principles of toxicology

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Slide 2: 

PRINCIPLES OF TOXICOLOGY

Toxicology is the science of the adverse effects of chemicals, including drugs, on living organisms. Toxicity

SCOPE OF TOXICITY : 

SCOPE OF TOXICITY The discipline often is divided into several major areas 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 Mechanistic toxicologist; attempts to determine how chemicals exert deleterious effects on living organisms. 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.

SCOPE OF TOXICITY (…) : 

SCOPE OF TOXICITY (…) Regulatory toxicologist; judges whether a drug or other chemical has a low enough risk to justify making it available for its intended purpose. 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 .

SCOPE OF TOXICITY (…) : 

SCOPE OF TOXICITY (…) 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.

Mechanism of toxicity : 

Mechanism of toxicity A. Nerve agents; These are potent organophosphorus agents cause inhibition of acetyl cholinesterase and subsequent excessive muscarinic and nicotinic stimulation (Organophosphorus and Carbamate Insecticides). B. Vesicants (blister agents); Nitrogen and sulfur mustards are hypothesized to act by alkylating cellular DNA and depleting glutathione, leading to lipid peroxidation by oxygen free radicals; Lewisite combines with thiol moieties in many enzymes and also contains trivalent arsenic.

Mechanism of toxicity(….) : 

Mechanism of toxicity(….) C. Choking agents; include chlorine and lacrimator agents. These gases and mists are highly irritating to mucous membranes. In addition, some may combine with the moisture in the respiratory tract to form free radicals that lead to lipid peroxidation of cell walls. Phosgene causes less acute irritation but may lead to delayed pulmonary injury D. Cyanides (blood agents); include cyanide, hydrogen cyanide, and cyanogen chloride. These compounds have high affinity for metalloenzymes such as cytochrome aa3, thus derailing cellular respiration and leading to the development of a metabolic acidosis.

Mechanism of toxicity(….) : 

Mechanism of toxicity(….) E. Incapacitating agents. A variety of agents have been considered, including strong anticholinergic agents such as scopolamine, stimulants such as amphetamines and cocaine, hallucinogens such as LSD (Lysergic Acid Diethylamide and Other Hallucinogens), and CNS depressants such as opioids (Opiates and Opioids).

BASIC PRINCIPLES : 

BASIC PRINCIPLES Dose–Response Relationship Evaluation of the dose–response or the dose–effect relationship is crucially important to toxicologists. There is a graded dose–response relationship in an individual and a quantal dose–response relationship in the population Graded doses of a drug given to an individual usually result in a greater magnitude of response as the dose is increased.

Dose–Response Relationship : 

Dose–Response Relationship In a quantal dose–response relationship, the percentage of the population affected increases as the dose is raised; the relationship is quantal in that the effect is specified to be either present or absent in a given individual. This quantal dose–response phenomenon is extremely important in toxicology and is used to determine the median lethal dose (LD50) of drugs and other chemicals.

Risk and Its Assessment : 

Risk and Its Assessment There are marked differences in the LD50 values of various chemicals. Some result in death at doses of a fraction of a microgram (LD50 for botulinum toxin equals 10 pg/kg); others may be relatively harmless in doses of several grams or more. The real concern is the risk associated with use of the chemical. In the assessment of risk, one must consider concentration or dose as well as the harmful effects of the chemical occrued directly or indirectly through adverse effects on the environment when used in the quantity and in the manner proposed.

