Cyclooxygenase inhibitors: Nonsteroidal anti-inflammatory drugs and acetaminophen

The family of cyclooxygenase inhibitors consists of aspirin and related drugs. Most of these agents have three useful effects: they can suppress inflammation, relieve pain, and reduce fever. In addition, aspirin—and only aspirin—can protect against myocardial infarction (MI) and stroke. All of these effects are produced through one central mechanism: inhibition of cyclooxygenase, the enzyme responsible for synthesis of prostanoids (prostaglandins and related compounds). This same mechanism underlies their principal adverse effects: gastric ulceration, bleeding, and renal impairment. Cyclooxygenase inhibition also underlies MI and stroke, which can occur with most of these drugs, but not with aspirin.

Mechanism of action

All of the drugs discussed in this chapter work by inhibiting cyclooxygenase (COX), the enzyme that converts arachidonic acid into prostanoids: prostaglandins and related compounds (prostacyclin, thromboxane A₂ [TXA₂]). To understand the drugs that inhibit COX, we must first understand COX itself.

Cyclooxygenase is found in all tissues and helps regulate multiple processes. At sites of tissue injury, COX catalyzes the synthesis of prostaglandin E₂ (PGE₂) and prostaglandin I₂ (PGI₂, aka prostacyclin), which promote inflammation and sensitize receptors to painful stimuli. In the stomach, COX promotes synthesis of PGE₂ and PGI₂, which help protect the gastric mucosa. Three mechanisms are involved: reduced secretion of gastric acid, increased secretion of bicarbonate and cytoprotective mucus, and maintenance of submucosal blood flow. In platelets, COX promotes synthesis of TXA₂, which stimulates platelet aggregation. In blood vessels, COX promotes synthesis of prostacyclin, which causes vasodilation. In the kidney, COX catalyzes synthesis of PGE₂ and PGI₂, which promote vasodilation and thereby maintain renal blood flow. In the brain, COX-derived prostaglandins mediate fever and contribute to perception of pain. In the uterus, COX-derived prostaglandins help promote contractions at term. It is important to appreciate that prostaglandins, prostacyclin, and TXA₂ act locally; these compounds do not affect sites distant from where they were made.

Cyclooxygenase has two forms, named cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Cyclooxygenase-1 is found in practically all tissues, where it mediates “housekeeping” chores. Important among these are protecting the gastric mucosa, supporting renal function, and promoting platelet aggregation. In contrast, COX-2 is produced mainly at sites of tissue injury, where it mediates inflammation and sensitizes receptors to painful stimuli. Cyclooxygenase-2 is also present in the brain (where it mediates fever and contributes to perception of pain), the kidney (where it supports renal function), blood vessels (where it promotes vasodilation), and the colon (where it can contribute to colon cancer). Because COX-1 primarily mediates beneficial processes, whereas COX-2 primarily mediates harmful processes, COX-1 has been dubbed the “good COX” and COX-2 the “bad COX.” Some important functions of COX-1 and COX-2 are summarized in Table 71–1.

TABLE 71–1

Cyclooxygenase-1 and Cyclooxygenase-2: Functions and Effect of Inhibition

Location	COX Isoform	COX Reaction Product	Response to COX Reaction Product	Effect of COX Inhibition
Stomach	COX-1	PGE₂, PGI₂	Gastric protection: Increased bicarbonate secretion Increased mucus production Decreased acid secretion Maintenance of submucosal blood flow	Gastric ulceration
Platelets	COX-1	TXA₂	Platelet aggregation	Bleeding tendencies Protection against MI
Blood vessels	COX-2	Prostacyclin	Vasodilation	Vasoconstriction (which can promote MI)
Kidney	COX-1, COX-2	PGE₂, PGI₂	Maintenance of renal function: Renal vasodilation Maintenance of renal perfusion	Renal impairment
Injured tissue	COX-2	PGE₂	Inflammation Pain	Reduced inflammation Analgesia
Brain	COX-2	??	Fever Pain	Reduced fever Analgesia
Colon/rectum	COX-2	??	Colorectal cancer promotion	Colorectal cancer protection

COX-1 = cyclooxygenase-1, COX-2 = cyclooxygenase-2, MI = myocardial infarction, PGE₂ = prostaglandin E₂, PGI₂ = prostaglandin I₂, (prostacyclin), TXA₂ = thromboxane A₂.

