Dimercaprol

Article Author:
Lauren Dawn
Article Editor:
Lacey Whited
Updated:
11/24/2019 9:37:35 AM
PubMed Link:
Dimercaprol

Indications

In 1940, Sir Rudolph Albert Peters’ group at the University of Oxford, UK, developed dimercaprol (2,3-dimercapto-1-propanol), also known as British anti-Lewisite (BAL), as an antidote to lewisite, the arsenical chemical weapon used during World War II.[1] Shortly after its development, dimercaprol was also found to be just as effective for other metals such as mercury, gold, lead, and copper.

Prior to the development of penicillamine and trientine, dimercaprol was the only therapy for copper excretion in Wilson disease. However, some have suggested that there may still be a need for short-term therapy with dimercaprol in patients with a severe neurological disability because it can penetrate the blood-brain barrier.[2]

Currently, dimercaprol is FDA-approved in the treatment of the following:

Arsenic

  • Toxic exposure to arsenic and markedly elevated urine arsenic concentrations
  • Arsenic-related skin injuries (e.g., lewisite)[3]

Mercury

  • Acute or chronic elemental mercury exposure with a whole blood mercury concentration or 24-hour urine concentration of ≥ 100 mcg/L
  • Acute inorganic mercury poisoning when whole blood mercury concentration or 24-hour urine concentration is greater than or equal to 100 mcg/L

Gold

  • Gold-induced thrombocytopenia: Injections with gold salts have been used in the treatment of rheumatoid arthritis.

Lead

  • Severe symptomatic lead poisoning, lead encephalopathy, or a whole blood lead concentration above 100 mcg/dL in adults and above 70 mcg/dL in children
  • Dimercaprol is given before calcium disodium edetate, another chelating agent, to prevent redistribution of lead to the brain.[4]
  • The water-soluble derivative of dimercaprol, 2,3-dimercaptosuccinic acid (DMSA), is FDA-approved for the treatment of toxic exposure to lead in children when whole blood concentrations are above 45 mcg/dL, although there have been case reports of its use in adult patients.[5]

The more modern chelating agent DMSA has largely replaced dimercaprol due to its broader therapeutic index and fewer adverse effects. Outside of the United States, another water-soluble derivative of dimercaprol, 2,3-dimercapto-1-propanesulfonic acid (DMPS), is often used instead.

Mechanism of Action

A major protein that is modified by heavy metal toxicity is lipoic acid, which is necessary for pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, leading to the disruption of the citric acid cycle and the accumulation of pyruvic acid.[6]

Dimercaprol is a dithiol that acts by forming a stable five-membered ring between its sulfhydryl groups and certain heavy metals, thereby neutralizing its toxicity and promoting its elimination.

Dimercaprol is more efficacious when given soon after the metal exposure because it is better at preventing enzyme inhibition rather than reactivating enzyme function.

Pharmacokinetics:

Absorption:

Dimercaprol undergoes rapid absorption after deep intramuscular injection. Peak plasma concentration occurs within 30 to 60 minutes.

Distribution:

Dimercaprol is highly lipophilic and readily crosses into the intracellular space. It gets distributed in all tissues, and it is most concentrated in the liver, kidneys, brain, and small intestines.

Metabolism:

Dimercaprol that is not complexed with metal undergoes hepatic metabolism via glucuronidation and gets converted into inactive metabolites.

Excretion:

Dimercaprol has a short half-life and is excreted as an inactive metabolite or complexed with metal. The kidneys mainly eliminate dimercaprol, but a small amount gets eliminated in bile. Dissociation of the bond between the metal and sulfhydryl group can occur in the acidic tubular urine and cause the redistribution of metal into renal tissue. Therefore, it is crucial to maintain a dimercaprol concentration in the plasma that favors the continuous formation and excretion of the stable dimercaprol-metal complex.

Administration

Dimercaprol is administered by a deep intramuscular injection in the top lateral quadrant of the buttocks.

Multiple doses must be given for several days to weeks, and the injection sites alternate between the right and left buttocks, approximately two inches below the previous ones. 

Maintaining an alkaline urine pH is also recommended to protect renal function.

Blood and urine concentrations, alleviation of symptoms, and dimercaprol toxicity are the major factors when determining management with dimercaprol.

Adult Dosing:

Arsenic or gold poisoning (mild): Deep IM: 2.5 mg/kg every 4 hours for 6 doses, then every 6 hours for 4 doses, then every 8 hours for 3 doses, then every 12 hours for 2 doses, followed by once daily for 10 days.

Arsenic or gold poisoning (moderate): Deep IM: 2.5 to 3.5 mg/kg every 4 hours for 6 doses, then every 6 hours for 4 doses, then every 8 hours for 3 doses, then every 12 hours for 2 doses, followed by once daily for 10 days.

