4. ASPIRIN & OTHER
NONSELECTIVE NSAIDs
• Classification and Prototypes
• Aspirin (acetylsalicylic acid) is the prototype of the
salicylates and other NSAIDs.
• Ibuprofen and naproxen have moderate effectiveness;
indomethacin has greater anti-inflammatory effectiveness;
and ketorolac has greater analgesic effectiveness.
• Celecoxib was the first member of a newer NSAID subgroup,
the cyclooxygenase-2 (COX-2)-selective inhibitors.
5. Mechanism of Action
• Cyclooxygenase has at least 2
isoforms: COX-1 and COX-2.
• COX-1 is primarily expressed in
noninflammatory cells, whereas
• COX-2 is expressed in activated
lymphocytes, polymorphonuclear
cells, and other inflammatory cells.
6. • Aspirin and nonselective NSAIDs inhibit both
cyclooxygenase isoforms and thereby decrease
prostaglandin and thromboxane synthesis throughout
the body.
• The COX-2-selective inhibitors have less effect on the
prostaglandins involved in homeostatic function,
particularly those in the gastrointestinal tract.
7. • The major difference between the mechanisms of
action of aspirin and other NSAIDs is that aspirin (but
not its active metabolite, salicylate) acetylates and
thereby irreversibly inhibits cyclooxygenase, whereas
the inhibition produced by other NSAIDs is reversible.
• The irreversible action of aspirin results in a longer
duration of its antiplatelet effect and is the basis for its
use as an antiplatelet drug
8.
9. Effects
• Anti Inflammatory
• Antipyretic action
• Activation of peripheral pain sensors may be
diminished.
• Autoregulation of renal function.
10. Pharmacokinetics and Clinical
Use
• 1. Aspirin—Aspirin has 3 therapeutic dose ranges:The
low range (<300 mg/d) is effective in reducing platelet
aggregation; intermediate doses (300–2400 mg/d) have
antipyretic and analgesic effects; and high doses (2400–
4000 mg/d) are used for an anti-inflammatory effect.
• Readily absorbed
• Excretion is via kidneys.
11. • 2. Other NSAIDs—The other NSAIDs are well absorbed
after oral administration. Ibuprofen has a half-life of
about 2 h, is relatively safe.
• Naproxen and piroxicam are noteworthy because of
their longer half-lives.
12. Toxicity
• 1. Aspirin
• Gastric upset.
• Chronic use: gastric ulceration, upper gastrointestinal bleeding,
and renal effects, including acute failure and interstitial nephritis.
• Aspirin increases the bleeding time.
• At higher doses of aspirin, tinnitus, vertigo, hyperventilation, and
respiratory alkalosis are observed.
• At very high doses, the drug causes metabolic acidosis,
dehydration, hyperthermia, collapse, coma, and death.
15. B. Mechanism of Action
• The mechanism of analgesic action of acetaminophen is
unclear.
• The drug is only a weak COX-1 and COX-2 inhibitor in
peripheral tissues, which accounts for its lack of anti-
inflammatory effect.
• Evidence suggests that acetaminophen may inhibit a
third enzyme, COX-3, in the CNS.
16. C. Effects
• Acetaminophen is an analgesic and antipyretic agent; it
lacks anti inflammatory or antiplatelet effects.
17. Toxicity
• Acetaminophen has negligible toxicity in most persons.
• However, when taken in overdose or by patients with
severe liver impairment, the drug is a dangerous
hepatotoxin.
• People who regularly consume 3 or more alcoholic
drinks per day are at increased risk of acetaminophen-
induced hepatotoxicity.
18. DISEASE-MODIFYING
ANTIRHEUMATIC
DRUGS (DMARDs)
• Mechanisms of Action and Effects
• The mechanisms of action of most DMARDs in treating
rheumatoid arthritis are complex. Cytotoxic drugs (eg,
methotrexate) probably act by reducing the number of
immune cells available to maintain the inflammatory
response.
20. • Other drugs appear to interfere with
the activity ofT lymphocytes (eg,
sulfasalazine, hydroxychloroquine,
cyclosporine, leflunomide,
mycophenolate mofetil, abatacept),
B lymphocytes (rituximab), or
macrophages (gold compounds).
• Biologic agents that inhibit the action
of tumor necrosis factor-α (TNF-α),
including infliximab, adalimumab,
and etanercept.
21. DRUGS USED IN GOUT
• Gout is associated with increased serum concentrations of uric acid.
• Acute attacks involve joint inflammation initiated by precipitation of
uric acid crystals.
• Treatment strategies include:
(1) Reducing inflammation during acute attacks (with colchicine, NSAIDs,
or glucocorticoids.
(2) Accelerating renal excretion of uric acid with uricosuric drugs
(probenecid or sulfinpyrazone)
(3) Reducing (with allopurinol or febuxostat) the conversion of purines to
uric acid by xanthine oxidase.
23. Anti-Inflammatory Drugs Used
for Gout
• 1. Mechanisms—NSAIDs such a indomethacin are
effective in inhibiting the inflammation of acute gouty
arthritis.
• These agents act through the reduction of
prostaglandin formation and the inhibition of crystal
phagocytosis by macrophages.
24. Toxicity
• NSAIDs can cause renal damage, and indomethacin can
additionally cause bone marrow depression.
• Short courses of glucocorticoids can cause behavioral
changes and impaired glucose control.
• Because colchicine can severely damage the liver and kidney,
dosage must be carefully limited and monitored.
• Overdose is often fatal.
25. Uricosuric Agents
• Mechanism—Normally, over 90% of the uric acid filtered by
the kidney is reabsorbed in the proximal tubules.
• Uricosuric agents (probenecid, sulfinpyrazone) are weak
acids that compete with uric acid for reabsorption by the
weak acid transport mechanism in the proximal tubules and
thereby increase uric acid excretion.
• At low doses, these agents may also compete with uric acid
for secretion by the tubule and occasionally can elevate,
rather than reduce, serum uric acid concentration.
• Elevation of uric acid levels by this mechanism occurs with
aspirin (another weak acid) over much of its dose range.
26. Effects
• Uricosuric drugs inhibit the secretion of a large number
of other weak acids (eg, penicillin, methotrexate) in
addition to inhibiting the reabsorption of uric acid.
27. Pharmacokinetics and clinical use
• Uricosuric drugs are used orally to treat chronic gout,
caused by under-excretion of uric acid.
• These drugs are of no value in acute episodes.
28. D. Xanthine Oxidase Inhibitors
• Mechanism
• The production of uric acid can be reduced by inhibition
of xanthine oxidase, the enzyme that converts
hypoxanthine to xanthine and xanthine to uric acid.
29. Effects
• Inhibition of xanthine oxidase increases the
concentrations of the more soluble hypoxanthine and
xanthine and decreases the concentration of the less
soluble uric acid.
• As a result, there is less likelihood of precipitation of
uric acid crystals in joints and tissues.
31. Toxicity
• Allopurinol causes gastrointestinal upset, rash, and
rarely, peripheral neuritis, vasculitis, or bone marrow
dysfunction, including aplastic anemia.
