BENZODIAZEPINES

Ben Tsutaoka, PharmD

The drug class of benzodiazepines includes many compounds that vary widely in potency, duration of effect, the presence or absence of
active metabolites, and clinical use (Table II–14). Three nonbenzodiazepines—eszopiclone, zaleplon, and zolpidem—have similar clinical effects
and are included here. In general, death from benzodiazepine overdose is rare unless the drugs are combined with other CNSdepressant agents,
such as ethanol, opioids, and barbiturates. Newer potent, shortacting agents have been considered the sole cause of death in recent forensic cases.
I. Mechanism of toxicity. Benzodiazepines enhance the action of the inhibitory neurotransmitter gamma-aminobutyric acid
(GABA). They also inhibit other neuronal systems by poorly defined mechanisms. The result is generalized depression of spinal
reflexes and the reticular activating system. This can cause coma and respiratory arrest.

A. Respiratory arrest is more likely with newer short-acting benzodiazepines such as triazolam (Halcion), alprazolam (Xanax), and
midazolam (Versed). It has also been reported with zolpidem (Ambien).
B. Cardiopulmonary arrest has occurred after rapid injection of diazepam, possibly because of CNS-depressant effects or because of the
toxic effects of the diluent propylene glycol.
C. Pharmacokinetics. Most of these agents are highly protein bound (80–100%). Time to peak blood level, elimination half-lives, the
presence or absence of active metabolites, and other pharmacokinetic values are given in Table II–66 (p 462).

II. Toxic dose. In general, the toxic-therapeutic ratio for benzodiazepines is very high. For example, oral overdoses of diazepam have been
reported in excess of 15–20 times the therapeutic dose without serious depression of consciousness. However, respiratory arrest has been reported
after ingestion of 5 mg of triazolam and after rapid IV injection of diazepam, midazolam, and many other benzodiazepines. Also, ingestion of
another drug with CNS-depressant properties (eg, ethanol, barbiturates, opioids) probably will produce additive effects.

III. Clinical presentation. Onset of CNS depression may be observed within 30–120 minutes of ingestion, depending on the compound.
Lethargy, slurred speech, ataxia, coma, and respiratory arrest may occur. Generally, patients with benzodiazepine-induced coma have
hyporeflexia and midposition or small pupils. Hypothermia may occur. Serious complications are more likely when newer shortacting agents are
involved or when other depressant drugs have been ingested.

IV. Diagnosis usually is based on the history of ingestion or recent injection. The differential diagnosis should include other sedative-hypnotic
agents, antidepressants, antipsychotics, and narcotics. Coma and small pupils do not respond to naloxone but will reverse with administration of
flumazenil (see below).
A. Specific levels. Serum drug levels are often available from commercial toxicology laboratories but are rarely of value in emergency
management. Urine and blood qualitative screening may provide rapid confirmation of exposure. Immunoassays are sensitive to the
 benzodiazepines that metabolize to oxazepam (eg, diazepam, chlordiazepoxide, and temazepam), but may not detect newer
benzodiazepines or those in low concentrations.
B. Other useful laboratory studies include glucose, arterial blood gases, and pulse oximetry.

V. Treatment

A. Emergency and supportive measures

1. Protect the airway and assist ventilation if necessary (pp 1–7).
2. Treat coma (p 18), hypotension (p 15), and hypothermia (p 20) if they occur. Hypotension usually responds promptly to supine
position and IV fluids.
B. Specific drugs and antidotes. Flumazenil (p 556) is a specific benzodiazepine receptor antagonist that can rapidly reverse coma. However,
because benzodiazepine overdose by itself is rarely fatal, the role of flumazenil in routine management has not been established. It is administered
IV with a starting dose of 0.1–0.2 mg, repeated as needed up to a maximum of 3 mg. It has
some important potential drawbacks:
1. It may induce seizures in patients who have co-ingested medications with proconvulsant activity.
2. It may induce acute withdrawal, including seizures and autonomic instability, in patients who are addicted to benzodiazepines.
3. Resedation is common when the drug wears off after 1–2 hours, and repeated dosing or a continuous infusion is often required.
C. Decontamination (p 50). Consider activated charcoal if the ingestion occurred within the previous 30 minutes and other conditions are
appropriate (see Table I–38, p 54). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
D. Enhanced elimination. There is no role for diuresis, dialysis, or hemoperfusion. Repeat-dose charcoal has not been studied.

