Review Article

Current Views on Antidotal Therapy in Managing Cases of

Poisoning and Overdose
VV Pillay*

Abstract
While it is an acknowledged dictum that in poisoning or overdose cases, the emphasis must be on general
management comprising supportive measures than the use of specific antidotes in the vast majority of cases, it
is nevertheless true that there are some instances where the timely use of a specific antidote or antagonist will
dramatically reverse or at least halt the progression of toxicity. For this reason, and also because the indications and
the exact manner in which antidotes must be used could be controversial or unfamiliar to the physician, an attempt
has been made to review the current concepts on antidotal therapy of poisoning. There is enough evidence that
the proper use of specific antidotes when combined with general supportive care does reduce the morbidity and
mortality associated with severe poisonings. Common antidotes used in a hospital setting have been discussed
in some detail. ©

INTRODUCTION titled Antitheriaka : An Essay on Mithridatum and Theriaka

I n the ancient days, a variety of exotic and even bizarre
drugs and potions were suggested as antidotes to
various poisonous substances. These antidotes generally
referred to as theriacs (Greek), included concoctions of wild
thyme, aniseed, fennel, parsley, etc.1 They were reputed
to make people “poison-proof”, especially against bites of
venomous animals, the commonest variety of poisoning
in those days. The quest for a universal antidote began
with the work of the Roman King Mithridates VI of Pontus
(132-63 B.C).2 He suffered from a paranoid fear of being
poisoned by his enemies and performed several toxicity
experiments on hapless slaves and criminals, and finally
came up with a concoction of 36 ingredients which came
to be known as Mithridatum. Regular daily intake of this
mixture was supposed to protect against all poisons. Later,
the mithridatum was “improved upon” by Andromachus
(A.D 37-68) the physician to emperor Nero, who increased
the number of ingredients to 73 and proclaimed that it was
the best antidote ever made.3 In fact experiments were
conducted on fowl to demonstrate its efficacy, though the
exact methodology followed in these experiments may
not have been as rigorous as today’s scientific practice!
Subsequently, several more theriacs were fomulated and
enjoyed great popularity as effective antidotes well into
the Middle Ages. It was only in the 18th century that for
the first time the actual efficacy of these concoctions was
questioned. William Heberden published a critical analysis
*Chief, Poison Control Centre and Head, Dept. of Analytical Toxicology,
Amrita Institute of Medical Sciences and Research, Cochin - 682 026.
in 1745.
Activated charcoal had its beginnings in the 5th century
B.C., when the first adsorbent clay called Serra sigillata
obtained from a particular hill on the Greek island of
Lemnos was promoted as a universal antidote.4 This clay
was formulated with goat’s blood to make it into a paste.
Other substances touted as universal antidotes in ancient
times included unicorn horns (actually obtained from
rhinoceros), and bezoar stones consisting of gastric or
intestinal calculi of goats or cows, impregnated with hair
and calcium phosphate.
The principle of modern day charcoal adsorption
was enunciated for the first time by Scheele (1773) and
Lowitz (1785).5 The antidotal properties of charcoal were
demonstrated by a series of heroic self-experiments
conducted in public by French chemist M. Bertrand in 1813.6
In the 1840s, Garod performed the first controlled study
of charcoal when he examined its efficacy on a variety of
poisons in animal models. The first charcoal efficacy studies
in humans were performed by the American physician B.
Rand in 1848. In 1900, the Russian investigator, Obstrejko
demonstrated that treating charcoal with super-heated
steam significantly enhanced its adsorbing power.5 This
came to be called “activated charcoal.” It finally heralded
the dawn of scientifically authentic antidotal therapies, and
the end of the era of potions and concoctions imbued with
mythical powers.
In the majority of cases of acute poisoning, all that is
required is intensive supportive therapy. Specific antidotes
are rarely necessary, besides the fact that only a few genuine
antidotes exist in actual practice, though there is no denying

© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 881

the dramatic results that can be achieved with some of them
in appropriate circumstances. Proper antidotal therapy
can be life-saving in some situations. Unfortunately, the
infrequent presentation of poisoned victims requiring
specific antidotes, coupled with the relatively high cost of
many of these drugs has resulted in many hospitals stocking
inadequate quantities of even the most commonly required
antidotes.7
Antidotes work in any one of a number of ways. Common
modes of action are as follows:
1. Inert complex formation - Some antidotes interact
with the poison to form an inert complex which is then
excreted from the body e.g., chelating agents for heavy
metals, Prussian Blue for thallium, specific antibody
fragments for digoxin, dicobalt edetate for cyanide,
etc.
2. Accelerated detoxification - Some antidotes accelerate
the detoxification of a poison, e.g., thiosulfate accelerates
the conversion of cyanide to non-toxic thiocyanate,
acetylcysteine acts as a glutathione substitute which
combines with hepatotoxic paracetamol metabolites
and detoxifies them.
3. Reduced toxic conversion - The best example of this
mode of action is provided by ethanol which inhibits
the metabolism of methanol to toxic metabolites
by competing for the same enzyme (alcohol
dehydrogenase).
4. Receptor site competition - Some antidotes displace
the poison from specific receptor sites, thereby
antagonising the effects completely. The best example
is provided by naloxone, which antagonizes the effects
of opiates at stereo-specific opioid receptor sites.
5. Receptor site blockade - This mode of action is best
exemplified by atropine which blocks the effects of
anticholinesterase agents such as organophosphates
at muscarinic receptor sites.
6. Toxic effect bypass - An example of this type of antidotal
action is provided by the use of 100% oxygen in cyanide
poisoning.
