NCLEX: Anti-inflammatory, Antipyretic, and Analgesic Agents

Inflammation is a normal, protective response to tissue injury caused by physical trauma, noxious chemicals, or microbiologic agents. Inflammation is the body’s effort to inactivate or destroy invading organisms, remove irritants, and set the stage for tissue repair. When healing is complete, the inflammatory process usually subsides. However, inappropriate activation of the immune system can result in inflammation, leading to immunemediated diseases such as rheumatoid arthritis (RA). Normally, the immune system can differentiate between self and nonself. In RA, white blood cells (WBCs) view the synovium (tissue that nourishes cartilage and bone) as nonself and initiate an inflammatory attack. WBC activation leads to stimulation of T lymphocytes (the cell-mediated part of the immune system), which recruit and activate monocytes and macrophages. These cells secrete proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-1, into the synovial cavity. The release of cytokines then causes 1) increased cellular infiltration into the endothelium due to release of histamines, kinins, and vasodilatory prostaglandins; 2) increased production of C-reactive protein by hepatocytes (a marker for inflammation); 3) increased production and release of proteolytic enzymes by chondrocytes (cells that maintain cartilage), leading to degradation of cartilage and joint space narrowing; 4) increased osteoclast activity (osteoclasts regulate bone breakdown), resulting in focal bone erosions and bone demineralization around joints; and 5) systemic manifestations in certain organs such as the heart. In addition to T-lymphocyte activation, B lymphocytes are also involved and produce rheumatoid factor (inflammatory marker) and other autoantibodies with the purpose of maintaining inflammation. These defensive reactions cause progressive tissue injury, resulting in joint damage and erosions, functional disability, significant pain, and reduction in quality of life. Pharmacotherapy in the management of RA includes anti-inflammatory and/or immunosuppressive agents that modulate/reduce the inflammatory process, with the goals of reducing inflammation and pain, and halting or slowing disease progression. The agents to be discussed include nonsteroidal anti-inflammatory drugs (NSAIDs) and celecoxib (cyclooxygenase-2 inhibitor), acetaminophen, and disease-modifying antirheumatic drugs (DMARDs). Additionally, agents used for the treatment of gout and migraine headache are reviewed.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents: PROSTAGLANDINS

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

The NSAIDs act by inhibiting the synthesis of prostaglandins. Thus, an understanding of NSAIDs requires comprehension of the actions and biosynthesis of prostaglandins—unsaturated fatty acid derivatives containing 20 carbons that include a cyclic ring structure. [Note: These compounds are sometimes referred to as eicosanoids; “eicosa” refers to the 20 carbon atoms.]

A. Role of prostaglandins as local mediators

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Prostaglandins and related compounds are produced in minute quantities by virtually all tissues. They generally act locally on the tissues in which they are synthesized, and they are rapidly metabolized to inactive products at their sites of action. Therefore, the prostaglandins do not circulate in the blood in significant concentrations. Thromboxanes and leukotrienes are related lipids that are synthesized from the same precursors as the prostaglandins.

B. Synthesis of prostaglandins

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Arachidonic acid is the primary precursor of the prostaglandins and related compounds. Arachidonic acid is present as a component of the phospholipids of cell membranes. Free arachidonic acid is released from tissue phospholipids by the action of phospholipase A2 via a process controlled by hormones and other stimuli. There are two major pathways in the synthesis of the eicosanoids from arachidonic acid, the cyclooxygenase and the lipoxygenase pathways.

1. Cyclooxygenase pathway: All eicosanoids with ring structures (that is, the prostaglandins, thromboxanes, and prostacyclins) are synthesized via the cyclooxygenase pathway. Two related isoforms of the cyclooxygenase enzymes have been described. Cyclooxygenase-1 (COX-1) is responsible for the physiologic production of prostanoids, whereas cyclooxygenase-2 (COX-2) causes the elevated production of prostanoids that occurs in sites of chronic disease and inflammation. COX-1 is a constitutive enzyme that regulates normal cellular processes, such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and reproductive and kidney functions. COX-2 is constitutively expressed in tissues such as the brain, kidney, and bone. Its expression at other sites is increased during states of chronic inflammation. Differences in binding site shape have permitted the development of selective COX-2 inhibitors. Another distinguishing characteristic of COX-2 is that its expression is induced by inflammatory mediators like TNF-α and IL-1 but can also be pharmacologically inhibited by glucocorticoids, which may contribute to the significant anti-inflammatory effects of these drugs.

2. Lipoxygenase pathway: Alternatively, several lipoxygenases can act on arachidonic acid to form leukotrienes. Antileukotriene drugs, such as zileuton, zafirlukast, and montelukast, are treatment options for asthma.

