Cyclooxygenase Inhibitors

Metabolism

Aspirin has a very short half-life (15–20 minutes) owing to rapid conversion to salicylic acid, an active metabolite. The rate of inactivation of salicylic acid depends on the amount present: at low therapeutic levels, salicylic acid has a half-life of approximately 2 hours, but at high therapeutic levels, the half-life may exceed 20 hours.

Distribution

Salicylic acid is extensively bound to plasma albumin. At therapeutic levels, binding is between 80% and 90%. Aspirin undergoes distribution to all body tissues and fluids, including breast milk, fetal tissues, and the central nervous system (CNS).

Excretion

Salicylic acid and its metabolites are excreted by the kidneys. Excretion of salicylic acid is highly dependent on urinary pH. Accordingly, by raising the pH of urine from 6 to 8, we can increase the rate of excretion fourfold.

Plasma Drug Levels

Low therapeutic doses of aspirin produce plasma salicylate levels less than100 mcg/mL. Antiinflammatory doses produce salicylate levels of about 150 to 300 mcg/mL. Signs of salicylism (toxicity) begin when plasma salicylate levels exceed 200 mcg/mL. Severe toxicity occurs at levels above 400 mcg/mL.

Analgesia

Aspirin is used widely to relieve mild to moderate pain. The degree of analgesia produced depends on the type of pain. Aspirin is most active against joint pain, muscle pain, and headache. For some forms of postoperative pain, aspirin can be more effective than opioids. However, aspirin is relatively ineffective against severe pain of visceral origin. In contrast to opioid analgesics, aspirin produces neither tolerance nor physical dependence. In addition, aspirin is safer than opioids.

Aspirin relieves pain primarily through actions in the periphery. At sites of injury, prostanoids sensitize pain receptors to mechanical and chemical stimulation. Aspirin reduces pain by inhibiting COX-2, thereby suppressing prostanoid production. In addition to this peripheral mechanism, aspirin works in the CNS to help relieve pain.

Reduction of Fever

Aspirin is a drug of choice for reducing temperature in febrile adults. However, because of the risk for Reye syndrome (see later), aspirin should not be used to treat fever in children. Although aspirin readily reduces fever, it will not lower normal body temperature, nor will it lower temperature that has become elevated in response to physical activity or to a rise in environmental temperature.

Body temperature is regulated by the hypothalamus, which maintains a balance between heat production and heat loss. Fever occurs when the set point of the hypothalamus becomes elevated, causing the hypothalamus to increase heat production and decrease heat loss. Set-point elevation is triggered by local synthesis of prostaglandins in response to endogenous pyrogens (fever-promoting substances). Aspirin lowers the set point by inhibiting COX-2 and thereby inhibits pyrogen-induced synthesis of prostaglandins.

Dysmenorrhea

Aspirin can provide relief from primary dysmenorrhea. Benefits derive from inhibiting prostaglandin synthesis in uterine smooth muscle. (Prostaglandins promote uterine contraction, so suppression of prostaglandin synthesis relieves cramping.) Some of the newer aspirin-like drugs (e.g., ibuprofen, naproxen) are superior to aspirin for dysmenorrhea. The efficacy of the newer drugs is attributed to a greater ability to inhibit COX in the uterus.

Suppression of Platelet Aggregation

Synthesis of TXA₂ in platelets promotes aggregation. Aspirin suppresses platelet aggregation by causing irreversible inhibition of COX-1, the enzyme that makes TXA₂. Because platelets lack the machinery to synthesize new COX-1, the effects of a single dose persist for the life of the platelet (about 8 days).

There is a large body of evidence demonstrating that aspirin, through its antiplatelet actions, can benefit a variety of patients. Accordingly, the U.S. Food and Drug Administration (FDA) recommended wider use of aspirin for antiplatelet effects. Professional labeling now recommends daily aspirin for men and women with the following:

According to a review published in the Journal of the American Medical Association—“Aspirin Dose for the Prevention of Cardiovascular Disease”—a dose of 75 to 81 mg/day for these indications is adequate. Higher doses, which are commonly prescribed in these circumstances, offer no greater protection but will increase the risk for gastrointestinal (GI) bleeding.

In addition to these applications, aspirin can be taken by healthy people for primary prevention of MI and stroke. However, more recent studies show that aspirin provides less protection against cardiovascular disease than once thought. The potential small benefit must be weighed against the major risk of aspirin use, namely, GI hemorrhage. Hence, to determine the net benefit of primary prevention for any man or woman, we must determine his or her individual risk for a GI bleed and compare that risk with his or her individual risk for a cardiovascular event (i.e., the risk for an MI in men, or the risk for ischemic stroke in women).^a Many organizations, including the American Heart Association (AHA), the American Thoracic Society, and the European Society of Cardiology, recommend against the use of aspirin for primary prevention of cardiovascular disease unless the patient has a 10-year risk greater than 10%.