Having established the roles of COX-1 and COX-2, we can now predict the effects of drugs that inhibit these enzymes. Inhibition of COX-1 (good COX) results largely in harmful effects:

• Gastric erosion and ulceration

• Bleeding tendencies

• Renal impairment

Inhibition of COX-1 also has one very beneficial effect:

• Protection against MI and stroke (secondary to reduced platelet aggregation)

Inhibition of COX-2 (bad COX) results largely in beneficial effects:

• Suppression of inflammation

• Alleviation of pain

• Reduction of fever

• Protection against colorectal cancer

Inhibition of COX-2 also has two adverse effects:

• Renal impairment

• Promotion of MI and stroke (secondary to suppressing vasodilation)

Classification of cyclooxygenase inhibitors

The cyclooxygenase inhibitors fall into two major categories: (1) drugs that have anti-inflammatory properties and (2) drugs that lack anti-inflammatory properties. Agents in the first group are referred to as nonsteroidal anti-inflammatory drugs (NSAIDs). Representative members include aspirin, ibuprofen [Advil, Motrin, others], naproxen [Aleve, others], and celecoxib [Celebrex]. The second class consists of just one drug: acetaminophen [Tylenol, others]. Acetaminophen can reduce pain and fever but cannot suppress inflammation.

The NSAIDs can be subdivided into two groups: (1) first-generation NSAIDs (conventional NSAIDs, traditional NSAIDs) and (2) second-generation NSAIDs (selective COX-2 inhibitors, coxibs). The first-generation agents inhibit COX-1 and COX-2. The second-generation agents inhibit COX-2 only. Because the first-generation agents inhibit both COX isoforms, they are unable to suppress pain and inflammation without posing a risk of serious side effects (gastric ulceration, bleeding, renal impairment). In contrast, because of their selectivity for COX-2, the second-generation NSAIDs, in theory, can suppress pain and inflammation while (possibly) causing fewer adverse effects than the first-generation NSAIDs. However, in reality, COX-2 inhibitors appear even less safe than the first-generation agents, owing to an increased risk of MI and stroke.

Table 71–2 summarizes the principal indications and adverse effects of the first-generation NSAIDs, second-generation NSAIDs, and acetaminophen.

TABLE 71–2

Principal Indications and Adverse Effects of the Four Major Types of Cyclooxygenase Inhibitors

	First-Generation NSAIDs: Aspirin	First-Generation NSAIDs: All Others	Second-Generation NSAIDs (Coxibs)	Acetaminophen
Indications
Inflammation	Yes	Yes	Yes	No
Pain	Yes	Yes	Yes	Yes
Fever	Yes	Yes	No	Yes
Prevention of MI and stroke	Yes	No	No	No
Adverse Effects
Gastric ulceration	Yes	Yes	Yes*	No
Renal impairment	Yes	Yes	Yes	No
Bleeding	Yes	Yes	No	No
MI and stroke	No	Yes	Yes	No
Liver damage with overdose	No	No	No	Yes

^*Despite their selectivity for cyclooxygenase-2, coxibs can still cause gastric ulceration, although it may be less than with other NSAIDs.

First-generation NSAIDs

The first-generation NSAIDs—a large and widely used group of drugs—inhibit COX-1 and COX-2. In the United States, more than 70 million prescriptions are written annually and more than 30 billion tablets are sold over the counter. The traditional NSAIDs are used to treat inflammatory disorders (eg, rheumatoid arthritis, osteoarthritis, bursitis), alleviate mild to moderate pain, suppress fever, and relieve dysmenorrhea. Because they cannot inhibit COX-2 without inhibiting COX-1, first-generation NSAIDs cannot suppress inflammation without posing a risk of serious harm: NSAID-induced ulcers are responsible for more than 100,000 hospitalizations and at least 16,500 deaths each year. Aspirin is the oldest member of the family and prototype for the group.

Aspirin

Aspirin is an important drug whose effectiveness is frequently underappreciated. Given that aspirin is available without prescription, widely advertised in the media, and used somewhat casually by the general public, you may be surprised to hear that aspirin is a highly valuable and effective medication. The drug provides excellent relief of mild to moderate pain, reduces fever, protects against thrombotic disorders, and remains a drug of choice for rheumatoid arthritis and other inflammatory conditions. You may also be surprised to hear that aspirin can cause serious toxicity, especially gastric ulceration. Despite the introduction of many new NSAIDs, aspirin remains one of the most widely used members of the group, and is the standard against which the others must be compared.

