Nonsteroidal Anti-Inflammatory Drugs Toxicity

Etiology

Most NSAIDs are derived from organic acids and are rapidly absorbed in the gastrointestinal (GI) tract, ensuring a quick onset of action. They undergo extensive hepatic metabolism, primarily through the cytochrome P450 2C9 enzymes, and are eliminated via renal excretion, which involves glomerular filtration and tubular secretion. Due to these metabolic pathways, NSAIDs are generally contraindicated in patients with significant hepatic impairment or renal dysfunction, as reduced clearance can lead to drug accumulation and increased toxicity risk.

Because NSAIDs are highly protein-bound in plasma, they effectively concentrate at sites of inflammation, allowing for rapid analgesic relief typically within 30 to 60 minutes of administration. However, recent studies have highlighted interindividual variability in NSAID metabolism, influenced by genetic polymorphisms in hepatic enzymes and renal function status. This highlights the importance of dose adjustments and careful patient selection, especially in individuals with pre-existing hepatic, renal, or cardiovascular conditions.[3][4][5]

Epidemiology

Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been utilized as effective over-the-counter and prescription medications for alleviating pain and reducing fever. As of 2010, approximately 29 million adults in the United States reported long-term NSAID use, a number that has likely increased with the aging population and the rising prevalence of conditions such as osteoarthritis and inflammatory diseases.

This widespread usage correlates with a notable incidence of adverse drug reactions (ADRs). In one study, approximately 5% of urgent hospital admissions are attributable to ADRs. It implicated NSAIDs as the cause for 16.8% of the hospital admissions.[6][7][8][9][7]

Pathophysiology

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a diverse class of medications that, despite their chemical differences, share common therapeutic and adverse effects. They alleviate inflammation, pain, and fever by inhibiting cyclooxygenase (COX) enzymes, specifically COX-1 and COX-2. These enzymes convert arachidonic acid into endoperoxide metabolites, including prostacyclin, prostaglandins, and thromboxane, which play roles in inflammation, regulation of smooth muscle tone, and thrombosis. COX-1 is constitutively expressed and primarily produces prostanoids essential for physiological functions like gastric mucosal protection. In contrast, COX-2 is inducible, and its production of prostanoids is significantly upregulated during stress and inflammation. While each isozyme has distinct roles, COX-1 and COX-2 contribute to the development of inflammatory responses.

Most NSAIDs are derived from organic acids and are rapidly absorbed from the gastrointestinal (GI) tract. They undergo extensive hepatic metabolism and are excreted through glomerular filtration and tubular secretion. Consequently, NSAIDs are typically contraindicated in patients with severe hepatic and renal dysfunction. Due to their high plasma protein binding, NSAIDs readily accumulate at sites of inflammation, providing rapid analgesic relief within 30 to 60 minutes.

NSAIDs have long been utilized as effective over-the-counter and prescription medications for pain relief and fever reduction. As the population ages, medical conditions requiring pain control are expected to rise. This escalation may result in a higher incidence of adverse events associated with NSAID use. Studies have indicated that 5% to 7% of hospital admissions are due to drug toxicity, with non-aspirin NSAIDs contributing to 11% to 12% of these cases.

The mechanisms of action of NSAIDs vary slightly depending on their chemical composition. Aspirin, derived from salicylic acid, irreversibly binds to cyclooxygenase, causing a conformational change that prevents further metabolism of arachidonic acid. In contrast, traditional NSAIDs like ibuprofen reversibly inhibit both COX-1 and COX-2, thereby decreasing the synthesis of prostanoids. Additionally, a subclass of NSAIDs, including celecoxib, was developed as selective COX-2 inhibitors with minimal COX-1 affinity to reduce unwanted GI adverse effects.

NSAIDs are commonly used to manage pain of low to moderate intensity. They are frequently part of treatment plans for acute musculoskeletal injuries, headaches, arthralgia, postoperative pain, inflammation-associated pain, and menstrual pain. Prostanoids, such as PGE2, are known effectors of pain and inflammation. The characteristic signs of inflammation—redness, heat, swelling, and pain—result from increased blood flow and vascular permeability mediated by PGE2-induced arterial dilation. Pain perception is partly due to PGE2’s excitation of peripheral sensory neurons and specific central nervous system sites. The antipyretic effects of NSAIDs are partly due to their ability to suppress PGE2-triggered hypothalamic elevation of body temperature in response to infection or inflammation. Aspirin's role in thrombosis and cardioprotection involves its irreversible inhibition of COX-1 in mature platelets, preventing the generation of thromboxane A2, a potent promoter of platelet activation and vasoconstriction. Aspirin’s irreversibility allows its effects to last the life of the platelet, approximately one week, leading to a cumulative antiplatelet effect with continued dosing. Beyond these significant uses, NSAIDs are also indicated for other conditions, such as neonatal cases of patent ductus arteriosus, increasing niacin tolerability, and rare disorders of upregulated prostaglandin synthesis like systemic mastocytosis resistant to antihistamines.

