InternalMed_Harrison

InternalMed_Harrison. Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion). Metal poisoning can also result from exposure to vapors (e.g., mercury vapor in creating dental amalgams). When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host. Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, protein binding, rates of biotransformation, availability of intracellular ligands, and other factors. Some organs (e.g., bone, liver, and kidney) sequester metals in relatively high concentrations for years. Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and


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InternalMed_Harrison. years. Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails. The intrinsic stability of metals facilitates tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear.


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InternalMed_Harrison. Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements (Chap. 96e) but are toxic at high levels of exposure. Others, such as lead and mercury, are xenobiotic and theoretically are capable of exerting toxic effects at any level of exposure. Indeed, much research is currently focused on the contribution of low-level xenobiotic metal exposure to chronic diseases and to subtle changes in health that may have significant public health consequences. Genetic factors, such as polymorphisms that encode for variant enzymes with altered properties in terms of metal binding, transport, and effects, also may modify the impact of metals on health and thereby account, at least in part, for individual susceptibility to metal effects.


InternalMed_Harrison

InternalMed_Harrison. The most important component of treatment for metal toxicity is the termination of exposure. Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion. The principal chelating agents are dimercaprol (British anti-Lewisite [BAL]), ethylenediamine tetraacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicillamine; their specific use depends on the metal involved and the clinical circumstances. Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion. In addition to the information provided in Table 472e-1, several other aspects of exposure, toxicity, or management are worthy of discussion with respect to the four most hazardous toxicants (arsenic, cadmium, lead, and mercury).


InternalMed_Harrison

InternalMed_Harrison. Arsenic, even at moderate levels of exposure, has been clearly linked with increased risks for cancer of the skin, bladder, renal pelvis, ureter, kidney, liver, and lung. These risks appear to be modified by smoking, folate and selenium status, genetic traits (such as ability to methylate arsenic), and other factors. Studies in community-based populations are beginning to demonstrate that arsenic exposure is a risk factor for increased coronary heart disease and stroke. Evidence is also emerging of “itai-itai” (“ouch-ouch”) disease, so named because of cadmium-induced bone toxicity that led to painful bone fractures. Modest exposures from environmental contamination have recently been associated in some studies with a lower bone density, a higher incidence of fractures, and a faster decline in height in both men and women, effects that may be related to cadmium’s calciuric effect on the kidney. There is some evidence for synergy between the adverse impacts of cadmium and lead on


InternalMed_Harrison

InternalMed_Harrison. decline in height in both men and women, effects that may be related to cadmium’s calciuric effect on the kidney. There is some evidence for synergy between the adverse impacts of cadmium and lead on kidney function. Environmental exposures have also been linked to lower lung function (even after adjusting for smoking cigarettes, which contain cadmium) as well as increased risk of cardiovascular disease and mortality, stroke, and heart failure. Several studies have also raised concerns that cadmium may be carcinogenic and contribute to elevated risks of prostate, breast, and pancreatic cancer. Overall, this growing body of research indicates that cadmium exposure may be contributing significantly to morbidity and mortality rates in the general population.


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InternalMed_Harrison. Advances in our understanding of lead toxicity have recently benefited by the development of K x-ray fluorescence (KXRF) instruments for making safe in vivo measurements of lead levels in bone (which, in turn, reflect cumulative exposure over many years, as opposed to blood lead levels, which mostly reflect recent exposure). Higher bone lead levels measured by KXRF have been linked to increased risk of hypertension and accelerated declines in cognition in both men and women from an urban population. Upon reviewing these studies in conjunction with other epidemiologic and toxicologic studies, a recent federal expert panel concluded that the impact of lead exposure on hypertension and cognition in adults was causal. Prospective studies have also demonstrated that higher bone lead levels are a major risk factor for increased cardiovascular morbidity and mortality rates in both community-based and occupational-exposed populations. Lead exposure at community levels has also been recently


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InternalMed_Harrison. a major risk factor for increased cardiovascular morbidity and mortality rates in both community-based and occupational-exposed populations. Lead exposure at community levels has also been recently associated with increased risks of hearing loss, Parkinson’s disease, and amyotrophic lateral sclerosis. With respect to pregnancy-associated risks, high maternal bone lead levels were found to predict lower birth weight, head circumference, birth length, and neurodevelopmental performance in offspring by age 2 years. In a randomized trial, calcium supplementation (1200 mg daily) was found to significantly reduce the mobilization of lead from maternal bone into blood during pregnancy.


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InternalMed_Harrison. The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on studies of the offspring of mothers who ingested mercury-contaminated fish. With respect to whether the consumption of fish by women during pregnancy is good or bad for offspring neurodevelopment, balancing the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs) in fish versus the adverse effects of mercury contamination in fish has led to some confusion and inconsistency in public health recommendations. Overall, it would appear that it would be best for pregnant women to either limit fish consumption to those species known to be low in mercury contamination but high in omega-3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources. Current evidence has not supported the recent contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early


InternalMed_Harrison

InternalMed_Harrison. through supplements or other dietary sources. Current evidence has not supported the recent contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early childhood, has played a significant role in causing neurodevelopmental problems such as autism. With regard to adults, there is conflicting evidence as to whether mercury exposure is associated with increased risk of hypertension and cardiovascular disease. At this point, conclusions cannot be drawn.


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InternalMed_Harrison. Heavy metals pose risks to health that are especially burdensome in selected parts of the world. For example, arsenic exposure from natural contamination of shallow tube wells inserted for drinking water is a major environmental problem for millions of Smelting and microelectronics industries; wood preservatives, pesticides, herbicides, fungicides; contaminant of deep-water wells; folk remedies; and coal; incineration of these products. Organic arsenic (arsenobetaine, arsenocholine) is ingested in seafood and fish, but is nontoxic; inorganic arsenic is readily absorbed (lung and GI); sequesters in liver, spleen, kidneys, lungs, and GI tract; residues persist in skin, hair, and nails; biomethylation results in detoxification, but this process saturates. Acute arsenic poisoning results in necrosis of intestinal mucosa with hemorrhagic gastroenteritis, fluid loss, hypotension, delayed cardiomyopathy, acute tubular necrosis, and hemolysis.


InternalMed_Harrison

InternalMed_Harrison. Acute arsenic poisoning results in necrosis of intestinal mucosa with hemorrhagic gastroenteritis, fluid loss, hypotension, delayed cardiomyopathy, acute tubular necrosis, and hemolysis. Chronic arsenic exposure causes diabetes, vasospasm, peripheral vascular insufficiency and gangrene, peripheral neuropathy, and cancer of skin, lung, liver (angiosarcoma), bladder, and kidney. Lethal dose: 120–200 mg (adults); 2 mg/kg (children). Nausea, vomiting, diarrhea, abdominal pain, delirium, coma, seizures; garlicky odor on breath; hyperkeratosis, hyperpigmentation, exfoliative dermatitis, and Mees’ lines (transverse white striae of the fingernails); sensory and motor polyneuritis, distal weakness. Radiopaque sign on abdominal x-ray; ECG–QRS broadening, QT prolongation, ST depression, T-wave flattening; 24-h urinary arsenic >67 μmol/d or 50 μg/d; (no seafood × 24 h); if recent exposure, serum arsenic >0.9 μmol/L (7 μg/dL). High arsenic in hair or nails.


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InternalMed_Harrison. If acute ingestion, ipecac to induce vomiting, gastric lavage, activated charcoal with a cathartic. Supportive care in ICU. Dimercaprol 3–5 mg/kg IM q4h × 2 days; q6h × 1 day, then q12h × 10 days; alternative: oral succimer. PART 18 Poisoning, Drug Overdose, and Envenomation Metal-plating, pigment, smelting, battery, and plastics industries; tobacco; incineration of these products; ingestion of food that concentrates cadmium (grains, cereals). Absorbed through ingestion or inhalation; bound by metallothionein, filtered at the glomerulus, but reabsorbed by proximal tubules (thus, poorly excreted). Biologic half-life: 10–30 y. Binds cellular sulfhydryl groups, competes with zinc, calcium for binding sites. Concentrates in liver and kidneys. Acute cadmium inhalation causes pneumonitis after 4–24 h; acute ingestion causes gastroenteritis.


InternalMed_Harrison

InternalMed_Harrison. Acute cadmium inhalation causes pneumonitis after 4–24 h; acute ingestion causes gastroenteritis. Chronic exposure causes anosmia, yellowing of teeth, emphysema, minor LFT elevations, microcytic hypochromic anemia unresponsive to iron therapy, proteinuria, increased urinary β2microglobulin, calciuria, leading to chronic renal failure, osteomalacia, and fractures. Possible risks of cardiovascular disease and cancer. With inhalation: pleuritic chest pain, dyspnea, cyanosis, fever, tachycardia, nausea, noncardiogenic pulmonary edema. With ingestion: nausea, vomiting, cramps, diarrhea. Bone pain, fractures with osteomalacia. If recent exposure, serum cadmium >500 nmol/L (5 μg/dL). Urinary cadmium >100 nmol/L (10 μg/g creatinine) and/or urinary β2-microglobulin >750 μg/g creatinine (but urinary β2-microglobulin also increased in other renal diseases such as pyelonephritis).


InternalMed_Harrison

InternalMed_Harrison. There is no effective treatment for cadmium poisoning (chelation not useful; dimercaprol can exacerbate nephrotoxicity). Avoidance of further exposure, supportive therapy, vitamin D for osteomalacia. Manufacturing of auto batteries, lead crystal, ceramics, fishing weights, etc.; demolition or sanding of lead-painted houses, bridges; stained glass–making, plumbing, soldering; environmental exposure to paint chips, house dust (in homes built <1975), firing ranges (from bullet dust), food or water from improperly glazed ceramics, lead pipes; contaminated herbal remedies, candies; exposure to the combustion of leaded fuels.


InternalMed_Harrison

InternalMed_Harrison. Absorbed through ingestion or inhalation; organic lead (e.g., tetraethyl lead) absorbed dermally. In blood, 95–99% sequestered in RBCs—thus, must measure lead in whole blood (not serum). Distributed widely in soft tissue, with half-life ~30 days; 15% of dose sequestered in bone with half-life of >20 years. Excreted mostly in urine, but also appears in other fluids including breast milk. Interferes with mitochondrial oxidative phosphorylation, ATPases, calcium-dependent messengers; enhances oxidation and cell apoptosis.