Acute versus Chronic Exposure : 

Acute versus Chronic Exposure Effects of acute exposure to a chemical often differ from those that follow chronic exposure. Acute exposure occurs when a dose is delivered as a single event. Chronic exposure is likely to be to small quantities of a substance over a long period of time, which often results in slow accumulation of the compound in the body. Evaluation of cumulative toxic effects is receiving increased attention because of chronic exposure to low concentrations of various natural and synthetic chemical substances in the environment

Chemical Forms of Drugs That Produce toxicity. : 

Chemical Forms of Drugs That Produce toxicity. The "parent" drug administered to the patient often is the chemical form producing the desired therapeutic effect; the parent drug also may produce the toxic effects of drug. However, both therapeutic and toxic effects also can be due to metabolites of the drug produced by enzymes, light, or reactive oxygen species. In considering the toxicity of drugs and chemicals, it is important to understand their metabolism, activation, or decomposition

Toxic Metabolites : 

Toxic Metabolites The metabolites of many chemicals are responsible for their toxicities. Most organophosphate insecticides are biotransformed by cytochrome P450 enzymes (CYPs) to produce the active toxin. For example, parathion is biotransformed to paraoxon. Paraoxon is a stable metabolite that binds to and inactivates cholinesterase. Some drug metabolites are not chemically stable and are referred to as reactive intermediates.

Toxic Metabolites(….) : 

Toxic Metabolites(….) . An example of a toxic reactive intermediate is the metabolite of acetaminophen, which is very reactive and binds to nucleophiles such as glutathione; when cellular glutathione is depleted, the metabolite binds to cellular macromolecules, the mechanism by which acetaminophen kills liver cells . Both parathion and acetaminophen are more toxic under conditions in which CYPs are increased, such as following ethanol or phenobarbital exposure, because CYPs produce the toxic metabolites

Phototoxic and Photoallergic Reactions : 

Phototoxic and Photoallergic Reactions Many chemicals are activated to toxic metabolites by hepatic enzymatic biotransformation. However, some chemicals can be activated in the skin by ultraviolet and/or visible radiation. In photoallergy, radiation absorbed by a drug, such as a sulfonamide, results in its conversion to a product that is a more potent allergen than the parent compound. Phototoxic reactions to drugs, in contrast to photoallergic ones, do not have an immunological component.

(………..) : 

(………..) Drugs that are either absorbed locally into the skin or have reached the skin through the systemic circulation may be the object of photochemical reactions within the skin; this can lead directly either to chemically induced photosensitivity reactions or to enhancement of the usual effects of sunlight. Tetracyclines, sulfonamides, chlorpromazine, and nalidixic acid are examples of phototoxic chemicals.

Reactive Oxygen Species : 

Reactive Oxygen Species Paraquat is an herbicide that produces severe lung injury. Its toxicity is not due to paraquat or its metabolites but rather to reactive oxygen species formed during one-electron reduction of paraquat paired with an electron donation to oxygen

Types of Toxic Reactions : 

Types of Toxic Reactions Toxic effects of drugs may be classified as pharmacological, pathological, genotoxic (alterations of DNA) Their incidence and seriousness are related, at least over some range, to the concentration of the toxic chemical in the body. An example of a pharmacological toxicity is excessive depression of the central nervous system (CNS) by barbiturates.

(….) : 

(….) Example of a pathological effect, hepatic injury produced by acetaminophen. Example of a genotoxic effect, a neoplasm produced by a nitrogen mustard. If the concentration of chemical in the tissues does not exceed a critical level, the effects usually will be reversible.

(….) : 

(….) . The pharmacological effects usually disappear when the concentration of drug or chemical in the tissues is decreased by biotransformation or excretion from the body. Pathological and genotoxic effects may be repaired. If these effects are severe, death may ensue within a short time; if more subtle damage to DNA is not repaired, cancer may appear in a few months or years in laboratory animals or in a decade or more in humans

Local versus Systemic Toxicity : 

Local versus Systemic Toxicity Local toxicity occurs at the site of first contact between the biological system and the toxicant. Local effects can be caused by ingestion of caustic substances or inhalation of irritant materials. Systemic toxicity requires absorption and distribution of the toxicant.

