Dimercaprol
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names,Trade names |
| 1.6 Manufacturers, Importers |
| 1.7 Presentation/formulation |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Properties of the substance |
| 3.3.1.1 Colour |
| 3.3.1.2 State/Form |
| 3.3.1.3 Description |
| 3.3.2 Properties of the locally available formulation |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulations |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indication |
| 4.1.1 Indications |
| 4.1.2 Description |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination and excretion |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Sample |
| 8.1.1 Collection |
| 8.1.2 Storage |
| 8.1.3 Transport |
| 8.2 Toxicological analytical methods |
| 8.2.1 Test for active ingredient |
| 8.2.2 Test for biological sample |
| 8.3 Other laboratory analyses |
| 8.3.1 Haematological investigations |
| 8.3.2 Biochemical investigations |
| 8.3.3 Arterial blood gas analysis |
| 8.3.4 Other relevant biomedical analyses |
| 8.4 Interpretation |
| 8.5 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central nervous system |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscles |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive system |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Other |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESSES |
1. NAME
1.1 Substance
Dimercaprol (INN)
(WHO,1992)
1.2 Group
ATC classification index
All other therapeutic products (V03)/Antidotes (V03B)
(WHO, 1992]
1.3 Synonyms
Dimercaprol
Dicaptol
Sulfactin
Dithioglycerol
British Anti-Lewisite
BAL
(Budavari, 1989)
1.4 Identification numbers
1.4.1 CAS number
59-52-9
1.4.2 Other numbers
RTECS
UB2625000
1.5 Brand names,Trade names
BAL, Dimercaprol, Sulfactin (Germany),
(To be completed by each Centre using local data)
1.6 Manufacturers, Importers
Boots (UK)
Hynson, Westcott & Dunning, Inc. (UK)
Société l'Arguenon (France).
(To be completed by each Centre using local data)
1.7 Presentation/formulation
Ampoules (2 ml) containing 50 mg/ml (100 mg/ampoule) (BAL-
Boots) (Dimercaprol 5% solution in peanut oil and 10% benzyl
benzoate).
Ampoules (3 ml) containing 100 mg/ml (300 mg/ampoule) (BAL-
Hynson, Westcott & Dunning, Inc.) (Dimercaprol 10% solution
in peanut oil and 10% benzyl benzoate)
Ampoules (2 ml) containing 100 mg/ml (200 mg/ampoule) (BAL-
Société l'Arguenon)(Dimercaprol 10% solution in peanut oil
with butacaine 1 mg).
(To be completed by each Centre using local data)
2. SUMMARY
2.1 Main risks and target organs
The main risks are hypertension, tachycardia, cardiovascular
collapse, convulsions, excitation, hyperglycaemia, and
hypoglycaemia.
Special care should be taken in cases of oliguria,
hypertension, and impaired hepatic function, when the
antidote has to be administered.
The target organs are the kidneys, the cardiovascular and the
central nervous systems.
Adverse reactions have been reported in 50% of patients who
were given more than 5 mg/kg IM.
2.2 Summary of clinical effects
The clinical effects are nausea, vomiting, headache, burning
sensation in the lips, throat, mouth, and eyes; lacrimation
and salivation; sweating, rhinorrhea, and burning sensation
of the penis; a feeling of constriction or pain in the throat
or chest, muscle pains and spasms, and tingling of the skin
of the hands; hypertension and tachycardia; abdominal pain,
anxiety, nervousness and weakness; urticaria and
hyperpyrexia.
Clinical effects peak 30 minutes after injection and subside
in a few hours.
Pain and sterile abscesses can occur at the injection site.
Irritation of the skin and mucous membranes can be observed
after local contact.
2.3 Diagnosis
Clinical diagnosis would be difficult in deliberate overdose,
but could be more readily made if poisoning was iatrogenic.
Determination of dimercaprol levels, heavy metal complexes
and dimercaprol metabolites in the urine may be done but is
not used in practice.
2.4 First aid measures and management principles
Interrupt parenteral administration by lowering the dosage or
increasing the time between doses.
Anti-histaminics may possibly alleviate some of the adverse
effects.
Strict clinical observation and monitoring of blood pressure
and diuresis.