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InternalMed_Harrison. Acute exposure with blood lead levels (BPb) of >60–80 μg/dL can cause impaired neurotransmission and neuronal cell death (with central and peripheral nervous system effects); impaired hematopoiesis and renal tubular dysfunction. At higher levels of exposure (e.g., BPb >80–120 μg/dL), acute encephalopathy with convulsions, coma, and death may occur. Subclinical exposures in children (BPb 25–60 μg/dL) are associated with anemia; mental retardation; and deficits in language, motor function, balance, hearing, behavior, and school performance. Impairment of IQ appears to occur at even lower levels of exposure with no measurable threshold above the limit of detection in most assays of 1 μg/dL.


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InternalMed_Harrison. In adults, chronic subclinical exposures (BPb >40 μg/dL) are associated with an increased risk of anemia, demyelinating peripheral neuropathy (mainly motor), impairments of reaction time and hearing, accelerated declines in cognition, hypertension, ECG conduction delays, higher risk of cardiovascular disease and death, interstitial nephritis and chronic renal failure, diminished sperm counts, and spontaneous abortions. Abdominal pain, irritability, lethargy, anorexia, anemia, Fanconi’s syndrome, pyuria, azotemia in children with blood lead level (BPb) >80 μg/ dL; may also see epiphyseal plate “lead lines” on long bone x-rays. Convulsions, coma at BPb >120 μg/ dL. Noticeable neurodevelopmental delays at BPb of 40–80 μg/dL; may also see symptoms associated with higher BPb levels. Screening of all U.S.


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InternalMed_Harrison. U.S. children when they begin to crawl (~6 months) is recommended by the CDC; source identification and intervention is begun if the BPb >10 μg/dL. In adults, acute exposure causes similar symptoms as in children as well as headaches, arthralgias, myalgias, depression, impaired short-term memory, loss of libido. Physical exam may reveal a “lead line” at the gingiva-tooth border, pallor, wrist drop, and cognitive dysfunction (e.g., declines on the mini-mental state exam); lab tests may reveal a normocytic, normochromic anemia, basophilic stippling, an elevated blood protoporphyrin level (free erythrocyte or zinc), and motor delays on nerve conduction. U.S. OSHA requires regular testing of lead-exposed workers with removal if BPb >40 μg/dL. New guidelines have been proposed recommending that BPb be maintained at <10 μg/dL, removal of workers if BPb >20 μg/dL, and monitoring of cumulative exposure parameters.


InternalMed_Harrison

InternalMed_Harrison. Identification and correction of exposure sources is critical. In some U.S. states, screening and reporting to local health boards of children with BPb >10 μg/ dL and workers with BPb >40 μg/dL is required. In the highly exposed individual with symptoms, chelation is recommended with oral DMSA (succimer); if acutely toxic, hospitalization and IV or IM chelation with ethylenediamine tetraacetic acid calcium disodium (CaEDTA) may be required, with the addition of dimercaprol to prevent worsening of encephalopathy. It is uncertain whether children with asymptomatic lead exposure (e.g., BPb 20–40 μg/dL) benefit from chelation; a recent randomized trial showed no benefit. Correction of dietary deficiencies in iron, calcium, magnesium, and zinc will lower lead absorption and may also improve toxicity. Vitamin C is a weak but natural chelating agent. Calcium supplements (1200 mg at bedtime) have been shown to lower blood lead levels in pregnant women.


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InternalMed_Harrison. Abbreviations: ATPase, adenosine triphosphatase; BPb, blood lead; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; DMSA, dimercaptosuccinic acid; ECG, electrocardiogram; GI, gastrointestinal; ICU, intensive care unit; IQ, intelligence quotient; LFT, liver function tests; OSHA, Occupational Safety and Health Administration; RBC, red blood cell.


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InternalMed_Harrison. residents in parts of Bangladesh and Western India. Contamination masked, expressionless face; tremor; and psychiatric symptoms. With was formerly considered only a problem with deep wells; however, the the introduction of methylcyclopentadienyl manganese tricarbonyl geology of this region allows most residents only a few alternatives for (MMT) as a gasoline additive, there is concern for the toxic potential potable drinking water. The combustion of leaded gasoline with result-of environmental manganese exposure. For example, a recent study ing contamination of air and soil with lead oxide remains a problem in found a high prevalence of parkinsonian disorders in a community some countries of Central Asia, Southeast Asia, Africa, and the Middle with risks proportionate to estimated manganese exposures emitted by East. Populations living in the Arctic have been shown to have particu-local ferroalloy industries. Epidemiologic studies have also suggested larly high exposures to mercury


InternalMed_Harrison

InternalMed_Harrison. exposures emitted by East. Populations living in the Arctic have been shown to have particu-local ferroalloy industries. Epidemiologic studies have also suggested larly high exposures to mercury due to long-range transport patterns that manganese may interfere with early childhood neurodevelopment that concentrate mercury in the polar regions, as well as the traditional in ways similar to that of lead. Nickel exposure induces an allergic dependence of Arctic peoples on the consumption of fish and other response, and inhalation of nickel compounds with low aqueous wildlife that bioconcentrate methylmercury. solubility (e.g., nickel subsulfide and nickel oxide) in occupational set-


InternalMed_Harrison

InternalMed_Harrison. A few additional metals deserve brief mention but are not covered tings is associated with an increased risk of lung cancer. Overexposure in Table 472e-1 because of the relative rarity of their being clinically to selenium may cause local irritation of the respiratory system and encountered or the uncertainty regarding their potential toxicities. eyes, gastrointestinal irritation, liver inflammation, loss of hair, depig-Aluminum contributes to the encephalopathy in patients with severe mentation, and peripheral nerve damage. Workers exposed to certain renal disease, who are undergoing dialysis (Chap. 424). High levels organic forms of tin (particularly trimethyl and triethyl derivatives) of aluminum are found in the neurofibrillary tangles in the cerebral have developed psychomotor disturbances, including tremor, convulcortex and hippocampus of patients with Alzheimer’s disease, as well sions, hallucinations, and psychotic behavior. as in the drinking water and soil of areas with an


InternalMed_Harrison

InternalMed_Harrison. including tremor, convulcortex and hippocampus of patients with Alzheimer’s disease, as well sions, hallucinations, and psychotic behavior. as in the drinking water and soil of areas with an unusually high inci-Thallium, which is a component of some insecticides, metal alloys, dence of Alzheimer’s. The experimental and epidemiologic evidence and fireworks, is absorbed through the skin as well as by ingestion and for the aluminum–Alzheimer’s disease link remains relatively weak, inhalation. Severe poisoning follows a single ingested dose of >1 g or however, and it cannot be concluded that aluminum is a causal agent >8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis or a contributing factor in neurodegenerative disease. Hexavalent precede confusion, psychosis, organic brain syndrome, and coma. chromium is corrosive and sensitizing. Workers in the chromate and Thallium is radiopaque. Induced emesis or gastric lavage is indicated chrome pigment production industries have


InternalMed_Harrison

InternalMed_Harrison. syndrome, and coma. chromium is corrosive and sensitizing. Workers in the chromate and Thallium is radiopaque. Induced emesis or gastric lavage is indicated chrome pigment production industries have consistently had a greater within 4–6 h of acute ingestion; Prussian blue prevents absorption risk of lung cancer. The introduction of cobalt chloride as a fortifier in and is given orally at 250 mg/kg in divided doses. Unlike other types beer led to outbreaks of fatal cardiomyopathy among heavy consum-of metal poisoning, thallium poisoning may be less severe when actiers. Occupational exposure (e.g., of miners, dry-battery manufacturers, vated charcoal is used to interrupt its enterohepatic circulation. Other and arc welders) to manganese can cause a parkinsonian syndrome measures include forced diuresis, treatment with potassium chloride within 1–2 years, including gait disorders; postural instability; a (which promotes renal excretion of thallium), and peritoneal dialysis.


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InternalMed_Harrison. Poisoning and Drug Overdose Mark B. Mycyk Poisoning refers to the development of dose-related adverse effects following exposure to chemicals, drugs, or other xenobiotics. To para-phrase Paracelsus, the dose makes the poison. In excessive amounts, substances that are usually innocuous, such as oxygen and water, 473e can cause toxicity. Conversely, in small doses, substances commonly regarded as poisons, such as arsenic and cyanide, can be consumed without ill effect. Although most poisons have predictable dose-related effects, individual responses to a given dose may vary because of genetic polymorphism, enzymatic induction or inhibition in the presence of other xenobiotics, or acquired tolerance. Poisoning may be local (e.g., skin, eyes, or lungs) or systemic depending on the route of exposure, the chemical and physical properties of the poison, and its mechanism of action. The severity and reversibility of poisoning also depend on the functional reserve of the individual or target


InternalMed_Harrison

InternalMed_Harrison. the chemical and physical properties of the poison, and its mechanism of action. The severity and reversibility of poisoning also depend on the functional reserve of the individual or target organ, which is influenced by age and preexisting disease.


InternalMed_Harrison

InternalMed_Harrison. More than 5 million poison exposures occur in the United States each year. Most are acute, are accidental (unintentional), involve a single agent, occur in the home, result in minor or no toxicity, and involve children <6 years of age. Pharmaceuticals are involved in 47% of exposures and in 84% of serious or fatal poisonings. Unintentional exposures can result from the improper use of chemicals at work or play; label misreading; product mislabeling; mistaken identification of unlabeled chemicals; uninformed self-medication; and dosing errors by nurses, pharmacists, physicians, parents, and the elderly. Excluding the recreational use of ethanol, attempted suicide (deliberate self-harm) is the most common reported reason for intentional poisoning. Recreational use of prescribed and over-the-counter drugs for psychotropic or euphoric effects (abuse) or excessive self-dosing (misuse) is increasingly common and may also result in unintentional self-poisoning.


InternalMed_Harrison

InternalMed_Harrison. About 20–25% of exposures require bedside health-professional evaluation, and 5% of all exposures require hospitalization. Poisonings account for 5–10% of all ambulance transports, emergency department visits, and intensive care unit admissions. Up to 30% of psychiatric admissions are prompted by attempted suicide via overdosage. Overall, the mortality rate is low: <1% of all exposures. It is much higher (1–2%) among hospitalized patients with intentional (suicidal) overdose, who account for the majority of serious poisonings. Acetaminophen is the pharmaceutical agent most often implicated in fatal poisoning. Overall, carbon monoxide is the leading cause of death from poisoning, but this prominence is not reflected in hospital or poison center statistics because patients with such poisoning are typically dead when discovered and are referred directly to medical examiners.


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InternalMed_Harrison. Although poisoning can mimic other illnesses, the correct diagnosis can usually be established by the history, physical examination, routine and toxicologic laboratory evaluations, and characteristic clinical course. The history should include the time, route, duration, and circumstances (location, surrounding events, and intent) of exposure; the name and amount of each drug, chemical, or ingredient involved; the time of onset, nature, and severity of symptoms; the time and type of first-aid measures provided; and the medical and psychiatric history.