Table 1 represents a list of genuine antidotes
recommended in toxicological practice today. In addition,
there are certain therapeutic agents which are not antidotes
as per the accepted definition, but which through their
importance and sometimes specific role in the treatment
of poisons, border on the concept of “antidotes.” Table
2 represents a list of such substances. Unfortunately in
India, cumbersome governmental regulations and a lack
of economic incentives for manufacturers have restricted
availability of a substantial number of these life-saving drugs.
As a result, doctors still use some substances which are more
readily available as antidotes, but are generally considered
obsolete or even dangerous in Western countries (Table 3).
It is imperative that medical professionals strive to phase
out these obsolete drugs, while working out strategies to

Table 1 : Specific antidotes

Antidote Main Indication Other Applications
N-Acetylcysteine Paracetamol Amanitin
Atropine Cholinergic agents —
Calcium salts Oxalates, fluorides Calcium antagonists
Dantrolene Malignant hyperthermia Malignant neuroleptic syndrome
Desferrioxamine Iron, aluminium Paraquat
Dicobalt edetate Cyanide —
Digoxin specific antibody fragments Digitalis glycosides —
Dimercaprol Arsenic Copper, gold, mercury
Ethanol Methanol, ethylene glycol —
Flumazenil Benzodiazepines —
Glucagon Beta blockers —
Glucose Insulin —
Hydroxocobalamin Cyanide —
4, Methylpyrazole (fomepizole) Ethylene glycol, methanol Disulfiram, coprin
Naloxone Opiates —
Oximes Organophosphates —
Oxygen Cyanide, carbon monoxide, hydrogen sulfide —
Oxygen (Hyperbaric) tetrachloride Carbon monoxide Cyanide, hydrogen sulfide,carbon
Penicillamine Copper Gold, lead, mercury
Physostigmine Central anticholinergics —
Phytomenadione (Vitamin K) Coumarin derivatives —
Potassium hexacyanoferrate Thallium —
(Prussian Blue)
Protamine sulfate Heparin —
Pyridoxine Isoniazid Ethylene glycol, gyrometrine, hydrazines
Sodium nitrite Cyanide Hydrogen sulfide
Sodium thiosulfate Cyanide Bromate, chlorate, iodine
Succimer (DMSA) Lead, mercury —

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 Table 2 : Adjunctival antidotes
Agent Indication
Activated charcoal For most poisons
Benztropine Dystonia
Chlorpromazine Psychotic states
Diazepam Convulsions
Diphenhydramine Dystonia
Dopamine Myocardial depression, vascular relaxation
Epinephrine Anaphylactic shock, cardiac arrest
Furosemide Fluid retention, left ventricular failure
Haloperidol Psychotic states
Heparin Hypercoagulability
Lidocaine Ventricular arrhythmias
Mannitol Cerebral oedema, fluid retention
Pancuronium Convulsions
Promethazine Allergic reactions
Salbutamol Bronchoconstriction
Sodium bicarbonate Metabolic acidosis
make genuine antidotes more readily available.
Given the complexity of antidotal management of
poisoned patients and problems that can arise in the use
of many antidotes, consultation with a medical toxicologist
or poison control centre should always be considered. A
brief discussion on some of the common specific antidotes
follows. Uncommonly indicated or unavailable antidotes
have not been discussed.
N-acetylcysteine
Although paracetamol possesses an excellent safety
profile at therapeutic doses, a rapidly progressive hepatic
failure leading to death can occur following large overdoses,
when appropriate treatment is delayed. Toxicity results from
paracetamol’s metabolism via cytochrome p450 to N-acetyl-
p-benzoquinoneimine (NAPQI). At therapeutic doses,
NAPQI is detoxified by glutathione to non-toxic conjugates.
However, with excess dosing, exhaustion of glutathione
reserves occurs, with accumulation of NAPQI, initiating a
cascade of events leading to fulminant hepatic failure.
N-acetylcysteine (NAC) prevents NAPQI-induced
hepatoxicity through several mechanisms. Firstly, it acts
as a glutathione (GSH) precursor that increases GSH
availability, as well as providing inorganic sulfate that
enhances paracetamol metabolism through the nontoxic
sulfation pathway. NAC also directly converts NAPQI to
relatively non-toxic cysteine and intercaptate conjugates,
besides reducing NAPQI back to paracetamol, which is
then eliminated by other non-toxic routes. NAC also offers
additional benefit because of its non-specific antioxidant
effects and free radical scavenging properties.
If administered early in the course of exposure, NAC
can prevent significant paracetamol-induced toxicity. Even
when given later, it can still ameliorate toxicity. NAC also has
a role in limiting toxicity caused by glutathione depletion
and free radical formation from poisoning due to carbon
tetrachloride, chloroform, pennyroyal oil, and even valproic
acid.8-10 There have also been some reports suggesting that
© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 883
Table 3 : Obsolete antidotes
Agent Indication
Copper sulfate Phosphorus
Cysteamine Paracetamol
Diethyldithiocarbamate Thallium
Fructose Ethanol
Levallorphan Opiates
Nalorphine Opiates
Silibinin Amanitin
Tocopherol Paraquat
Universal antidote Ingested poisons
NAC is potentially beneficial following exposure to certain
metals such as cobalt.11
In adults, NAC is usually given as a loading dose of 150
mg/kg in 200 mL of D5W infused over 15 minutes, followed
by a first maintenance dose of 50 mg/kg in 500 mL D5W
infused over 4 hours, followed by a second maintenance
dose of 100 mg/kg in 1000 mL D5W infused over 16 hours.
If it is decided to give the NAC orally, the patient should
receive a 140-mg/kg loading dose (either orally or by enteral
tube), and 4 hours later, 70 mg/kg should be given every
4 hours for an additional 17 doses. The solution should be
diluted to 5% with a soft drink to enhance palatability.
