Antiinflammatory and Antigout Drugs
Objectives
When you reach the end of this chapter, you will be able to do the following:
1 Discuss the inflammatory response and the part it plays in the generation of pain.
2 Compare the disease processes or pathologies that are inflammatory in nature with those of gout.
Drug Profiles
Key Terms
Done nomogram A standard data graph, originally published in 1960 in the journal Pediatrics, for rating the severity of aspirin toxicity following overdose. Serum salicylate levels are plotted against time elapsed since ingestion. (p. 710)
Gout Hyperuricemia (elevated blood uric acid level); the arthritis caused by tissue buildup of uric acid crystals. (p. 713)
Inflammation A localized protective response stimulated by injury to tissues that serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. (p. 707)
Nonsteroidal antiinflammatory drugs (NSAIDs) A large and chemically diverse group of drugs that possess analgesic, antiinflammatory, and antipyretic (fever-reducing) activity. (p. 707)
Salicylism The syndrome of salicylate toxicity, including symptoms such as tinnitus (ringing sound in the ears), nausea, and vomiting. (p. 710)
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Anatomy, Physiology, and Pathophysiology Overview
Inflammation is defined as a localized protective response stimulated by injury to tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Classic signs and symptoms of inflammation include pain, fever, loss of function, redness, and swelling. These symptoms result from arterial, venous, and capillary dilation; enhanced blood flow and vascular permeability; exudation of fluids, including plasma proteins; and leukocyte migration into the inflammatory focus. The inflammatory response is mediated by a host of endogenous compounds, including proteins of the complement system, histamine, serotonin, bradykinin, leukotrienes, and prostaglandins, the latter two being major contributors to the symptoms of inflammation.
Arachidonic acid is released from phospholipids in cell membranes in response to a triggering event (e.g., an injury). It is metabolized in either the prostaglandin pathway or the leukotriene pathway, both of which are branches of the arachidonic acid pathway, as shown in Figure 44-1. Both of these pathways lead to inflammation, edema, headache, and other pain characteristic of the body’s response to injury or inflammatory illnesses such as arthritis.
In the prostaglandin pathway, arachidonic acid is converted by the enzyme cyclooxygenase into various prostaglandins. Prostaglandins mediate inflammation by inducing vasodilation and enhancing vasopermeability. These effects in turn potentiate the action of proinflammatory substances such as histamine and bradykinin in the production of edema and pain. These symptoms arise as a result of prostaglandin-induced hyperalgesia (excessive sensitivity). In this situation, stimuli that normally would not be painful, such as simply moving a joint through its natural range of motion, become painful because of the inflammatory process at work. Fever occurs when prostaglandin E2 is synthesized in the preoptic hypothalamic region, the area of the brain that regulates temperature.
The leukotriene pathway utilizes lipoxygenases to metabolize the arachidonic acid and convert it into various leukotrienes. Although leukotrienes are more newly discovered than prostaglandins and not as well studied, they are also mediators of inflammation, promoting vasoconstriction, bronchospasm, and increased vascular permeability with resultant edema (see Chapter 37).
Pharmacology Overview
Nonsteroidal Antiinflammatory Drugs
Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly prescribed drugs. Every year, over 70 million prescriptions are written for these drugs. This represents more than 5% of all prescriptions. Currently more than 23 different NSAIDs are available in the United States. Some of these are used much more commonly than others. A given patient may respond better to one NSAID than to others, in terms of both symptom relief and adverse effects.
NSAIDs comprise a large and chemically diverse group of drugs that possess analgesic, antiinflammatory, and antipyretic (antifever) activity. They are also used for the relief of mild to moderate headaches, myalgia, neuralgia, and arthralgia; alleviation of postoperative pain; relief of the pain associated with arthritic disorders such as rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, and osteoarthritis; and treatment of gout and hyperuricemia (discussed later in the chapter). Aspirin is used for its effect in inhibiting platelet aggregation, which has been shown to have protective qualities against certain cardiovascular events such as myocardial infarction and stroke. Corticosteroid antiinflammatory drugs (e.g., prednisone, dexamethasone) are also used for similar purposes and were discussed in Chapter 33. NSAIDs have a generally more favorable adverse effect profile than the corticosteroid antiinflammatory drugs.
