Monograph of Dimercaprol

Introduction

Dimercaprol, also known as British anti-Lewisite (BAL), represents a pivotal member of the class of dithiol chelating agents employed in the treatment of heavy‑metal intoxication. The compound is chemically designated as 3,3′-dithiodipropionic acid bis(2-ethylhexyl ester), and its therapeutic activity is largely attributable to the presence of two sulfhydryl groups capable of forming stable complexes with divalent and trivalent metal ions. Historically, dimercaprol was discovered during World War II as a protective agent against chemical warfare agents such as Lewisite and subsequently expanded for use in arsenic, mercury, and lead poisoning. Its inclusion in contemporary pharmacotherapy underscores the continuing relevance of chelation strategies in toxicology and pharmacology curricula. The objectives of this chapter are to:

• Describe the chemical and pharmacodynamic properties of dimercaprol.
• Explain the mechanisms by which dimercaprol neutralizes heavy‑metal toxins.
• Outline the pharmacokinetic profile and dosing considerations in clinical practice.
• Illustrate clinical scenarios where dimercaprol is indicated and discuss potential complications.
• Integrate current evidence into the decision‑making process for chelation therapy.

Fundamental Principles

Core Concepts and Definitions

Dimercaprol is a low‑molecular‑weight, water‑soluble chelator characterized by the presence of two vicinal sulfhydryl (–SH) moieties. These groups confer a high affinity for soft metal ions (e.g., arsenic(III), mercury(II), and lead(II)), facilitating the formation of stable thioether complexes. The compound is usually administered intravenously or intramuscularly in an aqueous solution, commonly 20 % (w/v) dimercaprol in sterile water, due to its limited solubility in lipid solvents. The therapeutic action is mediated through the sequestration of free metal ions, rendering them less bioavailable for interaction with critical biomolecules, and promoting renal excretion. Dimercaprol is often used in conjunction with other chelators, such as 2,3‑dimercapto‑1‑propane‑sulfonic acid (DMPS), to enhance overall efficacy and reduce adverse effects.

Theoretical Foundations

The chelation theory underlying dimercaprol activity is predicated on the hard/soft acid–base concept. Soft metal ions possess a high polarizability and low charge density, which favors coordination with soft donor atoms such as sulfur. Dimercaprol’s dithiol configuration offers a bidentate ligand framework that satisfies the coordination number typically required by divalent metals, forming a six‑coordinate octahedral complex. The stability constant (K_stab) for the dimercaprol–arsenic(III) complex is notably high, implying a strong thermodynamic drive to form the chelate and a consequent displacement of metal ions from biological macromolecules. The kinetic inertness of the resulting metal–ligand complex further ensures that once formed, the complex remains stable in the physiological milieu, reducing the likelihood of re‑release of the toxic ion.

Key Terminology

• Thiolate – the deprotonated form of a sulfhydryl group, commonly involved in metal binding.
• Complexation – the process by which a ligand forms a coordination complex with a metal ion.
• Chelator – a molecule capable of binding multiple coordination sites on a metal ion.
• Stability Constant (K_stab) – a quantitative measure of the affinity of a ligand for a metal ion.
• Thermodynamic vs. Kinetic Stability – thermodynamic stability refers to the overall favorability of complex formation, while kinetic stability pertains to the resistance of the complex to dissociation over time.

Detailed Explanation

Mechanisms and Processes

Upon systemic administration, dimercaprol rapidly distributes within the vascular compartment and extravascular tissues. The sulfhydryl groups undergo deprotonation to form the thiolate anion, which exhibits a heightened nucleophilicity toward soft metal ions. The binding process can be represented as follows:

Metalⁿ⁺ + (–SH)₂ → Metal–(–S–) + H⁺

In the presence of an excess of dimercaprol, the equilibrium shifts toward the formation of a 1:1 stoichiometric complex, effectively reducing the concentration of free metal ions. The metal–dimercaprol complex is then recognized by renal transport mechanisms and excreted in urine. In addition to the direct metal sequestration, dimercaprol also exhibits antioxidant properties by scavenging reactive oxygen species generated during metal‑induced oxidative stress, thereby mitigating cellular damage. The overall pharmacodynamic effect can therefore be described as a dual action: chelation and antioxidant protection.

Mathematical Relationships

The pharmacokinetic behavior of dimercaprol is conventionally described using a two‑compartment model, characterized by the central (plasma) and peripheral (tissue) compartments. The concentration–time profile in the central compartment can be approximated by the exponential decay equation:

C(t) = C₀ × e^–k_elt

where C₀ denotes the initial concentration immediately post‑administration, k_el is the elimination rate constant, and t represents time. The area under the concentration–time curve (AUC) for dimercaprol is calculated as:

AUC = Dose ÷ Clearance

Given the rapid distribution and elimination of dimercaprol, the half‑life (t_1/2) is typically within the range of 2–4 hours, although it may be extended in cases of severe poisoning due to ongoing metal binding and redistribution.

