Arachidonic acid (on cell membrane) activated by phospholipase enzyme to become free arachidonic acid (AA) which goes to one of two pathways. (1) 5-hydroxyperoxy-arachidonic acid by lipoxygenase producing leukotriene. (2) Endoperoxides by COX, prostacyclin synthetase to prostaglandin, thromboxane synthetase to become thromboxane
The common over-the-counter NSAIDS are known as traditional NSAIDS (tNSAIDS) . Traditional NSAIDS reversibly compete with free arachidonic acid (AA) at the active site of COX-1 and COX-2 enzymes. Propionic acid derivatives (ibuprofen, naproxen), acetic acid derivatives (indomethacin), and enolic acids (piroxicam) are a few examples of tNSAIDS . Aspirin (ASA) acetylates both COX enzymes causing an irreversible inhibition of their activity. Acetaminophen provides fever reduction with analgesic properties. It has less gastrointestinal (GI) side effects, but has only minimal anti-inflammatory activity .
Mechanism of Action
Inhibition of Cyclooxygenases
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 . 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 . 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 . 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 Other coxibs have been withdrawn from the market due to significant adverse events.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 .
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 % .
The lipoxygenase (LOX) pathway is not affected by any NSAIDS; therefore, leukotriene formation is not suppressed (Fig. 27.1).
Aspirin’s Irreversible Inhibition
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 . 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 .
Importantly, platelet activity is affected. Platelets, being anucleated, have a limited capacity for protein synthesis . 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 .
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 . 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 . 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 pKa 3–5 and are well absorbed in the stomach and intestinal mucosa [4, 5]. Peak plasma concentration is reached at 2–3 h . 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 .
The majority of NSAIDs are highly protein bound (95–99 %), usually to albumin . 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 . 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 . 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 . The lipophilic property also enables them to access the hydrophobic arachidonate binding channel . Aspirin and acetaminophen are an exception .
Plasma t1/2 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) . When overdosed (usually >10 g of acetaminophen), the metabolic pathways are saturated, and hepatotoxic NAPQI concentrations can be formed . 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 . 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.
All NSAIDs, including selective COX-2 inhibitors, are antipyretic, analgesic, and anti-inflammatory, with the exception of acetaminophen, which is an antipyretic and analgesic, but possesses minimal anti-inflammatory activity .
Due to their ability to penetrate into the synovial space, the anti-inflammatory effect of NSAIDs is useful in treatment of musculoskeletal disorders, such as rheumatoid arthritis and osteoarthritis. They provide symptomatic relief from pain and inflammation associated with such diseases .
The antipyretic effect is indicated in patients in whom fever in itself may be deleterious and for those who experience considerable relief when fever is lowered . Fever prevention may obscure the clinical picture and must be considered in diagnostic evaluation. Although NSAIDs reduce fever in pathological states, this category of medications does not alter the circadian variation in temperature or the rise in response to exercise or to increased ambient temperature .
According to the WHO step ladder for cancer pain management, NSAIDs are the first line of therapy . Unfortunately, their analgesic property is limited and only effective for pain of low to moderate degree. Concomitant use of NSAIDs with opioids is indicated in the second and third step of the WHO step ladder . The advantage of this combination is the potential reduction in the amount of opioids required – potentially avoiding adverse opioid effects including respiratory depression, pruritus, nausea, and vomiting.
NSAIDs do not change the perception of sensory modalities other than pain [3, 4]. They are only effective when inflammation has caused peripheral and/or central sensitization of pain perception [3, 4]. Thus, postoperative discomfort or pain arising from inflammation, such as arthritic pain, is controlled well by NSAIDs, whereas visceral pain is not relieved. Menstrual pain is an exception. Prostaglandins released by the endometrium during menstruation result in menstrual cramps and other symptoms of primary dysmenorrhea . This etiology of visceral pain and discomfort can therefore be effectively treated with NSAIDs. NSAIDs are also used as first-line therapy to treat migraines and can be combined with second-line drugs, such as the triptans. NSAIDs have no effect against neuropathic pain.