TOXICOLOGY TODAY
Richard Clark, MD, Professor of Medicine, Director Division of Medical Toxicology, and Assistant Director,
Department of Emergency Medicine, University of California, San Diego School of Medicine
| Methamphetamines: ≥33% of jail inmates test positive for use; \>60% of cases of penetrating trauma (in San Diego) related
to sale, trade, or use of methamphetamines; rapid urine screens used in emergency department (ED) have low
specificity for methamphetamines (detect related compounds, eg, ephedrine and pseudoephedrine [eg, Sudafed]);
ephedrine—illegal in many states because of fatal hyperthermia that may occur in some athletes while training; appetite
suppressants—eg, Metabolife, contain derivatives of amphetamine; users develop tolerance over time and require
larger doses to achieve suppression of appetite; but, risk for cardiovascular effects (eg, stroke, hypertensive encephalopathy,
and myocardial infarction [MI]) increases with larger doses; ma huang—herbal ephedrine
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 | Ecstasy: 3,4-methylenedioxymethamphetamine (MDMA); ≈30% of seniors in high school have taken MDMA;
pills commonly contain compounds other than MDMA (eg, dextromethorphan); effects on brain—destruction of
serotonergic neurons; patient may appear flat or apathetic after bingeing or repeated use; brain imaging studies in
primates have shown effects with each dose, but considered safe by most users
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| Foxy: derivative of amphetamines, marketed as “love drug”; reports from users describe euphoria and heightened
sexual experience
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| Methamphetamine overdose: patients look wild, often violent and verbally abusive, and may arrive at ED in shackles
or handcuffs (presentation similar for all patients who have overdosed on sympathomimetic drugs); other signs
and symptoms include dilated pupils, dry mouth, tachycardia, perspiration, and paranoia (sometimes severe; toxic
psychosis typical); other clues include abrasions on cheeks caused by forceful restraint by law officers
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| Diphenhydramine: case—patient brought to ED from state penitentiary after overdosing on diphenhydramine
(Benadryl); patient passively psychotic and had antimuscarinic/anticholinergic syndrome; symptoms reversed with
physostigmine (adverse effects include convulsions, bradycardia, and death); use among teenagers—Benadryl parties;
teenagers take large quantities of Benadryl to induce (reportedly aphrodisiac) hallucinations
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| Heroin: injectable drugs have stigma (associated with human immunodeficiency virus [HIV]), and many people have
fear of needles; noninjectable forms developed to expand population of potential users (especially children); use of heroin
among teenagers has increased dramatically; pharmacokinetics—half-life ≈10 min, then metabolized to morphine;
heroin crosses blood-brain barrier quickly (resulting in fast “high”), then morphine circulates for ≈8 hr, causing extended
effect; problems—withdrawal symptoms; complications of injection include infection and subdermal necrosis
(intensified with concomitant use of cocaine); accidental injection into artery results in embolization and severe inflammation
(treat with topical nitroglycerine; may require amputation)
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| Dextromethorphan: ingredient in Robitussin DM and other cough suppressants, stimulates same receptor as phencyclidine
(PCP; patient may test positive for PCP on toxicology screen); effects include dissociation, depression of
central nervous system (CNS), and hallucinations; minimal dose to achieve effects ≈300 mg (4-8 oz); ingesting 600
mg (2-4 bottles) results in effects similar to those of lysergic acid diethylamide (LSD); ingesting 900 mg results in
hallucinations similar to those induced by taking LSD
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| OVER-THE-COUNTER ANALGESICS
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| Acetaminophen: properties—analgesic; antipyretic; possible anti-inflammatory effect (some patients with arthritis report
relief with use); overdose—common cause of hepatic necrosis (leading cause in United Kingdom); \>100,000
toxic exposures, resulting in \>50 fatalities annually in United States; acetaminophen toxicity important factor in patients
who have overdosed on combination products (eg, hydrocodone and acetaminophen [Vicodin])
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| Metabolism and toxicity: primary pathways include glucuronidation (primary pathway in adults) and sulfation (primary
pathway in children <8 yr of age); 5% to 10% of therapeutic dose metabolized through cytochrome P450
mixed-function oxidase system in liver; N-acetylbenzoquinoneimine (NAPQI)—metabolite of P450 system; kills
hepatocytes; damage occurs when glutathione stores (required for detoxification of NAPQI) depleted; treatment