InternalMed_Harrison

InternalMed_Harrison. In many cases the patient is confused, comatose, unaware of an exposure, or unable or unwilling to admit to one. Suspicious circumstances include unexplained sudden illness in a previously healthy person or a group of healthy people; a history of psychiatric problems (particularly depression); recent changes in health, economic status, or social relationships; and onset of illness during work with chemicals 473e-1 or after ingestion of food, drink (especially ethanol), or medications. When patients become ill soon after arriving from a foreign country or being arrested for criminal activity, “body packing” or “body stuffing” (ingesting or concealing illicit drugs in a body cavity) should be suspected. Relevant information may be available from family, friends, paramedics, police, pharmacists, physicians, and employers, who should be questioned regarding the patient’s habits, hobbies, behavioral changes, available medications, and antecedent events. A search of clothes, belongings, and


InternalMed_Harrison

InternalMed_Harrison. physicians, and employers, who should be questioned regarding the patient’s habits, hobbies, behavioral changes, available medications, and antecedent events. A search of clothes, belongings, and place of discovery may reveal a suicide note or a container of drugs or chemicals. The imprint code on pills and the label on chemical products may be used to identify the ingredients and potential toxicity of a suspected poison by consulting a reference text, a computerized database, the manufacturer, or a regional poison information center (800-222-1222). Occupational exposures require review of any available material safety data sheet (MSDS) from the worksite. Because of increasing globalization, unfamiliar poisonings may result in local emergency department evaluation. Pharmaceuticals, industrial chemicals, or drugs of abuse from foreign countries may be identified with the assistance of a regional poison center or via the World Wide Web.


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InternalMed_Harrison. The physical examination should focus initially on vital signs, the cardiopulmonary system, and neurologic status. The neurologic examination should include documentation of neuromuscular abnormalities such as dyskinesia, dystonia, fasciculations, myoclonus, rigidity, and tremors. The patient should also be examined for evidence of trauma and underlying illnesses. Focal neurologic findings are uncommon in poisoning, and their presence should prompt evaluation for a structural central nervous system (CNS) lesion. Examination of the eyes (for nystagmus and pupil size and reactivity), abdomen (for bowel activity and bladder size), and skin (for burns, bullae, color, warmth, moisture, pressure sores, and puncture marks) may reveal findings of diagnostic value. When the history is unclear, all orifices should be examined for the presence of chemical burns and drug packets. The odor of breath or vomitus and the color of nails, skin, or urine may provide important diagnostic clues.


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InternalMed_Harrison. The diagnosis of poisoning in cases of unknown etiology primarily relies on pattern recognition. The first step is to assess the pulse, blood pressure, respiratory rate, temperature, and neurologic status and to characterize the overall physiologic state as stimulated, depressed, discordant, or normal (Table 473e-1). Obtaining a complete set of vital signs and reassessing them frequently are critical. Measuring core temperature is especially important, even in difficult or combative patients, since temperature elevation is the most reliable prognosticator of poor outcome in poisoning or drug withdrawal. The next step is to consider the underlying causes of the physiologic state and to attempt to identify a pathophysiologic pattern or toxic syndrome (toxidrome) based on the observed findings. Assessing the severity of physiologic derangements (Table 473e-2) is useful in this regard and also for monitoring the clinical course and response to treatment. The final step is to attempt to


InternalMed_Harrison

InternalMed_Harrison. Assessing the severity of physiologic derangements (Table 473e-2) is useful in this regard and also for monitoring the clinical course and response to treatment. The final step is to attempt to identify the particular agent involved by looking for unique or relatively poison-specific physical or ancillary test abnormalities. Distinguishing among toxidromes on the basis of the physiologic state is summarized next.


InternalMed_Harrison

InternalMed_Harrison. The Stimulated Physiologic State Increased pulse, blood pressure, respiratory rate, temperature, and neuromuscular activity characterize the stimulated physiologic state, which can reflect sympathetic, antimuscarinic (anticholinergic), or hallucinogen poisoning or drug withdrawal (Table 473e-1). Other features are noted in (Table 473e-2). Mydriasis, a characteristic feature of all stimulants, is most marked in antimuscarinic (anticholinergic) poisoning since pupillary reactivity relies on muscarinic control. In sympathetic poisoning (e.g., due to cocaine), pupils are also enlarged, but some reactivity to light remains. The antimuscarinic (anticholinergic) toxidrome is also distinguished by hot, dry, flushed skin; decreased bowel sounds; and urinary retention. Other stimulant syndromes increase sympathetic activity and cause diaphoresis, pallor, and increased bowel activity with varying


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InternalMed_Harrison. Abbreviations: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic acidosis; CNS, central nervous system; GABA, γ-aminobutyric acid; GHB, γ-hydroxybutyrate; GI, gastrointestinal; LSD, lysergic acid diethylamide; MAO, monoamine oxidase.


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InternalMed_Harrison. Grade 1 Awake, lethargic, or sleeping but arousable by voice or tactile stimulation; able to converse and follow commands; may be confused Grade 2 Responds to pain but not voice; can vocalize but not converse; spontaneous motor activity present; brainstem reflexes intact Grade 3 Unresponsive to pain; spontaneous motor activity absent; brainstem reflexes depressed; motor tone, respirations, and temperature decreased Grade 4 Unresponsive to pain; flaccid paralysis; brainstem reflexes and respirations absent; cardiovascular vital signs decreased degrees of nausea, vomiting, abnormal distress, and occasionally diarrhea. The absolute and relative degree of vital-sign changes and neuromuscular hyperactivity can help distinguish among stimulant toxidromes. Since sympathetics stimulate the peripheral nervous system more directly than do hallucinogens or drug withdrawal, markedly increased vital signs and organ ischemia suggest sympathetic poisoning. Findings helpful in suggesting the


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InternalMed_Harrison. peripheral nervous system more directly than do hallucinogens or drug withdrawal, markedly increased vital signs and organ ischemia suggest sympathetic poisoning. Findings helpful in suggesting the particular drug or class causing physiologic stimulation include reflex bradycardia from selective α-adrenergic stimulants (e.g., decongestants), hypotension from selective β-adrenergic stimulants (e.g., asthma therapeutics), limb ischemia from ergot alkaloids, rotatory nystagmus from phencyclidine and ketamine (the only physiologic stimulants that cause this finding), and delayed cardiac conduction from high doses of cocaine and some anticholinergic agents (e.g., antihistamines, cyclic antidepressants, and antipsychotics). Seizures suggest a sympathetic etiology, an anticholinergic agent with membrane-active properties (e.g., cyclic antidepressants, orphenadrine, phenothiazines), or a withdrawal syndrome. Close attention to core temperature is critical in patients with grade 4 physiologic


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InternalMed_Harrison. membrane-active properties (e.g., cyclic antidepressants, orphenadrine, phenothiazines), or a withdrawal syndrome. Close attention to core temperature is critical in patients with grade 4 physiologic stimulation (Table 473e-2).


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InternalMed_Harrison. The Depressed Physiologic State Decreased pulse, blood pressure, respiratory rate, temperature, and neuromuscular activity are indicative of the depressed physiologic state caused by “functional” sympatholytics (agents that decrease cardiac function and vascular tone as well as sympathetic activity), cholinergic (muscarinic and nicotinic) agents, opioids, and sedative-hypnotic γ-aminobutyric acid (GABA)-ergic agents (Table 473e-1 and 473e-2). Miosis is also common and is most pronounced in opioid and cholinergic poisoning. Miosis is distinguished from other depressant syndromes by muscarinic and nicotinic signs and symptoms (Table 473e-1). Pronounced cardiovascular depression in the absence of significant CNS depression suggests a direct or peripherally acting sympatholytic. In contrast, in opioid and sedative-hypnotic poisoning, vital-sign changes are secondary to depression of CNS cardiovascular and respiratory centers (or consequent hypoxemia), and significant abnormalities in


InternalMed_Harrison

InternalMed_Harrison. in opioid and sedative-hypnotic poisoning, vital-sign changes are secondary to depression of CNS cardiovascular and respiratory centers (or consequent hypoxemia), and significant abnormalities in these parameters do not occur until there is a marked decrease in the level of consciousness (grade 3 or 4 physiologic depression; [Table 473e-2]). Other clues that suggest the cause of physiologic depression include cardiac arrhythmias and conduction disturbances (due to antiarrhythmics, β-adrenergic antagonists, calcium channel blockers, digitalis glycosides, propoxyphene, and cyclic antidepressants), mydriasis (due to tricyclic antidepressants, some antiarrhythmics, meperidine, and diphenoxylate-atropine [Lomotil]), nystagmus (due to sedative-hypnotics), and seizures (due to cholinergic agents, propoxyphene, and cyclic antidepressants).


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InternalMed_Harrison. The Discordant Physiologic State The discordant physiologic state is characterized by mixed vital-sign and neuromuscular abnormalities, as observed in poisoning by asphyxiants, CNS syndromes, membrane-active agents, and anion-gap metabolic acidosis (AGMA) inducers (Table 473e-1). In these conditions, manifestations of physiologic stimulation and physiologic depression occur together or at different times during the clinical course. For example, membrane-active agents can cause simultaneous coma, seizures, hypotension, and tachyarrhythmias. Alternatively, vital signs may be normal while the patient has an altered mental status or is obviously sick or clearly symptomatic. Early, pronounced vital-sign and mental-status changes suggest asphyxiant or membrane-active agent poisoning; the lack of such abnormalities suggests an AGMA inducer; and marked neuromuscular dysfunction without significant vital-sign abnormalities suggests a CNS syndrome.


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InternalMed_Harrison. The Normal Physiologic State A normal physiologic status and physical examination may be due to a nontoxic exposure, psychogenic illness, or poisoning by “toxic time-bombs”: agents that are slowly absorbed, are slowly distributed to their sites of action, require metabolic activation, or disrupt metabolic processes (Table 473e-1). Because so many medications have now been reformulated into a once-a-day preparations for the patient’s convenience and adherence, toxic time-bombs are increasingly common. Diagnosing a nontoxic exposure requires that the identity of the exposure agent be known or that a toxic time-bomb exposure be excluded and the time since exposure exceed 473e-3 the longest known or predicted interval between exposure and peak toxicity. Psychogenic illness (fear of being poisoned, mass hysteria) may also follow a nontoxic exposure and should be considered when symptoms are inconsistent with exposure history. Anxiety reactions resulting from a nontoxic exposure can cause


InternalMed_Harrison

InternalMed_Harrison. mass hysteria) may also follow a nontoxic exposure and should be considered when symptoms are inconsistent with exposure history. Anxiety reactions resulting from a nontoxic exposure can cause mild physiologic stimulation (Table 473e-2) and be indistinguishable from toxicologic causes without ancillary testing or a suitable period of observation.


