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Nonsteroidal Anti-Inflammatory Drugs


This overview is intended to provide the basic knowledge about Nonsteroidal Anti-Inflammatory Drugs at the advanced consumer level.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are classified into categories depending on their interactions with prostaglandin synthase enzymes along the inflammation pathway.

List of Nonsteroidal anti-inflammatory drugs

  • Aspirin
  • Celecoxib (Celebrex)
  • Choline magnesium trisalicylate
  • Diclofenac (Cataflam, Voltaren)
  • Diflunisal (Dolobid)
  • Etodolac (Lodine)
  • Fenoprofen (Nalfon)
  • Flurbiprofen (Ansaid, Flurprofen)
  • Ibuprofen (Advil, Motrin, Caldolor, NeoProfen)
  • Indomethacin (Indocin)
  • Ketorolac (Toradol)
  • Ketoprofen (Nexcede)
  • Naproxen (Aleve, Anaprox, Naprelan, Naprosyn, Treximet, Vimovo)
  • Mefenamic acid (Ponstel)
    Meclofenamic acid (Meclomen)
  • Meloxicam (Mobic)
  • Oxaprozin (Daypro)
  • Piroxicam (Feldene)
  • Salsalate (Disalcid)
  • Salicylamide
  • Sulindac (Clinoril)
  • Tolmetin (Tolectin)

Mechanism of action

Although different NSAIDs have their niches in particular disease and condition, their principal mechanism of action is the same mechanism with a few exceptions.

NSAIDs work act by inhibiting prostanoid biosynthesis through their activity on the cyclooxygenase (COX) enzymes COX-1 and COX-2. The two distinct isoforms of COX -- COX-1 and COX-2 -- have different functions, and the inhibition of these isoforms results in different therapeutic effects and adverse effects.

The inhibition of cyclooxygenase-2 (COX-2) contributes to the antipyretic (fever reducing), analgesic (pain relieving), and anti-inflammatory actions of NSAIDs. The inhibition of cyclooxygenase-1 (COX-1) considerably but not solely contributes to unwanted gastrointestinal side effects. The prostinoids produced by COX-1 protect the gastric mucosa, regulate renal blood flow, and induce platelet aggregation.

The mechanism of action of aspirin (acetylsalicylic acid) differs significantly from non-aspirin NSAIDs. It has a property of irreversibly inhibiting platelet function.

Traditional NSAIDs block both COX-1 and COX-2 enzymes. The development of selective COX-2 inhibitors was based on the postulate that selective inhibition of COX-2 would provide therapeutic benefits without the side effects associated with COX-1 inhibition. Although selective COX-2 inhibitors have a lower risk of gastrointestinal effects these drugs are associated with a higher incidence of cardiovascular side effects such as myocardial infarction.

COX-2 inhibitors rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market because of their cardiovascular problems13. Currently celecoxib (Celebrex) is the only COX-2 inhibitor on the market.

Renal side effects

Both nonselective NSAIDs and COX-2 inhibitors are associated with renal function adverse effects, including increased blood pressure and edema3. Occasional acute renal failure has also been reported4.

NSAIDs reversibly suppress the production of renal prostaglandins via inhibition of COX-1 and COX-2. Renal prostaglandins cause dilatation of the renal afferent arteriole and their suppression may lead to a transient decrease in renal function. This effect may occur more often in patients with underlying renal disease.

Recent 2015 study revealed that long-term treatment with NSAIDs can damage kidneys only in patients with advanced renal impairment. Negative impact on kidneys in NSAIDs users with normal renal function was not detected5.

Risk factors for NSAID induced kidney damage:

  • Underlying renal disease
  • Older adults ( >65 years), chronic hypertension, atherosclerosis
  • Intravascular volume depletion
  • Use of diuretics, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs)

GastroIntestinal side effects

The most common side effects with these drugs are gastrointestinal, including anorexia, nausea, dyspepsia, abdominal pain, diarrhea, ulceration, and mucosal injury. Long-term use of NSAIDs can cause gastrointestinal ulcers and potentially life-threatening complications such as bleeding, perforation, or obstruction. The drugs cause gastric ulceration by their ability to inhibit COX-1 in the gastric mucosa and suppress PG synthesis.