involves reduction of NAPQI; liver damage—highest concentration of NAPQI occurs around central vein, resulting
in centrilobular hepatic necrosis and distinguishing acetaminophen-induced necrosis from other forms,
eg, iron-induced (toxicity highest around portal triad)
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| Progression of toxicity: phase 1—patients asymptomatic or have mild GI symptoms (nausea, vomiting, pain in
right upper quadrant); slight elevation in liver enzymes may occur; phase 2—24 to 72 hr after ingestion, patient
has increasing gastroenteritis and pain and may develop jaundice; liver enzymes increase dramatically; note—to
ensure successful treatment with N-acetylcysteine (NAC; Mucomyst), initiate therapy before patient enters phase
2; phase 3—most deaths from overdose occur 72 to 96 hr after ingestion; almost all patients who survive phase
3 recover completely
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| Toxic dose: ingestions <200 mg/kg do not require decontamination or treatment with NAC; if amount of ingestion unknown,
plot 4-hr level on Rumack-Matthew nomogram; extrapolated level of acetaminophen of ≥200 µg/mL (in
California) or ≥150 µg/mL (in some other states) warrants treatment with NAC (initial laboratory studies used cutoff
of 500 µg/mL); ongoing study by California poison control system suggests 200 µg/mL cutoff safe
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| Increased risk: theoretic risk occurs with relative starvation, alcoholism, and agents that induce P450 activity; review
of literature yields conflicting data; some evidence that intoxication with alcohol protects against acetaminophen
toxicity by competing for P450 enzymes
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| Evidence for increased risk: registry (developed by HJ Zimmerman and WC Maddrey) collects cases involving interaction
of alcohol and acetaminophen; widely publicized article (Whitcomb and Block, 1994) reported association
between acetaminophen toxicity and fasting or ingestion of ethanol; studies with mice showed LD50 (dose at
which 50% of mice die) for acetaminophen decreased by 50% in animals given ethanol
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| Evidence against increased risk: therapeutic levels of acetaminophen, when taken with alcohol, did not produce deleterious
effects in baboons; 2 studies interviewing alcoholic patients found no case of toxicity with use of acetaminophen at
therapeutic doses; study conducted by Rocky Mountain Poison Center found no differences in liver function tests
(LFTs) between alcoholic patients and controls taking 4 g of acetaminophen for 2 days; even Whitcomb study found no
cases of hepatotoxicity with therapeutic doses; no epidemic documented in 40 yr of use; conclusions—daily doses of
10 g unlikely to cause problems in healthy adults; daily doses of <7.5 g unlikely to cause problems in alcoholic patients;
note—Zimmerman registry receives support from Whitehall Laboratories (makers of Advil)
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| P450 -inducing agents: study (Prescott) found no difference in levels of NAPQI between patients taking P450 -inducing
agents (eg, carbamazepine) and controls
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| Other concerns: study found no problems in patients with stable chronic liver disease, eg, hepatitis C, taking therapeutic
doses of acetaminophen; fasting or starvation state may lower glutathione stores and increase risk for toxicity
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| Treatment: activated charcoal (1 g/kg) binds acetaminophen, does not significantly bind NAC; NAC—140 mg/kg
loading dose followed by 70 mg/kg q4h for 72 hr; NAC increases stores of glutathione, provides reducing sulfur
groups, and may chelate toxic metabolite in liver; efficacy 100% when given within 12 hr of ingestion; intravenous
(IV) form (Acetadote) approved for shorter course (20-21 hr) of continuous infusion; persistent elevations (after
initial course) in LFTs warrant continued treatment with Acetadote or oral NAC (not stated in package insert);
studies suggest treatment with NAC effective even when given \>24 hr after ingestion; 24-hr course of NAC (at
same dosage as 72-hr course) often sufficient to treat acute overdose; check acetaminophen level and LFTs at 24
hr; if acetaminophen level zero (NAPQI presumed gone, since its half-life <30 min) and LFTs normal, stop NAC;
continue NAC if level of acetaminophen remains detectable or LFTs remain elevated
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| Nonsteroidal anti-inflammatory drugs (NSAIDs): OTC formulations—propionic acids (eg, ibuprofen, naproxen);
mechanism—inhibit synthesis of prostaglandins; effects—anti-inflammatory; analgesic; antipyretic; metabolism—no
toxic metabolites; elimination through kidneys without problems
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| Toxicity: acute toxicity—ingestions ≥250 mg/kg of ibuprofen and ≥200 mg/kg of naproxen; for smaller ingestions, no
treatment necessary unless patient symptomatic; no antidote for overdose (supportive treatment only); serum concentrations
