Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Toxicity

Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are being prescribed on a large scale globally.

Even when consumed in large amounts, most regularly used NSAIDs have fewer severe side effects; but, as over-the-counter and prescription NSAID use rises year after year, so do the number of overdoses and NSAID-related complications. Moreover, adverse events linked to medication interactions or exposure to patients at risk for developing NSAID toxicity are frequent and may have a severe impact on morbidity and mortality.

Most NSAID exposures involve mild-to-moderate gastrointestinal (GI) symptoms such as nausea, vomiting, and chemical and electrolyte abnormalities. These symptoms usually subside quickly with supportive therapy. In cases of massive ingestions, a few individuals may experience altered levels of consciousness that lead to coma. Metabolic acidosis and multisystem organ failure are other progressive symptoms.

What Are NSAIDs or Nonsteroidal Anti-Inflammatory Drugs?

• Nonsteroidal anti-inflammatory drugs, also known as NSAIDs, have a wide range of chemical compositions however many of the same beneficial and harmful effects.

• The drugs inhibit the cyclooxygenase (COX) enzymes responsible for endoperoxide synthesis. All the medications in this family work to reduce inflammation, pain, and fever.

• Arachidonic acid is transformed by the cyclooxygenase isozymes COX-1 and COX-2 (enzymes that are responsible for various normal processes in the body) into its endoperoxide metabolites, prostacyclin, prostaglandins, and thromboxane.

• These products play a role in various biological activities, such as inflammation, smooth muscle tone, and thrombosis.

The majority of NSAIDs are made from organic acids and are quickly absorbed from the GI tract. These medications are eliminated through glomerular filtration and tubular secretion after undergoing significant hepatic metabolism. NSAIDs are often contraindicated in patients with severe renal and hepatic impairment for these reasons. As NSAIDs are predominantly linked to plasma proteins, they accumulate easily and quickly in sites of inflammation, resulting in acute analgesia within 30 to 60 minutes.

What Is the Pathophysiology of NSAID Toxicity?

Depending on the chemical nature, the mechanism of action varies for the drugs within the same class. Aspirin, which is a salicylic acid derivative, forms a covalent bond and binds irreversibly to cyclooxygenase, causing structural changes and hence preventing any further metabolism of arachidonic acid.

There are two known isoforms of cyclooxygenase. The production of prostaglandins by cyclooxygenase-1 (COX-1) has been suggested to maintain organ function, safeguard the integrity of the stomach mucosa, and produce platelet-derived thromboxane, which is responsible for platelet aggregation (clumping of platelets to form a clot) and vasoconstriction (narrowing of the blood vessels). Every tissue expresses COX-1.

During the inflammatory response, cyclooxygenase-2 (COX-2) is produced and makes prostaglandins that control pain and inflammation. Moreover, the kidneys and vascular endothelium both express COX-2. The more traditional, older NSAIDs, like Ibuprofen, mostly inhibit COX-1 rather than COX-2, whereas the more recent family of NSAIDs, like Celecoxib, primarily inhibit COX-2, reducing gastrointestinal side effects. Nonetheless, an overdose may result in the loss of selectivity in inhibition.

Almost all NSAIDs reduce prostaglandin synthesis as they reversibly inhibit cyclooxygenase (COX), which is an enzyme that catalyzes the creation of prostaglandins and thromboxanes from its precursor, arachidonic acid.

What Are the Toxic Effects of NSAIDs?

• Gastrointestinal Tract - NSAID increases the risk of serious gastrointestinal side effects such as ulceration, bleeding, or perforation. Even though individuals of any age can experience these dangers at any moment, elderly people tend to experience these adverse events more frequently. Other gastrointestinal symptoms that result from erosion of the alimentary canal include nausea, dyspepsia, appetite loss, stomach discomfort, and diarrhea.

• Cardiovascular Effects - Elevated blood pressure and congestive heart failure are among the adverse effects. These risks are also dependent on the dose and duration of NSAID intake.

• Renal Effects - Renal effects are less commonly seen. Excess consumption of NSAIDs affects the afferent arterioles and hence decreases the glomerular filtration rate. Effects of renal toxicity also include interstitial nephritis and renal papillary necrosis. The decrease in renal blood flow is known to cause the renal papillae to become sensitive. Hematuria can be caused by ischemic damage from drug-associated vasoconstriction. People who are hypersensitive to the analgesic class may develop interstitial nephritis (a kidney disorder that causes inflammation or swelling of the spaces between the kidney tubules). which is characterized by acute kidney inflammation, eosinophilic pyuria (the presence of white blood cells in the urine), and azotemia (an increase in the level of urea and other nitrogenous waste in the body).