Arsenic or gold poisoning (severe): Deep IM: 3.5 to 5 mg/kg every 4 hours for 6 doses, then every 6 hours for 4 doses, then every 8 hours for 3 doses, then every 12 hours for 2 doses, followed by once daily for 10 days [7]

Elemental and inorganic mercury poisoning (moderate to severe): Deep IM: 5 mg/kg every 4 hours for 1 to 2 days, then 2.5 mg/kg 1 to 2 times/day for 10 days

Lead poisoning: Deep IM: 4 mg/kg every 4 hours for 3 days and 2.5 mg/kg for 1 to 4 days; dimercaprol is given in combination with calcium disodium edetate; dimercaprol should be administered first and calcium disodium edetate should be administered at a different site than dimercaprol

Pediatric Dosing:

Arsenic or gold poisoning (mild): Deep IM: 2.5 mg/kg every 4 hours for 6 doses, then every 6 hours for 4 doses, then every 8 hours for 3 doses, then every 12 hours for 2 doses, followed by once daily for 10 days.

Arsenic or gold poisoning (moderate): Deep IM: 2.5 to 3.5 mg/kg every 4 hours for 6 doses, then every 6 hours for 4 doses, then every 8 hours for 3 doses, then every 12 hours for 2 doses, followed by once daily for 10 days.

Arsenic or gold poisoning (severe): Deep IM: 3.5 to 5 mg/kg every 4 hours for 6 doses, then every 6 hours for 4 doses, then every 8 hours for 3 doses, then every 12 hours for 2 doses, followed by once daily for 10 days.

Elemental and inorganic mercury poisoning (moderate to severe): Deep IM: 5 mg/kg every 4 hours for 1 to 2 days, then 2.5 mg/kg 1 to 2 times/day for 10 days

Lead poisoning: 4 mg/kg every 4 hours for 3 days and 2.5 mg/kg for 1 to 4 days; dimercaprol is given in combination with calcium disodium edetate; dimercaprol should be administered first and calcium disodium edetate should be administered at a different site than dimercaprol

Renal impairment: 

No adjustments are needed in the presence of renal disease, but if acute kidney injury develops during treatment, discontinuation of dimercaprol is recommended.

Hepatic impairment:

Except due to arsenic toxicity, dimercaprol is contraindicated in hepatic insufficiency.

Drug interactions:

Iron supplements and preparations should be avoided with dimercaprol therapy. Dimercaprol potentially increases the nephrotoxic effects of iron salts.

Adverse Effects

There are many adverse effects associated with the chelating agent dimercaprol. Signs and symptoms appear to be dependent on dosage and the time between each dose with hypertension, tachycardia, nausea, and vomiting most frequently noted.

Other adverse effects observed are headaches, weakness, abdominal pain, burning sensations in the eyes, nose, and mouth, blepharospasm, lacrimation, salivation, rhinorrhea, sweating, flushing, restlessness, anxiety, chest tightness, and generalized myalgia in children and adults. Fever occurs in 30% of children.[8][1]

The administration of dimercaprol is also very painful due to the repeated deep intramuscular injections, and in many cases, patients have developed hematomas at the site of injection.[9]

Contraindications

Dimercaprol is formulated in peanut oil and is contraindicated in any patient with peanut allergies. Peanut oil is lipid-soluble and was inexpensive when dimercaprol came on the market. There is currently no other FDA-approved solvent for dimercaprol.

Dimercaprol is considered contraindicated in chronic inorganic and organic mercury exposure. Berlin and Rylander reported chronic exposure to organic mercury with dimercaprol therapy doubles the amount of mercury deposited in the brain compared to animals only receiving mercury. Therefore, DMSA is the optimal chelating agent in these cases.[10][11]

Dimercaprol is contraindicated in hepatic insufficiency. In animal studies by Cameron et al., toxic symptoms and death were observed in rabbits and mice with hepatic damage treated with dimercaprol. These results occurred with doses well below the lethal dose in healthy animals.[12] In patients with glucose 6-phosphate dehydrogenase deficiency, treatment with dimercaprol requires extreme caution due to an increased risk of hemolytic anemia.

Monitoring

The narrow therapeutic window of dimercaprol appears to be time and dose-dependent. Case reports have shown that doses above 3 mg/kg dimercaprol given every 4 hours or less will cause adverse effects in up to two-thirds of patients. Thus, toxicity in the majority of patients can be avoided by a dose of less than 3 mg/kg and allowing at least 4 hours between each dose.[13][14]

Several adverse effects have occurred with dimercaprol, such as nausea, vomiting, abdominal pain, tachycardia, hypertension, headache, burning sensation in the eyes, nose, and mouth, diaphoresis, lacrimation, blepharospasm, rhinorrhea, and anxiety. 

While the precise mechanism of toxicity is not known, some have speculated that it may result from the removal of metal from enzymes disrupting their normal function, while others have postulated toxicity occurs when there is excess dimercaprol that remains unbound to the metal in the body.[15][7]

In all the human volunteers and case reports of dimercaprol toxicity, signs and symptoms resolved within 1 to 4 hours after the injections, and no signs of cumulative toxicity occurred with repeated injections.[16] 

Toxicity

There are no antidotes available for dimercaprol. If toxicity presents with dimercaprol, cessation of therapy is the recommended course until resolution of symptoms, and clinical judgment should be used to determine whether to continue, taper off, or discontinue treatment with dimercaprol. 

