Factors Modifying Action Of Poison

Published Date: 02 Nov 2017

Toxicology is the branch of medical science dealing with properties, actions, toxicity, fatal dose, detection, estimation and treatment of poisons. Shortly, it the science that studies poisons in all its aspects. It has many categories:

Forensic Toxicology

Clinical Toxicology

Industrial Toxicology

Environmental toxicology

Forensic Toxicology deals with the medical and legal aspects of the harmful effects of chemicals on human beings.

POISON

A Poison can be defined as any substance which, when introduced in to a living body by any rout or comes in contact with the body produces ill health disease or death. In law, the real difference between a medicine and a poison is determined by the intent with which it is given or administered.

NATURE OF POISONING IN INDIA1-4

In India, poisoning usually occurs by the following modes:

A. HOMICIDAL POISONS

Criteria are of ideal homicidal poison:

1. Should be easily available.

2. Should be cheap.

3. Should be tasteless or have a good taste.

4. Should be colorless and soluble.

5. Fatal dose should be small.

6. The symptoms produced should simulate a pathological disease.

7. There should be a time gap between administration and appearance of symptoms.

8. Should not be easily detectable during post-mortem and subsequent examinations.

B. SUICIDAL POISONS

Criteria are of ideal suicidal poison:

1. Should be easily available and cheap.

2. Should have a good taste or should be tasteless.

3. The effects should be sure.

4. Death should be as far as possible painless and peaceful.

C. ACCIDENTAL POISONS

Ignorance, e.g., medicine-ignorance regarding dose, way of intake, etc.

Carelessness, e.g., in storing poison.

Misbelieve, e.g., love philter, aphrodisiac, for fairing complexion.

Industrial toxicity, while manufacturing and storing, viz., iron ore containing Arsenic during smelting liberates AsH3, careless storing of Methyl isocyanates.

IV. CATTLE AND ANIMAL POISONS

It is common especially in rural areas. The main motive is destruction of cattle and animal of an enemy.

V. STUPEFYING POISONS

Done in places where there is a confluence of unknown peoples. Legally it means making a person unconscious or semi-conscious, in the way of committing a crime.

ACTION OF POISON

Poisons act on the body in different ways. A poison may have:

1. Local action: There are certain poisons which act only at the site of contact and these are known as locally-acting poisons, e.g., corrosive mineral acids and alkalis.

2. Remote action: These poisons, act on selective areas after absorption and practically they do not even have any local effect, e.g., opium, datura aconite.

3. Both local and remote action: These poisons act locally and after being absorbed, they have action on a remote site, e.g., carbolic acid.

FATE OF POISONS IN THE BODY

After intake of the poison, the natural defense mechanism of the body always tries to get rid of the poison from the body and that can be done by the following ways:

By the way of vomiting, purging and through respiratory exhaled air,

By sweating, through milk or bile.

Through urine, e.g. carbolic acid, etc.

By biotransformation; metabolism of poison takes place in the body partly or completely mainly in the liver.

Deposited in issue, e.g. lead, Arsenic.

DIAGNOSIS OF POISON

IN LIVING

History of taking something.

Uniformity same type of symptoms in multiple person points to particular poison.

Rapid recovery or death.

Previous health, no history of similar illness.

Detection of poison, circumstantial evidence, colour, smell, etc.

Baffling signs and symptom.

Laboratory examination.

IN DEAD BODY

Finding of peculiar colour of post mortem lividity (Table 31.1).

Deep cyanosis.

Staining over the body, clothing.

Odour of the poison e.g. garlicky kerosene like smell in organo-phosphates, phenolic smell in carbolic acid etc.

Evidence of deep congestion of internal organs.

Laboratory examination including viscera and body fluid analysis for detection of poison.

Table 31.1 Poisons imparting colour on PM lividity

Poisoning

Colour of post mortem lividity

Carbon monoxide

Cherry pink

Cyanide

Brick red

Hydrogen sulfide

Greenish blue

Phosphorus

Brown

Nitrobenzene, aniline, potassium chloride

Brownish red

FACTORS MODIFYING ACTION OF POISON1–7, 15

1. Quantity: The natural assumption is, that, a large dose of a poison, will produce death more rapidly by causing severe symptoms than a smaller dose, but, in some cases, the ill effects are extenuated by vomiting excited by a large dose of it, e.g., copper sulphate. Moreover, action of poison varies with the quantity, e.g., Arsenic, when administered in a very heavy dose (more than 1 gm), it will produce death without causing irritant symptoms, while, in smaller, it acts like an irritant.