(….) : 

(….) most substances, with the exception of highly reactive chemical species, produce systemic toxic effects. The two categories are not mutually exclusive. Tetraethyl lead, for example, injures skin at the site of contact and deleteriously affects the CNS after it is absorbed into the circulation

Reversible and Irreversible Toxic Effects : 

Reversible and Irreversible Toxic Effects The effects of drugs on humans, whenever possible, must be reversible; otherwise, the drugs would be prohibitively toxic. If a chemical produces injury to a tissue, the capacity of the tissue to regenerate or recover largely will determine the reversibility of the effect. Injuries to a tissue such as liver, which has a high capacity to regenerate, usually are reversible; injury to the CNS is largely irreversible because the highly differentiated neurons of the brain have a more limited capacity to divide and regenerate.

Delayed Toxicity : 

Delayed Toxicity Most toxic effects of drugs occur at a predictable (usually short) time after administration. However, such is not always the case. For example, aplastic anemia caused by chloramphenicol may appear weeks after the drug has been discontinued. Carcinogenic effects of chemicals usually have a long latency period: 20 to 30 years may pass before tumors are observed. Because such delayed effects cannot be assessed during any reasonable period of initial

Allergic Reactions : 

Allergic Reactions Chemical allergy is an adverse reaction that results from previous sensitization to a particular chemical or to one that is structurally similar. Such reactions are mediated by the immune system. The terms hypersensitivity and drug allergy often are used to describe the allergic state evaluation of a chemical, there is an urgent need for reliably predictive short-term tests for such toxicity, as well as for systematic surveillance of the long-term effects of marketed drugs and other chemicals

Chemical Carcinogens : 

Chemical Carcinogens Chemical carcinogens are classified into two major groups, genotoxic and nongenotoxic Most genotoxic carcinogens are themselves unreactive (procarcinogens or proximate carcinogens) but are converted to primary or ultimate carcinogens in the body. The drug-metabolizing enzymes often convert the proximate carcinogens to reactive electron-deficient intermediates (electrophiles).

(….) : 

(….) These reactive intermediates can interact with electron-rich (nucleophilic) centers in DNA to produce a mutation Nongenotoxic carcinogens, also referred to as promoters, do not produce tumors alone but do potentiate the effects of genotoxic carcinogens. Promotion involves facilitation of the growth and development of so-called dormant or latent tumor cells

Idiosyncratic Reactions : 

Idiosyncratic Reactions Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a given individual. The idiosyncratic response may take the form of extreme sensitivity to low doses or extreme insensitivity to high doses of chemicals. We now know that certain idiosyncratic reactions can result from genetic polymorphisms that cause individual differences in drug pharmacokinetics; for example, an increased incidence of peripheral neuropathy is seen in patients with inherited deficiencies in acetylation when isoniazid is used to treat tuberculosis

Interactions between Chemicals : 

Interactions between Chemicals The existence of numerous toxicants requires consideration of their potential interactions . Concurrent exposures may alter the pharmacokinetics of drugs by changing rates of absorption, the degree of protein binding, or the rates of biotransformation or excretion of one or both interacting compounds.

Slide 32: 

The pharmacodynamics of chemicals can be altered by competition at the receptor; for example, atropine is used to treat organophosphate insecticide toxicity because it blocks muscarinic cholinergic receptors and prevents their stimulation by the excess acetylcholine accruing from inhibition of acetylcholinesterase by the insecticide.

Slide 33: 

Nonreceptor pharmacodynamic drug interactions also can occur when two drugs have different mechanisms of action: Aspirin and heparin given together can cause unexpected bleeding. The response to combined toxicants thus may be equal to, greater than, or less than the sum of the effects of the individual agents. An additive effect describes the combined effect of two chemicals that equals the sum of the effect of each agent given alone; the additive effect is the most common

Slide 34: 

A synergistic effect is one in which the combined effect of two chemicals exceeds the sum of the effects of each agent given alone. For example, both carbon tetrachloride and ethanol are hepatotoxins, but together they produce much more injury to the liver than expected from the sum of their individual effects. A Potentiation is the increased effect of a toxic agent acting simultaneously with a nontoxic one. Isopropanol alone, for example, is not hepatotoxic; however, it greatly increases the hepatotoxicity of carbon tetrachloride. Antagonism is the interference of one chemical with the action of another. An antagonistic agent is often desirable as an antidote.