OPIATES AND OPIOIDS

Timothy E. Albertson, MD, MPH, PhD
Opiates are a group of naturally occurring compounds derived from the juice of the poppy Papaver somniferum. Morphine and
codeine are classic opiate derivatives used widely in medicine; heroin (diacetylmorphine) is a well-known semi-synthetic, highly addictive street
narcotic. The term opioid refers to opiates and semi-synthetic derivatives of naturally occurring opium (eg, morphine, heroin, codeine, and
hydrocodone) as well as new, totally synthetic opiate analogs (eg, fentanyl, butorphanol, meperidine, and methadone [Table II–47]). A wide
variety of prescription medications contain opioids, often in combination with aspirin or acetaminophen. Dextromethorphan (p 215) is an opioid
derivative with potent antitussive but no analgesic or addictive properties. Tramadol (Ultram) is an analgesic that is unrelated chemically to the
opiates but acts on mu-opioid receptors and blocks serotonin reuptake. Butorphanol is available as a nasal spray with rapid absorption.
Buprenorphine is a partial opioid agonist that is approved for the treatment of opioid addiction. Suboxone is a sublingual tablet containing
buprenorphine plus naloxone to reduce intravenous abuse. Tapentadol alkaloid mitragynine is the active component of kratom found in the
Southeast Asian tree Mitragyna speciosa Kroth; it has stimulant and opioid-like effects, and has been used for self-treatment of opioid
withdrawal.
I. Mechanism of toxicity

A. In general, opioids share the ability to stimulate a number of specific opiate receptors in the CNS, causing sedation and respiratory
depression. Death results from respiratory failure, usually as a result of apnea or pulmonary aspiration of gastric contents. In addition,
acute noncardiogenic pulmonary edema may occur by unknown mechanisms. In addition to its opioid-like effects, kratom may also
stimulate postsynaptic alpha-2 adrenergic and serotonergic (5HT2A) receptors.
B. Pharmacokinetics. Usually, peak effects occur within 2–3 hours, but absorption may be slowed by the pharmacologic effects of
opioids on GI motility. Slow-release preparations of morphine (eg, MS Contin), oxymorphone (eg, Opana ER) or oxycodone (eg,
OxyContin) may have a delayed onset of action and prolonged effects. With fentanyl patches, dermal absorption can continue even
after removal. Smoking or ingesting fentanyl patches can result in rapid and high levels. Most of these drugs have large volumes of
distribution (3–5 L/kg). The rate of elimination is highly variable, from 1 to 2 hours for fentanyl derivatives to 15–30 hours for
methadone (see also Tables II–47 and II–66). Some patients have been found to be rapid metabolizers of codeine (to morphine
through the hepatic enzyme CYP2D6), which may increase the risk for acute intoxication.

II. Toxic dose. The toxic dose varies widely, depending on the specific compound, the route and rate of administration, and tolerance to
the effects of the drug as a result of chronic use. Some newer fentanyl derivatives have potency up to 2,000 times that of morphine.

