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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


in 1745.
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
Activated charcoal had its beginnings in the 5th century
B.C., when the first adsorbent clay called Serra sigillata
referred to as theriacs (Greek), included concoctions of wild obtained from a particular hill on the Greek island of
thyme, aniseed, fennel, parsley, etc.1 They were reputed Lemnos was promoted as a universal antidote.4 This clay
to make people “poison-proof”, especially against bites of was formulated with goat’s blood to make it into a paste.
venomous animals, the commonest variety of poisoning Other substances touted as universal antidotes in ancient
in those days. The quest for a universal antidote began times included unicorn horns (actually obtained from
with the work of the Roman King Mithridates VI of Pontus rhinoceros), and bezoar stones consisting of gastric or
(132-63 B.C).2 He suffered from a paranoid fear of being intestinal calculi of goats or cows, impregnated with hair
poisoned by his enemies and performed several toxicity and calcium phosphate.
experiments on hapless slaves and criminals, and finally The principle of modern day charcoal adsorption
came up with a concoction of 36 ingredients which came was enunciated for the first time by Scheele (1773) and
to be known as Mithridatum. Regular daily intake of this Lowitz (1785).5 The antidotal properties of charcoal were
mixture was supposed to protect against all poisons. Later, demonstrated by a series of heroic self-experiments
the mithridatum was “improved upon” by Andromachus conducted in public by French chemist M. Bertrand in 1813.6
(A.D 37-68) the physician to emperor Nero, who increased In the 1840s, Garod performed the first controlled study
the number of ingredients to 73 and proclaimed that it was of charcoal when he examined its efficacy on a variety of
the best antidote ever made.3 In fact experiments were poisons in animal models. The first charcoal efficacy studies
conducted on fowl to demonstrate its efficacy, though the in humans were performed by the American physician B.
exact methodology followed in these experiments may Rand in 1848. In 1900, the Russian investigator, Obstrejko
not have been as rigorous as today’s scientific practice! demonstrated that treating charcoal with super-heated
Subsequently, several more theriacs were fomulated and steam significantly enhanced its adsorbing power.5 This
enjoyed great popularity as effective antidotes well into came to be called “activated charcoal.” It finally heralded
the Middle Ages. It was only in the 18th century that for the dawn of scientifically authentic antidotal therapies, and
the first time the actual efficacy of these concoctions was the end of the era of potions and concoctions imbued with
questioned. William Heberden published a critical analysis mythical powers.
In the majority of cases of acute poisoning, all that is
*Chief, Poison Control Centre and Head, Dept. of Analytical Toxicology, required is intensive supportive therapy. Specific antidotes
Amrita Institute of Medical Sciences and Research, Cochin - 682 026. 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 4. Receptor site competition - Some antidotes displace
in appropriate circumstances. Proper antidotal therapy the poison from specific receptor sites, thereby
can be life-saving in some situations. Unfortunately, the antagonising the effects completely. The best example
infrequent presentation of poisoned victims requiring is provided by naloxone, which antagonizes the effects
specific antidotes, coupled with the relatively high cost of of opiates at stereo-specific opioid receptor sites.
many of these drugs has resulted in many hospitals stocking 5. Receptor site blockade - This mode of action is best
inadequate quantities of even the most commonly required exemplified by atropine which blocks the effects of
antidotes.7 anticholinesterase agents such as organophosphates
Antidotes work in any one of a number of ways. Common at muscarinic receptor sites.
modes of action are as follows: 6. Toxic effect bypass - An example of this type of antidotal
1. Inert complex formation - Some antidotes interact action is provided by the use of 100% oxygen in cyanide
with the poison to form an inert complex which is then poisoning.
excreted from the body e.g., chelating agents for heavy Table 1 represents a list of genuine antidotes
metals, Prussian Blue for thallium, specific antibody recommended in toxicological practice today. In addition,
fragments for digoxin, dicobalt edetate for cyanide, there are certain therapeutic agents which are not antidotes
etc. as per the accepted definition, but which through their
2. Accelerated detoxification - Some antidotes accelerate importance and sometimes specific role in the treatment
the detoxification of a poison, e.g., thiosulfate accelerates of poisons, border on the concept of “antidotes.” Table
the conversion of cyanide to non-toxic thiocyanate, 2 represents a list of such substances. Unfortunately in
acetylcysteine acts as a glutathione substitute which India, cumbersome governmental regulations and a lack
combines with hepatotoxic paracetamol metabolites of economic incentives for manufacturers have restricted
and detoxifies them. availability of a substantial number of these life-saving drugs.
