Pharmacology intersects with toxicology when the physiological response to a drug is an adverse effect. A poison is any substance, including any drug, that has the capacity to harm a living organism. Poisoning generally implies that damaging physiological effects result from exposure to pharmaceuticals, illicit drugs, or chemicals.
There is a graded dose-response relationship in an individual and a quantal dose-response relationship in the population (see Chapters 2 and 3). Graded doses of a drug given to an individual usually result in a greater magnitude of response as the dose increases. 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 judged to be either present or absent in a given individual. This quantal dose-response phenomenon is used to determine the median lethal dose (LD50) of drugs, as defined in Figure 4–1.
Figure 4–1 Dose-response relationships. The LD50 of a compound is determined experimentally, usually by administration of the chemical to mice or rats (orally or intraperitoneally). The midpoint of the curve representing percent of population responding (response here is death) versus dose (log scale) represents the LD50, or the dose of drug that is lethal in 50% of the population. The LD50 values for both compounds are the same (~10 mg/kg); however, the slopes of the dose-response curves are quite different. Thus, at a dose equal to one-half the LD50 (5 mg/kg), less than 5% of the animals exposed to compound B would die, but 30% of the animals given compound A would die.
One can also determine a quantal dose-response curve for the therapeutic effect of a drug to generate a median effective dose (ED50), the concentration of drug at which 50% of the population will have the desired response, and a quantal dose-response curve for lethality by the same agent. These 2 curves can be used to generate a therapeutic index (TI), which quantifies the relative safety of a drug:
Clearly, the higher the ratio, the safer the drug.
Values of TI vary widely, from 1-2 to >100. Drugs with a low TI must be administered with caution (e.g., cardiac glycoside digitalis and cancer chemotherapeutic agents). Agents with very high TI (e.g., penicillin) are extremely safe in the absence of a known allergic response in a given patient. Note that use of median doses fails to consider that the slopes of the dose-response curves for therapeutic and lethal (toxic) effects may differ (Figure 4–1). As an alternative the ED99 for the therapeutic effect can be compared to the LD1 for lethality (toxic effect), to yield a margin of safety.
These quantal dose-response relationships are typical sigmoidal dose-response curves. However, not all dose-response curves follow this shape. U-shaped dose-response curves can be observed for essential metals and vitamins (Figure 4–2). At low dose, adverse effects are observed since there is a deficiency of these nutrients to maintain homeostasis. As dose increases, homeostasis is achieved, and the bottom of the U-shaped dose-response curve is reached. As dose increases to surpass the amount required to maintain homeostasis, overdose toxicity can ensue. Thus, adverse effects are seen at both low and high dose.
Figure 4–2 U-Shaped dose-response curve for essential metals and vitamins. Vitamins and essential metals are essential for life and their lack can cause adverse responses (plotted on the vertical axis), as can their excess, giving rise to a U-shaped dose-dependence curve.
PHARMACOKINETICS VERSUS TOXICOKINETICS
Absorption, distribution, metabolism, and elimination (ADME; see Chapters 2, 5, and 6) may differ significantly after poisoning, and these differences can profoundly alter treatment decisions and prognosis. The pharmacokinetics of a drug under circumstances that produce toxicity or excessive exposure are referred to as toxicokinetics. Ingesting larger than therapeutic doses of a pharmaceutical may prolong its absorption, alter its protein binding and apparent volume of distribution, and change its metabolic fate. When confronted with a potential poisoning, 2 questions should be foremost in the clinician’s mind:
• How long will an asymptomatic patient need to be monitored (drug absorption and dynamics)?
• How long will it take an intoxicated patient to get better (drug elimination and dynamics)?
DRUG ABSORPTION. Aspirin poisoning is a leading cause of overdose morbidity and mortality as reported to U.S. poison control centers. In therapeutic dosing, aspirin reaches peak plasma concentrations in ~1 h. However, aspirin overdose may cause spasm of the pyloric valve, delaying entry of the drug into the small intestine. Aspirin, especially enteric-coated forms, may coalesce into bezoars, reducing the effective surface area for absorption. Peak plasma salicylate concentrations from aspirin overdose may not be reached for 4-35 h after ingestion.
DRUG ELIMINATION. After therapeutic dosing, valproic acid has an elimination t½ of ~14 h. Valproic acid poisoning may lead to coma. In predicting the duration of coma, it is important to consider that, after overdose, first-order metabolic processes appear to become saturated and the apparent elimination t½ may exceed 30-45 h. Table 4–1 lists some pharmaceuticals notorious for their predilection to have initial symptoms develop after a typical 4-6 h emergency medical observation period.
