Neurochemical Principles of NSAID Therapy

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme activity that converts polyunsaturated fatty acids to prostaglandins during the inflammatory process. The prostaglandin endoperoxide synthase or fatty acid cyclooxygenase (COX) catalyze the dioxygenation of arachidonic acid (AA) to form prostaglandin H2 (PGH2) and resultant prostaglandins.¹¹³Blobaum AL, Marnett LJ. Structural and Functional Basis of Cyclooxygenase Inhibition. Journal of Medicinal Chemistry, 2007, p1425

Functional characteristics of COX-1 and COX-2

The two principle COX isoforms, COX-1 and COX-2, are encoded by distinct genes with high amino acid sequence homology but differential expression profiles. COX-1 is involved in the production of prostaglandins that mediate basic housekeeping functions in the body. COX-2 is activated in response to cytokines, mitogens, endotoxin, and tumor promoters in a variety of cell types. COX-2 was initially believed to function only in acute or pathophysiological responses such as inflammation, hyperalgesia, and cell proliferation, but it is now clear that it also plays physiological roles in the brain, kidney, and cardiovascular systems.¹¹⁴ Blobaum AL, Marnett LJ. Structural and Functional Basis of Cyclooxygenase Inhibition. Journal of Medicinal Chemistry, 2007, p1425-1426.

Pharmacological effects of NSAIDs

The principal pharmacological effects of NSAIDs arise from their inhibition of COX enzymes. Evidence suggests that the anti-inflammatory and analgesic properties of traditional NSAIDs are due to the inhibition of COX-2, whereas the ulcerogenic side effects of these inhibitors are associated with the inhibition of COX-1. Because of the difference in expression profiles between COX-1 and COX-2, a hypothesis was advanced in the 1990s that selective inhibitors of COX-2 would share the beneficial anti-inflammatory properties of traditional NSAIDs but lack the gastric toxicity associated with these compounds.¹¹⁵Blobaum AL, Marnett LJ. Structural and Functional Basis of Cyclooxygenase Inhibition. Journal of Medicinal Chemistry, 2007, p1427

Selective and nonselective NSAIDs

NSAIDs are broadly classified as selective or nonselective based on their relative preference for the COX-2 enzyme inhibition. Structural differences among NSAIDs account for their ability to inhibit COX-1 and COX-2. However, the COX selectivity of particular NSAIDs is not limited to the structural properties of the compound. COX-1 and COX-2 selectivity is also affected by the dose of NSAIDs.¹¹⁶Hunter TS et al. Emerging Evidence in NSAID Pharmacology: Important Considerations for Product Selection. AJMC. 2015. P139-140.

Structural characteristics of COX-1 and COX-2

Both COX-1 and COX-2 contain a 25 Å length hydrophobic channel that originates at the membrane binding domain and extends into the core of the catalytic domain. The long hydrophobic channel can be divided into the lobby and the substrate/inhibitor binding site of COX by a constriction of three residues: Arg-120, Glu-524, and Tyr-355. Most inhibitors bind in the COX active site above the constriction residues, although some inhibitors have been shown to make interactions with lobby residues. Several residues in the lobby region are thought to be important for inhibitor interactions (Pro- 86, Ile-89, Leu-93, and Val-116). Twenty-four residues line the COX active site with only one difference between COX-2 and COX-1 (Val-523 to Ile-523).¹¹⁷Blobaum AL, Marnett LJ. Structural and Functional Basis of Cyclooxygenase Inhibition. Journal of Medicinal Chemistry, 2007, p1427

COX inhibition

COX inhibitors can be discussed on the basis of which steps, or series of steps, are observed in their inhibitory mechanisms. Aspirin is the only clinically used inhibitor to irreversibly inactivate COX-1 and COX-2 through time-dependent, covalent modification of the COX active site. All other COX inhibitors, whether nonselective or COX-2 selective, associate with the protein in a noncovalent manner. The most potent COX inhibitors are slow, tight binding inhibitors that form very stable binary complexes. In some cases, the dissociation rates of enzyme-inhibitor complexes are so slow that the inhibitors appear to be functionally irreversible. ¹¹⁸Blobaum AL, Marnett LJ. Structural and Functional Basis of Cyclooxygenase Inhibition. Journal of Medicinal Chemistry, 2007, p1428-1429

Acetaminophen

Acetaminophen (APAP) was initially categorized as a nonsteroidal antiinflammatory drug. However, NSAIDs inhibit COX-dependent production of prostaglandins while APAP largely lacks peripheral anti-inflammatory properties, suggesting that its site of pharmacological action is within the central nervous system. APAP crosses the blood brain barrier with ease and is distributed homogeneously throughout the central nervous system.¹¹⁹Ghanem C. Acetaminophen; From Liver to Brain: New Insights Into Drug Pharmacological Action and Toxicity Pharmacol Res. 2016 July ; 109: p2.

The effect of NSAID dosing on adverse events

The risks of gastrointestinal and cardiovascular adverse events are related to the same mechanisms associated with NSAID benefits—namely, inhibition of COX-dependent prostanoids synthesis. For example, COX-1 inhibition has been associated with decreased platelet aggregation and GI toxicity. Prostaglandin I2 (PGI2), a prostanoid with cardioprotective properties, is generated by COX-2 and promotes vasodilation and inhibition of platelet aggregation. The inhibition of PGI2 is thought to be a plausible mechanism for CV risks associated with the use of NSAIDs, such as myocardial infarction. Available data from observational studies strongly suggest that GI and CV events and renal failure are related to total daily dose in patients treated with NSAIDs.¹²⁰Hunter TS et al. Emerging Evidence in NSAID Pharmacology: Important Considerations for Product Selection. AJMC. 2015. p143.