Toxicology

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CHAPTER 30 Toxicology

I. Basic Definitions

A. Toxicology refers to the study of poisons and toxins and how they interact with the body, both internal and external.
B. Clinical toxicology focuses on the toxic effects of therapeutic agents and nontherapeutic agents including drugs of abuse, household products, pesticides, metals, radiation, and other chemicals entities.

II. General Approach

A. ABCs and D

1. Airway
2. Breathing
3. Circulation
4. Decontamination

B. Medical history

1. Medications (Prescription, over-the-counter [OTC], herbals, supplements, vitamins, illicit drugs)
2. Alcohol use
3. Allergies
4. Occupation

C. Physical examination

1. Vital signs: blood pressure, heart rate, respiratory rate, temperature
2. Mouth
3. Pupils
4. Breath sounds
5. Bowel sounds
6. Skin
7. Urination
8. Neurologic exam

D. Laboratory tests and imaging

1. Complete blood cell (CBC) count
2. Electrolytes
3. Urinalysis
4. Blood glucose
5. Blood urea nitrogen (BUN)

E. Diagnosis, antidotes

1. Decontamination

a. Skin

1. Protect yourself
2. Remove clothing
3. Flush with water or normal saline

b. Eye

1. Remove contact lens and discard it
2. Flush with water or normal saline

c. Inhalation

1. Observe for airway obstruction
2. Intubate if necessary

d. Gastrointestinal

1. Induce emesis

a. Syrup of ipecac

1) Consume within minutes of ingestion (30 mL repeated after 20 minutes if ineffective)
2) Contraindicated when the patient is comatose, lethargic, having convulsions, unable to protect his/her airway, caustic or alkali ingestions
3) Rarely given; no longer recommended by the American Association of Poison Control Centers

2. Gastric lavage

a) Use for ingestions of highly toxic substances and substances not well absorbed by active charcoal (lithium, lead, iron); patients with altered mental status or alertness

3. Activated charcoal

a) Cannot bind acids, bases, ethanol (EtOH), methanol, ethylene glycol, hydrocarbons, iron, lead, lithium, potassium, mercury
b) Commonly used for poisonings with carbamazepine, phenytoin, salicylates, digitalis, and theophylline
c) Multiple dosing: 1 g/kg every 2–6 hours
d) Most effective when given within 2 hours of ingestion
e) Most useful for poisons that are enterohepatic recycled
f) Adverse effects: chemical pneumonitis caused by charcoal aspiration

4. Cathartics

a) Purgative agent used to evacuate the bowels
b) Example: sorbitol

III. Specific Toxins and Management

A. Acetaminophen

1. Narrow therapeutic range. Maximum dose: 4 g daily or 90 mg/kg daily (children); lower in patients with hepatic disease or with concomitant alcohol use.
2. Presentation

a. Stage I (0–24 hours): nausea, vomiting (primarily asymptomatic)
b. Stage II, latent stage (24–48 hours): increase in liver function tests (e.g., Alanine Aminotransferase [ALT], Asparate Aminotransferase [AST], and bilirubin)
c. Stage III, hepatic stage (3–4 days): liver failure, jaundice, vomiting, hypoglycemia, renal failure, metabolic acidosis
d. Stage IV, recovery stage (4 days–2 weeks): resolution of hepatic dysfunction

3. Influential factors of toxicity

a. Chronic alcoholics and the elderly are at an increased risk for hepatic disease even at therapeutic doses
b. Glucose 6 phosphate dehydrogenase (G6PD) deficiency

4. Management

a. GI decontamination with activated charcoal
b. Antidote: in patients with toxic blood levels, N-acetylcysteine 140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses

B. Anticholinergics

1. Agents with anticholinergic properties

a. Atropine
b. Antihistamines (e.g., diphenhydramine, meclizine, promethazine)
c. Antipsychotics (e.g., clozapine, thioridazine)
d. Antispasmodics (e.g., dicyclomine, oxybutynin)
e. Tricyclic antidepressants (e.g., amitriptyline, imipramine)
f. Mydriatics (e.g., homatropine)
g. Botanicals (e.g., Atropa belladonna, Datura stramonium)

2. Presentation: dry mucous membranes, altered mental status, flushed skin, mydriasis, fever, tachycardia, hypertension, urinary retention, seizures
3. Laboratory evaluation: no specific diagnostic studies exist
4. Management

a. ABCs
b. GI decontamination
c. Activated charcoal
d. Supportive care

1) Tachycardia: crystalloid infusions
2) Agitation: benzodiazepines
3) Fever: fluids, antipyretics

e. Antidote: physostigmine 2 mg IV at a slow, controlled rate (no faster than 4 minutes)

