NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

Question 1

Aspirin

Answer 1

NONSELECTIVE COX INHIBITORS

Question 2

Diclofenac

Answer 2

NONSELECTIVE COX INHIBITORS

Question 3

Celecoxib

Answer 3

COX-2 SELECTIVE INHIBITORS

Question 4

Ibuprofen

Answer 4

NONSELECTIVE COX INHIBITORS

Question 5

Indomethacin

Answer 5

NONSELECTIVE COX INHIBITORS

Question 6

Meloxicam

Answer 6

COX-2 SELECTIVE INHIBITORS

Question 7

Ketorolac

Answer 7

NONSELECTIVE COX INHIBITORS

Question 8

Naproxen

Answer 8

NONSELECTIVE COX INHIBITORS

Question 9

Piroxicam

Answer 9

NONSELECTIVE COX INHIBITORS

Question 10

Actions of NSAIDS

Answer 10

ANTI-INFLAMMATORY ACTIONS

Inhibition of COX diminishes synthesis of prostaglandins and thus modulates those aspects of inflammation in which prostaglandins act as mediators.

ANALGESIC ACTIONS

PGE2 sensitizes nerve endings to action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. By decreasing PGE2 synthesis, NSAIDs repress the sensation of pain. NSAIDs are superior to opioids in management of pain in which inflammation is involved. In combinations with opioids NSAIDs are effective in treating pain of malignancy. The ability of NSAIDs to relieve headache may be related to the abrogation of the vasodilatory effect of prostaglandins in the cerebral vasculature.

ANTIPYRETIC ACTIONS

Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated. This can be caused by PGE2 synthesis, which is stimulated when cytokines are released from white cells activated by infection, hypersensitivity, malignancy or inflammation. NSAIDs inhibit fever by blocking PGE2 synthesis. COX-2 is the dominant source of prostaglandins that mediate the rise in temperature. This is consistent with the antipyretic clinical efficacy of both subclasses of NSAIDs.

NSAIDs do not influence body temperature when it is elevated by factors such as exercise or in response to ambient temperature.

Question 11

Theraputic Uses of NSAIDS

Answer 11

All NSAIDs are antipyretic, analgesic, and antiinflammatory.

NSAIDs are used for the treatment of mild to moderate pain, especially the pain of inflammation.

Chronic postoperative pain or pain arising from inflammation is controlled particularly well by NSAIDs. Pain arising from the hollow viscera usually is not relieved; an exception to this is menstrual pain.

NSAIDs are useful in the treatment of musculoskeletal disorders, such as rheumatoid arthritis and osteoarthritis. NSAIDs provide only symptomatic relief from pain and inflammation associated with the disease; they do not arrest the progression of pathological injury to tissue.

Many NSAIDs are approved for the treatment of rheumatoid arthritis, osteoarthritis, acute gouty arthritis, ankylosing spondylitis, and dysmenorrhea.

GOUT

Indomethacin is commonly used in the initial treatment of gout. All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes. Aspirin is not used for gout because it inhibits urate excretion at low doses, and through its uricosuric actions increases the risk of renal calculi at high doses. In addition, aspirin can inhibit the actions of uricosuric agents. Tolmetin is ineffective in gouty arthritis for unknown reasons.

COLON CANCER

Frequent use of aspirin is associated with a 50% decrease in the risk of colon cancer; similar observations have been made with other cancers. NSAIDs have been used in patients with familial adenomatous polyposis.

NIACIN TOLERABILITY

Large doses of niacin lower serum cholesterol levels, reduce LDL, and raise HDL. However, niacin is tolerated poorly because it induces intense flushing. This flushing is mediated by a release of PGD2 from the skin, which can be inhibited by treatment with aspirin.

CLOSURE OF DUCTUS ARTERIOSUS

Indomethacin is currently the drug of choice for closure of ductus arteriosus in premature infants. Other NSAIDs have also been used.

Question 12

Adverse Effects of NSAIDS

Answer 12

GI EFFECTS

NSAIDs are associated with significant gastrointestinal adverse effects. Gastric damage by NSAIDs can be brought about by at least two distinct mechanisms:

Inhibition of COX-1 in gastric epithelial cells depresses mucosal cytoprotective prostaglandins, especially PGI2 and PGE2. These eicosanoids inhibit acid secretion by the stomach, enhance mucosal blood flow, and promote the secretion of cytoprotective mucus in the intestine. Inhibition of PGI2 and PGE2 synthesis may render the stomach more susceptible to damage and can occur with oral, parenteral, or transdermal administration of aspirin or NSAIDs.

NSAIDs may cause ulceration by local irritation from contact of orally administered drug with the gastric mucosa.

COX-2 selective NSAIDs have fewer gastrointestinal side effects

Misoprostol, proton pump inhibitors, and H2 blockers reduce the risk of gastric ulcer and are used in the treatment of gastric damage induced by NSAIDs.

CARDIOVASCULAR RISK

NSAIDs can increase the risk of cardiovascular events (heart attack, stroke, death) to varying degrees, even in healthy people. Adverse cardiovascular events associated with NSAIDs are thought to be caused by NSAIDs upsetting the balance between vasoconstricting, platelet-aggregating thromboxane A2 (produced by COX-1) and vasodilating, platelet-inhibiting prostacyclin (produced by both COX-1 and COX-2). This may lead to vasoconstriction, platelet aggregation, and thrombosis.

NSAIDs that tend to be more COX-2 selective could therefore be assumed to have more cardiovascular risk. In fact, the COX-2 selective agents rofecoxib and valdecoxib were withdrawn from the market due to cardiovascular risk (see below). The usefulness of the coxibs has been reduced by their association with myocardial infarction and other thrombotic cardiovascular events.

