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.