Thuốc chống viêm: chọn lọc các chất ức chế ppt

Vol 10, No 2, March/April 2002 75 The nonsteroidal anti-inflammatory drugs (NSAIDs) generally possess anti-inflammatory, analgesic, and antipyretic activity. All of these medications have some adverse effects, but the most frequently associat- ed adverse effect with NSAIDs is gastrointestinal (GI) toxicity, a source of both morbidity and mortality, especially with prolonged usage in the elderly. Risk factors for the development of NSAID-induced gastric problems include individuals aged >60 years, history of GI ulcer or bleeding, concomitant use of cortico- steroids or anticoagulants, higher NSAID doses, and serious systemic illnesses. The incidence of GI toxicity is 20 to 40 per 1,000 patient-years of exposure. 1 Renal, platelet, and central nervous system toxicity also have been observed. Although no currently available NSAID lacks GI toxicity, specific cyclooxygenase-2 (COX-2) inhibition appears to be an improvement over conventional NSAIDs. The selective COX-2 inhibitor celecoxib was approved for use in the United States by the FDA in 1998 to treat osteoarthritis and rheumatoid arthritis. Rofecoxib was approved in 1999 for osteo- arthritis, acute pain, and primary dysmenorrhea. Currently, additional agents, such as a parenteral form, parecoxib, and its active metabolite, valdecoxib, are under development. Structure and Mechanism of Action The anti-inflammatory effect of NSAIDs is due mainly to the inhibition of the COX enzymes, which are required for the synthesis of prostaglandins and throm- boxanes. The recycled oxygenases are biofunctional hemoproteins that catalyze the oxygenation of arachi- donic acid to prostaglandin, a common precursor for the synthesis of the family of prostaglandins, prostacy- cline and thromboxanes. Two COX isoforms exist that catalyze the same reaction but are different in terms of regulation and expression (Fig. 1). COX-1, which is expressed constitutively in most tissues, is thought to protect the gastric mucosa and maintains renal homeo- stasis and normal platelet function. COX-2 is expressed constitutively in the brain and the kidney but can be induced in other tissues and at sites of inflammation. The discovery of a second isoform of COX established the rationale for the development of specific COX-2 inhibitors as a novel class of anti-inflammatory com- pounds as compared with current NSAIDs, which inhibit both COX-1 and COX-2 to a similar degree. Clinical trials have shown that a specific COX-2 inhibitor can achieve therapeutic efficacy in osteoarthritis and pain management while avoiding the serious side effects, in particular GI ulceration, dyspepsia, and bleeding, related to the COX-1 inhibition observed with the general NSAIDs. The COX-2 inhibitors are effective because the side chain on these drugs fits well into the COX-2 enzy- matic pocket but is too large to fit into the COX-1 enzy- matic pocket. In humans, therapeutic concentrations of the COX-2 inhibitors (coxibs) celecoxib and rofecoxib do not significantly inhibit the COX-1 isoenzyme. Pharmacokinetics Celecoxib is rapidly absorbed, reaching peak serum concentrations in about 3 hours. The drug is metabo- lized in the liver by CYP2CP (a cytochrome P-450 isoen- zyme) into carboxylic acid and glucuronide metabolites and excreted in feces and urine. It has a half-life of about 11 hours. Rofecoxib, which is metabolized in the liver by cytosolic enzymes, reaches maximum concen- tration within 2 hours and has an effective half-life of approximately 17 hours. With the ingestion of a fatty meal, the absorption of celecoxib is increased 10% to 20%, and the time to peak concentration for both drugs is delayed 1 to 2 hours. With the use of nonprescription antacids there is a decrease in the area under the plasma concentration curve, and thus the rate of absorption of Dr. Lane is Chief, Metabolic Bone Disease Service, and Medical Director, Os- teoporosis Prevention Center, Hospital for Special Surgery, New