Note: Dimercaprol should be given with caution in
hypertensive patients and in patients who have renal and
hepatic dysfunction.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Dimercaprol is a therapeutic synthetic substance developed
during World War II as an antidote against the vesicant
arsenic war gases (Lewisite).
The first experiments were based on the fact that arsenic
products react with SH radicals. Of all the compounds
originally tested, BAL was the most effective and the least
toxic. The intrinsic toxicity of BAL later led to the
development of its water soluble and less toxic derivatives
dimercaptosuccinic acid (DMSA) and dimercaptopropanesulfonic
acid (DMPS) (see 10.7).
Dimercaprol is prepared by the bromination of allyl alcohol
to glycerol di-bromine-hydrine followed by reaction with
sodium hydrosulfide under pressure. It can also be prepared
by hydrogenizing hydroxide propylene trisulfide (Budavari,
1989).
3.2 Chemical structure
Structural formula
Molecular formula
C3H8OS2
Molecular weight
124.21
Structural names
2,3-Dimercaptopropan-1-ol
2-3-dimercapto-1-propanol (IUPAC)
1,2-Thioglycerol
(Budavari, 1989)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
Clear, colourless, or slightly yellow
3.3.1.2 State/Form
Liquid
3.3.1.3 Description
Alliaceous, pungent odour of mercaptan.
Dimercaprol may be turbid or may contain small
amount of flocculated material. This material,
which develops during sterilization, is not an
indication of deterioration.
Water solubility is 1 in 20. The solution is
not stable in water so arachis or peanut oil is
used in pharmaceutical preparations.
Solubility in vegetable oils is 1 in 18
(Reynolds, 1982).
Dimercaprol is miscible with alcohol, benzyl,
benzoate, ether, methyl alcohol, and many other
organic solvents.
A saturated solution water has a pH 5 to 6.5.
Relative density 1.239 to 1.259 (BP)
1.242 to 1.244 (USP)
(Reynolds, 1989)
3.3.2 Properties of the locally available formulation
To be completed by each Centre using local data.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
No data available.
3.4.2 Shelf-life of the locally available formulations
To be completed by each Centre using local data
3.4.3 Storage conditions
Stability in light
Dimercaprol must be protected from the light. The
addition of benzyl benzoate increases its stability
(and solubility).
Thermal stability
Dimercaprol must be stored at between 2 and 10 °C in
small vials that are hermetically sealed and completely
filled (Reynolds, 1989).
3.4.4 Bioavailability
To be completed by each Centre using local data
3.4.5 Specific properties and composition
Dimercaprol is prepared in vegetable oil (peanut or
arachis oil) and stabilized with benzyl benzoate
(Reynolds, 1982).
(To be completed by each Centre using local data)
4. USES
4.1 Indication
4.1.1 Indications
In most recent studies of the use of dimercaprol it has
been compared to its water-soluble analogues DMPS and
DMSA. These studies suggest dimercaprol should never
be the first drug of choice in any form of poisoning
due to metals or metalloids. This statement is based
on the better efficacy and lower toxicity of the newer
antidotes referred above. The intrinsic toxicity or
dimercaprol is significant and should always be
considered whenever there might be an indication for
its use.
However, in some countries dimercaprol may remain more
readily available than DMPS and DMSA for some years,
and this being the case, dimercaprol may be found
useful in the treatment of poisonings due to:
- arsenic (organic & inorganic)
- gold
- inorganic mercury.
It should be noted that in none of these types of
poisoning is the indication for the use of dimercaprol
clearcut (even if DMSA/DMPS are not available).
The recommendation for the use of dimercaprol in
inorganic arsenic poisoning is based on documented
reduced mortality, and significantly decreased arsenic
content of body tissues, in animal studies. Increased
urinary excretion has been documented in at least one
human case, but other clinical data are not conclusive.
However, animal data uniformly shows that dimercaprol
treatment is associated with increased brain content of
arsenic and its value as an antidote has therefore been
questioned.
In organic arsenic poisonings, where data is mainly
from lewisite exposure, dimercaprol appears to remove
arsenic from the body and significantly lower lethality
without increasing the brain content of arsenic.
Clinical data are, however, non-conclusive.
The recommendation for the use of dimercaprol in gold
intoxication is based mainly on toxicokinetic data from
the one case studied by Lalanne (1980). No other
clinical reports provide conclusive data. A reduced
mortality has not been reported in animal studies, only
an increase in urinary gold excretion.
