PAMANTASAN NG LUNGSOD NG MAYNILA (University of the City of Manila) Intramuros, Manila

GRADUATE SCHOOL OF HEALTH SCIENCES

A WRITTEN REPORT:

TOXICOLOGY

Presented By: Joanne Paula O. Pineda, RN Lannz P. Batalla, RN

Presented To: Prof. Benjamin Tan Tablizo, Jr., MAN

September 3, 2011

Principles of Toxicology and Treatment of Poisoning

TOXICOLOGY Toxicology is the study of the nature and mechanisms underlying toxic effects exerted by substances on living organisms and other biologic systems. It is the science of the adverse effects of chemicals, including drugs, on living organisms. Toxicology also deals with quantitative assessment of the adverse effects in relation to the concentration or dosage, duration, and frequency of exposure of the organisms. Toxicology has a broad scope. It deals with toxicity studies of chemicals used (1) in medicine for diagnostic, preventive, and therapeutic purposes; (2) in the food industry as direct and indirect additives; (3) in agriculture as pesticides, growth regulators, artificial pollinators, and animal feed additives; and (4) in the chemical industry as solvents, components, and intermediates of plastics and many other types of chemicals. It is also concerned with the health effects of metals (as in mines and smelters), petroleum products, paper and pulp, toxic plants, and animal toxins. The discipline often is divided into several major areas. The descriptive toxicologist performs toxicity tests to obtain information that can be used to evaluate the risk that exposure to a chemical poses to humans and to the environment. The mechanistic toxicologist attempts to determine how chemicals exert deleterious effects on living organisms. Knowledge of the mechanism of action provides enhancement to the toxicological evaluation and provides a basis for other branches of toxicology. Such studies are essential for the development of tests for the prediction of risks, for facilitating the search for safer chemicals, and for rational treatment of the manifestations of toxicity. The regulatory toxicologist judges whether a drug or other chemical has a low enough risk to justify making it available for its intended purpose. It attempts to protect the public by setting laws, regulations, and standards to limit or suspend the use of very toxic chemicals as well as defines use conditions for others. Two specialized areas of toxicology are particularly important for medicine. Forensic toxicology, which combines analytical chemistry and fundamental toxicology, is concerned with the medico legal aspects of chemicals. Forensic toxicologists assist in postmortem investigations to establish the cause or circumstances of death. Clinical toxicology focuses on diseases that are caused by or are uniquely associated with toxic substances. Clinical toxicologists treat patients who are poisoned by drugs and other chemicals and develop new techniques for the diagnosis and treatment of such intoxications. Those in clinical toxicology administer antidotes to counter the specific toxicity, and take other measures to ameliorate the symptoms and signs and hasten the elimination of the toxicant from the body. The knowledge gained is then utilized to assess the risk of adverse effects to the environment and humans and is termed as risk assessment. A health risk assessment constitutes a written document that is based upon all pertinent scientific information regarding toxicology, human experiences, environmental fate, and exposure. These data are subject to critique and interpretation. The aim of this assessment is to estimate the potential of an adverse effect that occurs in humans and wildlife ecological system posed by a specific amount of exposure to a

chemical. Risk assessments include several elements such as (1) description of the potential adverse health effects based on an evaluation of results of epidemiologic, clinical, toxicological, and environmental research; (2) extrapolation from these results to predict the type and estimate the extent of health effects in humans under given conditions of exposure; (3) judgments as to the number and characteristics of individuals exposed at various intensities and durations; (4) and summary judgments on the existence and overall magnitude of the public health problem. Risk characterization represents the final and the most critical step in the risk assessment process whereby data on the doseresponse relationship of a chemical are integrated with estimates of the degree of exposure in a population to characterize the likelihood and severity of a health risk. The clinician must evaluate the possibility that a patient's signs and symptoms may be caused by toxic chemicals present in the environment or administered as therapeutic agents. Many of the adverse effects of drugs mimic symptoms of disease. Appreciation of the principles of toxicology is necessary for the recognition and management of such clinical problems.