York, NY. The author or the department with which he is affiliated has received something of value from a commercial or other party related directly or indirectly to the subject of this article. Reprint requests: Dr. Lane, 535 East 70th Street, New York, NY 10021. Copyright 2002 by the American Academy of Orthopaedic Surgeons. J Am Acad Orthop Surg 2002;10:75-78 Anti-inflammatory Medications: Selective COX-2 Inhibitors Joseph M. Lane, MD Advances in Therapeutics and Diagnostics both coxibs may be prolonged; but this effect should not be of clinical significance in the long-term treatment of arthritis. Elderly patients (aged >65 years) may exhibit a decrease of up to 30%, but this does not mandate a dose adjustment. Indications for Use Celecoxib has been shown to achieve a significant re- duction in joint pain compared with placebo. 4,5 Celecoxib was evaluated for treatment of the signs and symptoms of osteoarthritis of the knee and hip in approximately 4,200 patients in placebo- and active-con- trolled clinical trials of 12 weeks’ duration. In patients with osteoarthritis, treatment with celecoxib 100 or 200 mg qd resulted in a significant improvement as mea- sured by the Western Ontario and McMaster University (WOMAC) index, a composite of pain, stiffness, and functional measures in osteoarthritis. In three 12-week studies of pain accompanying osteoarthritis flare, cele- coxib doses of 100 and 200 mg bid provided notable reduction in pain within 24 to 48 hours of initiation of dos- ing. At doses of 100 mg or 200 mg bid, the effectiveness of celecoxib was similar to that of naproxen 500 mg bid. Doses of 200 mg bid provided no additional benefit over 100 mg bid. A total daily dose of 200 mg is equally ef- fective whether administered as 100 mg bid or 200 mg qd. Celecoxib has demonstrated significant (P < 0.05) reduction in rheumatoid arthritis in joint tenderness, pain, and joint swelling compared with placebo. It was evaluated for treatment of the signs and symptoms of rheumatoid arthritis in approximately 2,100 patients in placebo- and active-controlled clinical trials of up to 24 weeks’ duration. Celecoxib was shown to be superior to placebo as measured by the ACR20 Responder Index, a composite of clinical, laboratory, and functional mea- sures in rheumatoid arthritis. Doses of 100 and 200 mg bid were similar in effectiveness, and both were compa- rable to the effectiveness of naproxen 500 mg bid. Although celecoxib 100 and 200 mg bid provided similar overall effectiveness, some patients derived additional benefit from the 200 mg bid dose. Doses >200 mg bid provided no additional benefit above that seen with 100 to 200 mg bid. Rofecoxib has demonstrated significant (P < 0.001) reduction in joint pain of osteoarthritis compared with placebo. 6,7 The signs and symptoms of osteoarthritis of the knee and hip were assessed in placebo- and active- controlled clinical trials of 6 to 86 weeks’ duration that enrolled approximately 3,900 patients. In patients with osteoarthritis, treatment with rofecoxib 12.5 and 25 mg qd resulted in improvement in patient and physician global assessments and in the WOMAC osteoarthritis questionnaire, including pain, stiffness, and functional measures of osteoarthritis. In six studies of pain accom- panying osteoarthritis flare, rofecoxib provided a signif- icant (P < 0.05) reduction in pain at the first determina- tion (after 1 week in one study, after 2 weeks in the remaining five studies); this continued for the duration of the studies. In all of the osteoarthritis clinical studies, once-daily treatment in the morning with rofecoxib 12.5 and 25 mg was associated with a significant (P < 0.05) reduction in joint stiffness on first awakening in the morning. At doses of 12.5 and 25 mg, the effectiveness of rofecoxib was shown to be comparable to that of ibuprofen 800 mg tid and diclofenac 50 mg tid for osteoarthritis. The ibuprofen studies were 6-week stud- ies; the diclofenac studies were 12-month studies