Dimercaprol excretion

Unithiol and succimer increase urine mercury excretion following acute or chronic elemental mercury inhalation, but the impact of such treatment on clinical outcome is unknown. Dimercaprol has been shown to redistribute mercury to the central nervous system from other tissue sites, and since the brain is a key target organ, dimercaprol should not be used in treatment of exposure to elemental or organic mercury. Limited data suggest that succimer, unithiol, and N- acetyl-L-cysteine (NAC) may enhance body clearance of methylmercury. 

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. 

They act on the kidney by depressing the mechanisms that govern the active reabsorption of sodium and chloride ions. They are rapidly excreted by the kidney but their use is hazardous because their action is believed to be due to inorganic mercury ions released by rupture of the carbon-to-mercury bond, probably followed by the firm attachment of the mercury ion to a sulphydryl group of a renal enzyme. The administration of dimercaprol (SO), a strong chelating agent for mercury, removes mercury from the kidney and terminates the diuretic action. It is of interest that Paracelsus used calomel (mercurous chloride) as a diuretic. 

Dimercaprol (British Anti-Lewisite, BAL). Arsenic and other metal ions are toxic in low concentration because they combine with the SH groups of essential enzymes, thus inactivating them. Dimercaprol provides SH groups which combine with the metal ions to form relatively harmless ring compounds which are excreted, mainly in the urine. As dimercaprol, itself, is oxidised in the body and renally excreted, repeated administration is necessary to ensure that an excess is available imtil all the metal has been eliminated. 

Sodium calciumedetate is the calcium chelate of the disodium salt of ethylenediaminetetra-acetic acid (calcium EDTA). It is effective in acute lead poisoning because of its capacity to exchange calcium for lead the lead chelate is excreted in the urine, leaving behind a harmless amount of calcium. Dimercaprol may usefully be combined with sodium calciumedetate when lead poisoning is severe, e.g. with encephalopathy. 

In severe lead poisoning sodium calciumedetate is commonly used to initiate lead excretion. It chelates lead from bone and the extracellular space and urinary lead excretion of diminishes over 5 days thereafter as the extracellular store is exhausted. Subsequently symptoms (colic and encephalopathy) may worsen and this has been attributed to redistribution of lead from bone to brain. Dimercaprol is more effective than sodium calciumedetate at chelating lead from the soft tissues such as brain, which is the rationale for combined therapy with sodium calciumedetate. More recently succimer (2,3-dimercaptosuccinic acid, DMSA), a water-soluble analogue of dimercaprol, has been increasingly used instead. Succimer has a high affinity for lead, is suitable for administration by mouth and is better tolerated (has a wider therapeutic index) than dimercaprol. It is licenced for such use in the USA but not the UK. 

If the BAL-metal complex is oxidized, the metal is released and can exert its toxic effect again therefore, the dosage of dimercaprol must be high enough to ensure the excess of free BAL in body fluids until the metal is completely excreted. 

The heavy-metal chelating properties of thiols were taken advantage of in the design of dimercaprol ( British Anti-Lewisite, BAL) as counter poison of the arsenical war gas lewisite (Figure 20.43). Today dimercaprol is used to treat poisoning by compounds of gold, mercury, antimony and arsenic. The toxic nature of the heavy metals is masked and chelate is stable enough to be excreted as such in the urine. 

Enhanced excretion of vanadium was achieved with chelation therapy provided by deferoxamine mesylate (DFOA) (Gomez et al. 1988). Humans or animals with vanadium poisoning have not been helped by the chelating agent dimercaprol (BAL), which is often effective in lessening the toxicity of other metals (Lusky et al. 1949). Intraperitoneal injections of ascorbic acid and of ethylene diamine tetraacetate (EDTA) reduced vanadium-induced morbidity in mice and rats (Jones and Basinger 1983 Mitchell and Floyd 1954). 

DMPS and DMSA can be used to increase Hg excretion. Dimercaprol (BAL), used in the past for chelation, is contraindicated because it redistributes Hg to the brain. 

Treatment of acute and chronic arsenic poisoning is by supportive treatment and enhancement of excretion using initially a dimercaprol-typechelatingagent and. once symptoms have subsided. N-acetyl-penicillaminc. In ca.ses of renal failure, arsenic may be removed by haemodialysis. 

Lead is measured in whole blood or in urine (Table 1). Excretion can be enhanced using any of the chelating agents NaCaEDTA. dimercaprol or N-acetyl-pcnicillamine. but may require to be prolonged in order to deplete bone stores. 

Treatment of acute mercury poisoning is by use of the dimercaprol chelating agents which leads to excretion via both bile and urine. Chronic exptisure is best treated with N-aceiyl-penicillamine. unless renal function is compromised. 

Besides stopping the exposure to mercury and medically treating the symptoms, as in cases of acute or chronic mercury intoxication, the renal and fecal excretion of mercury may be increased by the application of a chelating agent. BAL (British Anti-Lewisite, Dimercaprol) is still used for this purpose in some countries, but has several disadvantages compared with more effective, water-soluble derivatives such as 2,3-dimer-... 

ABSORPTION, DISTRIBUTION, AND EXCRETION Dimercaprol cannot be administered orally it is given by deep intramuscular injection as a 100 mg/mL solution in peanut oil thus it should not be used in patients who are allergic to peanuts or peanut products. Peak concentrations in blood are attained in 30-60 minutes. The tj is short, and metabolic degradation and excretion are essentially complete within 4 hours. 

The dimercaprol-mercury chelate is excreted into both bile and urine, whereas the penicillamine-mercury chelate is excreted only into urine. Thus, penicillamine should be used with extreme caution when renal function is impaired. In fact, hemodialysis may be necessary in the poisoned patient whose renal function declines. Chelators still may be used because the dimercaprol-mercury complex is removed by dialysis. 

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