Toxicokinetics and Toxicodynamics Toxicokinetics denotes the absorption, distribution, excretion, and metabolism of toxins, toxic doses of therapeutic agents, and their metabolites. Toxicodynamics on the other hand is used to denote the injurious effects of these substances on vital functions. Special Aspects of Toxicokinetics: Volume Distribution The Volume Distribution (Vd) is defined as the apparent volume into which a substance is distributed. A large Vd implies that the drug is not readily accessible to measures aimed at purifying the blood, such as hemodyalisis. Examples of drugs with large volumes of distribution (> 5 L/kg) include antidepressants, antipsychotics, antimalarias, opioids, propranolol, and verapamil. Drugs with a relatively small volumes of distribution (<1 L/kg) include salicylate, ethanol, Phenobarbital, lithium, valproic acid, and phenytoin. Medication atenolol chloroquine chlorpromazine diazepam digoxin ethanol glibenclamide glyceryl nitrate heparin indometacin insulin Vd / kg body weight 0.1-0.2 200 2-5 1-2 2-5 0.7-0.9 0.1-0.2 2-5 0.05-0.1 1-2 0.05-0.1

lidocaine methotrexate morphine neostigmine nortriptyline NXY-059 paracetamol phenytoin propranolol sulfamethoxazole theophylline tubocurarine warfarin Special Aspects of Toxicokinetics: Clearance

1-2 1-2 2-5 0.7-0.9 2-5 0.1-0.2 1-2 0.7-0.9 2-5 0.1-0.2 0.4-0.7 0.2-0.4 0.1-0.2

Clearance is a measure of the volume of plasma that is cleared of drug per unit time. The total clearance for most drugs is the sum of clearances via excretion by the kidneys and metabolism by the liver. Overdosage of a drug can alter the usual pharmacokinetic processes, and this must be considered when applying kinetics to poisoned patients. For example, dissolution of tablets or gastric emptying time may be slowed so that absorption and peak toxic effects are delayed. Drugs may injure the epithelial barrier of the gastrointestinal tract and thereby increase absorption. If the capacity of the liver to metabolize a drug is exceeded, more drugs will be delivered to the circulation. With the dramatic increase in the circulation of the drug in the blood, protein-binding capacity may be exceeded, resulting in an increased fraction of free drug and greater toxic effect. At normal dosage, most drugs are eliminated at a rate proportional to the plasma concentration. If the plasma concentration is very high and normal metabolism is saturated, the rate of elimination may become fie. This change n kinetics may markedly prolong the apparent serum half-life and increase toxicity.

Special Aspects of Toxicodynamics The general dose-response principles are relevant when estimating the potential severity of intoxication. When considering quantal dose-response data, both the therapeutic index and the overlap of therapeutic and toxic response curves must be considered. For instance two drugs may have the same therapeutic index but unequal safe dosing ranges if the slopes of their doseresponse curves are not the same.

Medical Treatment: Physical Assessment and History The initial management of a patient with coma, seizures, or otherwise altered mental status should follow the same approach regardless of the poison involved. Attempting to make a specific toxicologic diagnosis only delays the application of supportive measures that form the basis (ABCDs) of poisoning treatment. Airway the airway should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed. For many patients, simple positioning in the lateral decubitus position is sufficient to move the flaccid tongue out of the airway. Breathing breathing should be assessed by observation and oximetry and, if in doubt, by measuring arterial blood gases. Patients with respiratory insufficiency should be intubated and mechanically ventilated. Circulation the circulation should be assessed by continuous monitoring of pulse rate, blood pressure, urinary output, and evaluation of peripheral perfusion. An intravenous line should be placed and blood drawn for serum glucose and other routine determinations. Dextrose patients with altered mental status should receive a challenge with concentrated dextrose, unless a rapid bedside blood glucose test demonstrates that the patient is not hypoglycemic. Adults are given 25 g (50mL of 50% dextrose solution) intravenously, and children are given 0.5 g/kg (2mL/kg of 25% dextrose).

One can begin a more detailed evaluation to make a specific diagnosis once the essential ABCD interventions have been initiated. Gathering available history and performing a toxicologically oriented physical examination are imperative in assessing the patient who is believed to be poisoned. History Obtaining an adequate history remains the most important aspect of the management of a potentially poisoned patient. In many cases, a precise medical history can define the exact nature of the exposure. In others it delineates the potential agents to which the patient may have access at home or work. Although occasionally unreliable (for example, in patients with dementia or suicidal ideation), the medical history permits a focused investigation into the potential for patient harm and guides initial management. The process of taking the medical history is guided by the clinical situation, but the history usually includes questions about the timing, nature and circumstances of the exposure and the patient's initial symptoms, symptom progression, and complicating medical conditions. Oral statements about the amount and even the type of drug ingested in toxic emergencies may be unreliable. Even so, family members, police, and fire department or paramedical personnel should be asked to describe the environment in which the toxic emergency occurred and should bring to the emergency department any syringes, empty bottles, household products, or over-the-counter medications in the immediate vicinity of the possibly poisoned patient.