If hepatic failure supervenes, IV NAC should be
administered at a dose of 150 mg/kg in D5W infused over
24 hours and continued until the patient recovers from
hepatic encephalopathy,12 or the international normalized
ratio (INR) becomes less than 2.0,13 or the patient receives
a liver transplant.14
Oral NAC often causes nausea, vomiting, flatus, and
diarrhoea; generalized urticaria occurs rarely. Anaphylactoid
reactions can occur after IV NAC dosing.15
Atropine
Atropine is a competitive antagonist at both central
and peripheral muscarinic receptors, and is effective in
the treatment of exposures to muscarinic agonists and
acetylcholinesterase inhibitors such as organophosphate
and carbamate pesticides, as well as some chemical warfare
agents. Like scopolamine (hyoscine), atropine is a tropane
alkaloid found in Datura and some other related plants, and
has a tertiary amine structure that allows CNS penetration.
This is an advantage that some other antimuscarinic agents
such as glycopyrrolate, ipratropium, and tiotropium do not
have, which are unable to cross the blood-brain barrier.16
Organophosphate and carbamate pesticides, as well as
some chemical warfare nerve agents are cholinesterase
inhibitors, and prevent the breakdown of acetylcholine by
acetylcholinesterase, thereby increasing the concentration
of acetylcholine at cholinergic receptors. These receptors
are composed of muscarinic and nicotinic components.
Muscarinic agonists such as muscarine, methacholine, and
pilocarpine stimulate muscarinic receptors, and do not have
any effect on nicotinic receptors. Atropine is a competitive
antagonist of acetylcholine primarily at muscarinic
receptors.17 These receptors are coupled to G proteins
and either inhibit adenylyl cyclase (M2, M4) or increase
phospholipase C (M1, M3, M5). They are widely distributed
throughout the peripheral and central nervous systems.
A precise dosage regimen of atropine for
organophosphate/carbamate pesticide poisoning has
never been arrived at for lack of randomized controlled
trials, and hence there is considerable confusion.18 However,
the usual practice is to begin atropine in doses of 1-2 mg IV
for mild-to-moderate poisoning, and 3-5 mg IV for severe
poisoning with altered consciuosness.19 This dose can be
doubled every few minutes.20 The endpoint for adequate
atropinization is clearing up of airways and lungs, and
the reversal of the muscarinic toxic syndrome. Once the
endpoint has been reached, a maintenance dose of atropine
must be given in the form of 10-20% of the loading dose
as an IV infusion every hour, with frequent evaluation and
titration.18 Over-administration of atropine can give rise to
hot and dry skin, flushing, urinary retention, absent bowel
sounds, tachycardia, mydriasis and central anticholinergic
activity characterized by agitation, confusion, and delirium,
or CNS depression. This may last as long as 12-24 hours.
Desferrioxamine (Deferoxamine)
Desferrioxamine (DFO or deferoxamine) is isolated from
the organism Streptomyces pilosus, and is an effective
chelator of iron. At physiologic pH values, DFO complexes
almost exclusively with ferric iron.21 It is useful in iron-
poisoned patients by chelating free iron (non-transferrin
plasma iron), and iron in transit between transferrin and
ferritin (chelatable labile iron pool).22 It does not affect the
iron of haemoglobin, haemosiderin, or ferritin. DFO is also
useful in treating aluminium toxicity.23
Serious systemic iron poisoning manifested by coma,
shock, or metabolic acidosis warrants IV infusion of DFO.
The duration of therapy should be limited to 24 hours
to minimize the risk of pulmonary toxicity. The usual
recommended dose is 15 mg/kg/h infused during the first
24 hours for life-threatening iron toxicity, though higher
doses have been given in some cases.24 Although patients
with mild toxicity can be treated with IM injections of DFO
(90 mg/kg), it can be associated with moderate to severe
pain, and hence most clinicians choose the IV route. The
total daily parenteral dose is 6-8 g in adults, although
doses as high as 16 g/d have been administered without
incident.25
DFO administration is associated with dose and rate-
related adverse effects including hypotension, pulmonary
toxicity, and infection. Adverse effects such as tachycardia,
hypotension, shock, erythema, and urticaria that occurred
when DFO was infused rapidly, resulted in the current
recommendations for less rapid IV infusions of DFO not
exceeding 15 mg/kg/h. However, higher rates have been
administered successfully in critically ill patients without
much toxicity.26
Acute lung injury (ALI) has been described in the setting
of acute iron overdoses following IV administration of DFO
(15 mg/kg/h) therapy for >24 hours.27 The mechanism for
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development of pulmonary toxicity is unclear, but may
be due to excessive DFO chelation of intracellular iron
and depletion of catalase, resulting in oxidant damage or
generation of free radicals.28
DFO therapy is known to result in infections from
a number of unusual organisms, including Yersinia
enterocolitica, Zygomycetes, and Aeromonas hydrophilia.
This may be because the DFO-iron complex acts as a
siderophore for their growth.29
Cyanide antidotes:
1. Amyl and Sodium nitrites and Sodium thiosulfate–
Amyl and sodium nitrite are highly effective cyanide
antidotes; but they must be administered without delay.
Amyl nitrite is a volatile liquid which is available in some
Western countries in ampoules that can be broken, and the
vapour is inhaled by the patient until intravenous sodium
nitrite can be begun.
Cyanide acts by binding to the ferric iron in cytochrome
oxidase, paralysing energy production throughout
the body. However, the ferric iron in methaemoglobin
has preferential affinity for cyanide, and combines
with it to form cyanmethaemoglobin. This helps to
free cyanide from cytochrome oxidase. In order to
induce methaemoglobinaemia, nitrites are administered,
which oxidize the iron in haemoglobin to produce
methaemoglobin. 30 There are other agents such as
4-dimethylaminophenol and hydroxylamine, which are
also efficient inducers of methaemoglobinaemia and can
be used as cyanide antidotes.31 Unfortunately, in India, none
of these antidotes are available. Amyl nitrite falls under the
category of banned drugs on account of its abuse potential,
while sodium nitrite is only available as a laboratory
chemical, which is not of pharmaceutical grade.