2. Form

a. Physical state

i. Poison in gaseous from is more lethal than liquids and then comes the solid form.

ii. Solid in finer molecular state acts better than coarse state.

iii. Concentrated poison acts more severely than diluted ones.

b. Chemical combination: The action of poison depends upon solubility and insolubility resulting from chemicals combination, e.g., silver nitrate (AgNO3) and hydrochloric acid (HCl), when taken separately, acts in severe way, whereas, the combined form an insoluble salt, viz., innocuous. In the same way strong acid and alkalis when administered together, are rendered harmless by their neutralizing effect. Similarly ingested opium is oxidized to oxydimorphine (which is inert) in stomach with potassium permanganate (KMnO4) solution.

c. Mechanical combination: The action of a poison may be changed much if combined mechanically with inert substances, e.g., a small dose of concentrated mineral acid diluted with water, may be taken orally without adverse effect.

3. Mode of administration: Rapidity of poison depends on the way it is being administered, thus a poison acts most rapidly when it is inhaled in gaseous form. Then comes in order of merit is introduction through IV or Intra-arterial route or injection by SC or IM route or application over a wound or application over serous or cellular surface or ingestion or introduction through rectal route or through unbroken skin.

4. Condition of the body

a. Age: Ordinarily poisons have a greater effect over the extremes of ages, but in certain poisons, viz., belladonna is better tolerated by children than by adults.

b. Idiosyncrasy: It means abnormal body response to a drug or substance. An individual may show toxic manifestation to a drug, even in normal dose.

c. Tolerance: By long continued use of certain drug, viz., opium and its preparation, tobacco, alcohol, strychnine, cocaine and arsenic, people aquir a tolerance towards a very large dose, which under ordinary circumstances, might have proved fatal.

d. Diseased condition: Certain drugs are tolerated better during certain diseases, viz. opium alkaloids in tetanus, barbiturate in delirium tremens and strychnine in paralysis. Similarly, digitalis or nicotine even if given in similar dose in a person suffering from cardiac disease, may prove fatal.

5. Synergistic effect: Effect of a poison may be enhanced in presence of another poison, e.g., alcohol with barbiturate.

TOXICITY RATING OF POISON (TRP)

The TRP has been developed to assess the nature of a poison by a physician while face a case of poisoning. Higher the toxicity rating for a given poison, the more would be its potency. It is based on the mortality and is applicable for acute exposure of a single poisonous substance. The toxicity rating of different poison is given in Table 31.2.

Table 31.2 Toxicity rating of poison

Fatal dose

Rating

Less than 5 mg/kg

6

Super toxic

5 to 50 mg/kg

5

Extremely toxic

51 to 500 mg/kg

4

Very toxic

501 mg/kg to 5 gram/kg

3

Moderately toxic

5.1 gm/kg to 15 gm/kg

2

Slightly toxic

More than 15 gm/kg

1

Practicaly non-toxic

CLASSIFICATIONS OF POISONS5, 7

A. CORROSIVE POISONS

I. Strong acids:

a. Inorganic acids: Sulphuric acid, Nitric acid, and Hydrochloric acid.

b. Organic acids: Carbolic, oxalic and acetic acids.

II. Alkalis: Carbonates of sodium, potassium, Bicarbonates and Ammonia.

III. Metallic salts: Zinc chloride, Potassium cyanide, Ferric chloride, etc.

B. IRRITANTS POISONS

I. Inorganic irritants

a. Non-metallic poisons: Phosphorous, Chlorine, Bromine, Iodine, Fluorine, etc.

b. Metallic poisons: Arsenic, Copper sulphate, Lead, Mercury, Iron, Zinc, Antimony, etc.

II. Organic irritants

a. Vegetable irritants: Castor seeds, Croton seeds, abrus precatorius (rati), Semicarpus, Plumbago, etc.

b. Animal irritants: Snake venom, Insect bites e.g., scorpions, spiders, poisonous insects, stings of wasps, bees, hornets and Cantharides etc.

III. Mechanical irritants: Powered glass, diamond dust, hairs, nails, dried sponge etc.

C. SYSTEMIC POISONS

I. Cerebral Poisons (Affecting the brain)

a. Somniferous and Narcotics (Sleep-inducing): Opium and its alkaloids, e.g., Morphine.

b. Inebriants (which elevates mood): Alcohol, chloroform, ether, etc.

c. Deliriants (causing delirium): Alkaloids of datura and cannabis Indica, cocaine, etc.

II. Spinal Poisons

a. Spinal stimulating poison: Nux vomica and its alkaloids, strychnine.

b. Spinal depressant: Gelsemium.

III. Peripheral nerve Poison: Conium and Curare.

IV. Cardiac poisons: Aconite, Digitalis, Oleander, etc.

V. Asphyxiants poisons: Carbon dioxide, Carbon monoxide, Hydrogen sulphide, Coal gas, War gases, Hydrocyanic Acid, Sewer gas, etc.

VI. Nephrotoxic Poison: Mercury

VII. Hepatotoxic Poison: Phosphorus

D. MISCELLANEOUS - Botulism poisoning (food poisoning), etc.

GENERAL LINE OF TREATMENT1-6

The general principle of treatment of poisoning is based on the following principles.