Physical Examination A brief examination should be performed, emphasizing those areas most likely to give clues to the toxicologic diagnosis. These include vital signs, eyes and mouth, skin, abdomen, and nervous system. Obtaining an adequate history remains the most important aspect of the management of a potentially poisoned patient. A precise medical history can define the exact nature of the exposure. It delineates the potential agents to which the patient may have access at home or work. Although occasionally unreliable (for example, in patients with dementia or suicidal ideation), the medical history permits a focused investigation into the potential for patient harm and guides initial management. The process of taking the medical history is guided by the clinical situation, but the history usually includes questions about the timing, nature and circumstances of the exposure and the patient's initial symptoms, symptom progression, and complicating medical conditions. A. Vital Signs Careful evaluation of vital signs (blood pressure, pulse, respirations, and temperature) is essential in all toxicologic emergencies. Hypertension and tachycardia are typical with amphetamines, cocaine, and antimuscarinic (anticholinergic) drugs. Hypotension and bradycardia are characteristic features of overdose with calcium channel blockers, blockers, clonidine, and sedative-hypnotics. Hypotension with tachycardia is common with tricyclic antidepressants, phenothiazines, vasodilators, and theophylline. Rapid respirations are typical of salicylates, carbon monoxide, and other toxins that produce metabolic acidosis or cellular asphyxia. Hyperthermia may be associated with sympathomimetics, anticholinergics, salicylates, and drugs producing seizures or muscular rigidity. Hypothermia can be caused by any CNS-depressant drug, especially when accompanied by exposure to a cold environment. B. Eyes The eyes are a valuable source of toxicologic information. Constriction of the pupils (miosis) is typical of opioids, clonidine, phenothiazines, and cholinesterase inhibitors (eg, organophosphate insecticides), and deep coma due to sedative drugs. Dilation of the pupils (mydriasis) is common with amphetamines, cocaine, LSD, and atropine and other anticholinergic drugs. Horizontal nystagmus is characteristic of intoxication with phenytoin, alcohol, barbiturates, and other sedative drugs. The presence of both vertical and horizontal nystagmus is strongly suggestive of phencyclidine poisoning. Ptosis and ophthalmoplegia are characteristic features of botulism. C. Mouth The mouth may show signs of burns due to corrosive substances, or soot from smoke inhalation. Typical odors of alcohol, hydrocarbon solvents, or ammonia may be noted. Poisoning due to cyanide can be recognized by some examiners as an odor like bitter almonds.

D. Skin The skin often appears flushed, hot, and dry in poisoning with atropine and other antimuscarinics. Excessive sweating occurs with organophosphates, nicotine, and sympathomimetic drugs. Cyanosis may be caused by hypoxemia or by methemoglobinemia. Icterus may suggest hepatic necrosis due to acetaminophen or Amanita phalloides mushroom poisoning. E. Abdomen Abdominal examination may reveal ileus, which is typical of poisoning with antimuscarinic, opioid, and sedative drugs. Hyperactive bowel sounds, abdominal cramping, and diarrhea are common in poisoning with organophosphates, iron, arsenic, theophylline, and A phalloides. F. Nervous System A careful neurologic examination is essential. Focal seizures or motor deficits suggest a structural lesion (such as intracranial hemorrhage due to trauma) rather than toxic or metabolic encephalopathy. Nystagmus, dysarthria, and ataxia are typical of phenytoin, carbamazepine, alcohol, and other sedative intoxication. Twitching and muscular hyperactivity are common with atropine and other anticholinergic agents, and cocaine and other sympathomimetic drugs. Muscular rigidity can be caused by haloperidol and other antipsychotic agents and by strychnine. Seizures are often caused by overdose with antidepressants (especially tricyclic antidepressants and bupropion), cocaine, amphetamines, theophylline, isoniazid, and diphenhydramine. Flaccid coma with absentreflexes and even an isoelectric EEG may be seen with deep coma due to opioid or sedativehypnotic intoxication and may be mistaken for brain death. G. Laboratory and Imaging Procedures Arterial Blood Gases Since the adequacy of ventilation and oxygenation may be difficult to assess clinically and with pulse oximetry, the determination of the arterial blood gases is crucial. Although invasive, important information is gleaned from the assessment of a symptomatic patient's acid-base (pH), ventilatory (PCO2) and oxygenation (PO2) status. For example, a metabolic acidosis in an unconscious patient may suggest that the patient ingested methanol or had a recent seizure. Alternatively, a combined metabolic acidosis and respiratory alkalosis suggests salicylate poisoning. Renal Function Tests Some toxins have direct nephrotoxic effects; in other cases, renal failure is due to shock or myoglobinuria. Blood urea nitrogen and creatinine levels should be measured and urinalysis performed. Elevated serum creatine kinase (CK) and myoglobin in the urine suggest muscle necrosis due to seizures or muscular rigidity. Oxalate crystals in the urine suggest ethylene glycol poisoning. Electrocardiograph