3. Reduced toxic conversion - The best example of this As a result, doctors still use some substances which are more
mode of action is provided by ethanol which inhibits readily available as antidotes, but are generally considered
the metabolism of methanol to toxic metabolites obsolete or even dangerous in Western countries (Table 3).
by competing for the same enzyme (alcohol It is imperative that medical professionals strive to phase
dehydrogenase). 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 —

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


Table 2 : Adjunctival antidotes Table 3 : Obsolete antidotes
Agent Indication Agent Indication
Activated charcoal For most poisons Copper sulfate Phosphorus
Benztropine Dystonia Cysteamine Paracetamol
Chlorpromazine Psychotic states Diethyldithiocarbamate Thallium
Diazepam Convulsions Fructose Ethanol
Diphenhydramine Dystonia Levallorphan Opiates
Dopamine Myocardial depression, vascular relaxation Nalorphine Opiates
Epinephrine Anaphylactic shock, cardiac arrest Silibinin Amanitin
Furosemide Fluid retention, left ventricular failure Tocopherol Paraquat
Haloperidol Psychotic states Universal antidote Ingested poisons
Heparin Hypercoagulability
Lidocaine Ventricular arrhythmias NAC is potentially beneficial following exposure to certain
Mannitol Cerebral oedema, fluid retention metals such as cobalt.11
Pancuronium Convulsions
Promethazine Allergic reactions
In adults, NAC is usually given as a loading dose of 150
Salbutamol Bronchoconstriction mg/kg in 200 mL of D5W infused over 15 minutes, followed
Sodium bicarbonate Metabolic acidosis 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.
make genuine antidotes more readily available. If it is decided to give the NAC orally, the patient should
Given the complexity of antidotal management of receive a 140-mg/kg loading dose (either orally or by enteral
poisoned patients and problems that can arise in the use tube), and 4 hours later, 70 mg/kg should be given every
of many antidotes, consultation with a medical toxicologist 4 hours for an additional 17 doses. The solution should be
or poison control centre should always be considered. A diluted to 5% with a soft drink to enhance palatability.
brief discussion on some of the common specific antidotes If hepatic failure supervenes, IV NAC should be
follows. Uncommonly indicated or unavailable antidotes administered at a dose of 150 mg/kg in D5W infused over
have not been discussed. 24 hours and continued until the patient recovers from
N-acetylcysteine hepatic encephalopathy,12 or the international normalized
ratio (INR) becomes less than 2.0,13 or the patient receives
Although paracetamol possesses an excellent safety
a liver transplant.14
profile at therapeutic doses, a rapidly progressive hepatic
failure leading to death can occur following large overdoses, Oral NAC often causes nausea, vomiting, flatus, and
when appropriate treatment is delayed. Toxicity results from diarrhoea; generalized urticaria occurs rarely. Anaphylactoid
paracetamol’s metabolism via cytochrome p450 to N-acetyl- reactions can occur after IV NAC dosing.15
p-benzoquinoneimine (NAPQI). At therapeutic doses, Atropine
NAPQI is detoxified by glutathione to non-toxic conjugates. Atropine is a competitive antagonist at both central
However, with excess dosing, exhaustion of glutathione and peripheral muscarinic receptors, and is effective in
reserves occurs, with accumulation of NAPQI, initiating a the treatment of exposures to muscarinic agonists and
cascade of events leading to fulminant hepatic failure. acetylcholinesterase inhibitors such as organophosphate
N-acetylcysteine (NAC) prevents NAPQI-induced and carbamate pesticides, as well as some chemical warfare
hepatoxicity through several mechanisms. Firstly, it acts agents. Like scopolamine (hyoscine), atropine is a tropane
as a glutathione (GSH) precursor that increases GSH alkaloid found in Datura and some other related plants, and
availability, as well as providing inorganic sulfate that has a tertiary amine structure that allows CNS penetration.
enhances paracetamol metabolism through the nontoxic This is an advantage that some other antimuscarinic agents
sulfation pathway. NAC also directly converts NAPQI to such as glycopyrrolate, ipratropium, and tiotropium do not
relatively non-toxic cysteine and intercaptate conjugates, have, which are unable to cross the blood-brain barrier.16
besides reducing NAPQI back to paracetamol, which is Organophosphate and carbamate pesticides, as well as
then eliminated by other non-toxic routes. NAC also offers some chemical warfare nerve agents are cholinesterase
additional benefit because of its non-specific antioxidant inhibitors, and prevent the breakdown of acetylcholine by
effects and free radical scavenging properties. acetylcholinesterase, thereby increasing the concentration
If administered early in the course of exposure, NAC of acetylcholine at cholinergic receptors. These receptors
can prevent significant paracetamol-induced toxicity. Even are composed of muscarinic and nicotinic components.
when given later, it can still ameliorate toxicity. NAC also has Muscarinic agonists such as muscarine, methacholine, and
a role in limiting toxicity caused by glutathione depletion pilocarpine stimulate muscarinic receptors, and do not have
and free radical formation from poisoning due to carbon any effect on nicotinic receptors. Atropine is a competitive
tetrachloride, chloroform, pennyroyal oil, and even valproic antagonist of acetylcholine primarily at muscarinic
acid.8-10 There have also been some reports suggesting that receptors.17 These receptors are coupled to G proteins

© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 883


and either inhibit adenylyl cyclase (M2, M4) or increase development of pulmonary toxicity is unclear, but may
phospholipase C (M1, M3, M5). They are widely distributed be due to excessive DFO chelation of intracellular iron
throughout the peripheral and central nervous systems. and depletion of catalase, resulting in oxidant damage or
A precise dosage regimen of atropine for generation of free radicals.28
organophosphate/carbamate pesticide poisoning has DFO therapy is known to result in infections from
never been arrived at for lack of randomized controlled a number of unusual organisms, including Yersinia
trials, and hence there is considerable confusion.18 However, enterocolitica, Zygomycetes, and Aeromonas hydrophilia.