How do we calculate 10-year risk for a cardiovascular event? Risk for an MI or stroke can be assessed using the calculator at http://cvdrisk.nhlbi.nih.gov/.

There is good evidence that regular use of aspirin decreases the risk for colorectal cancer, even when the dosage is low. Results from the Nurses’ Health Study showed that regular use of high-dose aspirin (650 mg/day or more) reduces the risk for colorectal cancer. This dosage is much greater than that used to prevent cardiovascular disease and hence poses a significant risk for bleeding. In fact, for every one or two cancers prevented, high-dose aspirin would cause eight additional serious bleeds. Fortunately, more recent studies indicate that low-dose aspirin is effective, too. For example, results of a study reported in The Lancet in 2010 indicate that taking low-dose aspirin (75–300 mg/day) for more than 5 years reduces the incidence of colorectal cancer (by 24%) as well as mortality from colon cancer (by 35%). At these low doses, the benefits of cancer protection may well outweigh the risk for possible bleeding and other adverse events.

Aspirin protects against colorectal cancer probably by inhibiting COX-2. In animal models, COX-2 promotes tumor growth and metastases, and inhibition of COX-2 slows tumor growth. In humans, most colorectal cancers express COX-2. Furthermore, protection by aspirin is limited to colon cancers that have high COX-2 levels. Aspirin does not protect against colon cancers with little or no COX-2.

Gastrointestinal Effects

The most common side effects are gastric distress, heartburn, and nausea. These can be reduced by taking aspirin with food or a full glass of water.

Occult GI bleeding occurs often. In most cases, the amount of blood lost each day is insignificant. However, with chronic aspirin use, cumulative blood loss can produce anemia.

Long-term aspirin—even in low doses—can cause life-threatening gastric ulceration, perforation, and bleeding. Ulcers result from four causes:

The first three occur secondary to inhibition of COX-1. Direct injury to the stomach is most likely with aspirin preparations that dissolve slowly: owing to slow dissolution, particulate aspirin becomes entrapped in folds of the stomach wall, causing prolonged exposure to high concentrations of the drug. Because aspirin-induced ulcers are often asymptomatic, perforation and upper GI hemorrhage can occur without premonitory signs. (Hemorrhage is due in part to erosion of the stomach wall and in part to suppression of platelet aggregation.) Factors that increase the risk for ulceration include the following:

What can we do to prevent ulcers? According to an expert panel—convened in 2008 by the American College of Gastroenterology, the AHA, and the American College of Cardiology—prophylaxis with a proton pump inhibitor (PPI) is recommended for patients at risk, including those with a history of peptic ulcers, those taking glucocorticoids, and older adults. Proton pump inhibitors (e.g., omeprazole, lansoprazole) reduce ulcer generation by suppressing production of gastric acid. In addition to PPIs, other drugs that may be considered include histamine-2 receptor antagonists (H₂RAs) and misoprostol. COX-2 inhibitors may also be tried instead of traditional NSAIDs because they are thought to produce fewer GI side effects. Because many ulcers are caused by infection with Helicobacter pylori (see Chapter 62), the panel recommends that patients with ulcer histories undergo testing and treatment for H. pylori before starting long-term aspirin use. Treatment of NSAID-induced ulcers is discussed in Chapter 62.

Bleeding

Aspirin promotes bleeding by inhibiting platelet aggregation. Taking just two 325-mg aspirin tablets can double bleeding time for about 1 week. (Recall that platelets are unable to replace aspirin-inactivated cyclooxygenase, and hence bleeding time is prolonged for the life of the platelet.) Because of its effects on platelets, aspirin is contraindicated for patients with bleeding disorders (e.g., hemophilia, vitamin K deficiency, hypoprothrombinemia). To minimize blood loss during childbirth and elective surgery, high-dose aspirin should be discontinued at least 1 week before these procedures. There is no need to stop aspirin before procedures with a low risk for bleeding (e.g., dental, dermatologic, or cataract surgery). In most cases, use of low-dose aspirin to protect against thrombosis should not be interrupted for elective surgery and dental procedures. Caution is needed when aspirin is used in conjunction with anticoagulants.

In patients taking daily aspirin, high blood pressure increases the risk for hemorrhagic stroke, even though aspirin protects against ischemic stroke. To reduce risk for hemorrhagic stroke, blood pressure should be 150/90 mm Hg (and preferably lower) before starting daily aspirin.