The electrocardiograph serves several important roles in the management of poisoned patients and should be performed in virtually all circumstances. In patients with cardiovascular abnormalities, the evaluation of an electrocardiograph may suggest the toxin. For example, calcium channel blockers typically produce bradycardia with atrioventricular nodal block, whereas digoxin typically produces ST segment abnormalities and first-degree arteriovenous (AV) block. Alternatively, and just as important, the electrocardiograph may have a prognostic value. Patients with tricyclic antidepressant poisoning usually have intraventricular conduction delays, such as QRS widening, the magnitude of which is related to the likelihood of both seizure and ventricular dysrhythmia. Imaging Findings A plain film of the abdomen may be useful because some tablets, particularly iron and potassium, may be radiopaque. Chest x-ray may reveal aspiration pneumonia, hydrocarbon pneumonia, or pulmonary edema. When head trauma is suspected, a CT scan is recommended. Toxicology Screen Tests The clinical examination of the patient and selected routine laboratory tests are usually sufficient to generate a tentative diagnosis and an appropriate treatment plan. While screening tests may be helpful in confirming a suspected intoxication or for ruling out intoxication as a cause of apparent brain death, they should not delay needed treatment. When a specific antidote or other treatment is under consideration, quantitative laboratory testing may be indicated. For example, determination of the acetaminophen serum level is useful in assessing the need for antidotal therapy with acetylcysteine. Serum levels of theophylline, carbamazepine, lithium, salicylates, valproic acid, and other drugs may indicate the need for hemodialysis.

POISONS The definitions of drug, toxin, and poison are cumbersome and vary with the context of the terms' uses. A drug is a substance normally taken for a specific purpose. This may be therapeutic in nature or for non-therapeutic use. A toxin is a substance that is not ordinarily consumed as a drug. Toxins are poisons produced via some biological function in nature, and venoms are usually defined as biological toxins that are injected by a bite or sting to cause their effect. A poison is a substance that interferes adversely with a physiological process. These are substances that can cause disturbances to an organisms physiological processes, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism. Other poisons are generally defined as substances which are absorbed through epithelial linings such as the skin or gut. Therefore, all drugs and toxins may be poisons.

Defining what constitutes a poison is not simple. Some substances have virtually no known beneficial effects in humans and can only be considered poisonous like cyanide. Many substances that are normally harmless, or even necessary for life (e.g., oxygen, water), become poisons when present in excess. In fact, all drugs in clinical use have the potential to have beneficial or deleterious effects, and can, at some dose, be a poison. These clinical drugs may be poisonous or therapeutic depending on the dose administered. TOXIN Acetaminophen Specific Drugs or Toxins and Their Toxic Syndromes VITAL SIGNS MENTAL SIGNS AND STATUS SYMPTOMS Normal (early) Normal Anorexia, nausea, vomiting Hypertension, tachycardia, tachypnea, hyperthermia Hypotension, hypertension, tachycardia, hyperthermia Hyperactive, agitated, toxic psychosis Altered (agitation, lethargy to coma), hallucinations Alert to coma CLINICAL FINDINGS Right upper quadrant tenderness, jaundice (late) Hyperalertness, Mydriasis, panic, anxiety hyperactive diaphoresis peristaltism, diaphoresis Blurred vision, Dry mucous dry mouth, membranes, inability to mydriasis, flush, urinate diminished peristaltism, urinary retention Abdominal pain, Dehydration vomiting, diarrhea, dysphagia Slurred speech, Dysconjugate ataxia gaze, bulae, hyporeflexia Dizziness Cyanosis, seizures

Amphetamines

Antihistamines

Arsenic (acute)

Hypotension, tachycardia

Barbiturates

Beta-adrenergic antagonists Botulism

Hypotension, bradypnea, hypothermia Hypotension, bradycardia Bradypnea

Altered (lethargy to coma) Altered (lethargy to coma) Normal unless Blurred vision, hypoxia diplopia, dysphagia, sore or dry throat, diarrhea Altered (lethargy to coma) Hallucinations, extrapyramidal movements,

Carbamazepine

Hypotension, tachycardia, bradypnea,

Opthalmoplegia, mydriasis, ptosis, cranial nerve abnormalities, descending paralysis Mydriasis, nystagmus