InternalMed_Harrison

InternalMed_Harrison. Laboratory assessment may be helpful in the differential diagnosis. Increased AGMA is most common in advanced methanol, ethylene glycol, and salicylate intoxication but can occur with any poisoning that results in hepatic, renal, or respiratory failure; seizures; or shock. The serum lactate concentration is more commonly low (less than the anion gap) in the former and high (nearly equal to the anion gap) in the latter. An abnormally low anion gap can be due to elevated blood levels of bromide, calcium, iodine, lithium, or magnesium. An increased osmolal gap—a difference of >10 mmol/L between serum osmolality (measured by freezing-point depression) and osmolality calculated from serum sodium, glucose, and blood urea nitrogen levels— suggests the presence of a low-molecular-weight solute such as acetone; an alcohol (benzyl, ethanol, isopropanol, methanol); a glycol (diethylene, ethylene, propylene); ether (ethyl, glycol); or an “unmeasured” cation (calcium, magnesium) or sugar


InternalMed_Harrison

InternalMed_Harrison. solute such as acetone; an alcohol (benzyl, ethanol, isopropanol, methanol); a glycol (diethylene, ethylene, propylene); ether (ethyl, glycol); or an “unmeasured” cation (calcium, magnesium) or sugar (glycerol, mannitol, sorbitol). Ketosis suggests acetone, isopropyl alcohol, salicylate poisoning, or alcoholic ketoacidosis. Hypoglycemia may be due to poisoning with β-adrenergic blockers, ethanol, insulin, oral hypoglycemic agents, quinine, and salicylates, whereas hyperglycemia can occur in poisoning with acetone, β-adrenergic agonists, caffeine, calcium channel blockers, iron, theophylline, or N-3-pyridylmethyl-N′-p-nitrophenylurea (PNU [Vacor]). Hypokalemia can be caused by barium, β-adrenergic agonists, caffeine, diuretics, theophylline, or toluene; hyperkalemia suggests poisoning with an α-adrenergic agonist, a β-adrenergic blocker, cardiac glycosides, or fluoride. Hypocalcemia may be seen in ethylene glycol, fluoride, and oxalate poisoning.


InternalMed_Harrison

InternalMed_Harrison. The electrocardiogram (ECG) can be useful for rapid diagnostic purposes. Bradycardia and atrioventricular block may occur in patients poisoned by α-adrenergic agonists, antiarrhythmic agents, beta blockers, calcium channel blockers, cholinergic agents (carbamate and organophosphate insecticides), cardiac glycosides, lithium, or tricyclic antidepressants. QRSand QT-interval prolongation may be caused by hyperkalemia, various antidepressants, and other membrane-active drugs (Table 473e-1). Ventricular tachyarrhythmias may be seen in poisoning with cardiac glycosides, fluorides, membrane-active drugs, methylxanthines, sympathomimetics, antidepressants, and agents that cause hyperkalemia or potentiate the effects of endogenous catecholamines (e.g., chloral hydrate, aliphatic and halogenated hydrocarbons).


InternalMed_Harrison

InternalMed_Harrison. Radiologic studies may occasionally be useful. Pulmonary edema (adult respiratory distress syndrome (ARDS) can be caused by poisoning with carbon monoxide, cyanide, an opioid, paraquat, phencyclidine, a sedative-hypnotic, or salicylate; by inhalation of irritant gases, fumes, or vapors (acids and alkali, ammonia, aldehydes, chlorine, hydrogen sulfide, isocyanates, metal oxides, mercury, phosgene, polymers); or by prolonged anoxia, hyperthermia, or shock. Aspiration pneumonia is common in patients with coma, seizures, and petroleum distillate aspiration. The presence of radiopaque densities on abdominal x-rays suggests the ingestion of calcium salts, chloral hydrate, chlorinated hydrocarbons, heavy metals, illicit drug packets, iodinated compounds, potassium salts, enteric-coated tablets, or salicylates.


InternalMed_Harrison

InternalMed_Harrison. Toxicologic analysis of urine and blood (and occasionally of gastric contents and chemical samples) can sometimes confirm or rule out suspected poisoning. Interpretation of laboratory data requires knowledge of the qualitative and quantitative tests used for screening and confirmation (enzyme-multiplied, fluorescence polarization, and radio-immunoassays; colorimetric and fluorometric assays; thin-layer, gas-liquid, or high-performance liquid chromatography; gas chromatography; mass spectrometry), their sensitivity (limit of detection) and specificity, the preferred biologic specimen for analysis, and the 473e-4 optimal time of specimen sampling. Personal communication with the hospital laboratory is essential to an understanding of institutional testing capabilities and limitations. Rapid qualitative hospital-based urine tests for drugs of abuse are only screening tests that cannot confirm the exact identity of the detected substance and should not be considered diagnostic or used for


InternalMed_Harrison

InternalMed_Harrison. qualitative hospital-based urine tests for drugs of abuse are only screening tests that cannot confirm the exact identity of the detected substance and should not be considered diagnostic or used for forensic purposes: False-positive and false-negative results are common. A positive screen may result from other pharmaceuticals that interfere with laboratory analysis (e.g., fluoroquinolones commonly cause “false-positive” opiate screens). Confirmatory testing with gas chromatography/mass spectrometry can be requested, but it often takes weeks to obtain a reported result. A negative screening result may mean that the responsible substance is not detectable by the test used or that its concentration is too low for detection at the time of sampling. For instance, recent new drugs of abuse that often result in emergency department evaluation for unexpected complications, such as synthetic cannabinoids (spice), cathinones (bath salts), and opiate substitutes (kratom), are not detectable by


InternalMed_Harrison

InternalMed_Harrison. often result in emergency department evaluation for unexpected complications, such as synthetic cannabinoids (spice), cathinones (bath salts), and opiate substitutes (kratom), are not detectable by hospital-based tests. In cases where a drug concentration is too low to be detected early during clinical evaluation, repeating the test at a later time may yield a positive result. Patients symptomatic from drugs of abuse often require immediate management based on the history, physical examination, and observed toxidrome without laboratory confirmation (e.g., apnea from opioid intoxication). When the patient is asymptomatic or when the clinical picture is consistent with the reported history, qualitative screening is neither clinically useful nor cost-effective. Thus, qualitative drug screens are of greatest value for the evaluation of patients with severe or unexplained toxicities, such as coma, seizures, cardiovascular instability, metabolic or respiratory acidosis, and nonsinus cardiac


InternalMed_Harrison

InternalMed_Harrison. are of greatest value for the evaluation of patients with severe or unexplained toxicities, such as coma, seizures, cardiovascular instability, metabolic or respiratory acidosis, and nonsinus cardiac rhythms. In contrast to qualitative drug screens, quantitative serum tests are useful for evaluation of patients poisoned with acetaminophen (Chap. 361), alcohols (including ethylene glycol and methanol), anticonvulsants, barbiturates, digoxin, heavy metals, iron, lithium, salicylate, and theophylline as well as for the presence of carboxyhemoglobin and methemoglobin. The serum concentration in these cases guides clinical management, and results are often available within an hour. The response to antidotes is sometimes useful for diagnostic purposes. Resolution of altered mental status and abnormal vital signs within minutes of IV administration of dextrose, naloxone, or flumazenil is virtually diagnostic of hypoglycemia, opioid poisoning, and benzodiazepine intoxication, respectively.


InternalMed_Harrison

InternalMed_Harrison. abnormal vital signs within minutes of IV administration of dextrose, naloxone, or flumazenil is virtually diagnostic of hypoglycemia, opioid poisoning, and benzodiazepine intoxication, respectively. The prompt reversal of dystonic (extrapyramidal) signs and symptoms following an IV dose of benztropine or diphenhydramine confirms a drug etiology. Although complete reversal of both central and peripheral manifestations of anticholinergic poisoning by physostigmine is diagnostic of this condition, physostigmine may cause some arousal in patients with CNS depression of any etiology.


InternalMed_Harrison

InternalMed_Harrison. PART 18 Poisoning, Drug Overdose, and Envenomation Treatment goals include support of vital signs, prevention of further poison absorption (decontamination), enhancement of poison elimination, administration of specific antidotes, and prevention of reexposure (Table 473e-3). Specific treatment depends on the identity of the poison, the route and amount of exposure, the time of presentation relative to the time of exposure, and the severity of poisoning. Knowledge of the offending agents’ pharmacokinetics and pharmacodynamics is essential.


InternalMed_Harrison

InternalMed_Harrison. During the pretoxic phase, prior to the onset of poisoning, decontamination is the highest priority, and treatment is based solely on the history. The maximal potential toxicity based on the greatest possible exposure should be assumed. Since decontamination is more effective when accomplished soon after exposure and when the patient is asymptomatic, the initial history and physical examination should be focused and brief. It is also advisable to establish IV access and initiate cardiac monitoring, particularly in patients with potentially serious ingestions or unclear histories. Prevention of Further Poison Absorption Enhancement of Poison Elimination Hemodialysis Alteration of urinary pH Administration of Antidotes Prevention of Reexposure Adult education Notification of regulatory agencies


InternalMed_Harrison

InternalMed_Harrison. Hemodialysis Alteration of urinary pH Administration of Antidotes Prevention of Reexposure Adult education Notification of regulatory agencies When an accurate history is not obtainable and a poison causing delayed toxicity (i.e., a toxic time-bomb) or irreversible damage is suspected, blood and urine should be sent for appropriate toxicologic screening and quantitative analysis. During poison absorption and distribution, blood levels may be greater than those in tissue and may not correlate with toxicity. However, high blood levels of agents whose metabolites are more toxic than the parent compound (acetaminophen, ethylene glycol, or methanol) may indicate the need for additional interventions (antidotes, dialysis). Most patients who remain asymptomatic or who become asymptomatic 6 h after ingestion are unlikely to develop subsequent toxicity and can be discharged safely. Longer observation will be necessary for patients who have ingested toxic time-bombs.


