THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

35. Toxicology and Chem-Bioterrorism - Peter A. Chyka, PharmD, FAACT, DABAT

35-1. Overview of Poisoning and Toxicology

Poisoning in America

Poisoning exposures and overdoses affect more than 2.5 million people annually, and more than 37,000 deaths occur yearly. A large number of poisonings occur in young children (< 1% of deaths are in preschool-age children), but most fatalities occur in adults.

Any chemical can become toxic if the exposure is too great in relation to body weight and tolerance. Medications are the most common cause of poisoning morbidity and mortality (

Table 35-1).

Most poisonings in preschool-age children are unintentional or accidental. Unintentional poisonings can also occur in adolescents and adults; however, intentional (suicide and drug abuse) poisonings and overdoses are common.

Toxicology is the study of the adverse effects of chemicals and other xenobiotics on living organisms. There are several specialized areas of toxicology, including basic science, clinical, analytical, forensic, regulatory, and occupational settings, that have a unique focus and purpose.

In general, toxicity occurs when too much of a substance is taken in relation to a normally tolerable dose. Different mechanisms by which a chemical can produce toxicity include the following:

• Exaggeration of pharmacologic effects

• Formation of reactive toxic metabolites

• Formation of intracellular free radicals

• Interference with enzyme action

• Interference with DNA (deoxyribonucleic acid) or RNA (ribonucleic acid) synthesis

• Inactivation of biochemical cofactors

• Initiation of premature cell aging (apoptosis)

• Tissue destruction on contact

The contributions of Adrianne Y. Butler, PharmD; Billie J. Holliman, PharmD; and C. Renee Adams-McDowell, PharmD, to the first edition of this chapter are acknowledged.

Poison Prevention Approaches and Pharmacy

Poison Prevention Packaging Act of 1970: Safety caps

This act was issued to prevent preschool-age children from opening and ingesting harmful substances or to delay the opening of packaging containing such substances (to limit the amount of harmful substance that may be ingested within a reasonable amount of time).

Drugs requiring safety caps include aspirin, ibuprofen, acetaminophen, and oral prescription drugs with certain exceptions (e.g., birth control pills and nitroglycerin).

Use of poison control centers

A poison control center determines if a true poisoning exists, recommends first aid, refers poisoning victims to health care facilities for further evaluation and treatment, monitors the progress and outcome of each poisoning case, and documents poisoning experiences. Programs and materials on poison prevention are also available.

Nationwide access is available by calling 1-800-222-1222 for 24-hour poison center services for the area from which the call is placed in the United States.

[Table 35-1. Ranking of Most Frequent Poisonings from U.S. Poison Centers and Emergency Departments, 2006]

Poison prevention tips for consumers

• Store all drugs and chemicals out of the reach of children.

• Never put chemicals in food containers.

• Choose products with safety caps when there is a choice, and use them properly.

• Read and follow all label directions carefully.

• Never call medicine "candy."

• Use safety latches.

Pharmacy Requirements of the Joint Commission on Accreditation of Healthcare Organizations

• Maintain and keep available the medical staff-approved stock of antidotes and other emergency drugs in both the pharmacy and patient care areas.

• Maintain authoritative and current antidote information.

• Keep the phone number of the poison control center readily available in areas outside of the pharmacy where drugs are stored.

Emergency Actions

First aid should be administered, if applicable.

Table 35-2 describes first-aid techniques.

Other considerations

• Avoid wasting time looking for an "antidote" at home.

• Do not use home remedies such as saltwater, mustard powder, raw eggs, hydrogen peroxide, cooking grease, or gagging.

• Immediately call 911 or an ambulance if the person is not breathing, has had a seizure, or is unresponsive.

• For other situations, contact a poison center immediately to determine whether first aid should be used or whether a poisoning emergency exists.

Decontamination of the Gastrointestinal Tract

The practice of using drugs to decrease the absorption of other drugs from the gastrointestinal tract is in a state of change. For example, ipecac syrup is being

[Table 35-2. First Aid for Poisoning Emergencies]

abandoned by many as a home- or hospital-based therapy, and its use is primarily at the preference of the consulting poison center or health care professional. Current recommendations are described in this section, as well as basic information about the drugs in case they are encountered.

Current recommendations

Ipecac syrup has questionable effectiveness, and its use is generally now avoided.

Gastric lavage involves placing a tube into the stomach through a nostril or the mouth and repetitively washing out the stomach contents with water or a saline solution. This method of gastric decontamination is of questionable effectiveness, particularly if it is performed more than 1 hour after ingestion of toxin.

Cathartics such as magnesium citrate are not routinely used any more.

Activated charcoal given orally is often the only treatment necessary if the toxin is adsorbed and the activated charcoal is used within 1-2 hours of ingestion of the toxin.

Whole bowel irrigation can be considered if the toxin is poorly or slowly adsorbed and its presence in the gastrointestinal tract is likely.

Ipecac syrup

Indications and dosage

Ipecac syrup was previously used for general prophylaxis of selected poisonings of expected minor or moderate severity in alert patients. Many clinicians have abandoned it as a prehospital or hospital treatment. In 2003, the American Academy of Pediatrics recommended that ipecac syrup no longer be used routinely as a home treatment for poisoning.

Contraindications

• The patient is experiencing pronounced sleepiness, coma, or seizures.

• The patient has ingested caustics, aliphatic hydrocarbons, and fast-acting agents that produce coma or seizures (e.g., tricyclic antidepressants, clonidine, calcium channel blockers, beta blockers, and hypoglycemic agents).

• Time since ingestion is believed to be 1 hour or more.

Adverse effects

• Common: Diarrhea, sleepiness, and protracted vomiting

• Uncommon: Mallory-Weiss tears and tracheal aspiration into the lungs.

Disadvantage

A disadvantage of ipecac syrup is that emesis and the drug's relative lack of efficacy complicate administration of other oral therapies.