MANAGEMENT OF POISONING

Evaluation and stabilization

Decontamination

Diagnostic testing

Antidotes

EVALUATION AND STABILISATION

The basic steps are:

i. Control the life threatening problems.

ii. Maintain ABCD, i.e.

A- Maintenance of airway: patency of the airway is to be maintained; any foreign body, aspirate or secretions are to be cleared, intubate if required.

B- Maintenance of breathing: maintain the breathing; oxygen inhalation should be started immediately whenever necessary; put the patient in ventilator if spontaneous breathing is impaired.

C- Maintenance of circulation: put a proper sized cannula as soon as possible and start I.V. fluid to maintain the line so that all the I.V. medications can be introduced at ease.

D- Prevention of depression of CNS: level of consciousness to be assessed and do as is necessary to prevent depression of CNS.

iii. Correction of: Hypothermia, hyperthermia, acid-base imbalance, electrolyte imbalance, convulsion and agitation.

DECONTAMINATION

Removal of unabsorbed poison

Removal of the absorbed poison

REMOVAL OF THE PATIENT FROM POISONED ENVIRONMENT

i. Inhaled poison: Patient should be removed to fresh air, clothing should be loosened, clear airway should be ensured, artificial respiration should be started and administration of O2 with mixture of CO2 (95% and 5%) should be started.

ii. Injected poison: For IM/IV injections, an elastic bandage is to be applied over the injection site to prevent the lymphatic drainage of the poison.

iii. Contact poisons: For removal of the unabsorbed poison:

Eyes: Wash with normal saline or tap water at least for 15 minutes.

Skin: Remove all the contaminated cloth, rinse it thoroughly with cold water or saline and do not use neutralizing solution.

Ingestion:

A. EMETICS

INDICATIONS

Conscious patient

Ingestion of toxic substance within 3 to 6 hours

CONTRAINDICATIONS

Unconscious or comatose patients

Absent gag reflex

Ingestion of corrosive or volatile poison

Pregnancy

I. Syrup of Ipecacuanha (Pediatric Ipecacuanha Emetic Mixture BP or Ipecac syrup USP): It’s dose:

6-12 months: 5-10 ml preceded or followed by 120-240 ml of water.

1 to 12 years: 15ml preceded or followed by 120-240 ml of water.

Over 12 years: 15-30 ml followed immediately by 240ml of water.

Can be repeated after ½ hr, if vomiting does not occur.

II. Apomorphine: The dose:

Adult: 6 mg

Child: 1-2 mg

Given subcutaneously

Contraindicated if chance of CNS depression is there.

Salt solutions, copper sulphate, large amount of water, tickling the posterior pharyngeal wall, etc. should not be used to induce emesis because of their high risk-benefit ratio.

B. CATHARTICS AND WHOLE BOWEL IRRIGATION

I. Cathartics: Saline or osmotic cathartics can be used to decontaminate the gut. The administration of cathartics alone has no role in management of poisoning case.

II. Whole bowel irrigation (WBI): An isotonic solution may be useful to empty the bowel for iron, lithium, ingested button batteries, ingested illicit drug packets and overdose of sustained release or enteric coated drugs, etc.

In WBI the intestine can be cleaned by the oral administration of large amounts of polyethylene glycol electrolyte solution.

C. GASTRIC LAVAGE

INDICATIONS

History of poison ingestion with symptoms.

Ingestion of toxic substance within 1/2 to 1 hours

images.jpg

Figure 31.1 Ewald tube (Gastric lavage tube)

CONTRAINDICATIONS

Ingestion of a corrosive substance such as a strong acid or alkali.

Ingestion of a hydrocarbon with high aspiration potential.

Unless intubated, in the patients with loss of airway protective reflexes, such as in a patient with a depressed state of consciousness.

Patients who are at risk of hemorrhage or gastrointestinal perforation due to pathology, recent surgery, or other medical condition, that could be further compromised by the use of gastric lavage.

COMPLICATIONS

Aspiration pneumonia

Laryngospasm

Hypoxia and hypercapnia

Mechanical injury to the throat, esophagus, and stomach

Fluid and electrolyte imbalance

Combative patients may be at greater risk of complications

MATERIAL USED

Ewald tube (Figure 31.1)

Lavacuator (Figure 31.2)

Ryle’s tube for children (Figure 31.3)

Boas tube

lavacuator tubes.jpg images.jpg

Figure 31.2 Lavacutor Figure 31.3 Ryle’s tube

PROCEDURE

Should be done by an experienced staff, not to be tried outside a health care center.

Procedure should be explained to the patient properly.

Endotracheal intubation (with edotracheal tube with a calf) should precede gastric lavage in the comatose/unconscious patient without a gag reflex.