Factors Affecting the Process

• Metal Load – Higher concentrations of circulating metal ions increase the demand for chelator and can prolong the effective half‑life of dimercaprol.
• pH – The deprotonation of sulfhydryl groups is pH‑dependent; a more alkaline environment favors thiolate formation and enhances metal binding.
• Co‑administered Chelators – Combination therapy with agents such as DMPS can improve overall chelation efficiency and reduce dose‑related adverse events.
• Renal Function – Impaired renal clearance may lead to accumulation of the metal–dimercaprol complex, necessitating dose adjustment or alternative elimination strategies.
• Protein Binding – Although dimercaprol displays limited protein binding, the presence of plasma proteins can modulate free drug concentration and influence pharmacokinetics.

Clinical Significance

Relevance to Drug Therapy

Dimercaprol remains a cornerstone in the management of acute arsenic, mercury, and lead poisoning. Its rapid onset of action and ability to form stable complexes justify its use as a first‑line agent in emergency settings. Additionally, dimercaprol has been employed as an adjunctive therapy in cases of organophosphate pesticide poisoning, where it may mitigate neurotoxic effects by binding to organophosphate metabolites.

Practical Applications

In clinical practice, dimercaprol is typically administered as a 20 % solution, with dosages ranging from 1 mL (0.5 g) IV over 10 minutes, followed by an immediate repeat dose, and then a maintenance infusion of 1 mL/h for 72 hours. The dosage may be adjusted based on patient weight, severity of intoxication, and response to therapy. Monitoring of serum metal concentrations, renal function, and potential adverse effects (e.g., hypotension, tachycardia, nausea) is essential throughout treatment.

Clinical Examples

• Arsenic Overdose – A 32‑year‑old male presented with gastrointestinal distress and seizures following ingestion of an unknown quantity of arsenic trioxide. Immediate administration of dimercaprol, coupled with supportive care, resulted in a rapid decline of serum arsenic levels and resolution of neurological symptoms.
• Mercury Poisoning – An artisanal gold miner exhibited symptoms of tremor and polyneuropathy after prolonged exposure to mercury vapor. Dimercaprol therapy, administered over 48 hours, led to significant improvement in motor function, corroborated by a marked decrease in urinary mercury excretion.
• Lead Toxicity in Chronic Exposure – A child with occupational lead exposure displayed anemia and abdominal pain. Dimercaprol infusion, in conjunction with chelators such as EDTA, was associated with normalization of blood lead levels and amelioration of clinical signs.

Clinical Applications/Examples

Case Scenarios

Case 1: A 45‑year‑old farmer is found unconscious after ingestion of a pesticide containing organophosphates. Initial management includes atropine and pralidoxime; however, persistent cholinergic crisis prompts the addition of dimercaprol to chelate organophosphate metabolites, leading to stabilization of the patient’s respiratory function.

Case 2: A 22‑year‑old laboratory technician develops acute renal failure following accidental exposure to mercury chloride. Dimercaprol infusion is initiated, and renal function gradually improves as the mercury–dimercaprol complex is cleared, illustrating the therapeutic utility of chelation in preventing long‑term organ damage.

Application to Specific Drug Classes

• Organophosphates – Dimercaprol helps to neutralize the active metabolites of organophosphate pesticides, thereby reducing the duration of acetylcholinesterase inhibition.
• Heavy Metals – The agent’s high affinity for arsenic, mercury, and lead makes it indispensable for treating acute intoxication by these metals.
• Metalloenzymes – In cases where metal ions act as cofactors for pathogenic enzymes, dimercaprol can disrupt enzymatic activity by removing the required metal.

Problem‑Solving Approaches

1. Identify the poison based on exposure history and clinical presentation.
2. Measure serum or urinary metal concentrations where feasible.
3. Initiate dimercaprol therapy promptly, following standard dosing protocols.
4. Monitor vital signs, renal function, and serum metal levels at regular intervals.
5. Adjust dosing or switch to alternative chelators (e.g., DMPS, EDTA) if adverse reactions occur or if metal removal proves inadequate.

Summary/Key Points

• Dimercaprol is a dithiol chelating agent with high affinity for arsenic, mercury, and lead.
• Its mechanism of action involves formation of stable metal–thiolate complexes, promoting renal excretion and exhibiting antioxidant effects.
• Pharmacokinetics follow a two‑compartment model with a typical half‑life of 2–4 hours.
• Standard dosing entails a rapid IV bolus followed by continuous infusion over 72 hours.
• Clinical efficacy is evidenced in cases of acute heavy‑metal poisoning and organophosphate exposure, with careful monitoring required to mitigate side effects.
• Dimercaprol is often combined with other chelators to enhance therapeutic outcomes and reduce toxicity.

In conclusion, dimercaprol occupies a critical role in the therapeutic armamentarium against heavy‑metal and certain organophosphate poisonings. Mastery of its pharmacological properties, dosing strategies, and clinical applications equips healthcare professionals to implement evidence‑based chelation therapy effectively and safely.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
7. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.