The recommendation for the use of dimercaprol in
poisoning due to inorganic mercury salts is based on
reduced mortality and reduced nephrotoxicity in animal
studies. However, an effect of mortality was not
observed when the antidote was administered more than
one hour after mercury exposure. Though clinical
reports have tended to be favourable, they are not
conclusive.
The use of dimercaprol (in conjunction with CaNa2EDTA)
in lead poisoning is considered controversial and is
therefore not recommended.
(IPCS dimercaprol antidote monograph, 1994)
No efficacy has been documented for poisonings due to
silver (argyria), thallium, tellurium, vanadium,
chromium, cobalt, copper, nickel, zinc, antimony, tin,
titanium, beryllium, magnesium, manganese, tungsten,
and organic compounds of mercury and lead.
Dimercaprol is more effective when given soon after
toxic exposure because it is more effective in
preventing inhibition of sulfhydryl enzymes than in
reactivating them (Gilman et al., 1985).
4.1.2 Description
Not applicable
4.2 Therapeutic dosage
4.2.1 Adults
Dimercaprol should always be administered as soon as
possible by deep intramuscular injection (never
intravenous nor subcutaneous), and rotating sites. The
generally recommended doses are similar for arsenic,
gold and inorganic mercury poisoning:
Mild cases
2.5 mg/kg every 4 hours on the lst day
2.5 mg/kg every 6 hours on the 2nd day
2.5 mg/kg every 12 hours on the 3rd day
2.5 mg/kg every 24 hours for 10 days (or until clinical
recovery)
Severe cases
3to 4 mg/kg every 4 hours on the first 2 days
3to 4 mg/kg every 6 hours on the 3rd day
3to 4 mg/kg every 12 hours for 10 days
(doses of 5 mg/kg can be employed in the most severe
cases).
(IPCS dimercaprol antidote monograph, 1994)
4.2.2 Children
Dimercaprol is well tolerated by children. The dosage
should be calculated according to body weight, using
the same unit-dose per kilogram of body weight as for
adults under similar clinical conditions.
4.3 Contraindications
Dimercaprol cannot be used in poisonings due to iron,
cadmium, tellurium, selenium, vanadium, and uranium. It is
also contraindicated in poisonings due to elemental mercury
vapour, because it can further increase the metal in the
brain (Berlin & Ullberg, 1963).
Dimercaprol should not be given in case of acute renal
failure (anuria) or extensive hepatic insufficiency (Cameron
et al., 1947), and should be used with special care in
hypertensive patients.
Note: Dimercaprol is not effective in massive, severe
poisonings because its antidotal effect is surpassed by the
toxicity of the toxic metal.
If given 7 days after arsenic exposure, it has little or no
effect on the subsequent course of the neuropathy (Heymann et
al., 1956).
5. ROUTES OF ENTRY
5.1 Oral
Dimercaprol is given only by intramuscular injection -
ingestion is only accidental or intentional.
5.2 Inhalation
Unknown.
5.3 Dermal
Skin absorption is possible and occurs with a rate of 3
µmol/cm2/h in rats and humans (Young, 1946; Simpson & Young,
1950). Dimercaprol can be applied to the skin to heal local
effects caused by arsenic vesicant substances (Stocken &
Thompson, 1946).
5.4 Eye
No data available.
5.5 Parenteral
Dimercaprol is usually administered by the parenteral route.
Because of its viscosity and lipid vehicle, a deep
intramuscular injection must be given. This will prevent fat
emboli that may occur with intravenous injections, the slow
and irregular absorption, and sterile abscesses that can
occur with intravenous and subcutaneous injections.
5.6 Other
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Peak concentrations in blood are obtained in about 30 to 60
minutes after intrasmuscular injection of dimercaprol (Gilman
et al., 1985).
It is readily absorbed through the skin after topical
application. Percutaneous absorption in rats and humans
equals 3 millimol (124 mg)/cm2 per hour (Tamboline et al.,
1955).
6.2 Distribution by route of exposure
Because it is a lipophilic drug, dimercaprol penetrates
rapidly the intracellular spaces. The highest concentrations
are found in the liver, kidneys, brain and small intestine
(Simpson & Young, 1950).
Due to its lipophilic characteristic, the complexes formed
with mercury and other metals may be redistributed into
sensitive cells in the brain following dimercaprol treatment
(Aaseth, 1983).
