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Pharmacology_Katzung. FIGURE 57–3 Chemical structures of several chelators. Ferroxamine (ferrioxamine) without the chelated iron is deferoxamine. It is represented here to show the functional groups; the iron is actually held in a caged system. The structures of the in vivo metal-chelator complexes for dimercaprol, succimer, penicillamine, and unithiol (see text) are not known and may involve the formation of mixed disulfides with amino acids. (Adapted, with permission from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. Originally published by Lange Medical Publications. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.) arsenic-containing warfare agent lewisite. It thus became known as British anti-lewisite, or BAL. Because aqueous solutions of dimercaprol are unstable and oxidize readily, it is dispensed in 10% solution in peanut oil and must be administered by intramuscular injection, which is often painful.


Pharmacology_Katzung

Pharmacology_Katzung. In animal models, dimercaprol prevents and reverses arsenic-induced inhibition of sulfhydryl-containing enzymes and, if given soon after exposure, may protect against the lethal effects of inorganic and organic arsenicals. Human data indicate that it can increase the rate of excretion of arsenic and lead and may offer therapeutic benefit in the treatment of acute intoxication by arsenic, lead, and mercury. Dimercaprol is FDA approved as single-agent treatment of acute poisoning by arsenic and inorganic mercury and for the treatment of severe lead poisoning when used in conjunction with edetate calcium disodium (EDTA; see below). Although studies of its metabolism in humans are limited, intramuscularly administered dimercaprol appears to be readily absorbed, metabolized, and excreted by the kidney within 4–8 hours. Animal models indicate that it may also undergo biliary excretion, but the role of this excretory route in humans and other details of its biotransformation are uncertain.


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Pharmacology_Katzung. When used in therapeutic doses, dimercaprol is associated with a high incidence of adverse effects, including hypertension, tachycardia, nausea, vomiting, lacrimation, salivation, fever (particularly in children), and pain at the injection site. Its use has also been associated with thrombocytopenia and increased prothrombin time—factors that may limit intramuscular injection because of the risk of hematoma formation at the injection site. Despite its protective effects in acutely intoxicated animals, dimercaprol may redistribute arsenic and mercury to the central nervous system, and it is not advocated for treatment of chronic poisoning. Water-soluble analogs of dimercaprol—unithiol and succimer—have higher therapeutic indices and have replaced dimercaprol in many settings. SUCCIMER (DIMERCAPTOSUCCINIC ACID, DMSA)


Pharmacology_Katzung

Pharmacology_Katzung. Succimer is a water-soluble analog of dimercaprol, and like that agent it has been shown in animal studies to prevent and reverse metal-induced inhibition of sulfhydryl-containing enzymes and to protect against the acute lethal effects of arsenic. In humans, treatment with succimer is associated with an increase in urinary lead excretion and a decrease in blood lead concentration. It may also decrease the mercury content of the kidney, a key target organ of inorganic mercury salts. In the USA, succimer is formulated exclusively for oral use, but intravenous formulations have been used successfully elsewhere. It is absorbed rapidly but somewhat variably after oral administration. Peak blood levels of succimer occur at approximately 3 hours. The drug binds in vivo to the amino acid cysteine to form 1:1 and 1:2 mixed disulfides, possibly in the kidney, and it may be these complexes that are the active chelating moieties. Experimental data suggest that multidrug-resistance protein 2


Pharmacology_Katzung

Pharmacology_Katzung. to form 1:1 and 1:2 mixed disulfides, possibly in the kidney, and it may be these complexes that are the active chelating moieties. Experimental data suggest that multidrug-resistance protein 2 (Mrp2), one of a group of transporter proteins involved in the cellular excretion of xenobiotics, facilitates the renal excretion of mercury compounds that are bound to the transformed succimer and to unithiol. The elimination half-time of transformed succimer is approximately 2–4 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Succimer is currently FDA approved for the treatment of children with blood lead concentrations >45 mcg/dL, but it is also commonly used in adults. The typical dosage is 10 mg/kg orally three times a day. Oral administration of succimer is comparable to parenteral EDTA in reducing blood lead concentration and has supplanted EDTA in outpatient treatment of patients who are capable of absorbing the oral drug. However, despite the demonstrated capacity of both succimer and EDTA to enhance lead elimination, their value in reversing established lead toxicity or in otherwise improving therapeutic outcome has yet to be established by a placebo-controlled clinical trial. In a recent study in lead-exposed juvenile rats, high-dose succimer did reduce lead-induced neurocognitive impairment when administered to animals with moderateand high-dose lead exposure. Conversely, when administered to the control group that was not lead exposed, succimer was associated with a decrement in neurocognitive


Pharmacology_Katzung

Pharmacology_Katzung. to animals with moderateand high-dose lead exposure. Conversely, when administered to the control group that was not lead exposed, succimer was associated with a decrement in neurocognitive performance. Based on its protective effects against arsenic in animals and its ability to mobilize mercury from the kidney, succimer has also been used in the treatment of arsenic and mercury poisoning.


Pharmacology_Katzung

Pharmacology_Katzung. In limited clinical trials, succimer has been well tolerated. It has a negligible impact on body stores of calcium, iron, and magnesium. It induces a mild increase in urinary excretion of zinc and, less consistently, copper. This effect on trace metal balance has not been associated with overt adverse effects, but its longterm impact on neurodevelopment is uncertain. Gastrointestinal disturbances, including anorexia, nausea, vomiting, and diarrhea, are the most common side effects, occurring in <10% of patients. Rashes, sometimes requiring discontinuation of the medication, have been reported in <5% of patients. Mild, reversible increases in liver aminotransferases have been noted in <5% of patients, and isolated cases of mild to moderate neutropenia have been reported. EDETATE CALCIUM DISODIUM (ETHYLENEDIAMINETETRAACETIC ACID, EDTA)


Pharmacology_Katzung

Pharmacology_Katzung. EDETATE CALCIUM DISODIUM (ETHYLENEDIAMINETETRAACETIC ACID, EDTA) Ethylenediaminetetraacetic acid (Figure 57–2) is an efficient chelator of many divalent and trivalent metals in vitro. To prevent potentially life-threatening depletion of calcium, treatment of metal intoxication should only be performed with the calcium disodium salt form of EDTA (edetate calcium disodium). EDTA penetrates cell membranes relatively poorly and therefore chelates extracellular metal ions much more effectively than intracellular ions.


Pharmacology_Katzung

Pharmacology_Katzung. EDTA penetrates cell membranes relatively poorly and therefore chelates extracellular metal ions much more effectively than intracellular ions. The highly polar ionic character of EDTA limits its oral absorption. Moreover, oral administration may increase lead absorption from the gut. Consequently, EDTA should be administered by intravenous infusion. In patients with normal renal function, EDTA is rapidly excreted by glomerular filtration, with 50% of an injected dose appearing in the urine within 1 hour. EDTA mobilizes lead from soft tissues, causing a marked increase in urinary lead excretion and a corresponding decline in blood lead concentration. In patients with renal insufficiency, excretion of the drug—and its metal-mobilizing effects—may be delayed.


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Pharmacology_Katzung. Edetate calcium disodium is indicated chiefly for the chelation of lead, but it may also have usefulness in poisoning by zinc, manganese, and certain heavy radionuclides. A recent randomized, double-blind, placebo-controlled prospective trial of edetate disodium (not edetate calcium disodium) observed a significant decrease in cardiovascular events in a subgroup consisting of diabetic patients with a prior history of myocardial infarction. Further study is indicated to replicate the findings and explore potential mechanisms of benefit.


Pharmacology_Katzung

Pharmacology_Katzung. Because the drug and the mobilized metals are excreted via the urine, the drug is relatively contraindicated in anuric patients. In such instances, the use of low doses of EDTA in combination with high-flux hemodialysis or hemofiltration has been described. Nephrotoxicity from EDTA has been reported, but in most cases can be prevented by maintenance of adequate urine flow, avoidance of excessive doses, and limitation of a treatment course to 5 or fewer consecutive days. EDTA may result in temporary zinc depletion that is of uncertain clinical significance. Analogs of EDTA, the calcium and zinc disodium salts of DTPA, pentetate, have been used for removal (“decorporation”) of certain transuranic, rare earth, and transition metal radioisotopes, and in 2004 were approved by the FDA for treatment of contamination with plutonium, americium, and curium. UNITHIOL (DIMERCAPTOPROPANESULFONIC ACID, DMPS)


Pharmacology_Katzung

Pharmacology_Katzung. Unithiol, a dimercapto chelating agent that is a water-soluble analog of dimercaprol, has been available in the official formularies of Russia and other former Soviet countries since 1958 and in Germany since 1976. It has been legally available from compounding pharmacies in the USA since 1999. Unithiol can be administered orally and intravenously. Bioavailability by the oral route is approximately 50%, with peak blood levels occurring in approximately 4 hours. Over 80% of an intravenous dose is excreted in the urine, mainly as cyclic DMPS sulfides. The elimination half-time of total unithiol (parent drug and its transformation products) is approximately 20 hours. Unithiol exhibits protective effects against the toxic action of mercury and arsenic in animal models, and it increases the excretion of mercury, arsenic, and lead in humans. Animal studies and a few case reports suggest that unithiol may also have usefulness in the treatment of poisoning by bismuth compounds.


Pharmacology_Katzung

Pharmacology_Katzung. Unithiol has no FDA-approved indications, but experimental studies and its pharmacologic and pharmacodynamic profile suggest that intravenous unithiol offers advantages over intramuscular dimercaprol or oral succimer in the initial treatment of severe acute poisoning by inorganic mercury or arsenic. Aqueous preparations of unithiol (usually 50 mg/mL in sterile water) can be administered at a dosage of 3–5 mg/kg every 4 hours by slow intravenous infusion over 20 minutes. If a few days of treatment are accompanied by stabilization of the patient’s cardiovascular and gastrointestinal status, it may be possible to change to oral administration of 4–8 mg/kg every 6–8 hours. Oral unithiol may also be considered as an alternative to oral succimer in the treatment of lead intoxication. Intravenous unithiol in conjunction with high flux hemodialysis or hemodiafiltration may be useful in the treatment of patients with anuric renal failure caused by mercury salts and bismuth.


Pharmacology_Katzung

Pharmacology_Katzung. Unithiol has been reported to have a low overall incidence of adverse effects (<4%). Self-limited dermatologic reactions (drug exanthems or urticaria) are the most commonly reported adverse effects, although isolated cases of major allergic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported. Because rapid intravenous infusion may cause vasodilation and hypotension, unithiol should be infused slowly over 15–20 minutes. Penicillamine (Figure 57–3) is a white, crystalline, water-soluble derivative of penicillin. d-Penicillamine is less toxic than the l-isomer and consequently is the preferred therapeutic form. Penicillamine is readily absorbed from the gut and is resistant to metabolic degradation.


