Browse the corpus

CHAPTER 191: Nonsteroidal Anti-Inflammatory Drugs 1259 Nonsteroidal Anti-Inflammatory Drugs Jonathan de Olano Rana Biary INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used therapeutic agents in the United States. All share inhibition of the cyclooxygenase enzyme as a mechanism of action. NSAIDs are effective antipyretics, analgesics, and anti-inflammatory agents. Because of their large therapeutic window, acute ingestion with overdoses rarely produces serious complications. 1,2 The morbidity from NSAIDs in acute overdose is far overshadowed by complications of NSAIDs at therapeutic doses, which include GI bleeding, drug-induced renal failure, and atherosclerotic heart disease. 3-6 PHARMACOLOGY NSAIDs are structurally varied compounds with common therapeu tic effects ( Table 191-1). NSAIDs reversibly inhibit COX, which is responsible for the production of prostaglandins from arachidonic acid. The anti-inflammatory effect of NSAIDs is through the inhibition of prostaglandin production and neutrophil migration. 7 NSAIDs are antipyretics via inhibition of prostaglandin E2 in the hypothalamus. Analgesia is mediated by attenuation of prostaglandin-mediated hyperalgesia and local pain fiber stimulus.  CYCLOOXYGENASE Two isoforms of COX (COX-1 and COX-2) vary in presence and distribution.8 COX-1 is present with a steady level of activity and is found primarily in blood vessels, kidneys, and the stomach. In contrast, COX-2 is found in low levels in human tissue unless induced by proinflammatory mediators. COX inhibitors can be categorized as nonselective, partially selec tive, or selective regarding their inhibition of COX enzyme isoforms (Table 191-1). Most NSAIDs nonselectively inhibit both COX-1 and COX-2. COX-1 inhibition is responsible for most of the unwanted GI side effects of NSAIDs. Drugs such as etodolac and meloxicam were created to inhibit COX-2 preferentially, theoretically reducing the unwanted GI effects. Unfortunately, the COX-2–selective compounds do not appear to be more effective mediators of inflammation or anal gesia and are still associated with GI side effects. 9,10  PHARMACOKINETICS All NSAIDs are rapidly absorbed from the GI tract, and most achieve peak serum levels within about 2 hours. They are highly protein bound, have low volumes of distribution (approximately 0.2 L/kg), and cross the blood–brain barrier. NSAIDs undergo metabolism mainly in the liver.

GI side effects. 9,10  PHARMACOKINETICS All NSAIDs are rapidly absorbed from the GI tract, and most achieve peak serum levels within about 2 hours. They are highly protein bound, have low volumes of distribution (approximately 0.2 L/kg), and cross the blood–brain barrier. NSAIDs undergo metabolism mainly in the liver. CHAPTER TABLE 191-1 Nonsteroidal Agents Available in the United States Class and Agent Half-Life With Therapeutic Doses of Standard Oral Tablets or Capsules * (h) Typical Initial Adult Oral Dose (milligrams) Maximum Recommended Adult Daily Oral Dose (milligrams) Nonselective NSAIDs Acetic acids Diclofenac 2 35 TID 150 Indomethacin 2.6–11.2 25 BID or TID 200 Ketorolac 5 10 QID 120 Meclofenamate 1–2 (15 †) 50 QID 400 Mefenamic acid 2 250 QID 1000 Nabumetone <1 (22–26 †) 1000 daily 2000 Sulindac 8 (16†) 150 BID 400 Tolmetin 5 400 TID 1800 Propionic acids Fenoprofen 3 300 TID 3200 Flurbiprofen 5–8 50 BID 300 Ibuprofen 2 400 QID 2400 (pain, dysmenorrhea) 3200 (osteoarthritis) Ketoprofen 2–4 50 TID 300 Naproxen 12–17 250 BID 1000 (pain) 1500 (osteoarthritis) Oxaprozin 16–45 (38–57 ‡) 1200 daily 1800 Oxicams Piroxicam 50 20 daily 20 Partially selective COX-2 inhibitors Etodolac 6–8 200 TID 1000 Meloxicam 20–24 5 daily 15 Selective COX-2 inhibitors Celecoxib 11 200 BID 400 Abbreviations: BID = twice per day; COX-2 = cyclooxygenase 2; QID = four times per day; TID = three times per day. *Not sustained-release or enteric-coated preparations. †Half-life of active metabolite. ‡Half-life of protein-bound drug. Tintinalli_Sec15_p1187-1332.indd 1259 8/2/19 8:39 PM

