Dimercaprol

Mechanism of Action

A major protein 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 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. As a result, 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 (IM) 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 depend 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, 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 injection site.[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 most 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 unknown, some have speculated that it may result from removing 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. Therefore, if toxicity presents with dimercaprol, cessation of therapy is recommended until the resolution of symptoms. 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 interprofessional healthcare team members must be aware of the signs and symptoms of acute heavy metal toxicity and the appropriate steps 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 chelation therapy. [Level 4]

Throughout their hospital course, the patient should be monitored 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 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]