Pharmacology_Katzung

Pharmacology_Katzung. Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson’s disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (see Chapter 36). Its ability to increase urinary excretion of lead and mercury had occasioned its use in outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower adverse-effect profile, has generally replaced penicillamine for these purposes.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects have been seen in up to one third of patients receiving penicillamine. Hypersensitivity reactions include rash, pruritus, and drug fever, and the drug should be used with extreme caution, if at all, in patients with a history of penicillin allergy. Nephrotoxicity with proteinuria has also been reported, and protracted use of the drug may result in renal insufficiency. Pancytopenia has been associated with prolonged drug intake. Pyridoxine deficiency is a frequent toxic effect of other forms of the drug but is rarely seen with the d isomer. An acetylated derivative, N-acetylpenicillamine, has been used experimentally in mercury poisoning and may have superior metal-mobilizing capacity, but it is not commercially available.


Pharmacology_Katzung

Pharmacology_Katzung. Deferoxamine is isolated from Streptomyces pilosus. It binds iron avidly (Figure 57–3) but binds essential trace metals poorly. Furthermore, though competing for loosely bound iron in iron-carrying proteins (hemosiderin and ferritin), it fails to compete for biologically chelated iron, as in microsomal and mitochondrial cytochromes and hemoproteins. Consequently, it is the parenteral chelator of choice for iron poisoning (see Chapters 33 and 58). Deferoxamine plus hemodialysis may also be useful in the treatment of aluminum toxicity in renal failure. Deferoxamine is poorly absorbed when administered orally and may increase iron absorption when given by this route. It should therefore be administered intramuscularly or, preferably, intravenously. It is believed to be metabolized, but the pathways are unknown. The iron-chelator complex is excreted in the urine, often turning the urine an orange-red color.


Pharmacology_Katzung

Pharmacology_Katzung. Rapid intravenous administration may result in hypotension. Adverse idiosyncratic responses such as flushing, abdominal discomfort, and rash have also been observed. Pulmonary complications (eg, acute respiratory distress syndrome) have been reported in some patients undergoing deferoxamine infusions lasting longer than 24 hours, and neurotoxicity and increased susceptibility to certain infections (eg, with Yersinia enterocolitica) have been described after long-term therapy of iron overload conditions (eg, thalassemia major).


Pharmacology_Katzung

Pharmacology_Katzung. Deferasirox is a tridentate chelator with a high affinity for iron and low affinity for other metals, eg, zinc and copper. It is orally active and well absorbed. In the circulation, it binds iron, and the complex is excreted in the bile. Deferasirox was approved by the FDA in 2005 for the oral treatment of iron overload caused by blood transfusions, a problem in the treatment of thalassemia and myelodysplastic syndrome. More than 5 years of clinical experience suggest that daily long-term usage is generally well tolerated, with the most common adverse effects consisting of mild to moderate gastrointestinal disturbances and skin rash. Monitoring of liver and renal function has been advised because renal and liver impairment and failure associated with deferasirox have been reported during treatment of older adults with myelodysplastic syndromes.


Pharmacology_Katzung

Pharmacology_Katzung. Deferiprone, a bidentate iron chelator cleared predominantly via the kidney, was approved by the FDA in 2011 as a second-line oral chelator for patients with transfusional iron overload due to thalassemia. Compared to deferasirox, deferiprone appears to be relatively more efficient in decreasing cardiac iron but less efficient in decreasing hepatic iron. Because neutropenia has occurred in 5–10% of patients, with agranulocytosis in approximately 1%, regular hematologic monitoring is recommended. Magnetic resonance imaging has been increasingly used to evaluate cardiac and hepatic iron burden and to guide iron chelation therapy. Regimens that combine iron-chelating agents have been used in cases when monotherapy has yielded suboptimal results.


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Pharmacology_Katzung. Ferric hexacyanoferrate (insoluble Prussian blue) is a hydrated crystalline compound in which Fe2+ and Fe3+ atoms are coordinated with cyanide groups in a cubic lattice structure. Although used as a dark blue commercial pigment for nearly 300 years, it was only three decades ago that its potential usefulness as a pharmaceutical chelator was recognized. Primarily by ion exchange, and secondarily by mechanical trapping or adsorption, the compound has high affinity for certain univalent cations, particularly cesium and thallium. Used as an oral drug, insoluble Prussian blue undergoes minimal gastrointestinal absorption (<1%). Because the complexes it forms with cesium or thallium are nonabsorbable, oral administration of the chelator diminishes intestinal absorption or interrupts enterohepatic and enteroenteric circulation of these cations, thereby accelerating their elimination in the feces. In clinical case series, the use of Prussian blue has been associated with a decline in the


Pharmacology_Katzung

Pharmacology_Katzung. and enteroenteric circulation of these cations, thereby accelerating their elimination in the feces. In clinical case series, the use of Prussian blue has been associated with a decline in the biologic half-life (ie, in vivo retention) of radioactive cesium and thallium.


Pharmacology_Katzung

Pharmacology_Katzung. In 2003, the FDA approved Prussian blue for the treatment of contamination with radioactive cesium (137Cs) and intoxication with thallium salts. Approval was prompted by concern over potential widespread human contamination with radioactive cesium caused by terrorist use of a radioactive dispersal device (“dirty bomb”). The drug is part of the Strategic National Stockpile of pharmaceuticals and medical material maintained by the CDC (https://www.cdc.gov/phpr/stockpile/). (Note: Although soluble forms of Prussian blue, such as potassium ferric hexacyanoferrate, may have better utility in thallium poisoning, only the insoluble form is currently available as a pharmaceutical.)


Pharmacology_Katzung

Pharmacology_Katzung. After exposure to 137Cs or thallium salts, the approved adult dosage of Prussian blue is 3 g orally three times a day; the corresponding pediatric dosage (2–12 years of age) is 1 g orally three times a day. Serial monitoring of urine and fecal radioactivity (137Cs) and urinary thallium concentrations can guide the recommended duration of therapy. Adjunctive supportive care for possible acute radiation illness (137Cs) or systemic thallium toxicity should be instituted as needed. Prussian blue has not been associated with significant adverse effects. Constipation, which may occur in some cases, should be treated with laxatives or increased dietary fiber. GENERIC NAME AVAILABLE AS Deferasirox Exjade, Jadenu Deferiprone Ferriprox Deferoxamine Generic, Desferal Penicillamine Cuprimine, Depen Succimer Chemet, Succicaptal (in Europe)


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Pharmacology_Katzung. GENERIC NAME AVAILABLE AS Deferasirox Exjade, Jadenu Deferiprone Ferriprox Deferoxamine Generic, Desferal Penicillamine Cuprimine, Depen Succimer Chemet, Succicaptal (in Europe) Advisory Committee on Childhood Lead Poisoning Prevention of the Centers for Disease Control and Prevention. Low Level Lead Exposure Harms Children: A Renewed Call for Primary Prevention. CDC: Atlanta, GA. 2012. http:// www.cdc.gov/nceh/lead/ACCLPP/Final_Document_030712.pdf. Brubaker CJ et al: The influence of age of lead exposure on adult gray matter volume. Neurotoxicology 2010;31:259. Burns MS et al: Implications of the new Centers for Disease Control and Prevention blood lead reference value. Am J Publ Health 2014;104:e27. Carlisle JC et al: A blood lead benchmark for assessing risks from childhood lead exposure. J Environ Sci Health Part A 2009;44:1200.


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Pharmacology_Katzung. Carlisle JC et al: A blood lead benchmark for assessing risks from childhood lead exposure. J Environ Sci Health Part A 2009;44:1200. Centers for Disease Control and Prevention (CDC): Guidelines for the Identification and Management of Lead Exposure in Pregnant and Lactating Women. CDC, 2010. http://www.cdc.gov/nceh/lead/publications/LeadandPregnancy2010.pdf. Environmental Protection Agency. Integrated Science Assessment for Lead. EPA: Research Triangle Park, NC. 2013. http://epa.gov/ncea/isa/lead.htm. Kosnett MJ et al: Recommendations for medical management of adult lead exposure. Environ Health Perspect 2007;115:463. Lanphear BP et al: Low-level environmental lead exposure and children’s intellectual development: An international pooled analysis. Environ Health Perspect 2005;113:894.


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Pharmacology_Katzung. Lanphear BP et al: Low-level environmental lead exposure and children’s intellectual development: An international pooled analysis. Environ Health Perspect 2005;113:894. Weisskopf MG et al: Biased exposure-health effect estimates from selection in cohort studies: are environmental studies at particular risk? Environ Health Perspect 2015;123:1113. [Note: Study reports relationship between bone lead concentration and cardiovascular mortality.] Antonelli R et al: AS3MT, GSTO, and PNP polymorphisms: Impact on arsenic methylation and implications for disease susceptibility. Environ Res 2014;132:156. Caldwell KL et al: Levels of urinary total and speciated arsenic in the US population: National Health and Nutrition Examination Survey 2003–2004. J Exp Sci Environ Epid 2009;19:59. James KA et al: Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 2015;123:128.


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Pharmacology_Katzung. James KA et al: Association between lifetime exposure to inorganic arsenic in drinking water and coronary heart disease in Colorado residents. Environ Health Perspect 2015;123:128. National Research Council: Critical Aspects of EPA’s IRIS Assessment of Inorganic Arsenic: Interim Report. Washington, DC: The National Academies Press, 2013. Naujokas MF et al: The broad scope of health effects from chronic arsenic exposure: Update on a worldwide public health problem. Environ Health Perspect 2013;121:295. Parvez F et al: A prospective study of respiratory symptoms associated with chronic arsenic exposure in Bangladesh: Findings from the Health Effects of Arsenic Longitudinal Study (HEALS). Thorax 2010;65:528. Quansah R et al: Association of arsenic with adverse pregnancy outcomes/infant mortality: A systematic review and meta-analysis. Environ Health Perspect 2015;123:412.


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Pharmacology_Katzung. Quansah R et al: Association of arsenic with adverse pregnancy outcomes/infant mortality: A systematic review and meta-analysis. Environ Health Perspect 2015;123:412. Agency for Toxic Substances and Disease Registry (ATSDR): Action Levels for Elemental Mercury Spills. ATSDR: Atlanta, GA 2012. http://www .atsdr.cdc.gov/emergency_response/action_levels_for_elemental_mercury_ spills_2012.pdf. Al-Saleh I: Potential health consequences of applying mercury-containing skin-lightening creams during pregnancy and lactation periods Int J Hyg Environ Health 2016;219:468. Beasley DMG et al: Full recovery from a potentially lethal dose of mercuric chloride. J Med Toxicol 2014;10:40. Bellinger DC et al: Dental amalgam restorations and children’s neuropsychological function: The New England Children’s Amalgam Trial. Environ Health Perspect 2007;115:440.


