Chapter 36. NSAIDs, Acetaminophen, & Drugs Used in Rheumatoid Arthritis & Gout

Inflammation is a complex response to cell injury that primarily occurs in vascularized connective tissue and often involves the immune response. The mediators of inflammation function to eliminate the cause of cell injury and clear away debris, in preparation for tissue repair. Unfortunately, inflammation also causes pain and, in instances in which the cause of cell injury is not eliminated, can result in a chronic condition of pain and tissue damage such as that seen in rheumatoid arthritis. The nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are often effective in controlling inflammatory pain. Other treatment strategies applied to the reduction of inflammation are targeted at immune processes. These include glucocorticoids and disease-modifying antirheumatic drugs (DMARDs). Gout is an inflammatory joint disease caused by precipitation of uric acid crystals. Treatment of acute episodes targets inflammation, whereas treatment of chronic gout targets both inflammatory processes and the production and elimination of uric acid.

Classification and Prototypes

Aspirin (acetylsalicylic acid) is the prototype of the salicylates and other NSAIDs (Table 36–1). The other older nonselective NSAIDs (ibuprofen, indomethacin, many others) vary primarily in their potency, analgesic and anti-inflammatory effectiveness, and duration of action. Ibuprofen and naproxen have moderate effectiveness; indomethacin has greater anti-inflammatory effectiveness; and ketorolac has greater analgesic effectiveness. Celecoxib was the first member of a newer NSAID subgroup, the cyclooxygenase-2 (COX-2)-selective inhibitors, which were developed in an attempt to lessen the gastrointestinal toxicity associated with COX inhibition while preserving efficacy. Unfortunately, clinical trials involving some of the highly selective COX-2 inhibitors have shown a higher incidence of cardiovascular thrombotic events than the nonselective drugs.

Mechanism of Action

As noted in Chapter 18, cyclooxygenase is the enzyme that converts arachidonic acid into the endoperoxide precursors of prostaglandins, important mediators of inflammation (Figure 36–1). Cyclooxygenase has at least 2 isoforms: COX-1 and COX-2. COX-1 is primarily expressed in noninflammatory cells, whereas COX-2 is expressed in activated lymphocytes, polymorphonuclear cells, and other inflammatory cells.

Aspirin and nonselective NSAIDs inhibit both cyclooxygenase isoforms and thereby decrease prostaglandin and thromboxane synthesis throughout the body. Release of prostaglandins necessary for homeostatic function is disrupted, as is release of prostaglandins involved in inflammation. The COX-2-selective inhibitors have less effect on the prostaglandins involved in homeostatic function, particularly those in the gastrointestinal tract.

The major difference between the mechanisms of action of aspirin and other NSAIDs is that aspirin (but not its active metabolite, salicylate) acetylates and thereby irreversibly inhibits cyclooxygenase, whereas the inhibition produced by other NSAIDs is reversible. The irreversible action of aspirin results in a longer duration of its antiplatelet effect and is the basis for its use as an antiplatelet drug (Chapter 34).

Effects

Arachidonic acid derivatives are important mediators of inflammation; cyclooxygenase inhibitors reduce the manifestations of inflammation, although they have no effect on underlying tissue damage or immunologic reactions. These inhibitors also suppress the prostaglandin synthesis in the CNS that is stimulated by pyrogens and thereby reduces fever (antipyretic action). The analgesic mechanism of these agents is less well understood. Activation of peripheral pain sensors may be diminished as a result of reduced production of prostaglandins in injured tissue; in addition, a central mechanism is operative. Cyclooxygenase inhibitors also interfere with the homeostatic function of prostaglandins. Most important, they reduce prostaglandin-mediated cytoprotection in the gastrointestinal tract and autoregulation of renal function.

Pharmacokinetics and Clinical Use

Aspirin

Aspirin has 3 therapeutic dose ranges: The low range (<300 mg/d) is effective in reducing platelet aggregation; intermediate doses (300–2400 mg/d) have antipyretic and analgesic effects; and high doses (2400–4000 mg/d) are used for an anti-inflammatory effect. Aspirin is readily absorbed and is hydrolyzed in blood and tissues to acetate and salicylic acid. Salicylate is a reversible nonselective inhibitor of cyclooxygenase. Elimination of salicylate is first order at low doses, with a half-life of 3–5 h. At high (anti-inflammatory) doses, half-life increases to 15 h or more and elimination becomes zero order. Excretion is via the kidney.