Drugs That Commonly Manifest Initial Symptoms More Than 4-6 Hours after Oral Overdosea
TYPES OF THERAPEUTIC DRUG TOXICITY
In therapeutics, a drug typically produces numerous effects, but usually only 1 is sought as the primary goal of treatment; most of the other effects are undesirable effects for that therapeutic indication (Figure 4–3). Side effects of drugs usually are bothersome but not deleterious. Other undesirable effects may be characterized as toxic effects.
Figure 4–3 Spectrum of the effects of pharmaceuticals.
DOSE-DEPENDENT REACTIONS. Toxic effects of drugs may be classified as pharmacological, pathological, or genotoxic. Typically, the incidence and seriousness of the toxicity is proportionately related to the concentration of the drug in the body and to the duration of the exposure.
Pharmacological Toxicity. The CNS depression produced by barbiturates is largely predictable in a dose-dependent fashion. The progression of clinical effects goes from anxiolysis to sedation to somnolence to coma. Similarly, the degree of hypotension produced by nifedipine is related to the dose of the drug administered. Tardive dyskinesia (see Chapter 16), an extrapyramidal motor disorder associated with use of antipsychotic medications, seems to be dependent on duration of exposure. Pharmacological toxicity can also occur when the correct dose is given: there is phototoxicity associated with exposure to sunlight in patients treated with tetracyclines, sulfonamides, chlorpromazine, and nalidixic acid.
Pathological Toxicity. Acetaminophen is metabolized to nontoxic glucuronide and sulfate conjugates, and to a highly reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) via CYP isoforms. At therapeutic dose, NAPQI binds to nucleophilic glutathione; but, in overdose, glutathione depletion may lead to the pathological finding of hepatic necrosis (Figure 4–4).
Figure 4–4 Pathways of acetaminophen metabolism and toxicity. The toxic intermediate NAPQI is N-acetyl-p-benzoquinoneimine.
Genotoxic Effects. Ionizing radiation and many environmental chemicals are known to injure DNA, and may lead to mutagenic or carcinogenic toxicities. Many of the cancer chemotherapeutic agents (seeChapters 60-63) may be genotoxic (see Chapters 6 and 7).
ALLERGIC REACTIONS. An allergy is an adverse reaction, mediated by the immune system, that results from previous sensitization to a particular chemical or to 1 that is structurally similar. Allergic responses have been divided into 4 general categories based on the mechanism of immunological involvement.
TYPE I: ANAPHYLACTIC REACTIONS. Anaphylaxis is mediated by IgE antibodies. The Fc portion of IgE can bind to receptors on mast cells and basophils. If the Fab portion of the antibody molecule then binds an antigen, various mediators (e.g., histamine, leukotrienes, and prostaglandins) are released and cause vasodilation, edema, and an inflammatory response. The main targets of this type of reaction are the GI tract (food allergies), the skin (urticaria and atopic dermatitis), the respiratory system (rhinitis and asthma), and the vasculature (anaphylactic shock). These responses tend to occur quickly after challenge with an antigen to which the individual has been sensitized and are termed immediate hypersensitivity reactions.
TYPE II: CYTOLYTIC REACTIONS. Type II allergies are mediated by both IgG and IgM antibodies and usually are attributed to their capacity to activate the complement system. The major target tissues for cytolytic reactions are the cells in the circulatory system. Examples of type II allergic responses include penicillin-induced hemolytic anemia, quinidine-induced thrombocytopenic purpura, and sulfonamide-induced granulocytopenia. These autoimmune reactions to drugs usually subside within several months after removal of the offending agent.
TYPE III: ARTHUS REACTIONS. Type III allergic reactions are mediated predominantly by IgG; the mechanism involves the generation of antigen-antibody complexes that subsequently fix complement. The complexes are deposited in the vascular endothelium, where a destructive inflammatory response called serum sickness occurs. The clinical symptoms of serum sickness include urticarial skin eruptions, arthralgia or arthritis, lymphadenopathy, and fever. Several drugs, including commonly used antibiotics, can induce serum sickness-like reactions. These reactions usually last 6-12 days and then subside after the offending agent is eliminated.