6.3 Biological half-life by route of exposure
Biological half-life is short and metabolic degradation and
renal excretion are complete within 6 to 24 hours according
to animal studies (Catsch & Harmuth-Hoene, 1976).
6.4 Metabolism
The metabolic contribution to its elimination is not clear.
The renal excretion is most often cited as its major
elimination route but there appears to be a significant
contribution from its conjugation with glucuronic acid.
The dimercaprol not fixed to the heavy metal is the fraction
that may be rapidly metabolized to inactive products, some of
which are glucuronide-conjugated.
Dimercaprol is not metabolically inert, and it can be broken
down to inactive and toxic metabolites (Tamboline & Matheson,
1955).
6.5 Elimination and excretion
The major portion of the drug is the fraction that may be
excreted rapidly in the urine, and part of it is eliminated
in the faeces (via bile). The dimercaprol-metal complexes
dissociate rapidly in the body, especially in an acid
internal medium; alkalinization of the urine may prevent this
dissociation and protect the kidneys from metal and BAL
nephrotoxicity (Reynolds 1982). 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 assure the excess of free BAL in body fluids
until the metal is completely excreted.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
The toxicity of BAL is due mainly to its effects on the
kidneys, liver, and the cardiovascular and central
nervous systems (CNS). The mechanisms are not clearly
understood, but may be explained in part by the
inactivation of metal-containing enzymes, and also by
increased capillary permeability.
7.1.2 Pharmacodynamics
Dimercaprol is a dithiol chelating agent, with an
affinity for the "sulfur-seeking" metals, such as
mercury and arsenic.
It forms heterocyclic ring complexes with some heavy
metals, preventing or reversing the binding of metallic
cations to body ligands, such as the essential
sulfhydryl-containing enzymes.
Its application is based on its high affinity for the
toxic metal, relatively low toxicity, minimal
interactions with the essential biological molecules,
penetration into the tissue deposits of the metal,
minimal metabolism, and rapid elimination of the
chelated metal (Aaseth, 1983). The toxic metal cation
accepts free electron pairs furnished by electron-donor
groups (sulfur) from the chelator.
Dimercaprol has to be used in a dosage high enough to
have an antidotal effect, but it is limited by its own
toxicity (Aaseth, 1983). When the affinity of the
toxic metal for Dimercaprol is greater than for the
enzymes, the "chelate" is formed. This new compound, a
mercaptide, has a certain stability and can be rapidly
excreted in the urine, thus preventing the noxious
effect of some metals.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
The highest therapeutic dose recommended is 5
mg/kg, repeated every 4 h initially. At this
dosage, 50% of patients develop side-effects
(Gilman et al., 1985) and if the dose exceeds 5
mg/kg, most patients will have toxic effects.
Doses under 5 mg/kg are well tolerated, and
side-effects, if they occur, are usually
transient, and disappear in a few hours.
7.2.1.2 Children
In a report by Bismuth et al. (1987), 2
children who received a dosage of about 20
mg/kg developed seizures and toxic effects, but
their clinical course was favourable.
7.2.2 Relevant animal data
In studies in rabbits and rats, the LD50 was 0.6 to
1 mmol/kg of SC injection and death occurred within the
first 4 hours.
The LD50 in rabbits and rats was in the range of 0.6 -
1.0 mmol/kg by IM, IP or SC absorption (Fitzhugh et al.
1946; Catsch & Harmuth-Hoene, 1976; Zvirblis & Ellin,
1976).
In another study (Sandmeyer, 1981), the LD50 in rats
after IM injection was 105 mg/kg.
In animals, a lethal dose of dithiols causes
convulsions and severe spasm of the abdominal muscles
shortly before death occurs. After injection of
sublethal amounts of dimercaprol, the animals become
apathetic and develop lacrimation, oedema of the
conjunctiva, blepharospasm, salivation, and vomiting.
With increasing doses, they develop ataxia, analgesia,
tachypnea, and hyper-excitability. Nystagmus and
muscle tremor develop, and tonic and clonic convulsions
occur at the final stages. Death occurs during coma
(Durlacher et al., 1946; Modell et al., 1946; Waters
and Stock, 1945).