Renal Impairment

Aspirin can cause acute, reversible impairment of renal function, resulting in salt and water retention and edema. Clinically significant effects are most likely in patients with additional risk factors: advanced age, existing renal impairment, hypovolemia, hepatic cirrhosis, or heart failure. Aspirin impairs renal function by inhibiting COX-1, thereby depriving the kidney of prostaglandins needed for normal function.

Development of renal impairment is signaled by reduced urine output, weight gain despite use of diuretics, and a rapid rise in serum creatinine and blood urea nitrogen. If any of these occurs, aspirin should be withdrawn immediately. In most cases, kidney function then returns to baseline level.

The risk for acute renal impairment can be reduced by identifying high-risk patients and treating them with the smallest dosages possible.

In addition to its acute effects on renal function, aspirin may pose a risk for renal papillary necrosis and other types of renal injury when used long term.

Salicylism

Salicylism is a syndrome that begins to develop when aspirin levels climb just slightly above therapeutic. Overt signs include tinnitus, sweating, headache, and dizziness. Acid-base disturbance may also occur (see later). If salicylism develops, aspirin should be withheld until symptoms subside. Aspirin should then resume, but with a small reduction in dosage. In some cases, development of tinnitus can be used to adjust aspirin dosage: when tinnitus occurs, the maximal acceptable dose has been achieved. However, this guideline may be inappropriate for older patients because they may fail to develop tinnitus even when aspirin levels become toxic.

Acid-base disturbance results from the effects of aspirin on respiration. When administered in high therapeutic doses, aspirin acts on the CNS to stimulate breathing. The resultant increase in CO₂ loss produces respiratory alkalosis. In response, the kidneys excrete more bicarbonate. There is also a subsequent buildup of acids, producing a resultant metabolic acidosis. Thus many patients that present with salicylate toxicity will have a mixed acid-base imbalance.

Reye Syndrome

Use of aspirin in children younger than 18 years is associated with Reye syndrome.

This syndrome is a rare but serious illness of childhood that has a mortality rate of 20% to 30%. Characteristic symptoms are encephalopathy and fatty liver degeneration. Epidemiologic data suggested a relationship between Reye syndrome and use of aspirin by children who have influenza or chickenpox. Although a direct causal link between aspirin and Reye syndrome was never established, the Centers for Disease Control and Prevention recommended that aspirin (and other NSAIDs) be avoided by children and teenagers suspected of having influenza or chickenpox. In response to this recommendation, aspirin was removed from most products intended for children, and aspirin use by children declined sharply. As a result, Reye syndrome essentially vanished: the incidence declined from a high of 555 cases in 1980 to no more than 2 cases per year since 1994. If a child with chickenpox or influenza needs an analgesic-antipyretic, acetaminophen can be used safely.

Adverse Effects Associated With Use During Pregnancy

Aspirin poses risks to the pregnant patient and her fetus. Accordingly, the drug is classified in FDA Pregnancy Risk Category D: there is evidence of human fetal risk, but the potential benefits from use of the drug during pregnancy may outweigh the potential for harm. The principal risks to pregnant women are (1) anemia (from GI blood loss) and (2) postpartum hemorrhage. In addition, by inhibiting prostaglandin synthesis, aspirin may suppress spontaneous uterine contractions and may thereby prolong labor.

Aspirin crosses the placenta and may adversely affect the fetus. Because prostaglandins help keep the ductus arteriosus patent, inhibition of prostaglandin synthesis by aspirin may induce premature closure of the ductus arteriosus. Aspirin use has also been associated with low birth weight, stillbirth, renal toxicity, intracranial hemorrhage in preterm infants, and neonatal death.

Hypersensitivity Reactions

Hypersensitivity develops in about 0.3% of aspirin users. Reactions are most likely in adults with a history of asthma, rhinitis, and nasal polyps. Hypersensitivity reactions are uncommon in children. The aspirin hypersensitivity reaction begins with profuse, watery rhinorrhea and may progress to generalized urticaria, bronchospasm, laryngeal edema, and shock. Despite its resemblance to severe anaphylaxis, this reaction is not allergic and is not mediated by the immune system. What does cause these reactions? Because individuals who react to aspirin are also sensitive to most other NSAIDs, we believe that the reactions are due to inhibition of COX-1, which triggers production of leukotrienes, which in turn causes bronchospasm, hives, and other signs of hypersensitivity. However, if this is the mechanism, it remains unclear why hypersensitivity is limited mainly to adults with the predisposing conditions noted earlier. As with severe anaphylactic reactions, epinephrine is the treatment of choice.