InternalMed_Harrison

InternalMed_Harrison. During the toxic phase—the interval between the onset of poisoning and its peak effects—management is based primarily on clinical and laboratory findings. Effects after an overdose usually begin sooner, peak later, and last longer than they do after a therapeutic dose. A drug’s published pharmacokinetic profile in standard references such as the Physician’s Desk Reference (PDR) is usually different from its toxicokinetic profile in overdose. Resuscitation and stabilization are the first priority. Symptomatic patients should have an IV line placed and should undergo oxygen saturation determination, cardiac monitoring, and continuous observation. Baseline laboratory, ECG, and x-ray evaluation may also be appropriate. Intravenous glucose (unless the serum level is documented to be normal), naloxone, and thiamine should be considered in patients with altered mental status, particularly those with coma or seizures. Decontamination should also be considered, but it is less likely to be


InternalMed_Harrison

InternalMed_Harrison. naloxone, and thiamine should be considered in patients with altered mental status, particularly those with coma or seizures. Decontamination should also be considered, but it is less likely to be effective during this phase than during the pretoxic phase.


InternalMed_Harrison

InternalMed_Harrison. Measures that enhance poison elimination may shorten the duration and severity of the toxic phase. However, they are not without risk, which must be weighed against the potential benefit. Diagnostic certainty (usually via laboratory confirmation) is generally a prerequisite. Intestinal (gut) dialysis with repetitive doses of activated charcoal (see “Multiple-Dose Activated Charcoal,” later) can enhance the elimination of selected poisons such as theophylline or carbamazepine. Urinary alkalinization may enhance the elimination of salicylates and a few other poisons. Chelation therapy can enhance the elimination of selected metals. Extracorporeal elimination methods are effective for many poisons, but their expense and risk make their use reasonable only in patients who would otherwise have an unfavorable outcome.


InternalMed_Harrison

InternalMed_Harrison. During the resolution phase of poisoning, supportive care and monitoring should continue until clinical, laboratory, and ECG abnormalities have resolved. Since chemicals are eliminated sooner from the blood than from tissues, blood levels are usually lower than tissue levels during this phase and again may not correlate with toxicity. This discrepancy applies particularly when extracorporeal elimination procedures are used. Redistribution from tissues may cause a rebound increase in the blood level after termination of these procedures. When a metabolite is responsible for toxic effects, continued treatment may be necessary in the absence of clinical toxicity or abnormal laboratory studies.


InternalMed_Harrison

InternalMed_Harrison. The goal of supportive therapy is to maintain physiologic homeostasis until detoxification is accomplished and to prevent and treat secondary complications such as aspiration, bedsores, cerebral and pulmonary edema, pneumonia, rhabdomyolysis, renal failure, sepsis, thromboembolic disease, coagulopathy, and generalized organ dysfunction due to hypoxemia or shock.


InternalMed_Harrison

InternalMed_Harrison. Admission to an intensive care unit is indicated for the following: patients with severe poisoning (coma, respiratory depression, hypo-tension, cardiac conduction abnormalities, cardiac arrhythmias, hypothermia or hyperthermia, seizures); those needing close monitoring, antidotes, or enhanced elimination therapy; those showing progressive clinical deterioration; and those with significant underlying medical problems. Patients with mild to moderate toxicity can be managed on a general medical service, on an intermediate care unit, or in an emergency department observation area, depending on the anticipated duration and level of monitoring needed (intermittent clinical observation versus continuous clinical, cardiac, and respiratory monitoring). Patients who have attempted suicide require continuous observation and measures to prevent self-injury until they are no longer suicidal.


InternalMed_Harrison

InternalMed_Harrison. Respiratory Care Endotracheal intubation for protection against the aspiration of gastrointestinal contents is of paramount importance in patients with CNS depression or seizures as this complication can increase morbidity and mortality rates. Mechanical ventilation may be necessary for patients with respiratory depression or hypoxemia and for facilitation of therapeutic sedation or paralysis of patients in order to prevent or treat hyperthermia, acidosis, and rhabdomyolysis associated with neuromuscular hyperactivity. Since clinical assessment of respiratory function can be inaccurate, the need for oxygenation and ventilation is best determined by continuous pulse oximetry or arterial blood-gas analysis. The gag reflex is not a reliable indicator of the need for intubation. A patient with CNS depression may maintain airway patency while being stimulated but not if left alone. Drug-induced pulmonary edema is usually noncardiac rather than cardiac in origin, although profound CNS


InternalMed_Harrison

InternalMed_Harrison. with CNS depression may maintain airway patency while being stimulated but not if left alone. Drug-induced pulmonary edema is usually noncardiac rather than cardiac in origin, although profound CNS depression and cardiac conduction abnormalities suggest the latter. Measurement of pulmonary artery pressure may be necessary to establish the cause and direct appropriate therapy. Extracorporeal measures (membrane oxygenation, venoarterial perfusion, cardiopulmonary bypass) and partial liquid (perfluorocarbon) ventilation may be appropriate for severe but reversible respiratory failure.


InternalMed_Harrison

InternalMed_Harrison. Cardiovascular Therapy Maintenance of normal tissue perfusion is critical for complete recovery to occur once the offending agent has been eliminated. If hypotension is unresponsive to volume expansion, treatment with norepinephrine, epinephrine, or high-dose dopamine may be necessary. Intraaortic balloon pump counterpulsation and venoarterial or cardiopulmonary perfusion techniques should be considered for severe but reversible cardiac failure. For patients with a return of spontaneous circulation after resuscitative treatment for 473e-5 cardiopulmonary arrest secondary to poisoning, therapeutic hypothermia should be used according to protocol. Bradyarrhythmias associated with hypotension generally should be treated as described in Chaps. 274 and 275. Glucagon, calcium, and high-dose insulin with dextrose may be effective in beta blocker and calcium channel blocker poisoning. Antibody therapy may be indicated for cardiac glycoside poisoning.


InternalMed_Harrison

InternalMed_Harrison. Supraventricular tachycardia associated with hypertension and CNS excitation is almost always due to agents that cause generalized physiologic excitation (Table 473e–1). Most cases are mild or moderate in severity and require only observation or nonspecific sedation with a benzodiazepine. In severe cases or those associated with hemodynamic instability, chest pain, or ECG evidence of ischemia, specific therapy is indicated. When the etiology is sympathetic hyperactivity, treatment with a benzodiazepine should be prioritized. Further treatment with a combined alpha and beta blocker (labetalol), a calcium channel blocker (verapamil or diltiazem), or a combination of a beta blocker and a vasodilator (esmolol and nitroprusside) may be considered for cases refractory to high doses of benzodiazepines. Treatment with an α-adrenergic antagonist (phentolamine) alone may sometimes be appropriate. If the cause is anticholinergic poisoning, physostigmine alone can be effective. Supraventricular


InternalMed_Harrison

InternalMed_Harrison. Treatment with an α-adrenergic antagonist (phentolamine) alone may sometimes be appropriate. If the cause is anticholinergic poisoning, physostigmine alone can be effective. Supraventricular tachycardia without hypertension is generally secondary to vasodilation or hypovolemia and responds to fluid administration.


InternalMed_Harrison

InternalMed_Harrison. For ventricular tachyarrhythmias due to tricyclic antidepressants and other membrane-active agents (Table 473e-1), sodium bicarbonate is indicated, whereas class IA, IC, and III antiarrhythmic agents are contraindicated because of similar electrophysiologic effects. Although lidocaine and phenytoin are historically safe for ventricular tachyarrhythmias of any etiology, sodium bicarbonate should be considered first for any ventricular arrhythmia suspected to have a toxicologic etiology. Intravenous emulsion therapy has shown benefit for treatment of arrhythmias and hemodynamic instability from various membrane-active agents. Beta blockers can be hazardous if the arrhythmia is due to sympathetic hyperactivity. Magnesium sulfate and overdrive pacing (by isoproterenol or a pacemaker) may be useful in patients with torsades des pointes and prolonged QT intervals. Magnesium and anti-digoxin antibodies should be considered in patients with severe cardiac glycoside poisoning. Invasive


InternalMed_Harrison

InternalMed_Harrison. be useful in patients with torsades des pointes and prolonged QT intervals. Magnesium and anti-digoxin antibodies should be considered in patients with severe cardiac glycoside poisoning. Invasive (esophageal or intracardiac) ECG recording may be necessary to determine the origin (ventricular or supraventricular) of wide-complex tachycardias (Chaps. 276 and 277). If the patient is hemodynamically stable, however, it is reasonable to simply observe him or her rather than to administer another potentially proarrhythmic agent. Arrhythmias may be resistant to drug therapy until underlying acid-base, electrolyte, oxygenation, and temperature derangements are corrected.


InternalMed_Harrison

InternalMed_Harrison. Central Nervous System Therapies Neuromuscular hyperactivity and seizures can lead to hyperthermia, lactic acidosis, and rhabdomyolysis and should be treated aggressively. Seizures caused by excessive stimulation of catecholamine receptors (sympathomimetic or hallucinogen poisoning and drug withdrawal) or decreased activity of GABA (isoniazid poisoning) or glycine (strychnine poisoning) receptors are best treated with agents that enhance GABA activity, such as benzodiazepine or barbiturates. Since benzodiazepines and barbiturates act by slightly different mechanisms (the former increases the frequency and the latter increases the duration of chloride channel opening in response to GABA), therapy with both may be effective when neither is effective alone. Seizures caused by isoniazid, which inhibits the synthesis of GABA at several steps by interfering with the cofactor pyridoxine (vitamin B6), may require high doses of supplemental pyridoxine. Seizures resulting from membrane


InternalMed_Harrison

InternalMed_Harrison. which inhibits the synthesis of GABA at several steps by interfering with the cofactor pyridoxine (vitamin B6), may require high doses of supplemental pyridoxine. Seizures resulting from membrane destabilization (beta blocker or cyclic antidepressant poisoning) require GABA enhancers (benzodiazepines first, barbiturates second). Phenytoin is contraindicated in toxicologic seizures: Animal and human data demonstrate worse outcomes after phenytoin loading, especially


InternalMed_Harrison

InternalMed_Harrison. PART 18 Poisoning, Drug Overdose, and Envenomation 473e-6 in theophylline overdose. For poisons with central dopaminergic effects (methamphetamine, phencyclidine) manifested by psychotic behavior, a dopamine receptor antagonist, such as haloperidol, may be useful. In anticholinergic and cyanide poisoning, specific antidotal therapy may be necessary. The treatment of seizures secondary to cerebral ischemia or edema or to metabolic abnormalities should include correction of the underlying cause. Neuromuscular paralysis is indicated in refractory cases. Electroencephalographic monitoring and continuing treatment of seizures are necessary to prevent permanent neurologic damage. Serotonergic receptor overstimulation in serotonin syndrome may be treated with cyproheptadine. Other Measures Temperature extremes, metabolic abnormalities, hepatic and renal dysfunction, and secondary complications should be treated by standard therapies.