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Pharmacology_Katzung. Bellinger DC et al: Dental amalgam restorations and children’s neuropsychological function: The New England Children’s Amalgam Trial. Environ Health Perspect 2007;115:440. Environmental Protection Agency: What you need to know about mercury in fish and shellfish. http://water.epa.gov/scitech/swguidance/fishshellfish/outreach/advice_index.cfm. Franzblau A et al: Low-level mercury exposure and peripheral nerve function. Neurotoxicology 2012;33:299. Grandjean P et al: Adverse effects of methylmercury: Environmental health research implications. Environ Health Perspect 2010;118:1137. Hertz-Picciotto I et al: Blood mercury concentrations in CHARGE study children with and without autism. Environ Health Perspect 2010;118:161. Mortensen ME: Total and methyl mercury in whole blood measured for the first time in the U.S. population: NHANES 2011-2012. Environ Res 2014;134:257.


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Pharmacology_Katzung. Mortensen ME: Total and methyl mercury in whole blood measured for the first time in the U.S. population: NHANES 2011-2012. Environ Res 2014;134:257. Yorifuji T et al: Long-term exposure to methylmercury and neurologic signs in Minamata and neighboring communities. Epidemiology 2008;19:3. Bradberry S, Vale A: A comparison of sodium calcium edetate (edetate calcium disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning. Clin Toxicol 2009;47:841. Dargan PI et al: Case report: Severe mercuric sulphate poisoning treated with 2,3-dimercaptopropane-1-sulphonate and haemodiafiltration. Crit Care 2003;7:R1. Escolar E et al: The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes 2014;7(1):15. Kosnett MJ: Chelation for heavy metals (arsenic, lead, and mercury): Protective or perilous? Clin Pharmacol Ther 2010;88:412.


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Pharmacology_Katzung. Kosnett MJ: Chelation for heavy metals (arsenic, lead, and mercury): Protective or perilous? Clin Pharmacol Ther 2010;88:412. Kosnett MJ: The role of chelation in the treatment of arsenic and mercury poisoning. J Med Toxicol 2013;9:347. Sheth S: Iron chelation: An update. Curr Opin Hematol 2014;21:179-185. Thompson DF, Called ED: Soluble or insoluble Prussian blue for radiocesium and thallium poisoning? Ann Pharmacother 2004;38:1509. Thurtle N et al: Description of 3,180 courses of chelation with dimercaptosuccinic acid in children ≤ 5 y with severe lead poisoning in Zamfara, Northern Nigeria: a retrospective analysis of programme data. PLOS Med 2014;11(10):e1001739.


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Pharmacology_Katzung. Bacterial food poisoning is the most common cause of gas-trointestinal signs and symptom appearing in a group of indi-viduals within several hours of a common meal. Consumption of food contaminated with preformed bacterial toxins such as Staphylococcus or Bacillus cereus toxins can result in vomiting after an incubation interval as short as 1–2 hours. However, the onset of vomiting in some individuals within 15 minutes and the progression to hypotension and metabolic acidosis in several individuals are not typical for bacterial food poisoning and are more suggestive of intoxication by certain toxic chemi-cals or drugs, including inorganic arsenic and mercury salts (eg, sodium arsenite or mercuric chloride). The absence of hematemesis, bloody diarrhea, or renal insufficiency lowered the likelihood that inorganic mercury was responsible. An epidemiologic investigation subsequently revealed that all affected individuals had consumed the deliberately adulter-ated coffee, which contained


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Pharmacology_Katzung. that inorganic mercury was responsible. An epidemiologic investigation subsequently revealed that all affected individuals had consumed the deliberately adulter-ated coffee, which contained 6300 ppm of inorganic arsenic. Analysis of urine for arsenic and mercury and stool and emesis for bacterial pathogens would be reasonable initial diagnostic tests. Pending test results, prompt empiric treat-ment of this constellation of findings with the chelating agents unithiol, succimer, or dimercaprol would be appropriate. [Based on an actual incident, see: Gensheimer KF et al: Arse-nic poisoning caused by intentional contamination of coffee at a church gathering: An epidemiological approach to a forensic investigation. J Forensic Sci 2010;55:1116].


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Pharmacology_Katzung. Management of the Poisoned Patient Kent R. Olson, MD A 62-year-old woman with a history of depression is found in her apartment in a lethargic state. An empty bottle of bupro-pion is on the bedside table. In the emergency department, she is unresponsive to verbal and painful stimuli. She has a brief generalized seizure, followed by a respiratory arrest. The emergency physician performs endotracheal intubation and administers a drug intravenously, followed by another sub-stance via a nasogastric tube. The patient is admitted to the intensive care unit for continued supportive care and recovers the next morning. What drug might be used intravenously to prevent further seizures? What substance is commonly used to adsorb drugs still present in the gastrointestinal tract?


Pharmacology_Katzung

Pharmacology_Katzung. Over 1 million cases of acute poisoning occur in the USA each year, although only a small number are fatal. Most deaths are due to intentional suicidal overdose by an adolescent or adult. Childhood deaths due to accidental ingestion of a drug or toxic household product have been markedly reduced in the last 50 years as a result of safety packaging and effective poisoning prevention education. Even with a serious exposure, poisoning is rarely fatal if the victim receives prompt medical attention and good supportive care. Careful management of respiratory failure, hypotension, seizures, and thermoregulatory disturbances has resulted in improved survival of patients who reach the hospital alive. This chapter reviews the basic principles of poisoning, initial management, and specialized treatment of poisoning, including methods of increasing the elimination of drugs and toxins.


Pharmacology_Katzung

Pharmacology_Katzung. This chapter reviews the basic principles of poisoning, initial management, and specialized treatment of poisoning, including methods of increasing the elimination of drugs and toxins. The term toxicokinetics denotes the absorption, distribution, excretion, and metabolism of toxins, toxic doses of therapeutic agents, and their metabolites. The term toxicodynamics is used to denote the injurious effects of these substances on body functions. Although many similarities exist between the pharmacokinetics and toxicokinetics of most substances, there are also important differences. The same caution applies to pharmacodynamics and toxicodynamics. Volume of Distribution


Pharmacology_Katzung

Pharmacology_Katzung. Volume of Distribution The volume of distribution (Vd) is defined as the apparent volume into which a substance is distributed in the body (see Chapter 3). A large Vd implies that the drug is not readily accessible to measures aimed at purifying the blood, such as hemodialysis. Examples of drugs with large volumes of distribution (>5 L/kg) include antidepressants, antipsychotics, antimalarials, opioids, propranolol, and verapamil. Drugs with a relatively small Vd (<1 L/kg) include salicylate, ethanol, phenobarbital, lithium, valproic acid, and phenytoin (see Table 3–1).


Pharmacology_Katzung

Pharmacology_Katzung. Clearance is a measure of the volume of plasma that is cleared of drug per unit time (see Chapter 3). The total clearance for most drugs is the sum of clearances via excretion by the kidneys and metabolism by the liver. In planning a detoxification strategy, it is important to know the contribution of each organ to total clearance. For example, if a drug is 95% cleared by liver metabolism and only 5% cleared by renal excretion, even a dramatic increase in urinary concentration of the drug will have little effect on overall elimination.


Pharmacology_Katzung

Pharmacology_Katzung. Overdosage of a drug can alter the usual pharmacokinetic processes, and this must be considered when applying kinetics to poisoned patients. For example, dissolution of tablets or gastric emptying time may be slowed so that absorption and peak toxic effects are delayed. Drugs may injure the epithelial barrier of the gastrointestinal tract and thereby increase absorption. If the capacity of the liver to metabolize a drug is exceeded, the first-pass effect will be reduced and more drug will be delivered to the circulation. With a dramatic increase in the concentration of drug in the blood, protein-binding capacity may be exceeded, resulting in an increased fraction of free drug and greater toxic effect. At normal dosage, most drugs are eliminated at a rate proportional to the plasma concentration (first-order kinetics). If the plasma concentration is very high and normal metabolism is saturated, the rate of elimination may become fixed (zero-order kinetics). This change in kinetics may


Pharmacology_Katzung

Pharmacology_Katzung. (first-order kinetics). If the plasma concentration is very high and normal metabolism is saturated, the rate of elimination may become fixed (zero-order kinetics). This change in kinetics may markedly prolong the apparent serum half-life and increase toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The general dose-response principles described in Chapter 2 are relevant when estimating the potential severity of an intoxication. When considering quantal dose-response data, both the therapeutic index and the overlap of therapeutic and toxic response curves must be considered. For instance, two drugs may have the same therapeutic index but unequal safe dosing ranges if the slopes of their dose-response curves are not the same. For some drugs, eg, sedative-hypnotics, the major toxic effect is a direct extension of the therapeutic action, as shown by their graded dose-response curve (see Figure 22–1). In the case of a drug with a linear dose-response curve (drug A), lethal effects may occur at 10 times the normal therapeutic dose. In contrast, a drug with a curve that reaches a plateau (drug B) may not be lethal at 100 times the normal dose.


Pharmacology_Katzung

Pharmacology_Katzung. For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures; the body’s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, β blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and that of any other drugs that may be given. HOW DOES THE POISONED PATIENT DIE?


Pharmacology_Katzung

Pharmacology_Katzung. HOW DOES THE POISONED PATIENT DIE? An understanding of common mechanisms of death due to poisoning can help prepare the caregiver to treat patients effectively. Many toxins depress the central nervous system (CNS), resulting in obtundation or coma. Comatose patients frequently lose their airway protective reflexes and their respiratory drive. Thus, they may die as a result of airway obstruction by the flaccid tongue, aspiration of gastric contents into the tracheobronchial tree, or respiratory arrest. These are the most common causes of death due to overdoses of narcotics and sedative-hypnotic drugs (eg, barbiturates and alcohol).


Pharmacology_Katzung

Pharmacology_Katzung. Cardiovascular toxicity is also frequently encountered in poisoning. Hypotension may be due to depression of cardiac contractility; hypovolemia resulting from vomiting, diarrhea, or fluid sequestration; peripheral vascular collapse due to blockade of α-adrenoceptor-mediated vascular tone; or cardiac arrhythmias. Hypothermia or hyperthermia due to exposure as well as the temperature-dysregulating effects of many drugs can also produce hypotension. Lethal arrhythmias such as ventricular tachycardia and fibrillation can occur with overdoses of many cardioactive drugs such as ephedrine, amphetamines, cocaine, digitalis, and theophylline; and drugs not usually considered cardioactive, such as tricyclic antidepressants, antihistamines, and some opioid analogs.