The usual dose of sodium nitrite in adults is 300 mg (10
mL of 3% solution), which should be given intravenously
at a rate of 2.5-5 mL/min. Half this dose can be repeated
if symptoms of cyanide toxicity reappear. If amyl nitrite is
available, it should be administered first. Break the amyl
nitrite ampoule and hold it in front of the patient’s mouth
for a few seconds. Amyl nitrite should be discontinued when
sodium nitrite therapy is begun.
For children, the dose of sodium nitrite is 6-8 mL/m2 (~0.2
mL/kg) of 3% sodium nitrite solution intravenously. The
administered dose must not exceed 10 mL, or 300 mg. Half
this dose can be repeated if symptoms of cyanide toxicity
reappear. If amyl nitrite administration is decided upon, the
same procedure must be followed as for an adult.
Administration of sodium nitrite should always be
followed by sodium thiosulfate. Sodium thiosulfate (which is
also available in India only as a laboratory chemical) acts by
donating a sulfur entity, which with the help of the enzymes
cyanide sulfurtransferase (formerly called rhodanese) and
mercaptopyruvate sulfurtransferase, transports sulfane
sulfur to bind with cyanide, producing thiocyanate.
Thiocyanate is relatively non-toxic, and is harmlessly
excreted by the kidneys. The usual dose of thiosulfate in
adults is 12.5 g (50 mL of 25% solution), which should be
given intravenously either as bolus injection, or infused
over 10 to 30 minutes. Half this dose can be repeated if
manifestations of cyanide toxicity reappear. For children,
the dose is 7 g/m2 or 0.5 g/kg (2 mL/kg) of 25% solution
of sodium thiosulfate, to be given intravenously. Half this
dose can be repeated if symptoms of cyanide toxicity
reappear. In a few reported cases of cyanide poisoning,
sodium thiosulfate alone was used, and all patients had
favorable outcome.32 However, it is always desirable to
administer amyl or sodium nitrite (or hydroxocobalamin if
available), prior to sodium thiosulfate, except in the case of
smoke inhalation where elevated carboxyhaemoglobin or
methaemoglobin levels are usually high to begin with.
Nitrites, while being effective cyanide antidotes, act as
double edged swords. It is a fact that methaemoglobinaemia
is helpful in the treatment of cyanide toxicity, but too much
methaemoglobinaemia can itself be lethal! Therefore, the
nitrite dose must be carefully worked out, and excessive
methaemoglobinaemia must be avoided at all costs. 33
Nitrites are also potent vasodilators, and usually cause
significant hypotension. Sodium thiosulfate has relatively
few side effects, and most of them are minor in nature (mild
hypotension, nausea, and vomiting).
2. Hydroxocobalamin –
Hydroxocobalamin has been used as a cyanide antidote
in some European countries, most notably France, for many
years, either as a sole agent or in combination with sodium
thiosulfate.34 It is not yet being used in India, though it can
easily be employed. The mechanism of action is related to its
cobalt content which is a known antidotal agent for cyanide.
The cobalt in hydroxocobalamin combines with cyanide to
form the relatively nontoxic cyanocobalamin.35 Other cobalt
chelators, such as dicobalt EDTA have been used in some
countries, but their margin of safety is very narrow.30 One
mole of hydroxocobalamin binds 1 mole of cyanide. Taking
into consideration the molecular weights of each, it would
require 52 g of hydroxocobalamin to bind 1 g of cyanide.34
The combined employment of hydroxocobalamin with
sodium thiosulfate is synergistic, and is as efficacious as the
use of sodium nitrite with sodium thiosulfate.36
The usual dose of hydroxocobalamin suggested is 70
mg/kg (to a maximum of 5-10 g initially) administered
intravenously over 30 minutes. This dose can be repeated
(up to a maximum total dose of 15 g) as necessary.37 The
second and subsequent doses should be administered over
a longer period (6-8 hours), except in severe cases.
The adult dose of sodium thiosulfate is as explained
earlier: 12.5 g (50 mL of 25% solution) administered
intravenously as either a bolus injection or infused over 10
to 30 minutes.
While hydroxocobalamin has a remarkably low incidence
of adverse effects even at massive doses, red discolouration
of mucous membranes, plasma, and urine may occur and
last from 12 hours to a few days after therapy. Prior exposure
© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 885
to hydroxocobalamin or cyanocobalamin (for treatment of
vitamin B12 deficiency) may rarely predispose a patient to
allergic reactions, including anaphylaxis.34
Metal chelating agents
Most chelating agents have similar mechanism of action.
Soft metal ions, such as Hg2+, Au+, Cu+, and Ag+ have large
ionic radii with a large number of electrons in their outer
shell. Therefore, they form the most stable complexes
with sulfur donors and are referred to as sulfur seekers.38
Chelating agents such as BAL (British Anti Lewisite) form
a coordinate bond with the metal by donating a pair of
free electrons. Hard metals such as Na+, K+, Mg2+, Ca2+, and
Al3+ are referred to as oxygen seekers and form complexes
with chelators containing a carboxyl (COO-) group, such as
calcium disodium edetate (CaNa2EDTA).39 Borderline metal
ions, such as Pb2+, Cd2+, Cu2+, As3+, and Zn2+, prefer nitrogen-
donating ligands but will also react with both hard and soft
ligands. Antidotes for metal poisoning often contain more
than one type of donating group, making them effective
for more than one type of metal.39
1. B.A.L (British Anti Lewisite; Dimercaprol)
BAL is available as a yellow, viscous liquid with a sulfur-like
odour, in 3-mL ampoules containing 100 mg/mL of BAL, 200
mg/mL of benzyl benzoate, and 700 mg/mL of groundnut
oil. It is given by deep intramuscular injection, and is useful
in the treatment of toxicity resulting from arsenic, mercury,
and lead (in combination with CaNa2EDTA).