itors Celecoxib 11 200 BID 400 Abbreviations: BID = twice per day; COX-2 = cyclooxygenase 2; QID = four times per day; TID = three times per day. *Not sustained-release or enteric-coated preparations. †Half-life of active metabolite. ‡Half-life of protein-bound drug. Tintinalli_Sec15_p1187-1332.indd 1259 8/2/19 8:39 PM 1260 SECTION 15: Toxicology Plasma half-lives of NSAIDs range from 2 hours for ibuprofen to greater than 50 hours for the long-acting agents piroxicam and phenylbutazone (Table 191-1). Creation of active metabolites may prolong the therapeutic effect beyond that of the parent compound. Ingestion of large amounts of some drugs, such as ibuprofen and naproxen, results in slower absorption, with 3 to 4 hours required to achieve peak plasma levels. As greater amounts of NSAIDs are absorbed in large overdoses, greater fractions of free drug become available for toxicity in a nonlinear manner because protein binding is limited. Topical NSAIDs Topical NSAIDs are well absorbed through the skin and reach therapeutic levels in synovial fluid. According to the most recent Cochrane review, topical diclofenac and ketoprofen provide good relief in acute muscular injuries but have limited efficacy in chronic conditions such as osteoarthritis.  SIGNIFICANT DRUG–DRUG INTERACTIONS Aspirin Daily aspirin therapy reduces the incidence of recurrent myo cardial infarction and stroke by impairment of platelet aggregation. Ibuprofen administered three times per day competitively inhibits this aspirin effect on platelets by its interaction with the thromboxane path way, thus undermining aspirin’s cardioprotective effect. 12,13 Ketorolac and diclofenac, unlike other NSAIDs, do not alter aspirin’s inhibition of platelet aggregation and thromboxane synthesis. Antihypertensive Agents NSAIDs decrease the effectiveness of anti hypertensive drugs through inhibition of prostaglandin synthesis. 15 NSAIDS can also aggravate preexisting hypertension or raise blood pressure through their renal effects. Anticoagulants When combined with warfarin or non–vitamin K oral anticoagulants, NSAIDs increase risk for upper GI bleeding, 16,17 although the risk may vary with specific agents. A recent meta-analysis demonstrated a small increase in risk of bleeding with the use of war farin and NSAIDs, 18 while other studies demonstrate that the risk is NSAID specific, with meloxicam being the only NSAID to increase INR with warfarin therapy. 19 Concomitant therapy with COX-2 inhibitors and warfarin still incurs some risk of GI bleeding, but the risk is less with nonselective NSAID–warfarin combinations. 20,21 Due to the drug– drug interactions and risk of GI bleeding, avoid chronic NSAID use in patients on warfarin or novel oral anticoagulants. 22,23 Decreased Renal Clearance of Drugs NSAIDs may also decrease renal clearance by inhibition of renal synthesis of prostaglandins (which serve as vasodilators) and by decreasing renal blood and glomerular filtration rate. NSAIDs increase concentrations of drugs such as lithium, methotrexate, and metformin. NSAIDs are a potential risk factor in the development of metformin-associated lactic acidosis.  TOXICITY AT THERAPEUTIC DOSES NSAIDs are generally safe drugs but have a number of well-reported side effects at therapeutic doses ( Table 191-2). Indomethacin, piroxicam, and diclofenac are responsible for a greater proportion of side effects, whereas the propionic acid agents (e.g., ibuprofen) are associ ated with fewer problems.