Pharmacology_Katzung

Pharmacology_Katzung. Cellular hypoxia may occur despite adequate ventilation and oxygen administration when poisoning is due to cyanide, hydrogen sulfide, carbon monoxide, and other poisons that interfere with transport or utilization of oxygen. Such patients may not be cyanotic, but cellular hypoxia is evident by the development of tachycardia, hypotension, severe lactic acidosis, and signs of ischemia on the electrocardiogram. Seizures, muscular hyperactivity, and rigidity may result in death. Seizures may cause pulmonary aspiration, hypoxia, and brain damage. Hyperthermia may result from sustained muscular hyperactivity and can lead to muscle breakdown and myoglobinuria, renal failure, lactic acidosis, and hyperkalemia. Drugs and poisons that often cause seizures include antidepressants, isoniazid (INH), diphenhydramine, cocaine, and amphetamines.


Pharmacology_Katzung

Pharmacology_Katzung. Other organ system damage may occur after poisoning and is sometimes delayed in onset. Paraquat attacks lung tissue, resulting in pulmonary fibrosis, beginning several days after ingestion. Massive hepatic necrosis due to poisoning by acetaminophen or certain mushrooms results in hepatic encephalopathy and death 48–72 hours or longer after ingestion. Finally, some patients may die before hospitalization because the behavioral effects of the ingested drug may result in traumatic injury. Intoxication with alcohol and other sedative-hypnotic drugs is a common contributing factor to motor vehicle accidents. Patients under the influence of hallucinogens such as phencyclidine (PCP) or lysergic acid diethylamide (LSD) may suffer trauma when they become combative or fall from a height.


Pharmacology_Katzung

Pharmacology_Katzung. The initial management of a patient with coma, seizures, or otherwise altered mental status should follow the same approach regardless of the poison involved: supportive measures are the basics (“ABCDs”) of poisoning treatment. First, the airway should be cleared of vomitus or any other obstruction and an oral airway or endotracheal tube inserted if needed. For many patients, simple positioning in the lateral, left-side-down position is sufficient to move the flaccid tongue out of the airway. Breathing should be assessed by observation and pulse oximetry and, if in doubt, by measuring arterial blood gases. Patients with respiratory insufficiency should be intubated and mechanically ventilated. The circulation should be assessed by continuous monitoring of pulse rate, blood pressure, urinary output, and evaluation of peripheral perfusion. An intravenous line should be placed and blood drawn for serum glucose and other routine determinations.


Pharmacology_Katzung

Pharmacology_Katzung. At this point, every patient with altered mental status should receive a challenge with concentrated dextrose, unless a rapid bedside blood glucose test demonstrates that the patient is not hypoglycemic. Adults are given 25 g (50 mL of 50% dextrose solution) intravenously, children 0.5 g/kg (2 mL/kg of 25% dextrose). Hypoglycemic patients may appear to be intoxicated, and there is no rapid and reliable way to distinguish them from poisoned patients. Alcoholic or malnourished patients should also receive 100 mg of thiamine intramuscularly or in the intravenous infusion solution at this time to prevent Wernicke’s syndrome.


Pharmacology_Katzung

Pharmacology_Katzung. The opioid antagonist naloxone may be given in a dose of 0.4–2 mg intravenously. Naloxone reverses respiratory and CNS depression due to all varieties of opioid drugs (see Chapter 31). It is useful to remember that these drugs cause death primarily by respiratory depression; therefore, if airway and breathing assistance have already been instituted, naloxone may not be necessary. Larger doses of naloxone may be needed for patients with overdose involving propoxyphene, codeine, and some other opioids. The benzodiazepine antagonist flumazenil (see Chapter 22) may be of value in patients with suspected benzodiazepine overdose, but it should not be used if there is a history of tricyclic antidepressant overdose or a seizure disorder, as it can induce convulsions in such patients.


Pharmacology_Katzung

Pharmacology_Katzung. Once the essential initial ABCD interventions have been instituted, one can begin a more detailed evaluation to make a specific diagnosis. This includes gathering any available history and performing a toxicologically oriented physical examination. Other causes of coma or seizures such as head trauma, meningitis, or metabolic abnormalities should be sought and treated. Some common intoxications are described under Common Toxic Syndromes. A. History Oral statements about the amount and even the type of drug ingested in toxic emergencies may be unreliable. Even so, family members, police, and fire department or paramedical personnel should be asked to describe the environment in which the toxic emergency occurred and should bring to the emergency department any syringes, empty bottles, household products, or overthe-counter medications in the immediate vicinity of the possibly poisoned patient. B. Physical Examination


Pharmacology_Katzung

Pharmacology_Katzung. B. Physical Examination A brief examination should be performed, emphasizing those areas most likely to give clues to the toxicologic diagnosis. These include vital signs, eyes and mouth, skin, abdomen, and nervous system. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Vital signs—Careful evaluation of vital signs (blood pressure, pulse, respirations, and temperature) is essential in all toxicologic emergencies. Hypertension and tachycardia are typical with amphetamines, cocaine, and antimuscarinic (anticholinergic) drugs. Hypotension and bradycardia are characteristic features of overdose with calcium channel blockers, β blockers, clonidine, and sedative hypnotics. Hypotension with tachycardia is common with tricyclic antidepressants, trazodone, quetiapine, vasodilators, and β agonists. Rapid respirations are typical of salicylates, carbon monoxide, and other toxins that produce metabolic acidosis or cellular asphyxia. Hyperthermia may be associated with sympathomimetics, anticholinergics, salicylates, and drugs producing seizures or muscular rigidity. Hypothermia can be caused by any CNS-depressant drug, especially when accompanied by exposure to a cold environment. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Eyes—The eyes are a valuable source of toxicologic information. Constriction of the pupils (miosis) is typical of opioids, clonidine, phenothiazines, and cholinesterase inhibitors (eg, organophosphate insecticides), and deep coma due to sedative drugs. Dilation of the pupils (mydriasis) is common with amphetamines, cocaine, LSD, and atropine and other anticholinergic drugs. Horizontal nystagmus is characteristic of intoxication with phenytoin, alcohol, barbiturates, and other sedative drugs. The presence of both vertical and horizontal nystagmus is strongly suggestive of phencyclidine poisoning. Ptosis and ophthalmoplegia are characteristic features of botulism. 3. Mouth—The mouth may show signs of burns due to corrosive substances, or soot from smoke inhalation. Typical odors of alcohol, hydrocarbon solvents, or ammonia may be noted. Poisoning due to cyanide can be recognized by some examiners as an odor like bitter almonds. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Skin—The skin often appears flushed, hot, and dry in poisoning with atropine and other antimuscarinics. Excessive sweating occurs with organophosphates, nicotine, and sympathomimetic drugs. Cyanosis may be caused by hypoxemia or by methemoglobinemia. Icterus may suggest hepatic necrosis due to acetaminophen or Amanita phalloides mushroom poisoning. 5. Abdomen—Abdominal examination may reveal ileus, which is typical of poisoning with antimuscarinic, opioid, and sedative drugs. Hyperactive bowel sounds, abdominal cramping, and diarrhea are common in poisoning with organophosphates, iron, arsenic, theophylline, A phalloides, and A muscaria. 6.


Pharmacology_Katzung

Pharmacology_Katzung. Nervous system—A careful neurologic examination is essential. Focal seizures or motor deficits suggest a structural lesion (eg, intracranial hemorrhage due to trauma) rather than toxic or metabolic encephalopathy. Nystagmus, dysarthria, and ataxia are typical of phenytoin, carbamazepine, alcohol, and other sedative intoxication. Twitching and muscular hyperactivity are common with atropine and other anticholinergic agents, and cocaine and other sympathomimetic drugs. Muscular rigidity can be caused by haloperidol and other antipsychotic agents, and by strychnine or by tetanus. Generalized hypertonicity of muscles and lower extremity clonus are typical of serotonin syndrome. Seizures are often caused by overdose with antidepressants (especially tricyclic antidepressants and bupropion [as in the case study]), cocaine, amphetamines, theophylline, isoniazid, and diphenhydramine. Flaccid coma with absent reflexes and even an isoelectric electroencephalogram may be seen with deep coma due


Pharmacology_Katzung

Pharmacology_Katzung. in the case study]), cocaine, amphetamines, theophylline, isoniazid, and diphenhydramine. Flaccid coma with absent reflexes and even an isoelectric electroencephalogram may be seen with deep coma due to sedative-hypnotic or other CNS depressant intoxication and may be mistaken for brain death.


Pharmacology_Katzung

Pharmacology_Katzung. A. Arterial Blood Gases Hypoventilation results in an elevated Pco2 (hypercapnia) and a low Po2 (hypoxia). The Po2 may also be low in a patient with aspiration pneumonia or drug-induced pulmonary edema. Poor tissue oxygenation due to hypoxia, hypotension, or cyanide poisoning will result in metabolic acidosis. The Po2 measures only oxygen dissolved in the plasma and not total blood oxygen content or oxyhemoglobin saturation and may appear normal in patients with severe carbon monoxide poisoning. Pulse oximetry may also give falsely normal results in carbon monoxide intoxication. B. Electrolytes Sodium, potassium, chloride, and bicarbonate should be measured. The anion gap is then calculated by subtracting the measured anions from cations:


Pharmacology_Katzung

Pharmacology_Katzung. B. Electrolytes Sodium, potassium, chloride, and bicarbonate should be measured. The anion gap is then calculated by subtracting the measured anions from cations: Normally, the sum of the cations exceeds the sum of the anions by no more than 12–16 mEq/L (or 8–12 mEq/L if the formula used for estimating the anion gap omits the potassium level). A larger than expected anion gap is caused by the presence of unmeasured anions (lactate, etc) accompanying metabolic acidosis. This may occur with numerous conditions, such as diabetic ketoacidosis, renal failure, or shock-induced lactic acidosis. Drugs that may induce an elevated anion gap metabolic acidosis TABLE 58–1 Examples of drug-induced anion gap acidosis. Note: The normal anion gap calculated from (Na++ K+) – (HCO−3 + Cl−) is 12–16 mEq/L; calculated from (Na+) – (HCO3− + Cl−), it is 8–12 mEq/L. (Table 58–1) include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron.