The patient should be placed in the left lateral, head down position (20 tilt on the table). The length of tube to be inserted is measured and marked before insertion (Figure 31.4).

A mouth gag is placed between teeth to prevent biting of the tube.

A large bore 36-40 French or 30 English gauge tube (external diameter approximately 12-13.3 mm) should be used in adults; and 24-28 French gauge (diameter 7.8-9.3 mm) tube in children.

The inserting end of tube is to be lubricated properly.

In an adult, 200-300 ml of warm normal saline (0.9%) or water should be used. In a child, 10 ml/kg body weight of warm normal saline (0.9%) should be given. Should be continued till a clear solution is returned.

Large volume of fluid is to be avoided to prevent entering of the gastric content into duodenum.

Anaesthetic gel/ointment should not be used

Always preserve the first wash fluid for toxicological analysis.

144-0550x0475.jpgchange this picture

Figure 32.4 Position of the patient at the time of gastric lavage

D. ACTIVATED CHARCOAL

It 1831, in front of his colleagues at the French Academy of Medicine, Professor Touery drank a lethal dose of strychnine and lived to tell the story. He had mixed the deadly poison with activated charcoal.

That's how powerful activated charcoal is as an emergency decontaminant in the gastrointestinal tract. It is considered to be the most effective single agent available. It is used when a person swallows or absorbs almost any toxic substance.

Activated charcoal itself is a fine, black powder that is odorless, tasteless, and nontoxic.

Activated charcoal works by adsorbing chemicals, thus reducing their toxicity (poisonous nature), through the entire length of the stomach and small and large intestines.

Activated charcoal is estimated to reduce absorption of poison up to 60%.

Activated charcoal is often given after the gastric lavage. Gastric lavage is only effective immediately after swallowing a toxic substance (within about ½ to 1 hour) and does not have effect on the poisons beyond the stomach as activated charcoal does

ELIMINATION OF THE ABSORBED POISON

Forced diuresis

Dialysis

Haemofiltration

Plasma perfusion, etc.

DIAGNOSIS OF POISON

A. CLINICAL DIAGNOSIS

SIGNS AND SYMPTOMS AND THE POISON1

Table 31.3 Few signs and the probable Poisons

Agitation

Anticholinergic, hypoglycemia, phencyclidine, sympathomimetics, withdrawal from ethanol and sedative-hypnotics

Alopecia

Alkylating agents, radiation, selenium, thallium

Ataxia

Benzodiazepines, carbamazepine, carbon monoxide, ethanol, hypoglycemia, lithium, mercury, nitrous oxide, phenytoin

Blindness or decreased visual acuity

Caustics (direct), cocaine, cisplatin, mercury, methanol, quinine, thallium

Constipation

Anticholinergics, botulism, lead, opioids, thallium (severe)

Diaphoresis

Amphetamines, cholinergic, hypoglycemia, opioid withdrawal, salicylates, serotonin syndrome, sympathomimetics, withdrawal from ethanol and sedative-hypnotics

Diarrhea

Arsenic and other metals, boric acid (blue-green), botanical irritants, cathartics, cholinergic, colchicines, iron, lithium, opioid withdrawal, radiation

Gum discoloration

Arsenic, bismuth, hypervitaminosis A, lead, mercury

Miosis

Cholinergics, clonidine, opioids, phencyclidine, phenothiazines

Mydriasis

Anticholinergics, botulism, opioid withdrawal, sympathomimetics

TOXIDROME1, 15

It is the association of several clinically recognizable features, signs, symptoms, phenomena or characteristics which often occur together, so that the presence of one feature alerts the physician to the presence of the others. Presence of the group of signs and symptoms will point towards the probable poisons and thus it helps in identification of the poison as well as starting the line of treatment for a particular group of poison.

Table 31.4 Cholinergic toxidrome

Syndrome

Signs and Symptoms

Poisons

Antidote

Cholinergic Sludge

Salivation

Lacrimation

Urination

Diarrhea

GI cramps

Emesis

Wheezing

Diaporesis

Bronchorrhoea

Bradycardia

Miosis

Carbamate

Organophosphates

Physostigmine

Pilocarpine

Atropine

Pralidoxime for organophosphates

Table 31.5 The anticholinergic toxidrome

Syndrome

Signs and Symptoms

Poisons

Antidote

Anticholinergic

Hot as a hare

Dry as a bone

Red as a beet

Mad as a hatter

Blind as a bat

Mydriasis

Blurred vision

Fever

Dry skin

Flushing

Ileus

Urinary retention

Tachycardia

Hypertension

Psychosis

Coma

Seizures

Myoclonus

Antihistamines

Atropine

Baclofen

Benztropine

Tricyclic

antidepressants

Phenothiazines

Propantheline

Scopolamine

Physostigmine

(do not use in cyclic antidepressant overdose as will worsen conduction disturbances)