not predictive of clinical effects; most common symptoms include nausea and vomiting; massive ingestion
may result in renal effects or self-limited convulsions (rare); long-term toxicity—almost every organ system affected
by long-term use; renal failure may occur (especially in diabetics); neuropsychiatric problems include vertigo, altered
mental status (especially in elderly patients), drowsiness, aseptic meningitis, and seizures (especially with meclofenamate
[Meclomen]); some drugs pulled from market because of problems with idiopathic hepatitis; treatment—
activated charcoal acceptable (but not necessary) in cases of acute overdose; observation and supportive care generally
sufficient; patient often cleared in ≈6 hr; warnings—recent label mandated by Food and Drug Administration
(FDA) advises patients who drink \>3 alcoholic beverages daily to check with physician before taking ibuprofen (Motrin)
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| Salicylates: best anti-inflammatory agents on market; very large doses (≥500 mg/kg) required for fatal ingestions, but
aspirin inexpensive and available in large quantities; oil of wintergreen—7000 mg salicylate per teaspoon (ie, potentially
fatal dose may occur with relatively small quantity)
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| Metabolic acidosis: salicylates highly protein bound; once binding sites saturated, level of unbound salicylates increases,
lowering pH (which increases spread to other organs); therapeutic doses metabolized into nontoxic metabolites in liver;
above therapeutic doses, hepatic enzymes become saturated, and importance of kidneys increases; mechanisms—
uncoupling; dehydration; buildup of acidic metabolites; aspirin prevents oxidative phosphorylation of adenosine diphosphate
(ADP) to adenosine triphosphate (ATP) on membrane of mitochondria; respiration increases but no ATP produced
(ie, respiration uncoupled from production of ATP); patients feel warm
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| Salicylate toxicity: acute toxicity—effects include electrolyte imbalance and effects on CNS, heart, and GI system;
long-term toxicity—subtle presentation; patients often do not provide history of taking aspirin; salicylate levels may
not indicate overdose, but patient may have large stores of salicylates in body; presentation—may include pulmonary
edema and altered mental status; sometimes called pseudosepsis syndrome (fever, tachycardia, elevated white blood
cell [WBC] count, and altered mental status); may progress to renal problems, fluid retention, and pulmonary edema
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| Treatment: rehydrate patient; check acid-base status; replace potassium; alkalinize serum (to prevent dissociation
from binding sites and minimize spread to tissues) by adding bicarbonate to IV fluids to get pH up to 7.4; note—
pH of urine may remain low because of hydrogen-potassium exchange in distal tubules; body retains potassium
and automatically dumps hydrogen ions into urine; dialysis—refer patients with altered mental status to nephrologist
for assessment; delayed dialysis may result in refractory acute respiratory distress syndrome (ARDS), hypoxia,
cerebral edema, herniation, and death
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| Case 1: woman, 67 yr of age, with chief complaint of acute loss of hearing; examination reveals mild confusion, sinus
tachycardia, with some hypoxia and hypotension; laboratory findings include mild hyperglycemia, metabolic
acidosis, and low potassium; salicylate level, 40 mg/dL (only somewhat elevated over therapeutic levels); medical
history—patient taking aspirin for osteoarthritis; diagnosis—chronic aspirin poisoning accounts for all symptoms;
treatment—consider dialysis; minimally, observe for several hours to follow level of salicylate and pH of blood;
may need to replace bicarbonate
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| Case 2: girl, 13 yr of age, overdosed on 1 bottle of aspirin; mother (holistic physician) called poison control to confirm
whether she could treat daughter at home with baking soda (to alkalinize) and Gatorade (to hydrate and replenish electrolytes);
although poison control urged treatment in ED, parents declined; second call to poison control reported convulsion;
poison control called 911 and ED; ED physician advised nephrologist; child arrived in ED appearing
antimuscarinic and hallucinating; heart rate elevated, but child hemodynamically stable; metabolic acidosis with pH
of 7.22 and PCO 2 of 36 mm Hg (higher than expected); treatment—bicarbonate added to IV; catheters placed; child
dialyzed within 2 hr of arrival and recovered fully
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Educational Objectives
| The goal of this activity is to provide information about toxic effects of common over-the-counter (OTC) medications
and drugs of abuse. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Recognize patients who have overdosed on methamphetamines.