III. Clinical presentation

A. With mild or moderate overdose, lethargy is common. The pupils are usually small, often of “pinpoint” size. Blood pressure and
pulse rate are decreased, bowel sounds are diminished, and the muscles are usually flaccid.
B. With higher doses, coma is accompanied by respiratory depression, and apnea often results in sudden death. Noncardiogenic
pulmonary edema may occur, often after resuscitation and administration of the opiate antagonist naloxone.
C. Seizures are not common after opioid overdose but occur occasionally with certain compounds (eg, codeine, dextromethorphan,
kratom, meperidine, methadone, propoxyphene, and tramadol). Seizures may occur in patients with renal compromise who receive
repeated doses of meperidine owing to accumulation of the metabolite normeperidine.
D. A leukoencephalopathy with typical magnetic resonance imaging (MRI) changes has been reported in some heroin smokers (“chasing
the dragon”).
E. Cardiotoxicity similar to that seen with tricyclic antidepressants (p 107) and quinidine (p 398) can occur in patients with severe
propoxyphene intoxication. Prolonged QTc intervals and torsade de pointes have been reported with methadone and may account for
 some of the sudden deaths associated with its use. The R-enantiomer of methadone is apparently more active at the mu receptor and
less likely to affect the hERG channel (and thus the QTc interval) compared with the S-enantiomer.
F. Some newer synthetic opioids have mixed agonist and antagonist effects, with unpredictable results in overdose. Buprenorphine
causes less maximal opioid effect than morphine does, and because of strong binding to opioid receptors it can cause acute withdrawal
symptoms in persons on high doses of conventional opioids.
G. Opioid withdrawal syndrome can cause anxiety, piloerection (goose bumps), heightened sensation of pain, abdominal cramps and
diarrhea, and insomnia.

IV. Diagnosis is simple when typical manifestations of opiate intoxication are present (pinpoint pupils and respiratory and CNS
depression) and is confirmed when the patient quickly awakens after administration of naloxone. Signs of intravenous drug abuse (eg,
needle track marks) may be present.
A. Specific levels are not usually performed because of poor correlation with clinical effects. Qualitative screening of the urine is an
effective way to confirm recent use (codeine, morphine, hydrocodone, hydromorphone). Fentanyl derivatives, tramadol, and some
other synthetic opioids are not detected by routine toxicologic screens (see Table I–31, p 45). Separate immunoassays are available for
oxycodone/oxymorphone and 6-acetylmorphine (heroin-specific metabolite).
B. Other useful laboratory studies include electrolytes, glucose, arterial blood gases or oximetry, chest radiography, and stat serum
acetaminophen or salicylate levels (if the ingested overdose was of a combination product.)
C. Genetic polymorphisms. Individuals who are ultra-rapid metabolizers for CYP2D6 (eg, *1 gene duplication) are at risk for morphine
toxicity at therapeutic codeine doses. CYP 2D6 tests are available through reference laboratories.

V. Treatment

A. Emergency and supportive measures

1. Maintain an open airway and assist ventilation if necessary (pp 1–7). Administer supplemental oxygen.
2. Treat coma (p 18), seizures (p 23), hypotension (p 15), ventricular arrhythmias (p 13) and noncardiogenic pulmonary edema (p 7) if
they occur.

B. Specific drugs and antidotes

1. Naloxone (p 584) is a specific opioid antagonist with no agonist properties of its own; large doses may be given safely.
a. As little as 0.2–0.4 mg IV or IM is usually effective for heroin overdose. Repeat doses every 2–3 minutes if there is no response, up to
a total dose of 10–20 mg if an opioid overdose is strongly suspected. Intranasal naloxone is effective but not as effective as IM
naloxone in the prehospital setting
b. Caution: The duration of effect of naloxone (1–2 hours) is shorter than that of many opioids. Therefore, do not release a patient who
has awakened after naloxone treatment until at least 3–4 hours has passed since the last dose of naloxone. In general, if naloxone was
required to reverse opioid-induced coma, it is safer to admit the patient for at least 6–12 hours of observation.
2. Nalmefene (p 584) is an opioid antagonist with a longer duration of effect (3–5 hours).
a. Nalmefene may be given in doses of 0.1–2 mg IV, with repeated doses of up to 10–20 mg if an opioid overdose is strongly suspected.
b. Caution: Although the duration of effect of nalmefene is longer than that of naloxone, it is still much shorter than that of methadone.
If a methadone overdose is suspected, the patient should be observed for at least 8–12 hours after the last dose of nalmefene.
3. Sodium bicarbonate (p 520) may be effective for QRS-interval prolongation or hypotension associated with propoxyphene
poisoning.