Anti-inflammatory, Antipyretic, and Analgesic Agents

C. Actions of prostaglandins

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Many of the actions of prostaglandins are mediated by their binding to a wide variety of distinct cell membrane receptors that operate via G-coupled proteins. Prostaglandins and their metabolites, produced endogenously in tissues, act as local signals that fine-tune the response of a specific cell type. Their functions vary widely, depending on the tissue and the specific enzymes within the pathway that are available at that particular site. For example, the release of thromboxane A2 (TXA2) from platelets during tissue injury triggers the recruitment of new platelets for aggregation, as well as local vasoconstriction. However, prostacyclin (PGI2), produced by endothelial cells, has opposite effects, inhibiting platelet aggregation and producing vasodilation. The net effect on platelets and blood vessels depends on the balance of these two prostanoids.

D. Therapeutic uses of prostaglandins

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Prostaglandins have a major role in modulating pain, inflammation, and fever. They also control many physiological functions, such as acid secretion and mucus production in the gastrointestinal (GI) tract, uterine contractions, and renal blood flow. Prostaglandins are also among the chemical mediators that are released in allergic and inflammatory processes. Therefore, they find use for a number of disorders discussed below.

E. Alprostadil

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Alprostadil [al-PROS-ta-dil] is a PGE1 that is naturally produced in tissues such as seminal vesicles and cavernous tissues, in the placenta, and in the ductus arteriosus of the fetus. Therapeutically, alprostadil can be used to treat erectile dysfunction or to keep the ductus arteriosus open in neonates with congenital heart conditions until surgery is possible. PGE1 maintains the patency of the ductus arteriosus during pregnancy. The ductus closes soon after delivery to allow normal blood circulation between the lungs and the heart. Infusion of the drug maintains the ductus open as it naturally occurs during pregnancy, allowing time until surgical correction is possible.

F. Lubiprostone

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Lubiprostone [loo-bee-PROS-tone] is a PGE1 derivative indicated for the treatment of chronic idiopathic constipation, opioid-induced constipation, and irritable bowel syndrome with constipation. It stimulates chloride channels in the luminal cells of the intestinal epithelium, thereby increasing intestinal fluid secretion. Nausea and diarrhea are the most common side effects of lubiprostone.

Anti-inflammatory, Antipyretic, and Analgesic Agents

G. Misoprostol

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Misoprostol [mye-soe-PROST-ole], a PGE1 analog, is used to protect the mucosal lining of the stomach during chronic NSAID treatment. Misoprostol interacts with prostaglandin receptors on parietal cells within the stomach, reducing gastric acid secretion. Furthermore, misoprostol has a GI cytoprotective effect by stimulating mucus and bicarbonate production. This combination of effects decreases the incidence of gastric ulcers caused by NSAIDs. [Note: There is a combination product containing diclofenac and misoprostol.] Misoprostol is also used off-label in obstetric settings for labor induction, since it increases uterine contractions by interacting with prostaglandin receptors in the uterus. Misoprostol has the potential risk to induce abortion in pregnant women. Therefore, the drug is contraindicated during pregnancy. Its use is limited by common side effects including diarrhea and abdominal pain.

H. Prostaglandin F2α analogs

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Bimatoprost [bih-MAT-o-prost], latanoprost [la-TAN-oh-prost], tafluprost [TAF-loo-prost], and travoprost [TRA-voe-prost] are PGF2α analogs that are indicated for the treatment of open-angle glaucoma. By binding to prostaglandin receptors, they increase uveoscleral outflow, reducing intraocular pressure. They are administered as ophthalmic solutions once a day and are as effective as timolol or better in reducing intraocular pressure. Bimatoprost increases eyelash prominence, length, and darkness and is approved for the treatment of eyelash hypotrichosis. Ocular reactions include blurred vision, iris color change (increased brown pigmentation), increased number and pigment of eyelashes, ocular irritation, and foreign body sensation.