Pharmacology_Katzung

Pharmacology_Katzung. (Table 58–1) include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron. Alterations in the serum potassium level are hazardous because they can result in cardiac arrhythmias. Drugs that may cause hyperkalemia despite normal renal function include potassium itself, β blockers, digitalis glycosides, potassium-sparing diuretics, and fluoride. Drugs associated with hypokalemia include barium, β agonists, caffeine, theophylline, and thiazide and loop diuretics. C. Renal Function Tests Some toxins have direct nephrotoxic effects; in other cases, renal failure is due to shock or myoglobinuria. Blood urea nitrogen and creatinine levels should be measured and urinalysis performed. Elevated serum creatine kinase (CK) and myoglobin in the urine suggest muscle necrosis due to seizures or muscular rigidity. Oxalate crystals in large numbers in the urine suggest ethylene glycol poisoning. D. Serum Osmolality


Pharmacology_Katzung

Pharmacology_Katzung. D. Serum Osmolality The calculated serum osmolality is dependent mainly on the serum sodium and glucose and the blood urea nitrogen and can be estimated from the following formula: This calculated value is normally 280–290 mOsm/L. Ethanol and other alcohols may contribute significantly to the measured serum osmolality but, since they are not included in the calculation, cause an osmol gap: Substances that are often associated with an abnormal osmol gap include acetone, ethanol, ethylene glycol, isopropyl alcohol, methanol, and propylene glycol. E. Electrocardiogram Widening of the QRS complex duration (to more than 100 milliseconds) is typical of overdose of tricyclic antidepressants and other drugs that block the sodium channel in cardiac conducting tissue (Figure 58–1). The QTc interval may be prolonged in many poisonings, including antidepressants and antipsychotics,


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 58–1 Changes in the electrocardiogram in tricyclic antidepressant overdosage. A: Slowed intraventricular conduction results in prolonged QRS interval (0.18 seconds; normal, 0.08 seconds). B and C: Supraventricular tachycardia with progressive widening of QRS complexes mimics ventricular tachycardia. (Reproduced, with permission, from Benowitz NL, Goldschlager N: Cardiac disturbances. In: Haddad LM, Shannon MW, Winchester JF [editors]. Clinical Management of Poisoning and Drug Overdose, 3rd ed. WB Saunders, 1998. © Elsevier.) lithium, and arsenic (see also https://www.crediblemeds.org/ everyone/composite-list-all-qtdrugs/). Variable atrioventricular (AV) block and a variety of atrial and ventricular arrhythmias are common with poisoning by digoxin and other cardiac glycosides. Hypoxemia due to carbon monoxide poisoning may result in ischemic changes on the electrocardiogram. F. Imaging Findings


Pharmacology_Katzung

Pharmacology_Katzung. F. Imaging Findings A plain film of the abdomen may be useful because some tablets, particularly iron and potassium, may be radiopaque. Chest radiographs may reveal aspiration pneumonia, hydrocarbon pneumonia, or pulmonary edema. When head trauma is suspected, a computed tomography (CT) scan is recommended.


Pharmacology_Katzung

Pharmacology_Katzung. It is a common misconception that a toxicology “screen” is the best way to diagnose and manage an acute poisoning. Unfortunately, rapid urine “drugs of abuse” screens are limited to a few classes of drugs and are subject to many false-positive and false-negative results, and more reliable comprehensive toxicology screening is time-consuming and expensive and results of tests may not be available for days. Moreover, many highly toxic drugs such as calcium channel blockers, β blockers, and isoniazid are not included in the screening process. The clinical examination of the patient and selected routine laboratory tests are usually sufficient to generate a tentative diagnosis and an appropriate treatment plan. Although screening tests (so-called “drugs of abuse” panels) may be helpful in confirming a suspected intoxication, they should not delay needed treatment. More formal, comprehensive screening may be necessary in cases of suspected brain death (to rule out drugs as a cause of coma),


Pharmacology_Katzung

Pharmacology_Katzung. a suspected intoxication, they should not delay needed treatment. More formal, comprehensive screening may be necessary in cases of suspected brain death (to rule out drugs as a cause of coma), child abuse, or as part of a postmortem examination.


Pharmacology_Katzung

Pharmacology_Katzung. When a specific antidote or other treatment is under consideration, quantitative laboratory testing may be indicated. For example, determination of the acetaminophen level is useful in assessing the need for antidotal therapy with acetylcysteine. Serum levels of salicylate (aspirin), ethylene glycol, methanol, theophylline, carbamazepine, lithium, valproic acid, and other drugs and poisons may indicate the need for hemodialysis (Table 58–2). Decontamination procedures should be undertaken simultaneously with initial stabilization, diagnostic assessment, and laboratory evaluation. Decontamination involves removing toxins from the skin or gastrointestinal tract. A. Skin Contaminated clothing should be completely removed and double-bagged to prevent illness in health care providers and for possible laboratory analysis. Wash contaminated skin with soap and water. B. Gastrointestinal Tract


Pharmacology_Katzung

Pharmacology_Katzung. B. Gastrointestinal Tract Controversy remains regarding the efficacy of gastrointestinal decontamination, especially when treatment is initiated more than 1 hour after ingestion. For most ingestions, clinical toxicologists recommend simple administration of activated charcoal to bind ingested poisons in the gut before they can be absorbed (as in the case study). In unusual circumstances, gastric lavage or whole bowel irrigation may also be used. TABLE 58–2 Hemodialysis in drug overdose and poisoning.1 Hemodialysis may be indicated depending on the severity of poisoning or the blood concentration: Hemodialysis is ineffective or is not useful: 1This listing is not comprehensive. 1.


Pharmacology_Katzung

Pharmacology_Katzung. Hemodialysis may be indicated depending on the severity of poisoning or the blood concentration: Hemodialysis is ineffective or is not useful: 1This listing is not comprehensive. 1. Emesis—Emesis induced by ipecac syrup was previously used to treat some childhood ingestions at home under telephone supervision of a physician or poison control center personnel. However, the risks involved with inappropriate use outweighed the unproven benefits, and this treatment is no longer used in the home or hospital. Other methods of inducing emesis such as fingertip stimulation of the pharynx, salt water, and apomorphine are ineffective or dangerous and should not be used. 2. Gastric lavage—If the patient is awake or if the airway is protected by an endotracheal tube, gastric lavage may be performed using an orogastric or nasogastric tube—as large a tube as possible. Lavage solutions (usually 0.9% saline) should be at body temperature to prevent hypothermia. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Activated charcoal—Owing to its large surface area, activated charcoal can adsorb many drugs and poisons. It is most effective if given in a ratio of at least 10:1 of charcoal to estimated dose of toxin by weight. Charcoal does not bind iron, lithium, or potassium, and it binds alcohols and cyanide only poorly. It does not appear to be useful in poisoning due to corrosive mineral acids and alkali. Repeated doses of oral activated charcoal may enhance systemic elimination of some drugs (including carbamazepine, dapsone, and phenobarbital) by a mechanism referred to as “gut dialysis,” although the clinical benefit is unproved. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Cathartics—Administration of a cathartic (laxative) agent may hasten removal of toxins from the gastrointestinal tract and reduce absorption, although no controlled studies have been done. Whole bowel irrigation with a balanced polyethylene glycol-electrolyte solution (GoLYTELY, CoLyte) can enhance gut decontamination after ingestion of iron tablets, enteric-coated medicines, illicit drug-filled packets, and foreign bodies. The solution is administered orally at 1–2 L/h (500 mL/h in children) for several hours until the rectal effluent is clear. There is a popular misconception that there is an antidote for every poison. Actually, selective antidotes are available for only a few classes of toxins. The major antidotes and their characteristics are listed in Table 58–3. Methods of Enhancing Elimination of Toxins


Pharmacology_Katzung

Pharmacology_Katzung. Methods of Enhancing Elimination of Toxins After appropriate diagnostic and decontamination procedures and administration of antidotes, it is important to consider whether measures for enhancing elimination, such as hemodialysis or urinary alkalinization, can improve the clinical outcome. Table 58–2 lists intoxications for which dialysis may be beneficial. A. Dialysis Procedures 1. Peritoneal dialysis—Although it is a relatively simple and available technique, peritoneal dialysis is inefficient in removing most drugs.


Pharmacology_Katzung

Pharmacology_Katzung. A. Dialysis Procedures 1. Peritoneal dialysis—Although it is a relatively simple and available technique, peritoneal dialysis is inefficient in removing most drugs. 2. Hemodialysis—Hemodialysis is more efficient than peritoneal dialysis and has been well studied. It assists in correction of fluid and electrolyte imbalance and may also enhance removal of toxic metabolites (eg, formic acid in methanol poisoning; oxalic and glycolic acids in ethylene glycol poisoning). The efficiency of both peritoneal dialysis and hemodialysis is a function of the molecular weight, water solubility, protein binding, endogenous clearance, and distribution in the body of the specific toxin. Hemodialysis is especially useful in overdose cases in which the precipitating drug can be removed and fluid and electrolyte imbalances are present and can be corrected (eg, salicylate intoxication). B. Forced Diuresis and Urinary pH Manipulation


Pharmacology_Katzung

Pharmacology_Katzung. B. Forced Diuresis and Urinary pH Manipulation Previously popular but of unproved value, forced diuresis may cause volume overload and electrolyte abnormalities and is not recommended. Renal elimination of a few toxins can be enhanced by alteration of urinary pH. For example, urinary alkalinization is useful in cases of salicylate overdose. Acidification may increase the urine concentration of drugs such as phencyclidine and amphetamines but is not advised because it may worsen renal complications from rhabdomyolysis, which often accompanies the intoxication. Acetaminophen is one of the drugs commonly involved in suicide attempts and accidental poisonings, both as the sole agent and in combination with other drugs. Acute ingestion of more than 150–200 mg/kg (children) or 7 g total (adults) is considered potentially toxic. A highly toxic metabolite is produced in the liver (see Figure 4–5).


Pharmacology_Katzung

Pharmacology_Katzung. Initially, the patient is asymptomatic or has mild gastrointestinal upset (nausea, vomiting). After 24–36 hours, evidence of liver injury appears, with elevated aminotransferase levels and hypoprothrombinemia. Fulminant liver failure may ensue, leading to metabolic acidosis, hypoglycemia, encephalopathy, and death. Renal failure may also occur. With acute massive ingestion and very high serum levels, metabolic acidosis can occur in the absence of liver failure. Rarely, acetaminophen ingestion can cause 5-oxoprolinuria due to glutathione depletion.


Pharmacology_Katzung

Pharmacology_Katzung. The severity of poisoning is estimated from a serum acetaminophen concentration measurement. If the level is greater than 150 mg/L approximately 4 hours after ingestion, the patient is at risk for liver injury. (Chronic alcoholics or patients taking drugs that enhance P450 production of toxic metabolites may be at risk with lower levels.) The antidote acetylcysteine acts as a glutathione substitute, binding the toxic metabolite as it is produced. It is most effective when given early and should be started within 8–10 hours if possible. Liver transplantation may be required for patients with fulminant hepatic failure. TABLE 58–3 Examples of specific antidotes. Acetylcysteine Acetaminophen (Acetadote, Mucomyst) Best results if given within 8–10 hours of overdose. Follow liver function tests and acetaminophen blood levels. Acetadote is given intravenously; Mucomyst is given orally.


Pharmacology_Katzung

Pharmacology_Katzung. Best results if given within 8–10 hours of overdose. Follow liver function tests and acetaminophen blood levels. Acetadote is given intravenously; Mucomyst is given orally. Stimulant drugs commonly abused in the USA include methamphetamine (“crank,” “crystal”), methylenedioxymethamphetamine (MDMA, “ecstasy”), and cocaine (“crack”) as well as pharmaceuticals such as pseudoephedrine (Sudafed) and ephedrine (as such and in the herbal agent Ma-huang) (see Chapter 32). Caffeine is often added to dietary supplements sold as “metabolic enhancers” or “fat burners.” Newer synthetic analogs of amphetamines (often sold on the street as “bath salts”) and synthetic agonists of the endogenous cannabinoid receptors (sold as “research chemicals” or “spice”) are becoming popular drugs of abuse.


