The Facts Of NSAIDs
Dateline: 06/10/97
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of drugs commonly used
to treat arthritis because of their analgesic (pain-killing), anti-inflammatory,
and antipyretic (fever-reducing) properties. The mechanism of action of NSAIDs
is the inhibition of the enzyme cyclooxygenase, which catalyzes arachidonic acid
to
prostaglandins and leukotrienes. Arachidonic acid is released from membrane
phospholipids as a response to inflammatory stimuli.
Prostaglandins establish the inflammatory
response.
inflammatory stimuli (disease, trauma)---->membrane phospholipids release
arachidonic acid--->cyclooxygenase catalyzes arachidonic acid to prostaglandins
and leukotrienes---->prostaglandins create an inflammatory response
NSAIDs interfere with prostaglandin production by inhibiting cyclooxygenase This
mechanism may relate to the variation in response between patients. Scientific
studies have shown a correlation between concentration of the drug and effect,
but do not explain the differences in individual patient responses. It is
thought that the pharmacokinetic (process by which a drug is absorbed,
distributed, metabolized, and eliminated) differences among the various NSAIDs
may account for the variability in response.
Other facts about NSAIDs:
---Pain and inflammation sometimes occur in a circadian rhythm (daily rhythmic
cycle based on a 24 hour interval). Therefore NSAIDs may be more effective at
certain times.
---NSAIDs are divided into two groups: those with plasma (blood) half-lives less
than 6 hours (i.e. aspirin, diclofenac, ibuprofen) and those with half-lives
greater than 10 hours (i.e. diflunisal, piroxicam, and sulindac). Since it takes
three to five half-lives to stabilize blood levels, NSAIDs with longer
half-lives require a loading dose to be given (large dose given initially). The
"half-life" is the time it takes
a drug to go down to half of its initial level.
---Prostaglandins, which are inhibited by NSAIDs, function in the body to
protect the stomach lining, promote clotting of the blood, regulate salt and
fluid balance, and maintain blood flow to the kidneys when kidney function is
reduced. By decreasing prostaglandins, NSAIDs can cause stomach irritation,
bleeding, fluid retention, and decreased kidney function.
---Synovial fluid (joint fluid) concentrations are 60% of plasma concentrations
regardless of type of NSAID or its half-life. Synovial fluid is mostly the site
of action of NSAIDs.
---NSAIDs are 95% albumin (protein) bound. The unbound fraction of the NSAID is
increased in patients with low albumin concentrations such as in active
rheumatoid arthritis and the elderly.
---Since NSAIDs bind to plasma proteins they may be displaced by or may displace
other plasma-bound drugs such as coumadin, methotrexate, digoxin, cyclosporine,
oral antidiabetic agents, and sulfa drugs. This interaction can enhance either
therapeutic or toxic effects of either drug.
---Due to their different chemical properties some NSAIDs have substantial
biliary (bile ducts, gallbladder) excretion (i.e. indomethacin , sulindac) and
others are metabolized pre-excretion, while a few are excreted in the urine
unchanged.
---NSAID studies which have shown a variation in patient response attribute a
lower rate of adherence to one NSAID when other NSAIDs are known to be
available. The response to and preference of an NSAID may relate to more than
just symptom control.
---About 60% of patients will respond to any single NSAID. A trial period of
three weeks should be given for anti-inflammatory effectiveness to be observed.
About 10% of rheumatoid arthritis patients will not respond to any NSAID.
---A study in the United Kingdom revealed ibuprofen as the lowest risk for
causing serious upper gastrointestinal distress. Naproxen, indomethacin, and
diclofenac were viewed as an intermediate risk. Azapropazone, and piroxicam had
the highest risk.
---Antipyretic and anti-inflammatory effects of NSAIDs can mask the signs and
symptoms of infection.
---Adverse effects of NSAIDs which can occur at any time include renal (kidney)
failure, hepatic (liver) dysfunction, bleeding, and gastric (stomach)
ulceration.
---NSAIDs (particularly indomethacin) can interfere with the pharmacologic
control of hypertension and cardiac failure in patients who take beta-adrenergic
antagonists, angiotensin-converting enzyme
inhibitors, or diuretics.
---Long-term use of NSAIDs may have a damaging effect on chondrocyte (cartilage)
function.
---Commonly used NSAIDs include: Voltaren, Dolobid, Nalfon, Ansaid, Motrin,
Indocin, Orudis, Meclomen, Naprosyn, Feldene, Clinoril, Tolectin, Daypro,
Relafen.
It can not be predicted which NSAID will best serve a particular patient. No
single NSAID has been proven to be superior over the others for pain relief.
Once an NSAID is selected, the dosage should be increased until pain is relieved
or until the maximum tolerated dose has been reached. The duration of analgesia
does not always correspond with the plasma half-life of the NSAID. The patient
response should be a guideline for selecting the proper dose, using the lowest
dose possible to obtain pain relief.
To read about a specific NSAID: The Internet Drug Index
REFERENCES:
The Duke University Medical Center Book of Arthritis, David S.
Pisetsky, M.D., Ph.D.
New England Journal of Medicine, 324(24):1716-1725, 1991.
