Toxicities of non-steroidal anti-inflammatory drugs

Patterns of toxicity and dangerous overdoses of acute non-steroidal anti-inflammatory drugs (NSAIDs). 

Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most widely used for their analgesic, anti-inflammatory, and antipyretic properties. 

Most patients with acute NSAID overdose are asymptomatic or have minor self-limiting gastrointestinal symptoms. However, among these patients with severe NSAID overdose, serious side effects have been reported more frequently. It also includes seizures, metabolic acidosis, coma, and acute renal failure.

There appears to be some difference between NSAIDs in terms of relative risk of these complications; Mefenamic acid in particular is commonly associated with seizures. Although management of these serious side effects is often straightforward, there are no specific antidotes for acute NSAID toxicity.

Background

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of structurally diverse drugs with a common mode of action (reversible inhibition of cyclooxygenase). They are widely used for their analgesic, antipyretic and anti-inflammatory properties; Also available as prescription and over-the-counter medications; and are also available as stand-alone pharmaceutical products, combination pain reliever products, and cough and cold products.

Pathology of acute NSAID poisoning

Fig-2
COX-1--Permanent
COX-2--Transient

NSAID pain medications are commonly consumed in high doses in many parts of the world. A 2009 annual report from the American Association of Poison Control Centers' National Poison Data System (NPDS) showed that analgesics were the most common type of drug overdose in adult patients (10%) and the second most common type in pediatric patients (9%).

Acetaminophen (Panadol, or Paracetamol) and its derivatives were found to be used in acute doses (42%) as common pain relievers.

NSAIDs account for 33% of acute consumption of analgesics. Ibuprofen (Brufen) was the most common NSAID taken in high doses (81%), followed by naproxen (11%). This data has not changed significantly over the last decade.

Pharmacology

Fig-2

Many of the toxic effects of NSAID therapy result from the reversible inactivation of the group of enzymes known as cycloxygenase 1 & 2 by NSAIDs (Figure-1,2).

The enzymes act on the thermoregulatory center in the hypothalamus to produce fever. They are also involved in regulating inflammation-regulating secretions and promoting the sensitivity of pain fibers.

Therefore NSAID inhibition of these effects is responsible for any adverse side effects of NSAID therapy as antipyretic (antipyretic), anti-inflammatory, and analgesic.

However, prostaglandins play an integral role in maintaining gastrointestinal mucosal integrity and renal blood flow and also play an important role in balancing platelet aggregation. The side effects of disabling these are responsible for many of the side effects seen in the therapeutic use of NSAIDs - particularly dyspepsia, gastric/small bowel ulceration, and renal failure. 

NSAIDs cause adverse effects in the gastrointestinal tract by inhibiting the formation of cytoprotective prostaglandins in the stomach.

Most NSAIDs act through both types of cyclooxygenase (COX-1 and COX-2) and are generally (UNSPECIFIED). In the early 1990s, two isoenzymes of cyclooxygenase (COX-1 and COX-2) were identified. COX-1 is present permanently in most tissues throughout the body. At the same time, COX-2 is transiently produced by inflammatory factors.

In light of this, recently developed NSAIDs have been designed to act more specifically on the COX-2 isoenzyme. However, several recent studies have shown that therapeutic use of NSAIDs that act specifically through COX-2 (eg, rofecoxib, celecoxib) is associated with cardiovascular disease.

Digestion, absorption, assimilation, and metabolism

NSAIDs are rapidly absorbed orally, with peak blood levels occurring within 2 hours of ingestion of stable releasing preparations. While delayed release and enteric coated preparations (Delayed Release, and Enteric Coated Preparations) usually reach peak concentrations within 2-5 hours of ingestion.

Super therapeutic doses have been approved to modify the kinetics of many NSAIDs, including naproxen and mefenamic acid. That's because those doses prolong absorption and delay peaking.

NSAIDs are weakly acidic and are more than 90% protein bound (>90% Albumin Bound), so their minimum volume of distribution is approximately 0.1-0.2 L/kg. Metabolism occurs mainly by oxidation and conjugation in the liver, less than 10%-20% of NSAIDs are excreted through the kidneys without any metabolic changes.

MECHANISMS OF TOXICITY

The mechanism of toxicity of excessive NSAIDs appears to be mainly a result of over-inhibition of COX-1 and decreased prostaglandin synthesis. The metabolic acidosis seen in acute NSAID toxicity is not related to COX inhibition, but rather to the accumulation of acidic waste products of acidic metabolites. The gastrointestinal tract, kidneys, and central nervous system (CNS) are mainly affected by therapeutic use and overdose.

Gastrointestinal (GI) disorders occur in two different ways. Prostaglandin inhibition reduces gastric mucosal viscosity and bicarbonate synthesis decreases gastric blood flow and improves acid production. The gastric effects of NSAIDs are also known to be due to direct cytotoxic or tissue damage to the mucous gland. Nausea and mild upper gastric discomfort with chronic use upper gastrointestinal discomfort,  gastric/ and anterior small bowel ulceration, gastrointestinal bleeding

leads to vulnerability.

Renal reactions seen with the therapeutic use of NSAIDs and NSAID overdose are related to the vasodilating effects of prostaglandins on the renal arteries. In patients with normal physiologic control of renal blood flow, NSAID renal damage is unlikely at therapeutic doses because the role of prostaglandins in protecting renal blood flow is minimal.

However, in patients with low blood volume (eg, associated with excessive vomiting) or high levels of angiotensin (eg, patients with heart failure or cirrhosis), prostaglandins contribute to maintaining adequate renal blood flow. In such patients, inhibition of prostaglandins, which help maintain glomerular filtration rates, can be harmful and lead to renal failure. Chronic NSAID use can lead to cellular interstitial nephritis.

Excess anionic release in the blood and metabolic acidosis is known to follow an overdose of NSAIDs. Acidity can also be increased by vomiting and alcohol consumption.

Inhibition of COX-1 also affects platelet aggregation by reducing thromboxane-A2 formation. This has implications for patients receiving concomitant anticoagulant (anticoagulant-prevention of blood clotting) or antiplatelet therapies, therefore creating an increased risk of excessive bleeding in these patients.

Patterns of NSAID Overdose Toxicity

Acute poisoning and death resulting from acute toxicity of NSAIDs are extremely rare. Most cases are asymptomatic or produce only minor gastrointestinal symptoms.

However, several reports of mefenamic acid overdose have been reported, with serious overdoses of this drug inducing seizures.

Very large NSAID overdoses have resulted in significant clinical events in some patients, including renal failure, acid/base disturbances, and CNS toxicity. It is important to note that deaths from single NSAID infusions have also been reported.