In 1899, acetylsalicylic acid (ASA; aspirin) was marketed and rapidly became the most widely used drug in the world. The success of aspirin established the importance of drugs with antipyretic, analgesic, and antiinflammatory properties—the properties that all NSAIDs share. The widespread use of aspirin also yielded evidence of its potential for causing major adverse effects. Gastrointestinal intolerance, bleeding, and renal impairment became major factors limiting its long-term administration. As a result, efforts were mounted to develop drugs that did not have the adverse effects of aspirin. This led to the discovery of other NSAIDs, which in general are associated with a lower incidence of and less serious adverse effects and are often better tolerated than aspirin in patients with chronic diseases. If aspirin were to be a newly discovered drug today, it would require a prescription.
As a single class, NSAIDs constitute an exceptional variety of drugs, and they are used for an equally wide range of indications. Box 44-1 categorizes these drugs into a number of distinct chemical classes. The NSAIDs have been approved for a variety of indications and are considered the drug of choice for most of the conditions listed in Box 44-2. Almost all NSAIDs are used for the treatment of rheumatoid arthritis (see Chapter 47) and degenerative joint disease (osteoarthritis). Several of these drugs are available in sustained-release formulations. This allows once- or twice-daily dosing, which is known to improve patients’ adherence to prescribed drug therapy regimens.
Mechanism of Action and Drug Effects
The NSAIDs work through inhibition of the leukotriene pathway, the prostaglandin pathway, or both. More specifically, NSAIDs relieve pain, headache, and inflammation by blocking the chemical activity of the enzyme called cyclooxygenase (COX). It is now recognized that there are at least two types of cyclooxygenase. Cyclooxygenase-1 (COX-1) is the isoform of the enzyme that promotes the synthesis of prostaglandins, which have primarily beneficial effects on various body functions. One example is their role in maintaining an intact gastrointestinal mucosa. In contrast, the cyclooxygenase-2 (COX-2) isoform promotes the synthesis of prostaglandins that are involved in inflammatory processes. In 1998, the newest class of NSAIDs, the COX-2 inhibitors, was approved. These drugs work by specifically inhibiting the COX-2 isoform of cyclooxygenase and theoretically have limited or no effects on COX-1. Previous NSAIDs nonspecifically inhibited both COX-1 and COX-2 activity. This greater enzyme specificity of the COX-2 inhibitors allows for the beneficial antiinflammatory effects while reducing the prevalence of adverse effects associated with the nonspecific NSAIDs, such as gastrointestinal ulceration. The leukotriene pathway is inhibited by some antiinflammatory drugs, but not by salicylates.
All NSAIDs can be ulcerogenic and induce gastrointestinal bleeding due to their activity against tissue COX-1. One notable effect of aspirin is its inhibition of platelet aggregation, also known as its antiplatelet activity. Aspirin has the unique property among NSAIDs of being an irreversible inhibitor of COX-1 receptors within the platelets themselves. This in turn results in reduced formation of thromboxane A2, a substance that normally promotes platelet aggregation. This antiplatelet action has made aspirin, along with thrombolytic drugs (see Chapter 26), a primary drug in the treatment of acute myocardial infarction and many other thromboembolic disorders. Other NSAIDs lack these antiplatelet effects.