C. Decontamination (p 50). Administer activated charcoal orally if conditions are appropriate (see Table I–38, p 54). Gastric lavage is not
necessary after small-to-moderate ingestions if activated charcoal can be given promptly. Consider whole-bowel irrigation after ingestion of
sustained-release products (eg, MS Contin, OxyContin, Opana ER).

D. Enhanced elimination. Because of the very large volumes of distribution of the opioids and the availability of an effective antidotal
treatment, there is no role for enhanced elimination procedures.

ACETAMINOPHEN
Kent R. Olson, MD
Acetaminophen (Anacin-3, Liquiprin, Panadol, Paracetamol, Tempra, Tylenol, and many other brands) is a widely used drug found in many over-
the-counter and prescription analgesics and cold remedies. When it is combined with another drug, such as diphenhydramine, codeine,
hydrocodone, oxycodone, dextromethorphan, or propoxyphene, the more dramatic acute symptoms caused by the other drug may mask the mild
and nonspecific symptoms of early acetaminophen toxicity, resulting in a missed diagnosis or delayed antidotal treatment. Common combination
products containing acetaminophen include the following: Darvocet, Excedrin ES, Lorcet, Norco, NyQuil, Percocet, Unisom Dual Relief
Formula, Sominex 2, Tylenol with Codeine, Tylenol PM, Tylox, Vicks Formula 44-D, and Vicodin.

I. Mechanism of toxicity

A. Hepatic injury. One of the products of normal metabolism of acetaminophen by cytochrome P450 (CYP) mixed-function oxidase
enzymes is highly toxic; normally this reactive metabolite (NAPQI) is detoxified rapidly by glutathione in liver cells. However, in an
overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts directly with hepatic macromolecules, causing
liver injury.
B. Renal damage may occur by the same mechanism, owing to renal CYP metabolism.
C. Overdose during pregnancy has been associated with fetal death and spontaneous abortion.
D. Very high levels of acetaminophen can cause lactic acidosis and altered mental status by uncertain mechanisms, probably involving
mitochondrial dysfunction.
E. Pharmacokinetics. Acetaminophen is rapidly absorbed, with peak levels usually reached within 30–120 minutes. (Note: Absorption
may be delayed after ingestion of sustained-release products [Tylenol Extended Release, Tylenol Arthritis] or with co-ingestion of
 opioids or anticholinergics.) Volume of distribution (Vd) is 0.8–1 L/kg. Elimination is mainly by liver conjugation (90%) to nontoxic
glucuronides or sulfates; mixed-function oxidase (CYP2E1, CYP1A2) accounts for only about 3–8% but produces a toxic
intermediate (see Item A above). The elimination half-life is 1–3 hours after a therapeutic dose but may be greater than 12 hours after
an overdose (see also Table II–66, p 462).

