A: Review of Medical Pharmacology, 7th ed. Originally published by Lange Medical Publications. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.) arsenic-containing warfare agent lewisite. It thus became known as British anti-lewisite, or BAL. Because aqueous solutions of dimercaprol are unstable and oxidize readily, it is dispensed in 10% solution in peanut oil and must be administered by intramuscular injection, which is often painful.
In animal models, dimercaprol prevents and reverses arsenic-induced inhibition of sulfhydryl-containing enzymes and, if given soon after exposure, may protect against the lethal effects of inorganic and organic arsenicals. Human data indicate that it can increase the rate of excretion of arsenic and lead and may offer therapeutic benefit in the treatment of acute intoxication by arsenic, lead, and mercury.
Dimercaprol is FDA approved as single-agent treatment of acute poisoning by arsenic and inorganic mercury and for the treatment of severe lead poisoning when used in conjunction with edetate calcium disodium (EDTA; see below). Although studies of its metabolism in humans are limited, intramuscularly administered dimercaprol appears to be readily absorbed, metabolized, and excreted by the kidney within 4–8 hours. Animal models indicate that it may also undergo biliary excretion, but the role of this excretory route in humans and other details of its biotransformation are uncertain.
When used in therapeutic doses, dimercaprol is associated with a high incidence of adverse effects, including hypertension, tachycardia, nausea, vomiting, lacrimation, salivation, fever (particularly in children), and pain at the injection site. Its use has also been associated with thrombocytopenia and increased prothrombin time—factors that may limit intramuscular injection because of the risk of hematoma formation at the injection site. Despite its protective effects in acutely intoxicated animals, dimercaprol may redistribute arsenic and mercury to the central nervous system, and it is not advocated for treatment of chronic poisoning. Water-soluble analogs of dimercaprol—unithiol and succimer—have higher therapeutic indices and have replaced dimercaprol in many settings.
SUCCIMER (DIMERCAPTOSUCCINIC ACID, DMSA)
Succimer is a water-soluble analog of dimercaprol, and like that agent it has been shown in animal studies to prevent and reverse metal-induced inhibition of sulfhydryl-containing enzymes and to protect against the acute lethal effects of arsenic. In humans, treatment with succimer is associated with an increase in urinary lead excretion and a decrease in blood lead concentration. It may also decrease the mercury content of the kidney, a key target organ of inorganic mercury salts. In the USA, succimer is formulated exclusively for oral use, but intravenous formulations have been used successfully elsewhere. It is absorbed rapidly but somewhat variably after oral administration. Peak blood levels of succimer occur at approximately 3 hours. The drug binds in vivo to the amino acid cysteine to form 1:1 and 1:2 mixed disulfides, possibly in the kidney, and it may be these complexes that are the active chelating moieties. Experimental data suggest that multidrug-resistance protein 2 (Mrp2), one of a group of transporter proteins involved in the cellular excretion of xenobiotics, facilitates the renal excretion of mercury compounds that are bound to the transformed succimer and to unithiol. The elimination half-time of transformed succimer is approximately 2–4 hours.