Other NSAIDs

The other NSAIDs are well absorbed after oral administration. Ibuprofen has a half-life of about 2 h, is relatively safe, and is the least expensive of the older, nonselective NSAIDs. Naproxen and piroxicam are noteworthy because of their longer half-lives (Table 36–1), which permit less frequent dosing. These other NSAIDs are used for the treatment of mild to moderate pain, especially the pain of musculoskeletal inflammation such as that seen in arthritis and gout. They are also used to treat many other conditions, including dysmenorrhea, headache, and patent ductus arteriosus in premature infants. Ketorolac is notable as a drug used mainly as a systemic analgesic, not as an anti-inflammatory (although it has typical nonselective NSAID properties). It is the only NSAID available in a parenteral formulation. Nonselective NSAIDs reduce polyp formation in patients with primary familial adenomatous polyposis. Long-term use of NSAIDs reduces the risk of colon cancer.

Toxicity

Aspirin

The most common adverse effect from therapeutic anti-inflammatory doses of aspirin is gastric upset. Chronic use can result in gastric ulceration, upper gastrointestinal bleeding, and renal effects, including acute failure and interstitial nephritis. Aspirin increases the bleeding time (Chapter 34). When prostaglandin synthesis is inhibited by even small doses of aspirin, persons with aspirin hypersensitivity (especially associated with nasal polyps) can experience asthma from the increased synthesis of leukotrienes. This type of hypersensitivity to aspirin precludes treatment with any NSAID. At higher doses of aspirin, tinnitus, vertigo, hyperventilation, and respiratory alkalosis are observed. At very high doses, the drug causes metabolic acidosis, dehydration, hyperthermia, collapse, coma, and death. Children with viral infections who are treated with aspirin have an increased risk for developing Reye's syndrome, a rare but serious syndrome of rapid liver degeneration and encephalopathy. There is no specific antidote for aspirin.

Nonselective NSAIDs

Like aspirin, these agents are associated with significant gastrointestinal disturbance, but the incidence is lower than with aspirin. There is a risk of renal damage with any of the NSAIDs, especially in patients with preexisting renal disease. Because these drugs are cleared by the kidney, renal damage results in higher, more toxic serum concentrations. Use of parenteral ketorolac is generally restricted to 72 h because of the risk of gastrointestinal and renal damage with longer administration. Serious hematologic reactions have been noted with indomethacin.

COX-2-Selective Inhibitors

The COX-2-selective inhibitors (celecoxib, rofecoxib, valdecoxib) have a reduced risk of gastrointestinal effects, including gastric ulcers and serious gastrointestinal bleeding. The COX-2 inhibitors carry the same risk of renal damage as nonselective COX inhibitors, presumably because COX-2 contributes to homeostatic renal effects. Clinical trial data suggest that highly selective COX-2 inhibitors such as rofecoxib and valdecoxib carry an increased risk of myocardial infarction and stroke. The increased risk of arterial thrombosis is believed to be due to the COX-2 inhibitors having a greater inhibitory effect on endothelial prostacyclin (PGI2) formation than on platelet TXA2 formation. Prostacyclin promotes vasodilation and inhibits platelet aggregation, whereas TXA2 has the opposite effects. Several COX-2 inhibitors have been removed from the market, and the others are now labeled with warnings about the increased risk of thrombosis.

Classification and Prototype

Acetaminophen is the only over-the-counter non-anti-inflammatory analgesic commonly available in the United States. Phenacetin, a toxic prodrug that is metabolized to acetaminophen, is still available in some other countries.

Mechanism of Action

The mechanism of analgesic action of acetaminophen is unclear. The drug is only a weak COX-1 and COX-2 inhibitor in peripheral tissues, which accounts for its lack of anti-inflammatory effect. Evidence suggests that acetaminophen may inhibit a third enzyme, COX-3, in the CNS.

Effects

Acetaminophen is an analgesic and antipyretic agent; it lacks anti-inflammatory or antiplatelet effects.

Pharmacokinetics and Clinical Use

Acetaminophen is effective for the same indications as intermediate-dose aspirin. Acetaminophen is therefore useful as an aspirin substitute, especially in children with viral infections and in those with any type of aspirin intolerance. Acetaminophen is well absorbed orally and metabolized in the liver. Its half-life, which is 2–3 h in persons with normal hepatic function, is unaffected by renal disease.

Toxicity

In therapeutic dosages, acetaminophen has negligible toxicity in most persons. However, when taken in overdose or by patients with severe liver impairment, the drug is a dangerous hepatotoxin. The mechanism of toxicity involves oxidation to cytotoxic intermediates by phase I cytochrome P450 enzymes. This occurs if substrates for phase II conjugation reactions (acetate and glucuronide) are lacking (Chapter 4). Prompt administration of acetylcysteine, a sulfhydryl donor, may be lifesaving after an overdose. People who regularly consume 3 or more alcoholic drinks per day are at increased risk of acetaminophen-induced hepatotoxicity (Chapters 4 and 23).