C. Benzodiazepines

1. Presentation: drowsiness, slurred speech, nystagmus, ataxia, hypotension, coma with respiratory depression
2. Management

a. Gastric lavage
b. Antidote: flumazenil (Romazicon)

1) Used in severe overdose (i.e., comatose patient) and patients with significant cardiorespiratory depression
2) IV dose: 0.2 mg IV in 30 seconds; repeat doses of 0.3 mg in 30 seconds at 1-minute intervals
3) Do not exceed 3 mg in 1 hour
4) Avoid in patients with mixed overdose particularly those who have taken tricyclic antidepressants; flumazenil may induce seizures

D. Digoxin

1. Presentation: nausea, vomiting, diarrhea

a. Acute: asytmptomatic for hours followed by gastrointestinal symptoms; bradydysrhythmias or supraventricular with AV block, high digoxin levels, hyperkalemia, visual changes (halos, blurred vision, changes in color perception)
b. Chronic: altered mental status, flu-like symptoms, gastroenteritis, dysrhythmias, lower potassium levels

2. Complications: hyperkalemia, arrhythmias (initially as sinus bradycardia, followed by atrial tachyarrhythmias with or without heart block)
3. Laboratory evaluation

a. Potassium

1) After acute poisoning, potassium may become dangerously elevated.
2) Temporary elevated potassium levels are acceptable in chronic toxicity.
3) High potassium levels may offer protection because hypokalemia increases glycoside binding to the Na-K pump and worsens poisoning of the pump.

b. Digoxin levels

1) Therapeutic level: 0.5–2 ng/μL

c. Renal and hepatic function

4. Management

a) Activated charcoal
b) Manage hyperkalemia or hypokalemia
c) Sinus bradyarrythmias and AV block: atropine
d) Ventricular tachycarrythmias: IV phenytoin
e) Digoxin-specific Fab antibodies (Digibind)

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1) Adverse effects: hypokalemia from rapid digoxin removal, cardiogenic shock, hypersensitivity reactions (rare)

E. Salicylates

1. Presentation: tachypnea, tachycardia, hyperthermia, altered serum glucose, dehydration, abdominal pain, nausea/vomiting, tinnitus, lethargy, altered mental status, seizures, respiratory alkalosis, metabolic acidosis
2. Toxic dose: 160 mg/kg
3. Lethal dose: 480 mg/kg
4. Complications: hypokalemia, hyperglycemia, pulmonary edema, acute renal failure, GI bleed, hypoprothrombinemia
5. Management

a. ABCs
b. Activated charcoal with sodium bicarbonate
c. Urinary alkalinization (initiate when serum level is > 35 mg/dL) achieved by administration of sodium bicarbonate
d. Dialysis for severe acidemia, volume overload, pulmonary edema, cardiac or renal failure, seizures, coma, or levels of more than 100 mg/dL in acute ingestion or more than 60–80 mg/dL in chronic ingestion

F. Cyclic antidepressants

1. Examples: amitriptyline, doxepin, imipramine
2. Presentation: dry mouth, blurred vision, sinus tachycardia, urinary retention, myoclonic jerking, agitation, hallucinations, quinidine-like arrhythmias, hypotension, convulsions, coma
3. Management

a. Activated charcoal
b. Alkalinization
c. Benzodiazepines (diazepam) or phenytoin to control seizures

G. Sympathomimetics

1. Examples: amphetamines, cocaine, PCP, LSD
2. Presentation: tremor, agitation, moist skin (sweating), mydriasis, hypertension, delirium, seizure
3. Laboratory evaluation: electrolytes, BUN, creatinine, blood glucose, creatinine kinase (CK) levels, urine drug screening
4. Management

a. Supportive care: ABCs
b. For agitation, benzodiazepines (diazepam, lorazepam) may be used.
c. Butyrophenones (e.g., haloperidol) are NOT recommended as they may lower seizure thresholds and prolong QT duration
d. For hypertension, an easily titrated agent such as nitroprusside may be used.
e. For QRS prolongation, ventricular arrhythmias, and hypotension, intravenous sodium bicarbonate is used.

H. Warfarin

1. Presentation: bleeding, nosebleeds, bleeding of gums, vomiting blood, dark brown urine, red or black color in stool, unusual pain or swelling, headache, dizziness, weakness
2. Laboratory evaluation

a. Prothrombin time (PT), international normalized ratio (INR), bleeding time

3. Management

a. Acute

1) Activated charcoal
2) Gastric lavage
3) If the PT is elevated, treat with vitamin K. Patients with acute hemorrhage may be administered fresh frozen plasma (FFP).

b. Chronic

1) If INR is higher than therapeutic levels but less than 6 and the patient is not bleeding, withhold warfarin for 2–3 days and restart when the INR approaches the therapeutic range.
2) If INR is between 6 and 10 and the patient is not bleeding, administer 5–10 mg of vitamin K1 orally.
3) If the INR is higher than 10 and the patient is not bleeding, a higher dose of vitamin K1 may be administered.
4) If INR > or = 9.0 and bleeding, vitamin K is given parenterally. Consult hematology. May require fresh frozen plasma.