• Toxic Effects Due to Drug Interaction - The capability of NSAIDs to lower natriuresis (sodium excretion in the urine) reduces the effectiveness of several antihypertensives. In addition to decreased effectiveness, the use of NSAIDs in particular combinations with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may worsen potassium retention, which leads to serious cardiac effects. When NSAIDs are taken in conjunction with alcohol or glucocorticoids, which prevent the activation of the arachidonic acid precursor phospholipase (name of an enzyme), the risk of peptic ulcer disease or a GI bleed is noticeably enhanced.

What Is the Pathophysiology of NSAID Toxicity?

• The breathing rate is altered. Slow (bradypnea) or rapid (tachypnea) breathing is seen in the patients.

• Seizures, muscle twitching, and coma are seen; however, they are not specific signs of NSAID toxicity.

• Perforations and bleeding of the gastrointestinal tract are seen.

• Metabolic acidosis and electrolyte imbalances are present.

• Delayed manifestations involve heart failure, kidney failure, and liver failure.

What Is the Treatment for NSAID Toxicity?

Acute nonsteroidal anti-inflammatory drug (NSAID) poisoning is mostly managed symptomatically and supportively. Airway, breathing, and circulatory stability are the first steps in stabilization (ABCs). The management of NSAID poisoning does not have a particular antidote; hence, in most cases, supportive care is needed, such as restoring electrolyte balance, replenishing intravascular volume, or treating any existing acid-base problems. On the other hand, NSAIDs should be kept to a minimum or, if at all possible, removed entirely from a patient's medication regimen to treat chronic toxicity.

1. Medication Therapy - Pharmacotherapy aims to lower hazardous medication levels, avoid problems, and reduce morbidity.

• Gastrointestinal Decontaminant -

1. These substances bind to NSAIDs and prevent their absorption from the gastrointestinal tract.

2. Gastric decontamination can be done in the patient with activated charcoal if there is no clinical sign of a perforated viscus. In order to avoid charcoal aspiration, the patient should be able to safeguard their airway (for example, normal mental status, preserved gag reflex, lack of vomiting).

3. In individuals who present later than one to four hours after ingesting, activated charcoal may not be necessary. There is no proof that administering activated charcoal to drug overdose patients on an emergency basis improves their clinical outcomes.

4. Orogastric lavage may be necessary for individuals who have been exposed to significant overdoses recently and especially if they are intubated.

• Alkalinizing Agents -

1. Sodium Bicarbonate - Though sodium bicarbonate is not an antidote for NSAID toxicity, it should be taken into consideration in addition to other supportive therapy in an acidosis situation. In mild to moderate NSAID toxicity, transient acidosis normally resolves quickly and on its own. Bicarbonate treatment may not be effective in treating lactic acidosis when there is tissue hypoperfusion and multisystem organ failure, hence vigorous supportive therapy aimed at reestablishing normal tissue oxygenation and perfusion is essential. Hemodialysis in an alkaline bath can help with volume management in critically ill patients as well as correction of acid-base and electrolyte abnormalities.

2. Hemodialysis - Hemodialysis can be considered for the correction of severe acidosis. Since NSAIDs are highly protein-bound, hemodialysis may not help clear the drug from the blood. However, it is indicated in patients who develop acute kidney injury as a complication of the ingestion. Acute renal failure is usually corrected after a few days.

3. Asymptomatic Patients - Patients who have consumed less toxic and fewer amounts of NSAID are discharged on the same day. Psychiatric evaluation is recommended for intentional ingestions.

4. Individuals who exhibit GI bleeding symptoms, such as hematemesis or feces positive for guaiac (guaiac is a substance obtained from the Guaiacum tree and is used to test the presence of hidden blood in the feces), have to undergo an endoscopic examination.

Conclusion:

NSAID poisoning leads to considerable morbidity and mortality in both acute and chronic cases. It causes symptoms in the gastrointestinal (GI), renal, central nervous system (CNS), hematologic, and dermatological systems. Acute ingestions of NSAIDs and long-term treatment with NSAIDs result in different complications. Any toxicity should be immediately attended to by the doctors and their team. Immediate medical attention greatly reduces the chances of mortality.