Pharmacology_Katzung

Pharmacology_Katzung. At the doses usually used by stimulant abusers, euphoria and wakefulness are accompanied by a sense of power and well-being. At higher doses, restlessness, agitation, and acute psychosis may occur, accompanied by hypertension and tachycardia. Prolonged muscular hyperactivity or seizures may contribute to hyperthermia and rhabdomyolysis. Body temperatures as high as 42°C (107.6°F) have been recorded. Hyperthermia can cause brain damage, hypotension, coagulopathy, and renal failure.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment for stimulant toxicity includes general supportive measures as outlined earlier. There is no specific antidote. Seizures and hyperthermia are the most dangerous manifestations and must be treated aggressively. Seizures are usually managed with intravenous benzodiazepines (eg, lorazepam). Temperature is reduced by removing clothing, spraying with tepid water, and encouraging evaporative cooling with fanning. For very high body temperatures (eg, >40–41°C [104–105.8°F]), neuromuscular paralysis (eg, with vecuronium) is used to abolish muscle activity quickly.


Pharmacology_Katzung

Pharmacology_Katzung. A large number of prescription and nonprescription drugs, as well as a variety of plants and mushrooms, can inhibit the effects of acetylcholine at muscarinic receptors. Some drugs used for other purposes (eg, antihistamines) also have anticholinergic effects, in addition to other potentially toxic actions. For example, antihistamines such as diphenhydramine can cause seizures; tricyclic antidepressants, which have anticholinergic, quinidine-like, and α-blocking effects, can cause severe cardiovascular toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The classic anticholinergic (technically, “antimuscarinic”) syndrome is remembered as “red as a beet” (skin flushed), “hot as a hare” (hyperthermia), “dry as a bone” (dry mucous membranes, no sweating), “blind as a bat” (blurred vision, cycloplegia), and “mad as a hatter” (confusion, delirium). Patients usually have sinus tachycardia, and the pupils are usually dilated (see Chapter 8). Agitated delirium or coma may be present. Muscle twitching is common, but seizures are unusual unless the patient has ingested an antihistamine or a tricyclic antidepressant. Urinary retention is common, especially in older men.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment for anticholinergic syndrome is largely supportive. Agitated patients may require sedation with a benzodiazepine or an antipsychotic agent (eg, haloperidol or olanzapine). The specific antidote for peripheral and central anticholinergic syndrome is physostigmine, which has a prompt and dramatic effect and is especially useful for patients who are very agitated. Physostigmine is given in small intravenous doses (0.5–1 mg) with careful monitoring, because it can cause bradycardia and seizures if given too rapidly. Physostigmine should not be given to a patient with serious tricyclic antidepressant overdose because it can aggravate cardiotoxicity, resulting in heart block or asystole. Catheterization may be needed to prevent excessive distention of the bladder.


Pharmacology_Katzung

Pharmacology_Katzung. Tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, many others; see Chapter 30) are among the most common prescription drugs involved in life-threatening drug overdose. Ingestion of more than 1 g of a tricyclic (or about 15–20 mg/kg) is considered potentially lethal. Tricyclic antidepressants are competitive antagonists at muscarinic cholinergic receptors, and anticholinergic findings (tachycardia, dilated pupils, dry mouth) are common even at moderate doses. Some tricyclics are also strong α blockers, which can lead to vasodilation. Centrally mediated agitation and seizures may be followed by depression and hypotension. Most important is the fact that tricyclics inhibit the cardiac sodium channel, causing slowed conduction with a wide QRS interval and depressed cardiac contractility. This cardiac toxicity may result in serious arrhythmias (Figure 58–1), including ventricular conduction block and ventricular tachycardia.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment of tricyclic antidepressant overdose includes general supportive care as outlined earlier. Endotracheal intubation and assisted ventilation may be needed. Intravenous fluids are given for hypotension, and dopamine or norepinephrine is added if necessary. Many toxicologists recommend norepinephrine as the initial drug of choice for tricyclic-induced hypotension. The antidote for cardiac toxicity (manifested by a wide QRS complex) is sodium bicarbonate: a bolus of 50–100 mEq (or 1–2 mEq/kg) provides a rapid increase in extracellular sodium that helps overcome sodium channel blockade. Although physostigmine does effectively reverse anticholinergic signs, it can aggravate depression of cardiac conduction and cause seizures and is not recommended.


Pharmacology_Katzung

Pharmacology_Katzung. Monoamine oxidase inhibitors (eg, tranylcypromine, phenelzine) are older antidepressants that are occasionally used for resistant depression. They can cause severe hypertensive reactions when interacting foods or drugs are taken (see Chapters 9 and 30), and they can interact with the selective serotonin reuptake inhibitors (SSRIs). Newer antidepressants (eg, fluoxetine, paroxetine, citalopram, venlafaxine) are mostly SSRIs and are generally safer than the tricyclic antidepressants and monoamine oxidase inhibitors, although they can cause seizures. Bupropion (not an SSRI) has caused seizures even in therapeutic doses. Some antidepressants have been associated with QT prolongation and torsades de pointes arrhythmia. SSRIs may interact with each other or especially with monoamine oxidase inhibitors to cause the serotonin syndrome, characterized by agitation, muscle hyperactivity, and hyperthermia (see Chapter 16).


Pharmacology_Katzung

Pharmacology_Katzung. Antipsychotic drugs include the older phenothiazines and butyrophenones, as well as newer so-called “atypical” drugs. All of these can cause CNS depression, seizures, and hypotension. Some can cause QT prolongation. The potent dopamine D2 blockers are also associated with parkinsonian movement disorders (dystonic reactions) and in rare cases with the neuroleptic malignant syndrome, characterized by “lead-pipe” rigidity, hyperthermia, and autonomic instability (see Chapters 16 and 29).


Pharmacology_Katzung

Pharmacology_Katzung. Salicylate poisoning (see Chapter 36) is a much less common cause of childhood poisoning deaths since the introduction of child-resistant containers and the reduced use of children’s aspirin. It still accounts for numerous suicidal and accidental poisonings. Acute ingestion of more than 200 mg/kg is likely to produce intoxication. Poisoning can also result from chronic overmedication; this occurs most commonly in elderly patients using salicylates for chronic pain who become confused about their dosing. Poisoning causes uncoupling of oxidative phosphorylation and disruption of normal cellular metabolism.


Pharmacology_Katzung

Pharmacology_Katzung. The first sign of salicylate toxicity is often hyperventilation and respiratory alkalosis due to medullary stimulation. Metabolic acidosis follows, and an increased anion gap results from accumulation of lactate as well as excretion of bicarbonate by the kidney to compensate for respiratory alkalosis. Arterial blood gas testing often reveals a mixed respiratory alkalosis and metabolic acidosis. Body temperature may be elevated owing to uncoupling of oxidative phosphorylation. Severe hyperthermia may occur in serious cases. Vomiting and hyperpnea as well as hyperthermia contribute to fluid loss and dehydration. With very severe poisoning, profound metabolic acidosis, seizures, coma, pulmonary edema, and cardiovascular collapse may occur. Absorption of salicylate and signs of toxicity may be delayed after very large overdoses or ingestion of enteric coated tablets.


Pharmacology_Katzung

Pharmacology_Katzung. General supportive care is essential. After massive aspirin ingestions (eg, more than 100 tablets), aggressive gut decontamination is advisable, including gastric lavage, repeated doses of activated charcoal, and consideration of whole bowel irrigation. Intravenous fluids are used to replace fluid losses caused by tachypnea, vomiting, and fever. For moderate intoxications, intravenous sodium bicarbonate is given to alkalinize the urine and promote salicylate excretion by trapping the salicylate in its ionized, polar form. For severe poisoning (eg, patients with severe acidosis, coma, and serum salicylate level >90–100 mg/dL), emergency hemodialysis is performed to remove the salicylate more quickly and restore acid-base balance and fluid status.


Pharmacology_Katzung

Pharmacology_Katzung. In overdose, β blockers inhibit both β1 and β2 adrenoceptors; selectivity, if any, is lost at high dosage. The most toxic β blocker is propranolol. As little as two to three times the therapeutic dose can cause serious toxicity. This may be because propranolol in high doses may cause sodium channel-blocking effects similar to those seen with tricyclic antidepressants, and it is lipophilic, allowing it to enter the CNS (see Chapter 10). Bradycardia and hypotension are the most common manifestations of toxicity. Agents with partial agonist activity (eg, pindolol) can cause tachycardia and hypertension. Seizures and cardiac conduction block (wide QRS complex) may be seen with propranolol overdose.


Pharmacology_Katzung

Pharmacology_Katzung. General supportive care should be provided as outlined earlier. The usual measures used to raise the blood pressure and heart rate, such as intravenous fluids, β-agonist drugs, and atropine, are generally ineffective. Glucagon is a useful antidote that—like β agonists—acts on cardiac cells to raise intracellular cAMP but does so independent of β adrenoceptors. It can improve heart rate and blood pressure when given in high doses (5–20 mg intravenously). Calcium antagonists can cause serious toxicity or death with relatively small overdoses. These channel blockers depress sinus node automaticity and slow AV node conduction (see Chapter 12). They also reduce cardiac output and blood pressure. Serious hypotension is mainly seen with nifedipine and related dihydropyridines, but in severe overdose all of the listed cardiovascular effects can occur with any of the calcium channel blockers.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment requires general supportive care. Since most ingested calcium antagonists are in sustained-release form, it may be possible to expel them before they are completely absorbed; initiate whole bowel irrigation and oral activated charcoal as soon as possible, before calcium antagonist-induced ileus intervenes. Calcium, given intravenously in doses of 2–10 g, is a useful antidote for depressed cardiac contractility but less effective for nodal block or peripheral vascular collapse. Other treatments reported to be helpful in managing hypotension associated with calcium channel blocker poisoning include high-dose insulin (0.5–1 unit/kg/h) plus glucose supplementation to maintain euglycemia; glucagon; veno-arterial extracorporeal membrane oxygenation (ECMO-VA); and methylene blue. A few case reports have suggested benefit from administration of lipid emulsion (normally used as an intravenous dietary fat supplement) for severe verapamil overdose.


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Pharmacology_Katzung. Carbon monoxide (CO) is a colorless, odorless gas that is ubiquitous because it is created whenever carbon-containing materials are burned. Carbon monoxide poisoning is the leading cause of death due to poisoning in the USA. Most cases occur in victims of fires, but accidental and suicidal exposures are also common. The diagnosis and treatment of carbon monoxide poisoning are described in Chapter 56. Many other toxic gases are produced in fires or released in industrial accidents (Table 58–4). Organophosphate and carbamate cholinesterase inhibitors (see Chapter 7) are widely used to kill insects and other pests. Most cases of serious organophosphate or carbamate poisoning result from intentional ingestion by a suicidal person, but poisoning has also occurred at work (pesticide application or packaging) or, rarely, as a result of food contamination or terrorist attack (eg, release of the chemical warfare nerve agent sarin in the Tokyo subway system in 1995).