Prostanoids have a wide range of effects on smooth muscle tonicity within the vasculature, respiratory and gastrointestinal tracts, reproductive organs, and kidneys. Thromboxane also has specific actions related to platelet function. These extensive physiological roles impart significant therapeutic utility upon NSAIDs but may also contribute to their adverse effects and toxicity.

The most common adverse effects of NSAIDs involve the GI system, including risks of ulceration, bleeding, or perforation. While these risks can occur at any time in patients of any age, they are more prevalent in the older population. Other undesirable GI events may include nausea, dyspepsia, loss of appetite, abdominal pain, and diarrhea resulting from erosion of the alimentary canal. Prostanoids, such as PGE2 and PGI2, contribute to GI mucous secretion and promote vasodilation, thereby enhancing blood flow and bicarbonate delivery to mucosal surfaces. Inhibition of COX-1 reduces these cytoprotective effects.

Serious cardiovascular adverse events may also be associated with NSAID use. Historically, attention has been drawn to the increased incidence of myocardial infarction and stroke, particularly with the selective COX-2 inhibitor rofecoxib, which was removed from the market in 2004. Subsequent studies have provided evidence that celecoxib is not associated with a higher rate of cardiovascular events compared to non-selective NSAIDs. However, widely recognized adverse effects include blood pressure elevation and exacerbation of congestive heart failure through inhibition of prostanoid-induced salt excretion and changes in renal arteriolar tone. These risks tend to be dose- and duration-dependent and are further increased with tobacco use, alcohol consumption, and unhealthy habits.[10][11][12][13][14][15][16]

Toxicokinetics

As previously described, prostanoids have a wide range of effects on smooth muscle tonicity within the vasculature, respiratory and gastrointestinal tracts, reproductive organs, and even the kidneys. Additionally, thromboxane has specific actions related to platelet function. Therefore, these extensive physiologic consequences impart incredible therapeutic utility upon NSAIDs but may also contribute to the adverse effects and toxicity of this drug class.

Most commonly, the risk of severe GI adverse effects, including ulceration, bleeding, or perforation, is increased with NSAID consumption. Though these risks can occur at any time in patients of any age, these adverse events tend to present more commonly in the elderly. Other undesirable GI events may include nausea, dyspepsia, loss of appetite, abdominal pain, and diarrhea from erosion of the alimentary canal. It is well understood that prostanoids such as PGE2 and PGI2 constitutively contribute to GI mucous secretion. Additionally, these prostanoids promote vasodilation, allowing for enhanced blood flow and bicarbonate delivery to mucosal surfaces. Primary inhibition of COX-1 reduces these cytoprotective effects.

Serious cardiovascular adverse events may also be associated with the use of NSAIDs. Historically, much attention had been drawn to the increased incidence of myocardial infarction and stroke, particularly with the selective COX-2 inhibitor rofecoxib, which was removed from the market in 2004. Since then, similar inquiries regarding the cardiovascular safety of the remaining selective COX-2 inhibitor, celecoxib, and non-selective NSAIDs have been investigated. A 2016 study, known as the PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) trial, provided strong evidence that celecoxib is not associated with a higher rate of cardiovascular events compared to non-selective drugs. However, widely recognized adverse effects include blood pressure elevation and the potentiation or exacerbation of congestive heart failure, resulting from the inhibition of natural prostanoid-induced salt excretion and changes in renal arteriolar tone. Such risks tend to be dose- and duration-dependent. Ultimately, it is essential to establish that the risk of unfavorable cardiovascular events associated with NSAID use is further increased with tobacco use, alcohol consumption, and generally unhealthy habits.

Less commonly, individuals who consume NSAID medication may experience renal adverse effects. As noted above, NSAIDs have been found to interfere with prostanoid-regulated mechanisms that affect afferent arterioles within nephrons, thereby reducing the glomerular filtration rate. With drug use, the loss of arteriolar dilation opposes prostanoids’ reno-protective effects and increases the risk of acute kidney injury due to decreased renal blood flow. Additional manifestations of NSAID-induced renal toxicity include renal papillary necrosis and interstitial nephritis. The renal papillae are known to be sensitive to the loss of renal blood flow. Ischemic injury from drug-associated vasoconstriction can result in gross hematuria. Interstitial nephritis may occur in individuals who are hypersensitive to the analgesic class, typically presenting with acute inflammation within the kidney, characterized by eosinophilic pyuria and azotemia.

Aside from these independent toxicities, NSAIDs may also result in adverse effects when taken concurrently with numerous other drugs. As a result of their pharmacokinetics, NSAIDs may interact with other high plasma protein-bound drugs, displacing them and leading to an increase in the free serum concentration of these drugs. Drugs with narrow therapeutic windows, such as warfarin or phenytoin, can theoretically reach toxic levels when displaced in this manner. Additionally, NSAIDs may increase the toxicity of drugs that are dependent on renal clearance (such as lithium) or hepatic metabolism because some NSAIDs reduce renal perfusion and inhibit cytochrome P450 (CYP) enzymes or glucuronidation.