Risk factors for NSAID induced gastrointestinal ulcers8:

  • History of peptic ulcer disease
  • Advanced age (>60 years)
  • Use of glucocorticoids
  • Tobacco smoking
  • heavy alcohol consumption
  • Prolonged, high dose or multiple NSAID therapy

Gastrointestinal toxicity of different NSAIDs varies considerably. Ibuprofen has the lowest risk of GI damage among NSAIDs. Diclofenac and naproxen have intermediate risk. Piroxicam and ketorolac carry the greatest risk11.

Cardiovascular side effects

Both traditional NSAIDs and COX-2 inhibitors may cause serious cardiovascular side effects, including thrombotic events, myocardial infarction, and stroke. Selective suppression of COX-2 may be responsible for the increased incidence of acute myocardial infarction reported with prolonged use of drugs functionally selective for COX-26, including diclofenac, nimesulide, and meloxicam7.

A nationwide cohort study2 found that patients with established cardiovascular disease who used NSAIDs had a 45% increased risk for recurrent myocardial infarction in comparison to those who did not take NSAIDs. This elevation of risk increases with increasing treatment duration and dose.

Bone healing impairment

Animal and laboratory studies have demonstrated that NSAIDs impair fracture healing9. However, limited data from human studies suggests that NSAIDs do not impair bone healing10.

Currently in the absence of clear clinical evidence, it is recommended to avoid use NSAIDs as analgesics in patients at risk for delayed fracture healing.

Bleeding

NSAIDs can cause short-term (<24 hours) reduction in platelet aggregation, which is re attributable to the inhibition of thromboxane synthesis.

NSAIDs potentiate the anticoagulant activity of warfarin, and should be used with a great caution in patients taking anticoagulants.

NSAID exacerbated respiratory disease (ERD)

Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, may cause bronchospasm and other respiratory reactions in susceptible patients with asthma1. This adverse effect is often termed Aspirin-exacerbated respiratory disease (AERD). COX-2 inhibitors and selective NSAIDs are suggested to carry a small risk of NSAID ERD.

Therapeutic uses

Aspirin:

  • Relief of minor aches and mild to moderate pain
  • Arthritis and related arthritic conditions (3.2–6.0 g/day)
  • Reduction of the risk of transient ischemic attacks
  • Coronary artery disease prophylaxis
  • Platelet aggregation inhibitor (80–325 mg per day). It is available in a large number of dosage forms and strengths as tablets, suppositories, capsules, enteric-coated tablets, and buffered tablets.

Celecoxib:

  • Osteoarthritis
  • Rheumatoid arthritis
  • Low back pain
  • Juvenile rheumatoid arthritis
  • Primary dysmenorrhea
  • Management of acute pain, including postoperative
  • Ankylosing spondylitis
  • Colorectal polyps
  • Dental pain12

Diflunisal:

  • Mild to moderate pain
  • Rheumatoid arthritis
  • Osteoarthritis

Diclofenac:

  • Long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis
  • Pain relief, including postoperative
  • Primary dysmenorrhea
  • Migraine
  • Actinic keratoses (topical gel)
  • Cataract surgery recovery (ophthalmic solution)

Etodolac:

  • Osteoarthritis
  • Rheumatoid arthritis
  • Mild to moderate pain

Fenoprofen:

  • Osteoarthritis
  • Rheumatoid arthritis
  • Mild to moderate pain

Flurbiprofen:

  • Acute or long-term treatment of rheumatoid arthritis and osteoarthritis
  • Inhibition of intraoperative miosis (ophthalmic solution)

Ibuprofen:

  • Fever
  • Mild to moderate pain
  • Relief of minor aches and pain associated with the common cold, flu, and sore throat
  • Headaches
  • Primary dysmenorrhea
  • Chronic pain in osteoarthritis, rheumatoid arthritis, low back pain, fibromyalgia, and peripheral neuropathy
  • Moderate to severe pain as an adjunct to opiod analgesics (injectable)

Indomethacin:

  • Osteoarthritis
  • Rheumatoid arthritis
  • Ankylosing spondylitis
  • Acute gout
  • Bursitis and/or tendinitis
  • Relief of pain, fever, and inflammation of pericarditis

Ketorolac:

  • Short-term treatment of moderately severe acute pain requiring opioid-level analgesia
  • Ocular itching caused by seasonal allergic conjunctivitis (ophthalmic)

Ketoprofen:

  • Long-term management of rheumatoid arthritis and osteoarthritis
  • Mild to moderate pain
  • Primary dysmenorrhea

Naproxen:

  • Fever
  • Rheumatoid arthritis
  • Osteoarthritis
  • Juvenile arthritis
  • Ankylosing spondylitis
  • Tendinitis, bursitis
  • Acute gout
  • Primary dysmenorrhea
  • Relief of mild to moderate pain

Mefenamic acid, Meclofenamic acid:

  • Short-term relief of acute pain of soft-tissue injuries
  • Dysmenorrhea

Meloxicam:

  • Osteoarthritis
  • Rheumatoid arthritis

Oxaprozin:

  • Acute and long-term management of osteoarthritis and rheumatoid arthritis

Piroxicam:

  • Long-term use in rheumatoid arthritis and osteoarthritis
  • Acute gout
  • Not recommended for acute analgesia

Salicylamide:

  • Minor aches and pain
  • Fever

Salsalate:

  • Rheumatoid arthritis
  • Osteoarthritis

Sulindac:

  • Ankylosing spondylitis
  • Osteoarthritis
  • Rheumatoid arthritis
  • Acute painful shoulder (subacromial bursitis/supraspinatus tendinitis)
  • Acute gout
  • Familial Adenomatous Polyposis ("Off-label")

Tolmetin:

  • Osteoarthritis
  • Rheumatoid athritis
  • Juvenile rheumatoid arthritis

References

  • 1. Morales DR, Lipworth BJ, Guthrie B3, Jackson C, Donnan PT, Santiago VH. Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors. J Allergy Clin Immunol. 2014 Jul;134(1):40-5. PubMed
  • 2. Schjerning Olson AM, Fosbol EL, Lindhardsen J. Duration of treatment with nonsteroidal antiinflammatory drugs and risk of myocardial infarction in patients with a prior myocardial infarction. Circulation. 2011;123:2226-223
  • 3. Brater DC. Anti-inflammatory agents and renal function. Semin Arthritis Rheum. 2002 Dec;32(3 Suppl 1):33-42. PubMed
  • 4. Ejaz P, Bhojani K, Joshi VR. NSAIDs and kidney. J Assoc Physicians India. 2004 Aug;52:632-40. PubMed
  • 5. Möller B, Pruijm M, Adler S, Scherer A, Villiger PM, Finckh A; Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) Foundation, CH-8048 Zurich, Switzerland. Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study. Ann Rheum Dis. 2015 Apr;74(4):718-23 PubMed
  • 6. Chen LC, Ashcroft DM. Risk of myocardial infarction associated with selective COX-2 inhibitors: meta-analysis of randomised controlled trials. Pharmacoepidemiol Drug Saf. 2007 Jul;16(7):762-72. PubMed
  • 7. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006 Jan;116(1):4-15. PubMed
  • 8. Agrawal N. Risk factors for gastrointestinal ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs). J Fam Pract. 1991 Jun;32(6):619-24. PubMed
  • 9. Altman RD, Latta LL, Keer R, Renfree K, Hornicek FJ, Banovac K. Effect of nonsteroidal antiinflammatory drugs on fracture healing: a laboratory study in rats. J Orthop Trauma. 1995;9(5):392-400. PubMed
  • 10. Taylor IC, Lindblad AJ, Kolber MR. Fracture healing and NSAIDs. Can Fam Physician. 2014 Sep;60(9):817
  • 11. Ong CK, Lirk P, Tan CH, Seymour RA. Evidence-Based Update on Nonsteroidal Anti-Inflammatory Drugs. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007 Mar;5(1):19-34. PubMed
  • 12. Jeske AH. COX-2 inhibitors and dental pain control. J Gt Houst Dent Soc. 1999 Nov;71(4):39-40.
  • 13. Sun SX, Lee KY, Bertram CT, Goldstein JL. Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization. Curr Med Res Opin. 2007 Aug;23(8):1859-66. PubMed

Written by HealthyStock.net, September 2009.
Last modified: May 2015


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