The most important systemic acute toxic effect of
dimercaprol, according to Catsch & Harmuth-Hoene
(1976), is cardiovascular depression as judged by a
fall in systemic and pulmonary artery pressure
following intravenous injection in cats (Chenoweth,
1946).
7.2.3 Relevant in vitro data
No relevant data.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Dimercaprol may be teratogenic in mice (see Section 9.4.15).
7.5 Mutagenicity
No data available.
7.6 Interactions
Iron therapy should be given 24 hours or more after the last
dose of dimercaprol. It should never be given at the same
time as dimercaprol.
Dimercaprol forms toxic complexes with iron, cadmium,
selenium, and uranium.
Dimercaprol decreases insulin effectiveness by reducing
disulfide bridges (Catsch & Harmuth-Hoene, 1976).
7.7 Main adverse effects
About 50% of patients who receive high therapeutic doses
(4 to 5mg/kg) have minor reactions: nausea, vomiting,
fatigue, restlessness, apprehension, headache, burning
sensation of the mouth, throat, and eyes, lacrimation,
blepharospasm, salivation, tingling of extremities, a feeling
of constriction in the chest muscle, diffuse pain and muscle
spasm, hypertension (systolic and diastolic) and tachycardia.
Large doses may cause convulsions and coma.
There may be pain at the injection site.
Dimercaprol gives the breath an odour of mercaptan.
Haemolytic anaemia was reported in individuals with a G6PD
deficiency (Janakiraman et al., 1978; Reynolds, 1982).
Dimercaprol is less toxic in patients who have heavy-metal
poisoning than in patients who are not poisoned. The adverse
effects are less severe in case of heavy metal poisoning,
presumably because the antidote bound to the metal does not
show its side-effects (Gilman et al., 1985).
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
8.1 Sample
8.1.1 Collection
8.1.2 Storage
8.1.3 Transport
8.2 Toxicological analytical methods
8.2.1 Test for active ingredient
8.2.2 Test for biological sample
8.3 Other laboratory analyses
8.3.1 Haematological investigations
8.3.2 Biochemical investigations
8.3.3 Arterial blood gas analysis
8.3.4 Other relevant biomedical analyses
8.4 Interpretation
8.5 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
No data available.
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
Dimercaprol is irritating to the skin and mucous
membranes. Studies in humans show that when undiluted
dimercaprol is applied to contaminated skin, a
scarlatina-like oedematous rash or erythema develops,
accompanied by severe tingling, slight lacrimation, and
conjunctival irritation. These symptoms disappear
within 4 to 6 h (Stocken & Thompson, 1946). "Repeated-
insult" of the skin with 10% dimercaprol can cause
extreme sensitization (Reynolds, 1982).
9.1.4 Eye contact
Dimercaprol may cause eye irritation.
9.1.5 Parenteral exposure
Dimercaprol may cause many adverse and toxic effects
that are usually dose-dependent and reversible. The
most common side-effects due to parenteral
administration are on the kidneys, the cardiovascular
and central nervous system, and metabolism, besides the
usual local pain at site of injection.
Minor reactions that occur with doses of 4 to 5 mg/kg
are: nausea, vomiting, headache, burning sensation of
the lips, throat, mouth, and eyes, lacrimation and
salivation, rhinorrhoea, urticaria, a feeling of
constriction or pain in the throat or chest, muscle
pains and spasms, tingling of the skin of the hands,
systolic and diastolic hypertension and tachycardia,
burning sensation in the penis, sweating, abdominal
pain and anxiety, nervousness, or weakness.
These effects usually peak within 30 to 60 min after
injection and subside in 1 hour, or when administering
low doses. Administration of ephedrine or an
antihistamine may prevent or relieve many of the mild
side-effects.
Dimercaprol has a strong odour and gives the breath an
unpleasant mercaptan-like odour.
Painful, sterile or purulent abscesses may occur at the
injection site, particularly if the drug is not given
by IM injection. Children treated with BAL often
develop hyperpyrexia after the second dosage that lasts
until the end of the treatment. This side-effect can
be alleviated by increasing the time between
injections. Repeated high doses lead to a severe
clinical state characterized by cardiovascular
collapse, convulsions, and further coma, acidosis with
hyperlactataemia, accompanied by hyperglycaemia that is
followed by hypoglycaemia.
9.1.6 Other
No data available.
9.2 Chronic poisoning
9.2.1 Ingestion
No data available.