HERAPEUTIC DOSES NSAIDs are generally safe drugs but have a number of well-reported side effects at therapeutic doses ( Table 191-2). Indomethacin, piroxicam, and diclofenac are responsible for a greater proportion of side effects, whereas the propionic acid agents (e.g., ibuprofen) are associ ated with fewer problems. 25,26 CNS CNS adverse effects at therapeutic doses include headache, cognitive difficulties, behavioral change, and aseptic meningitis.27,28 Acute psychosis has been reported with indomethacin and sulindac—agents with struc tural similarity to serotonin—and is more commonly in the elderly.29 Patients with NSAID-induced aseptic meningitis may experience symptoms of headache, fever, and neck stiffness occurring within hours of a therapeutic dose. 27,30,31 Cerebrospinal fluid analysis of these patients finds elevated WBC counts and protein levels with normal or decreased glucose levels. Symptoms resolve after NSAID use is stopped and may recur with repeat NSAID challenges. 31 This phenomenon, most often seen in patients who have underlying autoimmune diseases such as systemic lupus erythematosus, is thought to be a hypersensitivity reaction. Exclude infection before assuming NSAID-induced aseptic meningitis. Agents associated with aseptic meningitis include celecoxib, diclofenac, ibuprofen, ketoprofen, naproxen, rofecoxib, sulfasalazine, sulindac, and tolmetin. Cardiovascular Increased cardiovascular events, including myocardial infarction, can result from long-term use of both nonselective NSAIDs and selective COX-2 agents. 32,33 Risk depends on drug, drug dose, and duration and is also more profound in patients with established coro nary artery disease.32,34 The greatest risk for myocardial infarction occurs within the first month of any NSAID use and at higher doses. 33,35 Begin therapy with medications not associated with increased cardiovascular effects, such as acetaminophen, and progress to nonselective NSAIDs, or for patients over 75 years of age, use a topical rather than oral NSAID. 35-39 If NSAIDs are administered in patients with high cardiovascular risk, give short courses of the lowest dose. 40,41 Pulmonary NSAIDs have been associated with adverse pulmonary reactions, including bronchospasm in asthmatics, hypersensitivity pneumonitis, eosinophilic pneumonia, and rarely pulmonary edema. 42-44 Cessation of NSAID use resolves the symptoms. NSAIDs and aspirin can trigger bronchospasm in patients with reac tive airway disease.42 The spectrum of this reaction ranges from rhinitis to severe bronchospasm with laryngeal edema. 45 Patients with underlying reactive airways disease and nasal polyps are at greater risk for these complications. Hypersensitivity reaction to NSAIDs is due to increased proinflammatory cysteinyl leukotrienes and decreased prostaglandin E from COX-1 inhibition.42 GI GI effects from NSAIDs include dyspepsia, heartburn, nausea, and GI bleeding.10 These effects derive from inhibition of cytoprotective gastric prostaglandins resulting in injuries ranging from mild ulceration to life-threatening bleeding. 5 NSAIDs’ inhibition of gastric prostaglandins also increases permeability of the GI barrier.46 Hepatic Clinically apparent liver injury caused by NSAIDs is idiosyn cratic and rare. 47 Diclofenac and sulindac are the two NSAIDs most commonly linked to hepatotoxicity. Drug withdrawal should lead to complete recovery. Renal COX inhibition decreases prostaglandin synthesis and causes renal vasoconstriction. Continued NSAID use may lead to acute tubular necrosis. Interstitial nephritis and glomerular injury may result from NSAID-associated activation of inflammatory cells.

atotoxicity. Drug withdrawal should lead to complete recovery. Renal COX inhibition decreases prostaglandin synthesis and causes renal vasoconstriction. Continued NSAID use may lead to acute tubular necrosis. Interstitial nephritis and glomerular injury may result from NSAID-associated activation of inflammatory cells. 