After absorption, approximately 90% of acetaminophen is metabolized by the liver and conjugated to glucuronide and sulfate. A very small amount of the drug is excreted unchanged in the urine, and approximately 2% or less is metabolized by cytochrome P450 enzymes to a toxic metabolite called N-acetyl-benzoquinone imine (NAPQI). When acetaminophen is taken in therapeutic doses, NAPQI is conjugated with hepatic glutathione (an antioxidant tripeptide synthesized in the liver) and excreted in the urine and bile. This conjugation with glutathione prevents NAPQI from causing hepatic damage.

Acetaminophen toxicity represents an imbalance between how much NAPQI is formed and how much glutathione is available. When a toxic amount of acetaminophen is ingested, the glucuronide and sulfate pathways of metabolism become saturated and a larger proportion of the drug is metabolized to NAPQI. Glutathione stores in the liver are quickly diminished, and when the available amount of glutathione has been reduced to approximately 20% to 30% of the pre-exposure levels, liver damage occurs [8,9]. NAPQI covalently binds to mitochondrial proteins in the hepatocytes, causing oxidative stress that impairs mitochondrial function and causes hepatic cell death [10]. Other organ systems can be damaged by an overdose of acetaminophen, but liver damage is the most common effect.

Unless it is certain that acetaminophen has not been ingested, an acetaminophen level should be measured in all patients who have taken medications with the intent or a suspected intent to cause self-harm. The toxic amount of acetaminophen for adults and children 6 years of age or older is ≥10 grams or ≥200 mg/kg, whichever is less. [11] The amount of acetaminophen that is potentially toxic for children younger than 6 years of age is ≥200 mg/kg [11].

The initial signs and symptoms of acetaminophen toxicity are gastrointestinal, specifically nausea and vomiting. These are usually mild in severity and will resolve within 12 hours of the ingestion. Many patients are asymptomatic. The exception to this is a massive acetaminophen overdose. Patients who take 75–100 grams of acetaminophen may quickly develop coma, metabolic acidosis, and abnormal vital signs. However, these cases are very uncommon, and unless a massive overdose was taken or a co-ingestant was involved, the patient will have normal temperature, pulse, and blood pressure and will be awake, alert, and oriented. If a patient has taken an overdose of acetaminophen and is clinically unstable, it is prudent to first determine if other medications were taken.

A serum acetaminophen measurement should be obtained four hours or later from the time of ingestion. The level is plotted on the Rumack-Matthew nomogram (Figure 1), and depending on where on the nomogram the level falls, it will be considered toxic or non-toxic. Measuring the serum acetaminophen level and using the nomogram is the most reliable way of determining if a patient has ingested a toxic amount of the drug.

The serum transaminases, AST and ALT, are commonly measured on liver function tests (LFTs), and these tests are the most sensitive marker of liver injury caused by acetaminophen poisoning. The AST and ALT levels typically begin to rise 24 hours after ingestion of a toxic amount of acetaminophen, but this elevation can occur as early as eight hours and as late as 36 hours post-ingestion [12,39,40]. AST and ALT levels greater than 10,000 IU/L following acetaminophen poisoning are not uncommon.

NAC is a highly effective antidote if used correctly. It is most effective if it is given within 8 to 10 hours after the ingestion of acetaminophen, and its effectiveness begins to decline after that point [6,83]. Glutathione stores are depleted to 20% to 30% of pre-exposure levels at 8 to 10 hours post-ingestion, and this appears to be the critical point at which NAPQI binds to hepatocytes.

Aspirin adversely affects the hair cells of the cochlea. As a result, tinnitus is a well-known and commonly reported direct toxic effect of aspirin use and overdose. Hearing loss can occur, but fortunately this is rarely a permanent effect [103,104].

When a large amount of aspirin is taken, the absorption of the drug can be significantly delayed for several reasons. Aspirin is known to cause pylorospasm, which can delay the absorption of the drug [103,110]. Large amounts of aspirin can also form a bezoar, a concretion of foreign material in the gut [103,112]. This phenomenon is particularly common after an overdose of enteric-coated aspirin or when a patient has a gastric outlet obstruction [112].

Hyperventilation and tachypnea cause many patients to initially present with respiratory alkalosis. As the clinical course progresses and more aspirin is absorbed, the compensatory ability of the kidneys and the lungs become overwhelmed. In addition, the disruption of oxidative phosphorylation and changes in glucose and fatty acid metabolism become more pronounced and metabolic acidosis can occur [103,105]. This a very serious concern, because it affects aspirin pharmacokinetics and it also adversely affects cardiovascular functioning and neurological status [107,116]. The low serum pH of metabolic acidosis increases the amount of aspirin that is non-ionized, allowing aspirin to cross the blood-brain barrier and enter the CNS tissues and to be more easily reabsorbed by the kidney tubules. A mixed acid-base disturbance—metabolic acidosis with respiratory compensation—is also commonly seen.

Hypokalemia or hyperkalemia may also be seen after an aspirin overdose. Respiratory alkalosis increases renal excretion of bicarbonate and potassium, and metabolic acidosis shifts potassium from the intracellular space to the extracellular space.

