Direct Drug Effects

Nearly all drugs produce harmful effects if taken in excessive amounts. Systemic toxicity is due to selective effects of the toxin or a metabolite on specific targets, such as binding to specific receptors (therapeutic drugs), disruption of metabolic pathways (cyanide, salicylates, iron), cellular production of toxic metabolites (acetaminophen in the liver, methanol in the retina, ethylene glycol in the kidney), and enzymatic inhibition (Na⁺/K⁺-ATPase by digoxin; anticholinesterase by organophosphates). Some toxins produce effects by several mechanisms. For example, isoniazid causes both hepatotoxicity via a cytochrome P-450 pathway metabolite and neurotoxicity via the inhibition of pyridoxal 5′-phosphate. Pathologic effects may also occur at the site of exposure as a result of cytotoxic chemical reactions (e.g., caustic acid or alkali ingestions) that damage exposed tissue.

Complications

Aspiration occurs in poisoned patients as a complication of vomiting, orogastric lavage, endotracheal intubation, or loss of airway reflexes because of obtundation. Early assessment and definitive airway management are critical in diminishing the risk of aspiration. Acute lung injury may complicate recovery following life-threatening ingestions. Hyperthermia may occur for several reasons: increased motor activity that occurs with agitation or seizures, direct drug effects on the hypothalamus (sympathomimetics), or aspiration and pneumonia. Rhabdomyolysis (see Chapter 81) can occur in patients after prolonged periods of immobilization because of obtundation, protracted agitation or seizures, or cocaine or amphetamine use. Under these circumstances, aggressive hydration and maintenance of urine output are important. Acute renal failure (see Chapter 81) may occur directly, for example, from ethylene glycol direct toxic effects on the kidneys or secondarily, for example, from drug-induced hypotension. Acute hepatic failure (see Chapter 59) most commonly results from acetaminophen poisoning but may also occur because of the multiorgan effects of diffuse toxins such as mercury or iron.

Diagnostic Approach

Initial assessment of the airway, breathing, and circulatory status (ABCs) and frequent reassessment are critical to monitoring the dynamic status of ongoing toxicity. Empty pill bottles or discussions with family members regarding medicines available in the home are helpful in focusing the diagnostic workup. Physical examination should screen for manifestations of common toxic syndromes (“toxidromes”)—for example, anticholinergic, opioid, or salicylate toxicity. An electrocardiogram can screen for conduction defects associated with cyclic antidepressants, calcium channel antagonists, beta-blockers, or digoxin. QR and QT prolongation herald impending cardiotoxicity and should be followed serially. Toxicology screening should be performed if the results will be available in a sufficiently short time frame to be clinically relevant. All patients with intentional ingestions should have an acetaminophen level checked to exclude a clinically silent, potentially overlooked but treatable acetaminophen ingestion.

Therapeutic Approach

After initial stabilization of the ABCs, certain therapies should be considered in all poisoned patients. Suspected hypoglycemia should be treated with an intravenous (IV) bolus of concentrated dextrose solution (50 mL of 50% dextrose). Patients with the triad of signs suggesting opioid toxicity (respiratory depression, pinpoint pupils, and coma) warrant treatment with the opioid antagonist naloxone. IV fluid therapy is important in many patients with overdoses to compensate for volume losses associated with vomiting. Parenteral benzodiazepine sedation is indicated for agitated or uncooperative patients because it may prevent rhabdomyolysis, hyperthermia, and injuries to the patient or staff as well as decrease the risk of seizures.

Gastrointestinal (GI) decontamination is no longer routinely recommended for most overdose patients but may have a limited role in some patients with serious toxicity admitted to the ICU. Orogastric lavage via a large-bore tube (Ewald tube) may be critical in patients ingesting large quantities of drugs not bound by activated charcoal, such as iron or lithium. It can be life saving in serious calcium channel antagonist overdoses by removing a clinically significant fraction of drug, decreasing toxicity. Orogastric lavage should only be considered in patients manifesting signs of toxicity following a potentially life-threatening ingestion, and only perform it after the judging the patient’s airway to be protected, often necessitating endotracheal intubation.

Oral activated charcoal can diminish the absorption of many drugs and can enhance drug excretion for some agents via GI dialysis (the diffusion of high plasma drug levels back into the gut lumen to be bound to activated charcoal and excreted) or interruption of enterohepatic circulation of active metabolites. Sustained release preparations (e.g., calcium channel blockers) and drugs not bound to activated charcoal (e.g., lithium, iron) may be cleared from the gut using whole bowel irrigation. Bowel irrigation is performed with polyethylene glycol–electrolyte lavage solutions (e.g., GoLYTELY, CoLYTE) administered via nasogastric tube at a rate of 1 to 2 L/h in adults.

The regional poison control center should be consulted to obtain general management and toxin-specific therapeutic advice, as many common toxins have specific therapies or antidotes (Table 57.1).

Acetaminophen

Acetaminophen is one of the most commonly ingested medications. Few patients become seriously ill from acetaminophen overdose because of early diagnosis and antidote treatment with N-acetylcysteine (NAC). Life-threatening hepatotoxicity, however, occurs in the few who present late after their ingestions or in whom clinicians fail to recognize acetaminophen when it is co-ingested with other drugs.