the usual practice is to begin atropine in doses of 1-2 mg IV This may be because the DFO-iron complex acts as a
for mild-to-moderate poisoning, and 3-5 mg IV for severe siderophore for their growth.29
poisoning with altered consciuosness.19 This dose can be Cyanide antidotes:
doubled every few minutes.20 The endpoint for adequate
1. Amyl and Sodium nitrites and Sodium thiosulfate–
atropinization is clearing up of airways and lungs, and
the reversal of the muscarinic toxic syndrome. Once the Amyl and sodium nitrite are highly effective cyanide
endpoint has been reached, a maintenance dose of atropine antidotes; but they must be administered without delay.
must be given in the form of 10-20% of the loading dose Amyl nitrite is a volatile liquid which is available in some
as an IV infusion every hour, with frequent evaluation and Western countries in ampoules that can be broken, and the
titration.18 Over-administration of atropine can give rise to vapour is inhaled by the patient until intravenous sodium
hot and dry skin, flushing, urinary retention, absent bowel nitrite can be begun.
sounds, tachycardia, mydriasis and central anticholinergic Cyanide acts by binding to the ferric iron in cytochrome
activity characterized by agitation, confusion, and delirium, oxidase, paralysing energy production throughout
or CNS depression. This may last as long as 12-24 hours. the body. However, the ferric iron in methaemoglobin
Desferrioxamine (Deferoxamine) has preferential affinity for cyanide, and combines
with it to form cyanmethaemoglobin. This helps to
Desferrioxamine (DFO or deferoxamine) is isolated from
free cyanide from cytochrome oxidase. In order to
the organism Streptomyces pilosus, and is an effective
induce methaemoglobinaemia, nitrites are administered,
chelator of iron. At physiologic pH values, DFO complexes
which oxidize the iron in haemoglobin to produce
almost exclusively with ferric iron.21 It is useful in iron-
methaemoglobin. 30 There are other agents such as
poisoned patients by chelating free iron (non-transferrin
4-dimethylaminophenol and hydroxylamine, which are
plasma iron), and iron in transit between transferrin and
also efficient inducers of methaemoglobinaemia and can
ferritin (chelatable labile iron pool).22 It does not affect the
be used as cyanide antidotes.31 Unfortunately, in India, none
iron of haemoglobin, haemosiderin, or ferritin. DFO is also
of these antidotes are available. Amyl nitrite falls under the
useful in treating aluminium toxicity.23
category of banned drugs on account of its abuse potential,
Serious systemic iron poisoning manifested by coma, while sodium nitrite is only available as a laboratory
shock, or metabolic acidosis warrants IV infusion of DFO. chemical, which is not of pharmaceutical grade.
The duration of therapy should be limited to 24 hours
The usual dose of sodium nitrite in adults is 300 mg (10
to minimize the risk of pulmonary toxicity. The usual
mL of 3% solution), which should be given intravenously
recommended dose is 15 mg/kg/h infused during the first
at a rate of 2.5-5 mL/min. Half this dose can be repeated
24 hours for life-threatening iron toxicity, though higher
if symptoms of cyanide toxicity reappear. If amyl nitrite is
doses have been given in some cases.24 Although patients
available, it should be administered first. Break the amyl
with mild toxicity can be treated with IM injections of DFO
nitrite ampoule and hold it in front of the patient’s mouth
(90 mg/kg), it can be associated with moderate to severe
for a few seconds. Amyl nitrite should be discontinued when
pain, and hence most clinicians choose the IV route. The
sodium nitrite therapy is begun.
total daily parenteral dose is 6-8 g in adults, although
doses as high as 16 g/d have been administered without For children, the dose of sodium nitrite is 6-8 mL/m2 (~0.2
incident.25 mL/kg) of 3% sodium nitrite solution intravenously. The
administered dose must not exceed 10 mL, or 300 mg. Half
DFO administration is associated with dose and rate-
this dose can be repeated if symptoms of cyanide toxicity
related adverse effects including hypotension, pulmonary
reappear. If amyl nitrite administration is decided upon, the
toxicity, and infection. Adverse effects such as tachycardia,
same procedure must be followed as for an adult.
hypotension, shock, erythema, and urticaria that occurred
when DFO was infused rapidly, resulted in the current Administration of sodium nitrite should always be
recommendations for less rapid IV infusions of DFO not followed by sodium thiosulfate. Sodium thiosulfate (which is
exceeding 15 mg/kg/h. However, higher rates have been also available in India only as a laboratory chemical) acts by
administered successfully in critically ill patients without donating a sulfur entity, which with the help of the enzymes
much toxicity.26 cyanide sulfurtransferase (formerly called rhodanese) and
mercaptopyruvate sulfurtransferase, transports sulfane
Acute lung injury (ALI) has been described in the setting
sulfur to bind with cyanide, producing thiocyanate.