I. Prostacyclin (PGI2) analogs

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Epoprostenol [ee-poe-PROST-en-ol], the pharmaceutical form of naturally occurring prostacyclin, and the synthetic analogs of prostacyclin (iloprost [EYE-loe-prost] and treprostinil [tre-PROS-ti-nil]) are potent pulmonary vasodilators that are used for the treatment of pulmonary arterial hypertension. These drugs mimic the effects of prostacyclin in endothelial cells, producing a significant reduction in pulmonary arterial resistance with a subsequent increase in cardiac index and oxygen delivery. These agents all have a short half-life. Epoprostenol and treprostinil are administered as a continuous intravenous infusion, and treprostinil may also be administered orally or via inhalation or subcutaneous infusion. Inhaled iloprost requires frequent dosing due to the short half-life. Dizziness, headache, flushing, and fainting are the most common adverse effects. Bronchospasm and cough can also occur after inhalation of iloprost.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents: NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti-inflammatory activities. The class includes derivatives of salicylic acid (aspirin [AS-pir-in], diflunisal [dye-FLOO-ni-sal], salsalate [SAL-sa-late]), propionic acid (ibuprofen [eye-bue-PROE-fen], fenoprofen [fen-oh-PROE-fen], flurbiprofen [flure-BI-proe-fen], ketoprofen [kee-toe-PROE-fen], naproxen [na-PROX-en], oxaprozin [ox-a-PROE-zin]), acetic acid (diclofenac [dye-KLOE-fenak], etodolac [ee-toe-DOE-lak], indomethacin [in-doe-METH-a-sin], ketorolac [kee-toe-ROLE-ak], nabumetone [na-BUE-me-tone], sulindac [sul-IN-dak], tolmetin [TOLE-met-in]), enolic acid (meloxicam [mel-OKS-ikam], piroxicam [peer-OX-i-kam]), fenamates (mefenamic [me-fe-NAM-ik] acid, meclofenamate [me-kloe-fen-AM-ate]), and the selective COX-2 inhibitor (celecoxib [sel-e-KOX-ib]). They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This leads to decreased prostaglandin synthesis with both beneficial and unwanted effects. [Note: Differences in safety and efficacy of the NSAIDs may be explained by relative selectivity for the COX-1 or COX-2 enzyme. Inhibition of COX-2 is thought to lead to the anti-inflammatory and analgesic actions of NSAIDs, while inhibition of COX-1 is responsible for prevention of cardiovascular events and most adverse events.]

A. Aspirin and other NSAIDs

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Aspirin can be thought of as a traditional NSAID, but it exhibits anti-inflammatory activity only at relatively high doses that are rarely used. It has gained much more usage at lower doses for the prevention of cardiovascular events such as stroke and myocardial infarction (MI). Aspirin is often differentiated from other NSAIDs, since it is an irreversible inhibitor of cyclooxygenase activity.

1. Mechanism of action: Aspirin is a weak organic acid that irreversibly acetylates (and, thus, inactivates) cyclooxygenase. The other NSAIDs are all reversible inhibitors of cyclooxygenase. The NSAIDs, including aspirin, have three major therapeutic actions: they reduce inflammation (anti-inflammatory), pain (analgesic effect), and fever (antipyretic effect; However, as outlined below, not all NSAIDs are equally effective in each of these actions.

  • Anti-inflammatory actions: Cyclooxygenase inhibition diminishes the formation of prostaglandins and, thus, modulates aspects of inflammation in which prostaglandins act as mediators. NSAIDs inhibit inflammation in arthritis, but they neither arrest the progression of the disease nor induce remission.
  • Analgesic action: PGE2 is thought to sensitize nerve endings to the action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. Thus, by decreasing PGE2 synthesis, the sensation of pain can be decreased. As COX-2 is expressed during times of inflammation and injury, it is thought that inhibition of this enzyme is responsible for the analgesic activity of NSAIDs. No single NSAID has demonstrated superior efficacy over another, and all agents are generally considered to have equivalent efficacy. The NSAIDs are used mainly for the management of mild to moderate pain arising from musculoskeletal disorders. One exception is ketorolac, which can be used for more severe pain but for only a short duration.
  • Antipyretic action: Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated. This can be caused by PGE2 synthesis, which is stimulated when endogenous fever-producing agents (pyrogens), such as cytokines, are released from WBCs that are activated by infection, hypersensitivity, malignancy, or inflammation. The NSAIDs lower body temperature in patients with fever by impeding PGE2 synthesis and release. These agents essentially reset the “thermostat” toward normal. This rapidly lowers the body temperature of febrile patients by increasing heat dissipation as a result of peripheral vasodilation and sweating. NSAIDs have no effect on normal body temperature.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