Hypersensitivity to aspirin is considered a contraindication to using other drugs with aspirin-like properties. Nonetheless, if an aspirin-like drug must be taken, four such drugs are probably safe. One of these—celecoxib—is selective for COX-2. Another—meloxicam—is somewhat selective for COX-2, but only at low doses. The other two—acetaminophen and salsalate—are only weak inhibitors of COX-1.

Cardiovascular Events

In contrast to all other NSAIDs, aspirin does NOT increase the risk for thrombotic events, including MI and ischemic stroke. In fact, when taken in low doses, aspirin protects against these events.

Erectile Dysfunction

Daily use of aspirin and other NSAIDs is associated with a 22% increase in the risk for erectile dysfunction, as shown in a study of 80,966 men in California. However, a causal relationship has not been established.

Anticoagulants: Warfarin, Heparin, and Others

Aspirin’s most important interactions are with anticoagulants. Because aspirin suppresses platelet function and can decrease prothrombin production, aspirin can intensify the effects of warfarin, heparin, and other anticoagulants. Furthermore, because aspirin can initiate gastric bleeding, augmenting anticoagulant effects can increase the risk for gastric hemorrhage. Accordingly, the combination of aspirin with anticoagulants must be used with care—even when aspirin is taken in low doses to reduce the risk for thrombotic events.

Glucocorticoids

Like aspirin, glucocorticoids promote gastric ulceration. As a result, the risk for ulcers is greatly increased when these drugs are combined—as may happen when treating arthritis. To reduce the risk for gastric ulceration, patients can be given a PPI or H₂RA for prophylaxis.

Alcohol

Combining alcohol with aspirin and other NSAIDs increases the risk for gastric bleeding. To alert the public to this risk, the FDA now requires that labels for aspirin include the following statement: Alcohol Warning: If you consume three or more alcoholic drinks every day, ask your doctor whether you should take aspirin or other pain relievers/fever reducers. Aspirin [and related drugs] may cause stomach bleeding. A similar label is required for all other NSAIDs and acetaminophen.

Nonaspirin NSAIDs

Ibuprofen, naproxen, and other nonaspirin NSAIDs can reduce the antiplatelet effects of aspirin by blocking access of aspirin to COX-1 in platelets. This interaction is important: in patients taking low-dose aspirin to prevent MI or ischemic stroke, other NSAIDs could negate aspirin’s benefits. Because immediate-release aspirin produces complete platelet inhibition about 1 hour after dosing, we can prevent interference by giving aspirin about 2 hours before giving other NSAIDs. Of course, we could eliminate interference entirely by using high-dose aspirin, rather than another NSAID, when conditions call for NSAID therapy.

ACE Inhibitors and ARBs

Like aspirin, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can impair renal function. In susceptible patients, combining aspirin with drugs in either class can increase the risk for acute renal failure. High-dose aspirin should be avoided in patients taking these drugs. However, low-dose aspirin taken for antiplatelet effects should be continued.

Vaccines

Aspirin and other NSAIDs may blunt the immune response to vaccines. Accordingly, these drugs should not be used routinely to prevent vaccination-associated fever and pain.

Signs and Symptoms

Initially, aspirin overdose produces a state of compensated respiratory alkalosis—the same state seen in mild salicylism. As poisoning progresses, respiratory excitation is replaced with respiratory depression. Acidosis, hyperthermia, sweating, and dehydration are prominent, and electrolyte imbalance is likely. Stupor and coma result from effects in the CNS. Death usually results from respiratory failure.

Treatment

Aspirin poisoning is an acute medical emergency that requires hospitalization. The immediate threats to life are respiratory depression, hyperthermia, dehydration, and acidosis. Treatment is largely supportive. If respiration is inadequate, mechanical ventilation should be instituted. External cooling (e.g., sponging with tepid water) can help reduce hyperthermia. Intravenous fluids are given to correct dehydration; the composition of these fluids is determined by electrolyte and acid-base status. Slow infusion of bicarbonate is given to reverse acidosis. Several measures (e.g., gastric lavage, giving activated charcoal) can reduce further GI absorption of aspirin. Alkalinization of the urine with bicarbonate accelerates excretion of aspirin and salicylate. If necessary, hemodialysis or peritoneal dialysis can be used to remove salicylates.

Aspirin Tablets, Plain

All brands are essentially the same with respect to analgesic efficacy, onset, and duration. Some less expensive tablets have greater particle size, which results in slower dissolution and prolonged contact with the gastric mucosa, which increases gastric irritation. When aspirin tablets decompose, they smell like vinegar (acetic acid) and should be discarded.

Aspirin Tablets, Buffered

The amount of buffer in buffered aspirin tablets is too small to produce significant elevation of gastric pH. An equivalent effect on pH can be achieved by taking plain aspirin tablets with food or a glass of water. Buffered aspirin tablets are no different from plain tablets with respect to analgesic effects and gastric distress. Buffered tablets may dissolve faster than plain tablets, resulting in somewhat faster onset.

