The therapeutic effects of NSAIDs are due to their ability to inhibit prostaglandin (PG) production. The key enzyme in the PG pathway is collectively known as prostaglandin synthase, commonly known as cyclooxygenases (COX), cyclooxygenase-1 and cyclooxygenase-2 [4]. These two enzymes convert free arachidonic acid (AA) to endoperoxides which will produce either thromboxanes or prostaglandins (Fig. 27.1).

Two forms of COX exist, COX-1 and COX-2. Both contribute to prostaglandin formation, inflammation, and pain. COX-2 is induced by cytokines, shear stress, and tumor promoters. COX-1 is expressed constitutively in most cells primarily for housekeeping functions, such as gastric epithelial cells and hemostasis. It is the cytoprotective PG [3]. Thus, inhibition of COX-1 is the underlying mechanism for the adverse gastrointestinal effects that frequently accompany tNSAID therapy.

Selective COX-2 inhibitors are Y-shaped in structure and were created to avoid the adverse gastrointestinal side effects seen with tNSAID therapy. The selective COX-2 inhibitors have a bulky side group which fits into a large “side pocket” along the COX-2 enzyme. This large side group prevents its access into the smaller binding channel of COX-1 [4]. Celecoxib (Celebrex) is currently the only COX-2 inhibitor licensed for use in the USA. Other coxibs have been withdrawn from the market due to significant adverse events. For example, rofecoxib (Vioxx) is associated with an increased incidence of myocardial infarction and cerebral vascular accidents [5].

Acetaminophen, a very weak anti-inflammatory agent, is associated with a reduced incidence of gastrointestinal adverse effects compared to tNSAIDs. At 1,000 mg, acetaminophen inhibits both COXs by approximately 50 % [4].

The lipoxygenase (LOX) pathway is not affected by any NSAIDS; therefore, leukotriene formation is not suppressed (Fig. 27.1).

Aspirin acetylates and, hence, irreversibly inhibits the activity of both cyclooxygenase enzymes. The significance of the difference in mechanism of action is that the recovery of enzymes is dependent on the turnover rate of the prostaglandin enzymes [4]. The duration of effect for the reversible, competitive drugs is dependent on the time course of drug disposition. Arachidonic acid metabolite formation is therefore also dependent on the turnover of COX enzymes [4].

Importantly, platelet activity is affected. Platelets, being anucleated, have a limited capacity for protein synthesis [4]. Whereas other arachidonic acid metabolites such as prostacyclin, made primarily in the reticuloendothelial cells of the gut, are nucleated and will maintain levels, resulting in a change in the ratio between platelet aggregation and disaggregation. Inhibition of platelet COX-1 lasts for the lifetime of the platelet (COX-2 is expressed in megakaryocytes). Therefore, COX-1 inhibition disrupts the formation of thromboxane A₂, decreasing vasoconstriction and secondary platelet aggregation. Inhibition of platelet COX-1-dependent thromboxane formation is cumulative with repeated doses of aspirin (as low as 30 mg/day). It takes approximately 8–12 days for platelets to turnover and to fully recover once aspirin is discontinued. A few days after the last aspirin dose, there may be some normal functioning platelets, sufficient enough hemostasis allowing for some elective surgery to proceed [4].

The antiplatelet effect of aspirin is exploited in its use as a cardioprotective agent. Aspirin use has consistently demonstrated a pattern of reduced mortality in all primary prevention trials [6]. Even a small dose of aspirin (81 mg daily) provides adequate cardioprotection in patients who are at high risk (i.e., history of myocardial infarction) for thrombotic vascular events. Caution is advised as use of low-dose aspirin minimizes, not eliminates, the potential associated adverse GI events. Placebo-controlled trials demonstrate that aspirin, at any dose, increases the incidence of serious GI bleeds and intracranial bleeds [4]. The benefits of aspirin’s antiplatelet effect are also appreciated in treatment of Kawasaki disease in children (see Sect. 6).

Traditional NSAIDs are generally weak acids with pK_a 3–5 and are well absorbed in the stomach and intestinal mucosa [4, 5]. Peak plasma concentration is reached at 2–3 h [4]. Concomitant food intake can delay absorption and may decreases systemic availability. Antacids that commonly are taken with NSAIDs may contribute to variable delays of absorption, but will not usually reduce absorption. Some compounds (e.g., diclofenac, nabumetone) undergo first-pass or pre-systemic elimination. Acetaminophen is metabolized to a small extent during absorption. Aspirin begins to acetylate platelets within minutes of reaching the pre-systemic circulation [4].

The majority of NSAIDs are highly protein bound (95–99 %), usually to albumin [4]. Caution is advised in patients with disease states that decrease protein concentrations (cirrhosis) as they are at increased risk of toxicity due to an increased free fraction of the drug. Plasma protein binding often is concentration dependent (i.e., naproxen, ibuprofen), saturated at high concentrations, and can displace other drugs. Most NSAIDs are distributed widely throughout the body and can be readily found in synovial fluid after repeated dosing [7]. Counterintuitively, drugs with short half-lives stay in the synovial fluid longer than predicted from their half-lives, while drugs with longer half-lives are cleared from the synovial space at a rate proportional to their half-lives [7]. Most NSAIDs are lipophilic; therefore, they can achieve sufficient concentrations in the CNS which is responsible for its central analgesic effect. Celecoxib is particularly lipophilic and accumulates in fat and is readily transported into the CNS [4]. The lipophilic property also enables them to access the hydrophobic arachidonate binding channel [4]. Aspirin and acetaminophen are an exception [4].

Plasma t_1/2 is highly inconsistent among the NSAIDS. The primary route of elimination is via hepatic biotransformation and renal excretion. Some have active metabolites. For example, acetaminophen, at therapeutic doses, is oxidized to form traces of the highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI) [4]. When overdosed (usually >10 g of acetaminophen), the metabolic pathways are saturated, and hepatotoxic NAPQI concentrations can be formed [4]. If renal excretion is compromised or competition for renal excretion of other drugs exists, some NSAIDs can be hydrolyzed back to the parent compound. This is true for the propionic acid derivatives naproxen and ketoprofen [4]. Elimination can thus be significantly prolonged. Because NSAIDs are extensively protein bound, they cannot be removed with dialysis; salicylic acids are the exception. NSAIDs should, therefore, be avoided in patients with severe hepatic or renal impairment.