Pharmacology of Dimercaprol

Introduction/Overview

Dimercaprol, historically known as British Anti-Lewisite (BAL), represents a foundational agent in the therapeutic armamentarium for acute heavy metal poisoning. Developed during World War II as an antidote against the arsenical warfare agent lewisite, its utility has since expanded to encompass the treatment of poisoning by other toxic metals. As a dithiol chelating agent, dimercaprol functions by forming stable, non-toxic complexes with specific metal ions, facilitating their excretion from the body and preventing their interaction with critical cellular enzymes. The clinical relevance of dimercaprol persists despite the development of newer chelators, as it remains a first-line agent for certain severe intoxications, particularly those involving arsenic and mercury. Its use is characterized by a narrow therapeutic index and a significant adverse effect profile, necessitating precise clinical knowledge for safe and effective application.

Learning Objectives

• Describe the chemical structure of dimercaprol and explain its classification as a dithiol chelating agent.
• Elucidate the molecular mechanism by which dimercaprol binds to heavy metals and facilitates detoxification.
• Analyze the pharmacokinetic profile of dimercaprol, including its absorption, distribution, metabolism, and excretion.
• Identify the approved clinical indications for dimercaprol therapy and discuss its role in the management of specific heavy metal poisonings.
• Evaluate the major adverse effects, contraindications, and drug interactions associated with dimercaprol, and apply this knowledge to special patient populations.

Classification

Dimercaprol is definitively classified within the broad category of chelating agents or antidotes. More specifically, it belongs to the chemical and pharmacological class of dithiol compounds. This classification is based on its molecular structure, which contains two sulfhydryl (-SH) groups on adjacent carbon atoms. These thiol groups are the functional moieties responsible for its metal-chelating activity. Unlike monothiol agents such as N-acetylcysteine, the proximity of the two thiol groups in dimercaprol allows for the formation of particularly stable, heterocyclic ring complexes with specific “soft” metal ions that have high affinity for sulfur. It is not classified among the more modern synthetic aminopolycarboxylate chelators like EDTA or DTPA, which primarily target “hard” metal ions like lead and plutonium. The pharmacological action of dimercaprol is thus intrinsically linked to its chemical identity as a dithiol.

Mechanism of Action

The pharmacodynamic action of dimercaprol is centered on its ability to chelate, or bind, toxic heavy metal ions. This process prevents the metals from exerting their toxic effects and promotes their elimination from the body.

Molecular and Cellular Mechanisms

The mechanism operates at the molecular level through the formation of stable, water-soluble complexes between the sulfhydryl groups of dimercaprol and the metal cation. Metals such as arsenic, mercury, and gold exert toxicity primarily by binding to and inhibiting essential sulfhydryl-containing enzymes, particularly those involved in cellular energy production (e.g., pyruvate dehydrogenase) and antioxidant defense (e.g., glutathione). The affinity of dimercaprol’s thiol groups for these metals is greater than the affinity of the endogenous enzyme thiol groups. Consequently, dimercaprol competes effectively for the metal, displacing it from the inhibited enzymes and restoring their function. The resulting dimercaprol-metal complex is relatively non-toxic and is excreted predominantly in the urine.

The stoichiometry of binding is crucial. For trivalent arsenicals (As³⁺), a single arsenic atom typically binds to two molecules of dimercaprol, forming a stable 2:1 complex. For other metals, the ratio may vary. The chelation reaction can be represented conceptually as: R-(SH)₂ + M²⁺/³⁺ → R-S-M-S-R + 2H⁺, where R represents the dimercaprol backbone and M the metal ion. This reaction not only inactivates the metal but also mobilizes it from tissue storage sites, primarily the liver, kidneys, and nervous system, into the bloodstream for subsequent renal elimination. It is critical to recognize that dimercaprol does not reverse established tissue damage but prevents further intoxication and allows for natural repair processes to occur.

Spectrum of Activity

The efficacy of dimercaprol is highly metal-specific. It demonstrates the highest affinity for trivalent arsenicals (inorganic arsenic, lewisite) and inorganic mercury salts. Its activity against gold is also well-established. It has variable and less reliable efficacy against other metals. For instance, while it can chelate lead, it is generally not the agent of choice due to the potential for redistributing lead to the brain and its inferior efficacy compared to succimer (DMSA) or EDTA. Its utility in cadmium poisoning is limited because the dimercaprol-cadmium complex is nephrotoxic. It is ineffective against selenium and is contraindicated in iron poisoning, as the dimercaprol-iron complex is itself toxic.

Pharmacokinetics

The pharmacokinetic profile of dimercaprol is a critical determinant of its dosing regimen, therapeutic efficacy, and toxicity. Its properties necessitate parenteral administration and influence the frequency of dosing.

Absorption

Dimercaprol is not effectively absorbed from the gastrointestinal tract. Oral administration results in poor bioavailability and is not clinically useful. Consequently, it must be administered via deep intramuscular injection. Following intramuscular injection, absorption into the systemic circulation is rapid, with therapeutic blood levels being achieved within 30 to 60 minutes. The oily preparation in which it is formulated (typically in peanut oil with benzyl benzoate) is designed to prolong its release from the injection site, though the absolute bioavailability via this route is considered to be high.