in which patients could receive additional arthritis med- ication during the last 6 months. In acute analgesic models 8-10 of postoperative dental pain, postorthopaedic surgical pain, and primary dys- menorrhea, rofecoxib relieved pain rated by patients as moderate to severe. The analgesic effect (including onset of action) of a single 50-mg dose was generally similar to that of naproxen 550 mg or ibuprofen 400 mg. In a single-dose postoperative dental pain study, the onset of analgesia with a single 50-mg dose occurred within 45 minutes. In a multiple-dose study of postorthopaedic surgical pain in which patients received rofecoxib or placebo for up to 5 days, 50 mg qd was effective in reducing pain. In this study, patients on rofecoxib con- sumed a significantly smaller amount of additional anal- gesic medication than did patients treated with placebo (1.5 versus 2.5 doses per day of additional analgesic medication for rofecoxib and placebo, respectively). In a randomized, placebo- and active-comparator- controlled clinical trial using a postoperative dental pain model, 272 patients with moderate to severe pain ran- Selective COX-2 Inhibitors Journal of the American Academy of Orthopaedic Surgeons 76 (−) Glucorticoids (−) NSAIDs Physiologic stimulus Inflammatory stimulus COX-1 Constitutive Platelets Endothelium Stomach Mucosa Intestines Kidney Brain Kidney COX-2 Constitutive Inducible Macrophages Synoviocytes Endothelial cells Figure 1 The distribution, regulation, and function of COX-1 and COX-2. The black boxes indicate drug interventions that inhibit the pathway. (Adapted with permission. 2,3 ) domly received a single dose of placebo, rofecoxib 50 mg, celecoxib 200 mg, or ibuprofen 400 mg. 8 Overall analgesic effect, time to onset, peak effect, and duration of effect were assessed. Rofecoxib was significantly (P < 0.001) more effective than celecoxib and placebo in all measures of analgesic efficacy. Rofecoxib and ibuprofen had similar time to onset and time to confirmed percep- tible pain relief (approximately 30 minutes compared with 1 hour for celecoxib); there were no measurable effects for placebo. In addition, rofecoxib had a longer duration of action compared with median time to use of rescue medication: approximately 5 hours for celecoxib, 10 hours for ibuprofen, and >24 hours for rofecoxib. Valdecoxib also has been shown to be efficacious as an opioid-sparing analgesic in patients undergoing total hip arthroplasty. Patients receiving either 20 or 40 mg of valdecoxib bid for 48 hours after total hip arthroplasty required 40% less morphine than did those in control groups. 11 Other uses of NSAIDs, such as in the preven- tion of heterotopic ossification, have not been tested with COX-2 inhibitors. Drug Interactions and Adverse Effects Because rofecoxib is not metabolized by the cytochrome P450 pathway, it has fewer confirmed drug interactions. However, potent inducers of cytochrome oxidase, such as rifampin, may decrease rofecoxib concentrations sim- ply by increasing hepatic metabolism in general. Clini- cal studies with celecoxib have identified potentially important interactions with fluconazole and lithium, making careful patient monitoring mandatory. Similar to other NSAIDs, rofecoxib has the potential to interact with furosemide and with angiotensin-converting enzyme inhibitors. These agents may interact with war- farin; thus, coagulation studies should be monitored after initiating celecoxib or rofecoxib. Rofecoxib is asso- ciated with an 8% increase in the international normal- ized ratio (INR). The most common effects of COX-2 inhibitors have been abdominal pain, diarrhea, and dyspepsia. 