9.2.2 Inhalation
No data available.
9.2.3 Skin exposure
After repeated local applications in animals, a
sensitization dermatitis may develop (Peters et al.
1947).
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Since dimercaprol is rapidly metabolized and eliminated, the
clinical course is brief. If the most serious complications
do not occur, the prognosis is good, although it also depends
on the patient's previous pathology.
The major causes of death are usually related to the cause of
poisoning. But Dimercaprol could cause convulsions and coma;
irreversible cardiovascular collapse; acidosis and
hydroelectrolytic disturbances, renal failure; and secondary
consequences of hypertension such as brain injury or cardiac
failure.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Only acute effects have been described, such as
hypertension and tachycardia (Reynolds, 1989).
9.4.2 Respiratory
The respiratory system is affected only secondarily
(e.g., acute pulmonary oedema after cardiac failure).
Dimercaprol very often causes a feeling of constriction
or pain in the chest.
9.4.3 Neurological
9.4.3.1 Central nervous system
Headache, anxiety, nervousness, weakness,
convulsions, and coma. (Only acute effects have
been described).
9.4.3.2 Peripheral nervous system
Muscle pains and spasms, tingling of
extremities. (Only acute effects have been
described).
9.4.3.3 Autonomic nervous system
Sweating, trembling, salivation, hypertension,
and other effects can be attributed to the
autonomic nervous system. (Only acute effects
have been described).
9.4.3.4 Skeletal and smooth muscles
Muscle pain and cramps.
9.4.4 Gastrointestinal
Nausea and vomiting.
9.4.5 Hepatic
Dimercaprol is contraindicated in patients with
impaired hepatic function (except those with jaundice
due to arsenic poisoning).
Chronic effects in the animals are fatty degeneration
of the liver and impairment of liver function.
9.4.6 Urinary
9.4.6.1 Renal
If acute renal failure develops during
dimercaprol therapy, the drug should be
discontinued or used with care because serum
concentrations of dimercaprol may reach toxic
levels and impair normal elimination.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive system
BAL interferes with the normal accumulation of iodine
by the thyroid and may decrease iodine-131 thyroidal
uptake (Gilman et al., 1985).
BAL decreases insulin's effectiveness by reducing
disulfide bridges.
9.4.8 Dermatological
Acute dermatological effects may occur after parenteral
or topical application.
Urticaria is the most common symptom that occurs after
parenteral administration. Skin application may
produce a scarlatina-like, oedematous rash or erythema.
Chronic effect: If BAL is frequently applied to the
skin, extreme sensitization may develop.
9.4.9 Eye, ear, nose, throat: local effects
Parenteral or topical administration may cause:
lacrimation and conjunctival irritation, burning
sensation of the throat, mouth, and eyes, rhinorrhea, a
feeling of constriction or pain in the throat.
9.4.10 Haematological
Acute effects
Children may have a transient reduction in
polymorphonuclear leucocytes.
Dimercaprol can cause haemolytic anaemia in people who
have glucose-phosphate dehydrogenase deficiency.
Chronic effects
In animals, chronic parenteral administration
increases the white blood cell count by 30%.
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Dimercaprol may cause metabolic acidosis with
hyperlactacidaemia and hyperglycaemia, which
is followed by hypoglycaemia and glycosuria.
The mechanism by which BAL increases blood
glucose is not fully understood, but since
the hyperglycaemia does not occur in
adrenalectomized animals, it may be
attributed to a release of adrenalin from the
adrenal medulla.
9.4.12.2 Fluid and electrolyte disturbances
Disturbances in fluids and electrolytes may
occur.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
May be observed.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
In studies in mice, there were malformations of the
skeletal system, growth retardation, and increased
embryo mortality.
However, a woman with Wilson's disease was treated
with dimercaprol during two pregnancies and had normal
infants (Reynolds, 1982).
9.5 Other
No data available.
10. MANAGEMENT
10.1 General principles
There is no specific treatment, but symptomatic measures
can be taken to improve the clinical course.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Blood and urine for routine clinical analysis.
10.2.2 Biomedical analysis
Patients who have overdosed should be studied.
Tests for the following abnormalities should be
done:
Metabolic effects: hyperglycaemia, glycosuria,
hyperlactataemia, pH, electrolytes, etc.