Indications
Some of the therapeutic uses of this broad class of drugs are listed in Table 44-1; however, NSAIDs are primarily used for their analgesic, antiinflammatory, and antipyretic effects, and for platelet inhibition. NSAIDs are also widely used for the treatment of rheumatoid arthritis (see Chapter 47) and osteoarthritis, as well as other inflammatory conditions, rheumatic fever, mild to moderate pain, and acute gout. They also have proved beneficial as adjunctive pain relief medications in patients with chronic pain syndromes, such as pain from bone cancer and chronic back pain. For the relief of pain, NSAIDs are sometimes combined with an opioid (see Chapter 10). They tend to have an opioid-sparing effect when given together with opioids, because the drugs attack pain using two different mechanisms. This often allows less opioids to be used. Unlike opioids, NSAIDs show a ceiling effect that limits their effectiveness; that is, any further increase in the dosage beyond a certain level increases the risk for adverse effects without a corresponding increase in the therapeutic effect. In contrast, opioid dosages may be titrated almost indefinitely to increasingly higher levels, especially in terminally ill patients with severe pain.
TABLE 44-1
SUGGESTED NSAIDs FOR PATIENTS WITH VARIOUS MEDICAL CONDITIONS
| MEDICAL CONDITION | RECOMMENDED NSAID |
| Ankylosing spondylitis | indomethacin, diclofenac |
| Diabetic neuropathy | sulindac |
| Dysmenorrhea | Fenamates, naproxen, ibuprofen |
| Gout | indomethacin, naproxen, sulindac |
| Headaches | aspirin, naproxen, ibuprofen |
| Hepatotoxicity | tolmetin, naproxen, ibuprofen, piroxicam, fenamates |
| History of aspirin or NSAID allergy | Avoid if possible; if deemed necessary, consider a nonacetylated salicylate |
| Hypertension | sulindac, nonacetylated salicylate, ibuprofen, etodolac |
| Osteoarthritis | diclofenac, oxaprozin, indomethacin |
| Risk for gastrointestinal toxicity | COX-2 inhibitors (celecoxib), nonacetylated salicylate, enteric-coated aspirin, diclofenac, nabumetone, etodolac, ibuprofen, oxaprozin |
| Risk for nephrotoxicity | sulindac, nonacetylated salicylate, nabumetone, etodolac, diclofenac, oxaprozin |
| Warfarin therapy | sulindac, tolmetin, naproxen, ibuprofen, oxaprozin |
COX, Cyclooxygenase; NSAID, nonsteroidal antiinflammatory drug.
The appropriate selection of an NSAID is a clinical judgment based on consideration of the patient’s history, including any previous medical conditions; the intended use of the drug; the patient’s previous experience with NSAIDs; the patient’s preference; and the cost.
Contraindications
Contraindications to NSAIDs include known drug allergy and conditions that place the patient at risk for bleeding, such as rhinitis (risk for epistaxis [nosebleed]), vitamin K deficiency, and peptic ulcer disease. Patients with documented aspirin allergy must not receive NSAIDs. Other common contraindications are those that apply to most drugs and include severe renal or hepatic disease. NSAIDs are generally categorized as pregnancy category C drugs for use during the first two trimesters of pregnancy but are categorized as pregnancy category D (not recommended) for use during the third trimester. This is because NSAID use has been associated with both excessive maternal bleeding and neonatal toxicity during the perinatal period. These drugs also are not recommended for nursing mothers, because they are known to be excreted into human milk. Because of the potential of NSAIDs to increase bleeding, patients undergoing elective surgery need to stop taking NSAIDs at least 1 week prior to surgery.
Adverse Effects
Although NSAIDs are the most widely used class of drugs, and some are available without prescription, their potential for serious adverse events has been underemphasized. Over 100,000 hospitalizations occur each year due to NSAID use, with over 16,000 deaths reported annually. One of the more common and potentially serious adverse effects of the NSAIDs is their effect on the gastrointestinal tract. Symptoms can range from mild symptoms such as heartburn to the most severe gastrointestinal complication, gastrointestinal bleeding. Most fatalities associated with NSAID use are related to gastrointestinal bleeding. In addition, acute renal failure is quite common with NSAID use, especially if the patient is dehydrated. The potential adverse effects of NSAIDs are listed in Table 44-2. Not all of the adverse effects necessarily apply to all drugs, but many do. In 2006, the U.S. Food and Drug Administration (FDA) began requiring a black box warning on all of the NSAIDs (see Box 44-3).