TYPE IV: DELAYED HYPERSENSITIVITY REACTIONS. These reactions are mediated by sensitized T-lymphocytes and macrophages. When sensitized cells come in contact with antigen, an inflammatory reaction is generated by the production of lymphokines and the subsequent influx of neutrophils and macrophages. An example of type IV or delayed hypersensitivity is the contact dermatitis caused by poison ivy.
IDIOSYNCRATIC REACTIONS; PHARMACOGENETIC CONTRIBUTIONS. Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a given individual; the idiosyncratic response may be extreme sensitivity to low doses or extreme insensitivity to high doses of drugs.
Many interindividual differences in drug responses have a pharmacogenetic basis (see Chapter 7). Some black males (~10%) develop a serious hemolytic anemia when they receive primaquine as an antimalarial therapy, due to a genetic deficiency of erythrocyte glucose-6-phosphate dehydrogenase. Variability in the anticoagulant response to warfarin is due to polymorphisms in CYP2C9 and VKORC1 (vitamin K epoxide reductase complex 1) (see Figure 30–6 and Table 30–2).
DRUG–DRUG INTERACTIONS. Patients are commonly treated with more than 1 drug, may also be using over-the-counter (OTC) medications, vitamins, and other “natural” supplements, and may have unusual diets; all of these factors can contribute to interactions of drugs, a failure of therapy, and toxicity. Figure 4–5 summarizes the mechanisms and types of interactions.
Figure 4-5 Mechanisms and classification of drug interactions.
INTERACTION OF ABSORPTION. A drug may cause either an increase or a decrease in the absorption of another drug from the intestinal lumen. Ranitidine, an antagonist of histamine H2 receptors, raises gastrointestinal pH and may increase the absorption of basic drugs such as triazolam. Conversely, the bile-acid sequestrant cholestyramine leads to significantly reduced serum concentrations of propranolol.
INTERACTION OF PROTEIN BINDING. Many drugs, such as aspirin, barbiturates, phenytoin, sulfonamides, valproic acid, and warfarin, are highly protein-bound in the plasma, and it is the free (unbound) drug that produces the clinical effects. These drugs may have enhanced toxicity in overdose if protein binding sites become saturated, in physiological states that lead to hypoalbuminemia, or when displaced from plasma proteins by other drugs.
INTERACTION OF METABOLISM. A drug can frequently influence the metabolism of 1 or several other drugs (see Chapter 6), especially when hepatic CYPs are involved. Acetaminophen is partially transformed by CYP2E1 to the toxic metabolite NAPQI (see Figure 4–4). Intake of ethanol, a potent inducer of CYP2E1, may lead to increased susceptibility to acetaminophen poisoning after overdose.
INTERACTION OF RECEPTOR BINDING. Buprenorphine is an opioid with partial agonist and antagonist receptor activities, commonly used to treat opioid addiction. The drug binds opioid receptors with high affinity, and can prevent euphoria from concomitant use of narcotic drugs of abuse.
INTERACTION OF THERAPEUTIC ACTION. Aspirin is an inhibitor of platelet aggregation and heparin is an anticoagulant; given together they may increase risk for bleeding. Sulfonylureas cause hypoglycemia by stimulating pancreatic insulin release, whereas biguanide drugs (metformin) lead to decreased hepatic glucose production, and these drugs can be used together to control diabetic hyperglycemia.
Such drug interactions are additive when the combined effect of 2 drugs equals the sum of the effect of each agent given alone and synergistic when the combined effect exceeds the sum of the effects of each drug given alone. Potentiation describes the creation of a toxic effect from 1 drug due to the presence of another drug. Antagonism is the interference of 1 drug with the action of another. Functional orphysiological antagonism occurs when 2 chemicals produce opposite effects on the same physiological function. Chemical antagonism, or inactivation, is a reaction between 2 chemicals to neutralize their effects, such as is seen with chelation therapy. Dispositional antagonism is the alteration of the disposition of a substance (its absorption, biotransformation, distribution, or excretion) so that less of the agent reaches the target organ or its persistence in the target organ is reduced. Receptor antagonism is the blockade of the effect of 1 drug by another drug that competes at the receptor site.
DESCRIPTIVE TOXICITY TESTING IN ANIMALS
Two main principles or assumptions underlie all descriptive toxicity tests performed in animals.
First, those effects of chemicals produced in laboratory animals, when properly qualified, apply to human toxicity. When calculated on the basis of dose per unit of body surface, toxic effects in human beings usually are encountered in the same range of concentrations as those in experimental animals. On the basis of body weight, human beings generally are more vulnerable than experimental animals.