of acute iron overdoses following IV administration of DFO
Thiocyanate is relatively non-toxic, and is harmlessly
(15 mg/kg/h) therapy for >24 hours.27 The mechanism for
884 www.japi.org © JAPI  •  VOL. 56  •  NOVEMBER 2008
excreted by the kidneys. The usual dose of thiosulfate in to hydroxocobalamin or cyanocobalamin (for treatment of
adults is 12.5 g (50 mL of 25% solution), which should be vitamin B12 deficiency) may rarely predispose a patient to
given intravenously either as bolus injection, or infused allergic reactions, including anaphylaxis.34
over 10 to 30 minutes. Half this dose can be repeated if Metal chelating agents
manifestations of cyanide toxicity reappear. For children,
Most chelating agents have similar mechanism of action.
the dose is 7 g/m2 or 0.5 g/kg (2 mL/kg) of 25% solution
Soft metal ions, such as Hg2+, Au+, Cu+, and Ag+ have large
of sodium thiosulfate, to be given intravenously. Half this
ionic radii with a large number of electrons in their outer
dose can be repeated if symptoms of cyanide toxicity
shell. Therefore, they form the most stable complexes
reappear. In a few reported cases of cyanide poisoning,
with sulfur donors and are referred to as sulfur seekers.38
sodium thiosulfate alone was used, and all patients had
Chelating agents such as BAL (British Anti Lewisite) form
favorable outcome.32 However, it is always desirable to
a coordinate bond with the metal by donating a pair of
administer amyl or sodium nitrite (or hydroxocobalamin if
free electrons. Hard metals such as Na+, K+, Mg2+, Ca2+, and
available), prior to sodium thiosulfate, except in the case of
Al3+ are referred to as oxygen seekers and form complexes
smoke inhalation where elevated carboxyhaemoglobin or
with chelators containing a carboxyl (COO-) group, such as
methaemoglobin levels are usually high to begin with.
calcium disodium edetate (CaNa2EDTA).39 Borderline metal
Nitrites, while being effective cyanide antidotes, act as ions, such as Pb2+, Cd2+, Cu2+, As3+, and Zn2+, prefer nitrogen-
double edged swords. It is a fact that methaemoglobinaemia donating ligands but will also react with both hard and soft
is helpful in the treatment of cyanide toxicity, but too much ligands. Antidotes for metal poisoning often contain more
methaemoglobinaemia can itself be lethal! Therefore, the than one type of donating group, making them effective
nitrite dose must be carefully worked out, and excessive for more than one type of metal.39
methaemoglobinaemia must be avoided at all costs. 33
1. B.A.L (British Anti Lewisite; Dimercaprol)
Nitrites are also potent vasodilators, and usually cause
significant hypotension. Sodium thiosulfate has relatively BAL is available as a yellow, viscous liquid with a sulfur-like
few side effects, and most of them are minor in nature (mild odour, in 3-mL ampoules containing 100 mg/mL of BAL, 200
hypotension, nausea, and vomiting). mg/mL of benzyl benzoate, and 700 mg/mL of groundnut
oil. It is given by deep intramuscular injection, and is useful
2. Hydroxocobalamin –
in the treatment of toxicity resulting from arsenic, mercury,
Hydroxocobalamin has been used as a cyanide antidote and lead (in combination with CaNa2EDTA).
in some European countries, most notably France, for many
The recommended dose of BAL for inorganic arsenic
years, either as a sole agent or in combination with sodium
poisoning is 3 mg/kg IM every 4 hours for 48 hours, followed
thiosulfate.34 It is not yet being used in India, though it can
by twice daily for 7-10 days. Alternatively, 3-5 mg/kg IM can
easily be employed. The mechanism of action is related to its
be administered every 4-6 hours on the first day, followed
cobalt content which is a known antidotal agent for cyanide.
by gradual tapering of the dose and frequency. Some
The cobalt in hydroxocobalamin combines with cyanide to
investigators suggest decreasing the number of injections
form the relatively nontoxic cyanocobalamin.35 Other cobalt
by day 2, and termination of therapy within 5-7 days.
chelators, such as dicobalt EDTA have been used in some
countries, but their margin of safety is very narrow.30 One For poisoning due to inorganic mercury salts, the dose
mole of hydroxocobalamin binds 1 mole of cyanide. Taking of BAL is 5 mg/kg IM initially, followed by 2.5 mg/kg every
into consideration the molecular weights of each, it would 8-12 hours for 1 day, followed by 2.5 mg/kg every 12-24
require 52 g of hydroxocobalamin to bind 1 g of cyanide.34 hours, for a maximum of 10 days.
The combined employment of hydroxocobalamin with The dose of BAL for lead encephalopathy is 75 mg/m2
sodium thiosulfate is synergistic, and is as efficacious as the IM every 4 hours for 5 days.40 The first dose of dimercaprol
use of sodium nitrite with sodium thiosulfate.36 should precede the first dose of CaNa2EDTA by 4 hours.
The usual dose of hydroxocobalamin suggested is 70 Subsequently, CaNa2EDTA is given IV in a dose of 1500 mg/
mg/kg (to a maximum of 5-10 g initially) administered m2/d (up to a maximum of 2-3 g) as a continuous infusion,
intravenously over 30 minutes. This dose can be repeated or divided into 2-4 doses.