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Pharmacology_Katzung. Stimulation of muscarinic receptors causes abdominal cramps, diarrhea, excessive salivation, sweating, urinary frequency, and increased bronchial secretions (see Chapters 6 and 7). Stimulation of nicotinic receptors causes generalized ganglionic activation, which can lead to hypertension and either tachycardia or bradycardia. Muscle twitching and fasciculations may progress to weakness and respiratory muscle paralysis. CNS effects include agitation, confusion, and seizures. The mnemonic DUMBELS (diarrhea, urination, miosis and muscle weakness, bronchospasm, excitation, lacrimation, and seizures, sweating, and salivation) helps recall the common findings. Blood testing may be used to document depressed activity of red blood cell (acetylcholinesterase) and TABLE 58–4 Characteristics of poisoning with some gases. plasma (butyrylcholinesterase) enzymes, which provide an indirect estimate of synaptic cholinesterase activity.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 58–4 Characteristics of poisoning with some gases. plasma (butyrylcholinesterase) enzymes, which provide an indirect estimate of synaptic cholinesterase activity. General supportive care should be provided as outlined above. Precautions should be taken to ensure that rescuers and health care providers are not poisoned themselves by exposure to contaminated clothing or skin. This is especially critical for the most potent substances such as parathion or nerve gas agents. Antidotal treatment consists of atropine and pralidoxime (see Table 58–3). Atropine is an effective competitive inhibitor at muscarinic sites but has no effect at nicotinic sites. Pralidoxime given early enough may be capable of restoring the cholinesterase activity and is active at both muscarinic and nicotinic sites; however, studies are conflicting regarding its effect on clinical outcome.


Pharmacology_Katzung

Pharmacology_Katzung. Cyanide (CN–) salts and hydrogen cyanide (HCN) are highly toxic chemicals used in chemical synthesis, as rodenticides (eg, “gopher getter”), formerly as a method of execution, and as agents of suicide or homicide. Hydrogen cyanide is formed from the burning of plastics, wool, and many other synthetic and natural products. Cyanide is also released after ingestion of various plants (eg, cassava) and seeds (eg, apple, peach, and apricot). Cyanide binds readily to cytochrome oxidase, inhibiting oxygen utilization within the cell and leading to cellular hypoxia and lactic acidosis. Symptoms of cyanide poisoning include shortness of breath, agitation, and tachycardia followed by seizures, coma, hypotension, and death. Severe metabolic acidosis is characteristic. The venous oxygen content may be elevated because oxygen is not being taken up by cells.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment of cyanide poisoning includes rapid administration of activated charcoal (although charcoal binds cyanide poorly, it can reduce absorption) and general supportive care. The conventional antidote kit available in the USA includes two forms of nitrite (amyl nitrite and sodium nitrite) and sodium thiosulfate. The nitrites induce methemoglobinemia, which binds CN–, creating the less toxic cyanomethemoglobin; thiosulfate is a cofactor in the enzymatic conversion of CN – to the much less toxic thiocyanate (SCN–). In 2006, the FDA approved a new cyanide antidote, a concentrated form of hydroxocobalamin, which is now available as the Cyanokit (EMD Pharmaceuticals, Durham, North Carolina). Hydroxocobalamin (one form of vitamin B12) combines rapidly with CN– to form nontoxic cyanocobalamin (another form of vitamin B12).


Pharmacology_Katzung

Pharmacology_Katzung. Digitalis and other cardiac glycosides and cardenolides are found in many plants (see Chapter 13) and in the skin of some toads. Toxicity may occur as a result of acute overdose or from accumulation of digoxin in a patient with renal insufficiency or from taking a drug that interferes with digoxin elimination. Patients receiving long-term digoxin treatment are often also taking diuretics, which can lead to electrolyte depletion (especially potassium). Vomiting is common in patients with digitalis overdose. Hyperkalemia may be caused by acute digitalis overdose or severe poisoning, whereas hypokalemia may be present in patients as a result of long-term diuretic treatment. (Digitalis does not cause hypokalemia.) A variety of cardiac rhythm disturbances may occur, including sinus bradycardia, AV block, atrial tachycardia with block, accelerated junctional rhythm, premature ventricular beats, bidirectional ventricular tachycardia, and other ventricular arrhythmias.


Pharmacology_Katzung

Pharmacology_Katzung. General supportive care should be provided. Atropine is often effective for bradycardia or AV block. The use of digoxin antibodies (see Chapter 13) has revolutionized the treatment of digoxin toxicity; they should be administered intravenously in the dosage indicated in the package insert. Symptoms usually improve within 30–60 minutes after antibody administration. Digoxin antibodies may also be tried in cases of poisoning by other cardiac glycosides (eg, digitoxin, oleander), although larger doses may be needed due to incomplete cross-reactivity. Overdosage with ethanol and sedative-hypnotic drugs (eg, benzodiazepines, barbiturates, γ-hydroxybutyrate [GHB], carisoprodol [Soma]; see Chapters 22 and 23) occurs frequently because of their common availability and use.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with ethanol or other sedative-hypnotic overdose may be euphoric and rowdy (“drunk”) or in a state of stupor or coma (“dead drunk”). Comatose patients often have depressed respiratory drive. Depression of protective airway reflexes may result in pulmonary aspiration of gastric contents, leading to pneumonia. Hypothermia may be present because of environmental exposure and depressed shivering. Ethanol blood levels greater than 300 mg/dL usually cause deep coma, but regular users are often tolerant to the effects of ethanol and may be ambulatory despite even higher levels. Patients with GHB overdose are often deeply comatose for 3–4 hours and then awaken fully in a matter of minutes.


Pharmacology_Katzung

Pharmacology_Katzung. General supportive care should be provided. With careful attention to protecting the airway (including endotracheal intubation) and assisting ventilation, most patients recover as the drug effects wear off. Hypotension usually responds to intravenous fluids, body warming if cold, and, if needed, dopamine. Patients with isolated benzodiazepine overdose may awaken after intravenous flumazenil, a benzodiazepine antagonist. However, this drug is not widely used as empiric therapy for drug overdose because it may precipitate seizures in patients who are addicted to benzodiazepines or who have ingested a convulsant drug (eg, a tricyclic antidepressant). There are no antidotes for ethanol, barbiturates, or most other sedative-hypnotics.


Pharmacology_Katzung

Pharmacology_Katzung. Ethylene glycol and methanol are alcohols that are important toxins because of their metabolism to highly toxic organic acids (see Chapter 23). They are capable of causing CNS depression and a drunken state similar to ethanol overdose. In addition, their products of metabolism—formic acid (from methanol) or hippuric, oxalic, and glycolic acids (from ethylene glycol)—cause a severe metabolic acidosis and can lead to coma and blindness (in the case of formic acid) or renal failure (from oxalic acid and glycolic acid). Initially, the patient appears drunk, but after a delay of up to several hours, a severe anion gap metabolic acidosis becomes apparent, accompanied by hyperventilation and altered mental status. Patients with methanol poisoning may have visual disturbances ranging from blurred vision to blindness. Metabolism of ethylene glycol and methanol to their toxic products can be blocked by inhibiting the enzyme alcohol


Pharmacology_Katzung

Pharmacology_Katzung. Metabolism of ethylene glycol and methanol to their toxic products can be blocked by inhibiting the enzyme alcohol CHAPTER 58 Management of the Poisoned Patient 1045 dehydrogenase with a competing drug, such as fomepizole (4-methylpyrazole). Ethanol is also an effective antidote, but it can be difficult to achieve a safe and effective blood level. Iron is widely used in over-the-counter vitamin preparations and is a leading cause of childhood poisoning deaths. As few as 10–12 prenatal multivitamins with iron may cause serious illness in a small child. Poisoning with other metals (lead, mercury, arsenic) is also important, especially in industry. See Chapters 33, 56, and 57 for detailed discussions of poisoning by iron and other metals.


Pharmacology_Katzung

Pharmacology_Katzung. Opioids (opium, morphine, heroin, meperidine, methadone, etc) are common drugs of abuse (see Chapters 31 and 32), and overdose is a common result of using the poorly standardized preparations sold on the street. See Chapter 31 for a detailed discussion of opioid overdose and its treatment. In the USA, rattlesnakes are the most common venomous reptiles. Bites are rarely fatal, and 20% do not involve envenomation. However, about 60% of bites cause significant morbidity due to the destructive digestive enzymes found in the venom. Evidence of rattlesnake envenomation includes severe pain, swelling, bruising, hemorrhagic bleb formation, and obvious fang marks. Systemic effects include nausea, vomiting, muscle fasciculations, tingling and metallic taste in the mouth, shock, and systemic coagulopathy with prolonged clotting time and reduced platelet count.


Pharmacology_Katzung

Pharmacology_Katzung. Studies have shown that emergency field remedies such as incision and suction, tourniquets, and ice packs are far more damaging than useful. Avoidance of unnecessary motion, on the other hand, does help to limit the spread of the venom. Definitive therapy relies on intravenous antivenom (also known as antivenin), and this should be started as soon as possible. Although it has been largely replaced by inhaled β agonists, theophylline continues to be used for the treatment of bronchospasm by some patients with asthma and bronchitis (see Chapter 20). A dose of 20–30 tablets can cause serious or fatal poisoning. Chronic or subacute theophylline poisoning can also occur as a result of accidental overmedication or use of a drug that interferes with theophylline metabolism (eg, cimetidine, ciprofloxacin, erythromycin; see Chapter 4). Caffeine produces similar toxic effects and it is available in several “energy” supplements.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to sinus tachycardia and tremor, vomiting is common after overdose. Hypotension, tachycardia, hypokalemia, and hyperglycemia may occur, probably owing to β2-adrenergic activation. The cause of this activation is not fully understood, but the effects can be ameliorated by β blockers (see below). Cardiac arrhythmias include atrial tachycardias, premature ventricular contractions, and ventricular tachycardia. In severe poisoning (eg, acute overdose with serum level >100 mg/L), seizures often occur and are usually resistant to common anticonvulsants. Toxicity may be delayed in onset for many hours after ingestion of sustained-release tablet formulations.


