprol (09).

Retained shrapnel is an uncommon cause of systemic lead toxicity. Lead foreign bodies in joint spaces may be a source of systemic lead absorption, causing elevated blood lead levels. In such patients, chelation therapy with dimercaprol can bring significant clinical improvement. Dimercaprol (British anti-Lewisite) crosses the blood-brain barrier, and chelate central nervous system lead as well (14; 18; 37).

Dimercaprol compounds are helpful in treatment of mercury and arsenic toxicities as well (15). A patient with altered mental status, hyponatremia, and abnormal thyroid functions was diagnosed to have mercury poisoning (07). Blood Hg level was greater than 9 ng/mL. Following chelating therapy with 2,3-dimercaptopropane-1-sulfonate of 8 months duration, the patient improved remarkably. Another patient ingested 37.5 g of arsenic for suicide, but prompt chelating therapy with 2,3-dimercaptopropane-1-sulphonate resulted in complete recovery (17). With early treatment, development of peripheral neuropathy was prevented.

Mobilization of cerebral deposits of mercury in chronic toxicities is difficult to achieve. Newer information indicates that a combination of low-dosed British anti-Lewisite plus dimercaptopropane sulfonic acid can help in mobilizing cerebral mercury into the blood circulation, which can result in prompt removal from body via urinary excretion (04).

In an isolated case, dimercaprol was found effective in a pregnant patient with bismuth intoxication (08). In an adolescent pregnant girl who developed acute kidney injury due to an overdose of colloidal bismuth subcitrate administration of parenteral chelating agent dimercaprol for 14 days resulted in complete clinical reversal. She gave birth to a healthy baby as well.

Cobalt-containing alloys in orthopedic implants, such as hip replacements, release cobalt ions causing local and systemic toxicity. This leads to complications requiring complex revision surgeries. To address this, a synovial fluid-mimicking chelator composed of hyaluronic acid functionalized with British anti-Lewisite (BAL-HA), was developed. BAL-HA effectively binds cobalt, improving cell vitality and accelerating cobalt clearance. This biocompatible chelator, injectable into the joint, shows promise in reducing cobalt toxicity from metal-on-metal implants without risking kidney failure (28).

In in vitro testing, it has been observed that dimercaprol has a potential to treat snakebite. Viper snake envenomation leads to a profound coagulopathy and systemic hemorrhage. Coagulopathy is mediated by Zn2+-dependent metalloproteinases. Dimercaprol, a metal ion chelator, has an in vitro activity against this enzyme. Administration of dimercaprol also provided survival benefits in murine preclinical models of viper snakebites (01; 38). Unfortunately, dimercaprol and 2,3-Dimercapto-1-propanesulfonic acid (DMPS) in preclinical murine models failed to demonstrate sufficient potency against Dispholidus typus (boomslang) venom-induced consumption coagulopathy (19).

Experimental observations revealed that dimercaprol may be an effective neuroprotective agent. Acrolein is a toxic byproduct of lipid peroxidation, and it has been shown to be associated with neuropathogenesis in spinal cord injury, multiple sclerosis, and Alzheimer disease. Suppressing acrolein using acrolein scavengers has been noted as a novel strategy of neuroprotection. Dimercaprol, when administered through intraperitoneal injection, significantly reduces acrolein contents in spinal cord following a spinal cord injury in rats. Spinal cord injury in rats is a condition known to produce increased acrolein concentration (27). In another experimental study, a combination of arsenic trioxide and dimercaprol has been found a promising enhancer of radiosensitivity in mice with pancreatic cancer xenografts (26).

Contraindications

The following are contraindications for the use of British anti-Lewisite:

Goals and duration of treatment

The goal of treatment with British anti-Lewisite is the excretion of the poisonous metal. Treatment should be discontinued when blood levels of the metal reach safe levels, or at approximately 10 days.

Dosing

British anti-Lewisite is applied by deep intramuscular injections of 2 to 5 mg/kg, one to four times per day for up to 10 days. Specific dosages vary depending on the intoxicating metal.

Special considerations

Pediatric. British anti-Lewisite is recommended for use in both children and adults at similar dosing levels. Fever is a more likely side effect in children than in adults and a temporary reduction in polymorphonuclear leukocytes may also be seen in children.

Geriatric. There is no information available on the use of British anti-Lewisite in geriatric patients.

Pregnancy. British anti-Lewisite should not be used during pregnancy unless the condition is life-threatening. It is not known if British anti-Lewisite is present in breast milk.

G6PD deficiency. Patients with G6PD deficiency should not be treated with British anti-Lewisite unless the condition is life-threatening.

Organic mercury poisoning. In cases with organic mercury poisoning, British anti-Lewisite enhances distribution of mercury to the brain.

Interactions

Concurrent administration of medicinal iron should be discontinued during treatment with British anti-Lewisite.

Adverse effects

The common adverse effects of British anti-Lewisite are fever, sweating, headache, nausea, vomiting, increased blood pressure, tachycardia, pain and sterile abscess at the injection site, conjunctivitis, and convulsions (24).