The initial physical assessment should focus on the patient's neurologic and pulmonary status. CNS depression, tachypnea, and low oxygen saturation are specific indications that the patient has a serious poisoning. Intubation and mechanical ventilation may be needed to stabilize the patient, but this is a potentially dangerous procedure when attempted in patients with aspirin overdose. If airway control is necessary, a high tidal volume and rapid respiratory rate are essential to allow the normal compensatory hyperventilation [103,105,116]. However, this is difficult to accomplish, and a worsening acidosis is a definite possibility. It is not part of the physical exam, but metabolic acidosis indicates the potential for serious toxicity.

Gastric decontamination techniques may be used to remove drugs before they are absorbed. The decontamination technique of choice for aspirin poisoning is activated charcoal.

Serial salicylate levels should be measured every two hours until at least two successive levels are noted to be within or below the normal range and are decreasing. However, serial measurements of aspirin alone should not be used for determining whether the patient is or is not at risk. The patient's acid-base status should be evaluated, and a physical exam performed every two hours to determine the level of risk and the patient's progress. Salicylate levels should be interpreted in the context of the patient's acid-base and neurologic status. Periodic measurements of serum glucose and potassium should also be done, as hypokalemia and changes in serum glucose are common in aspirin overdose.

Urinary alkalinization is the primary therapeutic intervention for treating mild-to-moderate aspirin overdoses [103]. Increasing the serum pH and creating an alkaline environment will ionize aspirin, preventing it from crossing the blood-brain barrier and being re-absorbed by the renal tubules. This effect is called "ion trapping," and it lowers serum aspirin levels, changes concentration gradients, moves aspirin out of the tissues, and increases the renal excretion of the drug. In addition, the urinary excretion of salicylate is dependent on urine pH; increasing the urine pH from 5.0 to 8.0 will dramatically increase renal clearance.

The usual formula for urinary alkalinization is to give the patient an IV bolus of 50% sodium bicarbonate, 1–2 mEq per kg, and then begin a continuous infusion with three 50-mL ampules of 50% sodium bicarbonate in 1,000 mL of 5% dextrose in water [103,105]. Some sources recommend that 40 mEq of potassium chloride be added to the continuous infusion fluid, but alkalinization will not work if the patient is hypokalemic or if she/he is dehydrated. So hypokalemia and volume depletion should be corrected before or during alkalinization [103,105]. The solution should be infused at 1.5 to 2 times the patient's basic fluid requirement, at least, and the primary goals of this therapy are to attain a urinary pH of ≥7.5 and to ensure a good urine output [103,105,116]. Done correctly, urinary alkalinization can increase the urinary excretion of aspirin 10-fold [116]. Urine pH should be checked every one to two hours and the infusion rate adjusted as needed. Therapy should be continued until successive serum salicylate levels are less than 30–40 mg/dL and the patient has no clinical or laboratory evidence of salicylate poisoning [103].

Most patients who take an overdose of ibuprofen have minor, temporary signs and symptoms; serious toxicity and death are rare [134,135,136,137]. The clinical effects are usually seen within four hours of the ingestion, and most patients experience mild, temporary gastrointestinal distress and CNS depression [129]. Gastrointestinal symptoms include anorexia, epigastric pain, nausea, and vomiting. Significant gastrointestinal bleeding is uncommon. Metabolic acidosis is a well-described but rarely seen effect of ibuprofen overdose, and there have been reports of coma, hypotension, shock, seizures, oliguria, elevations of BUN and creatinine, and other signs of renal damage after ibuprofen overdose [138,139,140,141,142,143,144,145,146,147,148]. In severe cases, liver damage is possible [134].

Less than 100 mg/kg of ibuprofen is considered nontoxic, and ingestions of more than 400 mg/kg are potentially serious [129,149,150,151]. Reports of serious morbidities like coma, metabolic acidosis, and renal failure have all involved ingestions of more than 20 grams or 400 mg/kg (e.g., 600 mg/kg, 1,200 mg/kg, 72 grams, 100 grams) [135,152,153,154,155].

Less than 100 mg/kg of ibuprofen is considered nontoxic, and ingestions of more than 400 mg/kg are potentially serious [129,149,150,151]. Reports of serious morbidities like coma, metabolic acidosis, and renal failure have all involved ingestions of more than 20 grams or 400 mg/kg (e.g., 600 mg/kg, 1,200 mg/kg, 72 grams, 100 grams) [135,152,153,154,155].

Patients who have taken a potentially toxic amount of ibuprofen should be observed for at least four to six hours [129,149]. Treatment is symptomatic and supportive; there is no antidote for ibuprofen poisoning. Depending on the patient's clinical condition, age, and prior medical history, IV hydration may be administered. At the end of the observation period, it may be prudent to measure BUN, creatinine, and serum electrolytes again. Patients who are very young or who have or are at risk for renal disease may require longer periods of observation and more frequent measurements of acid-base status and renal function.