Chemistry

Aspirin belongs to a chemical family known as salicylates. All members of this group are derivatives of salicylic acid (Fig. 71–1). Aspirin is produced by substituting an acetyl group onto salicylic acid. Because of this acetyl group, aspirin is commonly known as acetylsalicylic acid, or simply ASA.

Figure 71–1 Structural formulas of aspirin and related salicylates.

Mechanism of action

Aspirin is a nonselective inhibitor of cyclooxygenase. Most beneficial effects—reductions of inflammation, pain, and fever—result from inhibiting COX-2. One beneficial effect—protection against MI and ischemic stroke—results from inhibiting COX-1. Major adverse effects—gastric ulceration, bleeding, and renal impairment—result from inhibiting COX-1.

It is important to note that aspirin is an irreversible inhibitor of cyclooxygenase. In contrast, all other NSAIDs are reversible (competitive) inhibitors. Because inhibition of cyclooxygenase by aspirin is irreversible, duration of action depends on how quickly specific tissues can synthesize new molecules of COX-1 and COX-2. With other NSAIDs, effects decline as soon as drug levels fall.

Pharmacokinetics

Therapeutic uses

Suppression of inflammation.

Aspirin is an initial drug of choice for rheumatoid arthritis, osteoarthritis, and juvenile arthritis. Aspirin is also indicated for other inflammatory disorders, including rheumatic fever, tendinitis, and bursitis. The dosages employed to suppress inflammation are considerably larger than dosages used for analgesia or reduction of fever. The use of aspirin and other NSAIDs to treat arthritis is discussed further in Chapter 73.

The precise mechanisms by which aspirin decreases inflammation have not been established. We do know that prostanoids contribute to several, but not all, components of the inflammatory process. Hence, inhibition of COX-2 provides a partial explanation of anti-inflammatory effects. Other possible mechanisms include modulation of T-cell function, suppression of inflammatory cell infiltration, and stabilization of lysosomes.

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 of Reye’s syndrome (see below), 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.

How does aspirin reduce fever? 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, and hence suppression of prostaglandin synthesis relieves cramping.) Some of the newer aspirin-like drugs (eg, 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, in 1999, the 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:

• Ischemic stroke (to reduce the risk of death and nonfatal stroke)

• Transient ischemic attacks (to reduce the risk of death and nonfatal stroke)

• Acute MI (to reduce the risk of vascular mortality)

• Previous MI (to reduce the combined risk of death and nonfatal MI)

• Chronic stable angina (to reduce the risk of MI and sudden death)

• Unstable angina (to reduce the combined risk of death and nonfatal MI)

• Angioplasty and other revascularization procedures (in patients who have a pre-existing condition for which aspirin is already indicated)

According to a 2007 review published in JAMA—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 of GI bleeding.

In addition to these applications, aspirin can be taken by healthy people for primary prevention of MI and stroke. However, benefits differ for men and women. In men, daily aspirin reduces the risk of a first MI, but not the risk of a first ischemic stroke. In women, the opposite applies: daily aspirin reduces the risk of a first ischemic stroke, but not the risk of a first MI. In both sexes, these potential benefits must be weighed against the major risk of aspirin, namely, GI hemorrhage. Hence, to determine the net benefit of primary prevention for any man or woman, we need to determine his or her individual risk for a GI bleed, and compare that risk with his or her individual risk for a cardiovascular (CV) event (ie, the risk for an MI in men, or the risk for ischemic stroke in women).* In 2009, the U.S. Preventive Services Task Force (USPSTF) employed this approach when making the following recommendations for primary prevention:

• For men ages 45 to 79 years—Encourage aspirin use when the potential for preventing an MI outweighs the potential harm of a GI hemorrhage.

• For women ages 55 to 79 years—Encourage aspirin use when the potential for preventing a stroke outweighs the potential harm of a GI hemorrhage.

How do we know when the potential to prevent a CV event outweighs the risk of GI hemorrhage? By using the data in Table 71–3. For example, if the patient is a 65-year-old woman, and her 10-year risk for stroke is 8% or higher, then the benefits of primary prevention are considered to outweigh the risks of a GI bleed. Conversely, if this patient’s 10-year stroke risk were below 8%, then the risks of a GI bleed would outweigh the benefits. How do we calculate 10-year risk for a CV event? Risk for ischemic stroke can be assessed using the online calculator at http://www.westernstroke.org/PersonalStrokeRisk1.xls. Risk for an MI can be assessed using the online calculator at www.mcw.edu/calculators/CoronaryHeartDiseaseRisk.htm.