II. Toxic dose

A. Acute ingestion of more than 200 mg/kg in children or 6–7 g in adults is potentially hepatotoxic.
1. Children younger than 10–12 years appear to be less susceptible to hepatotoxicity because of the smaller contribution of CYP to
acetaminophen metabolism.
2. In contrast, the margin of safety may be lower in patients with induced CYP microsomal enzymes because more of the toxic
metabolite may be produced. High-risk patients include alcoholics and patients taking inducers of CYP2E1, such as isoniazid.
Fasting and malnutrition may also increase the risk for hepatotoxicity, presumably by lowering cellular glutathione stores.
B. Chronic toxicity has been reported after daily consumption of supratherapeutic doses. A consensus guideline from the American
Association of Poison Control Centers (AAPCC) recommends medical evaluation if more than 150 mg/kg/d (or 6 g/d) has been
ingested for 2 days or longer. One study reported elevated transaminases in more than one-third of healthy volunteers given doses of 4
g/d for several days.
1. Children have developed toxicity after receiving as little as 100–150 mg/ kg/d for 2–8 days. The AAPCC
guideline recommends medical evaluation for doses of more than 150 mg/kg/d for 2 days or 100 mg/kg/d for
3 days or more. There is a single case report of hepatotoxicity in an infant receiving 72 mg/kg/d for 10 days.
2. As with acute overdose, the risk for injury from chronic use may be greater in alcoholic patients and persons
taking isoniazid and other drugs that induce CYP2E1.
C. Intravenous acetaminophen (10 mg/mL) is now available and 10-fold dosing errors have occurred. An acute overdose of more than
150 mg/kg is considered potentially toxic. (One report of hepatotoxicity after 75 mg/kg IV acetaminophen was probably due to other
complications leading to ischemic liver injury.)

III. Clinical presentation. Clinical manifestations depend on the time after ingestion.

A. Early after acute acetaminophen overdose, there are usually no symptoms other than anorexia, nausea, or vomiting. Rarely, a massive
overdose may cause altered mental status, hypotension, and metabolic acidosis in the absence of any laboratory evidence of liver
damage. Transient prolongation of the prothrombin time/international normalized ratio (PT/INR) in the absence of hepatitis has been
noted in the first 24 hours; some, but not all, of these patients go on to develop liver injury.
B. After 24–48 hours, when aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise, hepatic necrosis
becomes evident. If acute fulminant hepatic failure occurs, death may ensue. Encephalopathy, metabolic acidosis, and a continuing
rise in PT/INR indicate a poor prognosis. Acute renal failure occasionally occurs, with or without concomitant liver failure.
C. Chronic excessive use of acetaminophen.
1. Patients often have nausea and vomiting, and may already show evidence of hepatic injury by the time they seek medical care.
2. Glutathione depletion associated with chronic acetaminophen ingestion has also been associated with anion gap metabolic acidosis
due to the accumulation of 5-oxoproline.

IV. Diagnosis. Prompt diagnosis is possible only if the ingestion is suspected and a serum acetaminophen level is obtained. However, patients
may fail to provide the history of acetaminophen ingestion because they are unable (eg, comatose from another ingestion), unwilling, or unaware
of its importance. Therefore, many clinicians routinely order acetaminophen levels in all overdose patients regardless of the history of substances
ingested.
A. Specific levels. Note: 1 mg/L = 1 mcg/mL = 6.6 mcmol/L.
1. After an acute oral or intravenous overdose, obtain a serum acetaminophen level 4 hours after the overdose and use the nomogram
(Figure II–1) to predict the likelihood of toxicity. Do not attempt to interpret a level drawn before 4 hours unless it is
“nondetectable.” Obtain a second level at 8 hours if the 4-hour value is borderline or if delayed absorption is anticipated.
2. The nomogram should not be used to assess chronic or repeated ingestions.
3. Falsely elevated acetaminophen levels may occur in the presence of high levels of salicylate and other interferents by certain older
laboratory methods (see Table I–33, p 46). This problem is rare with currently used analytic methods.
B. Other useful laboratory studies include electrolytes (presence of an anion gap), glucose, BUN, creatinine, liver aminotransferases,
bilirubin, and PT/INR.