Activated charcoal

Indications and dosage

This agent is occasionally used to adsorb poisons in an alert or comatose patient. Administer as a slurry by mouth or through a lavage tube:

• Children: 25-50 g

• Adults: 25-100 g

Contraindications

• Ingestions of aliphatic hydrocarbons and caustics

• Absence of patient's bowel sounds

• Ingestions of heavy metals (sodium, lithium, iron, or lead) or simple alcohols

Adverse effects

• Uncommon: Tracheal aspiration and pneumonitis

• Common: Emesis and soiling of clothes and furnishings

Advantages and disadvantages

• Advantages: Rapid onset of action, nonspecific action for a wide variety of chemicals, and reasonable effectiveness within 1 hour of ingestion

• Disadvantages: Messy and difficult administration and possible removal of beneficial drugs together with the toxin

Cathartics

Cathartics were previously used as an adjunct to activated charcoal administration to decrease gastrointestinal transit time. Their efficacy is unproved. Fluid and electrolyte disturbances are possible with repeated doses.

Cathartics may contribute to emesis following activated charcoal use.

Agents previously used include magnesium citrate, magnesium sulfate, sodium sulfate, and sorbitol. Some activated charcoal products contain sorbitol mixed in the preparation. The sorbitol concentration varies from brand to brand.

Whole bowel irrigation

Indications and technique

Whole bowel irrigation is generally used to wash out the gastrointestinal tract when using charcoal may be inappropriate (e.g., if iron or lithium was ingested) and the toxin is suspected to be present in the gastrointestinal tract (e.g., when drugs are sustained-release formulations or when the patient ingested illicit drugs packed in condoms).

Use larger volumes of polyethylene glycol electrolyte solutions (e.g., Colyte, GoLYTELY) than the amounts conventionally used for bowel preparation. Administer by mouth or through a gastric or duodenal tube for treatment of poisoning:

• Children: 25 mL/kg/h (approximately 500 mL/h) up to 2-5 L

• Adults: 2 L/h up to 5-10 L

Contraindications

• Ingestion of caustics or aliphatic hydrocarbons

• Patients with absent bowel sounds or gastrointestinal tract obstruction

Adverse effects

Few adverse effects have been reported, but limited results are available from which to draw conclusions. Some nausea and vomiting have been reported.

Advantages and disadvantages

• Advantages: Prompt whole-bowel evacuation within 2 hours

• Disadvantages: Messy procedure because of rectal effluent

Other hospital-based therapies

These therapies include supportive and symptomatic care, multiple doses of activated charcoal (to enhance systemic elimination when appropriate), hemodialysis (to enhance systemic elimination when appropriate), and use of antidotes (to antagonize or reverse toxic effects when indicated).

35-2. Substance Abuse and Toxicology

Substance abuse often leads to acute and chronic toxicity.

Table 35-3 shows selected drugs of abuse.

During 2007, 35.7 million Americans age 12 and older (14.4% of the population) admitted using an illicit drug in the past year, and 9.9 million (4.0%) reported driving under the influence of an illicit drug during the past year.

Approximately 1.4 million adults are treated in emergency departments annually for abuse and misuse of drugs not including alcohol, with one-third involving alcohol in combination with other drugs.

Management of the acute condition generally follows the same guidelines as those for management of poisonings and overdoses. A challenge in treating patients during acute drug overdose is determining the possible agents taken and possible adulterants (e.g., talc, strychnine, other drugs) or contaminants.

Chronic abuse can foster dependence, which often leads to withdrawal symptoms when the patient stops using the drugs. Detoxification programs, long-term behavioral counseling, and drugs to produce aversion or substitution to drug-taking behaviors are often needed.

35-3. Antidotes

Role of Antidotes

An antidote counteracts or changes the nature of a poison. Few antidotes are available relative to the large number of potential poisons.

Table 35-4 lists antidotes that are commonly used in the treatment of a patient with a poisoning or an overdose.

Many hospitals have an insufficient stock of antidotes. The pharmacy and therapeutics committee of a hospital should regularly review the inventory of antidotes.

Selected Antidotes

Acetylcysteine

Acetylcysteine is available under the trade names Mucomyst (10%, 20% oral solution) and Acetadote (20% for injection).

Uses

Acetylcysteine is used to treat acute acetaminophen overdose. An unapproved indication is to treat adverse reactions to drugs that may produce free radicals as part of the adverse reaction; the dosage regimen is unique to the application.

Mechanism of action

Acetylcysteine protects the liver from the toxic effects of an acetaminophen metabolite by supplying glutathione to aid in metabolism of the reactive metabolite. Other mechanisms are also proposed, which include providing sulfate for acetaminophen metabolism and minimizing the formation of free radicals.

This agent may be useful in minimizing hepatotoxic injury once it has begun. It also may aid in cases of fulminant hepatic failure.

[Table 35-3. Selected Drugs of Abuse and Addictive Substances]

[Table 35-4. Commonly Used Antidotes]

Indications

Acute overdoses of acetaminophen produce a reactive metabolite that leads to hepatotoxicity (jaundice, coagulopathy, hypoglycemia, hepatic failure, hepatic encephalopathy, hepatorenal failure). Symptoms become evident 1-2 days after ingestion.

Acetylcysteine can prevent or minimize hepatic injury if given early. For best results, administer within 10 hours of ingestion of acetaminophen overdose. It is minimally effective when started 24 hours after ingestion.

The need for therapy is determined by obtaining a serum concentration of acetaminophen at least 4 hours after ingestion (and within 24 hours) and plotting it on the acetaminophen nomogram to determine whether there is a risk for hepatotoxicity.

Contraindications

Use of acetylcysteine is contraindicated if there is a known hypersensitivity to the drug.

Adverse effects

With oral administration, nausea and vomiting are common.

With intravenous (IV) administration, anaphylactoid reactions (rash, hypotension, wheezing, and dyspnea) have been reported. Acute flushing and erythema may occur during the first hour of infusion and typically resolve spontaneously.