Second, exposure of experimental animals to toxic agents in high doses is a necessary and valid method to discover possible hazards to human beings who are exposed to much lower doses. This principle is based on the quantal dose-response concept. As a matter of practicality, the number of animals used in experiments on toxic materials usually will be small compared with the size of human populations potentially at risk. For example, 0.01% incidence of a serious toxic effect (such as cancer) represents 25,000 people in a population of 250 million. Such an incidence is unacceptably high. Yet, detecting an incidence of 0.01% experimentally probably would require a minimum of 30,000 animals. To estimate risk at low dosage, large doses must be given to relatively small groups. The validity of the necessary extrapolation is clearly a crucial question.
The parent text, 12th edition, briefly discusses the rationale, design, size, and duration of such toxicity studies.
SAFETY PHARMACOLOGY AND CLINICAL TRIALS
Fewer than one-third of the drugs tested in clinical trials reach the marketplace. U.S. federal law and ethical considerations require that the study of new drugs in humans be conducted in accordance with stringent guidelines.
Once a drug is judged ready to be studied in humans, a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA. The IND includes: (1) information on the composition and source of the drug; (2) chemical and manufacturing information; (3) all data from animal studies; (4) proposed clinical plans and protocols; (5) the names and credentials of physicians who will conduct the clinical trials; and (6) a compilation of the key data relevant to study the drug in man made available to investigators and their institutional review boards (IRBs).
It often requires 4-6 years of clinical testing to accumulate and analyze all required data. Testing in humans is begun after sufficient acute and subacute animal toxicity studies have been completed. Chronic safety testing in animals, including carcinogenicity studies, is usually done concurrently with clinical trials. In each of the 3 formal phases of clinical trials, volunteers or patients must be informed of the investigational status of the drug as well as the possible risks and must be allowed to decline or to consent to participate and receive the drug. These regulations are based on the ethical principles set forth in the Declaration of Helsinki. In addition, an interdisciplinary IRB at the facility where the clinical drug trial will be conducted must review and approve the scientific and ethical plans for testing in humans.
The prescribed phases, time lines, and costs for developing a new drug are presented in Table 1–1 and Figure 1–1.
EPIDEMIOLOGY OF ADVERSE DRUG RESPONSES AND PHARMACEUTICAL POISONING
Poisoning can occur in many ways following both therapeutic and nontherapeutic drug or chemical exposures (Table 4–2). In U.S., it is estimated that ~2 million hospitalized patients have serious adverse drug reactions each year, and ~100,000 suffer fatal adverse drug reactions. Use of good principles of prescribing, as described in Appendix I and Table 4–6, can aid in avoiding such adverse outcomes.
Potential Scenarios for Poisoning
Some toxicities of pharmaceuticals can be predicted based on their known pharmacological mechanism; however, it is often not until the postmarketing period that the therapeutic toxicity profile of a drug becomes fully appreciated. The Adverse Event Reporting System of the FDA relies on 2 signals to detect rarer adverse drug events. First, the FDA requires drug manufacturers to perform postmarketing surveillance of prescription drugs and nonprescription products. Second, the FDA operates a voluntary reporting system (MedWatch, at http://www.fda.gov/Safety/MedWatch/default.htm) available to both health professionals and consumers. Hospitals may also support adverse drug event committees to investigate potential adverse drug events. Unfortunately, any national dataset will significantly underestimate the morbidity and mortality attributable to adverse drug events because of underreporting and because it is difficult to estimate the denominator of total patient exposures for each event reported once a drug is available on the open market.
Therapeutic drug toxicity is only a subset of poisoning, as noted in Table 4–2. Misuse and abuse of both prescription and illicit drugs is a major public health problem. The incidence of unintentional, non-iatrogenic poisoning is bimodal, primarily affecting exploratory young children, ages 1-5 years, and the elderly. Intentional overdose with pharmaceuticals is most common in adolescence and through adulthood. The top 5 drugs involved in drug-related deaths reported in 2005 are presented in Table 4–3. The substances most frequently involved in human exposures and fatalities are presented in Tables 4–4 and 4–5.
