Antidote

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

Review Article

Current Views on Antidotal Therapy in Managing Cases of Poisoning and OverdoseVV Pillay*

AbstractWhile 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. ©

titled Antitheriaka : An Essay on Mithridatum and Theriaka 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

*Chief, Poison Control Centre and Head, Dept. of Analytical Toxicology, Amrita Institute of Medical Sciences and Research, Cochin - 682 026.

INTRODUCTION

In 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

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

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 AmanitinAtropine Cholinergic agents —Calcium salts Oxalates, fluorides Calcium antagonistsDantrolene Malignant hyperthermia Malignant neuroleptic syndromeDesferrioxamine Iron, aluminium ParaquatDicobalt edetate Cyanide —Digoxin specific antibody fragments Digitalis glycosides —Dimercaprol Arsenic Copper, gold, mercuryEthanol Methanol, ethylene glycol —Flumazenil Benzodiazepines —Glucagon Beta blockers —Glucose Insulin —Hydroxocobalamin Cyanide —4, Methylpyrazole (fomepizole) Ethylene glycol, methanol Disulfiram, coprinNaloxone Opiates —Oximes Organophosphates —Oxygen Cyanide, carbon monoxide, hydrogen sulfide —Oxygen (Hyperbaric) tetrachloride Carbon monoxide Cyanide, hydrogen sulfide,carbon Penicillamine Copper Gold, lead, mercuryPhysostigmine Central anticholinergics —Phytomenadione (Vitamin K) Coumarin derivatives —Potassium hexacyanoferrate Thallium —(Prussian Blue)Protamine sulfate Heparin —Pyridoxine Isoniazid Ethylene glycol, gyrometrine, hydrazinesSodium nitrite Cyanide Hydrogen sulfideSodium thiosulfate Cyanide Bromate, chlorate, iodineSuccimer (DMSA) Lead, mercury —


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

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

AtropineAtropine 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

Table 2 : Adjunctival antidotes

Agent Indication

Activated charcoal For most poisons Benztropine DystoniaChlorpromazine Psychotic statesDiazepam ConvulsionsDiphenhydramine DystoniaDopamine Myocardial depression, vascular relaxationEpinephrine Anaphylactic shock, cardiac arrestFurosemide Fluid retention, left ventricular failureHaloperidol Psychotic statesHeparin HypercoagulabilityLidocaine Ventricular arrhythmiasMannitol Cerebral oedema, fluid retentionPancuronium ConvulsionsPromethazine Allergic reactionsSalbutamol BronchoconstrictionSodium bicarbonate Metabolic acidosis

Table 3 : Obsolete antidotes

Agent Indication

Copper sulfate PhosphorusCysteamine ParacetamolDiethyldithiocarbamate ThalliumFructose EthanolLevallorphan OpiatesNalorphine OpiatesSilibinin AmanitinTocopherol ParaquatUniversal antidote Ingested poisons


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 p re c i s e d o s a g e re g i m e n o f a t ro p i n e fo r 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

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

to hydroxocobalamin or cyanocobalamin (for treatment of vitamin B12 deficiency) may rarely predispose a patient to allergic reactions, including anaphylaxis.34

Metal chelating agentsMost 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

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, P2AM 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.

O r g a n o p h o s p h a t e p e s t i c i d e s a r e p o w e r f u l 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.

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

EthanolEthanol 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

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

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 K1 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

REFERENCES1. Wax PM. Historical principles and perspectives. In: Flomenbaum

NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin NA, Nelson LS (editors). Goldfrank’s Toxicologic Emergencies. 8th edn, 2006. McGraw Hill, 2-17.

2. Jarcho S. Medical numismatic notes. VII Mithridates IV. Bull N Y Acad Med 1972;48:1059-64.

3. Watson G. Theriac and Mithradatum: A Study in Therapeutics. 1966. Wellcome Historical Medical Library, London.

4. Thompson CJ. Poison and Poisoners. 1931. Harold Shaylor, London.

5. Cooney DO. Activated Charcoal in Medical Applications. 1995. Marcel Dekker, New York.

6. Holt LE, Holz PH. The black bottle: A consideration of the role of charcoal in the treatment of poisoning in children. J Pediatr 1963;63:306-14.