Pharmacology_Katzung

Pharmacology_Katzung. General supportive care should be provided. Aggressive gut decontamination should be carried out using repeated doses of activated charcoal and whole bowel irrigation. Propranolol or other β blockers (eg, esmolol) are useful antidotes for β-mediated hypotension and tachycardia. Phenobarbital is preferred over phenytoin for convulsions; most anticonvulsants are ineffective. Hemodialysis is indicated for serum concentrations >100 mg/L and for intractable seizures in patients with lower levels. Dart RD (editor): Medical Toxicology, 3rd ed. Lippincott Williams & Wilkins, 2004. Goldfrank LR et al (editors): Goldfrank’s Toxicologic Emergencies, 10th ed. McGraw-Hill, 2015. Olson KR et al (editors): Poisoning & Drug Overdose, 6th ed. McGraw-Hill, 2011. POISINDEX. (Revised Quarterly.) Thomson/Micromedex.


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Pharmacology_Katzung. Overdose of bupropion can cause seizures that are often recurrent or prolonged. Drug-induced seizures are treated with an intravenous benzodiazepine such as lorazepam or diazepam. If this is not effective, phenobarbital or another more potent central nervous system depressant may be used. To prevent ingested drugs and poisons from being absorbed systemically, a slurry of activated charcoal is often given orally or by nasogastric tube. Special Aspects of Perinatal & Pediatric Pharmacology Gideon Koren, MD, FRCPC, FACMT


Pharmacology_Katzung

Pharmacology_Katzung. Special Aspects of Perinatal & Pediatric Pharmacology Gideon Koren, MD, FRCPC, FACMT The effects of drugs on the fetus and newborn infant are based on the general principles set forth in Chapters 1–4 of this book. However, the physiologic contexts in which these pharmacologic laws operate are different in pregnant women and in rapidly maturing infants. At present, the special pharmacokinetic factors operative in these patients are beginning to be understood, whereas information regarding pharmacodynamic differences (eg, receptor characteristics and responses) is still incomplete.


Pharmacology_Katzung

Pharmacology_Katzung. Most drugs taken by pregnant women can cross the placenta and expose the developing embryo and fetus to their pharmacologic and teratogenic effects. Critical factors affecting placental drug transfer and drug effects on the fetus include the following: the physicochemical properties of the drug; (2) the rate at which the drug crosses the placenta and the amount of drug reaching the fetus; (3) the duration of exposure to the drug; distribution characteristics in different fetal tissues; (5) the stage of placental and fetal development at the time of exposure to the drug; and (6) the effects of drugs used in combination. A. Lipid Solubility


Pharmacology_Katzung

Pharmacology_Katzung. As is true also of other biologic membranes, drug passage across the placenta is dependent on lipid solubility and the degree of drug ionization. Lipophilic drugs tend to diffuse readily across the placenta and enter the fetal circulation. For example, thiopental, a drug commonly used for cesarean sections, crosses the placenta almost immediately and can produce sedation or apnea in the newborn infant. Highly ionized drugs such as succinylcholine and tubocurarine, also used for cesarean sections, cross the placenta slowly and achieve very low concentrations in the fetus. Impermeability of the placenta to polar compounds is relative rather than absolute. If high enough maternal-fetal concentration gradients are achieved, polar compounds cross the placenta in measurable amounts. Salicylate, which is almost completely ionized at physiologic pH, crosses the placenta rapidly. This occurs because the small amount of salicylate that is not ionized is highly lipid-soluble.


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B. Molecular Size and pH

Pharmacology_Katzung. B. Molecular Size and pH


Pharmacology_Katzung

Pharmacology_Katzung. The molecular weight of the drug also influences the rate of transfer and the amount of drug transferred across the placenta. Drugs with molecular weights of 250–500 can cross the placenta easily, depending upon their lipid solubility and degree of ionization; those with molecular weights of 500–1000 cross the placenta with more difficulty; and those with molecular weights >1000 cross very poorly. An important clinical application of this property is the choice of heparin as an anticoagulant in pregnant women. Because it is a very large (and polar) molecule, heparin is unable to cross the placenta. Unlike warfarin, which is teratogenic and should be avoided during the first trimester and even beyond (as the brain continues to develop), heparin may be safely given to pregnant women who need anticoagulation. Yet the placenta contains drug transporters, which can carry larger molecules to the fetus. For example, a variety of maternal antibodies cross the placenta and may cause fetal


Pharmacology_Katzung

Pharmacology_Katzung. need anticoagulation. Yet the placenta contains drug transporters, which can carry larger molecules to the fetus. For example, a variety of maternal antibodies cross the placenta and may cause fetal morbidity, as in Rh incompatibility. Starting in the second trimester of pregnancy, the placenta develops transporters that allow immunoglobulins to cross from the mother to the fetus despite their large molecular size. This has important clinical implications, because an increasing number of biological drugs (eg, anti-tumor necrosis factor therapy) have been shown to cross the placenta. In addition to the detection of biologicals in cord blood, cases of severe neonatal neutropenia and fetal dissemination of bacillus Calmette-Guérin (BCG) have been reported. With an increasing number of infants exposed to immunoglobulin biologicals in utero, there is a need to address the challenges in vaccinating these infants.


Pharmacology_Katzung

Pharmacology_Katzung. Because maternal blood has a pH of 7.4, whereas the fetal blood is 7.3, basic drugs with a pKa above 7.4 will be more ionized in the fetal compartment, leading to ion trapping and, hence, to higher fetal levels (see Chapter 1, Ionization of Weak Acids and Weak Bases). C. Placental Transporters


Pharmacology_Katzung

Pharmacology_Katzung. During the last decade, many drug transporters have been identified in the placenta, with increasing recognition of their effects on drug transfer to the fetus. For example, the P-glycoprotein transporter encoded by the MDR1 gene pumps back into the maternal circulation a variety of drugs, including cancer drugs (eg, vinblastine, doxorubicin) and other agents. Similarly, viral protease inhibitors, which are substrates to P-glycoprotein, achieve only low fetal concentrations—an effect that may increase the risk of vertical HIV infection from the mother to the fetus. The hypoglycemic drug glyburide has lower plasma levels in the fetus as compared with the mother. Recent work has documented that this agent is effluxed from the fetal circulation by the BCRP transporter as well as by the MRP3 transporter located in the placental brush border membrane. In addition, very high maternal protein binding of glyburide (>98.8%) also contributes to lower fetal levels as compared with maternal


Pharmacology_Katzung

Pharmacology_Katzung. MRP3 transporter located in the placental brush border membrane. In addition, very high maternal protein binding of glyburide (>98.8%) also contributes to lower fetal levels as compared with maternal concentrations.


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D. Protein Binding

Pharmacology_Katzung. D. Protein Binding


Pharmacology_Katzung

Pharmacology_Katzung. The degree to which a drug is bound to plasma proteins (particularly albumin) may also affect the rate of transfer and the amount transferred. However, if a compound is very lipid-soluble (eg, some anesthetic gases), it will not be affected greatly by protein binding. Transfer of these more lipid-soluble drugs and their overall rates of equilibration are more dependent on (and proportionate to) placental blood flow. This is because very lipid-soluble drugs diffuse across placental membranes so rapidly that their overall rates of equilibration do not depend on the free drug concentrations becoming equal on both sides. If a drug is poorly lipid-soluble and is ionized, its transfer is slow and will probably be impeded by its binding to maternal plasma proteins. Differential protein binding is also important since some drugs exhibit greater protein binding in maternal plasma than in fetal plasma because of a lower binding affinity of fetal proteins. This has been shown for sulfonamides,


Pharmacology_Katzung

Pharmacology_Katzung. is also important since some drugs exhibit greater protein binding in maternal plasma than in fetal plasma because of a lower binding affinity of fetal proteins. This has been shown for sulfonamides, barbiturates, phenytoin, and local anesthetic agents.


Pharmacology_Katzung

Pharmacology_Katzung. E. Placental and Fetal Drug Metabolism Two mechanisms help protect the fetus from drugs in the maternal circulation: (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Several different types of aromatic oxidation reactions (eg, hydroxylation, N-dealkylation, demethylation) have been shown to occur in placental tissue. Pentobarbital is oxidized in this way. Conversely, it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites, and the placenta may therefore augment toxicity (eg, ethanol, benzpyrenes).


Pharmacology_Katzung

Pharmacology_Katzung. (2) Because of the ability of the placenta to convert prednisolone to the inactive prednisone, prednisolone can be used in pregnant patients requiring corticosteroid treatment without the risk of fetal exposure to an active corticosteroid. Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. About 40–60% of umbilical venous blood flow enters the fetal liver; the remainder bypasses the liver and enters the general fetal circulation. A drug that enters the liver may be partially metabolized there before it enters the fetal circulation. In addition, a large proportion of drug present in the umbilical artery (returning to the placenta) may be shunted through the placenta back to the umbilical vein and into the liver again. It should be noted that metabolites of some drugs may be more active than the parent compound and may affect the fetus adversely. A. Maternal Drug Actions


Pharmacology_Katzung

Pharmacology_Katzung. A. Maternal Drug Actions The effects of drugs on the reproductive tissues (breast, uterus, etc) of the pregnant woman are sometimes altered by the endocrine environment appropriate for the stage of pregnancy. Drug effects on other maternal tissues (heart, lungs, kidneys, central nervous system, etc) are not changed significantly by pregnancy, although the physiologic context (cardiac output, renal blood flow, etc) may be altered, requiring the use of drugs that are not needed by the same woman when she is not pregnant. For example, cardiac glycosides and diuretics may be needed for heart failure precipitated by the increased cardiac workload of pregnancy, or insulin may be required for control of blood glucose in pregnancy-induced diabetes. B. Therapeutic Drug Actions in the Fetus


Pharmacology_Katzung

Pharmacology_Katzung. Fetal therapeutics is an emerging area in perinatal pharmacology. This involves drug administration, mostly to the pregnant woman, with the fetus as the target of the drug. At present, corticosteroids are used to stimulate fetal lung maturation when preterm birth is expected. Phenobarbital, when given to pregnant women near term, can induce fetal hepatic enzymes responsible for the glucuronidation of bilirubin, and the incidence of jaundice is lower in newborns when mothers are given phenobarbital than when phenobarbital is not used. Before phototherapy became the preferred mode of therapy for neonatal indirect hyperbilirubinemia, phenobarbital was used for this indication. Administration of phenobarbital to the mother was suggested recently as a means of decreasing the risk of intracranial bleeding in preterm infants. However, large randomized studies failed to confirm this effect. Antiarrhythmic drugs have also been given to mothers for treatment of fetal cardiac arrhythmias.


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Pharmacology_Katzung. bleeding in preterm infants. However, large randomized studies failed to confirm this effect. Antiarrhythmic drugs have also been given to mothers for treatment of fetal cardiac arrhythmias. Although their efficacy has not yet been established by controlled studies, digoxin, flecainide, procainamide, verapamil, and other antiarrhythmic agents have been shown to be effective in case series. Similarly, it has been shown that maternal use of zidovudine and other HIV drugs substantially decreases transmission of HIV from the mother to the fetus, and use of combinations of three antiretroviral agents can eliminate fetal infection almost entirely (see Chapter 49).