Patients with a history of acetaminophen ingestion should have a > 4-hour post ingestion acetaminophen level obtained and interpreted using the Rumack-Matthew nomogram (Figure 57.1). Nausea, vomiting, and sometimes right upper quadrant abdominal pain are associated with toxic hepatitis from ingestions a day or two earlier. Patients with jaundice or coagulopathy or those reporting a large acetaminophen ingestion 1 to 3 days previously should be presumed to have hepatotoxicity and should have treatment initiated immediately. When presentations are delayed more than 24 hours after ingestion, acetaminophen levels may be low or zero, but significant elevations in transaminases and prothrombin time reflect severe acetaminophen poisoning.

Therapeutic doses of acetaminophen are metabolized in the liver by glucuronidation (60%), sulfation (30%), or by the P-450 cytochrome oxidase system (4%). The last pathway results in a toxic intermediate, N-acetyl-p-benzoquinoneamine (NAPQI). NAPQI is then normally reduced by glutathione, which prevents toxicity. With increasing dose or overdose, more acetaminophen metabolism is shunted into the P-450 system, depleting glutathione. As a result, NAPQI accumulates and induces centrilobular necrosis of the liver. The antidote NAC replenishes the glutathione and prevents hepatic necrosis (Chapter 59).

Patients with toxic acetaminophen levels require a loading dose of NAC (140 mg/kg) and subsequent dosing every 4 hours (70 mg/kg) for an additional 17 doses over 72 hours. NAC can also be given parenterally with a loading dose of 150 mg/kg IV over 60 minutes then by continuous IV infusion over 20 hours (see Table 57.1). Although most effective within the first 8 hours after overdose, NAC therapy is effective up to 24 hours after overdose as well as in patients with fulminant hepatic failure secondary to acetaminophen. The current recommended dose and route of administration (orally versus IV) in these situations can be obtained via the local poison center. NAC should be continued until the acetaminophen level is zero and the liver function tests are trending down.

Alcohols

The clinical effects of ethanol intoxication can range from giddiness to coma and is affected by time and quantity ingested, tolerance, and co-ingestants. When presented with patients with presumed ethanol-induced altered mental status, although debated in the literature, measurement of ethanol levels may confirm the clinical correlation as well as prevent inappropriate assumptions that high ethanol levels are the etiology of the altered mental status in any one patient. The initial evaluation of any patient acutely intoxicated with alcohol should address whether significant co-ingestants may be present and add to impending morbidity. Such considerations include ingestion of other central nervous system (CNS) depressants that may add to eventual respiratory depression such as benzodiazepines or other sedatives, as well as the ingestion of toxic alcohols as ethanol substitutes.

The toxic alcohols to consider include methanol, ethylene glycol, and isopropanol. Methanol is found in Sterno, windshield washer fluids, and industrial solvents. Ethylene glycol is the principal ingredient in most antifreeze preparations and is also used in deicing agents. Isopropanol is commonly used as rubbing alcohol and as a solvent in home products. These substances are readily available to ingest as an alcohol substitute in patients who are made abstinent from alcohol or, in other cases, secondary to suicidal intention. The presence of an anion gap acidosis in a patient with suspected ethanol intoxication should promote a diagnostic search for the presence of methanol or ethylene glycol. The findings of an osmolar gap or anion gap acidosis can be helpful when making the diagnosis but must be interpreted with caution depending on the time since ingestion and the amount of metabolism that may have occurred. Soon after ingestion, either ethanol or a toxic alcohol will cause an elevated osmolar gap because all alcohols are osmotically active. Over several hours, this osmolar gap will diminish, whereas an anion gap acidosis will develop if methanol or ethylene glycol were ingested instead of ethanol. These toxic alcohols will undergo metabolism to an organic acid (formic acid in methanol poisoning and glycolic acid and oxalic acid in ethylene glycol poisoning). This acidosis, as well as the exclusion of other causes of metabolic acidosis (lactic acid, salicylate ingestion), helps confirm the suspicion of toxic alcohol ingestion while confirmatory methanol and ethylene glycol levels are obtained.

Other clinical symptoms that suggest toxic alcohol ingestion are alcohol specific. Methanol exposure is characterized by visual symptoms that develop within 12 to 24 hours of exposure. Patients complain of “snow field” vision that occurs from formic acid–mediated retinal toxicity. Ethylene glycol may cause acute tubular necrosis and acute renal failure 12 to 48 hours after ingestion because of calcium oxalate precipitants in the kidneys. The principal toxicity of isopropanol ingestion is CNS depression, lethargy, and coma as well as ketosis but not a metabolic acidosis because isopropanol is metabolized to acetone contributing to an osmolar gap but not an anion gap acidosis.

Laboratory testing should include finger-stick glucose, electrolytes, ethanol level with other alcohols, and serum osmolarity. Urine fluorescence with a Wood’s lamp can detect the presence of antifreeze (and presumably ethylene glycol) shortly after ingestion; however, this finding is not always present. An electrocardiogram (EKG) may show QT prolongation secondary to hypocalcemia from calcium oxalate precipitation in the kidneys.

Fomepizole, like ethanol, blocks metabolism of the toxic alcohols by competitively inhibiting the enzyme alcohol dehydrogenase and is the recommended treatment for suspected ethylene glycol and methanol poisoning. When available, fomepizole is preferred to an ethanol infusion because it does not require following serum ethanol levels and increases safety by not adding synergistic respiratory depression. Hemodialysis still has a role in toxic alcohol ingestions and should be discussed with the nephrology team. Traditional indications for hemodialysis include severe acidosis, renal failure, or inability to obtain fomepizole or ethanol therapy. If an elevated level of ethylene glycol or methanol is discovered, administer fomepizole, but if an acidosis is not yet present, some patients can be managed expectantly with fomepizole and not dialysis.