Slide 35: 

Functional or physiological antagonism occurs when two chemicals produce opposite effects on the same physiological function. For example, this principle is applied to the use of intravenous infusion of dopamine to maintain perfusion of vital organs during certain severe intoxications characterized by marked hypotension. Chemical antagonism or inactivation is a reaction between two chemicals to neutralize their effects. For example, dimercaprol chelates various metals to decrease their toxicity.

Clinical presentation : 

Clinical presentation A. Nerve agents are potent cholinesterase-inhibiting organophosphorus compounds ( Organophosphorus and Carbamate Insecticides). Symptoms of muscarinic and nicotinic overstimulation include abdominal pain, vomiting, diarrhea, excessive salivation and sweating, bronchospasm, copious pulmonary secretions, muscle fasciculations and weakness, and respiratory arrest. Seizures, bradycardia, or tachycardia may be present. Severe dehydration can result from volume loss caused by sweating, vomiting, and diarrhea.

Clinical presentation(…) : 

Clinical presentation(…) B. Vesicants (blister agents). The timing of onset of symptoms depends on the agent, route, and degree of exposure 1. Skin blistering is the major cause of morbidity and can lead to severe tissue damage. 2. Ocular exposure causes tearing, itching, and burning and can lead to severe corneal damage, chronic conjunctivitis, and keratitis. Permanent blindness usually does not occur. 3. Pulmonary effects include cough and dyspnea, chemical pneumonitis, and chronic bronchitis.

Clinical presentation : 

Clinical presentation C. Choking agents can cause varying degrees of mucous membrane irritation, cough, wheezing, and chemical pneumonitis. Phosgene exposure may also present with delayed pulmonary edema that can be severe and sometimes lethal. D. Cyanides cause dizziness, dyspnea, confusion, agitation, and weakness, with progressive obtundation and even coma. Seizures and hypotension followed by cardiovascular collapse may occur rapidly. The effects tend to be all or nothing in a gas exposure, so if patients survive the initial insult, they can be expected to recover. E. Incapacitating agents. The clinical features depend on the agent (see previous section, Incapacitating agents).

Slide 39: 

1. Anticholinergics. As little as 1.5 mg of scopolamine can cause delirium, poor coordination, stupor, tachycardia, and blurred vision. BZ (3-quinuclidinyl benzilate, or QNB) is about 3 times more potent than scopolamine. Other signs include dry mouth, flushed skin, and dilated pupils. 2. LSD and similar hallucinogens cause dilated pupils, tachycardia, CNS stimulation, and varying degrees of emotional and perceptual distortion. 3. CNS stimulants can cause acute psychosis, paranoia, tachycardia, sweating, and seizures. 4. CNS depressants generally cause somnolence and depressed respiratory drive (with apnea a serious risk).

PREVENTION AND TREATMENT OF POISONING : 

PREVENTION AND TREATMENT OF POISONING Many acute poisonings from drugs could be prevented if physicians provided common-sense instructions about the storage of drugs and other chemicals and if patients or parents of patients accepted this advice. For clinical purposes, all toxic agents can be divided into two classes: Those for which a specific treatment or antidote exists. Those for which there is no specific treatment. For the vast majority of drugs and other chemicals, there is no specific treatment; symptomatic medical care that supports vital functions is the only strategy

(……) : 

(……) "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.

Prevention of Further Absorption of Poison : 

Prevention of Further Absorption of Poison Emesis Chemical Adsorption, Activated charcoal Purgation Enhanced Elimination of the Poison a).Biotransformation b). Excretion c). Dialysis

Emesis : 

Emesis Historically, emesis was one of the major tools of gastric decontamination in the management of acute poisoning. However, its routine use in the emergency room is declining. Although emesis still may be indicated for immediate intervention after poisoning by oral ingestion of chemicals, it is contraindicated in certain situations 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. if the patient is comatose or in a state of stupor or delirium, emesis may cause aspiration of the gastric contents.