The recommended dose of BAL for inorganic arsenic
poisoning is 3 mg/kg IM every 4 hours for 48 hours, followed
by twice daily for 7-10 days. Alternatively, 3-5 mg/kg IM can
be administered every 4-6 hours on the first day, followed
by gradual tapering of the dose and frequency. Some
investigators suggest decreasing the number of injections
by day 2, and termination of therapy within 5-7 days.
For poisoning due to inorganic mercury salts, the dose
of BAL is 5 mg/kg IM initially, followed by 2.5 mg/kg every
8-12 hours for 1 day, followed by 2.5 mg/kg every 12-24
hours, for a maximum of 10 days.
The dose of BAL for lead encephalopathy is 75 mg/m2
IM every 4 hours for 5 days.40 The first dose of dimercaprol
should precede the first dose of CaNa2EDTA by 4 hours.
Subsequently, CaNa2EDTA is given IV in a dose of 1500 mg/
m2/d (up to a maximum of 2-3 g) as a continuous infusion,
or divided into 2-4 doses.
Adverse effects resulting from BAL are dose dependent,
and also dependent on urinary pH. Acidic urine leads to
dissociation of the BAL-metal chelate, and hence it should
be alkalinized with hypertonic NaHCO3 to a pH of 7.5-8.0.
Common adverse effects comprise pain at the injection
site, nausea, vomiting, headache, fever, burning sensation
of lips, mouth, throat, and eyes, lacrimation, rhinorrhea,
salivation, and myalgia. In some cases, there may be
burning and tingling of extremities, toothache, sweating,
and rarely chest pain. Hypertension and tachycardia can
occur with high doses.41 Doses greater than 25 mg/kg can
give rise to hypertensive encephalopathy with convulsions
and coma.
It is important to note that unless hepatotoxicity
encountered in a patient is arsenic-induced, hepatic
dysfunction is a contraindication to BAL use.
BAL is not useful in methylmercury poisoning, because
animal studies have shown a redistribution of mercury to
the brain.42
Unintentional IV infusion of BAL can cause fat embolism,
lipoid pneumonia, and chylothorax.43
2. Calcium disodium edetate (CaNa2 EDTA)
Calcium disodium edetate (CaNa2EDTA) is practically the
only chelating agent that is used in India for the treatment
of lead poisoning, though in most Western countries it has
been replaced to a large extent by its safer counterpart,
succimer (2,3-dimercaptosuccinic acid). There is evidence
to show that CaNa2EDTA is capable of reducing blood lead
concentrations, enhancing renal excretion of lead, and
reversing the effects of lead on haemoglobin synthesis,44
but no rigorous clinical studies have ever been performed
to evaluate its actual efficacy.45 One study of children with
moderately high blood lead levels, who were given 5 days
of CaNa2EDTA treatment, showed hardly any difference
in blood lead, bone lead, or erythrocyte protoporphyrin
concentrations, when compared to pretreatment values.46
The once popular CaNa2EDTA mobilization test which was
recommended as a diagnostic aid for assessing the potential
benefits of chelation therapy has now been abandoned as
useless.47
The recommended dose of CaNa2EDTA depends on
the patient’s body surface area or weight, the severity
of the poisoning, and the status of renal function. For
patients with lead encephalopathy, the dose of CaNa2EDTA
generally recommended is 1500 mg/m2/d by continuous IV
infusion, starting 4 hours after the first dose of dimercaprol.
Combined dimercaprol and CaNa2EDTA therapy is given
for 5 days, followed by cessation for 2 to 4 days, which
permits lead redistribution. Blood lead concentration
should be measured 1 hour after the CaNa2EDTA infusion
is discontinued, to avoid falsely elevated blood lead
concentration determinations.
In children without evidence of lead encephalopathy,
the dose of CaNa2EDTA is 1000 mg/m2/d, in addition to
dimercaprol at 50 mg/m2 every 4 hours. In most Western
countries however, succimer is the chelator of choice
in lead-poisoned children without encephalopathy. 48
CaNa2EDTA should be administered at 0.5% concentration
by continuous IV infusion over 24 hours in 5% dextrose or
0.9% NaCl. Concentrations greater than 0.5% may lead to
thrombophlebitis and must be avoided. In children with
lead encephalopathy, BAL must be started 4 hours prior
to CaNa2EDTA.45
The main adverse effect of CaNa2EDTA is related to
renal function. Therefore, it is important to monitor renal
function closely during CaNa2EDTA administration, and to
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adjust the dose and schedule accordingly. Nephrotoxicity
can be minimized by taking care to ensure that the total
daily dose of CaNa2EDTA does not exceed 1 g in children
or 2 g in adults, as far as possible. Other, less common
adverse effects include malaise, loss of appetite, chills, fever,
myalgia, dermatitis, headache, increased urinary frequency,
rhinorrhoea, lacrimation, glycosuria, and anaemia. 41
Extravasation may result in the development of painful
calcinosis at the injection site. Depletion of endogenous
metals, particularly zinc, iron, and manganese, can result
from chronic therapy.49
3. Succimer (2,3-Dimercaptosuccinic Acid)
Chinese investigators first reported on the beneficial
effects of IV succimer in the treatment of lead and mercury
poisoning, after which several studies were conducted
around the world, which finally led to FDA approval in
1991 in the United States of America for the treatment of
lead-poisoning.50-52 Since then, a large body of evidence
has accumulated clearly indicating the efficacy of succimer,
and its superiority over CaNa2EDTA in the treatment of lead
poisoning.53-55
Succimer can also be used for the treatment of
arsenic and mercury toxicity.56,57 There is one study from
India demonstrating the efficacy of succimer in arsenic
poisoning.58 The tragedy is that succimer is at present not
available in India, and has to be imported from the West. In
the US, succimer is available under the brand name Chemet®,
in the form of 100-mg bead-filled capsules. For patients who
find it difficult to swallow the capsule, it can be opened out,
and the contents sprinkled onto juice, or ice cream, or soft
food. The recommended dose is 350 mg/m2 in children, 3
times a day for 5 days, followed by 350 mg/m2 twice a day
for 14 days.59 In adults, it can be administered at 10 mg/kg,
following the same regimen as above.