7. Howland MA, Weisman R, Sauter D, Goldfrank LR. Non-availability of poison antidotes. N Engl J Med 1986;314: 927-8.

8. Chyka P, Butler A, Holliman B, Herman M. Utility of acetylcysteine in treatment of poisonings and adverse drug reactions. Drug Saf 2000;2:123-48.

9. G o p a u l S V, Fa r re l l K , A b b o t t F S . I d e n t i f i c a t i o n a n d characterization of N-acetylcysteine conjugates of valproic acid in humans and animals. Drug Metab Dispos 2000;28: 823-32.

10. Wong CK, Ooi VE, Kim C. Protective effects of N-acetylcysteine against carbon tetrachloride and trichloroethylene-induced poisoning in rats. Environ Toxicol Pharmacol 2003;14:109-116.

11. Llobet JM, Domingo JL, Corbella J. Comparative effects of repeated parenteral administration of several chelators on the distribution and excretion of cobalt. Res Commun Chem Pathol Pharmacol 1988;60:225-33.


12. Harrison P, Wendon J, Gimson A, et al. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852-7.

13. Riordan SM, Williams R. Fulminant hepatic failure. Clin Liver Dis 2000; 4: 25-45.

14. K e a y s R , H a r r i s o n P, We n d o n J , e t a l . I n t r a v e n o u s acetylcysteine in paracetamol-induced fulminant hepatic fa i lure : A prospec t ive control led tr ia l . BMJ 1991;303: 1026-9.

15. Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: A prospective case controlled study. Accid Emerg Nurs 2004;12:10-15.

16. Berghem L, Bergman U, Schildt B, et al. Plasma atropine concentrations determined by radioimmunoassay after single-dose I.V. and I.M. administration. Br J Anaesth 1980;52:597-601.

17. Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998;50:279-90.

18. Eddleston M, Buckley NA, Checketts H, et al. Speed of initial atropinisation in significant organophosphorus pesticide poisoning: A systematic comparison of recommended regimens. J Toxicol Clin Toxicol 2004;42:865-75.

19. Namba T, Nolte CT, Jackrel J, et al. Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Am J Med 1971;50:475-92.

20. Eddleston M, Dawson A, Karalliedde L, et al. Early management after self-poisoning with an organophosphorus or carbamate pesticide: A treatment protocol for junior doctors. Crit Care 2004;8:R391-397.

21. Whitten C, Gibson G, Good M, et al. Studies in acute iron poisoning: Desferrioxamine in the treatment of acute iron poisoning: Clinical observations, experimental studies and theoretical considerations. Pediatrics 1965;36:322-35.

22. Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload. Ann N Y Acad Sci 1998;850:191-201.

23. Nakamura H, Rose PG, Blumer JL, et al. Acute encephalopathy due to aluminum toxicity successfully treated by combined intravenous deferoxamine and hemodialysis. J Clin Pharmacol 2000;40:296-300.

24. Howland MA. Risks of parenteral deferoxamine. J Toxicol Clin Toxicol 1996;34:491-7.

25. Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. J Toxicol Clin Toxicol 1996;34:485-9.

26. Cheney K, Gumbiner C, Benson B, et al. Survival after a severe iron poisoning treated with intermittent infusions of deferoxamine. J Toxicol Clin Toxicol 1995;33:61-66.

27. Ioannides AS, Panisello JM. Acute respiratory distress syndrome in children with acute iron poisoning: The role of intravenous desferrioxamine. Eur J Pediatr 2000;159:158-9.

28. Adamson I, Sienko A, Tenenbein M. Pulmonary toxicity of deferoxamine in iron-poisoned mice. Toxicol Appl Pharmacol 1993;120:13-9.

29. Lin S, Shieh S, Lin Y, et al. Fatal Aeromonas hydrophilia bacteremia in a hemodialysis patient treated with deferoxamine. Am J Kidney Dis 1996;27:733-5.