5,6,48 TABLE 191-2 NSAID Toxicity at Therapeutic Doses Organ System Clinical Toxicity CNS Behavioral changes, cognitive difficulties, headache, psychosis, aseptic meningitis, seizures Cardiovascular Increased risk of myocardial infarction and risk of sudden death following myocardial infarction Pulmonary Bronchospasm, hypersensitivity pneumonitis, pulmonary edema GI Dyspepsia, * nausea,* heartburn,* gastritis, gastric and duodenal erosions, mucosal bleeding,* gastric and duodenal perforation Hepatic Spectrum of hepatic injury ranging from asymptomatic ele vation of serum transaminases to fulminant hepatic failure Renal Sodium and water retention,* hyperkalemia, azotemia,* acute tubular necrosis, interstitial nephritis, renal failure Hematologic Increased risk of bleeding, bone marrow suppression, aplastic anemia, agranulocytosis, red cell aplasia, hemolytic anemia, thrombocytopenia Dermatologic Maculopapular rashes, photosensitivity reactions, Stevens- Johnson syndrome, toxic epidermal necrolysis Bone Delayed wound and fracture healing Reproductive Slowed uterine contractions, premature closure of ductus arteriosus, fetal intracranial hemorrhage, necrotizing enterocolitis, oligohydramnios *Common side effects. Tintinalli_Sec15_p1187-1332.indd 1260 8/2/19 8:39 PM

ens- Johnson syndrome, toxic epidermal necrolysis Bone Delayed wound and fracture healing Reproductive Slowed uterine contractions, premature closure of ductus arteriosus, fetal intracranial hemorrhage, necrotizing enterocolitis, oligohydramnios *Common side effects. Tintinalli_Sec15_p1187-1332.indd 1260 8/2/19 8:39 PM CHAPTER 191: Nonsteroidal Anti-Inflammatory Drugs 1261 Hematologic Nonselective NSAIDs inhibit platelet formation of thromboxane A2, a potent stimulator of platelet aggregation. The new COX-2 inhibitors have far fewer antiplatelet effects than traditional NSAIDs. Most NSAIDs decrease platelet aggregation only when sig nificant concentrations of the drug are present, and therefore, increased bleeding tendencies from NSAIDs are not widely reported. Bone marrow suppression and aplastic anemia are rare hematologic complications of almost all NSAIDs, with indomethacin, diclofenac, and phenylbutazone responsible for most reported cases. NSAID use has also resulted in agranulocytosis, hemolytic anemia, red cell aplasia, and thrombotic thrombocytopenic purpura. 49-51 Dermatologic Rash, angioedema, and urticaria are the most common manifestations of hypersensitivity reactions to NSAIDs. 52 The agents most frequently involved in dermatologic complications include ben oxaprofen, phenylbutazone, and piroxicam. Drug reactions to NSAIDs range from benign maculopapular rashes to Stevens-Johnson syndrome and toxic epidermal necrolysis. NSAIDs are among the most commonly implicated drugs in cases of toxic epidermal necrolysis, accounting for up to one third of drug-related cases. NSAIDs of all types (oral and topical) can cause photosensitivity reactions including increased sensi tivity to sun exposure (phototoxic) and true photoallergic reactions (see Chapter 249, “Generalized Skin Disorders”). Ketoprofen and piroxicam are the most frequently involved in photoallergic reactions. Bone Bone healing is a complex cascade of events that involves prostaglandins’ influence on the balance between bone formation and resorption. 53,54 The most recent guidelines by the American Pain Soci ety recommend the use of NSAIDs for postoperative pain in fractures because there is not sufficient evidence against its use in humans. Reproductive Prostaglandins are found in high concentration in the uterus at term and have a stimulatory effect on normal labor. NSAIDs will impair uterine motility through inhibition of prostaglandin syn thesis. They may be associated with increased risk of miscarriage when used around conception. 56 One of the most significant effects of fetal exposure to NSAIDs is premature constriction of the ductus arteriosus that may result in fetal pulmonary hypertension. 57 The many other reported effects of in utero exposure to NSAIDs have resulted in the U.S. Food and Drug Administration recommendation against the use of NSAIDs after 29 weeks of pregnancy.  TOXICITY WITH ACUTE OVERDOSE Although the vast majority of patients with acute overdoses suffer little morbidity, with massive NSAID ingestions, some fatalities can occur; these cases may present with altered mental status, metabolic acidosis, and shock. 58-61 Historically, phenylbutazone was most commonly asso ciated with severe toxicity following an overdose, and although it was withdrawn from the U.S. market in the 1970s, it is still available from veterinary sources and in other countries. By a wide margin, ibuprofen is the most common agent currently reported in NSAID overdoses. Patients who develop symptoms following an ibuprofen overdose usually ingest more than 100 milligrams/kg. Initial symptoms predomi nantly include abdominal pain, nausea, and vomiting, all beginning within 4 hours of ingestion ( Table 191-3).