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InternalMed_Harrison. PREVENTION OF POISON ABSORPTION Gastrointestinal Decontamination Whether or not to perform gastrointestinal decontamination and which procedure to use depends on the time since ingestion; the existing and predicted toxicity of the ingestant; the availability, efficacy, and contraindications of the procedure; and the nature, severity, and risk of complications. The efficacy of all decontamination procedures decreases with time, and data are insufficient to support or exclude a beneficial effect when they are used >1 h after ingestion. The average time from ingestion to presentation for treatment is >1 h for children and >3 h for adults. Most patients will recover from poisoning uneventfully with good supportive care alone, but complications of gastrointestinal decontamination, particularly aspiration, can prolong this process. Hence, gastrointestinal decontamination should be performed selectively, not routinely, in the management of overdose patients. It is clearly unnecessary when


InternalMed_Harrison

InternalMed_Harrison. aspiration, can prolong this process. Hence, gastrointestinal decontamination should be performed selectively, not routinely, in the management of overdose patients. It is clearly unnecessary when predicted toxicity is minimal or the time of expected maximal toxicity has passed without significant effect.


InternalMed_Harrison

InternalMed_Harrison. Activated charcoal has comparable or greater efficacy; has fewer contraindications and complications; and is less aversive and invasive than ipecac or gastric lavage. Thus it is the preferred method of gastrointestinal decontamination in most situations. Activated charcoal suspension (in water) is given orally via a cup, straw, or small-bore nasogastric tube. The generally recommended dose is 1 g/kg body weight because of its dosing convenience, although in vitro and in vivo studies have demonstrated that charcoal adsorbs ≥90% of most substances when given in an amount equal to 10 times the weight of the substance. Palatability may be increased by adding a sweetener (sorbitol) or a flavoring agent (cherry, chocolate, or cola syrup) to the suspension. Charcoal adsorbs ingested poisons within the gut lumen, allowing the charcoal-toxin complex to be evacuated with stool. Charged (ionized) chemicals such as mineral acids, alkalis, and highly dissociated salts of cyanide, fluoride, iron,


InternalMed_Harrison

InternalMed_Harrison. the gut lumen, allowing the charcoal-toxin complex to be evacuated with stool. Charged (ionized) chemicals such as mineral acids, alkalis, and highly dissociated salts of cyanide, fluoride, iron, lithium, and other inorganic compounds are not well adsorbed by charcoal. In studies with animals and human volunteers, charcoal decreases the absorption of ingestants by an average of 73% when given within 5 min of ingestant administration, 51% when given at 30 min, and 36% when given at 60 min. For this reason, charcoal given before hospital arrival increases the potential clinical benefit. Side effects of charcoal include nausea, vomiting, and diarrhea or constipation. Charcoal may also prevent the absorption of orally administered therapeutic agents. Complications include mechanical obstruction of the airway, aspiration, vomiting, and bowel obstruction and infarction caused by inspissated charcoal. Charcoal is not recommended for patients who have ingested corrosives because it obscures


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InternalMed_Harrison. of the airway, aspiration, vomiting, and bowel obstruction and infarction caused by inspissated charcoal. Charcoal is not recommended for patients who have ingested corrosives because it obscures endoscopy.


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InternalMed_Harrison. Gastric lavage should be considered for life-threatening poisons that cannot be treated effectively with other decontamination, elimination, or antidotal therapies (e.g., colchicine). Gastric lavage is performed by sequentially administering and aspirating ~5 mL of fluid per kilogram of body weight through a no. 40 French orogastric tube (no. 28 French tube for children). Except in infants, for whom normal saline is recommended, tap water is acceptable. The patient should be placed in Trendelenburg and left lateral decubitus positions to prevent aspiration (even if an endotracheal tube is in place). Lavage decreases ingestant absorption by an average of 52% if performed within 5 min of ingestion administration, 26% if performed at 30 min, and 16% if performed at 60 min. Significant amounts of ingested drug are recovered from <10% of patients. Aspiration is a common complication (occurring in up to 10% of patients), especially when lavage is performed improperly. Serious complications


InternalMed_Harrison

InternalMed_Harrison. of ingested drug are recovered from <10% of patients. Aspiration is a common complication (occurring in up to 10% of patients), especially when lavage is performed improperly. Serious complications (esophageal and gastric perforation, tube misplacement in the trachea) occur in ~1% of patients. For this reason, the physician should personally insert the lavage tube and confirm its placement, and the patient must be cooperative during the procedure. Gastric lavage is contraindicated in corrosive or petroleum distillate ingestions because of the respective risks of gastroesophageal perforation and aspiration pneumonitis. It is also contraindicated in patients with a compromised unprotected airway and those at risk for hemorrhage or perforation due to esophageal or gastric pathology or recent surgery. Finally, gastric lavage is absolutely contraindicated in combative patients or those who refuse, as most published complications involve patient resistance to the procedure.


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InternalMed_Harrison. Syrup of ipecac, an emetogenic agent that was once the substance most commonly used for decontamination, no longer has a role in poisoning management. Even the American Academy of Pediatrics—traditionally the strongest proponent of ipecac—issued a policy statement in 2003 recommending that ipecac should no longer be used in poisoning treatment. Chronic ipecac use (by patients with anorexia nervosa or bulimia) has been reported to cause electrolyte and fluid abnormalities, cardiac toxicity, and myopathy.


InternalMed_Harrison

InternalMed_Harrison. Whole-bowel irrigation is performed by administering a bowel-cleansing solution containing electrolytes and polyethylene glycol (Golytely, Colyte) orally or by gastric tube at a rate of 2 L/h (0.5 L/h in children) until rectal effluent is clear. The patient must be in a sitting position. Although data are limited, whole-bowel irrigation appears to be as effective as other decontamination procedures in volunteer studies. It is most appropriate for those who have ingested foreign bodies, packets of illicit drugs, and agents that are poorly adsorbed by charcoal (e.g., heavy metals). This procedure is contraindicated in patients with bowel obstruction, ileus, hemodynamic instability, and compromised unprotected airways.


InternalMed_Harrison

InternalMed_Harrison. Cathartics are salts (disodium phosphate, magnesium citrate and sulfate, sodium sulfate) or saccharides (mannitol, sorbitol) that historically have been given with activated charcoal to promote the rectal evacuation of gastrointestinal contents. However, no animal, volunteer, or clinical data have ever demonstrated any decontamination benefit from cathartics. Abdominal cramps, nausea, and occasional vomiting are side effects. Complications of repeated dosing include severe electrolyte disturbances and excessive diarrhea. Cathartics are contraindicated in patients who have ingested corrosives and in those with preexisting diarrhea. Magnesium-containing cathartics should not be used in patients with renal failure.


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InternalMed_Harrison. Dilution (i.e., drinking water, another clear liquid, or milk at a volume of 5 mL/kg of body weight) is recommended only after the ingestion of corrosives (acids, alkali). It may increase the dissolution rate (and hence absorption) of capsules, tablets, and other solid ingestants and should not be used in these circumstances. Endoscopic or surgical removal of poisons may be useful in rare situations, such as ingestion of a potentially toxic foreign body that fails to transit the gastrointestinal tract, a potentially lethal amount of a heavy metal (arsenic, iron, mercury, thallium), or agents that have coalesced into gastric concretions or bezoars (heavy metals, lithium, salicylates, sustained-release preparations). Patients who become toxic from cocaine due to its leakage from ingested drug packets require immediate surgical intervention.


InternalMed_Harrison

InternalMed_Harrison. Decontamination of Other Sites Immediate, copious flushing with water, saline, or another available clear, drinkable liquid is the initial treatment for topical exposures (exceptions include alkali metals, calcium oxide, phosphorus). Saline is preferred for eye irrigation. A triple wash (water, soap, water) may be best for dermal decontamination. Inhalational exposures should be treated initially with fresh air or oxygen. The removal of liquids from body cavities such as the vagina or rectum is best accomplished by irrigation. Solids (drug packets, pills) should be removed manually, preferably under direct visualization.


InternalMed_Harrison

InternalMed_Harrison. Although the elimination of most poisons can be accelerated by therapeutic interventions, the pharmacokinetic efficacy (removal of drug at a rate greater than that accomplished by intrinsic elimination) and clinical benefit (shortened duration of toxicity or improved outcome) of such interventions are often more theoretical than proven. Accordingly, the decision to use such measures should be based on the actual or predicted toxicity and the potential efficacy, cost, and risks of therapy.


InternalMed_Harrison

InternalMed_Harrison. Multiple-Dose Activated Charcoal Repetitive oral dosing with charcoal can enhance the elimination of previously absorbed substances by binding them within the gut as they are excreted in the bile, are secreted by gastrointestinal cells, or passively diffuse into the gut lumen (reverse absorption or enterocapillary exsorption). Doses of 0.5–1 g/kg of body weight every 2–4 h, adjusted downward to avoid regurgitation in patients with decreased gastrointestinal motility, are generally recommended. Pharmacokinetic efficacy approaches that of hemodialysis for some agents (e.g., phenobarbital, theophylline). Multiple-dose therapy should be considered only for selected agents (theophylline, phenobarbital, carbamazepine, dapsone, quinine). Complications include intestinal obstruction, pseudo-obstruction, and nonocclusive intestinal infarction in patients with decreased gut motility. Because of electrolyte and fluid shifts, sorbitol and other cathartics are absolutely contraindicated when


InternalMed_Harrison

InternalMed_Harrison. and nonocclusive intestinal infarction in patients with decreased gut motility. Because of electrolyte and fluid shifts, sorbitol and other cathartics are absolutely contraindicated when multiple doses of activated charcoal are administered.


InternalMed_Harrison

InternalMed_Harrison. Urinary Alkalinization Ion trapping via alteration of urine pH may prevent the renal reabsorption of poisons that undergo excretion by glomerular filtration and active tubular secretion. Since membranes are more permeable to non-ionized molecules than to their ionized counterparts, acidic (low-pK a) poisons are ionized and trapped in alkaline urine, whereas basic ones become ionized and trapped in acid urine. Urinary alkalinization (producing a urine pH ≥7.5 and a urine output of 3–6 mL/kg of body weight per hour by the addition of sodium bicarbonate to an IV solution) enhances the excretion of chlorophenoxyacetic acid herbicides, chlorpropamide, diflunisal, fluoride, methotrexate, phenobarbital, sulfonamides, and salicylates. Contraindications include congestive heart failure, renal failure, and cerebral edema. Acid-base, fluid, and electrolyte parameters should be monitored carefully. Although acid diuresis may make theoretical sense for some overdoses (amphetamines), it is never


InternalMed_Harrison

InternalMed_Harrison. and cerebral edema. Acid-base, fluid, and electrolyte parameters should be monitored carefully. Although acid diuresis may make theoretical sense for some overdoses (amphetamines), it is never indicated and is potentially harmful.