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| 2. Identify OTC medications that can be abused for recreational purposes.
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| 3. Discuss advantages and disadvantages of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and
salicylates.
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| 4. Identify and treat patients with acetaminophen toxicity.
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| 5. Identify and treat patients with salicylate toxicity.
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Discussed on This Program
Acetylcysteine (N-acetylcysteine) [Acetadote, Mucomyst, Mucomyst 10 IV, Mucosil-10, -20]
Acetaminophen (several formulations and trade names)
Carbamazepine [Atretol, Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR]
Celecoxib [Celebrex]
Dextromethorphan HBr (Robitussin DM, others)
Diphenhydramine HCl (Benadryl, others)
Ephedrine sulfate [Pretz-D]
Hydrocodone bitartrate and acetaminophen (Vicodin, others)
Ibuprofen (Advil, Motrin, others)
Meclofenamate sodium [Meclomen]
Naproxen [Aleve, Anaprox, Anaprox DS, EC-Naprosyn, Naprosyn, Naprelan]
Pseudoephedrine HCl (d-isoephedrine HCl) [Sudafed, others]
Rofecoxib [Vioxx] (withdrawn from market 9/30/04)
Salicylic acid (several formulations and trade names)
Valdecoxib [Bextra]
Suggested Reading
Batki SL, Harris DS: Quantitative drug levels in stimulant psychosis: relationship to symptom severity, catecholamines,
and hyperkinesia. Am J Addict 13:461, 2004; Benson GD, et al: The therapeutic use of acetaminophen in patients
with liver disease. Am J Ther 12:133, 2005; Compton WM, et al: Developments in the epidemiology of drug
use and drug use disorders. Am J Psychiatry 162:1494, 2005; Fischer LM, et al: Current use of nonsteroidal antiinflammatory
drugs and the risk of acute myocardial infarction. Pharmacotherapy 25:503, 2005; Graham GG, et al:
Tolerability of paracetamol. Drug Saf 28:227, 2005; Konstantinopoulos PA, Lehmann DF: The cardiovascular toxicity
of selective and nonselective cyclooxygenase inhibitors: comparisons, contrasts, and aspirin confounding. J Clin
Pharmacol 45:742, 2005; Rumack BH: Acetaminophen misconceptions. Hepatology 40:10, 2004; Schwartz RH:
Adolescent abuse of dextromethorphan. Clin Pediatr (Phila) 44:565, 2005; Sivilatti ML, et al: A new predictor of
toxicity following acetaminophen overdose based on pretreatment exposure. Clin Toxicol (Phila) 43:229, 2005; Sivilotti
ML, et al: A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine.
Ann Emerg Med 46:263, 2005; Thomasius R, et al: Mental disorders in current and former heavy ecstasy
(MDMA) users. Addiction 100:1310, 2005; Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicity
with fasting and ethanol use. JAMA 272:1845, 1994; White SJ, Rumack BH: The acetaminophen toxicity equations:
“solutions” for acetaminophen toxicity based on the Rumack-Matthew nomogram. Ann Emerg Med 45:563, 2005; Ziaee
V, et al: Side effects of dextromethorphan abuse, a case series. Addict Behav 30:1607, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the faculty reported nothing to disclose.
Dr. Clark was recorded in Hot Springs, Virginia, at 2005 Scientific Assembly, sponsored by Virginia College of Emergency
Physicians, and held February 13-18, 2005. The Audio-Digest Foundation thanks the speaker and the sponsor
for their cooperation in the production of this program.
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