Dosage

Table 35-4 gives dosage information on drug products for oral or IV administration available in the United States.

Atropine

Indications

Atropine is used in cases of organophosphate (including chem-bioterrorism nerve agents) and carbamate anticholinesterase insecticide poisoning:

• For control of pulmonary hypersecretion, atropine is given in repeated doses intravenously until secretions have dried. Atropinization may have to be maintained for hours to days.

• For control of bradycardia, atropine is given until the heart rate increases or until a need for alternatives is indicated.

Nontoxicologic indications include atropine use for premedication to anesthesia induction (for antisecretory effects) and ophthalmic mydriasis and cycloplegia.

Mechanism of action

Atropine is an anticholinergic agent that competitively inhibits acetylcholine at muscarinic receptors. It has little effect on nicotinic receptors.

Contraindications

There are no contraindications in cases of insecticide poisoning. Contraindications for other indications are as follows:

• Hypersensitivity to atropine or anticholinergics

• Narrow-angle glaucoma

• Reflux esophagitis

• Obstructive gastrointestinal disease

• Ulcerative colitis or toxic megacolon

• Obstructive uropathy

• Unstable cardiovascular status in acute hemorrhage or thyrotoxicosis

• Paralytic ileus or intestinal atony

• Myasthenia gravis

Adverse effects

Exaggeration of anticholinergic effects (e.g., tachycardia, hypertension, sedation, hallucinations, mydriasis, changes in intraocular pressure, warm red skin, dry mouth, urinary retention, ileus, dysrhythmias, and seizures) can occur.

When large doses of atropine are used, the agent should be free of preservatives, because agents such as benzyl alcohol or chlorobutanol can produce their own toxicity.

Dosage

For bronchorrhea and bronchospasm from organophosphates or carbamates, the adult dose is 2-5 mg (pediatric dose is 0.05 mg/kg) slowly administered intravenously. This dose is repeated at 10- to 30-minute intervals until bronchial hypersecretion is resolved. Severe poisonings may require up to 100 mg over a few hours to several grams over several weeks. If atropinization is required for several days, continuous atropine infusion may be used (rates of 0.02-0.08 mg/kg/h are recommended).

For symptomatic bradycardia (for mild poisonings), the adult dose is 1 mg (pediatric dose is 0.01 mg/kg) intravenously. For moderate to severe poisonings, adult doses increase to 2-5 mg (pediatric doses are 0.02-0.05 mg/kg) and should be repeated every few minutes until heart rate increases.

Digoxin immune Fab (Digibind and DigiFab)

Uses

Digoxin immune Fab is used to treat life-threatening acute or chronic digoxin poisoning.

Some cross-reactivity with digitoxin and other digoxin-like compounds (digitalis, foxglove, lily of the valley, and bufadienolide from cane frogs) can occur.

Mechanism of action

Digoxin immune Fab binds digoxin in plasma, promotes redistribution from tissues, and enhances elimination in the urine. The digoxin bound to digoxin immune Fab is inactive. Each 40 mg (1 vial) binds 0.6 mg of digoxin.

Digoxin immune Fab is a monovalent, digoxin-specific, antigen-binding fragment (Fab) that is produced in healthy sheep.

Indications

Chronic digoxin toxicity typically begins with nausea, vomiting, diarrhea, fatigue, confusion, blurred vision, diplopia, and the observation of white borders or halos around dark objects. Deterioration of renal function, hypokalemia, or drug interactions often lead to toxicity.

Acute digoxin poisoning has early symptoms similar to those of chronic poisoning, but the onset is more abrupt. Nausea and vomiting are common, and the serum potassium concentration is typically normal or elevated.

A wide variety of arrhythmias occur with acute or chronic digoxin poisoning.

Digoxin immune Fab is reserved for life-threatening symptoms such as bradycardia, second- and third-degree heart block that is unresponsive to atropine, ventricular arrhythmias, and hyperkalemia (typically in excess of 5 mEq/L).

Contraindications

Digoxin immune Fab is contraindicated in patients with hypersensitivity to sheep.

Adverse effects

Common adverse effects include hypokalemia, allergic reactions (1% of patients), and hypotension. For patients on maintenance digoxin therapy, the abrupt binding of digoxin will lead to loss of therapeutic effect and a prompt decrease in potassium concentrations.

Dosage

Digoxin immune Fab is administered by IV infusion or rapid IV bolus (Table 35-4).

Dosage is determined by one of several approaches, depending on available information, as follows: empiric dosage of 10-20 vials (Table 35-4), dosing based on the dose of digoxin ingested, or dosing based on the serum digoxin concentration.

Flumazenil (Romazicon)

Uses

Flumazenil is used in cases of benzodiazepine overdose and in reversal of conscious sedation and general anesthesia from benzodiazepines.

Mechanism of action

Flumazenil is a competitive antagonist of the benzodiazepine receptor in the central nervous system (CNS).

Indications

Flumazenil should be used adjunctively with supportive care. Sedation can recur following ingestion of a benzodiazepine with a long half-life, requiring additional doses of flumazenil. In a suicidal overdose, it is rarely used because of the risk of potential co-ingestants. If no response occurs to a 5 mg cumulative dose, the sedation is probably not related to a benzodiazepine.

Contraindications

Flumazenil is contraindicated in patients with known hypersensitivity to it.

Co-ingestion of tricyclic antidepressants may precipitate ventricular dysrhythmias or seizures. Other mixed overdoses can decrease the seizure threshold (i.e., haloperidol, bupropion, lithium).

Abrupt withdrawal of flumazenil in patients on maintenance therapy, such as for treatment of epilepsy, can precipitate seizures.

Flumazenil is contraindicated in patients with increased intracranial pressure, because the antidote may potentially alter cerebral blood flow.

It can produce withdrawal in the benzodiazepine-dependent patient.