30. Way JL. Cyanide intoxication and its mechanism of antagonism. Annu Rev Pharmacol Toxicol 1984;24:451-81.

31. Marrs TC. The choice of cyanide antidotes. In: Ballantyne B, Marrs TC (editors). Clinical and Experimental Toxicology of Cyanides. Bristol, Wright, 1987:383-401.

32. Meredith TJ, Jacobsen D, Haines JA, et al (editors). Antidotes for Poisoning by Cyanide. New York, Cambridge Press, 1993.

33. Hall AH, Kulig KW, Rumack BH. Suspected cyanide poisoning in smoke inhalation: Complications of sodium nitrite therapy. J Toxicol Clin Exp 1989;9:3-9.

34. Hall AH, Rumack BH, Schaffer MI, et al. Clinical toxicology of cyanide: North American experiences. In: Ballantyne B, Marrs TC (editors). Clinical and Experimental Toxicology of Cyanides. Bristol, Wright, 1987:313-333.

35. Marrs TC. Antidotal treatment of acute cyanide poisoning. Adverse Drug React Acute Poisoning Rev 1988;7:179-206.

36. Rose CL, Worth RM, Chen KK. Hydroxocobalamine and acute cyanide poisoning in dogs. Life Sci 1965;4:1785-9.

37. Borron S, Baud F. Toxicity, Cyanide. Available at http://www.emedicine.com/emerg/topic118.htm. Last accessed: August 12, 2008.

38. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, et al. Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;97:23-38.

39. Howland MA. Antidotes in depth: Dimercaprol (British Anti-lewisite or BAL). In: Flomenbaum NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin NA, Nelson LS (editors). Goldfrank’s Toxicologic Emergencies. 8th edn, 2006. McGraw Hill, 1266-1269.

40. Committee on Drugs. Treatment guidelines for lead exposure in children. Pediatrics 1995;96:155-60.

41. Klaassen CD. Heavy metals and heavy metal antagonists. In: Hardman JG, Limbird LE (editors). The Pharmacological Basis of Therapeutics. 10th edn, 2001. New York, Macmillan. 1851-1875.

42. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, et al. Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;97:23-38.

43. Seifert SA, Dart RC, Kaplan EH. Accidental, intravenous infusion of a peanut oil-based medication. J Toxicol Clin Toxicol 1998;36:733-6.


45. Corey-Slechta DA. Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic, and glutamatergic neurotransmitter system functions. Annu Rev Pharmacol Toxicol 1995;35:391-415.

46. Markowitz M, Bijur P, Ruff M, et al. Effects of calcium disodium versenate (CaNa2-EDTA) chelation in moderate childhood lead poisoning. Pediatrics 1993;92:265-71.

47. Cory-Slechta DA, Weiss B, Cox C. Mobilization and redistribution of lead over the course of calcium disodium ethylenediamine tetraacetate chelation therapy. J Pharmacol Exp Ther 1987;243:804-13.

48. C h i s o l m J J J r . S a f e t y a n d e f f i c a c y o f m e s o - 2 , 3 -dimercaptosuccinic acid (DMSA) in children and elevated blood lead concentrations. J Toxicol Clin Toxicol 2000;38: 365-75.

49. Thomas DJ, Chisolm J. Lead, zinc, copper decorporation during Ca EDTA treatment of lead poisoned children. J Pharmacol Exp Ther 1986;229:829-35.

50. Wang SC, Ting KS, Wu CC. Chelating therapy with NaDMS in occupational lead and mercury intoxication. Chin Med J 1965;84:437-9.

51. Fournier L, Thomas G, Garnier R, et al. 2,3-Dimercaptosuccinic acid treatment of heavy metal poisoning in humans. Med Toxicol 1988;3:499-504.

52. Singh PK, Jones MM, Xu Z, et al. Mobilization of lead by esters of meso-2,3-dimercaptosuccinic acid. J Toxicol Environ Health 1989;27:423-34.