Buffered Aspirin Solution

A buffered aspirin solution is produced by dissolving effervescent aspirin tablets [Alka-Seltzer] in a glass of water. This solution has considerable buffering capacity owing to its high content of sodium bicarbonate. Effects on gastric pH are sufficient to decrease the incidence of gastric irritation and bleeding. In addition, aspirin absorption is accelerated and peak blood levels are raised. Unfortunately, these benefits come with a price. The sodium content of buffered aspirin solution can be detrimental to individuals on a sodium-restricted diet. Also, absorption of bicarbonate can elevate urinary pH, which will accelerate aspirin excretion. Lastly, this highly buffered preparation is expensive. Because of this combination of benefits and drawbacks, the buffered aspirin solution is well suited for occasional use but is generally inappropriate for long-term therapy.

Enteric-Coated Preparations

Enteric-coated preparations dissolve in the intestine rather than the stomach, thereby reducing gastric irritation. Unfortunately, absorption from these formulations can be delayed and erratic. Patients should be advised not to crush or chew them.

Timed-Release Tablets

Timed-release tablets offer no advantage over plain aspirin tablets. Because the half-life of salicylic acid is long to begin with, and because aspirin produces irreversible inhibition of cyclooxygenase, timed-release tablets cannot prolong effects.

Rectal Suppositories

Rectal suppositories have been employed for patients who cannot take aspirin orally. Absorption can be variable, resulting in plasma drug levels that are insufficient in some patients and excessive in others. Also, rectal irritation can occur. Because of these undesirable properties, aspirin suppositories are not generally recommended.

Oral Preparations and Dosages

Ibuprofen, by itself, is available in five oral formulations: (1) standard tablets (100, 200, 400, 600, and 800 mg); (2) chewable tablets (50 and 100 mg); (3) capsules (200 mg); (4) a 20-mg/mL oral suspension [Children’s Advil, Children’s Motrin, PediaCare Fever]; and (5) a 40-mg/mL oral suspension [Advil Pediatric Drops, Motrin Infant’s, PediaCare Fever]. Administration with meals or milk can reduce gastric distress.

Dosages for adults are as follows:

Dosages for children are as follows:

Oral ibuprofen is also available in three fixed-dose combinations: (1) ibuprofen/oxycodone [Combunox] for short-term oral therapy of moderate to severe pain, (2) ibuprofen/hydrocodone [Vicoprofen] for short-term oral therapy of moderate to severe pain, and (3) ibuprofen/famotidine [Duexis] for treatment of rheumatoid arthritis and osteoarthritis, while reducing the risk for GI ulcers.

Contrasts With Aspirin

In contrast to aspirin, the nonacetylated salicylates cause little or no suppression of platelet aggregation. As a result, these drugs cannot protect against MI and stroke and may actually increase risk.

Because of its sodium content, sodium salicylate should be avoided in patients on a sodium-restricted diet (e.g., patients with hypertension or heart failure).

Magnesium salicylate may accumulate to toxic levels in patients with chronic renal insufficiency and hence should not be used by these people.

Salsalate is a prodrug that breaks down to release two molecules of salicylate in the alkaline environment of the small intestine. Because the stomach is not exposed to salicylate, salsalate produces less gastric irritation than aspirin.

Preparations, Dosage, and Administration

Magnesium salicylate [Doan’s Tablets, others] is supplied in 580-mg caplets and tablets for oral use. The usual dosage is 1090 mg every 6 hours. The maximal dosage is 4640 mg/day, administered in three or four doses.

Sodium salicylate (generic) is supplied in a combination pill with methenamine marketed as Cystex (162.5 mg/162 mg). Dosing is 2 tablets with a full glass of water 4 times a day for treatment of urinary pain.

Salsalate is supplied in capsules (500 mg) and tablets (500 and 750 mg) for oral use. The usual dosage is 3000 mg/day in divided doses.

Adverse Effects

Naproxen is among the better tolerated NSAIDs. The most common adverse effects are GI disturbances. Like other NSAIDs, the drug can compromise renal function and may increase the risk for MI and stroke. However, because naproxen is COX-1 selective, the risk for MI and stroke appears lower than with other traditional NSAIDs. Bleeding time can be prolonged secondary to reversible inhibition of platelet aggregation.