Other notable drug interactions occur during concurrent use of NSAIDs and antihypertensives, anticoagulants and antiplatelets, selective serotonin receptor inhibitors (SSRIs), and substances that injure GI mucosa. The effects of many antihypertensives are diminished due to the ability of NSAIDs to reduce natriuresis. Besides decreased efficacy, specific use of NSAIDs with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may exacerbate potassium retention, known to have significant cardiac consequences. Simultaneous use of NSAIDs and anticoagulants or antiplatelets can result in an increased risk of bleeding due to reduced platelet aggregation. Bleeding risk is also similarly increased with concomitant use of SSRIs and NSAIDs, as serotonin is one of many substances taken up by and released from platelets to stimulate aggregation and hemostasis. Lastly, the risk of peptic ulcer disease or a GI bleed is markedly increased when NSAIDs are ingested in combination with alcohol or glucocorticoids, which inhibit the activation of the arachidonic acid precursor phospholipase A2.[17][18][11][19][20]

History and Physical

In cases of suspected drug toxicity, the appropriate history must include the specific medication taken, the amount consumed, and the time it was ingested. Additional information, such as potential co-ingestants, is also crucial to the history of the presenting illness to rule out other life-threatening overdoses or drug interactions. Besides an acute change in a patient's mental status, the physical exam is generally unremarkable. Other clinical manifestations may include GI distress, such as nausea and vomiting, dizziness, drowsiness, and blurred vision. However, clinical features of toxicity may depend on other comorbidities that may influence NSAID toxicity. Healthcare providers must be attentive in history-taking to identify risk factors or comorbidities that may potentiate NSAID adverse effects or possible drug interactions.[21]

Evaluation

After a history and physical have been obtained, evaluation for suspected NSAID toxicity should include pertinent laboratory testing for levels of common co-ingestants such as acetaminophen and salicylate. Other laboratory assessments may be guided by clinical presentation. For instance, a baseline assessment of renal function, as indicated by blood urea nitrogen, creatinine, and electrolyte levels, may be helpful in symptomatic patients or those who have consumed a significantly large amount (ie, greater than 6 grams in an adult or greater than 400 mg/kg in a child) of the drug. If a patient presents with bleeding likely induced by NSAID use, a complete blood count will allow for monitoring of hemoglobin and platelet counts. An arterial blood gas can help determine the acid-base status of a patient if there is concern for massive ingestion, and an electrocardiogram can provide evidence of QT interval prolongation in the setting of potential coingestant consumption that may result in adverse effects on the cardiac conduction system. Last, clinicians must always consider other possible etiologies of altered mental status and may order tests to assess for differential diagnoses such as hypoglycemia. By conducting these targeted laboratory assessments, healthcare providers can more effectively identify and manage the multifaceted effects of NSAID toxicity, thereby ensuring comprehensive patient care.

Treatment / Management

Management of nonsteroidal anti-inflammatory drug (NSAID) toxicity primarily involves supportive care, with specific interventions tailored to the severity of the overdose and the time elapsed since ingestion. Initial assessment should focus on stabilizing the patient's airway, breathing, and circulation. For patients presenting within two hours of a significant NSAID ingestion, administration of activated charcoal is recommended to limit gastrointestinal absorption, provided there are no contraindications such as compromised airway protection or decreased consciousness. In cases of massive ingestion, continuous monitoring of vital signs, renal function, and acid-base balance is essential, as severe toxicity can lead to complications like metabolic acidosis, acute renal failure, and central nervous system effects, including seizures and coma.

Aspirin (acetylsalicylic acid), while classified as an NSAID, has distinct pharmacokinetic and toxicological properties compared to other NSAIDs. Aspirin overdose can result in a unique clinical presentation characterized by mixed respiratory alkalosis and metabolic acidosis, tinnitus, and hyperthermia. Management of aspirin toxicity may require specific interventions, such as urinary alkalinization with intravenous sodium bicarbonate to enhance salicylate excretion, and, in severe cases, hemodialysis to rapidly reduce salicylate levels. These measures are generally not applicable to overdoses involving non-aspirin NSAIDs. 

While the fundamental management of  NSAID toxicity centers on supportive care and symptomatic management, recognizing the differences between aspirin and other NSAIDs is crucial. Aspirin toxicity may necessitate more aggressive interventions, including urinary alkalinization and hemodialysis, due to its unique toxicokinetics. Healthcare providers should be vigilant in identifying the specific NSAID involved in an overdose to implement the most appropriate and effective treatment strategies. 

Differential Diagnosis

Differential diagnoses include: 

• Abdominal pain in the older patients 
• Acute lactic acidosis 
• Anxiety disorders
• Chronic anaemia
• Delirium, dementia, and amnesia in emergency medicine
• Encephalitis 
• Peptic ulcer disease 
• Stevens-johnson syndrome
• Toxic epidermal necrolysis