Distribution

Dimercaprol distributes widely throughout all tissues, including the central nervous system. Its lipid solubility facilitates penetration across the blood-brain barrier, which is a significant advantage in treating heavy metal poisoning that affects the CNS, such as from organic mercury compounds. The volume of distribution is large, reflecting this extensive tissue penetration. The drug and its metal complexes are found in highest concentrations in tissues that are rich in the target metals, namely the liver, kidneys, brain, and intestinal wall. The distribution phase is rapid, and equilibrium between plasma and tissues is established quickly post-administration.

Metabolism and Excretion

Dimercaprol undergoes minimal hepatic metabolism. The primary route of elimination for both the free drug and its metal complexes is renal excretion. The intact dimercaprol-metal complex is excreted in the urine. A small fraction may be excreted in the bile. The elimination is relatively rapid. The plasma half-life (t_1/2) of dimercaprol is short, approximately 4 to 6 hours following a single intramuscular dose. This short half-life is the rationale behind the frequent dosing intervals required during initial therapy (e.g., every 4-6 hours). The elimination kinetics can be described by a one-compartment model: C(t) = C₀ × e⁻ᵏᵗ, where k_el is the elimination rate constant. Clearance is primarily renal, and thus, urinary output must be monitored and maintained during therapy to ensure excretion of the toxic complexes.

Therapeutic Uses/Clinical Applications

The use of dimercaprol is reserved for specific, often severe, cases of heavy metal poisoning. Its application is guided by the type of metal involved, the severity of poisoning, and the timing of intervention.

Approved Indications

The primary approved indications for dimercaprol are as follows:

• Acute Arsenic Poisoning: This remains a cardinal indication. Dimercaprol is effective against poisoning by inorganic trivalent arsenic compounds, which are potent enzyme inhibitors. It is most effective when administered soon after exposure, ideally within hours. In severe cases, it is often used in combination with other supportive measures and sometimes followed by oral succimer for continued chelation.
• Mercury Poisoning: Dimercaprol is indicated for acute, severe poisoning by inorganic mercury salts. Its efficacy in poisoning by elemental mercury vapor is less clear. For organic mercury poisoning (e.g., methylmercury), its ability to cross the blood-brain barrier is advantageous, but its use may be controversial due to the risk of redistributing mercury within the CNS; other agents like succimer may be preferred.
• Gold Poisoning: It is used in the treatment of toxicity resulting from gold therapy (chrysotherapy) for rheumatoid arthritis, particularly in cases of severe dermatitis, nephrotoxicity, or hematologic toxicity.
• Lead Poisoning (in combination): While not a first-line monotherapy, dimercaprol is used in conjunction with calcium disodium edetate (CaNa₂EDTA) for the treatment of severe, symptomatic lead encephalopathy, particularly in children. The dimercaprol is believed to chelate lead in soft tissues and the brain, while EDTA chelates lead from the blood and bone. This combination is initiated before EDTA monotherapy in encephalopathic patients to theoretically prevent the redistribution of lead to the brain.

Off-Label and Historical Uses

Historically, dimercaprol was investigated for other metal poisonings, but its use has been supplanted or is contraindicated. It has been used for acute antimony and bismuth poisoning, though evidence is limited. Its use in Wilson’s disease (copper overload) has been superseded by more effective and less toxic agents like D-penicillamine and trientine. As noted, it is contraindicated in cadmium, iron, and selenium poisoning due to the formation of toxic complexes or lack of efficacy.

Adverse Effects

The adverse effect profile of dimercaprol is substantial and occurs with high frequency, even at therapeutic doses. These effects are often dose-dependent and may limit therapy.

Common Side Effects

A multitude of effects are commonly observed. These include:

• Local Reactions: Pain, tenderness, and sterile abscess formation at the intramuscular injection site are frequent due to the oily vehicle.
• Systemic Reactions: A constellation of symptoms often described as a “BAL reaction” can occur within minutes to hours of administration. This includes hypertension with tachycardia, nausea and vomiting, headache, burning sensation in the lips and mouth, a feeling of constriction in the chest and throat, lacrimation, rhinorrhea, salivation, and sweating. Fever may also occur, particularly in children.
• Other Frequent Effects: Anxiety, restlessness, and paresthesias are common. A garlic-like odor on the breath is characteristic due to the excretion of volatile sulfur compounds.

Serious and Rare Adverse Reactions

More severe reactions necessitate careful monitoring:

• Renal Toxicity: The dimercaprol-metal complexes can be nephrotoxic. This may manifest as proteinuria, hematuria, or a rise in serum creatinine. Maintaining adequate hydration and urine output is essential to mitigate this risk.
• Hepatic Toxicity: Elevations in liver transaminases and, rarely, frank hepatitis have been reported.
• Hematologic Effects: Neutropenia and hemolytic anemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, can occur.
• Neurological Effects: Seizures have been reported, particularly with high doses. Muscle spasms or pain may also occur.