Preparations, Dosage, and Administration

Naproxen is supplied in immediate-release tablets (220, 250, 275, 375, and 500 mg) sold as Aleve, Anaprox, and Naprosyn; a 550-mg double-strength tablet sold as Anaprox DS; delayed-release enteric-coated tablets (375 and 500 mg) sold as EC-Naprosyn; controlled-release tablets (375, 500, and 750 mg) sold as Naprelan; and an oral suspension (25 mg/mL) sold as Naprosyn and Naproxen. For all products, the usual dosage for rheumatoid arthritis is 250 to 500 mg of naproxen twice daily. The dosage for mild to moderate pain is 500 mg initially followed by 250 mg every 6 to 8 hours as needed.

Topical

Diclofenac is available in three topical formulations—Voltaren Gel, Flector Patch, and Pennsaid (solution)—for treatment of pain and inflammation. Voltaren Gel is for osteoarthritis, Flector Patch is for minor pain, and Pennsaid is for osteoarthritis of the knee. A fourth topical formulation—Solaraze—is used for actinic keratoses (see Chapter 85). Topical diclofenac is more expensive than oral diclofenac, but also safer: with topical therapy, blood levels are only about 5% of those achieved with oral therapy, and hence the risk for systemic toxicity is low. Efficacy of topical diclofenac appears about equal to that of oral therapy. Whether topical diclofenac shares the drug interactions of oral diclofenac has not been determined.

Voltaren Gel (1% diclofenac sodium) was the first prescription topical NSAID for treating pain and inflammation. Application is done to the knees, elbows, and other amenable joints. For joints of the lower extremity (knees, ankles, feet), the dosage is 4 g of gel applied 4 times a day. For joints of the upper extremity (elbows, wrists, hands), the dosage is 2 g of gel applied 4 times a day. Total body exposure should not exceed 32 g/day. Treated areas should be protected from sunlight (natural or artificial). Local dermatitis is the principal adverse effect.

Flector Patch (1.3% diclofenac epolamine) is the first prescription NSAID patch indicated for pain of strains, sprains, and contusions. One patch is applied over the injury twice a day—but only to skin that is intact. The patch should not be worn while bathing or showering. Local reactions—pruritus, dermatitis, burning—are the principal adverse effects.

Pennsaid is a 1.5% or 2% solution of diclofenac sodium, formulated with 45% dimethyl sulfoxide (DMSO) to facilitate skin penetration. The product has only one indication: osteoarthritis of the knee. Efficacy equals that of oral diclofenac. Application is done 4 times a day. For each application, 40 drops are spread around the entire knee (front, back, and sides). Application-site reactions are common. Among these are dry skin, erythema and induration, pruritus, and contact dermatitis with vesicles. Systemic effects are minimal. Patients may experience a garlicky odor or taste owing to the DMSO. As with Voltaren Gel, the treated area should not be exposed to sunlight, natural or artificial.

Pharmacokinetics

Indomethacin is well absorbed after oral administration and distributes to all body fluids and tissues. The drug is metabolized in the liver. Metabolites and parent drug are excreted in the urine and feces.

Adverse Effects

Untoward effects are seen in 35% to 50% of patients, causing about 20% to discontinue treatment. The most common adverse effect is severe frontal headache, which occurs in 25% to 50% of patients. Other CNS effects (dizziness, vertigo, confusion) are also common. Seizures and psychiatric changes (e.g., depression, psychosis) have occurred. Mild GI reactions (nausea, vomiting, indigestion) develop in 3% to 9% of users. More severe GI effects (ulceration with perforation, hemorrhage) may also occur. Hematologic reactions (neutropenia, thrombocytopenia, aplastic anemia) have occurred but are rare. Indomethacin suppresses platelet aggregation.

Precautions and Contraindications

Because of its adverse effects, indomethacin is generally contraindicated for infants and children younger than 14 years, patients with peptic ulcer disease, and women who are pregnant or breastfeeding. Caution is required in patients with seizures and psychiatric disorders, in patients involved in hazardous activities, and in patients receiving anticoagulant therapy.

Preparations, Dosage, and Administration

Indomethacin [Indocin] is available in immediate-release capsules (25 and 50 mg), extended-release capsules (75 mg), an oral suspension (5 mg/mL), and rectal suppositories (50 mg). For treatment of rheumatoid arthritis, the initial dosage is 25 mg 2 or 3 times a day. The maximal daily dosage is 200 mg. Gastrointestinal reactions can be reduced by dosing with meals.

A new form of indomethacin was recently approved and is available in 20- and 40-mg capsules sold as Tivorbex. Tivorbex is unique because the capsules contain particles that are 20 times smaller than traditional indomethacin particles. This allows for increased dissolution, thus producing an equianalgesic effect at smaller doses and therefore less toxic side effects.