Top Agents in Drug-Related Deaths
Substances Most Frequently Involved in Human Poisoning
Poisons Associated with the Largest Number of Human Fatalities
PREVENTION OF POISONING
REDUCTION OF MEDICATION ERRORS. Over the past decade considerable attention has been given to the reduction of medication errors and adverse drug events. Medication errors can occur in any part of the medication prescribing or use process, whereas adverse drug events (ADEs) are injuries related to the use or nonuse of medications. It is believed that medication errors are 50-100 times more common than ADEs. The “5 Rights” of safe medication administration attempt to help practitioners avoid medication errors:
Right drug, right patient, right dose, right route, right time.
In practice, accomplishing a reduction in medication errors involves scrutiny of the systems involved in prescribing, documenting, transcribing, dispensing, administering, and monitoring a therapy, as presented in Appendix I. Good medication use practices have mandatory and redundant checkpoints (Figure 4–6), such as having a pharmacist, a doctor, and a nurse all review and confirm that an ordered dose of a medication is appropriate for a patient prior to the drug’s administration. Several practical strategies have can help to reduce medication errors within healthcare settings (Table 4–6).
Figure 4–6 The “Swiss cheese” model of medication error. Several checkpoints typically exist to identify and prevent an adverse drug event, and that adverse event can only occur if holes in several systems align. A. One systematic error does not lead to an adverse event, because it is prevented by another check in the system. B. Several systematic errors align to allow an adverse event to occur. (Adapted from Reason J, Br Med J, 2000;320:768–770.)
Best Practice Recommendations to Reduce Medication Administration Errorsa
POISONING PREVENTION IN THE HOME. Table 4–2 demonstrates that there are several contexts into which poisoning prevention can be directed. Depression and suicidal ideation need to be identified and treated. Exposure to hazards in the home, outdoor, and work environments need to be reduced to reasonably achievable levels.
Poisoning prevention strategies may be categorized as being passive, requiring no behavior change on the part of the individual, or active, requiring sustained adaptation to be successful. Passive prevention strategies are the most effective (Table 4–7). The incidence of poisoning in children has decreased dramatically over the past 4 decades. This favorable trend is largely due to improved safety packaging of drugs, drain cleaners, turpentine, and other household chemicals; improved medical training and care; and increased public awareness of potential poisons.
Passive Poisoning Prevention: Strategies and Examples
PRINCIPLES OF TREATMENT OF POISONING
When toxicity is expected or occurs, the priorities of poisoning treatment are to:
• Maintain vital physiological functions from impairment
• Keep the concentration of poison in tissues as low as possible by preventing absorption and enhancing elimination
• Combat the toxicological effects of the poison at the effector sites
INITIAL STABILIZATION OF THE POISONED PATIENT. The “ABC” mnemonic of emergency care applies to the treatment of acute poisoning (Table 4–8). In severe cases, endotracheal intubation, mechanical ventilation, pharmacological blood pressure support, and/or extracorporeal circulatory support may be necessary and appropriate.
ABCDE: Initial Approach for Acute Poisoning
IDENTIFICATION OF CLINICAL PATTERNS OF TOXICITY. A medical history may allow for the creation of a list of available medications or chemicals that might be implicated in a poisoning event. Often, an observation of physical symptoms and signs may be the only additional clues to a poisoning diagnosis. Groups of physical signs and symptoms associated with specific poisoning syndromes are known as toxidromes (Table 4–9).
The urine drug toxicology test is an immunoassay designed to detect common drugs of abuse such as amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, and opiates. Acute poisoning with these substances can usually be determined on clinical grounds, and the results of these assays are infrequently available fast enough to guide stabilization. Additionally, detection of drugs or their metabolites on a urine immunoassay does not mean that the detected drug is responsible for the currently observed poisoning illness. When ingestion of acetaminophen or aspirin cannot clearly be excluded via the exposure history, serum quantification of these drugs is recommended. An ECG may be useful at detecting heart blocks, Na+ channel blockade, or K+ channel blockade associated with specific medication classes (Table 4–10). Further laboratory analysis should be tailored to the individual poisoning circumstance.
Differential Poisoning Diagnosis (Partial Listing) for Electrocardiographic Manifestations of Toxicity
DECONTAMINATION OF THE POISONED PATIENT. Poisoning exposures may be by inhalation, by dermal or mucosal absorption, by injection, or by ingestion. The first step in preventing absorption of poison is to stop any ongoing exposure. If necessary, eyes and skin should be washed copiously. GI decontamination prevents or reduces absorption of a substance after it has been ingested. The strategies for GI decontamination are gastric emptying, adsorption of poison, and catharsis. Minimal indications for considering GI decontamination include: (1) the poison must be potentially dangerous; (2) the poison must still be unabsorbed in the stomach or intestine, so it must be soon after ingestion; and (3) the procedure must be able to be performed safely and with proper technique. Gastric emptying is rarely recommended anymore, but the administration of activated charcoal and the performance of whole bowel irrigation remain therapeutic options. Gastric emptying reduces drug absorption by ~1/3 under optimal conditions.
