Nonsteroidal anti-Inflammatory drugs (NSAIDs) have analgesic, antipyretic, and anti-inflammatory effects and are among the most commonly used drugs in the world. While acute therapeutic use is regarded as safe in most patients, adverse reactions at therapeutic doses and with chronic use has resulted in a reevaluation of its safety in recent years. The introduction and subsequent withdrawal of cyclooxygenase (COX)-2-selective agents have resulted a decrease in the use of these agents. Ibuprofen and naproxen are currently the only nonprescription NSAIDs available in the United States. They are also available in combination cough and cold preparations as well as the prescription combination drug, Vicoprofen (ibuprofen and hydrocodone). Other prescription forms of NSAIDs are also available in the United States and globally.

Due to its nonprescription status and wide use, unintentional and intentional ingestions are common. The 2015 Annual Report of the American Association of Poison Control Centers listed 58 deaths in which NSAIDs were a contributing factor, with 11 deaths related to a single substance (ibuprofen, ibuprofen/diphenhydramine combination product, and colchicine). NSAIDs accounted for more than 76,000 single exposures, of which more than 61,000 were attributed to ibuprofen. As expected, children younger than 6 years had the majority of exposures, with over 41,000 single exposures to NSAIDs.¹ In addition, unintentional ibuprofen exposures resulted in 16% of visits for over-the-counter liquid medication exposures in young children.² Symptoms in the overdose setting are rare; however, severe toxicity can occur.

NSAIDs have numerous classifications including their COX activity, biochemical properties, and pharmacologic action that have been well documented³ (Table 116-1). They are similar in their biochemical characteristics in that they are relatively lipophilic, weak acids. While most are absorbed readily from the gastrointestinal tract, their pharmacokinetic properties differ. Thus the clinician can select for specific indications. The duration of action and half-life guides dosing with short half-life NSAIDs (e.g., ibuprofen) administered every 6 to 8 hours and longer half-life NSAIDs (e.g., naproxen) dosed once or twice daily. Metabolism and elimination are important pharmacokinetic properties to consider when dosing NSAIDs. Polymorphisms in the drug metabolizing enzyme cytochrome P450 2C9 (CYP2C9) can affect pharmacokinetics.⁴ Specifically, those individuals with the *2 and/or *3 alleles (nonfunctioning alleles) are predisposed to higher risks of adverse drug reactions.⁵ In addition, adverse reactions are likely to occur with hepatic and renal disorders. Drug interactions can result in adverse effects when taking into account metabolism and other substrates that can affect enzyme function.

NSAIDs have analgesic, anti-inflammatory, and antipyretic properties through their binding to the COX enzyme.^6,7 They work by preventing the binding of arachidonic acid to the COX enzyme active site resulting in inhibition of prostaglandin synthesis. It has been found to exist in several isoforms—COX-1, COX-2, and possibly COX-3. COX-1 is responsible for the synthesis of prostaglandins involved in many physiologic functions including maintenance of normal renal functions, protection in the gastrointestinal tract, and thromboxane-A in platelets. COX-2 can be induced by cytokines and inflammation and has a role in the development of pain, inflammation, and fever. COX-3 has been poorly elucidated but is thought to be involved in the mechanism of acetaminophen. Many NSAIDs are nonselective in their binding to the COX enzyme. Newer forms of NSAIDs have marketed as selective COX-2 inhibitors, but with the exception of celecoxib, have been removed from use due to cardiac toxicity.

To overcome the risks for adverse effects, novel protective mediators have been introduced as chemical moieties bound to the NSAID structure.⁸ Phosphatidylcholine (PC)-associated NSAIDs have been developed to overcome the drug’s interaction with phospholipid in an attempt to overcome the alteration of the beneficial properties in the gastrointestinal (GI) tract. In addition, the GI toxicity has been associated with the acidity of these compounds and the accumulation of ionized NSAIDs in the epithelial cells. Phospho-NSAIDs are generated by attaching their carboxylic acid to dialkylphosphate moieties. Studies have shown efficacy without damage to the GI tract. The addition of nitric oxide (NO) has shown similar promise in that the entire moiety acts as a prodrug with ultimately releasing the protective component, NO, to prevent adverse effects; however, clinical trials have not found this to be the case. The addition of hydrogen sulfide has shown similar efficacy.