Carbon monoxide

hypothermia Often normal

Altered (lethargy to coma) Altered (lethargy to coma) Altered (anxiety, agitation, delirium) Altered (lethargy to coma)

Clonidine

Cocaine

Cyclic antidepressants

Hypotension, hypertension, bradycardia, bradypnea Hypertension, tachycardia, tachypnea, hyperthermia Hypotension, tachycardia

seizures Headache, dizziness, nausea, vomiting Dizziness, confusion

Seizures

Miosis

Hallucinations, paranoia, panic anxiety, restlessness Confusion, dizziness, dry mouth, inability to urinate

Mydriasis, nystagmus

Digitalis

Hypotension, bradycardia

Normal to altered, visual distortion Normal

Disulfiram/ethanol

Hypotension, tachycardia

Ethylene glycol

Tachypnea

Iron

Hypotension, tachycardia

Altered (lethargy to coma) Normal or lethargy

Nausea, vomiting, anorexia, visual disturbances Nausea, vomiting, headache, vertigo Abdominal pain

Mydriasis, dry mucous membranes, distended bladder, flush, seizures None

Flush, diaphoresis, tender abdomen Slurred speech, ataxia Tender abdomen

Isoniazid

Often normal

Isopropanol

Lead

Hypotension, tachycardia, bradypnea Hypertension

Normal or altered (lethargy to coma) Altered (lethargy to coma) Altered

Nausea, vomiting, diarrhea, abdominal pain, hematemesis Nausea, vomiting

Seizures

Nausea, vomiting Irritability,

Hyporeflexia, ataxia, acetone odor on breath Peripheral

(lethargy to coma)

Lithium

Hypotension (late)

Altered (lethargy to coma) Altered (psychiatric disturbances) Altered (lethargy to coma) Altered (lethargy to coma) Altered (lethargy to coma)

abdominal pain (colic), nausea, vomiting, constipation Diarrhea, tremor, nausea

neuropathy, seizures, gingival pigmentation Weakness, tremor, ataxia, myoclonus, seizures Stomatitis, ataxia, tremor Hyperemic disks, mydriasis Miosis, decreased peristaltism

Mercury

Hypotension (late) Hypotension, tachypnea

Methanol

Opioids

hypotension, bradycardia, bradypnea, hypothermia Organophosphates/ Hypotension/ carbamates hypertension, bradycardia/ tachycardia, bradypnea/ tachypnea

Salivation, diarrhea, abdominal pain Blurred vision, blindness, abdominal pain Slurred speech, ataxia

Diarrhea, abdominal pain, blurred vision, vomiting

Phencyclidine

Hypertension, tachycardia, hyperthermia

Altered (agitation, lethargy to coma) Altered (lethargy to coma) Altered (agitation, lethargy to coma) Altered (lethargy to coma)

Hallucinations

Phenothiazines

Hypotension, tachycardia, hypothermia Hypotension, tachycardia, tachypnea, hyperthermia Hypotension, bradypnea, hypothermia

Dizziness, dry mouth, inability to urinate Tinnitus, nausea, vomiting Slurred speech, ataxia

Salicylates

Sedative-hypnotics

Salivation, diaphoresis, lacrimation, urination, bronchorrhea defecation, miosis, fasciculations, seizures Miosis, diaphoresis, myoclonus, blank stare, nystagmus, seizures Miosis or mydriasis, decreased bowel sounds, dystonia Diaphoresis, tender abdomen, pulmonary edema Hyporeflexia, bullae

Theophylline

Hypotension, tachycardia, tachypnea, hyperthermia SOURCE: From Goldfrank et al. 1998.

Altered (agitation)