Adverse effects

Flumazenil has a wide margin of safety when not contraindicated.

Side effects include agitation, sweating, headache, abnormal vision, dizziness, and pain at the administration site. Rarely reported side effects include bradycardia, tachycardia, hypotension, and hypertension.

Dosage

Table 35-4 gives dosage information for IV administration.

Naloxone (Narcan)

Uses

Naloxone is used in the following cases:

• Reversal of opioid anesthesia

• Respiratory or CNS depression related to opioid toxicity

• Empiric administration in patients with altered mental status of unknown etiology

Mechanism of action

Naloxone is an opioid antagonist. It competes at three CNS opioid receptors (mu, kappa, and delta) and leads to reversal of the depressive opioid effects.

Indications

Opioids cause sedation, respiratory depression, hypotension, miosis, and analgesia. Because it has no agonist activity, naloxone will not worsen respiratory depression. The goal of therapy is to restore adequate spontaneous respirations.

When being administered naloxone, a patient should be monitored for respiratory rate changes and for opiate withdrawal symptoms (anxiety, hypertension, tachycardia, diarrhea, and seizure). To avoid withdrawal, use the lowest possible dose that maintains proper ventilation. The patient should be observed for respiratory depression once naloxone therapy is discontinued because the half-life of naloxone may be shorter than that of the opioid. If a patient is not responsive to 10 mg of naloxone, it is doubtful that an opioid is causing the respiratory depression.

Contraindications

• Avoid in patients with a known hypersensitivity to it.

• Use with caution in the opiate-dependent patient.

• Use with caution in patients with preexisting cardiovascular disease or those receiving cardiotoxic drugs.

Adverse effects

Use in an opiate-dependent patient can precipitate withdrawal. Withdrawal convulsions in a neonate can be life threatening.

Hypertension and dysrhythmias occur more often with opioid reversal in postoperative patients who have underlying cardiac and pulmonary complications.

Dosage

The IV route is preferred in emergency situations because of the rapid onset of action within 1-2 minutes (Table 35-4).

Naloxone has poor oral bioavailability.

The intramuscular and subcutaneous routes have erratic absorption.

Pralidoxime (Protopam)

Uses

Pralidoxime is used in cases of severe poisoning by an organophosphate anticholinesterase insecticide or chem-bioterrorism nerve agent.

Mechanism of action

Pralidoxime dephosphorylates acetylcholinesterase and regenerates acetylcholinesterase activity.

Indications

Pralidoxime is indicated in severe organophosphate or nerve agent poisoning, in combination with atropine, to resolve nicotinic (muscle and diaphragmatic weakness, fasciculations, muscle cramps) and central (coma, seizures) cholinergic manifestations. It is ineffective for organophosphates without anticholinesterase activity.

Its use in cases of carbamate poisoning is controversial, but some sources do recommend it for severe cases.

Contraindications

Pralidoxime should not be used in patients who are hypersensitive to the drug.

Adverse effects

• Tachycardia, dizziness, hyperventilation, and laryngospasm associated with rapid IV infusion

• Nausea, vomiting, diarrhea, bitter aftertaste, and rash after oral doses

• Blurred vision and diplopia

• Possible neuromuscular blockade (weakness) with high levels or in patients with myasthenia gravis

Dosage

See Table 35-4 for IV doses.

35-4. Terrorism and Disaster Preparedness

Introduction

The world faces the growing threat of attacks with biological, chemical, explosive, and radiological weapons. Health care professionals should have an awareness of the potential for biological terrorism, an appreciation for epidemiologic clues of a chem-bioterrorist event, and a basic understanding of the classes of agents that can be weaponized and their effects.

Biological Threats

Bioterrorism is the deliberate use of infectious biological agents to cause illness and is categorized for risk by the Centers for Disease Control and Prevention (CDC) as follows:

• Category A agents are high-priority agents that can be easily transmitted, can result in high mortality rates, and have the potential for major public health impact. They include smallpox, anthrax, plague, botulism, tularemia, and viral hemorrhagic fevers (filoviruses [e.g., Ebola and Marburg] and arenaviruses [e.g., Lassa and Machupo]).

• Category B agents include brucellosis; epsilon toxin of Clostridium perfringens; food safety threats (e.g., Salmonella species, Escherichia coli O157:H7, Shigella); glanders (Burkholderia mallei); melioidosis (B pseudomallei); psittacosis (Chlamydia psittaci); Q fever (Coxiella burnetii); ricin; staphylococcal enterotoxin B; typhus fever; viral encephalitis (alphaviruses such as Venezuelan equine encephalitis, eastern equine encephalitis, and western equine encephalitis), and water safety threats (e.g., Vibrio cholerae, Cryptosporidium parvum).

• Category C agents include emerging infectious disease threats such as Nipah virus and hantavirus.

See

Table 35-5 for clinical features and suggested treatment for likely forms of category A diseases and for ricin, a category B agent that has been weaponized and used in terrorism.

The mode of transmission for biological agents is essentially the same as that of all other infectious diseases:

• Aerosol (most common form for biological weapons)

• Dermal contact

• Injection

• Food

• Water

Chemical Threats

Toxic chemicals that may be used in warfare and in a chemical terrorism attack include nerve, vesicant or blister, blood, choking or pulmonary, incapacitating, and tear- and vomit-inducing (riot control) agents. See

Table 35-6 for descriptions, symptoms, and treatment of chemicals most likely to be used.

Normally, toxic chemicals used for these purposes are liquids or solids. Often they are dispersed in the air in aerosols.

The CDC also considers several commonly available agents to be threats, including hydrofluoric acid; benzene; ethylene glycol (antifreeze); and various metals such as arsenic, mercury, and thallium. These agents are not detailed in Table 35-6.

Radiological Threats

Radiological weapons involve nuclear radiation or radioactive materials with various radionucleotides. Radionucleotides can produce topical and systemic effects that may be immediate or delayed, depending on the agent, route of exposure, and extent of exposure.