2. Therapeutic uses:

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

  • Anti-inflammatory and analgesic uses: NSAIDs are used in the treatment of osteoarthritis, gout, and RA. These agents are also used to treat common conditions (for example, headache, arthralgia, myalgia, and dysmenorrhea) requiring analgesia. Combinations of opioids and NSAIDs may be effective in treating pain caused by malignancy. Furthermore, the addition of NSAIDs may lead to an opioid-sparing effect, allowing for lower doses of opioids to be utilized. The salicylates exhibit analgesic activity at lower doses. Only at higher doses do these drugs show anti-inflammatory activity. For example, two 325-mg aspirin tablets administered four times daily produce analgesia, whereas 12 to 20 tablets per day produce both analgesic and anti-inflammatory activity.
  • Antipyretic uses: Aspirin, ibuprofen, and naproxen may be used to treat fever. [Note: Aspirin should be avoided in patients less than 20 years old with viral infections, such as varicella (chickenpox) or influenza, to prevent Reye syndrome (a syndrome that can cause fulminating hepatitis with cerebral edema, often leading to death).]
  • Cardiovascular applications: Aspirin is used to inhibit platelet aggregation. Low-dose aspirin inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-mediated vasoconstriction and platelet aggregation and the subsequent risk of cardiovascular events. Low doses (doses less than 325 mg; many classify it as doses of 75 to 162 mg—commonly 81 mg) of aspirin are used prophylactically to 1) reduce the risk of recurrent cardiovascular events and/or death in patients with previous MI or unstable angina pectoris, 2) reduce the risk of recurring transient ischemic attacks (TIAs) and stroke or death in those who have had a prior TIA or stroke, and 3) reduce the risk of cardiovascular events or death in high-risk patients such as those with chronic stable angina or diabetes. As aspirin irreversibly inhibits COX-1 the antiplatelet effects persist for the life of the platelet. Chronic use of low doses allows for continued inhibition as new platelets are generated. Aspirin is also used acutely to reduce the risk of death in acute MI and in patients undergoing certain revascularization procedures.
  • External applications: Salicylic acid is used topically to treat acne, corns, calluses, and warts. Methyl salicylate (“oil of wintergreen”) is used externally as a cutaneous counterirritant in liniments, such as arthritis creams and sports rubs.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

3. Pharmacokinetics:

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

  • Aspirin: After oral administration, aspirin is rapidly deacetylated by esterases in the body, thereby producing salicylate. Unionized salicylates are passively absorbed mostly from the upper small intestine (dissolution of the tablets is favored at the higher pH of the gut). Salicylates (except for diflunisal ) cross both the blood–brain barrier and the placenta and are absorbed through intact skin (especially methyl salicylate). Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney, resulting in first-order elimination and a serum half-life of 3.5 hours. At anti-inflammatory dosages (more than 4 g/day), the hepatic metabolic pathway becomes saturated, and zero-order kinetics are observed, leading to a half-life of 15 hours or more. Being an organic acid, salicylate is secreted into the urine and can affect uric acid excretion. At low doses of aspirin (less than 2 g/day), uric acid secretion is decreased, whereas at high doses, uric acid secretion may be unchanged or increased. Therefore, aspirin is avoided in gout or in patients taking probenecid.
  • Other NSAIDs: Most NSAIDs are well absorbed after oral administration and circulate highly bound to plasma proteins. The majority are metabolized by the liver, mostly to inactivate metabolites. Few (for example, nabumetone and sulindac) have active metabolites. Elimination of active drug and metabolites is primarily via the urine.

4. Adverse events: Because of the associated adverse events below, it is preferable to use NSAIDs at the lowest effective dose for the shortest duration possible.