V. Treatment

A. Emergency and supportive measures

[Link] vomiting may delay the oral administration of antidote or charcoal (see below) and can be treated with metoclopramide
(p 581) or a serotonin (5-HT3) receptor antagonist such as ondansetron (p 597).
2. Provide general supportive care for hepatic or renal failure if it occurs. Emergency liver transplant may be necessary for fulminant
hepatic failure. Encephalopathy, metabolic acidosis, hypoglycemia, and a progressive rise in the prothrombin time are indications of
severe liver injury.
B. Specific drugs and antidotes
1. Acute single ingestion or intravenous overdose
a. If the serum level falls above the treatment line on the nomogram or if stat serum levels are not immediately available,
initiate antidotal therapy with N-acetylcysteine (NAC; p 499). The effectiveness of NAC depends on early treatment,
 before the toxic metabolite accumulates; it is of maximal benefit if started within 8–10 hours and of diminishing value after
12–16 hours; however, treatment should not be withheld even if the delay is 24 hours or more. If vomiting interferes with
or threatens to delay oral acetylcysteine administration, give the NAC IV.
b. If the serum level falls below but near the nomogram line, consider giving NAC if the patient is at increased risk for
toxicity—for example, if the patient is alcoholic, is taking a drug that induces CYP2E1 activity (eg, isoniazid [INH]), or
has taken multiple or subacute overdoses—or if the time of ingestion is uncertain or unreliable.
c. If the serum level falls well below the nomogram line, few clinicians would treat with NAC unless the time of ingestion is
very uncertain or the patient is considered to be at particularly high risk.
d. Note: After ingestion of extended-release tablets (eg, Tylenol Extended Release, Tylenol Arthritis Pain), which are
designed for prolonged absorption, there may be a delay before the peak acetaminophen level is reached. This can also
occur after co-ingestion of drugs that delay gastric emptying, such as opioids and anticholinergics (eg, Tylenol PM). In
such circumstances, repeat the serum acetaminophen level at 8 hours and possibly 12 hours. In such cases, it may be
prudent to initiate NAC therapy before 8 hours while waiting for subsequent levels.
e. Duration of NAC treatment. The conventional US protocol for the treatment of acetaminophen poisoning calls for 17
doses of oral NAC given over approximately 72 hours. However, for decades successful protocols in the United States,
Canada, the United Kingdom, and Europe have used IV NAC for only 20 hours. In uncomplicated cases, give NAC (orally
or IV) for 20 hours (or until acetaminophen levels are no longer detectable) and follow hepatic transaminase levels and the
PT/INR; if evidence of liver injury develops, continue NAC until liver function tests are improving.
f. Massive ingestion. Although data is lacking, it is recommended to use a higher dose of NAC to treat very large overdoses.
The intravenous NAC protocol delivers a total of only 300 mg/kg NAC over 21 hours, compared with the oral regimen
which delivers a total of 1,190 mg/kg NAC over 72 hours. See NAC, p 499 for detailed recommendations.
2. Chronic or repeated acetaminophen ingestions: Patients may give a history of several doses taken over 24 hours or more, in which
case the nomogram cannot accurately estimate the risk for hepatotoxicity. In such cases, we advise NAC treatment if the amount
ingested was more than 200 mg/kg within a 24-hour period, 150 mg/kg/d for 2 days, or 100 mg/kg/d for 3 days or more; if liver
enzymes are elevated; if there is detectable acetaminophen in the serum; or if the patient falls within a high-risk group (see above).
Treatment may be stopped when acetaminophen is no longer detectable if the liver enzymes and PT/INR are normal.
C. Decontamination (p 50). Administer activated charcoal orally if conditions are appropriate (see Table I–38, p 54). Gastric lavage is not
necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
1. Although activated charcoal adsorbs some of the orally administered antidote NAC, this effect is not considered clinically important.
2. Do not administer charcoal if more than 1–2 hours has passed since ingestion unless delayed absorption is suspected (eg, as with
Tylenol Extended Release, Tylenol Arthritis Pain, or co-ingestants containing opioids or anticholinergic agents).
D. Enhanced elimination. Hemodialysis effectively removes acetaminophen from the blood but is not generally indicated because antidotal
therapy is so effective. Dialysis should be considered for massive ingestions with very high levels (eg, over 900–1,000 mg/L) complicated
by severe acidosis, coma and/or hypotension.

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