Nausea, vomiting, diaphoresis, anxiety

Diaphoresis, tremor, seizures dysrhythmias

POISON MANAGEMENT Preventing Absorption: Decontamination Just like other medical emergencies, supportive therapy is the mainstay of the treatment of drug poisoning. The adage, "Treat the patient, not the poison," remains the most basic and important principle of clinical toxicology. Treatment of acute poisoning must be prompt. The first goal is to maintain the vital functions if their impairment is imminent. The second goal is to keep the concentration of poison in the crucial tissues as low as possible by preventing absorption and enhancing elimination. The third goal is to combat the pharmacological and toxicological effects at the effector sites. Primary prevention of toxicity, such as parental education, drug storage in child-resistant containers, or the use of computerized adverse drug effects programs by medical professionals, are the optimal means of reducing the incidence of poisoning. Although typically helpful, such measures cannot eliminate poisoning. Those patients who are exposed to a potentially toxic substance subsequently require decontamination as a method of secondary prevention. As most exposures occur through the gastrointestinal tract, the major focus must be on gastrointestinal decontamination. This form of decontamination is often invasive and difficult to perform. Additionally, it includes small but genuine risks such as gastrointestinal perforation or pulmonary aspiration. However, gastrointestinal decontamination is the cornerstone in the early management of acutely poisoned patients. Eyes, Skin, or through Inhalation When a poison has been inhaled, the first priority is to remove the patient from the source of exposure. Similarly, if the skin has had contact with a poison, contaminated clothing should be completely removed and wash contaminated skin thoroughly with water. Contaminated clothing should be double-bagged to prevent illness in health care providers and for possible laboratory analysis. Initial treatment of all types of chemical injuries to the eye must be rapid; thorough irrigation of the eye with water for 15 minutes should be performed immediately. Gastrointestinal Decontamination Prevention of absorption of toxin remaining in the GI tract is important in managing the poisoned patient. The method used to provide gastrointestinal decontamination following ingestion of a potential toxin primarily depends on the clinical condition of the patient, the

nature and quantity of the toxin, and the relative risk of toxin-associated or therapy-associated morbidity and mortality. 1. Emesis Emesis still may be indicated for immediate intervention after poisoning by oral ingestion of chemicals, it is contraindicated in certain situations: (1) If the patient has ingested a corrosive poison, such as a strong acid or alkali (e.g., drain cleaners), emesis increases the likelihood of gastric perforation and further necrosis of the esophagus; (2) if the patient is comatose or in a state of stupor or delirium, emesis may cause aspiration of the gastric contents; (3) if the patient has ingested a CNS stimulant, further stimulation associated with vomiting may precipitate convulsions; and (4) if the patient has ingested a petroleum distillate (e.g., kerosene, gasoline, or petroleum-based liquid furniture polish), regurgitated hydrocarbons can be aspirated readily and cause chemical pneumonitis. In contrast, emesis should be considered if the ingested solution contains potentially dangerous compounds, such as pesticides. Vomiting or emesis can be induced mechanically by fingertip stimulation of the posterior pharynx. Ipecac Syrup The most common household emetic is syrup of ipecac (not ipecac fluid extract, which is 14 times more potent and may cause fatalities). Syrup of ipecac is available in 0.5- and 1-fluid ounce containers (approximately 15 and 30 ml), which may be purchased without prescription. The drug can be given orally, but it takes 15 to 30 minutes to produce emesis; this compares favorably with the time usually required for adequate gastric lavage. The oral dose is 15 ml in children from 6 months to 12 years of age and 30 ml in older children and adults. Because emesis may not occur when the stomach is empty, administration of ipecac should be followed by a drink of water. Ipecac is sometimes used to treat childhood ingestions at home under telephone supervision of a physician or poison control center personnel. Ipecac should not be used if the suspected intoxicant is a corrosive agent, a petroleum distillate, or a rapidly acting convulsant.

2. Gastric Lavage Gastric lavage involves the insertion of a large-bore tube (36-French tube or larger for adults and a 24-French tube or larger for children) via the esophagus into the stomach and washing the stomach with water, normal saline, or one-half normal saline to remove the unabsorbed poison. Lavage solutions (usually 0.9% saline) should be at body temperature to prevent hypothermia. The procedure should be performed as soon as possible, but only if vital functions are adequate or supportive procedures have been implemented. The contraindications to this procedure generally are the same as for emesis, and there is the additional potential complication of mechanical injury to the throat, esophagus, and stomach. According to the American and European clinical toxicologists, they concluded that gastric lavage should not be used routinely in the management of the poisoned patient but should be reserved for patients who have