(See Chapter 31)

Although NSAIDs and acetaminophen are extremely useful for the treatment of mild to moderate pain, adequate control of more intense pain often requires treatment with an opioid.

1. Name 1 strong, 1 moderate, and 1 weak opioid drug.

2. Briefly describe the most common adverse effects of strong and moderate opioids.

3. What drug should be administered in the event of an opioid overdose?

The Skill Keeper Answers appear at the end of the chapter.

Classification

This heterogeneous group of agents (Table 36–2) has anti-inflammatory actions in several connective tissue diseases. They are called disease-modifying drugs because some evidence shows slowing or even reversal of joint damage, an effect never seen with NSAIDs. They are also called slow-acting antirheumatic drugs because it may take 6 wk to 6 mo for their benefits to become apparent. Corticosteroids can be considered anti-inflammatory drugs with an intermediate rate of action (ie, slower than NSAIDs but faster than other DMARDs). However, the corticosteroids are too toxic for routine chronic use (Chapter 39) and are reserved for temporary control of severe exacerbations and long-term use in patients with severe disease not controlled by other agents.

Mechanisms of Action and Effects

The mechanisms of action of most DMARDs in treating rheumatoid arthritis are poorly understood. Cytotoxic drugs (eg, methotrexate) probably act by reducing the number of immune cells available to maintain the inflammatory response; many of these drugs are also used in the treatment of cancer (Chapter 54). Other drugs appear to interfere with the activity of T lymphocytes (eg, sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide, mycophenolate mofetil, abatacept), B lymphocytes (rituximab), or macrophages (gold compounds). In recent years, immunoglobulin-based biologic agents that inhibit the action of tumor necrosis factor-α (TNF-α), including infliximab, adalimumab, and etanercept, have also shown efficacy in rheumatoid arthritis, as has the recombinant human interleukin-1 receptor antagonist anakinra. The immunosuppressant effects of these drugs are discussed in more detail in Chapter 55.

Pharmacokinetics and Clinical Use

Sulfasalazine, hydroxychloroquine, methotrexate, cyclosporine, penicillamine, and leflunomide are given orally. Anti-TNF-α drugs are given by injection. Gold compounds are available for parenteral use (gold sodium thiomalate and aurothioglucose) and for oral administration (auranofin).

Increasingly, DMARDs, particularly low doses of methotrexate, are initiated fairly early in patients with moderate to severe rheumatoid arthritis in an attempt to ameliorate disease progression. Some of these drugs are also used in other rheumatic diseases such as lupus erythematosus, arthritis associated with Sjögren's syndrome, juvenile rheumatoid arthritis, and ankylosing spondylitis, and in other immunologic disorders (Chapter 55).

Toxicity

All DMARDs can cause severe or fatal toxicities. Careful monitoring of patients who take these drugs is mandatory. Their major adverse effects are listed in Table 36–2.

Classification and Prototypes

Gout is associated with increased serum concentrations of uric acid. Acute attacks involve joint inflammation initiated by precipitation of uric acid crystals. Treatment strategies include (1) reducing inflammation during acute attacks (with colchicine, NSAIDs, or glucocorticoids; Figure 36–2); (2) accelerating renal excretion of uric acid with uricosuric drugs (probenecid or sulfinpyrazone); and (3) reducing (with allopurinol or febuxostat) the conversion of purines to uric acid by xanthine oxidase (Figure 36–3).

Anti-Inflammatory Drugs Used for Gout

Mechanisms

NSAIDs such as indomethacin are effective in inhibiting the inflammation of acute gouty arthritis. These agents act through the reduction of prostaglandin formation and the inhibition of crystal phagocytosis by macrophages (Figure 36–2). Colchicine, a selective inhibitor of microtubule assembly, reduces leukocyte migration and phagocytosis; the drug may also reduce production of leukotriene B4 and decrease free radical formation.

Effects

NSAIDs and glucocorticoids reduce the synthesis of inflammatory mediators in the gouty joint. Because it reacts with tubulin and interferes with microtubule assembly, colchicine is a general mitotic poison. Tubulin is necessary for normal cell division, motility, and many other processes.

Pharmacokinetics and Clinical Use

An NSAID or a glucocorticoid is preferred for the treatment of acute gouty arthritis. Although colchicine can be used for acute attacks, the doses required cause significant gastrointestinal disturbance, particularly diarrhea. Lower doses of colchicine are used to prevent attacks of gout in patients with a history of multiple acute attacks. Colchicine is also of value in the management of familial Mediterranean fever, a disease of unknown cause characterized by fever, hepatitis, peritonitis, pleuritis, arthritis, and, occasionally, amyloidosis. Indomethacin, some glucocorticoids, and colchicine are used orally; parenteral preparations of glucocorticoids and colchicine are also available.