(……) : 

(……) if the patient has ingested a CNS stimulant, further stimulation associated with vomiting may precipitate convulsions; and 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.

METHODS : 

METHODS Vomiting can be induced mechanically by stroking the posterior pharynx. However, this technique is not as effective as the administration of ipecac or apomorphine.

Chemical Adsorption, Activated charcoal : 

Chemical Adsorption, Activated charcoal Chemical Inactivation, Agents can change the chemical nature of a poison by rendering it less toxic or preventing its absorption. Formaldehyde poisoning can be treated with ammonia to form hexamethylenetetramine; sodium formaldehyde sulfoxylate can convert mercuric ion to the less soluble metallic mercury; and sodium bicarbonate converts ferrous iron to ferrous carbonate, which is poorly absorbed. Chemical inactivation techniques seldom are used today, however, because valuable time may be lost, whereas emetics, activated charcoal, and gastric lavage are rapid and effective.

Purgation : 

Purgation The rationale for using an osmotic cathartic is to minimize absorption by hastening the passage of the toxicant through the gastrointestinal tract.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.

Whole-bowel irrigation (WBI : 

Whole-bowel irrigation (WBI It is a technique that not only promotes defecation but also eliminates the entire contents of the intestines. This technique uses a high-molecular-weight polyethylene glycol and isosmolar electrolyte solution that does not alter serum electrolytes.

Inhalation and Dermal Exposure to Poisons : 

Inhalation and Dermal Exposure to Poisons 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, it should be washed thoroughly with water. Contaminated clothing should be removed. 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.

Biotransformation : 

Biotransformation Once a chemical has been absorbed, procedures sometimes can be employed to enhance its rate of elimination. Many drugs are metabolized by hepatic CYPs, and components of this system can be induced by a number of compounds. However, induction of these oxidative enzymes is too slow (days) to be valuable in the treatment of acute poisoning by most chemical agents. Many chemicals are toxic because they are biotransformed into more toxic chemicals. Thus inhibition of biotransformation should decrease the toxicity of such drugs. For example, ethanol is used to inhibit the conversion of methanol to its highly toxic metabolite, formic acid, by alcohol dehydrogenase.

(…) : 

(…) Some drugs are detoxified by conjugation with Glucuronic acid or sulfate before elimination from the body, and the availability of the endogenous cosubstrates for conjugation may limit the rate of elimination; such is the case in the detoxication of acetaminophen. Methods to replete these compounds will provide an additional mechanism to treat poisoning. Similarly, detoxication of cyanide by conversion to thiocyanate can be accelerated by the administration of thiosulfate.

(……) : 

(……) Acetaminophen is converted by the CYP system to an electrophilic metabolite that is detoxified by glutathione, a cellular nucleophile. Acetaminophen does not cause hepatotoxicity until glutathione is depleted, whereupon the reactive metabolite binds to essential macromolecular constituents of the hepatocyte, resulting in cell death. The liver can be protected by maintenance of the concentration of glutathione, and this can be accomplished by the administration of N-acetylcysteine.

Biliary Excretion : 

Biliary Excretion The liver excretes many drugs and other foreign chemicals into bile, but little is known about efficient ways to enhance biliary excretion of xenobiotics for the treatment of acute poisoning. Inducers of microsomal enzyme activity enhance biliary excretion of some xenobiotics, but the effect is slow in onset.

Urinary Excretion : 

Urinary Excretion Drugs and poisons are excreted into the urine by glomerular filtration and active tubular secretion, they can be reabsorbed into the blood if they are in a lipid-soluble form that will penetrate the tubule or if there is an active mechanism for their transport. There are no methods known to accelerate the active transport of poisons into urine, and enhancement of glomerular filtration is not a practical means to facilitate elimination of toxicants. However, passive reabsorption from the tubular lumen can be altered. Diuretics inhibit reabsorption by decreasing the concentration gradient of the drug from the lumen to the tubular cell and by increasing flow through the tubule.