(up to a maximum total dose of 15 g) as necessary.37 The Adverse effects resulting from BAL are dose dependent,
second and subsequent doses should be administered over and also dependent on urinary pH. Acidic urine leads to
a longer period (6-8 hours), except in severe cases. dissociation of the BAL-metal chelate, and hence it should
The adult dose of sodium thiosulfate is as explained be alkalinized with hypertonic NaHCO3 to a pH of 7.5-8.0.
earlier: 12.5 g (50 mL of 25% solution) administered Common adverse effects comprise pain at the injection
intravenously as either a bolus injection or infused over 10 site, nausea, vomiting, headache, fever, burning sensation
to 30 minutes. of lips, mouth, throat, and eyes, lacrimation, rhinorrhea,
While hydroxocobalamin has a remarkably low incidence salivation, and myalgia. In some cases, there may be
of adverse effects even at massive doses, red discolouration burning and tingling of extremities, toothache, sweating,
of mucous membranes, plasma, and urine may occur and and rarely chest pain. Hypertension and tachycardia can
last from 12 hours to a few days after therapy. Prior exposure occur with high doses.41 Doses greater than 25 mg/kg can
© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 885
give rise to hypertensive encephalopathy with convulsions adjust the dose and schedule accordingly. Nephrotoxicity
and coma. can be minimized by taking care to ensure that the total
It is important to note that unless hepatotoxicity daily dose of CaNa2EDTA does not exceed 1 g in children
encountered in a patient is arsenic-induced, hepatic or 2 g in adults, as far as possible. Other, less common
dysfunction is a contraindication to BAL use. adverse effects include malaise, loss of appetite, chills, fever,
myalgia, dermatitis, headache, increased urinary frequency,
BAL is not useful in methylmercury poisoning, because
rhinorrhoea, lacrimation, glycosuria, and anaemia. 41
animal studies have shown a redistribution of mercury to
Extravasation may result in the development of painful
the brain.42
calcinosis at the injection site. Depletion of endogenous
Unintentional IV infusion of BAL can cause fat embolism, metals, particularly zinc, iron, and manganese, can result
lipoid pneumonia, and chylothorax.43 from chronic therapy.49
2. Calcium disodium edetate (CaNa2 EDTA) 3. Succimer (2,3-Dimercaptosuccinic Acid)
Calcium disodium edetate (CaNa2EDTA) is practically the Chinese investigators first reported on the beneficial
only chelating agent that is used in India for the treatment effects of IV succimer in the treatment of lead and mercury
of lead poisoning, though in most Western countries it has poisoning, after which several studies were conducted
been replaced to a large extent by its safer counterpart, around the world, which finally led to FDA approval in
succimer (2,3-dimercaptosuccinic acid). There is evidence 1991 in the United States of America for the treatment of
to show that CaNa2EDTA is capable of reducing blood lead lead-poisoning.50-52 Since then, a large body of evidence
concentrations, enhancing renal excretion of lead, and has accumulated clearly indicating the efficacy of succimer,
reversing the effects of lead on haemoglobin synthesis,44 and its superiority over CaNa2EDTA in the treatment of lead
but no rigorous clinical studies have ever been performed poisoning.53-55
to evaluate its actual efficacy.45 One study of children with
Succimer can also be used for the treatment of
moderately high blood lead levels, who were given 5 days
arsenic and mercury toxicity.56,57 There is one study from
of CaNa2EDTA treatment, showed hardly any difference
India demonstrating the efficacy of succimer in arsenic
in blood lead, bone lead, or erythrocyte protoporphyrin
poisoning.58 The tragedy is that succimer is at present not
concentrations, when compared to pretreatment values.46
available in India, and has to be imported from the West. In
The once popular CaNa2EDTA mobilization test which was
the US, succimer is available under the brand name Chemet®,
recommended as a diagnostic aid for assessing the potential
in the form of 100-mg bead-filled capsules. For patients who
benefits of chelation therapy has now been abandoned as
find it difficult to swallow the capsule, it can be opened out,
useless.47
and the contents sprinkled onto juice, or ice cream, or soft
The recommended dose of CaNa2EDTA depends on food. The recommended dose is 350 mg/m2 in children, 3
the patient’s body surface area or weight, the severity times a day for 5 days, followed by 350 mg/m2 twice a day
of the poisoning, and the status of renal function. For for 14 days.59 In adults, it can be administered at 10 mg/kg,
patients with lead encephalopathy, the dose of CaNa2EDTA following the same regimen as above.
generally recommended is 1500 mg/m2/d by continuous IV
Succimer is generally well tolerated, and does not appear
infusion, starting 4 hours after the first dose of dimercaprol.