Pharmacokinetics

Ketorolac is administered orally and parenterally (intramuscularly or intravenously). The drug is eliminated by hepatic metabolism and urinary excretion. In young adults, ketorolac has a half-life of 4 to 6 hours. The half-life may be prolonged in older adults and in those with renal impairment.

Adverse Effects and Contraindications

Ketorolac can cause all of the adverse effects associated with other NSAIDs, including peptic ulcers, GI bleeding or perforation, prolonged bleeding time, renal impairment, hypersensitivity reactions, suppression of uterine contractions, and premature closure of the ductus arteriosus. Concurrent use with other NSAIDs increases the risk for these effects and hence is contraindicated. Other contraindications include active peptic ulcer disease, history of peptic ulcer disease or recent GI bleeding, advanced renal impairment, confirmed or suspected intracranial bleeding, use before major surgery, history of NSAID hypersensitivity reactions, and use during labor and delivery.

Ketorolac is available in 10-mg tablets for oral dosing. Dosing is parenteral initially, followed by oral dosing if needed. Owing to risks associated with prolonged use, treatment (parenteral plus oral) should not exceed 5 days.

Oral ketorolac is indicated only as a follow-up to parenteral therapy. Initial oral doses are based on preceding parenteral doses. The usual oral maintenance dosage is 10 mg every 4 to 6 hours. Combined oral and parenteral treatment should not exceed 5 days.

Mechanism of Action

Celecoxib causes selective inhibition of COX-2, the COX isoform whose products mediate inflammation and pain. At therapeutic doses, celecoxib does not inhibit COX-1, the COX isoform whose products protect the stomach, help maintain renal function, and promote platelet aggregation.

Pharmacokinetics

Celecoxib is well absorbed after oral administration. Plasma levels peak in 3 hours. Binding to plasma proteins is extensive (97%). The drug undergoes hepatic metabolism followed by renal excretion. The half-life is 11 hours.

Adverse Effects

In premarketing trials, celecoxib was well tolerated. The discontinuation rate owing to adverse effects was 7.1% for celecoxib versus 6.1% for placebo. The most common complaints were dyspepsia and abdominal pain. Celecoxib does not decrease platelet aggregation and hence does not promote bleeding. Possible cardiovascular events are the biggest concern.

Celecoxib may increase the anticoagulant effects of warfarin and may thereby increase the risk for bleeding. Celecoxib itself does not inhibit platelet aggregation and does not promote bleeding. However, the drug may enhance the anticoagulant effects of warfarin (perhaps by increasing warfarin levels). Celecoxib may be combined with warfarin, but effects of warfarin should be monitored closely, especially during the first few days of treatment.

Preparations, Dosage, and Administration

Celecoxib [Celebrex] is available in capsules (50, 100, 200, and 400 mg). To minimize cardiovascular risk, the drug should be used in the lowest effective dosage for the shortest time needed. Approved dosages are as follows:

Mechanism of Action

Differences between the effects of acetaminophen and aspirin are thought to result from selective inhibition of cyclooxygenase, the enzyme needed to make prostaglandins and related compounds. Whereas aspirin can inhibit cyclooxygenase in both the CNS and the periphery, inhibition by acetaminophen is limited to the CNS; acetaminophen has only minimal effects on cyclooxygenase at peripheral sites. By decreasing prostaglandin synthesis in the CNS, acetaminophen is able to reduce fever and pain. The inability to inhibit prostaglandin synthesis outside the CNS may explain the absence of antiinflammatory effects, gastric ulceration, and adverse effects on the kidneys and platelets.

Pharmacokinetics

Acetaminophen is readily absorbed after oral dosing and undergoes wide distribution. Most of each dose is metabolized by the liver, and the metabolites are excreted in the urine. The plasma half-life is approximately 2 hours.

Acetaminophen can be metabolized by two pathways; one is major, and the other is minor (Fig. 55.1). In the major pathway, acetaminophen undergoes conjugation with glucuronic acid and other compounds to form nontoxic metabolites. In the minor pathway, acetaminophen is oxidized by a cytochrome P450–containing enzyme into a highly reactive toxic metabolite: N-acetyl-p-benzoquinone imine. At therapeutic doses, practically all of the drug is converted to nontoxic metabolites through the major pathway. Only a small fraction is converted into the toxic metabolite through the minor pathway. Furthermore, under normal conditions, the toxic metabolite undergoes rapid conversion to a nontoxic form; glutathione is required for the conversion. In the event of acetaminophen overdose, a larger than normal amount is processed through the minor pathway, and hence a large quantity of the toxic metabolite is produced. As the liver attempts to clear the metabolite, glutathione is rapidly depleted, and further detoxification stops. As a result, the toxic metabolite accumulates, causing damage to the liver (see later).