Table 31.6 Hallucinogenic Sympathomimetic toxidrome

Syndrome

Signs and Symptoms

Poisons

Antidote

Hallucinogenic

Disorientation

Hallucinations

Hyperactive Bowel

Panic

Seizure

Tachycardia

Hypertension

Tachypnoea

Amphetamine

Cocaine

Pseudoephedrine

Phencyclidine

Ephedrine

Benzodiazepines

Table 31.7 Sedative/hypnotic toxidrome

Syndrome

Signs and Symptoms

Poisons

Antidote

Sedative/hypnotic

Stupor and coma

Confusion

Slurred speech

Apnoea

Anticonvulsants

Antipsychotics

Barbiturates

Benzodiazepines

Ethanol

Meprobamate

Opiates

Naloxone

Flumazenil

Urinary alkanisation for Phenobarbital

Table 31.8 Opiate toxidrome

Syndrome

Signs and Symptoms

Poisons

Antidote

Narcotic

Altered mental status

Slow shallow breaths

Meiosis

Bradycardia

Hypotension

Hypothermia

Decreased bowel sounds

Dextromethorphan

Opiates

Pentazocine

Propoxyphene

Naloxone

Table 31.9 Serotonergic syndrome

Syndrome

Signs and Symptoms

Poisons

Antidote

Serotonergic

Irritability

Hyperreflexia

Flushing

Diarrhea

Diaphoresis

Fever

Trismus

Tremor

Myoclonus

Fluoxetine

Meperidine

Paroxetine

Trazodone

Clomipramine

Benzodiazepine

Apart from these, the routine laboratory tests as well the different tests for the detection of specific poison are of help.

B. DIAGNOSTIC TESTS

Routine Blood and other body fluid can give some information about the state of the patient.

All the body fluid and excreta of the patient can give information about the poisoning.

ANALYTICAL TECHNIQUES1, 2, 6

(DETAILS MENTIONED IN CHAPTER ON Forensic Science Lboratory)

Different analytical techniques used for detection of the poisons gives more accurate results than any other tests for detection of the poisons. The most commonly used analytical techniques used in the field are:

Qualitative assays: This qualitative assay includes different colour tests for detection of the poisons.

Spectrophotometry: This includes different colorimeters and autoanalysers.

Chromatography: Which includes the thin layer chromatograph (TLC), gas liquid chromatography (GLC), high performance liquid chromatography (HPLC), gas chromatography and mass spectrometry (GCMS), which can be used depending up on the poison for qualitative as well as quantitative assessment of the poisons.

Competitive binding and immunological tests: Which includes Radioimmunoassay (RIA), Enzyme Immunoassay (EIA), etc.

POISON RESEARCH CENTRE/POISON LAB/POISON INFORMATION CENTRE

POISON INFORMATION CENTRE

The concept of it first adopted in Netherland in 1949. The main objective of the centre is to provide various information regarding the poisons, through a call centre. In India, the first such centre was established in the year 1994, in the form of National Poison Information Centre at AIMS, New Delhi. At present in India, a total of four poison information centers are there which include The National Institute of Occupational Health, Ahmadabad, Poison Information Centers at Govt. General Hospital, Chennai and Amrita Institute of Medical Sciences, Cochin.

POISON CONTROL CENTRE

The only WHO accredited Poison control centre in India is at Amrita Institute of Medical Science and Research, Cochin, Kerala, which come into existence in July 2003. The centre has its full fledged Poison Information Centre as well as Analytical Toxicological Laboratory.

ANTIDOTE THERAPY

An antidote is a remedy to counteract the effect of a poison.

MODE OF ACTION OF THE ANTIDOTES

i. Inert complex formation, e.g., chelating agent for heavy metals.

ii. Accelerated detoxification, e.g., Thiosulphate accelerates conversion of cyanide to nontoxic thiocyanate.

iii. Reduced toxic conversion, e.g., ethanol inhibits metabolism of methanol.

iv. Receptor site competition, e.g., Naloxone antagonizes effect of opiates at stereo-specific opioid receptor sites.

v. Receptor site blockade, e.g., Atropine blocking effect of ACh at muscarinic receptors.

vi. Toxic effect bypass, e.g., Use of 100% oxygen in cyanide poisoning.

TYPES OF ANTIDOTES

PHYSICAL OR MECHANICAL ANTIDOTE

They prevent the action of the poison mechanically, without destroying or inactivating the poison.

Demulcents: Egg albumin, starch or barley or milk, which have a soothing effect and form a protective layer on the mucous membrane of stomach. Sucrlafate suspension can be used to protect the gastric mucosa.

Adsorbents: Adsorb the poisons in to their surface, so that the poison cannot come in contact with the stomach wall.

Diluents: water, milk or similar drinks that dilute the poison and delay its absorption.