Succimer is generally well tolerated, and does not appear
to have any serious adverse effects.60 Common problems
are gastrointestinal in nature, comprising nausea, vomiting,
flatus, diarrhoea, and a metallic taste. Rarely, chills, fever,
urticaria, rash, reversible neutropenia, and eosinophilia
may occur.61,62
Oximes
The most commonly used oxime for organophosphate
pesticide (OP) poisoning in India is pralidoxime
(2-hydroxyiminomethyl-1-methyl pyridinium chloride,
pyridine-2-aldoxime methiodide, P 2AM or PAM). The
others, asoxime and obidoxime are not available in India.
Pralidoxime must invariably be administered together with
atropine in the management of OP poisoning.
Organophosphate pesticides are power ful
inhibitors of carboxylic esterase enzymes, especially
acetylcholinesterase, which is found in red blood cells,
nerve cells, and skeletal muscle, as well as plasma
cholinesterase or butyrylcholinesterase, which is found
in plasma, liver, heart, pancreas, and brain). The former is
often referred to as true cholinesterase, and the latter as
pseudocholinesterase. Organophosphorus pesticides bind
to the serine-containing esteratic site of either enzyme,
inactivating it by phosphorylation.63 This results in the
accumulation of acetylcholine at muscarinic and nicotinic
synapses of the central and peripheral nervous systems,
leading to cholinergic excess. The enzyme is subsequently
inactivated, and may undergo one of three reactions:
hydrolysis of the phosphorylated enzyme; reactivation by a
strong nucleophile, or aging, which is a process that renders
the phosphorylated molecule inactive.
Hydrolysis of OP compounds can be quite slow, and is
generally considered to be insignificant in contrast to the
rapid hydrolysis of most carbamate (CM) pesticides. Oximes
have the ability to reactivate cholinesterase bound to OP
compounds.64 Pralidoxime is capable of a nucleophilic attack
on the phosphate moiety, successfully competing for it and
releasing it from the acetylcholinesterase enzyme.65 This
enables the restoration of enzymatic function. Previously it
was believed that pralidoxime therapy can succeed only if
started within 24-48 hours of exposure to the OP compound,
and that later, the acetylcholinesterase would be irreversibly
inactivated. But recent information suggests that oximes
can be beneficial even when started much later.66,67
In the case of carbamate (CM) poisoning, the
acetylcholinesterases which are inactivated, usually get
reactivated spontaneously over a few hours, though in
severe cases, symptoms may persist for 24 hours or more.68
Pralidoxime is therefore rarely required for carbamate
poisoning; but it is important to note that it is NOT
contraindicated as was previously suggested. Such an
erroneous conclusion was based solely on data derived from
the study of a single carbamate (carbaryl). There are several
studies which demonstrate the beneficial effects of oximes
in treating most kinds of carbamate exposure.69 Pralidoxime
should therefore not be withheld in a seriously poisoned
patient out of concern that a carbamate is involved.70
Though obidoxime is not available in India, it is
actually 10-20 times more effective in reactivating
acetylcholinesterase than is pralidoxime.71 To improve the
central effects of pralidoxime, a new derivative known as
pro-2-PAM, which is actually the dihydropyridine derivative
of pralidoxime was synthesized and introduced into
practice. It has the ability of passing through the blood-
brain barrier. After passage across the membrane, in vivo
oxidation converts it to its active form, demonstrating a 13-
fold higher level of PAM in the brain, than when PAM itself
is administered directly.72 Some organophosphates which
are used as chemical warfare nerve agents can only be
tackled by the H series of oximes (named after Hagedorn).
They demonstrate far greater efficacy against sarin, VX and
some other newer pesticides.73-75 They are however not as
efficacious in traditional OP poisoning.
There is a great deal of controversy regarding the
exact dosage regimen for pralidoxime in OP poisoning.
Conventionally, the recommended initial adult dose is 1-2
g in 100 mL of 0.9% saline given IV over 15-30 minutes.
© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 887
The paediatric dose is said to be 20-40 mg/kg (up to a
maximum of 2 g) given IV over 30-60 minutes.76 These
doses can be repeated in 1 hour if muscle weakness and
fasciculations are not controlled. Additional doses may be
given every 4-8 hours if signs of poisoning keep recurring.
An alternative regimen involves administration of a loading
dose of pralidoxime, followed by a continuous IV infusion.77
Severe cases may require a continuous infusion of 500 mg/h
in adults and 10-20 mg/kg/h (up to 500 mg/h) in children.
Pralidoxime therapy should be continued for a minimum
of 24 hours after symptoms have resolved.
Pralidoxime does not have serious adverse effects
when given at recommended doses. There may be mild
vertigo, diplopia, and hypertension in some cases.78 Rapid
IV administration can rarely cause sudden cardiac and
respiratory arrest because of laryngospasm and muscle
rigidity.79
Ethanol
Ethanol is used as an antidote in those cases where
a particular toxic substance is metabolized by alcohol
dehydrogenase, for e.g., methanol and ethylene glycol.