gin, ibuprofen is the most common agent currently reported in NSAID overdoses. Patients who develop symptoms following an ibuprofen overdose usually ingest more than 100 milligrams/kg. Initial symptoms predomi nantly include abdominal pain, nausea, and vomiting, all beginning within 4 hours of ingestion ( Table 191-3). Most patients who manifest severe toxicity, including apnea, coma, and metabolic acidosis, ingest more than 400 milligrams/kg. There is limited published experience concerning acute overdose of COX-2 inhibitors, but they are assumed to have similar profiles as the nonselective NSAIDs. CNS CNS manifestations of acute NSAID overdose are usually minimal, although patients with significant overdose may have headache, diplo pia, nystagmus, and altered mental status including coma. 27 Mefenamic acid has high potential for seizures in overdose. 62 Muscle twitching and seizures that are responsive to benzodiazepines have been reported.63 Cardiovascular Acute NSAID overdose can be associated with hypo tension and dysrhythmias ranging from bradycardia to ventricular tachycardia and fibrillation. NSAIDs are not known to be a primary cause of dysrhythmias, but fluid and electrolyte abnormalities pro voked by NSAID toxicity may induce cardiac rhythm abnormalities. Cardiovascular dysfunction from acute NSAID overdose is responsive to conventional critical care management. Metabolic Electrolyte and acid-base abnormalities may occur in acute NSAID overdoses. Alterations in serum electrolytes may develop sec ondary to decreased prostaglandin synthesis or from NSAID-induced renal failure. Sodium and water retention may lead to volume overload in patients with preexisting cirrhosis, heart failure, or renal failure. Hyperkalemia, hypocalcemia, and hypomagnesemia have been reported in NSAID overdoses complicated by acute renal failure. Increased anion gap metabolic acidosis has been observed with large overdoses of ibuprofen and naproxen, which may be due to these NSAIDs and their metabolites being weak acids. Concurrent lactic acid production in the setting of NSAID-induced seizures or shock may exacerbate the acidosis. GI and Hepatic Patients presenting after acute NSAID overdose may have abdominal pain, nausea, and vomiting, but life-threatening GI hemorrhage is not a typical finding after acute overdoses. Overdose may also result in hepatic injury, as measured by cholestasis and elevated transaminase levels. Rare cases of pancreatitis have been reported after overdoses of ibuprofen, naproxen, and indomethacin. 64-66 Renal NSAID overdose rarely causes acute kidney injury, but may place a stressed renal system at risk for failure. The clinical presentation may include hematuria and oliguria. Most patients with acute renal failure due to an NSAID overdose have eventual recovery of renal function, but some may need long-term dialysis. TREATMENT Most patients who present following an NSAID overdose will be asymptomatic. Follow the general principles for managing the poisoned patient (see Chapter 176, “General Management of Poisoned Patients”). Determine if the amount of drug ingested was less than 100 milligrams/ kg (unlikely to result in toxicity) or more than 400 milligrams/kg (sig nificant risk for toxicity). Asymptomatic NSAID ingestions usually require minimal laboratory evaluation and supportive care (Figure 191-1). Activated charcoal is recommended for the majority of patients with NSAID overdose who have an intact mental status and are protecting their airway. IV fluids and an H 2 blocker or proton pump inhibitor can be given empirically. Replace electrolytes. Screen for potentially dangerous co-ingestants by measuring the serum acetaminophen and salicylate levels and obtaining a 12-lead ECG.

th NSAID overdose who have an intact mental status and are protecting their airway. IV fluids and an H 2 blocker or proton pump inhibitor can be given empirically. Replace electrolytes. Screen for potentially dangerous co-ingestants by measuring the serum acetaminophen and salicylate levels and obtaining a 12-lead ECG. Patients who are symptomatic with altered mental status, seizures, shock, respiratory distress, or cardiac dysrhythmias require aggressive resuscitation and stabilization (Figure 191-1). Establish an airway as needed, institute mechanical ventilation when necessary, treat hypotension with fluid boluses and/or vasopressors, and manage seizures ini tially with IV benzodiazepines. Activated charcoal is recommended in all symptomatic patients with a protected airway. Consider gastric lavage for recent ingestions involving mefenamic acid or phenylbutazone. TABLE 191-3 NSAID Toxicity After an Acute Overdose Initial symptoms within 4 h after ingestion Abdominal pain, nausea, vomiting CNS Headache, nystagmus, diplopia, altered mental status, coma, muscle twitching, and seizures (mefenamic acid) Cardiovascular Hypotension, shock, bradydysrhythmia, ventricular tachycardia or fibrillation and QT prolongation Metabolic Hyperkalemia, hypocalcemia, hypomagnesemia GI and hepatic Continued abdominal pain, nausea, vomiting, hepatic injury, pancreatitis (rare) Renal Acute kidney injury Tintinalli_Sec15_p1187-1332.indd 1261 8/2/19 8:39 PM