Adverse Effects

Adverse effects are extremely rare at therapeutic doses. Acetaminophen does not cause gastric ulceration or renal impairment and does not inhibit platelet aggregation. In addition, there is no evidence linking acetaminophen with Reye syndrome. Individuals who are hypersensitive to aspirin only rarely experience cross-hypersensitivity with acetaminophen. Overdose can cause severe liver injury (see later).

Data from the Nurses’ Health Study show an association between daily use of acetaminophen (500 mg or more/day) and development of hypertension. Additional studies that examined a possible relationship between acetaminophen and hypertension in both men and women found conflicting results. Until more data become available, it would be prudent to monitor blood pressure in patients who take acetaminophen daily. The mechanism by which acetaminophen might raise blood pressure is unknown.

Studies have shown an association between acetaminophen and development of asthma. However, as with hypertension, a causal relationship has not been established. In fact, regarding asthma, the association may well be the other way around. That is, people may be taking acetaminophen because they have respiratory symptoms, rather than having respiratory symptoms because they took acetaminophen. To prove that acetaminophen actually does cause asthma, stronger data are needed.

Rarely, patients experience anaphylaxis, a severe hypersensitivity reaction characterized by breathing difficulty associated with swelling of the face, mouth, and throat. If these symptoms develop, patients should seek immediate medical help.

Acetaminophen use has also been associated with Stevens-Johnson Syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and toxic epidermal necrolysis (TEN). SJS and TEN are characterized by painful rash, blistering of the skin and mucous membranes, and detachment of the epidermis. These are considered medical emergencies because they can result in death. Recovery can take weeks to months. AGEP is characterized by pustular lesions that predominately affect the upper trunk and body folds. AGEP usually resolves within 2 weeks of onset. These reactions can occur at any time, even if the patient has taken acetaminophen previously. If rash appears while taking acetaminophen, the drug should be stopped and the patient should seek medical attention.

Regular alcohol consumption increases the risk for liver injury from acetaminophen—but only if acetaminophen dosage is excessive. Three mechanisms are involved. First, alcohol induces synthesis of the P450-containing enzyme in the minor metabolic pathway, thereby increasing production of acetaminophen’s toxic metabolite (see Fig. 55.1). Second, stores of glutathione are depleted in chronic alcoholics. As a result, the liver is unable to convert the toxic metabolite to a nontoxic form. Third, chronic alcohol abusers often have preexisting liver damage, which renders them less able to tolerate injury from acetaminophen.

Alcohol in combination with acetaminophen can increase the risk for liver and kidney damage. Although information regarding liver disease and acetaminophen has existed for some time, newer data reveal that even low-dose combinations of alcohol and acetaminophen can lead to renal dysfunction. Authorities recommend that, if you drink alcohol on a regular basis, you should consume no more than 2000 mg of acetaminophen a day (one half the normal maximum).

Although therapeutic doses of acetaminophen may be safe for alcohol drinkers, high doses certainly are not. Accordingly, to alert the public to the potential risk of combining alcohol with acetaminophen, the FDA requires that acetaminophen labels bear the following statement: Alcohol Warning: If you consume three or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers.

Therapeutic Uses

Acetaminophen is indicated for relief of pain and fever. Because acetaminophen is not associated with Reye syndrome, the drug is preferred to NSAIDs for use by children suspected of having chickenpox or influenza. Because it does not cause GI injury, acetaminophen is preferred to NSAIDs for patients with peptic ulcer disease. In addition, acetaminophen may be a safe alternative to aspirin for patients who have experienced aspirin hypersensitivity reactions. Because of its weak antiinflammatory actions, acetaminophen is not useful for treating arthritis or rheumatic fever.

Acute Toxicity: Liver Damage

Overdose with acetaminophen can cause severe liver injury and death. The cause is accumulation of the toxic metabolite discussed earlier. In the United States acetaminophen overdose—intentional or unintentional—is the leading cause of acute liver failure, accounting for about 50% of all cases. Risk for liver injury is increased by fasting, chronic alcohol use, and taking more than 4000 mg of acetaminophen a day.

Numerous acetaminophen-containing products are on the market, including a wide assortment of fixed-dose combinations. The drug is available in rectal suppositories, solution for intravenous dosing, and multiple oral formulations (standard tablets, chewable tablets, effervescent granules, capsules, liquids, elixirs, and solutions). Many products are available over the counter, and many others require a prescription. Furthermore, product strengths vary widely. All these products are mentioned here because they create a significant risk for overdose—either from taking two or more products that both contain acetaminophen or from taking too much of a single-ingredient product (owing to failure to carefully read the label). You should alert patients to these dangers.