to have any serious adverse effects.60 Common problems
Combined dimercaprol and CaNa2EDTA therapy is given
are gastrointestinal in nature, comprising nausea, vomiting,
for 5 days, followed by cessation for 2 to 4 days, which
flatus, diarrhoea, and a metallic taste. Rarely, chills, fever,
permits lead redistribution. Blood lead concentration
urticaria, rash, reversible neutropenia, and eosinophilia
should be measured 1 hour after the CaNa2EDTA infusion
may occur.61,62
is discontinued, to avoid falsely elevated blood lead
concentration determinations. Oximes
In children without evidence of lead encephalopathy, The most commonly used oxime for organophosphate
the dose of CaNa2EDTA is 1000 mg/m2/d, in addition to pesticide (OP) poisoning in India is pralidoxime
dimercaprol at 50 mg/m2 every 4 hours. In most Western (2-hydroxyiminomethyl-1-methyl pyridinium chloride,
countries however, succimer is the chelator of choice pyridine-2-aldoxime methiodide, P 2AM or PAM). The
in lead-poisoned children without encephalopathy. 48 others, asoxime and obidoxime are not available in India.
CaNa2EDTA should be administered at 0.5% concentration Pralidoxime must invariably be administered together with
by continuous IV infusion over 24 hours in 5% dextrose or atropine in the management of OP poisoning.
0.9% NaCl. Concentrations greater than 0.5% may lead to Organophosphate pesticides are power ful
thrombophlebitis and must be avoided. In children with inhibitors of carboxylic esterase enzymes, especially
lead encephalopathy, BAL must be started 4 hours prior acetylcholinesterase, which is found in red blood cells,
to CaNa2EDTA.45 nerve cells, and skeletal muscle, as well as plasma
The main adverse effect of CaNa2EDTA is related to cholinesterase or butyrylcholinesterase, which is found
renal function. Therefore, it is important to monitor renal in plasma, liver, heart, pancreas, and brain). The former is
function closely during CaNa2EDTA administration, and to often referred to as true cholinesterase, and the latter as

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


pseudocholinesterase. Organophosphorus pesticides bind The paediatric dose is said to be 20-40 mg/kg (up to a
to the serine-containing esteratic site of either enzyme, maximum of 2 g) given IV over 30-60 minutes.76 These
inactivating it by phosphorylation.63 This results in the doses can be repeated in 1 hour if muscle weakness and
accumulation of acetylcholine at muscarinic and nicotinic fasciculations are not controlled. Additional doses may be
synapses of the central and peripheral nervous systems, given every 4-8 hours if signs of poisoning keep recurring.
leading to cholinergic excess. The enzyme is subsequently An alternative regimen involves administration of a loading
inactivated, and may undergo one of three reactions: dose of pralidoxime, followed by a continuous IV infusion.77
hydrolysis of the phosphorylated enzyme; reactivation by a Severe cases may require a continuous infusion of 500 mg/h
strong nucleophile, or aging, which is a process that renders in adults and 10-20 mg/kg/h (up to 500 mg/h) in children.
the phosphorylated molecule inactive. Pralidoxime therapy should be continued for a minimum
Hydrolysis of OP compounds can be quite slow, and is of 24 hours after symptoms have resolved.
generally considered to be insignificant in contrast to the Pralidoxime does not have serious adverse effects
rapid hydrolysis of most carbamate (CM) pesticides. Oximes when given at recommended doses. There may be mild
have the ability to reactivate cholinesterase bound to OP vertigo, diplopia, and hypertension in some cases.78 Rapid
compounds.64 Pralidoxime is capable of a nucleophilic attack IV administration can rarely cause sudden cardiac and
on the phosphate moiety, successfully competing for it and respiratory arrest because of laryngospasm and muscle
releasing it from the acetylcholinesterase enzyme.65 This rigidity.79
enables the restoration of enzymatic function. Previously it Ethanol
was believed that pralidoxime therapy can succeed only if
Ethanol is used as an antidote in those cases where
started within 24-48 hours of exposure to the OP compound,
a particular toxic substance is metabolized by alcohol
and that later, the acetylcholinesterase would be irreversibly
dehydrogenase, for e.g., methanol and ethylene glycol.
inactivated. But recent information suggests that oximes
It acts by competitive inhibition as a result of which toxic
can be beneficial even when started much later.66,67
metabolites of methanol and ethylene glycol are not
In the case of carbamate (CM) poisoning, the formed, and the parent compound is excreted unchanged.
acetylcholinesterases which are inactivated, usually get The affinity of ethanol for alcohol dehydrogenase is 67 times
reactivated spontaneously over a few hours, though in that of ethylene glycol and 15.5 times that of methanol.80
severe cases, symptoms may persist for 24 hours or more.68 A relatively smaller quantity of ethanol is required to
Pralidoxime is therefore rarely required for carbamate inhibit the metabolism of ethylene glycol, when compared
poisoning; but it is important to note that it is NOT to the amount required to block the metabolism of
contraindicated as was previously suggested. Such an methanol, since the affinity of ethylene glycol for alcohol
erroneous conclusion was based solely on data derived from dehydrogenase is much less than that of methanol.81 The
the study of a single carbamate (carbaryl). There are several usual recommendation is to maintain a serum ethanol
studies which demonstrate the beneficial effects of oximes concentration of 100 mg/dL, or at least a 1:4 molar ratio
in treating most kinds of carbamate exposure.69 Pralidoxime of ethanol to methanol or ethylene glycol, whichever is
should therefore not be withheld in a seriously poisoned greater.82
patient out of concern that a carbamate is involved.70
Ethanol can be given orally or intravenously. The
Though obidoxime is not available in India, it is usual concentrations recommended for oral and IV
actually 10-20 times more effective in reactivating administration are 20-30% and 5-10% respectively.