Toxicity

NSAIDs can cause renal damage, and indomethacin can additionally cause bone marrow depression. Short courses of glucocorticoids can cause behavioral changes and impaired glucose control. Because colchicine can severely damage the liver and kidney, dosage must be carefully limited and monitored. Overdose is often fatal.

Uricosuric Agents

Mechanism

Normally, over 90% of the uric acid filtered by the kidney is reabsorbed in the proximal tubules. Uricosuric agents (probenecid, sulfinpyrazone) are weak acids that compete with uric acid for reabsorption by the weak acid transport mechanism in the proximal tubules and thereby increase uric acid excretion. At low doses, these agents may also compete with uric acid for secretion by the tubule and occasionally can elevate, rather than reduce, serum uric acid concentration. Elevation of uric acid levels by this mechanism occurs with aspirin (another weak acid) over much of its dose range.

Effects

Uricosuric drugs inhibit the secretion of a large number of other weak acids (eg, penicillin, methotrexate) in addition to inhibiting the reabsorption of uric acid.

Pharmacokinetics and Clinical Use

Uricosuric drugs are used orally to treat chronic gout. These drugs are of no value in acute episodes.

Toxicity

Uricosuric drugs can precipitate an attack of acute gout during the early phase of their action. This can be avoided by simultaneously administering colchicine or indomethacin. Because they are sulfonamides, the uricosuric drugs may share allergenicity with other classes of sulfonamide drugs (diuretics, antimicrobials, oral hypoglycemic drugs).

Xanthine Oxidase Inhibitors

Mechanism

The production of uric acid can be reduced by inhibition of xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid (Figure 36–3). Allopurinol is converted to oxypurinol (alloxanthine) by xanthine oxidase; alloxanthine is an irreversible suicide inhibitor of the enzyme. The newer drug febuxostat is a nonpurine inhibitor of xanthine oxidase that is more selective than allopurinol and alloxanthine, which inhibit other enzymes involved in purine and pyrimidine metabolism.

Effects

Inhibition of xanthine oxidase increases the concentrations of the more soluble hypoxanthine and xanthine and decreases the concentration of the less soluble uric acid. As a result, there is less likelihood of precipitation of uric acid crystals in joints and tissues. Clinical trials suggest that febuxostat is more effective than allopurinol in lowering serum uric acid.

Pharmacokinetics and Clinical Use

The xanthine oxidase inhibitors are given orally in the management of chronic gout. Like uricosuric agents, these drugs are usually withheld for 1–2 wk after an acute episode of gouty arthritis and are administered in combination with colchicine or an NSAID to avoid an acute attack. Allopurinol is also used as an adjunct to cancer chemotherapy to slow the formation of uric acid from purines released by the death of large numbers of neoplastic cells.

Toxicity and Drug Interactions

Allopurinol causes gastrointestinal upset, rash, and rarely, peripheral neuritis, vasculitis, or bone marrow dysfunction, including aplastic anemia. It inhibits the metabolism of mercaptopurine and azathioprine, drugs that depend on xanthine oxidase for elimination. Febuxostat can cause liver function abnormalities, headache, and gastrointestinal upset.

(See Chapter 31)

1. Morphine is the prototype strong opioid. Fentanyl is a strong agent with a rapid onset that is commonly used in the hospital. Methadone is a strong agonist used in maintenance programs for patients addicted to opioids. Codeine, oxycodone, and hydrocodone are moderate agonists, whereas propoxyphene is a weak agonist.

2. Constipation and sedation occur with therapeutic doses; constipation should be managed with stool softeners. In overdose, opioids cause a triad of pinpoint pupils, coma, and respiratory depression.

3. Naloxone, a nonselective opioid receptor antagonist, is an antidote for opioid overdose.

When you complete this chapter, you should be able to:

• □ Describe the effects of NSAIDs on prostaglandin synthesis.
• □ Contrast the functions of COX-1 and COX-2.
• □ Compare the actions and toxicity of aspirin, the older nonselective NSAIDs, and the COX-2-selective drugs.
• □ Explain why several of the highly selective COX-2 inhibitors have been withdrawn from the market.
• □ Describe the toxic effects of aspirin.
• □ Describe the effects and the major toxicity of acetaminophen.
• □ Name 5 disease-modifying antirheumatic drugs (DMARDs) and describe their toxicity.
• □ Contrast the pharmacologic treatment of acute and chronic gout.
• □ Describe the mechanisms of action and toxicity of 3 different drug groups used in gout.