Bulky food: Boiled rice, boiled vegetables etc. act by getting admixed with the poison and thereby allow small amount of the poison to come in contact with the gut mucosa.

CHEMICAL ANTIDOTE

Inactivate poisons by undergoing chemical reaction with them.

Weak Alkalis: In poisoning by acids. Carbonate alkalis are to be avoided as they produce CO2 and inflate the stomach, may even lead to rupture.

Weak Vegetable acids: In poisoning by alkalis, e.g., citric acid, acetic acid, etc.

Potassium Permanganate: Is a strong oxidizing agent. Dilute solution of KMnO4 is used 1:10,000 dilution in poisoning by strychnine, nicotine, aluminium phosphide, opium, phosphorous, hydrocyanic acid, cyanides, morphine, atropine, etc. It can be used in gastric lavage fluid also.

PHYSIOLOGICAL ANTIDOTE

Produce sign and symptoms just the opposite to those of the poison, thus counteracting the effect of the poisons, e.g., atropine in organophosphate poisoning.

UNIVERSAL ANTIDOTE

Combination of physical and chemical antidotes used when exact nature of the poison is not known.

Activated charcoal: 2 parts

Magnesium oxide: 1 part

Tannic acid: 1 part.

CHELATION THERAPY– TOXIC METALS

The objective is to administer a non-toxic compound that binds metal ions more strongly than cell macromolecules and forms a water-soluble compound which can be excreted.

Chelate are coordination compound in which the central atom (usually a metal) is covalently bonded to two or more other atoms.

Heterocyclic rings are formed with the metal atom as part of each ring.

A key concern is the risk of enhancing toxicity by forming complexes that favour absorption and/or distribution of the metal ion to tissues.

Risk of trace element depletion is there if chelating agents are given for prolonged periods.

CHELATION THERAPY IS APPLIED TO TREAT

When poisoning with metal ions.

In disease conditions like metal storage diseases, notably Wilson’s disease (genetic ceruloplasmin deficiency) and hemachromatosis.

Sometimes it can be used to aid elimination of metallic radionuclides.

While the metal ion is still in the extracellular compartment, treatment will be most effective.

Haemodialysis sometimes may be essential to remove the chelate if renal function is impaired, although chelator such as DMSA probably chelates metal ions in the gut, facilitating faecal elimination.

It is important to maintain constant excess of chelating agent to minimize dissociation of the chelate.

Some of the antidotes and their uses:

ACTIVATED CHARCOAL

Very effective in many other drugs.

Not effective in iron, lithium, alcohols and glycol

DOSE

Up to one year: 1 gm/kg

1 - 12 years: 25 to 50 gm

Over 12 years: 50 to 100 gm

Activated charcoal mixed in 200 ml of water is administered orally or instilled via a nasogastric tube, after emesis or gastric lavage.

CONTRAINDICATED

Impaired consciousness

Gastrointestinal bleeding

Gastrointestinal perforation

In absence of activated charcoal, any charcoal prepared by burning and then by grinding the egg albumin or bread toast can be used as substitute.

Multiple-dose activated charcoal (MDAC) therapy (repeated administration of oral activated charcoal) enhances elimination of poisons by disturbing the entero-enteric and in some cases, the entero-hepatic circulation. Initial dose: 50 to 100 gm, then 12.5 gm/hour until recovery or the plasma drug concentration comes down to the normal therapeutic or non toxic range.

Table 31.10 efficacy of activated charcoal on different poisons

Well adsorbed

Moderately adsorbed

Poorly adsorbed

Amphetamines

Antidepressants

Antiepileptic

Antihistamines

Atropine

Barbiturates

Benzodiazepines

Beta-blockers

Digitalis

NSAIDs

Opiates

Strychnine

Phenothiazines

Anitidiabetics

Kerosene

Paracetamol

Phenol

Salicylates

Alcohols

Carbamates

Corrosives

Cyanide

Ethylene glycol

Heavy Metals

Hydrocarbons

Organophosphates

ATROPINE

It is a physiological antidote.

It counteracts the action of organophosphates poison.

Atropine alone if given has less effect as the muscarinic effects are only neutralized, the nicotinic effects remain, so should be given along with the oxime. Delayed neurological symptoms like muscular weakness, etc., may be present if given alone.

Atropine and its uses as physiological antidote are mentioned in Table 31.11.

Table 31.11 Atropine and its uses as physiological antidote

Antidote

Atropine

Indications

Organophosphates, Carbamates, Pilocarpine, Physostigmine

Available as

Atropa inj. 0.6 mg/ml, 2 ml ampoules; Tropine inj. 0.6 mg/ml, 1 ml ampoules

Dose

2–4 mg, IV at 10–15 min, till signs of atropinisation. Children: 0.05 mg/kg, IV at 10 – 15 Min

PRECAUTIONS

May contain benzyl alcohol or chlorobutanol as preservative; may lead to toxicity of these at high dose. Preservative free atropine should be used if higher dose is required.