It acts by competitive inhibition as a result of which toxic
metabolites of methanol and ethylene glycol are not
formed, and the parent compound is excreted unchanged.
The affinity of ethanol for alcohol dehydrogenase is 67 times
that of ethylene glycol and 15.5 times that of methanol.80
A relatively smaller quantity of ethanol is required to
inhibit the metabolism of ethylene glycol, when compared
to the amount required to block the metabolism of
methanol, since the affinity of ethylene glycol for alcohol
dehydrogenase is much less than that of methanol.81 The
usual recommendation is to maintain a serum ethanol
concentration of 100 mg/dL, or at least a 1:4 molar ratio
of ethanol to methanol or ethylene glycol, whichever is
greater.82
Ethanol can be given orally or intravenously. The
usual concentrations recommended for oral and IV
administration are 20-30% and 5-10% respectively.
Intravenous administration is always preferable since it
leads to complete absorption, does not produce GI effects,
and can be administered to an unconscious patient. The
main problem is the difficulty in obtaining and preparing
an IV ethanol solution. The amount of ethanol absorbed
after oral administration depends on a number of factors,
such as nutritional status, rate of gastric emptying, sex and
age of the patient, genetic factors, chronic alcoholism, etc.
Adequate concentration is usually achieved with 0.8 g/kg
of ethanol given orally over 20 minutes.83
Mode of administration84
10% ethanol at a dose of 10 ml/kg administered IV over
30 minutes, followed by 1.5 ml/kg/hr, so as to produce
and maintain a blood ethanol level of 100 mg/100 ml.
Blood ethanol levels should be maintained at 100 to 130
mg/100 ml (21.7 to 28.2 mmol/L). Alternatively, 1 ml/kg
of 95% ethanol in fruit juice (180 ml) can be given orally
over 30 minutes. For maintenance, administer 0.17 to 0.28
ml/kg/hr as 50% ethanol in fruit juice. If neither of these is
practicable, give 125 ml of a distilled alcoholic beverage (gin,
vodka, whisky, or rum) orally, diluted in glucose solution or
juice, and repeat as required cautiously. If single use vials
of pyrogen-free absolute ethanol are not available, bulk
ethanol can be used. A 0.22 micron filter should be used to
minimize particulate matter.
Ethanol therapy should be continued until the following
criteria are met:
 Methanol blood concentration, measured by a reliable
technique, is less than 10 mg/100 ml.
 Formate blood concentration is less than 1.2 mg/100
ml.
 Methanol-induced acidosis (pH, blood gases), clinical
findings (CNS), electrolyte abnormalities (bicarbonate),
serum amylase, and osmolal gap have resolved.
Adverse effects of ethanol administration include
aggravation of CNS depression, hepatitis, pancreatitis,
hypoglycaemia, dehydration, etc.
Fomepizole (4-Methyl Pyrazole)
Fomepizole, like ethanol is a competitive inhibitor of
alcohol dehydrogenase (ADH), minimizing the formation
of toxic metabolites from ethylene glycol and methanol. It
however, has the advantage of being much more potent
than ethanol, and does not aggravate the already existing
CNS toxicity. Administration is also much easier without
need for serum concentration monitoring, thus allowing for
every-12-hour dosing except during haemodialysis, when
dosing should occur every 4 hours. Adverse effects are
milder and of less frequency, and comprise local reactions
at the site of infusion (when the concentration exceeds 25
mg/mL), nausea, vertigo, headache, rash, etc. Fomepizole
must therefore always be preferred to ethanol, but it is
unfortunately not yet available in India.
The usual dosing recommendation is as follows.85,86 A
loading dose of 15 mg/kg IV is first administered, followed
in 12 hours by 10 mg/kg every 12 hours for 4 doses. If it is
necessary to continue with fomepizole beyond 48 hours, the
dose may be increased to 15 mg/kg every 12 hours, for as
long as necessary. This increase is recommended because
fomepizole stimulates its own metabolism. Fomepizole
must always be diluted in 100 mL of normal saline or 5%
dextrose prior to IV administration, to avoid venous irritation
and phlebosclerosis.
Flumazenil
Flumazenil is a competitive antagonist for benzodiazepine
receptors. While it does not directly reverse the respiratory
depression induced by benzodiazepines, it is very effective
in reversing CNS depression. An important point to note
is that since the duration of action of flumazenil is shorter
than that of most benzodiazepines, repeat doses are usually
necessary at relatively short intervals. Flumazenil is also said
to be effective for zolpidem and zaleplon overdoses, which
interact with a subclass of benzodiazepine receptors.87,88
888 www.japi.org © JAPI  •  VOL. 56  •  NOVEMBER 2008
Even though flumazenil is very effective in benzodiazepine
overdose, its actual use in practice is controversial, primarily
because of the low morbidity and mortality associated
with benzodiazepine poisoning. One double-blind
controlled study covering 702 cases over a 14-year period
demonstrated a mortality of only 0.7%.89 In fact, the mortality
rate for nonbenzodiazepine-related overdoses was more
(1.6%). Therefore the current view is to use flumazenil only
in the small minority of “seriously overdosed” patients, and
to rely only on supportive measures in all other cases. If it is
decided to be given, the usual dose is 0.1 mg/min by slow
IV titration, to a total dose of 1 mg. Re-sedation may occur
in half hour to 2 hours, and re-administration of flumazenil
may be necessary.
The main problems associated with flumazenil use
include precipitation of seizures in benzodiazepine-
dependent patients, unmasking of arrhythmias in patients
who coingest benzodiazepine with tricyclic antidepressants,
and the need for frequent re-administration.