InternalMed_Harrison

InternalMed_Harrison. Extracorporeal Removal Hemodialysis, charcoal or resin hemoperfusion, hemofiltration, plasmapheresis, and exchange transfusion are capable of removing any toxin from the bloodstream. Agents most amenable to enhanced elimination by dialysis have low molecular mass (<500 Da), high water solubility, low protein binding, small volumes of distribution (<1 L/kg of body weight), prolonged elimination (long half-life), and high dialysis clearance relative to total-body clearance. Molecular weight, water solubility, and protein binding do not limit the efficacy of the other forms of extracorporeal removal.


InternalMed_Harrison

InternalMed_Harrison. Dialysis should be considered in cases of severe poisoning due to carbamazepine, ethylene glycol, isopropyl alcohol, lithium, methanol, theophylline, salicylates, and valproate. Although hemoperfusion may be more effective in removing some of these poisons, it does not correct associated acid-base and electrolyte abnormalities, and most hospitals no longer have hemoperfusion cartridges readily available. Fortunately, recent advances in hemodialysis technology make it as effective as hemoperfusion for removing poisons such as caffeine, carbamazepine, and theophylline. Both techniques require central venous access and systemic anticoagulation and may result in transient hypotension. Hemoperfusion may also cause hemolysis, hypocalcemia, and thrombocytopenia.


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InternalMed_Harrison. Peritoneal dialysis and exchange transfusion are less effective but 473e-7 may be used when other procedures are unavailable, contraindicated, or technically difficult (e.g., in infants). Exchange transfusion may be indicated in the treatment of severe arsineor sodium chlorate–induced hemolysis, methemoglobinemia, and sulfhemoglobinemia. Although hemofiltration can enhance elimination of aminoglycosides, vancomycin, and metal-chelate complexes, the roles of hemofiltration and plasmapheresis in the treatment of poisoning are not yet defined. Candidates for extracorporeal removal therapies include patients with severe toxicity whose condition deteriorates despite aggressive supportive therapy; those with potentially prolonged, irreversible, or fatal toxicity; those with dangerous blood levels of toxins; those who lack the capacity for self-detoxification because of liver or renal failure; and those with a serious underlying illness or complication that will adversely affect recovery.


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InternalMed_Harrison. Other Techniques The elimination of heavy metals can be enhanced by chelation, and the removal of carbon monoxide can be accelerated by hyperbaric oxygenation.


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InternalMed_Harrison. Antidotes counteract the effects of poisons by neutralizing them (e.g., antibody-antigen reactions, chelation, chemical binding) or by antagonizing their physiologic effects (e.g., activation of opposing nervous system activity, provision of a competitive metabolic or receptor substrate). Poisons or conditions with specific antidotes include acetaminophen, anticholinergic agents, anticoagulants, benzodiazepines, beta blockers, calcium channel blockers, carbon monoxide, cardiac glycosides, cholinergic agents, cyanide, drug-induced dystonic reactions, ethylene glycol, fluoride, heavy metals, hypoglycemic agents, isoniazid, membrane-active agents, methemoglobinemia, opioids, sympathomimetics, and a variety of envenomations. Intravenous lipid emulsion has been shown to be a successful antidote for poisoning from various anesthetics and membrane-active agents (e.g., cyclic antidepressants), but the exact mechanism of benefit is still under investigation. Antidotes can significantly reduce


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InternalMed_Harrison. for poisoning from various anesthetics and membrane-active agents (e.g., cyclic antidepressants), but the exact mechanism of benefit is still under investigation. Antidotes can significantly reduce morbidity and mortality rates but are potentially toxic if used for inappropriate reasons. Since their safe use requires correct identification of a specific poisoning or syndrome, details of antidotal therapy are discussed with the conditions for which they are indicated (Table 473e-4).


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InternalMed_Harrison. Poisoning is a preventable illness. Unfortunately, some adults and children are poison-prone, and recurrences are common. Unintentional polypharmacy poisoning has become especially common among adults with developmental delays, among the growing population of geriatric patients who are prescribed a large number of medications, and among adolescents and young adults experimenting with pharmaceuticals for recreational euphoria. Adults with unintentional exposures should be instructed regarding the safe use of medications and chemicals (according to labeling instructions). Confused patients may need assistance with the administration of their medications. Errors in dosing by health care providers may require educational efforts. Patients should be advised to avoid circumstances that result in chemical exposure or poisoning. Appropriate agencies and health departments should be notified in cases of environmental or workplace exposure. The best approach to young children and patients with


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InternalMed_Harrison. chemical exposure or poisoning. Appropriate agencies and health departments should be notified in cases of environmental or workplace exposure. The best approach to young children and patients with intentional overdose (deliberate self-harm or attempted suicide) is to limit their access to poisons. In households where children live or visit, alcoholic beverages, medications, household products (automotive, cleaning, fuel, pet-care, and toiletry products), inedible plants, and vitamins should be kept out of reach or in locked or child-proof cabinets. Depressed or psychotic patients should undergo psychiatric assessment, disposition, and follow-up. They should be given prescriptions for a limited supply of drugs with a limited number of refills and should be monitored for compliance and response to therapy.


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InternalMed_Harrison. Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments PART 18 Poisoning, Drug Overdose, and Envenomation Sympathomimetics α1-Adrenergic agonists (decongestants): phenylephrine, phenylpropanolamine β2-Adrenergic agonists (bronchodilators): albuterol, terbutaline Nonspecific adrenergic agonists: amphetamines, cocaine, ephedrine Ergot alkaloids Ergotamine, methysergide, bromocriptine, pergolide Methylxanthines Caffeine, theophylline Monoamine oxidase Phenelzine, tranylcypromine, inhibitors selegiline Antihistamines Diphenhydramine, doxylamine, pyrilamine Antipsychotics Chlorpromazine, olanzapine, quetiapine, thioridazine Belladonna alkaloids Atropine, hyoscyamine, scopolamine Stimulation of central and peripheral sympathetic receptors directly or indirectly (by promoting release or inhibiting reuptake of norepinephrine and sometimes dopamine)


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InternalMed_Harrison. Stimulation and inhibition of serotonergic and α-adrenergic receptors; stimulation of dopamine receptors Inhibition of adenosine synthesis and adenosine receptor antagonism; stimulation of epinephrine and norepinephrine release; inhibition of phosphodiesterase resulting in increased intracellular cyclic adenosine and guanosine monophosphate Inhibition of monoamine oxidase resulting in impaired metabolism of endogenous catecholamines and exogenous sympathomimetic agents Inhibition of central and post-ganglionic parasympathetic muscarinic cholinergic receptors. At high doses, amantadine, diphenhydramine, orphenadrine, phenothiazines, and tricyclic antidepressants have additional nonanticholinergic activity (see below). Inhibition of α-adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. Some agents also inhibit sodium, potassium, and calcium channels.


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InternalMed_Harrison. Inhibition of α-adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. Some agents also inhibit sodium, potassium, and calcium channels. Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors Physiologic stimulation (Table 473e-2). Reflex bradycardia can occur with selective α1 agonists; β agonists can cause hypotension and hypokalemia. Physiologic stimulation (Table 473e-2); formication; vasospasm with limb (isolated or generalized), myocardial, and cerebral ischemia progressing to gangrene or infarction. Hypotension, bradycardia, and involuntary movements can also occur. Physiologic stimulation (Table 473e-2); pronounced gastrointestinal symptoms and β agonist effects (see above). Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning.


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InternalMed_Harrison. Physiologic stimulation (Table 473e-2); pronounced gastrointestinal symptoms and β agonist effects (see above). Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. Physiologic stimulation (Table 473e-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction. Physiologic depression (Table 473e-2), miosis, anticholinergic effects (see above), extrapyramidal reactions (see below), tachycardia Physiologic stimulation (Table 473e-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction.


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InternalMed_Harrison. Phentolamine, a nonselective α1-adrenergic receptor antagonist, for severe hypertension due to α1-adrenergic agonists; propranolol, a nonselective β blocker, for hypotension and tachycardia due to β2 agonists; either labetalol, a β blocker with α-blocking activity, or phentolamine with esmolol, metoprolol, or another cardioselective β blocker for hypertension with tachycardia due to non-selective agents (β blockers, if used alone, can exacerbate hypertension and vasospasm due to unopposed α stimulation.); benzodiazepines; propofol Nitroprusside or nitroglycerine for severe vasospasm; prazosin (an α1 blocker), captopril, nifedipine, and cyproheptadine (a serotonin receptor antagonist) for mild-to-moderate limb ischemia; dopamine receptor antagonists (antipsychotics) for hallucinations and movement disorders


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InternalMed_Harrison. Propranolol, a nonselective β blocker, for tachycardia with hypotension; any β blocker for supraventricular or ventricular tachycardia without hypotension; elimination enhanced by multiple-dose charcoal, hemoperfusion, and hemodialysis. Indications for hemoperfusion or hemodialysis include unstable vital signs, seizures, and a theophylline level of 80–100 μg/mL after an acute overdose and 40–60 μg/mL with chronic exposure. Short-acting agents (e.g., nitroprusside, esmolol) for severe hypertension and tachycardia; direct-acting sympathomimetics (e.g., norepinephrine, epinephrine) for hypotension and bradycardia Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and nonanticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias).


