Chapter 3 Anti-inflammatory Medications

1. Chapter 3Anti-inflammatory Medications

2. NSAIDs • The use of NSAIDs for the treatment of sports-related injuries, as well as other maladies, (namely osteoarthritis) continues to rise. • In 2001, sales of NSAID prescriptions accounted for $10.9 billion in the United States.

3. NSAIDs (cont.) • A thorough understanding of drug actions, interactions, and effects allows the athletic trainer to educate athletes on treatment plans and symptoms resulting from NSAIDs

4. NSAIDs (cont.) • A recent study of high school football players revealed that 75% of those surveyed had used NSAIDs in the previous 3 months and 15% of the respondents were daily NSAID users. The daily users often used the drugs prophylactically prior to practices and games.

5. The Inflammatory Response • The acute inflammatory cascade is set into motion by the initial tissue insult. • Grossly, acute inflammation is recognized by the classic and familiar signs of pain (dolor), heat (calor), erythema (rubor), swelling (tumor), and loss of function (functio laesa).

6. Figure 3-1: The Inflammatory Response

7. Inflammatory Response (cont.) • Following a short period of vasoconstriction - cellular injury signals the release of chemical mediators, such as histamine, serotonin, anaphylatoxins, bradykinin, thromboxane, leukotrienes, and prostaglandins.

8. Box 3-2 page 36 • Major actions of the Eicosanoids • Prostaglandins • Thromboxane • Leukotrienes

9. Anti-inflammatory Medications • Aspirin (acetylsalicylic acid) - a derivative of salicylic acid. • Salicylic acid, in turn, was created from salicin, which is found in the bark of willow trees. • Aspirin was first synthesized by a Bayer Company chemist in the late 19th century. • It proved to be far less of a gastric irritant than salicylic acid and was introduced to the marketplace in the spring of 1899.

10. In 1971, Sir John Vane discovered that the aspirin molecule transfers a functional group onto the cyclooxygenase enzyme. Until this time the actual mechanism of action for aspirin was unknown.

11. Cyclooxygenase Enzyme (COX) • This enzyme is irreversibly inhibited and unable to bind arachidonic acid, therefore, the enzyme can no longer convert arachidonic acid to prostaglandins and thromboxane. • The Leukotriene pathway, however, is unaffected

12. Effects of Aspirin • Analgesic • Antipyretic • Anticoagulant • Anti-inflammatory

13. Effects of Aspirin • 3000 – 6000 mg per day for anti-inflammatory action; a series of chemical events results from the blockage of cyclooxygenase • 325 mg aspirin = 12 to 18 aspirin per day to reach an anti-inflammatory effect

14. Effects of Aspirin • The decrease in prostaglandin production leads to a corresponding reduction in inflammation and edema.

15. Effects of Aspirin • Blocks prostaglandin production, even the “cytoprotection.” • In the GI tract, aspirin can cause gastric upset, bleeding, and even ulcers. • Various studies have shown GI disturbance incidence of anywhere from 2 percent to 40 percent.

16. Effects of Aspirin • The mechanism of gastric irritation appears related to the direct effect of aspirin upon the lining of the stomach. • Mild gastrointestinal upset can often be avoided if aspirin is taken with a meal, due to the "buffering" action of the food.

17. Effects of Aspirin • Aspirin use may also result in complications, such as prolonged bleeding and tinnitus. • Decreased platelet function lasts from 4 to 6 days (used for blood thinning in heart patients). • Tinnitus may be an indication of aspirin toxicity.

18. Reye’s Syndrome • Reye’s syndrome is a rare and potentially devastating, acute illness that usually strikes children following a viral infection when they are given aspirin to lower fever. • This syndrome is now suspected in teens and young adults with viral infections who take aspirin.

19. Table 3-1: The Five Clinical Stages of Reye’s Syndrome

20. Aspirin Sensitive Asthma • Upon exposure to even small quantities of aspirin, those affected may develop nasal congestion and acute, often severe bronchospasm. • There is an almost universal cross-reactivity with other NSAIDs. • Patients can be desensitized over time with daily administration of aspirin and cross-tolerance to other NSAIDs usually occurs.

21. Acetaminophen • Acetaminophen (Tylenol) is not an anti-inflammatory agent, it has antipyretic and analgesic properties. • Will be discussed with the analgesics (Chapter 10).