Medical management of radiological emergencies and terrorist attacks is specific for radionucleotides. Guidance on treatment is available from the Radiation Emergency Assistance Center/Training Site (REAC/TS) at the Oak Ridge Institute for Science and Education (Oak Ridge, Tennessee). The emergency response phone number is 1-865-576-1005; ask for REAC/TS. For program information, visit www.orise.orau.gov/reacts.

The early use of stable iodine, taken as potassium iodide or sodium iodide tablets, can reduce the uptake of radioiodine by the thyroid. Many individuals near nuclear reactors will maintain a stock of stable iodine tablets in the event of a radioactive accident. Ingestion of stable iodine is of little value for other radionucleotide exposures unless the radioactive constituents are unknown, as in a "dirty bomb."

Prussian blue 500-mg capsules are approved for the treatment of patients with exposures to radioactive cesium (Cs-137) and thallium (Tl-201). Prussian blue absorbs the radioactivity that is recirculated in the intestines and thereby enhances its elimination in the stool. The drug is available from the CDC.

Calcium and zinc salts of diethylene triamine pentaacetic acid for IV infusion and aerosol nebulization are approved to treat patients who have been exposed to radionucleotides that may be found in a "dirty bomb" such as plutonium, americium, and curium. The drugs form chelates with the radionucleotides that are excreted in the urine. The drugs are available from the CDC.

Emergency Preparedness

Pharmacists are in a unique position to quickly recognize communitywide patterns of symptoms, illness, and mortality in humans and animals that can be important clues to terrorist events.

The CDC advises that if citizens believe that they have been exposed to a biological or chemical agent, or if they believe an intentional biological threat will occur or is occurring, they should contact their local health or police department or another law enforcement agency (e.g., the Federal Bureau of Investigation). These agencies will notify the state health department and other response partners, through a preestablished notification list that channels to the CDC.

The CDC maintains the Strategic National Stockpile (SNS) to ensure the availability and rapid deployment of life-saving pharmaceuticals, antidotes, and other medical supplies and equipment necessary to counter nerve agents, biological pathogens, and chemical agents. The SNS program stands ready for immediate deployment to any U.S. location in the event of a terrorist attack using a biological toxin or chemical agent

[Table 35-5. Biological Agents That May Be Used in a Terrorist Attack]

directed against a civilian population. A limited stock of drugs to treat nerve agents (CHEMPACK) has been deployed to emergency medical services and hospital sites throughout the United States and is maintained by the CDC. For further information, visit the CDC Web site at www.cdc.gov.

Pharmacists should consider volunteering in their communities to assist with emergency preparedness. Roles in mass dispensing and vaccination clinics, SNS deployment, and general disaster medical relief are possible opportunities. Contact the local health department or emergency medical services agency.

Essential steps to volunteering for emergency preparedness include reaching an understanding with one's family and employer, registering as a volunteer and identifying skills to contribute, obtaining security credentials, participating in training, and doing whatever it takes when needed.

35-5. Key Points

• Medications are the most common cause of poisoning morbidity and mortality. Any chemical can become toxic if too much is taken in relation to body weight and tolerance. A large number of poisonings occur in young children, but most fatalities occur in adults.

• Several approaches can minimize the risk of unintentional childhood poisonings (e.g., use of safety latches, proper storage of poisonous substances, and adherence to label instructions), but the proper use of child-resistant containers (safety caps) is one of the most effective means.

• As part of the Poison Prevention Packaging Act of 1970, pharmacists are required to dispense oral prescription drugs (with certain exceptions such as nitroglycerin and oral contraceptives) in

[Table 35-6. Chemical Agents That May Be Used in a Terrorist Attack]

   child-resistant containers unless the patient or prescriber indicates the desire for a nonsafety cap.

• Immediate first aid for a poison exposure can minimize potential toxic effects and involves water and fresh air, depending on the route of exposure. Contact a poison center immediately through the nationwide access number (1-800-222-1222) to determine whether first aid should be administered or whether a poisoning emergency exists.

• The use of drugs to decrease the absorption of drugs from the gastrointestinal tract after a poisoning or overdose is in a state of change.

• Ipecac syrup—an orally administered emetic—has questionable effectiveness, and its use is now generally avoided. It should not be used when (1) the person exhibits sleepiness, coma, or seizures; (2) agents such as caustics and aliphatic hydrocarbons and fast-acting agents that produce coma or seizures (e.g., tricyclic antidepressants, clonidine, strychnine, hypoglycemic agents) have been ingested; (3) the ingestion was greater than 1 hour ago; or (4) there is an obvious need for hospital referral.

• Cathartics such as magnesium citrate are not routinely used.

• Activated charcoal—an orally administered adsorbent—is often the only treatment necessary if the toxin can be adsorbed and it is used within 1-2 hours of ingestion. It should be avoided in ingestions of aliphatic hydrocarbons and caustics and in patients with absent bowel sounds, and it is not useful with ingestion of heavy metals (sodium, lithium, iron, or lead) or simple alcohols.

• Whole-bowel irrigation, with products such as CoLyte and GoLYTELY, can be considered if the toxin is poorly adsorbed and its presence in the gastrointestinal tract is likely.

• Other hospital-based therapies include supportive and symptomatic care, multiple doses of activated charcoal (to enhance systemic elimination when appropriate), hemodialysis (to enhance systemic elimination when appropriate), and use of antidotes (to antagonize or reverse toxic effects when indicated).

• Substance abuse often leads to acute and chronic toxicity from a variety of medications, commercial products, and illicit agents. The management of acute toxicity from substance abuse typically follows the same general approaches as those for poisoning and overdose. A challenge faced in many acute drug overdose episodes is determining the agents taken and possible adulterants or contaminants. Chronic abuse can lead to dependence and withdrawal symptoms when use is stopped.