Half lives of atropine in children bellow 2 years and adults above 60 years, is longer, so, dose should be adjusted accordingly.

ADVERSE EFFECTS

Atrial arrhythmias, A-V dissociation, ventricular ectopic, photophobia, raised intraocular pressure, hyperpyrexia, hallucinations, delirium.

PRALIDOXIME (2-PAM)

MODE OF ACTION

Competes for the phosphate moiety of the organophosphates and release them from acetyl cholinesterase enzyme, thereby reactivating the enzyme.

Once the organophosphates are bound to the ChE receptor sites, and remain there for 48 hours, the reversal becomes impossible, the condition is known as the aging of the enzyme. So, the oximes should be stated within 48 hours of the ingestion of the poison. Pralidoxime as an antidote in poison treatment is narrated in Table 31.12.

Table 31.12 Pralidoxime as an antidote

Antidote

Pralidoxime

Indication

Organophosphates,

Available preparations

PAM tab, 500 mg for oral use

PAM-A inj. 500 mg in 20 ml for I.V. use

Dose

Adult: 1 to 2 gm in 100 to 150 ml of normal saline over 30 min period. Can be repeated every 6 to 12 hours for 24 to 48 hours. Children: 20 to 40 mg/kg, in 100 to 150 ml of normal saline infusion. Repeated every 6 to 12 hours, for 24 to 48 hours and to be given along with atropine

"WHO" RECOMMENDATION

Initial bolus dose of 30 mg/kg, followed by infusion of 8 mg/kg/hour is necessary for maintaining the plasma concentration of at least 4 mg/L for pralidoxime to be effective.

ADVERSE EFFECT

Rapid administration can cause tachycardia, laryngospasm or even cardiac or respiratory arrest; apart from drowsiness, vertigo, headache and muscular weakness.

BRITISH ANTI LEWISITE (BAL)

Synonyms: Dimercaprol; 2, 3-dimercaptopropanol

British anti-lewisite has been in use in the medical community for more than 60 years. It is most commonly used chelator (remove a heavy metal from the body) in the treatment of poisoning from arsenic, mercury, lead, and gold. It is also well-known for its role in World War II as an antidote to the chemical warfare agent Lewisite. Although other chelator has now been developed with less toxicity, BAL maintains a prominent role in the treatment of various medical conditions. BAL as a chelator is narrated in Table 31.13.

Table 31.13 BAL as a chelating agent

Chelating agent

British anti lewisite (BAL)

Indications

Arsenic, Mercury, bismuth, copper, antimony and nickel

Available preparation

B.A.L., (Knoll Pharma), 2 ml ampoule, 100 mg/ml, in arachis oil

Doses

3 mg/kg, 4 hourly, on day 1 and 2

3 mg/kg, 6 hourly, on day 3

3 mg/kg, 12 hourly, next 10 days

It should be given as deep IM

SIDE EFFECTS

Pain at the injection site

Hypertension and tachycardia

Abdominal pain, nausea, and vomiting

Headaches

Burning sensation of the lips

Excessive salivation

Rhinorrhoea, and tearing

Fever

Muscle pain, muscle spasms, and a feeling of chest constriction

Profuse sweating

CONTRAINDICATION

Poisonings due to iron, cadmium, tellurium, selenium, vanadium, and uranium.

Elemental mercury vapors, because it can further increase the metal in the brain.

Should not be given in case of acute renal failure (anuria) or extensive hepatic insufficiency and should be used with special care in hypertensive patients.

DMSA

DMSA is less toxic than BAL, and it is sometimes substituted for BAL when the patient's condition improves. It is also used when intolerance to BAL develops. DMSA as a chelator is narrated in Table 31.14.

Table 31.14 DMSA as Chelating agent

Chelating agent

DMSA (Succimer)

Indication

Lead, Mercury, Arsenic

Contraindication

Preexisting kidney or liver disease and pregnancy

Dose

10 gm/kg 8 hourly for 5 days, orally

SIDE EFFECTS

Nausea

Vomiting

Diarrhea

Rhinitis and cough

Rash.

CONTRAINDICATIONS

They are contraindicated in preexisting kidney or liver disease and pregnancy. Hydration is essential. DMSA is not used in conjunction with ETDA or D-penicillamine.