Slide 55: 

Furosemide is used most often, but osmotic diuretics also are employed. Forced diuresis should be used with caution, especially in patients with renal, cardiac, or pulmonary complications.

Slide 56: 

Nonionized compounds are reabsorbed far more rapidly than ionized polar molecules; therefore, a shift from the nonionized to the ionized species of the toxicant by alteration of the pH of the tubular fluid may hasten elimination. Acidic compounds such as phenobarbital and salicylates are cleared much more rapidly in alkaline than in acidic urine. Urine alkalinization increases the urine elimination of chlorpropamide, 2,4-dichlorophenoxyacetic acid, diflunisal, fluoride, methotrexate, phenobarbital, and salicylate. However, urine alkalinization is recommended as first-line treatment only for patients with moderately severe salicylate poisoning who do not meet the criteria for hemodialysis. Urine alkalinization and high urine flow (approximately 600 ml/h) should also be considered in patients with severe 2,4-dichlorophenoxyacetic acid.

Slide 57: 

Even though it has been shown to be effective in enhancing elimination of Phenobarbital, urine alkalinization is not recommended as first-line treatment in cases of phenobarbital poisoning because multiple-dose activated charcoal has been shown to be superior. Urine alkalinization is contraindicated in the case of compromised renal function or failure. Hypokalemia is the most common complication but can be corrected by giving potassium supplements. Intravenous sodium bicarbonate is used to alkalinize the urine. Renal excretion of basic drugs such as amphetamine theoretically can be enhanced by acidification of the urine. Acidification can be accomplished by the administration of ammonium chloride or ascorbic acid. Urinary excretion of an acidic compound is particularly sensitive to changes in urinary pH if its pKa is within the range of 3.0 to 7.5; for bases, the corresponding range is 7.5 to 10.5.

Dialysis : 

Dialysis Hemodialysis usually has limited use in the treatment of intoxication with chemicals. However, under certain circumstances, such procedures can be lifesaving. The utility of dialysis depends on the amount of poison in the blood relative to the total-body burden. Thus, if a poison has a large volume of distribution, as is the case for the tricyclic antidepressants, the plasma will contain too little of the compound for effective removal by dialysis. Extensive binding of the compound to plasma proteins impairs dialysis greatly. The elimination of a toxicant by dialysis also depends on dissociation of the compound from binding sites in tissues; for some chemicals, this rate may be slow and limiting.

Peritoneal Dialysis : 

Peritoneal Dialysis Although peritoneal dialysis requires a minimum of personnel and can be started as soon as the patient is admitted to the hospital, it is too inefficient to be of value for the treatment of acute intoxications. 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.

SPECIFIC DRUGS AND ANTIDOTES : 

SPECIFIC DRUGS AND ANTIDOTES Specific chemical antagonists of a toxicant, such as opioid antagonists and atropine as an antagonist of pesticide-induced acetylcholine excess, are valuable but unfortunately rare. A recently approved antagonist is fomepizole, an inhibitor of alcohol dehydrogenase, approved for treatment for poisoning by ethylene glycol and methanol. Chelating agents with high selectivity for certain metal ions are used more commonly. Antibodies offer the potential for the production of specific antidotes for a host of common poisons and for drugs that frequently are abused or misused. A notable example of such success is the use of purified digoxin-specific Fab fragments of antibodies in the treatment of potentially fatal cases of poisoning with digoxin.

Slide 61: 

The development of human monoclonal antibodies directed against specific toxins has significant potential therapeutic value

Nerve agents : 

Nerve agents Organophosphorus and Carbamate Insecticides a. Atropine. Give 0.5–2 mg IV initially and repeat the dose as needed. Initial doses may be given intramuscularly. The most clinically important indication for continued atropine administration is persistent wheezing or bronchorrhea. Atropine will reverse muscarinic but not nicotinic (muscle weakness) effects.