22. NSAIDs • COX-2 Inhibitors • Primarily induced at sites of inflammation • COX-2 inhibitor could block the production of proinflammatory prostaglandins without interfering with gastric protection or platelet activity • Research is controversial and the drugs are expensive

23. Overview of Selected NSAIDs • Box 3-4 Page 42 – Factors to Consider in Choosing an NSAID • Age of Patient • Duration of Treatment • Time of Onset • Compliance • Other Medications • General Health of Patient • Cost of Treatment

24. Ibuprofen • Advil, Motrin, Nuprin • Most frequently used NSAID • Introduced to the OTC market in 1985, it is available in 200 to 800 mg tablets by prescription, and 200 mg tablets OTC • Frequently used as an antipyretic in adults and children, as its longer duration of action makes it a popular alternative to acetaminophen

25. Ibuprofen • Peak plasma levels are achieved within 15 to 30 minutes of ingestion • Rapid onset of action can be quite beneficial for quick relief of pain • Half-life of about 2 hours, it must be taken every 6 to 8 hours to maintain effect • An anti-inflammatory regimen requires 2400 – 3200 mg daily

26. Ibuprofen • Taken in three separate doses, allowing it to be taken at meal times, lessening the likelihood of gastric irritation. • Sufficient analgesia should be achieved by daily dosages of less than 2400 mg per day. • Approximately 10 percent to 15 percent of individuals must discontinue use secondary to gastrointestinal symptoms.

27. Naproxen • Naprosyn, Aleve. • Chemically similar to ibuprofen. • Naproxen is available as the OTC preparation Aleve, and as Anaprox by prescription. • Due to naproxen's long half-life (approximately 12 hours), the daily recommended dosage of 750 – 1000 mg can be taken on a twice daily schedule, reducing gastric upset due to only two exposures and improving compliance.

28. Naproxen • Peak plasma levels are achieved within 2 to 4 hours • Incidence of upper gastrointestinal bleeding in OTC use is double that of OTC ibuprofen

29. Indomethacin • Indocin. • Although particularly effective in maladies such as rheumatoid arthritis, ankylosing spondylitis, and gout, indomethacin is typically not recommended for use as a simple analgesic or antipyretic due to potentially severe side-effects. • Up to half of those using indomethacin may experience some side-effects and almost one-third will discontinue use.

30. Indomethacin • Common side-effects include gastrointestinal symptoms (ulceration, nausea, abdominal pain) and headaches (15 percent to 25 percent of patients). • Peak concentrations can be achieved in 1 to 2 hours (in fasting subjects, onset is delayed by food intake).

31. Indomethacin • A half-life of about 2.5 hours. • Daily dosage ranges from 75 mg – 100 mg taken in two to three doses. • Indomethacin’s use has declined as newer agents with a lower side-effect profile have emerged.

32. Nabumetone (Relafen) • Only nonacid NSAID currently available • Once-a-day treatment; half-life is 24 hours

33. Rofecoxib • Vioxx • One of only three potent and highly selective COX-2 inhibitors available. • It does not inhibit COX-1 and has no effect on platelet function. • It is FDA approved for the treatment of osteoarthritis, dysmenorrhea, and acute pain.

34. Rofecoxib • Dosages range from 12.5 mg – 50 mg. It is administered once daily given its nearly 17-hour half-life. • Long-term toxic effects, including gastrointestinal and renal effects, are not yet known given the drug’s relatively recent introduction.

35. Celecoxib • Celebrex • COX-2 inhibitor • 200 mg tablets • Peak Plasma levels = 3 hours • Half-life (approximate-effective) = 11 hours • Problems include: • Liver and kidneys • Heart ?

36. Ketorolac • Toradol. • Not typically employed for its anti-inflammatory properties. • It is the only NSAID available for intramuscular or intravenous injection as well as oral administration.

37. Ketorolac • Although it also has anti-inflammatory and antipyretic properties, it is most commonly marketed and used as an analgesic, particularly in postoperative patients. • As an analgesic, ketorolac offers great promise as it avoids the most common shortcomings of opioids, i.e., tolerance, withdrawal effects, and respiratory depression.

38. Ketorolac • Interestingly, Tokish et al (1992) recently reported that 28 of 30 National Football League team medical staffs commonly use ketorolac intramuscular injections on game days for pain relief. • Due to high risk of renal effects, duration of ketorolac treatment is typically held to less than 5 days.

39. NSAID Indications

40. NSAID Adverse Effects

41. NSAID Use

42. Drug-Drug Interactions

43. Glucocorticosteroids • Animal studies demonstrate: • Potent anti-inflammatory actions of glucocorticosteroids and their subsequent effects upon healing • Glucocorticosteroids induced an early, transient recovery of the force-generating capacity of the effected muscle • Long-term findings revealed irreversible damage to the healing muscle, including atrophy and diminished force-generating capacity

44. Actions of Corticosteroids

45. Corticosteroids in Sports Medicine • Stanley and Weaver (1989) state that “inconsistency in the studies on glucocorticosteroid use does not lend adequate support or direction to the sports medicine clinician in their use.” • Extremely powerful anti-inflammatory medications but no good research to demonstrate their effectiveness in activity-related injury.

46. Box 3-7: Most Common Indications for Injectable Corticosteroids

47. Box 3-8: Potential Complications of Injectable Corticosteroids