53. Grandjean P, Jacobsen IA, Jorgensen PJ. Chronic lead poisoning treated with dimercaptosuccinic acid. Pharmacol Toxicol 1991;68:266-9.


54. Thomas PS, Ashton C. An oral treatment for lead toxicity. Postgrad Med J 1991; 67: 63-65.

55. Tuntunji MF, al-Mahasneh QM. Disappearance of heme metabolites following chelation therapy with meso 2,3-dimercaptosuccinic acid (succimer). J Toxicol Clin Toxicol 1994;32:267-76.

56. Cullen NA, Wolf LR, St. Clair D. Pediatric arsenic ingestion. Am J Emerg Med 1995;13:432-5.

57. Keith RL, Setiarahardjo I , Fernando Q, et al. Util ization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney. Toxicology 1997;116: 67-75.

58. Mazumder DN, Das Gupta J, Santra A, et al. Chronic arsenic toxicity in West Bengal: The worst calamity in the world. J Indian Med Assoc 1998;96:4-7,18.

59. Mortensen ME. Succimer chelation: What is known? J Pediatr 1994;125:233-4.

60. C h i s o l m J J . S a f e t y a n d e f f i c a c y o f m e s o - 2 , 3 -dimercaptosuccinic acid (succimer) in children with elevated blood lead concentrations. J Toxicol Clin Toxicol 2000;38: 365-75.

61. Besunder JB, Anderson RL, Super DM. Short-term efficacy of oral dimercaptosuccinic acid in children with low to moderate lead intoxication. Pediatrics 1995;96:683-7.


63. Karczmar A. Invited review: Anticholinesterases: Dramatic aspects of their use and misuse. Neurochem Int 1998;32: 401-11.

64. Wong L, Radic Z, Bruggemann RJ, et al. Mechanism of oxime reactivation of acetylcholinesterase analyzed by chirality and mutagenesis. Biochemistry 2000;39:5750-7.

65. Willems JL, Langenberg JP, Verstraete AC, et al. Plasma concentrations of pralidoxime methyl sulfate in organophosphorus poisoned patients. Arch Toxicol 1992;66:260-6.

66. Eddleston M, Szinicz L, Eyer P, et al. Oximes in acute organophosphorous pesticide poisoning: A systematic review of clinical trials. QJ Med 2002;95:275-83.

67. Eyer P. The role of oximes in the management of organophosphorus pesticide poisoning. Toxicol Rev 2003;22:166-90.

68. Burgess JL, Bernstein JN, Hurlbut K. Aldicarb poisoning: A case report with prolonged cholinesterase inhibition and improvement after pralidoxime therapy. Arch Intern Med 1994;154:221-4.

69. Sterri S, Rognerud B, Fiskum S, Lyngaas S. Effect of toxogenin and P2S on the toxicity of carbamates and organophosphorus compounds. Acta Pharmacol Toxicol 1979;45:9-15.

70. Lotti M, Becker C. Treatment of acute organophosphate-poisoning: Evidence of a direct effect on central nervous system by 2-PAM (pyridine-2-aldoxime methyl chloride). J Toxicol Clin Toxicol 1982;19:121-7.

71. Wo re k F, B a c k e r M , Th i e r m a n n H , e t a l . R e a p p ra i s a l o f i n d i c a t i o n s a n d l i m i t a t i o n s o f o x i m e t h e r a p y in organophosphate poisoning. Hum Exp Toxicol 1997;16: 466-72.

72. Rump S, Faff J, Borkowska G, et al. Central therapeutic effects of dihydro-derivative of pralidoxime (pro-2-PAM) in organophosphate intoxication. Arch Int Pharmacodyn Ther 1978;232:321-31.

73. Clement JG, Bailey DG, Madill HD, et al. The acetylcholinesterase oxime reactivator HI-6, in man: Pharmacokinetics and tolerability in combination with atropine. Biopharm Drug Dispos 1995;16:415-25.