ETHYLENEDIAMINETETRAACETIC ACID, EDETATE DISODIUM (EDTA)

EDTA is one of the oldest chelating agents, coming into prominence in the 1950s. It has an affinity for lead. It is often used as a second-line of treatment in combination with BAL and given by IV infusion. The clinical uses are mentioned in Table 31.15

Table 31.15 EDTA Chelating agent

Chelating agent

EDTA

Indication

Lead, mercury, zinc, cadmium, copper, manganese poisoning

Contraindication

Preexisting kidney or liver disease, pregnancy and raised ICP

Dose

25–30 mg/kg in 250 to 500 ml of 5% dextrose or normal saline infusion I.V., 12 hourly for 5 days

SIDE EFFECTS

Common side effects: gastrointestinal upset and headache

More serious side effects: Seizures, numbness or tingling in the hands and feet, irregular heartbeat, skin rashes, fever or chills, and blood in the urine (Ferner 2001).

CONTRAINDICATIONS

EDTA is contraindicated in pregnancy

If there is kidney disease

It can also interact with insulin and heart medicines.

DMPS (DIMERCAPTOPROPANESULFONATE)

2, 3-Dimercapto-1-propanesulfonic acid (DMPS) and its sodium salt known as Unithiol are chelating agents that form complexes with various heavy metals. They are related to dimercaprol, which is another chelating agent. It is another analogue of BAL. DMPS was found to have some protective effect, prolonging the survival time8, but shown to be less effective and have more side effects than DMSA.

DMPS is the drug of choice in Europe and Asia; however, the FDA has not approved DMPS for chelating purposes in the United States. It does, however, appear on the FDA list of drugs that appear to be safe. In the United States, DMPS is distributed to pharmacists in bulk form for compounding and dispensing in oral and injection forms (FDA 1999; Marcus 2001). The indications and doses are mentioned in Table 31.16.

Table 31.16 DMPA as chelating agent

Antidote

DMPS (Dimercaptopropanesulfonate)

Indication

Arsenic and mercury poisoning

Dose

5 mg/kg I.V. in 6 divided doze

PENICILLAMINE (D-PENICILLAMINE)

Synonyms: Cuprimine

Penilcillamine is 3-mercapto-D-valine. It is a white or practically white, crystalline powder, freely soluble in water, slightly soluble in alcohol, and insoluble in ether, acetone, benzene, and carbon tetrachloride. Although its configuration is D, it is levorotatory as usually measured and is an oral chelating agent used to treat heavy metal toxicity. The indications, available preparations and doses are mentioned in Table 31.17.

Table 31.17 Penicillamine chelating agent

Antidote

D-penicillamine

Indication

Copper (Wilson's disease), arsenic, mercury (alternative to BAL), Chronic lead poisoning. Also used to reduce Cysteine excretion in cystinuria and patients with severe, active rheumatoid arthritis unresponsive to conventional therapy

Available as

Artin, Cilamin 150 mg, 200 mg and 250 mg capsules

Dose

Children: 30 mg/kg/day

Adult: 1 to 2 gm daily in divided dose, orally, 1 hour before food

SIDE EFFECTS

Gastrointestinal intolerance

Bone marrow suppression, anorexia, vomiting and diarrhea are the most common side effects, occurring in 20-30% of the patients treated with penicillamine9, 10.

Itchy skin (wheals)

Aplastic anaemia (idiosyncratic)11

Fever

Nephropathy9 , membranous glomerulonephritis

Hepatotoxicity11

Antibody-mediated myasthenia gravis9 and Lambert-Eaton myasthenic syndrome, which may persist even after its withdrawal

Drug-induced systemic lupus erythematosus12

Besides, people allergic to penicillin may have hypersensitivity to penicillamine13.

CONTRAINDICATIONS

Patient who are allergy to penicillin

Possible interaction with other drugs (immunosuppressant, digoxin)

Severe blood disorders

Renal insufficiency

Pregnancy.

DESFERRIOXAMINE

Desferrioxamine is used to chelate iron, especially in acute iron poisoning in small children and administered by injection or intravenously. The indications, different preparations of Desferrioxamine and its doses are mentioned in Table 31.18.

Table 31.18 Desferrioxamine as chelating agent

Antidote

Desferrioxamine

Indication

Acute iron poisoning, iron overload, aluminum overload, transfusion siderosis, diagnosis of aluminium overload and diagnosis of iron storage disease and certain anaemias

Available preparation

Desfereal 500 mg vials

Dose

0.5 to 1 gm I.M. followed by 500 mg every 4 hourly for 2 doses, then 400 mg 4 to 12 hourly (maximum 6 gm/day). In severe life threatening poisoning or patient with shock should receive 15 mg/kg/hour in laevulose solution I.V., with a maximum daily dose up to 360 mg/kg or up to 6 gm total14

ADVERSE EFFECTS

Common side effects: Blurred vision, wheezing, rapid heartbeat, seizures, itching, skin rash, bluish skin, and redness and pain at the injection site.

Less common side effects: Gastrointestinal discomfort, fever, cramping, and bruising.

CONTRAINDICATIONS

Known sensitivity or allergy to any ingredient or who are allergies to certain foods or dyes, other medicines currently being taken, pregnancy or breast feeding, and kidney disease.