• Few antidotes are available relative to the large number of potential poisons. The use of an antidote is usually an adjunct to conventional and supportive therapies. Many hospitals have an insufficient stock of antidotes.

• Acetylcysteine is a glutathione substitute in the metabolism of the acetaminophen-toxic reactive metabolite. It is most effective in preventing hepatotoxicity if given orally within 10 hours of an acetaminophen overdose, and it may also help later to minimize hepatic injury once it has begun. Oral (Mucomyst) and IV (Acetadote) preparations are available.

• Atropine is used to treat the muscarinic effects (bronchorrhea, bradycardia, etc.) produced by organophosphate and carbamate insecticides and anticholinesterase nerve gas agents by competing with acetylcholine for binding at muscarinic receptors in the nervous system.

• Pralidoxime (Protopam) reactivates the enzyme acetylcholinesterase by dephosphorylation and allows metabolism of accumulated amounts of acetylcholine produced by enzyme inhibition from exposures to anticholinesterase nerve gas agents and organophosphate and carbamate insecticides.

• Digoxin immune Fab (Digibind, DigiFab) is a specific antibody for digoxin, but it exhibits some cross-reactivity with other digoxin-like compounds. It is an ovine-derived antigen-binding fragment reserved for the treatment of life-threatening symptoms of digoxin overdose (e.g., bradycardia, ventricular arrhythmias, second- and third-degree heart block, hyperkalemia).

• Flumazenil (Romazicon) is a competitive antagonist of benzodiazepines at the benzodiazepine receptor in the CNS. It is used in the treatment of severe CNS and respiratory depression that may occur when benzodiazepines are used as an anesthetic or taken as an overdose. Seizures may occur when flumazenil is administered to patients with co-ingestants of tricyclic antidepressants—drugs that lower the seizure threshold—and to patients requiring benzodiazepines for seizure control.

• Administration of naloxone (Narcan), a competitive antagonist of opiate binding at the opioid receptors in the CNS, reverses the CNS and respiratory depression of opiate toxicity. Naloxone may precipitate withdrawal symptoms in opiate-dependent patients.

• Bioterrorism is the deliberate use of infectious biological agents to cause illness. High-priority agents can be easily transmitted, result in high mortality rates, and have the potential for major public health impact. They include smallpox (Variola virus), anthrax (Bacillus anthracis), plague (Yersinia pestis), botulism (Clostridium botulinum), tularemia (Francisela tularensis), and viral hemorrhagic fevers (e.g., Ebola, Marburg, Lassa, Machupo).

• These chemicals can be used in warfare and may be used in a terrorist attack:

• Substances that act on nerves (e.g., anticholinesterase agents such as sarin)

• Substances that are blistering or vesicant agents (e.g., mustard agents, lewisites)

• Substances that act on blood (e.g., arsine, cyanide)

• Substances that act on the pulmonary system (e.g., phosgene, chlorine, ammonia)

• Substances that are incapacitating (e.g., fast-acting CNS depressants or hallucinogens)

• Substances that can also be used in riot control (e.g., various lacrimating agents such as chloroacetophenone and vomiting agents such as adamsite).

• Health care providers must have an awareness of the potential for terrorism, an appreciation for epidemiologic clues of a chem-bioterrorist event, and a basic understanding of the classes of agents that can be weaponized and their effects. The CDC maintains the Strategic National Stockpile. The SNS can be rapidly deployed to communities to ensure the availability of life-saving pharmaceuticals, antidotes, other medical supplies, and equipment necessary to counter nerve agents, biological pathogens, and chemical agents.

35-6. Questions

1.

Flumazenil is contraindicated in which of the following?

I. A patient with QRS widening with a known ingestion of Elavil

II. A patient who was previously given flumazenil and who now complains of abnormal vision and dizziness

III. A patient with known use of cocaine

A. I only

B. II only

C. III only

D. I and III

E. I and II

 

2.

A patient is brought to the emergency department. She is experiencing CNS and respiratory depression, which are suspected to be related to ingestion of her sister's MS Contin. You recommend supportive care and the administration of which of the following?

A. Flumazenil

B. Naloxone

C. Lorazepam

D. Flumazenil and Narcan

E. Pyridoxine

 

3.

A police officer presents to the emergency room with a rash. He fears that he was exposed to a biological weapon several days before the rash appeared. You notice the rash is forming pustules and is most prominent on the face and extremities. The patient says the rash developed all at once. He has possibly contracted which of the following?

A. Smallpox

B. Chickenpox

C. Anthrax

D. Tularemia

E. None of the above

 

4.

What is the recommended treatment for the likely disease?

I. Supportive, as there is no specific treatment

II. Ciprofloxacin

III. Doxycycline

A. II or III

B. II and III

C. I only

D. II only

E. III only

 

5.

Which of the following is the currently available prevention for smallpox?

I. Dryvax

II. A live-virus preparation of the vaccinia virus

III. Avoidance of direct contact with infected persons and their body fluids

A. I only

B. I and II only

C. II and III only

D. I, II, and III

E. No vaccine is currently available.

 

6.

A patient presents with a black, necrotic, painless skin lesion on her arm. She also complains of fever, malaise, headache, and swelling of her underarm lymph nodes. Which of the following is the possible biological agent responsible for these symptoms?

A. Hemorrhagic fever virus

B. Anthrax

C. Botulism

D. Tularemia

E. Arsine

 

7.

The recommended antibiotic treatment of the infection in question 6 may include which of the following?

A. Ciprofloxacin

B. Doxycycline

C. Amoxicillin

D. All of the above

E. Supportive therapy, as there is no specific treatment

 

8.

Inhalation exposure to the agent in question 6 requires which of the following?

A. Postexposure prophylaxis with ciprofloxacin, doxycycline, or levofloxacin for 60 days

B. Immediate vaccination of civilian personnel

C. Early treatment with streptomycin or gentamicin

D. Early treatment with ribavirin

E. None of the above

 

9.