Based upon review of existing evidence, the American Academy of Pediatrics no longer recommends syrup of ipecac as part of its childhood injury prevention program, and the American Academy of Clinical Toxicology dissuades routine use of gastric emptying in the poisoned patient.
ADSORPTION. Adsorption of a poison refers to the binding of a poison to the surface of another substance so that the poison is less available for absorption into the body. Fuller’s earth has been suggested as an adsorbent for paraquat, Prussian blue binds thallium and cesium, and sodium polystyrene can adsorb lithium. The most common adsorbent used in the treatment of acute drug overdose is activated charcoal.
ACTIVATED CHARCOAL. Charcoal is created through controlled pyrolysis of organic matter, and is activated through steam or chemical treatment that increases its internal pore structure and adsorptive surface capacity. The surface of activated charcoal contains carbon moieties that are capable of binding poisons. The recommended dose is typically 0.5-2 g/kg of body weight, up to a maximum tolerated dose of ~75-100 g. As a rough estimate, 10 g of activated charcoal is expected to bind ~1 g of drug. Alcohols, corrosives, hydrocarbons, and metals are not well adsorbed by charcoal. Complications of activated charcoal therapy include vomiting, constipation, pulmonary aspiration, and death. Nasogastric administration of charcoal increases the incidence of vomiting, and may increase the risk for pulmonary aspiration. Charcoal should not be given to patients with suspected GI perforation, or to patients who may be candidates for endoscopy.
WHOLE BOWEL IRRIGATION. Whole bowel irrigation (WBI) involves the enteral administration of large amounts of a high molecular weight, iso-osmotic polyethylene glycol electrolyte solution with the goal of passing poison by the rectum before it can be absorbed. Potential candidates for WBI include: (1) “body-packers” with intestinal packets of illicit drugs; (2) patients with iron overdose; (3) patients who have ingested patch pharmaceuticals; and (4) patients with overdoses of sustained-release or bezoar-forming drugs. Polyethylene glycol electrolyte solution is typically administered at a rate of 25 to 40 mL/kg/h until the rectal effluent is clear and no more drug is being passed. To achieve these high administration rates, a nasogastric tube may be used. WBI is contraindicated in the presence of bowel obstruction or perforation, and may be complicated by abdominal distention or pulmonary aspiration.
CATHARTICS. The 2 most common categories of simple cathartics are the magnesium salts, such as magnesium citrate and magnesium sulfate, and the nondigestible carbohydrates, such as sorbitol. The use of simple cathartics has been abandoned as a GI decontamination strategy.
Gastric Lavage. The procedure for gastric lavage involves passing an orogastric tube into the stomach with the patient in the left-lateral decubitus position with head lower than feet. After withdrawing stomach contents, 10 to 15 mL/kg (up to 250 mL) of saline lavage fluid is administered and withdrawn. This process continues until the lavage fluid returns clear. Complications of the procedure include mechanical trauma to the stomach or esophagus, pulmonary aspiration of stomach contents, and vagus nerve stimulation.
Syrup of Ipecac. The alkaloids cephaeline and emetine within syrup of ipecac act as emetics because of both a local irritant effect on the enteric tract and a central effect on the chemoreceptor trigger zone in the area postrema of the medulla. Ipecac is given orally at a dose of 15 mL for children up to 12 years, and 30 mL for older children and adults. Administration of ipecac is typically followed by a drink of water, and reliably produces emesis in 15-30 min. Contraindications for syrup of ipecac administration include existing or impending CNS depression, ingestion of a corrosive or hydrocarbon drug (due to the emergence of chemical pneumonia), or presence of a medical condition that might be exacerbated by vomiting.
ENHANCING THE ELIMINATION OF POISONS. Once absorbed, the deleterious toxicodynamic effects of some drugs may be reduced by methods that hasten their elimination from the body, as described below.