TABLE 71–3

Risk Level at Which CVD Events Prevented Exceed GI Harms

Men	Women
Age (years)	10-yr CHD Risk	Age (years)	10-yr Stroke Risk
45–59	4% or higher	55–59	3% or higher
60–69	9% or higher	60–69	8% or higher
70–79	12% or higher	70–79	11% or higher

CHD = coronary heart disease, CVD = cardiovascular disease.

Data are from U.S. Preventive Services Task Force: Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 150:396, 2009.

Cancer prevention.

Colorectal cancer.

There is good evidence that regular use of aspirin decreases the risk of colorectal cancer, even when the dosage is low. Results from the Nurses’ Health Study, reported in 2005, showed that regular use of high-dose aspirin (650 mg/day or more) reduces the risk of colorectal cancer. This dosage is much greater than that used to prevent cardiovascular disease, and hence poses a significant risk of 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 (2010; 376:1741), indicate that taking low-dose aspirin (75 to 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 of possible bleeding and other adverse events.

How does aspirin protect 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.

Other cancers.

Available data suggest that protection may not be limited to colorectal cancer. Results of a meta-analysis reported in The Lancet (2011; 377:31) show that daily low-dose aspirin reduces the risk of death from all solid tumors (by 34%), but does not reduce the risk of death from hematologic cancers. Earlier studies have shown protection against specific cancers. In a study involving men over the age of 60, daily use of aspirin and other NSAIDs was associated with a 50% decrease in the incidence of prostate cancer. In a study involving 2884 women, aspirin appeared to reduce the risk of breast cancer, especially among women with hormone receptor–positive tumors, and among those who took 7 or more aspirin tablets a week. In another study, taking aspirin at least 3 times a week for at least 6 months was associated with a 40% reduction in the incidence of ovarian cancer. In contrast to these positive results, results from the Women’s Health Study, released in 2005, found no protection with low-dose aspirin against cancer of the breast, colon, or any other tissue. The reasons for this discrepancy are not clear.

Adverse effects

When administered short term in analgesic or antipyretic (fever-reducing) doses, aspirin rarely causes serious adverse effects. However, toxicity is common when treating inflammatory disorders, which require long-term high-dose treatment.

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:

• Increased secretion of acid and pepsin

• Decreased production of cytoprotective mucus and bicarbonate

• Decreased submucosal blood flow

• The direct irritant action of aspirin on the gastric mucosa

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 of ulceration include:

• Advanced age

• A history of peptic ulcer disease

• Previous intolerance to aspirin or other NSAIDs

• Cigarette smoking

• History of alcohol abuse (Alcohol intensifies the irritant effects of aspirin and should not be consumed.)

What can we do to prevent ulcers? According to an expert panel—convened in 2008 by the American College of Gastroenterology, the American Heart Association, 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, the elderly, and those taking glucocorticoids. Proton pump inhibitors (eg, omeprazole, lansoprazole) reduce ulcer generation by suppressing production of gastric acid. Since many ulcers are caused by infection with Helicobacter pylori (see Chapter 78), 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 78.

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 (eg, hemophilia, vitamin K deficiency, hypoprothrombinemia). In order to minimize blood loss during parturition and elective surgery, high-dose aspirin should be discontinued at least 1 week before these procedures. There is no need to stop aspirin prior to procedures with a low risk of bleeding (eg, 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 of a brain bleed (ie, hemorrhagic stroke), even though aspirin protects against ischemic stroke. To reduce risk of 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 of 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 of 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 (ringing in the ears), sweating, headache, and dizziness. Acid-base disturbance may also occur (see below). 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 maximum 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. As a result, plasma pH returns to normal and a state of compensated respiratory alkalosis is produced.

Reye’s 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 published in 1980 suggested a relationship between Reye’s syndrome and use of aspirin by children who have influenza or chickenpox. Although a direct causal link between aspirin and Reye’s 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’s syndrome essentially vanished: The incidence declined from a high of 555 cases in 1980 to no more than 2 cases per year between 1994 and 1997. 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. Since 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 above. 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 of 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 of erectile dysfunction (ED), as shown in a 2011 study of 80,966 men in California. However, a causal relationship has not been established.