A cab driver presents to the emergency department with vomiting, diarrhea, sweating, salivation, moist rales, bradycardia, muscle tremor, and weakness. He reports inhaling a mist dropped from a low-flying plane several hours earlier. You also note that he has miosis and his respiratory difficulty is increasing rapidly. Which of the following is the likely mechanism of toxicity of the poison?

A. Inhibition of protein synthesis

B. Binding of the agent to cytochrome oxidase

C. Inhibition of acetylcholinesterase

D. An alkylating agent that cross-links DNA strands

E. None of the above

 

10.

The recommended initial management of the symptoms in question 9 includes all except which of the following?

A. Immediate decontamination of skin and eyes

B. Disposal of contaminated clothes

C. British antilewisite

D. Atropine

E. Pralidoxime

 

11.

The patient in question 9 deteriorates and develops seizures. Which of the following do you recommend?

A. Phenytoin

B. Diazepam

C. Lithium

D. Dryvax

E. All of the above

 

12.

Which of the following conditions or situations is not a contraindication to the use of ipecac syrup?

A. High blood pressure controlled with drug therapy

B. Seizures shortly before administration

C. Unresponsiveness to verbal commands

D. Ingestion of a corrosive agent

E. A and C

 

13.

Which of the following is an effect of activated charcoal?

A. Promotes dissolution of tablets

B. Minimizes drug absorption from the gastrointestinal tract

C. Increases urinary flow

D. Enhances systemic elimination of certain drugs

E. B and D

 

14.

Which of the following is useful in the treatment of acetaminophen poisoning?

A. Acetylcysteine

B. Dimercaprol

C. Pralidoxime

D. Atropine

E. Dryvax

 

15.

Digoxin immune Fab is used to treat which of the following signs or symptoms of digoxin poisoning?

A. Hypokalemia

B. Diplopia

C. Ventricular tachycardia

D. Second-degree heart block unresponsive to atropine

E. C and D

 

16.

How does crack cocaine differ from pharmaceutical cocaine?

A. Crack cocaine is more stable under heat and can be smoked.

B. Pharmaceutical cocaine is the hydrochloride salt.

C. Crack cocaine is the free-base form of cocaine.

D. Crack cocaine may be contaminated with other substances.

E. All of the above.

 

17.

Which of the following mechanisms is associated with the production of hepatic injury from an acute overdose of acetaminophen?

A. Interference with RNA (ribonucleic acid) synthesis

B. Interference with transaminase enzyme activity

C. Direct toxicity of acetaminophen

D. Formation of a toxic metabolite

E. Exaggeration of its pharmacologic effects

 

18.

Which of the following signs or symptoms is characteristic of an acute exposure to an organophosphate as an insecticide or terrorist weapon?

A. Dry mouth and mucous membranes

B. Excessive bronchial secretions

C. Muscle rigidity

D. Urinary retention

E. All of the above

 

35-7. Answers

1.

D. Flumazenil is contraindicated in all patients who have ingested a tricyclic antidepressant and have cardiac symptoms because its use could cause ventricular dysrhythmias. It is not recommended in mixed overdose where the co-ingested drug can cause a seizure (i.e., cocaine). Statement II describes associated adverse effects with that may occur with the administration of flumazenil; they are not contraindications.

 

2.

B. Naloxone is an opioid antagonist.

 

3.

A. See Table 35-5. Smallpox is the most likely agent. The agent causes formation of a pustular rash that is typically most prominent on the face and extremities. Lesions form at the same time. Chickenpox rash is most prominent on the trunk and develops in successive groups of lesions over several days. Anthrax forms painless necrotic lesions. Tularemia causes a nonspecific febrile illness that rapidly develops into pneumonia.

 

4.

C. See Table 35-5. Smallpox has no specific treatment, but the live-vaccine (Dryvax) may lessen the disease if given within 4 days of the exposure. Ciprofloxacin and doxycycline are used in the management of anthrax, plague, and tularemia.

 

5.

D. See Table 35-5. All options are correct.

 

6.

B. See Tables 35-5 and 35-6. Anthrax forms a painless, necrotic ulcer. Hemorrhagic fever viruses cause a rash that develops into petechiae, ecchymosis, hemorrhages, and other bleeding symptoms. Botulism causes a symmetric descending paralysis. Tularemia causes a nonspecific febrile illness that rapidly develops into pneumonia. Arsine is a chemical agent that causes nausea, vomiting, hemolysis, and secondary renal failure. Arsine is produced when water comes into contact with metallic arsenide or when acids come into contact with metallic arsenic or arsenical compounds. The mechanism of hemolysis is not specifically known, but the most recent mechanism postulated involves a direct arsine-hemoglobin interaction that forms arsenic metabolites, causing direct alteration of the erythrocyte cell membrane.

 

7.

D. See Table 35-5. Ciprofloxacin, levofloxacin, and doxycycline are approved by the U.S. Food and Drug Administration (FDA) for treatment of anthrax, while amoxicillin can be used when the other drugs are not tolerated or pose patient-specific risks. These agents can be used separately or in combination, depending on the symptoms and the patient's sensitivity to the agents. Antimicrobial resistance to ciprofloxacin has been growing rapidly because of widespread overuse after the anthrax-contaminated mail episodes in 2002.

 

8.

A. See Table 35-5. Persons at risk for inhalational anthrax need 60 days of prophylactic antibiotics. Ciprofloxacin and doxycycline are FDA-approved for postexposure prophylaxis (PEP) in adults and children; levofloxacin is used in adults 18 years of age and older. If these drugs are not tolerated, amoxicillin can be used. In 2009, a vaccine (BioThraxT) became available that can be given postexposure in conjunction with antibiotics or as a vaccination for high-risk personnel (e.g., military or lab personnel likely to be in contact with the bacteria). Streptomycin and gentamicin are among the suggested treatments for pneumonic plague. Ribavirin is a potential treatment for some hemorrhagic fever viruses.