TABLE 44-2
| BODY SYSTEM | ADVERSE EFFECTS |
| Cardiovascular | Moderate to severe noncardiogenic pulmonary edema |
| Gastrointestinal | Dyspepsia, heartburn, epigastric distress, nausea, vomiting, anorexia, abdominal pain, gastrointestinal bleeding, mucosal lesions (erosions or ulcerations) |
| Hematologic | Altered hemostasis through effects on platelet function |
| Hepatic | Acute reversible hepatotoxicity |
| Renal | Reduction in creatinine clearance, acute tubular necrosis with renal failure |
| Other | Skin eruption, sensitivity reactions, tinnitus, hearing loss |
Many of the adverse effects of NSAIDs are secondary to their inactivation of protective prostaglandins that help maintain the normal integrity of the stomach lining. The drug misoprostol (Cytotec) (see Chapter 50) has proved successful in preventing the gastric ulcers and hence gastrointestinal bleeding that can occur in patients receiving NSAIDs. Misoprostol is a synthetic prostaglandin E1 analogue that inhibits gastric acid secretion and also has a cytoprotective component, although the mechanism responsible for this action is unclear. This drug also has abortifacient properties, which were discussed in Chapter 34.
Renal function depends partly on prostaglandins. Disruption of prostaglandin function by NSAIDs is sometimes strong enough to precipitate acute or chronic renal failure, depending on the patient’s current level of renal function. The use of NSAIDs can compromise existing renal function. Renal toxicity can occur in patients who are dehydrated, those with heart failure or liver dysfunction, and those taking diuretics or angiotensin-converting enzyme inhibitors.
Toxicity and Management of Overdose
Salicylate toxicity, usually from aspirin, is not as common as it was; however, there are both chronic and acute manifestations of salicylate toxicity. Chronic salicylate intoxication is also known as salicylism and results from either short-term administration of high dosages or prolonged therapy with high or even lower dosages. The most common signs and symptoms of acute or chronic salicylate intoxication are listed in Table 44-3.
TABLE 44-3
ACUTE OR CHRONIC SALICYLATE INTOXICATION: SIGNS AND SYMPTOMS
| BODY SYSTEM | SIGNS AND SYMPTOMS |
| Cardiovascular | Increased heart rate |
| Central nervous | Tinnitus, hearing loss, dimness of vision, headache, dizziness, mental confusion, lassitude, drowsiness |
| Gastrointestinal | Nausea, vomiting, diarrhea |
| Metabolic | Sweating, thirst, hyperventilation, hypoglycemia or hyperglycemia |
The most common manifestations of chronic salicylate intoxication in adults are tinnitus and hearing loss. Those in children are hyperventilation and central nervous system (CNS) effects such as dizziness, drowsiness, and behavioral changes. Metabolic complications such as metabolic acidosis and respiratory alkalosis often occur to varying degrees in cases of chronic salicylate intoxication. Metabolic acidosis can also occur with acute intoxication, but it is usually less severe than that in patients with chronic intoxication. Hypoglycemia may also arise and can be life-threatening. The treatment of chronic intoxication is based on the presenting symptoms.