ingested a potentially life-threatening amount of poison and when the procedure can be undertaken within 60 minutes of ingestion. For patients who are comatose, have seizures, or has lost gag reflex, an endotracheal tube with an inflatable cuff should be positioned before lavage is initiated to prevent. During gastric lavage, the patient should be placed on his or her left side because of the anatomical asymmetry of the stomach, with the head hanging face down over the edge of the examining table. If possible, the foot of the table should be elevated. This technique minimizes chances of aspiration. The contents of the stomach should be aspirated with an irrigating syringe and saved for chemical analysis. The stomach then may be washed with saline solution. Only small volumes (120 to 300 ml) of lavage solution should be instilled into the stomach at one time so that the poison is not pushed into the intestine. Lavage is repeated until the returns are clear, which usually requires 10 to 12 washings and a total of 1.5 to 4 L of lavage fluid. When the lavage is complete, the stomach may be left empty, or an antidote may be instilled through the tube. If no specific antidote for the poison is known, an aqueous suspension of activated charcoal and a cathartic often is given. 3. Activated Charcoal Activated charcoal can adsorb many drugs and poisons because of its large surface area. It is most effective if given in a ratio of at least 10:1 of charcoal to estimated dose of toxin by weight. It is effective immediately after administration, and its utility is not so compromised by pyloric outflow, since toxins may bind within the duodenum. It may be administered as a drink to conscious patients and through a conventional nasogastric tube in patients with altered consciousness, minimizing the complications associated with large-bore orogastric tubes. Many, but not all, chemicals are adsorbed by charcoal. Charcoal does not bind to iron, lithium, or potassium, and it binds to alcohols and cyanide only poorly. It does not appear to be useful in poisoning due to corrosive mineral acids and alkali. Recent studies suggest that oral activated charcoal given alone may be just as effective as gut emptying followed by charcoal. Also, other studies have shown that repeated doses of oral activated charcoal may enhance systemic elimination of some drugs (including carbamazepine, dapsone, and theophylline) by a mechanism referred to as "gut dialysis." Activated charcoal usually is prepared as a mixture of at least 50 g (about 10 heaping tablespoons) in a glass of water. The mixture is then administered either orally or via a gastric tube. Because most poisons do not appear to desorb from the charcoal if charcoal is present in excess, the adsorbed poison need not be removed from the gastrointestinal tract. Activated charcoal should not be used simultaneously with ipecac because charcoal can adsorb the emetic agent in ipecac and thus reduce the drug's emetic effect. Charcoal also may adsorb and decrease the effectiveness of specific antidotes.

4. Cathartics Administration of a cathartic (laxative) agent may hasten removal of toxins from the gastrointestinal tract and reduce absorption, although no controlled studies have been done. Cathartics generally are considered harmless unless the poison has injured the gastrointestinal tract. Cathartics are indicated after the ingestion of enteric-coated tablets, when the time after ingestion is greater than 1 hour, and for poisoning by volatile hydrocarbons. Sorbitol is the most effective, but sodium sulfate and magnesium sulfate also are used; all act promptly and usually have minimal toxicity. However, magnesium sulfate should be used cautiously in patients with renal failure or in those likely to develop renal dysfunction, and Na+-containing cathartics should be avoided in patients with congestive heart failure. 5. Whole Bowel Irrigation Whole-bowel irrigation has been used extensively to prepare the colon for surgery or endoscopy. The administration of a non-absorbable, isotonic polyethylene glycol solution (GoLYTELY, CoLyte) results in the evacuation of all intestinal contents after ingestion of iron tablets, enteric-coated medicines, illicit drug-filled packets, and foreign bodies. The solution is administered at 12 L/h (500 mL/h in children) for several hours until the rectal effluent is clear over several hours. The critical determinants for the success of whole-bowel irrigation are speed and volume of administration. Delivery of 2 L/h to most adult patients results in gastrointestinal clearance of drug within 3 hours. Enhanced Elimination 1. Urine pH Manipulation In manipulation of urine pH, the pH of the urine is most commonly raised to allow toxins with low pKa values (e.g., weak acids or onions such as salicylate) to become ionized within the renal tubule and collecting system. The ionized drug is trapped in the urine since only nonionized substances can diffuse back across cellular membranes to be reabsorbed. A pH change can only be of benefit if a drug or toxin is ionizable within the pH range of urine, such as salicylic acid, phenobarbital, or formic acid. Alkalinization of the urine is most commonly achieved by the administration of sodium bicarbonate intravenously. Acidification of the urine, which would conceivably enhance the elimination of weak bases with high pKa values, is considered dangerous, since many of the toxins that might benefit from this maneuver (e.g., phencyclidine or amphetamine) are associated with rhabdomyolysis. Acidification of the urine in this situation would allow myoglobin to precipitate within and to obstruct the renal tubule. For example, urinary alkalinization is useful in cases of salicylate overdose. Acidification may increase the urine concentration of drugs such as phencyclidine and amphetamines