 

9.

C. See Table 35-6. The symptoms exhibited are classically cholinergic, and the likely chemical agents causing these symptoms are organophosphates such as nerve agents or possibly organophosphate pesticides. Both can be spread by low-flying planes. Inhibition of protein synthesis is the mechanism of toxicity of ricin or abrin. Cyanides bind to cytochrome oxidase, thereby interrupting normal cellular respiration and causing rapid convulsions. Blister agents such as sulfur and nitrogen mustards are thought to be alkylating agents that cross-link DNA strands, thereby separating dermal layers in the skin and causing fluid-filled blisters to form.

 

10.

C. British antilewisite is a specific antidote for lewisite. See Table 35-6. It also is used as a chelator for treatment of acute arsenic, inorganic or elemental mercury, gold, and other heavy metal poisonings. See Table 35-4. The other measures are treatments for organophosphate agents. Good decontamination and disposal of contaminated clothes (especially leather) are needed, because organophosphates are well absorbed across the skin, through the lungs, and through ingestion—essentially all possible routes of exposure. Atropine is used for muscarinic symptoms (miosis; nausea and vomiting; diarrhea; urination; bradycardia; and excessive bronchial, lacrimal, dermal, nasal, and salivary secretions). Pralidoxime is used with atropine to resolve severe organophosphate symptoms (such as those from exposure to nerve agents), including nicotinic symptoms of muscle weakness and cramps, fasciculations, and tachycardia, and CNS symptoms such as coma and seizures.

 

11.

B. See Table 35-6. Recommended treatment for seizures attributable to organophosphate agents is either diazepam or lorazepam. Phenytoin is a seizure medication, but benzodiazepines (then barbiturates if benzodiazepines fail) are generally preferred over phenytoin for the control of overdose- or withdrawal-related seizures. Lithium is not a seizure medicine and, in fact, may cause seizures with elevated blood concentrations. Dryvax is a vaccine for smallpox.

 

12.

A. Controlled high blood pressure is not a problem with the use of ipecac syrup, but the other situations are clear contraindications because of potential aspiration (seizures and unresponsiveness) and additional esophageal burns on vomiting up gastric contents (corrosive).

 

13.

E. Activated charcoal adsorbs chemicals on contact and prevents their absorption into the bloodstream. For certain drugs (e.g., phenobarbital, theophylline), multiple doses of activated charcoal can promote the back diffusion of drugs across the intestinal capillary bed into the lumen of the gut, trap it there, and promote its elimination. The elimination half-life can be decreased by as much as one-half.

 

14.

A. Acetylcysteine prevents the development of liver injury from acetaminophen if given early after ingestion and, in some cases, may help minimize the effects of hepatotoxicity after it has occurred.

 

15.

E. Digoxin immune Fab is reserved for life-threatening symptoms because of its profound effects, scarcity, and high cost. Most serious cases of digoxin poisoning have normal or high potassium concentrations because of the digoxin's interference with the sodium-potassium ATPase pump.

 

16.

E. All are differences between the two forms of cocaine.

 

17.

D. Acetaminophen forms a toxic metabolite that has a direct toxic effect within the hepatocyte. It has other proposed mechanisms, but this mechanism is thought to be the inciting event. See the description for acetylcysteine in Section 35-3.

 

18.

B. Excessive bronchial secretions are one of the principal causes of death from exposure to organophosphates. The other symptoms are not observed. See the description for atropine and pralidoxime in Section 35-3.

 

35-8. References

General Toxicology

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Bronstein AC, Spyker DA, Cantelina LR, et al. 2006 annual report of the American Association of Poison Control Centers' National Poison Data System (NCDS). Clin Toxicol. 2007;45:815-917.

Chyka PA. Clinical toxicology. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:69-90.

Dart RC, ed. Medical Toxicology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004.

Diversion Control Program, Drug Enforcement Administration, U.S. Department of Justice. Drugs and chemicals of concern. Available at: www.deadiversion.usdoj.gov/drugs_concern/index.html.

Flomenbaum NE, Goldfrank LR, Hoffman RS, et al., eds. Goldfrank's Toxicologic Emergencies. 8th ed. New York: McGraw-Hill; 2006.

Ford MD, Delaney KA, Ling LJ, Erickson T. Clinical Toxicology. Philadelphia: WB Saunders; 2001.

Klaassen CD. Principles of toxicology and treatment of poisoning. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill; 2006:1739-51.

National Institute on Drug Abuse, National Institutes of Health. NIDA InfoFacts: Science-based facts on drug abuse and addiction. Available at: www.nida.nih.gov/Infofacts/Infofaxindex.html.

Office of Applied Studies, Substance Abuse and Mental Health Services Administration. Drug Abuse Warning Network, 2006. DHHS publication SMA 08-4339. Rockville, Md.: Substance Abuse and Mental Health Services Administration; 2008.

Olson KR, ed. Poisoning and Drug Overdose. 5th ed. New York: Lange/McGraw-Hill; 2007.

Terrorist Threats

Abramowicz M, ed. Prevention and treatment of injury from chemical warfare agents. Med Letter. 2002;44:1-4.

Kales SN, Christiani DC. Acute chemical emergencies. N Engl J Med. 2004;350:800-8.

Oak Ridge Institute for Science and Education. Managing radiation emergencies: Guidance for hospital medical management. Available at: www.orise.orau.gov/reacts/.

Setlak P. Bioterrorism preparedness and response: Emerging role for health-system pharmacists. Am J Health-Syst Pharm. 2004;61:1167-75.

Shepherd G, Schwartz RB. Emergency preparedness: Identification and management of chemical and radiological exposures. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:93.

Terriff CM, Brouillard JE, Costanigro LT, Gruber JS. Emergency preparedness: Identification and management of biological exposures. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York: McGraw-Hill; 2008:91.

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