Serum creatinine, uric acid, urinalysis.
Electrocardiogram.
Other routine studies, as required.
10.2.3 Toxicological analysis
"Dimercaprol-metal" complexes can be measured in the
urine (but are not usually indicated in clinical
practice).
10.2.4 Other investigations
As required by patient's clinical condition.
10.3 Life supportive procedures and symptomatic/specific
treatment
Stop dimercaprol immediately if adverse reactions are
observed.
Convulsions should be treated as usual with benzodiazepines
and barbiturates.
If cardiovascular collapse develops, give fluids according
to the patient's hydroelectrolytic balance. Dopamine can
be used, if necessary.
Bicarbonate solution is useful, not only to correct
acidosis but also to increase renal elimination of BAL-
metal complexes, (in preventing their dissociation and
decreasing their toxicity) (Reynolds, 1989).
If interruption of the chelating treatment is not possible,
treatment should be re-installed with lower doses or
increasing the time intervals between doses.
10.4 Decontamination
If there has been dermal exposure, wash the skin with a
non-irritating soap and water. If the eyes have been
exposed, irrigate them with tap water. If ingested give
activated charcoal.
10.5 Elimination
No special measures should be taken unless there are signs
of renal failure. The use of intravenous bicarbonated
fluids, under clinical and biochemical control, is
recommended (Reynolds, 1989)
10.6 Antidote treatment
No antidotal treatment is available.
10.6.1 Adults
None.
10.6.2 Children
None.
10.7 Management discussion
Even though dimercaprol is still recommended as the drug of
choice in poisoning due to arsenic and several other heavy
metals, it appears that much evidence is now available
showing that DMSA (dimercapto-succinic acid) and DMPS
(dimercaptopropane sulphonate) are more efficient and
significantly less toxic than BAL. (Aaseth, 1987).
It is suggested that the formation of lipophilic heavy
metal-BAL complexes may lead to redistribution of these
metals to the central nervous system and to increased
toxicity. (Aaseth, 1987).
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Bismuth et al. (1987) reported two children who had
received doses above 20 mg/kg. They developed hypertension,
seizures, and coma, but completely recovered in less than 1
hour.
Janakiraman et al. (1978) reported the occurrence of
haemolysis during dimercaprol chelation therapy for high
lead blood levels in two children who had glucose-6-
phosphate-de-hydrogenase deficiency.
Epidemiological, clinical, and laboratory features in 41
patients with arsenic neuropathy were analyzed and the
effects of BAL therapy were reviewed. BAL administered 7
or more days after arsenic exposure had little effect on
the subsequent course of the neuropathy (Heymann et al.
1956).
Freeman & Couch (1978) reported prolonged arsenic
encephalopathy in a 51-year-old woman. She improved after 5
weeks of BAL chelation therapy in hospital.
11.2 Internally extracted data on cases
According to the experience of CIAT (Poisons Control
Centre, Montevideo, Uruguay), when Dimercaprol is given in
large doses adverse effects occur. They consist of
uneasiness, chest constriction and dyspnea, itching of
skin, peri-oral paresthesia, and hypertension. The patient
becomes very anxious and sometimes even excited.
Large doses have been given under two circumstances:
firstly, when samples of out-dated Dimercaprol had to be
used and a higher dosage was thought to be required;
secondly, in cases where patients falsely reported the
ingestion of massive amounts of arsenic. The outcome of
Dimercaprol overdoses has always been favourable in our
experience. But massive arsenic poisoning does not respond
to chelating therapy with Dimercaprol in our experience.
11.3 Internal cases
To be completed by each Centre using local data.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
None.
12.2 Specific preventive measures
Dimercaprol should be administered by deep intramuscular
injection.
It should be administered carefully and under strict
clinical control in patients with hypertension, hepatic or
renal impairment, and G6PD deficiency.
12.3 Other
None.
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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESSES
Author Dr R Peyraube
CIAT piso° 7
Hospital de Clinicas
Av Italia s/n
Montevideo
Uruguay
Tel 598-2-808300/470300
Fax 598-2-470300
Date June 1988
Reviewer Dr D Jacobsen
Medical Department
Ulleval Hospital
0407 Oslo 4
Norway
Tel 47-2-119100/1191359
Fax 47-2-119181
Date August 1990
Peer Strasbourg, France, April 1990
Review