acetylcholinesterase than is pralidoxime.71 To improve the Intravenous administration is always preferable since it
central effects of pralidoxime, a new derivative known as leads to complete absorption, does not produce GI effects,
pro-2-PAM, which is actually the dihydropyridine derivative and can be administered to an unconscious patient. The
of pralidoxime was synthesized and introduced into main problem is the difficulty in obtaining and preparing
practice. It has the ability of passing through the blood- an IV ethanol solution. The amount of ethanol absorbed
brain barrier. After passage across the membrane, in vivo after oral administration depends on a number of factors,
oxidation converts it to its active form, demonstrating a 13- such as nutritional status, rate of gastric emptying, sex and
fold higher level of PAM in the brain, than when PAM itself age of the patient, genetic factors, chronic alcoholism, etc.
is administered directly.72 Some organophosphates which Adequate concentration is usually achieved with 0.8 g/kg
are used as chemical warfare nerve agents can only be of ethanol given orally over 20 minutes.83
tackled by the H series of oximes (named after Hagedorn).
Mode of administration84
They demonstrate far greater efficacy against sarin, VX and
some other newer pesticides.73-75 They are however not as 10% ethanol at a dose of 10 ml/kg administered IV over
efficacious in traditional OP poisoning. 30 minutes, followed by 1.5 ml/kg/hr, so as to produce
and maintain a blood ethanol level of 100 mg/100 ml.
There is a great deal of controversy regarding the
Blood ethanol levels should be maintained at 100 to 130
exact dosage regimen for pralidoxime in OP poisoning.
mg/100 ml (21.7 to 28.2 mmol/L). Alternatively, 1 ml/kg
Conventionally, the recommended initial adult dose is 1-2
of 95% ethanol in fruit juice (180 ml) can be given orally
g in 100 mL of 0.9% saline given IV over 15-30 minutes.
over 30 minutes. For maintenance, administer 0.17 to 0.28
© JAPI  •  VOL. 56  •  NOVEMBER 2008 www.japi.org 887
ml/kg/hr as 50% ethanol in fruit juice. If neither of these is Even though flumazenil is very effective in benzodiazepine
practicable, give 125 ml of a distilled alcoholic beverage (gin, overdose, its actual use in practice is controversial, primarily
vodka, whisky, or rum) orally, diluted in glucose solution or because of the low morbidity and mortality associated
juice, and repeat as required cautiously. If single use vials with benzodiazepine poisoning. One double-blind
of pyrogen-free absolute ethanol are not available, bulk controlled study covering 702 cases over a 14-year period
ethanol can be used. A 0.22 micron filter should be used to demonstrated a mortality of only 0.7%.89 In fact, the mortality
minimize particulate matter. rate for nonbenzodiazepine-related overdoses was more
Ethanol therapy should be continued until the following (1.6%). Therefore the current view is to use flumazenil only
criteria are met: in the small minority of “seriously overdosed” patients, and
to rely only on supportive measures in all other cases. If it is
 Methanol blood concentration, measured by a reliable
decided to be given, the usual dose is 0.1 mg/min by slow
technique, is less than 10 mg/100 ml.
IV titration, to a total dose of 1 mg. Re-sedation may occur
 Formate blood concentration is less than 1.2 mg/100 in half hour to 2 hours, and re-administration of flumazenil
ml. may be necessary.
 Methanol-induced acidosis (pH, blood gases), clinical The main problems associated with flumazenil use
findings (CNS), electrolyte abnormalities (bicarbonate), include precipitation of seizures in benzodiazepine-
serum amylase, and osmolal gap have resolved. dependent patients, unmasking of arrhythmias in patients
Adverse effects of ethanol administration include who coingest benzodiazepine with tricyclic antidepressants,
aggravation of CNS depression, hepatitis, pancreatitis, and the need for frequent re-administration.
hypoglycaemia, dehydration, etc. Naloxone
Fomepizole (4-Methyl Pyrazole) Naloxone is a pure competitive opioid antagonist at the
Fomepizole, like ethanol is a competitive inhibitor of mu (µ) receptor, while nalmefene and naltrexone act at the
alcohol dehydrogenase (ADH), minimizing the formation kappa and delta receptors. Naloxone is most commonly
of toxic metabolites from ethylene glycol and methanol. It used in opioid overdose, and is available in India. The usual
however, has the advantage of being much more potent dose is 0.05 mg IV to begin with, increasing it as indicated to
than ethanol, and does not aggravate the already existing 0.4 mg, 2 mg, and up to a maximum of 10 mg. Continuous
CNS toxicity. Administration is also much easier without monitoring is necessary for the return of respiratory
need for serum concentration monitoring, thus allowing for depression, and if this happens, repeated doses of naloxone
every-12-hour dosing except during haemodialysis, when will have to be given. Alternatively, another bolus followed
dosing should occur every 4 hours. Adverse effects are by a continuous infusion may be embarked upon. 90
milder and of less frequency, and comprise local reactions Naloxone is best administered intravenously in normal
at the site of infusion (when the concentration exceeds 25 saline. It can also be given by intramuscular, subcutaneous,
mg/mL), nausea, vertigo, headache, rash, etc. Fomepizole endotracheal, intranasal, and intralingual routes, as well as
must therefore always be preferred to ethanol, but it is in the form of nebulization.