74. Kassa J, Cabal J. A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6, with currently available oximes and H

oximes against soman in in vitro and in vivo methods. Toxicology 1999;132:111-8.

75. Worek F, Thiermann H, Szinicz L. Reactivation and aging kinetics of human acetylcholinesterase inhibited by organophosphonylcholines. Arch Toxicol 2004;78:212-7.

76. Rotenberg J, Newmark J. Nerve agent attacks on children: Diagnosis and management. Peds 2003;112:648-58.

77. Schexnayder S, James L, Kearns G, Farrar H. The pharmacokinetics of continuous infusion pralidoxime in children with organophosphate poisoning. J Toxicol Clin Toxicol 1998;36:549-55.

78. Medicis JJ, Stork CM, Howland MA, et al. Pharmacokinetics following a loading plus a continuous infusion of pralidoxime compared with the traditional short infusion regimen in human volunteers. J Toxicol Clin Toxicol 1996;34:289-95.

79. Scott RJ. Repeated asystole following PAM in organophosphate self-poisoning. Anesth Intensive Care 1986;4:458-60.

80. Howland MA. Antidotes in depth: Ethanol. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin NA, Nelson LS (editors). Goldfrank’s Toxicologic Emergencies. 8th edn, 2006. McGraw Hill, 1465-1468.

81. Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings: Mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1:309-34.

82. Tarr B, Winters L, Moore M, et al. Low-dose ethanol in the treatment of ethylene glycol poisoning. J Vet Pharm Ther 1985;8:254-62.

83. Cobaugh DJ, Gibbs M, Shapiro DE, et al. A comparison of the bioavailabilities of oral and intravenous ethanol in healthy male volunteers. Acad Emerg Med 1999;6:984-8.

84. Pillay VV. Alcohols. In: Comprehensive Medical Toxicology. 2nd edn, 2008. Paras Medical Publisher, Hyderabad, India. 179-215.

85. Barceloux DG, Bond GR, Krenzelok EP. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol 2002;40:415-46.

86. Barceloux DG, Krenzelok EP, Olson K, Watson W. American Academy of Clinical Toxicology Practice guidelines on the treatment of ethylene glycol poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol 1999;37:537-60.

87. L’heureux P. Continuous flumazenil for zolpidem toxicity: Commentary. J Toxicol Clin Toxicol 1998;36:745-6.

88. Noguchi H, K itazumi K , Mori M, Shiba T. Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic. Eur J Pharmacol 2002;434:21-8.

89. Hojer J, Baehrendtz S. The effect of f lumazenil in the management of self-induced benzodiazepine poisoning: A double-blind controlled study. Acta Med Scand 1988;224: 357-65.

90. Lewis JM, Klein-Schwartz W, Benson BE, et al. Continuous naloxone infusion in pediatric narcotic overdose. Am J Dis Child 1984;138:944-6.

91. Southgate HJ, Masterson R. Lessons to be learned: A case study approach. Prolonged methemoglobinemia due to inadvertent dapsone poisoning; Treatment with methylene blue and exchange transfusion. J R Soc Health 1999;119:52-5.

92. Whitwam JG, Taylor AR, White JM. Potential hazard of methylene blue. Anesthesiology 1979;34:181-2.

93. Raimer S, Quevedo E, Johnston R. Dye rashes. Cutis 1999;63:103-106.

94. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K reversed warfarin-associated coagulopathy faster than subcutaneous vitamin K. Ann Intern Med 2002;137:251-4.


95. Baglin T. Management of warfarin (Coumadin) overdose. Blood Rev 1998;12:91-8.

96. Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: Brodifacoum kinetics and optimal vitamin K1 dosing. Ann Emerg Med 2000;36:262-7.

97. La Rosa F, Clarke S, Lefkowitz J. Brodifacoum intoxication with marijuana smoking. Arch Pathol Lab Med 1997;121: 67-9.

98. O’Reilly R, Kearns P. Intravenous vitamin K1 injections: Dangerous prophylaxis. Arch Intern Med 1995;155:2127-8.

Documents

Antidote