I. Beta blockers

1. Presentation: hypotension, bradycardia, lethargy, bronchospasm (rare), seizures
2. Laboratory evaluation

a. Blood glucose, electrolytes (potassium), electrocardiogram

3. Management

a. Activated charcoal, gastric lavage
b. Glucagon (adults): 3–10 mg IV bolus followed by 2–5 mg/h infusion
c. Benzodiazepines if seizures occur

J. Calcium channel blockers

1. Presentation: hypotension, bradycardia, altered mental status, seizures
2. Laboratory evaluation

a. Blood glucose, arterial blood gas (ABG)

3. Management

a. Activated charcoal
b. Gastric lavage
c. Glucagon 5–15 mg IV bolus followed by infusion of 10–15 mg/h
d. Calcium chloride bolus of 1–2 grams (10–20 mL 10%) plus continuous infusion of 20–40 mg/kg per hour (0.2–0.4 mL/kg per hour 10%)

K. Cyanide

1. Presentation: tachypnea, bradypnea, tachycardia, bradycardia, hypoxia, hypotension, mydriasis, shock, seizures
2. Laboratory evaluation: cyanide levels, blood gases, serum lactate, hemoglobin, electrolytes
3. Management

a. Hydroxocobalamin: 50 mg/kg IV in 30 minutes or 5 g IV in 30 minutes (faster if patient is in cardiac arrest); may repeat dose once. Do not exceed total dose of 15 g; when repeated, infusion should be slow, lasting 8 hours.
b. Amyl nitrite: one ampule crushed and inhaled every 30 seconds until IV access is available for administration of sodium nitrite
c. Sodium nitrite: 10 mL of 3% solution slow IV push during 2–5 minutes
d. Sodium thiosulfate: 50 mL of a 25% solution (12.5 g) IV infused at 5 mL/min; 25 mL of solution may be administered 30 minutes after first dose

L. Ethylene glycol (antifreeze)

1. Ingredient in radiator fluid
2. Presentation

a. Stage 1, neurological (30 minutes to 12 hours after ingestion): nausea, vomiting, transient inebriation, euphoria, coma associated with hypotonia, hyporeflexia, occasional seizures, and meningismus
b. Stage 2, cardiopulmonary (12–24 hours after ingestion): tachycardia, hypertension, compensatory hyperventilation
c. Stage 3, renal (24–72 hours after ingestion): oliguria, flank pain, acute tubular necrosis, renal failure, bone marrow suppression (rare)

3. Laboratory test: calcium level, arterial blood gas, urinalysis
4. Management

a. Gastric lavage within 30 minutes of ingestion
b. Fomepizole: Loading dose: 15 mg/kg IV in 30 minutes; maintenance dose: 15 mg/kg IV every 12 hours until patient is asymptomatic with a normal pH level and the ethylene glycol level is <20 mg/dL
c. Ethanol (EtOH) (when fomepizole is not available):

1) Loading dose (IV): 7.6–10 mL/kg IV of 10% ethanol (v/v) in dextrose 5% in water during 30 minutes to achieve blood EtOH concentration of 100–130 mg/dL (21.7–28.2 mmol/L)
2) Loading dose (oral): 0.8–1 mL/kg PO of 95% ethanol in 6 oz of orange juice during 30 minutes
3) Maintenance doses (PO/IV): 0.15 mL/kg per hour PO of 95% EtOH; 1.4 mL/kg per hour IV of a 10% solution

a) Add Pyridoxine 100 mg IV four times daily for 2 days
b) Add Thiamine 50 mg IV four times daily for 2 days

M. Iron

1. Presentation: somnolence, hyperventilation from acidosis, cardiovascular collapse, abdominal tenderness, muscle rigidity, loose stool, pulmonary edema, altered mental status
2. Laboratory evaluation: serum iron concentration, CBC, electrolytes, renal profile, liver function tests, PT/INR, acid-base measurements

a. Iron levels drawn more than 6 hours after ingestion may not accurately portray level of toxicity due to ferritin-binding and iron redistribution