Summary of precautions and contraindications

Aspirin is contraindicated in patients with peptic ulcer disease, bleeding disorders (eg, hemophilia, vitamin K deficiency, hypoprothrombinemia), and hypersensitivity to aspirin itself or other NSAIDs. In addition, the drug should be used with extreme caution by pregnant women and by children who have chickenpox or influenza. Caution should also be exercised when treating elderly patients, patients who smoke cigarettes, and patients with H. pylori infection, heart failure, hepatic cirrhosis, hypovolemia, renal dysfunction, asthma, hay fever, chronic urticaria, nasal polyps, or a history of alcoholism. Aspirin should be withdrawn 1 week prior to elective surgery or the anticipated date of parturition.

Drug interactions

Because of its widespread use, aspirin has been reported to interact with many other medications. However, most of these interactions have little clinical significance. Significant interactions are discussed below.

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, since aspirin can initiate gastric bleeding, augmenting anticoagulant effects can increase the risk of 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 of thrombotic events.

Glucocorticoids.

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

Alcohol.

Combining alcohol with aspirin and other NSAIDs increases the risk of 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. How? 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. Since 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 of 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.

Acute poisoning

Aspirin overdose is a common cause of poisoning. Although rarely fatal in adults, aspirin poisoning may be lethal in children. The lethal dose for adults is 20 to 25 gm. In contrast, as little as 4000 mg (4 gm) can kill a child.

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. The mechanisms that underlie these clinical manifestations are described below.

Many symptoms of aspirin overdose occur secondary to uncoupling of oxidative phosphorylation, the process by which the energy released during the oxidation of carbohydrates, fats, and proteins is used to form ATP from ADP. When oxidative phosphorylation becomes uncoupled, energy from metabolism of carbohydrates and other nutrients can no longer be transferred to ATP and stored. The consequences of this uncoupling are threefold: (1) Production of CO₂ is increased (secondary to the increased rates of metabolism that take place in futile attempts to form needed ATP). (2) There is increased production of lactic and pyruvic acids (as by-products of increased metabolism). (3) Production of heat is increased because the energy that would normally be used to make ATP is released in the form of heat. Increased heat production is responsible for hyperthermia and dehydration, two of the more serious consequences of aspirin overdose.

Acidosis results from multiple causes. Respiratory acidosis occurs because CO₂ production is increased and because toxic levels of salicylate act on the CNS to decrease respiration, thereby allowing even more CO₂ to accumulate. Respiratory acidosis remains uncompensated because bicarbonate stores become depleted during the initial phase of poisoning. Superimposed on respiratory acidosis is true metabolic acidosis. Metabolic acidosis results from (1) the acidity of aspirin and its metabolites, (2) increased production of lactic and pyruvic acids, and (3) accumulation of acidic products of metabolism (eg, sulfuric and phosphoric acids) owing to aspirin-induced impairment of renal excretion.

Acidosis is intensified by the following cycle: (1) Because of the pH partitioning effect, acidosis promotes penetration of salicylate into the CNS. (2) Increased entry of salicylate deepens respiratory depression. (3) Deepening of respiratory depression increases accumulation of CO₂, thereby increasing acidosis. (4) Increasing acidosis causes even more salicylate to enter the CNS, producing even further deepening of respiratory depression. This cycle continues until respiration stops.

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 (eg, 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 (eg, 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.

Formulations

Aspirin is available in multiple formulations, including plain and buffered tablets, enteric-coated preparations, and tablets used to produce a buffered solution. These different formulations reflect efforts to increase rates of absorption and decrease gastric irritation. For the most part, the clinical utility of the more complex formulations is no greater than that of plain aspirin tablets.

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 due 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. Since the half-life of salicylic acid is long to begin with, and since 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.

Dosage and administration

Aspirin is almost always administered by mouth. Gastric irritation can be minimized by dosing with water or food. Dosage depends on the age of the patient and the condition being treated. Adult and pediatric dosages for major indications are summarized in Table 71–4.

TABLE 71–4

Aspirin Dosage

Indication	Adult Dosage	Pediatric Dosage*
Aches and pains; fever	325–650 mg every 4 hr	2–3 yr old: 160 mg 4–5 yr old: 240 mg 6–8 yr old: 325 mg 9–10 yr old: 405 mg 11 yr old: 485 mg Over 11 yr old: 650 mg All of the above doses are administered every 4 hr
Acute rheumatic fever	5–8 gm/day in divided doses	100 mg/kg/day (initially), then 75 mg/kg/day for 4–6 wk
Rheumatoid arthritis	3.6–5.4 gm/day in divided doses	90–130 mg/kg/day in divided doses every 4–6 hr
Suppression of platelet aggregation
Initial therapy	325 mg once a day
Chronic therapy	80 mg once a day