Naloxone
Naloxone is a pure competitive opioid antagonist at the
mu (µ) receptor, while nalmefene and naltrexone act at the
kappa and delta receptors. Naloxone is most commonly
used in opioid overdose, and is available in India. The usual
dose is 0.05 mg IV to begin with, increasing it as indicated to
0.4 mg, 2 mg, and up to a maximum of 10 mg. Continuous
monitoring is necessary for the return of respiratory
depression, and if this happens, repeated doses of naloxone
will have to be given. Alternatively, another bolus followed
by a continuous infusion may be embarked upon. 90
Naloxone is best administered intravenously in normal
saline. It can also be given by intramuscular, subcutaneous,
endotracheal, intranasal, and intralingual routes, as well as
in the form of nebulization.
Adverse effects associated with naloxone (excepting
withdrawal and resedation), are rarely encountered.
Patients tolerant to opioids may manifest withdrawal
reaction, characeterized by yawning, lacrimation, sweating,
rhinorrhea, piloerection, mydriasis, vomiting, diarrhoea,
etc. There are rare reports of acute lung injury (non-
cardiogenic pulmonary oedema), hypertension, and cardiac
arrhythmias.
Naltrexone is administered orally in chronic opioid
abusers following detoxification, to maintain opioid
abstinence. Nalmefene is a new entrant whose duration of
action falls between that of naloxone and naltrexone.
Methylene Blue
Methylene blue is a very effective antidote for
toxins causing methaemoglobinaemia. Symptomatic
methaemoglobinaemia usually occurs when the
methaemoglobin level exceeds 20%, and in such cases,
methylene blue is given at a dose of 1-2 mg/kg IV over 5
minutes, followed immediately by a fluid flush of 15-30
mL to minimize local pain. The onset of action is rapid, but
repetitive dosing may be required in association with GI
decontamination, in the case of drugs such as dapsone,
which is one of the commonest agents implicated in
methaemoglobinaemia in the toxicological setting.91
It is important to note that methylene blue has the
paradoxical ability of itself inducing methaemoglobinaemia
when given in excess. This means that there is normally
an equilibrium between the ability of methylene blue to
oxidize haemoglobin directly to methaemoglobin, and
to reduce methaemoglobin to haemoglobin through the
NADPH and NADPH methaemoglobin reductase pathway,
and leukomethylene blue production. The equilibrium gets
disturbed when excessively large doses of methylene blue
are administered or when the NADPH methaemoglobin
reductase system is abnormal.92 Other major adverse effects
of methylene blue include tachypnoea, chest discomfort,
bluish discolouration of skin and mucous membranes,
paraesthesias, restlessness, nausea, and vomiting. Urine and
vomitus usually have a bluish tinge. Intravenous methylene
blue is quite painful, and may cause local tissue damage
even in the absence of extravasation.93
Vitamin K
Vitamin K is an essential fat-soluble vitamin, and
is actually a generic term that includes two distinct
natural forms: vitamin K1 (phytonadione, phylloquinone)
and vitamin K2 (menaquinones) comprising a series of
compounds with the same 2-methyl-1,4-naphthoquinone
ring structure as phylloquinone, but with a variable number
(1-13) of repeating 5-carbon units on the side chain. Most of
the dietary vitamin K is in the form of phytonadione.
Phytonadione is antidotal in nature for reversing elevated
prothrombin time/international normalized ratio (INR)
induced by toxins or drugs such as warfarin, or long-acting
anticoagulant rodenticides (LAARs), such as brodifacoum. It
is usually given orally, because IV administration of vitamin
K1 is associated with anaphylactoid reactions. Subcutaneous
administration may be considered if a patient is unable to
tolerate oral vitamin K, and is not seriously poisoned enough
to necessitate IV vitamin K1.94
Oral anticoagulants are vitamin K antagonists that
interfere with the vitamin K cycle, causing the accumulation
of vitamin K 2,3-epoxide, an inactive metabolite. Warfarin
is a strong irreversible inhibitor of the dithiol-dependent
vitamin K reductases (epoxide reductase and quinone
reductase), which maintain vitamin K in its active (quinol,
hydroquinone) form.95 The superwarfarins (long acting) are
even more potent inhibitors. NADPH-dependent quinone
reductase is an enzyme capable of reducing vitamin K1
to its active hydroquinone form, but it is incapable of
regenerating vitamin K from vitamin K epoxide following
carboxylation of the coagulation factor. Thus, in the
presence of warfarin or superwarfarin, additional vitamin
K1 must be administered to supply this active cofactor for
each and every carboxylation step, as it can no longer be
recycled.96
The usual dose of vitamin K1 in LAAR poisoning varies
© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 889
from 50 to 250 mg daily for weeks to months. 97 The
recommended starting dose is 25 to 50 mg orally, 8th or 6th
hourly, for one or two days. The INR should be constantly
monitored, and the dose adjusted if necessary. When the
INR drops below 2, a downward titration of vitamin K1
can be made, based on factor VII analysis. In the case of
brodifacoum poisoning, serum levels of brodifacoum may
be helpful in deciding the duration of treatment.96
Intravenous administration of vitamin K 1 should be
reserved for life-threatening bleeding. In such a case, the
patient may be supplemented with prothrombin complex
concentrate. If it is not available, fresh-frozen plasma or
recombinant factor VIIa can be considered as alternatives.
Vitamin K1 can be begun at a dose of 10 mg, taking care to
dilute with preservative-free 5% dextrose, normal saline,
or 5% dextrose in saline, and administered slowly, at a
rate not exceeding 1 mg/min, to minimize the risk of an
anaphylactoid reaction. The dose may have to be repeated
3 to 4 times daily.
When given orally, vitamin K1 is virtually free of adverse
effects, except for overcorrection of the INR in the setting
of a patient who requires maintenance anticoagulation.
Intravenous administration has resulted in death secondary
to anaphylactoid reactions, probably as a result of the
preparation’s colloidal formulation.98
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