There are no formal FDA black box warnings for dimercaprol, but its significant toxicity profile is prominently featured in its prescribing information. Contraindications include hepatic insufficiency (unless due to the metal poisoning itself), pre-existing renal disease, and known hypersensitivity to the drug or its peanut oil vehicle.

Drug Interactions

Concurrent use of dimercaprol with other agents requires caution due to potential interactions that may enhance toxicity or reduce efficacy.

Major Drug-Drug Interactions

• Iron Supplements and Iron-Containing Preparations: This is a critical contraindication. The dimercaprol-iron complex is highly toxic and can lead to serious adverse effects. Iron therapy must be withheld during dimercaprol treatment.
• Other Metal-Ion Containing Agents: Concurrent use with other chelatable metals (e.g., medicinal gold, selenium, cadmium) should be avoided, as dimercaprol may mobilize these metals and potentially increase their toxicity or form toxic complexes.
• G6PD Deficiency-Inducing Drugs: In patients with G6PD deficiency, drugs known to precipitate hemolysis (e.g., sulfonamides, nitrofurantoin, primaquine) should be used with extreme caution alongside dimercaprol, as the combination may increase the risk of hemolytic anemia.
• Antihypertensive Medications: Since dimercaprol can cause hypertension, the effects of antihypertensive drugs may be antagonized. Blood pressure requires close monitoring.

Contraindications

Absolute contraindications to dimercaprol therapy include:

1. Known hypersensitivity to dimercaprol or peanut oil (a common excipient).
2. Established severe hepatic disease not attributable to the metal poisoning.
3. Concurrent iron supplementation or iron overload states.
4. Poisoning with metals for which the dimercaprol complex is toxic (cadmium, selenium, uranium).

Relative contraindications include pre-existing renal impairment, hypertension, and G6PD deficiency, where the risks and benefits must be carefully weighed.

Special Considerations

The use of dimercaprol in specific patient populations requires tailored risk-benefit analysis and dosage adjustments.

Pregnancy and Lactation

Dimercaprol is classified as a Pregnancy Category C drug. Animal reproduction studies have not been conducted, and there are no adequate and well-controlled studies in pregnant women. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In cases of life-threatening maternal arsenic or mercury poisoning, treatment would likely be indicated. It is not known whether dimercaprol is excreted in human milk. Given the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric and Geriatric Considerations

In pediatric patients, dimercaprol is used with the same indications, particularly in severe lead encephalopathy in combination with EDTA. Dosage is typically weight-based (mg/kg). Children may be more prone to fever as a side effect. In geriatric patients, age-related declines in renal and hepatic function may alter pharmacokinetics and increase the risk of toxicity. Dose selection should be cautious, starting at the low end of the dosing range, and renal function must be closely monitored.

Renal and Hepatic Impairment

Renal Impairment: Dimercaprol and its metal complexes are renally excreted. In patients with pre-existing renal disease, the risk of nephrotoxicity is heightened, and excretion may be impaired, leading to drug and toxic metal accumulation. If use is unavoidable in a patient with renal impairment due to life-threatening poisoning, dosage reduction and extremely close monitoring of renal function and fluid balance are mandatory. Hemodialysis does not effectively remove the dimercaprol-metal complexes.

Hepatic Impairment: Dimercaprol is contraindicated in patients with significant hepatic disease, except when the hepatic damage is a result of the metal poisoning being treated. In such cases, the benefit of chelation may outweigh the risk of further hepatic insult. Liver function tests should be monitored serially during therapy.

Summary/Key Points

Dimercaprol is a critical, though challenging, agent in clinical toxicology.

• Dimercaprol (BAL) is a dithiol chelating agent used primarily for acute, severe poisoning by arsenic, mercury, and gold.
• Its mechanism involves the formation of stable, water-soluble complexes with toxic metal ions via its two sulfhydryl groups, displacing the metals from inhibited enzymes and promoting renal excretion.
• Pharmacokinetically, it requires deep intramuscular administration, distributes widely including into the CNS, has a short half-life (~4-6 hours), and is excreted renally as the metal complex.
• Therapeutic applications are specific: it is a first-line agent for severe arsenic poisoning, used for inorganic mercury and gold toxicity, and employed in combination with EDTA for lead encephalopathy.
• The adverse effect profile is significant and frequent, including injection site pain, hypertension, nausea, fever, and potential renal and hepatic toxicity. Contraindications include iron therapy and peanut allergy.
• Special caution is required in patients with renal or hepatic impairment, G6PD deficiency, and in pregnant or lactating women.

Clinical Pearls

• Therapy is most effective when initiated as soon as possible after metal exposure.
• Administration is via deep IM injection in a peanut oil base; ensure the patient has no peanut allergy.
• Monitor vital signs (especially blood pressure), renal function, and fluid balance closely during therapy. Pre-treatment and post-treatment urine metal levels can guide therapy.
• Always maintain adequate hydration and urine output to facilitate excretion of the chelate and reduce nephrotoxicity.
• In severe lead encephalopathy, the standard protocol involves administering dimercaprol first, followed several hours later by the first dose of CaNa₂EDTA, to prevent lead redistribution to the brain.
• Be prepared to manage the common “BAL reaction” with supportive care; these symptoms are often self-limiting.

References

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