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InternalMed_Harrison. Sodium bicarbonate for ventricular tachydysrhythmias associated with QRS prolongation; magnesium, isoproterenol, and overdrive pacing for torsades des pointes. Avoid class IA, IC, and III antiarrhythmics. Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and nonanticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypotension, and ventricular arrhythmias). Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Cyclic antidepres-Amitriptyline, doxepin, sants imipramine Mushrooms and Amanita muscaria and plants A. pantherina, henbane, jimson weed, nightshade α2-Adrenergic Clonidine, guanabenz, agonists tetrahydrozoline and other imidazoline decongestants, tizanidine and other imidazoline muscle relaxants


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InternalMed_Harrison. Antipsychotics Chlorpromazine, clozapine, haloperidol, risperidone, thioridazine β-Adrenergic Cardioselective (β1) blockers: blockers atenolol, esmolol, metoprolol Nonselective (β1 and β2) blockers: nadolol, propranolol, timolol Partial β agonists: acebutolol, pindolol α1 Antagonists: carvedilol, labetalol Membrane-active agents: acebutolol, propranolol, sotalol Calcium channel Diltiazem, nifedipine and blockers other dihydropyridine derivatives, verapamil Cardiac glycosides Digoxin, endogenous cardioactive steroids, foxglove and other plants, toad skin secretions (Bufonidae spp.) Inhibition of α-adrenergic, dopaminergic, GABA-ergic, histaminergic, muscarinic, and serotonergic receptors; inhibition of sodium channels (see membrane-active agents); inhibition of norepinephrine and serotonin reuptake Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors


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InternalMed_Harrison. Inhibition of central and postganglionic parasympathetic muscarinic cholinergic receptors Stimulation of α2-adrenergic receptors leading to inhibition of CNS sympathetic outflow. Activity at nonadrenergic imidazoline binding sites also contributes to CNS effects. Inhibition of α-adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. Some agents also inhibit sodium, potassium, and calcium channels. Inhibition of β-adrenergic receptors (class II antiarrhythmic effect). Some agents have activity at additional receptors or have membrane effects (see below). Inhibition of slow (type L) cardiovascular calcium channels (class IV antiarrhythmic effect) Inhibition of cardiac Na+, K+-ATPase membrane pump Physiologic depression (Table 473e-2), seizures, tachycardia, cardiac conduction delays (increased PR, QRS, JT, and QT intervals; terminal QRS right-axis deviation) with aberrancy and ventricular tachydysrhythmias; anticholinergic toxidrome (see above)


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InternalMed_Harrison. Physiologic stimulation (Table 473e-2); dry skin and mucous membranes, decreased bowel sounds, flushing, and urinary retention; myoclonus and picking activity. Central effects may occur without significant autonomic dysfunction. Physiologic depression (Table 473e-2), miosis. Transient initial hypertension may be seen. Physiologic depression (Table 473e-2), miosis, anticholinergic effects (see above), extrapyramidal reactions (see below), tachycardia. Cardiac conduction delays (increased PR, QRS, JT, and QT intervals) with ventricular tachydysrhythmias, including torsades des pointes, can sometimes develop. Physiologic depression (Table 473e-2), atrioventricular block, hypoglycemia, hyperkalemia, seizures. Partial agonists can cause hypertension and tachycardia. Sotalol can cause increased QT interval and ventricular tachydysrhythmias. Onset may be delayed after sotalol and sustained-release formulation overdose.


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InternalMed_Harrison. Physiologic depression (Table 473e-2), atrioventricular block, organ ischemia and infarction, hyperglycemia, seizures. Hypotension is usually due to decreased vascular resistance rather than to decreased cardiac output. Onset may be delayed for ≥12 h after overdose of sustained-release formulations. Physiologic depression (Table 473e-2); gastrointestinal, psychiatric, and visual symptoms; atrioventricular block with or without concomitant supra-ventricular tachyarrhythmia; ventricular tachyarrhythmias; hyperkalemia in acute poisoning. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning. Hypertonic sodium bicarbonate (or hypertonic saline) for ventricular tachydysrhythmias associated with QRS prolongation. Use of phenytoin is controversial. Avoid class IA, IC, and III antiarrhythmics. IV emulsion therapy may be beneficial in some cases.


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InternalMed_Harrison. Physostigmine, an acetylcholinesterase inhibitor (see below), for delirium, hallucinations, and neuromuscular hyperactivity. Contraindications include asthma and nonanticholinergic cardiovascular toxicity (e.g., cardiac conduction abnormalities, hypo-tension, and ventricular arrhythmias). Sodium bicarbonate for ventricular tachydysrhythmias associated with QRS prolongation; magnesium, isoproterenol, and overdrive pacing for torsades des pointes. Avoid class IA, IC, and III antiarrhythmics. Glucagon for hypotension and symptomatic bradycardia. Atropine, isoproterenol, dopamine, dobutamine, epinephrine, and norepinephrine may sometimes be effective. High-dose insulin (with glucose and potassium to maintain euglycemia and normokalemia), electrical pacing, and mechanical cardiovascular support for refractory cases


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InternalMed_Harrison. Calcium and glucagon for hypotension and symptomatic bradycardia. Dopamine, epinephrine, norepinephrine, atropine, and isoproterenol are less often effective but can be used adjunctively. High-dose insulin (with glucose and potassium to maintain euglycemia and normokalemia), IV lipid emulsion therapy, electrical pacing, and mechanical cardiovascular support for refractory cases Digoxin-specific antibody fragments for hemodynamically compromising dysrhythmias, Mobitz II or third-degree atrioventricular block, hyperkalemia (>5.5 meq/L; in acute poisoning only). Temporizing measures include atropine, dopamine, epinephrine, and external cardiac pacing for bradydysrhythmias and magnesium, lidocaine, or phenytoin, for ventricular tachydysrhythmias. Internal cardiac pacing and cardioversion can increase ventricular irritability and should be reserved for refractory cases. Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments


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InternalMed_Harrison. Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments PART 18 Poisoning, Drug Overdose, and Envenomation Cyclic antidepres-Amitriptyline, doxepin, sants imipramine esterase inhibitors carb, carbaryl, propoxur) and medicinals (neostigmine, physostigmine, tacrine); nerve gases (sarin, soman, tabun, VX); organophosphate insecticides (diazinon, chlorpyrifosethyl, malathion) Muscarinic agonists Bethanechol, mushrooms (Boletus, Clitocybe, Inocybe spp.), pilocarpine Nicotinic agonists Lobeline, nicotine (tobacco) Anticonvulsants Carbamazepine, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, tiagabine, topiramate, valproate, zonisamide Barbiturates Short-acting: butabarbital, pentobarbital, secobarbital Long-acting: phenobarbital, primidone Benzodiazepines Ultrashort-acting: estazolam, midazolam, temazepam, triazolam Short-acting: alprazolam, flunitrazepam, lorazepam, oxazepam


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InternalMed_Harrison. Long-acting: phenobarbital, primidone Benzodiazepines Ultrashort-acting: estazolam, midazolam, temazepam, triazolam Short-acting: alprazolam, flunitrazepam, lorazepam, oxazepam Long-acting: chlordiazepoxide, clonazepam, diazepam, flurazepam Pharmacologically related agents: zaleplon, zolpidem GABA precursors γ-Hydroxybutyrate (sodium oxybate; GHB), γ-butyrolactone (GBL), 1,4-butanediol Muscle relaxants Baclofen, carisoprodol, cyclobenzaprine, etomidate, metaxalone, methocarbamol, orphenadrine, propofol, tizanidine and other imidazoline muscle relaxants Inhibition of α-adrenergic, dopaminergic, GABA-ergic, histaminergic, muscarinic, and serotonergic receptors; inhibition of sodium channels (see membrane-active agents); inhibition of norepinephrine and serotonin reuptake Inhibition of acetylcholinesterase leading to increased synaptic acetylcholine at muscarinic and nicotinic cholinergic receptor sites


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InternalMed_Harrison. Inhibition of acetylcholinesterase leading to increased synaptic acetylcholine at muscarinic and nicotinic cholinergic receptor sites Stimulation of CNS and post-ganglionic parasympathetic cholinergic (muscarinic) receptors Stimulation of preganglionic sympathetic and parasympathetic and striated muscle (neuromuscular junction) cholinergic (nicotine) receptors


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InternalMed_Harrison. Stimulation of preganglionic sympathetic and parasympathetic and striated muscle (neuromuscular junction) cholinergic (nicotine) receptors Potentiation of the inhibitory effects of GABA by binding to the neuronal GABA–A chloride channel receptor complex and increasing the frequency or duration of chloride channel opening in response to GABA stimulation. Baclofen and, to some extent, GHB act at the GABA–B receptor complex. Meprobamate, its metabolite carisoprodol, felbamate, and orphenadrine antagonize NDMA excitatory receptors. Ethosuximide, valproate, and zonisamide decrease conduction through T-type calcium channels. Valproate decreases GABA degradation, and tiagabine blocks GABA reuptake. Carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate, and zonisamide slow the rate of recovery of inactivated sodium channels. Some agents also have α2 agonist, anticholinergic, and sodium channel–blocking activity (see above and below).


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InternalMed_Harrison. Physiologic depression (Table 473e-2), seizures, tachycardia, cardiac conduction delays (increased PR, QRS, JT, and QT intervals; terminal QRS right-axis deviation) with aberrancy and ventricular tachydysrhythmias; anticholinergic toxidrome (see above) Physiologic depression (Table 473e-2). Muscarinic signs and symptoms: seizures, excessive secretions (lacrimation, salivation, bronchorrhea and wheezing, diaphoresis), and increased bowel and bladder activity with nausea, vomiting, diarrhea, abdominal cramps, and incontinence of feces and urine. Nicotinic signs and symptoms: hypertension, tachycardia, muscle cramps, fasciculations, weakness, and paralysis. Death is usually due to respiratory failure. Cholinesterase activity in plasma and red cells is <50% of normal in acetylcholinesterase inhibitor poisoning. Physiologic depression (Table 473e-2), nystagmus. Delayed absorption can occur with carbamazepine, phenytoin, and valproate.


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InternalMed_Harrison. Physiologic depression (Table 473e-2), nystagmus. Delayed absorption can occur with carbamazepine, phenytoin, and valproate. Myoclonus, seizures, hypertension, and tachyarrhythmias can occur with baclofen, carbamazepine, and orphenadrine. Tachyarrhythmias can also occur with chloral hydrate. AGMA, hypernatremia, hyperosmolality, hyperammonemia, chemical hepatitis, and hypoglycemia can be seen in valproate poisoning. Carbamazepine and oxcarbazepine may produce hyponatremia from SIADH. Some agents can cause anticholinergic and sodium channel (membrane) blocking effects (see above and below). Hypertonic sodium bicarbonate (or hypertonic saline) for ventricular tachydysrhythmias associated with QRS prolongation. Use of phenytoin is controversial. Avoid class IA, IC, and III antiarrhythmics. IV emulsion therapy may be beneficial in some cases.


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InternalMed_Harrison. Atropine for muscarinic signs and symptoms; 2-PAM, a cholinesterase reactivator, for nicotinic signs and symptoms due to organophosphates, nerve gases, or an unknown anticholinesterase Benzodiazepines, barbiturates, or propofol for seizures. Hemodialysis and hemoperfusion may be indicated for severe poisoning by some agents (see “Extracorporeal Removal,” in text). See above and below for treatment of anticholinergic and sodium channel (membrane)–blocking effects. Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Other agents Chloral hydrate, ethchlorvynol, glutethimide, meprobamate, methaqualone, methyprylon Cytochrome oxidase Cyanide, hydrogen sulfide inhibitors