but is not advised because it may worsen renal complications from rhabdomyolysis, which often accompanies the intoxication. 2. Dialysis The utility of dialysis depends on the amount of poison in the blood relative to the totalbody burden Petironeal dialysis This is a relatively simple and available technique which requires a minimum of personnel and can be started as soon as the patient is admitted to the hospital. However, it is too inefficient to be of value for the treatment of acute intoxications. Hemodialysis Hemodialysis (extracorporeal dialysis) is much more effective than peritoneal dialysis and may be essential in a few life-threatening intoxications, such as with methanol, ethylene glycol, and salicylates.. It assists in correction of fluid and electrolyte imbalance and may also enhance removal of toxic metabolites (e.g., formate in methanol poisoning, oxalate and glycolate in ethylene glycol poisoning). Hemodialysis involves the passage of blood over a semipermeable membrane, through which equilibration occurs with a balanced dialysate solution lacking the toxin or substance that is to be removed. Toxins in the blood that are small enough to pass through the membrane are cleared from the blood. However, even small toxins may not pass through the membrane if they are bound to plasma proteins. Moreover, toxins that are not predominantly in the blood compartment cannot be substantially removed from the blood, even if they easily cross the membrane. The volume of distribution (V d) determines whether a sufficient amount of toxin exists within the blood space to be cleared by hemodialysis. Therefore, small, water-soluble molecules having masses less than 500 daltons and a Vd less than 1 L/kg and exhibiting low protein binding are removed by hemodialysis. Hemoperfusion Blood is pumped from the patient via a venous catheter through a column of adsorbent material and then recirculated to the patient. Hemoperfusion does not improve fluid and electrolyte balance. However, it does remove many high-molecular-weight toxins that have poor water solubility because the perfusion cartridge has a large surface area for adsorption that is directly perfused with the blood and is not impeded by a membrane. The ratelimiting factors in removal of toxins by hemoperfusion are the affinity of the charcoal or adsorbent resin for the drug, the rate of blood flow through the cartridge, and the rate of equilibration of the drug from the peripheral tissues to the blood. Hemoperfusion may enhance whole body clearance of salicylate, phenytoin, ethchlorvynol, phenobarbital, theophylline, and carbamazepine.

Antidotes Selected Antidotes, Their Indications, and Other Comments

Selected Antidotes, Their Indications, and Mechanisms of Action ANTIDOTE INDICATION (TOXIN) MECHANISM OF ACTION Antivenin Pit viper bite Binding of toxin by antibody Coral snake bite Black Widow spider bite Botulinal trivalent antitoxin Botulism Binding of toxin by antibody Cyanide kit (amyl nitrite Cyanide poisoning Bind cyanide to inhalation, sodium nitrite methemoglobin, then parenteral, sodium thiosulfate enhance conversion to parenteral thiocyanate for excretion Deferoxamine mesylate Iron poisoning Chelate iron, enhance renal (Desferal) excretion Digoxin-specific antibody Digoxin poisoning (and Binding of digoxin to fragments (Digibind) other cardiac antibody glycosides) Dimercaptosuccinic acid (DMSA, Lead, mercury, arsenic Chelate heavy metal, Succimer, Chemet) poisoning enhance renal excretion Ethanol Methanol, ethylene Inhibit alcohol

glycol poisoning

Ethylenediaminetetraacetic acid (calcium disodium EDTA) Methylene blue

Lead poisoning Methemoglobinemia

N-Acetylcysteine (Mucomyst)

Acetaminophen poisoning Poisoning with oral hypoglycemic agents Carbon monoxide poisoning Some cases of poisoning with anticholinergic drugs

Octreotide Oxygen Physostigmine salicylate (Antilirium)

Pralidoxime chloride (Protopam)

Organophosphate or carbamate poisoning Iodine poisoning Warfarin poisoning

Starch Vitamin K1 (Aquamephyton Konakion)

dehydrogenase, slow conversion to toxic aldehydes and acids Chelate heavy metal, enhance renal excretion Help reduce Fe+++ to Fe++, thereby improving oxygen delivery to tissues Bind to toxic reactive metabolite, protect liver cells from damage Block release of insulin from pancreas Displace CO from hemoglobin Enhance duration of action of acetylcholine at cholinergic receptors by inhibiting acetylcholinesterase Reactivate cholinesterase inactivated by organophosphate Convert iodine to iodide (nontoxic) Enhance vitamin K1dependent synthesis of clotting factors II, VII, IX, and I

References Brunton, L. L., Lazo, J. S., and Parker, K. L. (2006). Goodman & Gilmans the Pharmacological Basis of Therapeutics, 11th Ed. New York: McGraw-Hill. Carruthers, S. G., Hoffman, B. B., Melmon, K. L., Nierenberg, D. W. (2000). Melmon and Morrelli's Clinical Pharmacology, 4th Ed. New York: McGraw-Hill. Klaasen, C. D. (2001). Casarett and Doull's Toxicology: The Basic Science of Poisons, 6th Ed. New York: McGraw-Hill. Williams, P.R.D., and Paustenbach, D. J. (2002). Risk Characterization. In: Human and Ecological Risk Assessment: Theory and Practice. New York: John Wiley & Sons. http:// www.wikipedia.com