unfortunately not yet available in India. Adverse effects associated with naloxone (excepting
The usual dosing recommendation is as follows.85,86 A withdrawal and resedation), are rarely encountered.
loading dose of 15 mg/kg IV is first administered, followed Patients tolerant to opioids may manifest withdrawal
in 12 hours by 10 mg/kg every 12 hours for 4 doses. If it is reaction, characeterized by yawning, lacrimation, sweating,
necessary to continue with fomepizole beyond 48 hours, the rhinorrhea, piloerection, mydriasis, vomiting, diarrhoea,
dose may be increased to 15 mg/kg every 12 hours, for as etc. There are rare reports of acute lung injury (non-
long as necessary. This increase is recommended because cardiogenic pulmonary oedema), hypertension, and cardiac
fomepizole stimulates its own metabolism. Fomepizole arrhythmias.
must always be diluted in 100 mL of normal saline or 5% Naltrexone is administered orally in chronic opioid
dextrose prior to IV administration, to avoid venous irritation abusers following detoxification, to maintain opioid
and phlebosclerosis. abstinence. Nalmefene is a new entrant whose duration of
Flumazenil action falls between that of naloxone and naltrexone.
Flumazenil is a competitive antagonist for benzodiazepine Methylene Blue
receptors. While it does not directly reverse the respiratory Methylene blue is a very effective antidote for
depression induced by benzodiazepines, it is very effective toxins causing methaemoglobinaemia. Symptomatic
in reversing CNS depression. An important point to note methaemoglobinaemia usually occurs when the
is that since the duration of action of flumazenil is shorter methaemoglobin level exceeds 20%, and in such cases,
than that of most benzodiazepines, repeat doses are usually methylene blue is given at a dose of 1-2 mg/kg IV over 5
necessary at relatively short intervals. Flumazenil is also said minutes, followed immediately by a fluid flush of 15-30
to be effective for zolpidem and zaleplon overdoses, which mL to minimize local pain. The onset of action is rapid, but
interact with a subclass of benzodiazepine receptors.87,88 repetitive dosing may be required in association with GI

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


decontamination, in the case of drugs such as dapsone, from 50 to 250 mg daily for weeks to months. 97 The
which is one of the commonest agents implicated in recommended starting dose is 25 to 50 mg orally, 8th or 6th
methaemoglobinaemia in the toxicological setting.91 hourly, for one or two days. The INR should be constantly
It is important to note that methylene blue has the monitored, and the dose adjusted if necessary. When the
paradoxical ability of itself inducing methaemoglobinaemia INR drops below 2, a downward titration of vitamin K1
when given in excess. This means that there is normally can be made, based on factor VII analysis. In the case of
an equilibrium between the ability of methylene blue to brodifacoum poisoning, serum levels of brodifacoum may
oxidize haemoglobin directly to methaemoglobin, and be helpful in deciding the duration of treatment.96
to reduce methaemoglobin to haemoglobin through the Intravenous administration of vitamin K 1 should be
NADPH and NADPH methaemoglobin reductase pathway, reserved for life-threatening bleeding. In such a case, the
and leukomethylene blue production. The equilibrium gets patient may be supplemented with prothrombin complex
disturbed when excessively large doses of methylene blue concentrate. If it is not available, fresh-frozen plasma or
are administered or when the NADPH methaemoglobin recombinant factor VIIa can be considered as alternatives.
reductase system is abnormal.92 Other major adverse effects Vitamin K1 can be begun at a dose of 10 mg, taking care to
of methylene blue include tachypnoea, chest discomfort, dilute with preservative-free 5% dextrose, normal saline,
bluish discolouration of skin and mucous membranes, or 5% dextrose in saline, and administered slowly, at a
paraesthesias, restlessness, nausea, and vomiting. Urine and rate not exceeding 1 mg/min, to minimize the risk of an
vomitus usually have a bluish tinge. Intravenous methylene anaphylactoid reaction. The dose may have to be repeated
blue is quite painful, and may cause local tissue damage 3 to 4 times daily.
even in the absence of extravasation.93 When given orally, vitamin K1 is virtually free of adverse
Vitamin K effects, except for overcorrection of the INR in the setting
Vitamin K is an essential fat-soluble vitamin, and of a patient who requires maintenance anticoagulation.
is actually a generic term that includes two distinct Intravenous administration has resulted in death secondary
natural forms: vitamin K1 (phytonadione, phylloquinone) to anaphylactoid reactions, probably as a result of the
and vitamin K2 (menaquinones) comprising a series of preparation’s colloidal formulation.98
compounds with the same 2-methyl-1,4-naphthoquinone
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