The signs and symptoms of acute salicylate toxicity are similar to those of chronic intoxication, but the effects are often more pronounced and occur more quickly. Acute salicylate overdose usually results from the ingestion of a single toxic dose, and its severity can be judged based on the estimated amount ingested (in milligrams per kilogram of body weight), as follows:
• Little or no toxicity: less than 150 mg/kg
• Mild to moderate toxicity: 150 to 300 mg/kg
• Severe toxicity: 300 to 500 mg/kg
However, doses lower than 150 mg/kg have resulted in fatal toxicity. A serum salicylate concentration measured 6 hours or longer after the ingestion may be used in conjunction with the Done nomogram to estimate the severity of intoxication and help guide treatment. The Done nomogram is a graphic plot of serum salicylate level as a function of time since salicylate ingestion. It was first published in a 1960 issue of the journal Pediatrics and is still used today for gauging salicylate toxicity. This nomogram is intended for estimating only the severity of acute intoxications and not the severity of chronic salicylate intoxication. Table 44-4 describes, in general terms, the treatment for cases of varying severity. Treatment goals include removing salicylate from the gastrointestinal tract and/or preventing its further absorption; correcting fluid, electrolyte, and acid-base disturbances; and implementing measures to enhance salicylate elimination, including hemodialysis.
TABLE 44-4
ACUTE SALICYLATE INTOXICATION: TREATMENT
| SEVERITY | TREATMENT |
| Mild | |
| Severe |
An acute overdose of nonsalicylate NSAIDs (e.g., ibuprofen) causes effects similar to those of salicylate overdose, but they are generally not as extensive or as dangerous. Symptoms include CNS toxicities such as drowsiness, lethargy, mental confusion, paresthesias (abnormal touch sensations), numbness, aggressive behavior, disorientation, and seizures, and gastrointestinal toxicities such as nausea, vomiting, and gastrointestinal bleeding. Intense headache, dizziness, cerebral edema, cardiac arrest, and death have also been known to occur in extreme cases. Treatment consists of the administration of activated charcoal, with supportive and symptomatic treatment initiated thereafter. Unlike in the case of salicylates, hemodialysis appears to be of no value in enhancing the elimination of nonsalicylate NSAIDs.
Interactions
Drug interactions associated with the use of salicylates and other NSAIDs can result in significant complications and morbidity. Some of the more common of these are listed in Table 44-5.
DOSAGES
Most Commonly Used NSAIDs
| DRUG (PREGNANCY CATEGORY∗) | PHARMACOLOGIC CLASS | USUAL DOSAGE RANGE | INDICATIONS |
| ♦ aspirin (ASA; many product names) (C/D) | Salicylate | Adult PO/PR: 325-650 mg 4-6 times daily (max 4 g/day) | Fever, pain |
| PO/PR: 3 g/day divided q4-6h | Arthritis | ||
| PO: 81-325 mg once daily | Thromboprevention | ||
| PO/PR: 90-130 mg/kg/day | Juvenile rheumatoid arthritis | ||
| ♦ celecoxib (Celebrex) (C/D) | COX-2 inhibitor | Adult and adolescent older than 15 yr PO: 100-200 mg/day given in 1 or 2 doses | Arthritis, acute pain, primary dysmenorrhea |
| Pediatric Less than 25 kg: 50 mg twice daily More than 25 kg: 100 mg twice daily | Juvenile rheumatoid arthritis | ||
| ♦ ibuprofen (Motrin, Advil, others) (C/D) | Propionic acid derivative | Adult 1200-3200 mg/day divided 3-4 times daily Pediatric 30-40 mg/kg/day divided 3-4 times daily | Arthritis, fever, pain, dysmenorrhea |
| ♦ indomethacin (Indocin, Indocin SR) (C/D) | Acetic acid derivative | Adult PO/PR: 25-50 mg 2-3 times daily (max 200 mg/day) Pediatric PO/PR: 1-2 mg/kg/day divided 2-4 times daily (max 200 mg/day) | Arthritis, including acute gouty arthritis, bursitis or tendonitis |
| ♦ ketorolac (Toradol) (C/D) | Acetic acid derivative | Adult† PO‡: 10 mg q4-6h (max 40 mg/day) IV/IM: 15-60 mg q6-12h (max 120 mg/day if younger than 65 yr; max 60 mg/day if 65 yr or older) Maximum treatment 5 days | Acute painful conditions that would otherwise require opioid-level analgesia |
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