MANIPULATING URINARY pH: URINARY ALKALINIZATION. Drugs subject to renal clearance are excreted into the urine by glomerular filtration and active tubular secretion; nonionized compounds may be reabsorbed far more rapidly than ionized polar molecules (see Chapter 2). Weakly acidic drugs are susceptible to “ion-trapping” in the urine. Aspirin is a weak acid with a pKa = 3.0. As the pH of the urine increases, more salicylate is in its ionized form at equilibrium, and more salicylic acid is diffused into the tubular lumen of the kidney. Urinary alkalinization is also believed to speed clearance of phenobarbital, chlorpropamide, methotrexate, and chlorophenoxy herbicides. The American Academy of Clinical Toxicologists recommends urine alkalinization as first-line treatment only for moderately severe salicylate poisoning that does not meet criteria for hemodialysis. To achieve alkalinization of the urine, 100-150 mEq of sodium bicarbonate in 1 L of D5W is infused intravenously at twice the maintenance fluid requirements and then titrated to effect. Hypokalemia should be treated since it will hamper efforts to alkalinize the urine due to H+-K+ exchange in the kidney. Urine alkalinization is contraindicated in renal failure, or if fluid administration may worsen pulmonary edema or congestive heart failure. Acetazolamide is not used to alkalinize urine as it promotes acidemia.
MULTIPLE-DOSE ACTIVATED CHARCOAL. Activated charcoal adsorbs drug to its surface and promotes enteral elimination. Multiple doses of activated charcoal can speed elimination of absorbed drug by 2 mechanisms. Charcoal may interrupt enterohepatic circulation of hepatically metabolized drug excreted in the bile, and charcoal may create a diffusion gradient across the GI mucosa and promote movement of drug from the bloodstream onto the charcoal in the intestinal lumen. Activated charcoal may be administered in multiple doses, 12.5 g/h every 1, 2, or 4 h (smaller doses may be used for children). Charcoal enhances the clearance of many drugs of low molecular weight, small volume of distribution, and long elimination t½. Multiple-dose activated charcoal is believed to have the most potential utility in overdoses of carbamazepine, dapsone, phenobarbital, quinine, theophylline, and yellow oleander.
EXTRACORPOREAL DRUG REMOVAL. The ideal drug amenable to removal by hemodialysis has a low molecular weight, a low volume of distribution, high solubility in water, and minimal protein binding. Hemoperfusion involves passing blood through a cartridge containing adsorbent particles. The most common poisonings for which hemodialysis is sometimes used include salicylate, methanol, ethylene glycol, lithium, carbamazepine, and valproic acid.
ANTIDOTAL THERAPIES. Antidotal therapy involves antagonism or chemical inactivation of an absorbed poison. Among the most common specific antidotes used are N-acetyl-L-cysteine for acetaminophen poisoning, opioid antagonists for opioid overdose, and chelating agents for poisoning from certain metal ions. A list of antidotes used is presented in Table 4–11.
Some Common Antidotes and Their Indications
The pharmacodynamics of a poison can be altered by competition at a receptor, as in the antagonism provided by naloxone therapy in the setting of heroin overdose. A physiological antidote may use a different cellular mechanism to overcome the effects of a poison, as in the use of glucagon to circumvent a blocked β adrenergic receptor and increase cellular cyclic AMP in the setting of propranolol overdose. Antivenoms and chelating agents bind and directly inactivate poisons. The biotransformation of a drug can also be altered by an antidote; for example, fomepizole will inhibit alcohol dehydrogenase and stop the formation of toxic acid metabolites from ethylene glycol and methanol. Many drugs used in the supportive care of a poisoned patient (anticonvulsants, vasoconstricting agents, etc.) may be considered nonspecific functional antidotes.
The mainstay of therapy for poisoning is good support of the airway, breathing, circulation, and vital metabolic processes of the poisoned patient until the poison is eliminated from the body.
IMPORTANT RESOURCES FOR INFORMATION RELATED TO DRUG TOXICITY AND POISONING
Additional information on poisoning from drugs and chemicals can be found in many dedicated books of toxicology. A popular computer database for information on toxic substances is POISINDEX (Micromedex, Inc., Denver, CO). The National Library of Medicine offers information on toxicology and environmental health (http://sis.nlm.nih.gov/enviro.html), including a link to ToxNet (http://toxnet.nlm.nih.gov/). Regional poison control centers are a resource for valuable poisoning information and may be contacted within the U.S. through a national PoisonHelp hotline: 1-800-222-1222.