4,12 Both coxibs have been evaluated through endoscopic studies. Over a 12-week period, duodenal ulcers occurred in 7% of patients treated with celecoxib 200 mg bid, compared with 10% treated with diclofenac 75 mg bid, 35% with naproxen 500 mg bid, 23% with ibuprofen 800 mg tid, and 4% given a placebo. In another treatment study, the cumulative incidence of ulcers at 12 weeks was 9.9% in patients treated with placebo, 4.1% in those given rofe- coxib 25 mg qd, 7.3% in those given rofecoxib 50 mg qd, and 27% in those given ibuprofen 2,400 mg qd or 800 mg tid. Thus, both agents are associated with a notable decline in GI irritation. Unlike other NSAIDs, celecoxib and rofecoxib do not inhibit platelet aggregation or increase bleeding time. However, in a study in which aspirin in any dosage was an exclusion criterion, the risk of myocardial infarction was five times higher in the rofecoxib than in the na- proxen group (0.5% versus 0.1%, respectively; P < 0.05). 13 In a study in which 22% of patients received low-dose aspirin therapy, rates of myocardial infarction were not different between the two groups; however, similarly, there was no difference in the rate of significant perfora- tion or bleeding unless the group taking aspirin was excluded from the study. 12 Differences in cardiovascu- lar results between the two trials may represent trial design and chance or differences in the specific pharma- cology of the various COX-2 inhibitors. 14 These issues question the need for the concurrent use of low-dose aspirin in appropriate patients and the resultant effec- tiveness of the COX-2 inhibitors in diminishing GI toxic- ity in that setting. Both coxibs may lead to a significant (P < 0.02) rise in systolic blood pressure in 10% to 17% of patients, greater with rofecoxib. 15 Fluid retention and edema have been observed in some patients (5% celecoxib, 10% rofecoxib). COX-2 inhibitors should not be given to patients with aspirin-induced asthma. Celecoxib is contraindicated in patients with known allergic reaction to sulfonamide. Although other NSAIDs that inhibit COX-1 and COX-2 taken in the postoperative period may have a deleterious effect on achieving spinal fusion, there are no such data for the coxibs. However, an animal model study demonstrated that a specific COX-2 in- hibitor more effectively blocked lamellar bone forma- tion elicited by strain than did indomethacin. 16 COX-2 inhibitors in a rat femoral fracture model resulted in a 65% nonunion rate compared with 18% in the NSAID group and 0% in the control group. The animals also had greater angulation and a poorer histologic score, suggesting that COX-2 inhibitors should be used with caution in humans when bone healing is required. 17 Dosage and Cost Celecoxib is available in 100- and 200-mg tablets (Table 1). The recommended dose for osteoarthritis is 200 mg qd or 100 mg bid and for rheumatoid arthritis, 100 to 200 mg bid. Rofecoxib is available in 12.5-, 25-, and 50-mg tablets. The recommended dose for osteoarthritis is 12.5 mg qd. Some patients may receive additional benefit by increas- ing the dose to 25 mg qd. For acute pain and treatment of primary dysmenorrhea, the recommended dose is 50 mg qd with subsequent doses of 50 mg qd as needed. Use for more than 5 days to manage pain has not been studied. Both coxibs may be taken with or without food. Joseph M. Lane, MD Vol 10, No 2, March/April 2002 77 Summary Celecoxib and rofecoxib appear to be as effective as the conventional NSAIDs for the treatment of osteoarthritis. Celecoxib is also labeled for rheumatoid arthritis and rofecoxib for acute pain. Both may also be effective for short-term pain relief. The safety profile of the COX-2 inhibitors appears to be superior to that of the other NSAIDs and their efficacy, comparable. However, there is an apparently increased rate of myocardial infarction and the loss of the gastroprotective advantage in patients who also must take daily aspirin. Therefore, what is the current role of these agents with reference to other NSAIDs? The patient who has had a previously favorable result with or is currently using a standard NSAID can be maintained on that agent. If the patient previously had a GI toxicity, then use of a COX-2 inhibitor would be appropriate. For the patient who has not taken NSAIDs and has any of the