Enhancing Healthcare Team Outcomes

Heavy metal toxicity is a serious condition that can cause high morbidity and mortality, and prompt management with chelation therapy is crucial in severe cases. [Level 5] All members of the interprofessional healthcare team must be aware of the signs and symptoms of acute heavy metal toxicity and the appropriate steps that are necessary. In suspected or known exposures, the clinician and pharmacist should consult the regional poison control center, and chelating agents such as dimercaprol should be obtained from the facility if not already in supply.

Emergency department physicians, nurses, pharmacists, laboratory technologists, and physicians of other specialties must all work together when coordinating a plan of care for the patient. Whole blood concentrations and 24-hour urine concentrations of arsenic, mercury, gold, or lead are necessary for determining the level of toxicity, the dose of the chelating agent, and monitoring therapy. Other labs to assess hepatic and renal function are also important when managing with chelation therapy. [Level 4] The patient should be monitored throughout their hospital course for signs and symptoms of worsening heavy metal toxicity, adverse effects of dimercaprol or other chelating agents, and the alleviation of symptoms. Nursing can help the team assess the effectiveness of treatment, administer dimercaprol, and report any concerns to the treating clinician. A social worker may also be consulted to assist the patient and family members when dealing with occupational or home exposures. These are only some examples of how working as an interprofessional team can significantly impact the morbidity and mortality of heavy metal toxicity and the appropriate use of dimercaprol. [Level 5]


References

[1] PETERS RA,STOCKEN LA,THOMPSON RH, British anti-lewisite (BAL). Nature. 1945;     [PubMed PMID: 21006485]
[2] Scheinberg IH,Sternlieb I, Treatment of the neurologic manifestations of Wilson's disease. Archives of neurology. 1995 Apr;     [PubMed PMID: 7710368]
[3] Mouret S,Wartelle J,Emorine S,Bertoni M,Nguon N,Cléry-Barraud C,Dorandeu F,Boudry I, Topical efficacy of dimercapto-chelating agents against lewisite-induced skin lesions in SKH-1 hairless mice. Toxicology and applied pharmacology. 2013 Oct 15;     [PubMed PMID: 23806213]
[4] Chisolm JJ Jr, The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. The Journal of pediatrics. 1968 Jul;     [PubMed PMID: 4969284]
[5] Arnold J,Morgan B, Management of Lead Encephalopathy with DMSA After Exposure to Lead-Contaminated Moonshine. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2015 Dec;     [PubMed PMID: 26245877]
[6] Porru S,Alessio L, The use of chelating agents in occupational lead poisoning. Occupational medicine (Oxford, England). 1996 Feb;     [PubMed PMID: 8672793]
[7] WOODY NC,KOMETANI JT, BAL in the treatment of arsenic ingestion of children. Pediatrics. 1948 Mar;     [PubMed PMID: 18908858]
[8] GOLDSTEIN NP,RANDALL RV,GROSS JB,ROSEVEAR JW,McGUCKIN WF, Treatment of Wilson's disease (hepatolenticular degeneration) with DL-penicillamine. Neurology. 1962 Apr;     [PubMed PMID: 13899920]
[9] Kosnett MJ, The role of chelation in the treatment of arsenic and mercury poisoning. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2013 Dec;     [PubMed PMID: 24178900]
[10] BERLIN M,RYLANDER R, INCREASED BRAIN UPTAKE OF MERCURY INDUCED BY 2,3-DIMERCAPTOPROPANOL (BAL) IN MICE EXPOSED TO PHENYLMERCURIC ACETATE. The Journal of pharmacology and experimental therapeutics. 1964 Nov;     [PubMed PMID: 14236935]
[11] Andersen O, Principles and recent developments in chelation treatment of metal intoxication. Chemical reviews. 1999 Sep 8;     [PubMed PMID: 11749497]
[12] Cameron GR,Burgess F,Trenwith VS, The possibility of toxic effects from 2:3-dimercaptopropanol in conditions of impaired renal or hepatic function. British journal of pharmacology and chemotherapy. 1947 Mar;     [PubMed PMID: 19108105]
[13] Bunch TW, Gold overdose treated with BAL. Arthritis and rheumatism. 1976 Jan-Feb;     [PubMed PMID: 1252266]
[14] ZAROWITZ H,NELSON L, A case of acute BAL toxicity during treatment of gold glossitis. New York state journal of medicine. 1949 Aug 15;     [PubMed PMID: 18136352]
[15] Webb EC,Van Heyningen R, The action of British anti-lewisite (BAL) on enzyme systems. The Biochemical journal. 1947;     [PubMed PMID: 16748122]
[16] Sulzberger MB,Baer RL,Kanof A, CLINICAL USES OF 2,3-DIMERCAPTOPROPANOL (BAL). III. STUDIES ON THE TOXICITY OF BAL ON PERCUTANEOUS AND PARENTERAL ADMINISTRATION. The Journal of clinical investigation. 1946 Jul;     [PubMed PMID: 16695340]