Slide 63: 

b. Pralidoxime It is a specific antidote for organophosphorus agents. It should be given immediately to reverse muscular weakness and fasciculations: 1–2 g initial bolus dose (20–40 mg/kg) IV over 5–10 minutes, followed by a continuous infusion (Pralidoxime (2-PAM) and Other Oximes). It is most effective if started early, before irreversible phosphorylation of the enzyme, but may still be effective if given later. Initial doses can be given by the intramuscular route if IV access is not immediately available.Oximes such as Obidoxime offer promise for better reactivation of cholinesterases in the setting of nerve agent exposure.

Slide 64: 

c.Diaepam anticonvulsant therapy may be beneficial even before the onset of seizures and should be administered as soon as exposure is recognized. The initial dose is 10 mg IM or IV in adult patients (0.1–0.3 mg/kg in children).

. Vesicants : 

. Vesicants These are treated primarily as a chemical burn. a. British anti-Lewisite , a chelating agent used in the treatment of arsenic, mercury, and lead poisoning, originally was developed for treatment of Lewisite exposures. Topical BAL has been recommended for eye and skin exposure to Lewisite; however, preparations for ocular and dermal use are not widely available. b. Sulfur donors such as sodium thiosulfate have shown promise in animal models of mustard exposures when given before or just after an exposure. The role of this antidote in human exposures is not clear.

Choking agents : 

Choking agents Treatment is mainly symptomatic with the use of bronchodilators as needed for wheezing. Hypoxia should be treated with humidified oxygen, but caution should be exercised in treating severe chlorine or phosgene exposure because excessive oxygen administration may worsen the lipid peroxidation caused by oxygen free radicals. Steroids are indicated for patients with underlying reactive airways disease

Cyanides : 

Cyanides The cyanide antidote package (Taylor Pharmaceuticals) consists of amyl and sodium nitrites (Nitrite, Sodium and Amyl), which produce cyanide-scavenging methemoglobinemia, and sodium thiosulfate (Thiosulfate, Sodium), which accelerates the conversion of cyanide to thiocyanate.

Incapacitating agents : 

Incapacitating agents a. Anticholinergic delirium may respond to physostigmine (see Physostigmine and Neostigmine). b. Stimulant toxicity and bad reactions to hallucinogens may respond to lorazepam, diazepam, and other benzodiazepines (see Benzodiazepines [Diazepam, Lorazepam, and Midazolam]). c. Treat suspected opioid overdose with naloxone (Naloxone and Nalmefene

Decontamination. : 

Decontamination. Rescuers should wear appropriate chemical protective clothing, as some agents can penetrate clothing and latex gloves. Butyl chemical protective gloves should be worn, especially in the presence of mustard agents. Preferably, a well-trained hazardous materials team should perform initial decontamination prior to transport to a health-care facility. Decontamination of exposed equipment and materials may also be necessary but can be difficult because agents may persist or even polymerize on surfaces. Currently, the primary methods of decontamination are physical removal and chemical deactivation of the agent.

Slide 70: 

Gases and vapors in general do not require any further decontamination other than simple physical removal of the victim from the toxic environment. Off-gassing is unlikely to cause a problem unless the victim was thoroughly soaked with a volatile liquid

Chemical deactivation of chemical agents : 

Chemical deactivation of chemical agents Nerve agents typically contain phosphorus groups and are subject to deactivation by hydrolysis, whereas mustard contains sulfur moieties subject to deactivation via oxidation reactions. Various chemical means of promoting these reactions have been utilized. a. Oxidation. Dilute sodium or calcium hypochlorite (0.5%) can oxidize susceptible chemicals. This alkaline solution is useful for both organophosphorus compounds and mustard agents. Caution: Dilute hypochlorite solutions should NOT be used for ocular decontamination or for irrigation of wounds involving the peritoneal cavity, brain, or spinal cord. A 5% hypochlorite solution is used for equipment.

Slide 72: 

b. Hydrolysis. Alkaline hydrolysis of phosphorus-containing nerve agents is an effective means of decontamination of personnel exposed to these agents. Dilute hypochlorite is slightly alkaline. The simple use of water with soap to wash an area may also cause slow hydrolysis.