  • Gastrointestinal: The most common adverse effects of NSAIDs are GI related, ranging from dyspepsia to bleeding. Normally, production of prostacyclin (PGI2) inhibits gastric acid secretion, and PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach and small intestine. Agents that inhibit COX-1 reduce beneficial levels of these prostaglandins, resulting in increased gastric acid secretion, diminished mucus protection, and increased risk for GI bleeding and ulceration. Agents with a higher relative selectivity for COX-1 may have a higher risk for GI events compared to those with a lower relative selectivity for COX-1 (that is, higher COX-2 selectivity). NSAIDs should be taken with food or fluids to diminish GI upset. If NSAIDs are used in patients with a high risk for GI events, proton pump inhibitors or misoprostol should be used concomitantly to prevent NSAID-induced ulcers.
  • Increased risk of bleeding (antiplatelet effect): TXA2 enhances platelet aggregation, whereas PGI2 decreases it. Aspirin irreversibly inhibits COX-1–mediated TXA2 formation, while other NSAIDs reversibly inhibit the production of TXA2. Because platelets lack nuclei, they cannot synthesize new enzyme when inhibited by aspirin, and the lack of thromboxane persists for the lifetime of the platelet (3 to 7 days). Because of the decrease in TXA2 production, platelet aggregation (the first step in thrombus formation) is reduced, producing an antiplatelet effect with a prolonged bleeding time. For this reason, aspirin is often held, or not given, at least 1 week prior to surgery. NSAIDs other than aspirin are not utilized for their antiplatelet effect but can still prolong bleeding time. [Note: As agents become more COX-2 selective, they are expected to have less effect on platelet inhibition and bleeding time.] NSAIDs can also block aspirin binding to cyclooxygenase when used concomitantly. Patients who take aspirin for cardioprotection should avoid concomitant NSAID use if possible.
  • Actions on the kidney: NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are responsible for maintaining renal blood flow. Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema in some patients. Patients with a history of heart failure or kidney disease are at particularly high risk. These effects can also mitigate the beneficial effects of antihypertensive medications.
  • Cardiac effects: Agents such as aspirin, with a very high degree of COX-1 selectivity, have shown a cardiovascular protective effect thought to be due to a reduction in the production of TXA2. Agents with higher relative COX-2 selectivity have been associated with an increased risk for cardiovascular events, possibly by decreasing PGI2 production mediated by COX-2. An increased risk for cardiovascular events, including MI and stroke, has been associated with all NSAIDs except aspirin. Use of NSAIDs, other than aspirin, is discouraged in patients with established cardiovascular disease. For patients with cardiovascular disease in whom NSAID treatment cannot be avoided, naproxen appears to be the least likely to be harmful. NSAID use should be limited to the lowest dose possible for the shortest duration.
  • Other side effects: NSAIDs are inhibitors of cyclooxygenases and, therefore, inhibit the synthesis of prostaglandins but not of leukotrienes. For this reason, NSAIDs should be used with caution in patients with asthma, as inhibition of prostaglandin synthesis can cause a shift toward leukotriene production and, therefore, increase the risk of exacerbations of asthma. Central nervous system (CNS) adverse events, such as headache, tinnitus, and dizziness, may occur. Approximately 15% of patients taking aspirin experience hypersensitivity reactions. Symptoms of true allergy include urticaria, bronchoconstriction, and angioedema. Fatal anaphylactic shock is rare. Patients with severe hypersensitivity to aspirin should avoid using NSAIDs.
  • Drug interactions: Salicylate is roughly 80% to 90% plasma protein bound (albumin) and can be displaced from protein-binding sites, resulting in increased concentration of free salicylate. Alternatively, aspirin can displace other highly protein-bound drugs, such as warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of these agents.
  • Toxicity: Salicylate intoxication may be mild or severe. The mild form is called salicylism and is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus (ringing or roaring in the ears). When large doses of salicylate are administered, severe salicylate intoxication may result. Restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure may occur. Children are particularly prone to salicylate intoxication. Ingestion of as little as 10 g of aspirin can cause death in children.
  • Pregnancy: Most NSAIDs are pregnancy risk category C in the first two trimesters. [Note: Acetaminophen is preferred if analgesic or antipyretic effects are needed during pregnancy.] In the third trimester, NSAIDs should generally be avoided due to the risk of premature closure of the ductus arteriosus.

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

Anti-inflammatory, Antipyretic, and Analgesic Agents

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B. Celecoxib

Focus topic: Anti-inflammatory, Antipyretic, and Analgesic Agents

Celecoxib [SEL-e-KOX-ib], a selective COX-2 inhibitor, is significantly more selective for inhibition of COX-2 than COX-1. Unlike the inhibition of COX-1 by aspirin (which is rapid and irreversible), the inhibition of COX-2 is reversible.

  • Therapeutic uses: Celecoxib is approved for the treatment of RA, osteoarthritis, and acute mild to moderate pain. Celecoxib has similar efficacy to NSAIDs in the treatment of pain.
  • Pharmacokinetics: Celecoxib is readily absorbed after oral administration. It is extensively metabolized in the liver by cytochrome P450 (CYP2C9) and is excreted in feces and urine. The half-life is about 11 hours, and the drug may be dosed once or twice daily. The dosage should be reduced in those with moderate hepatic impairment, and celecoxib should be avoided in patients with severe hepatic or renal disease.
  • Adverse effects: Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects. Celecoxib, when used without concomitant aspirin therapy, is associated with less GI bleeding and dyspepsia than other NSAIDs. However, this benefit is lost when aspirin is added to celecoxib therapy. Patients who are at high risk of ulcers and require aspirin for cardiovascular prevention should avoid the use of celecoxib. Like other NSAIDs, the drug has a similar risk for cardiovascular events. Celecoxib should be used with caution in patients who are allergic to sulfonamides. Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects with celecoxib. Inhibitors of CYP2C9, such as fluconazole and fluvastatin, may increase serum levels of celecoxib.

Anti-inflammatory, Antipyretic, and Analgesic Agents

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