risk factors out- lined above for GI side effects, use of a COX-2 inhibitor is indicated. For those without any risk factors, the pro- jected length of administration (short course versus chronic use), cost, and relative risks and benefits can be discussed with the patient. In summary, these agents appear to offer an improved safety profile compared with the classic NSAIDs, and where bleeding or indi- gestion is an issue, they are the drugs of choice. Selective COX-2 Inhibitors Journal of the American Academy of Orthopaedic Surgeons 78 References 1. MacDonald TM, Morant SV, Robinson GC, et al: Association of upper gastrointestinal toxicity of non-steroidal anti-inflam- matory drugs with continued exposure: Cohort study. BMJ 1997;315:1333-1337. 2. Garnett WR: Clinical implications of drug interactions with coxibs. Pharmacotherapy 2001;21:1223-1232. 3. Verburg KM, Maziasz TJ, Weiner E, Loose L, Geis GS, Isakson PC: COX-2-specific inhibitors: Definition of a new therapeutic concept. Am J Ther 2001;8:49-64. 4. Bensen WG, Fiechtner JJ, McMillen JI, et al: Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: A randomized controlled trial. Mayo Clin Proc 1999;74:1095-1105. 5. Williams GW, Hubbard RC, Yu SS, Zhao W, Geis GS: Com- parison of once-daily and twice-daily administration of cele- coxib for the treatment of osteoarthritis of the knee. Clin Ther 2001;23:213-227. 6. Cannon GW, Caldwell JR, Holt P, et al: Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy compara- ble with that of diclofenac sodium: Results of a one-year, ran- domized, clinical trial in patients with osteoarthritis of the knee and hip: Rofecoxib Phase III Protocol 035 Study Group. Arthritis Rheum 2000;43;978-987. 7. Day R, Morrison B, Luza A, et al: A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis: Rofecoxib/Ibuprofen Comparator Study Group. Arch Intern Med 2000;160:1781-1787. 8. Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ: Comparison of rofecoxib and celecoxib, two cyclooxyge- nase-2 inhibitors, in postoperative dental pain: A randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther 1999;21:1653-1663. 9. Morrison BW, Daniels SE, Kotey P, Cantu N, Seidenberg B: Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary dysmenorrhea: A randomized controlled trial. Obstet Gynecol 1999;94:504-508. 10. Reicin A, Brown J, Jove M, et al: Efficacy of single-dose and multidose rofecoxib in the treatment of post-orthopedic surgery pain. Am J Orthop 2001;30:40-48. 11. Camu F, Beecher T, Recker DP, Verburg KM: Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing anal- gesic in patients undergoing hip arthroplasty. Am J Ther 2002;9:43-51. 12. Silverstein FE, Faich G, Goldstein JL, et al: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial: Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-1255. 13. Bombardier C, Laine L, Reicin A, et al: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis: VIGOR Study Group. N Engl J Med 2000;343:1520-1528. 14. FitzGerald GA, Cheng Y, Austin S: COX-2 inhibitors and the cardiovascular system. Clin Exp Rheumatol 2001;19(6 suppl 25):S31-S36. 15. Whelton A, Fort JG, Puma JA, et al: Cyclooxygenase-2–specif- ic inhibitors and cardiorenal function: A randomized, con- trolled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001;8:85-95. 16. Forwood MR: Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo. J Bone Miner Res 1996;11:1688-1693. 17. Leonelli S, Goldberg B, Safanda J, Bagwe M, King S, Sethuratnam S: Abstract: The effect of cyclooxygenase 2 (COX- 2) inhibitors on bone healing. Trans Orthop Res Soc 2002;27:65. Table 1 Cost Comparison of Coxibs and NSAIDs Drug Usual Dosage Cost * Celecoxib 100 mg bid $84.95 200 mg qd $71.73 Rofecoxib 25 mg qd $73.29 Generic diclofenac 150 mg bid $26.83 Voltaren 150 mg bid $100.50 Generic naproxen 500 mg bid $17.93 Naprosyn 500 mg bid $90.28 Generic ibuprofen 800 mg tid $11.45 Motrin 800 mg tid $38.15 * Cost for 30 days’ treatment on www.drugstore.com. Accessed August 2001.