3. Management: deferoxamine mesylate

a. Indication: peak serum iron level greater than 500 mcg/dL, shock, lethargy/coma, persistent diarrhea or vomiting, anion gap acidosis, or a significant number of pills visualized on radiograph
b. Dose: 1000 mg IM, followed by 500 mg 4 and 8 hours later; based on the response of the patient, 500 mg may be administered every 4–12 hours IM; do not exceed 6000 mg in 24 hours

N. Opioids

1. Presentation: drowsiness, euphoria, depressed consciousness, CNS depression, respiratory depression, papillary miosis, ventricular arrhythmias, seizures, mydriasis
2. Laboratory evaluations

a. ABGs
b. Toxicology screen
c. CBC
d. Metabolic panel

3. Management

a. Naloxone (Narcan)

1) Opioid antagonist
2) Short half-life
3) Dose: 0.1–2 mg/dose IV/IM (dose varies depending on the circumstance); may repeat in 1- to 2-minute intervals following IV use and 10-minute intervals after IM administration
4) Discontinue treatment as soon as desired degree of opioid reversal achieved

O. Organophosphates

1. Presentation: cholinergic stimulation (SLUDGE = salivation, lacrimation, urination, diarrhea, GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and salivation)
2. Laboratory evaluation: RBC cholinesterase
3. Management

a. Decontamination
b. Atropine: 1–2 mg IV bolus, repeat every 3–5 minutes as needed for desired effects (drying of pulmonary secretions and adequate oxygenation)
c. Pralidoxime (2-PAM): 1–2 g IV in 100 mL isotonic sodium chloride solution/D5W in 15–30 minutes; repeat in 1 hour. If muscle weakness is not relieved, repeat every 3–8 hours if signs of poisoning reoccur
d. Benzodiazepines (e.g., diazepam): for treatment of seizures

REVIEW QUESTIONS

(Answers and Rationales on page 384.)

1. A 62-year-old African American man presents to the emergency department complaining of weakness, palpitations and dizziness; he also has low blood pressure. The patient has prolonged QRS complex. It appears that the patient has ingested a toxic amount of amitriptyline. The patient should receive which of the following?

a. Sodium bicarbonate
b. Ipecac
c. Calcium chloride
d. Epinephrine
e. None of the above

2. Which of the following may be used in treatment of cyanide overdose?

I. Amyl nitrite
II. Sodium thiosulfate
III. Hydroxocobalamin
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

3. A 22-year-old woman presents to the emergency department 3 hours after ingesting 50 acetaminophen tablets (500 mg). Her initial acetaminophen level was 122 mcg/mL approximately 4 hours after ingestion. What is the most appropriate treatment for this patient?

a. Forced hyperventilation
b. Sodium bicarbonate
c. Lorazepam
d. Esmolol
e. N-Acetylcysteine repeated in 4 hours

4. An elderly woman presents to the pharmacy inquiring about ipecac. She would like to keep a bottle in her daughter’s house in case of an emergency. What is the most appropriate response?

I. Providing her the phone number of a poison control center
II. Informing her that ipecac is no longer recommended by the American Association of Poison Control Centers
III. Dispensing a bottle of ipecac that is kept behind the counter
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

5. What is/are the major effect(s) of anticholinergic toxicity?

I. Tachycardia
II. Dry mucus membranes
III. Urinary retention
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

6. A 28-year-old woman with a history of depression and post-traumatic stress disorder presents to the emergency department 5 hours after ingesting 500 tablets of aspirin (325 mg each) as a suicide attempt. She denies ingesting any other chemical or drug. Vital signs: heart rate 118 beats per minute; blood pressure 112/60 mm Hg; respiratory rate 22 breaths per minute; temperature 99°F. Serum drug screen reveals a salicyalte level of 630 mcg/mL. What is the most appropriate initial treatment for this patient?

a. N-Acetylcysteine
b. Vitamin K
c. Sodium bicarbonate
d. Charcoal and sorbitol
e. Ipecac

7. Which of the following agents would NOT be used for ethylene glycol toxicity?

a. Ethanol (EtOH)
b. Fomepizole
c. Pyridoxine
d. Atropine
e. Thiamine

8. Which of the following is the antidote for morphine overdose?

a. Sodium bicarbonate
b. Naloxone
c. Thiamine
d. Haloperidol
e. Diazepam

9. Flumazenil is used as an antidote for which of the following circumstances?

a. Cocaine overdose
b. Acetaminophen overdose
c. Amitriptyline overdose
d. Alprazolam overdose
e. Iron overdose

10. A 72-year-old woman (80 kg) with normal renal function has accidentally been taking twice the prescribed dose of digoxin. Her digoxin serum concentration is 4.1 ng/mL. What is the appropriate dose of Digibind for this patient?

a. 2 vials
b. 4 vials
c. 6 vials
d. 8 vials
e. 10 vials

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