Question 13

NSAIDS Actions on the Kidney

Answer 13

ACTIONS ON THE KIDNEY

Decrease In Renal Blood Flow

NSAIDs have little effect on renal function or blood pressure in normal human subjects. However, in patients with congestive heart failure, chronic kidney disease, and other situations in which there is reduced renal perfusion (due to vasoconstriction stimulated by angiotensin II, vasopressin, or norepinephrine), synthesis of vasodilating PGs (PGE2 and PGI2) becomes crucial in maintaining GFR. NSAID-induced decreases in PGs may lead to decreased GFR, sodium and water retention, edema, increased blood pressure, hyperkalemia, and acute renal failure.

NSAIDs should be avoided in patients with hypertension, heart failure, or CKD. In these patients NSAIDs can elevate blood pressure, reduce the action of anti-hypertensive agents, cause fluid retention, and worsen kidney function. Alternatives to NSAIDs, such as acetaminophen, tramadol, or opioids should be considered in these patients.

Analgesic Nephropathy

Analgesic nephropathy is a condition in which chronic interstitial nephritis is caused by prolonged and excessive consumption of analgesics, particularly combinations of different agents. The use of the NSAID phenacetin, which is no longer available, was particularly associated with analgesic nephropathy.

Question 14

Aspirin Hypersensitivity and Other Adverse Effects

Answer 14

ASPIRIN HYPERSENSITIVITY

Certain individuals display hypersensitivity to aspirin and NSAIDs, as manifested by symptoms that range from vasomotor rhinitis with profuse watery secretions, angioedema, generalized urticaria, and bronchial asthma to laryngeal edema, bronchoconstriction, flushing, hypotension, and shock.

This syndrome may occur in 10% - 25% of patients with asthma, nasal polyps, or chronic urticaria, and in 1% of apparently healthy individuals.

Aspirin hypersensitivity is associated with an increase in biosynthesis of leukotrienes, reflecting diversion of arachidonate to lipoxygenase metabolism as a consequence of COX inhibition.

OTHER ADVERSE EFFECTS

Celecoxib is a sulfonamide and may cause hypersensitivity reactions (typically rashes).

Question 15

Drug Interations and Contraindications of NSAIDS

Answer 15

DRUG INTERACTIONS

ACE-inhibitors: ACEIs act partly by preventing breakdown of kinins that stimulate PG production. NSAIDs inhibit the production of vasodilator and natriuretic PGs. The concomitant use of a NSAID and an ACEI has been associated with a decrease in the antihypertensive effect of the ACEI, as well as the potential to cause acute renal failure. The adverse effects may include sodium and water retention, and reduction of GFR, especially in the elderly or renally insufficient. In patients with hypertension, COX inhibition by a NSAID may cause worsening of hypertension and edema.

Diuretics. The effects of loop diuretics, thiazide, and K-sparing diuretics depend on renal prostaglandin production. Their diuretic effects can be reduced by NSAIDs.

The Triple Whammy: The term refers to the risk of acute kidney injury when an ACEI (or ARB) is combined with a diuretic, and a NSAID. The mechanism is as follows: NSAIDs constrict the afferent arteriole and reduce GFR. ACEIs dilate the efferent arteriole and reduce GFR. Diuretics reduce plasma volume and GFR. When used in combination, these medications can lead to acute renal failure. The combination should be avoided in the elderly, and patients with renal insufficiency or heart failure. Patients on the combination should be monitored for creatinine and potassium levels

Corticosteroids: NSAIDs may increase frequency or severity of gastrointestinal ulceration when combined with corticosteroids.

Warfarin: NSAIDs may increase risk of bleeding in patients receiving warfarin.

CONTRAINDICATIONS

Due to the association with Reye’s syndrome, aspirin and other salicylates are contraindicated in children and young adults less than 20 years old with fever associated with viral illness. Acetaminophen is the drug of choice for antipyresis in children and teens. Ibuprofen is also appropriate.

Pregnancy, especially close to term, is a relative contraindication to the use of all NSAIDs and their use must be weighed against potential fetal risk.

Question 16

COX-2 SELECTIVE INHIBITORS (COXIBS)

Answer 16

Coxibs selectively block the active site of the COX-2 isozyme much more effectively than that of COX-1.

COX-2 inhibitors have analgesic, antipyretic and antiinflammatory effects similar to those of nonselective NSAIDs but with fewer gastrointestinal side effects.

COX-2 is constitutively active in the kidney, therefore COX-2 inhibitors cause renal toxicities similar to those caused by the non-selective NSAIDs.

Coxibs appear to be associated with increased risk of cardiovascular thrombotic events. Such events are believed to be related to the balance between the biological effects of COX-1 and COX-2. In platelets, COX-1 mediates the synthesis of thromboxane A2 (TXA2), which promotes platelet aggregation and vasoconstriction; in endothelial cells, both COX-1 and COX-2 mediate synthesis of prostacyclin (PGI2), which inhibits platelet aggregation and causes vasodilation. It has been suggested that the ability of non-selective NSAIDs to inhibit both COX-1 and COX-2 maintains a balance between reductions in the levels of PGI2 and TXA2. In contrast, COX-2 inhibitors selectively inhibit synthesis of PGI2 without inhibiting TXA2. This would result in a prothrombotic state.

Currently, celecoxib is the only selective COX-2 inhibitor available in the USA.

Rofecoxib and valdecoxib were withdrawn due to their association with thrombotic events.

Meloxicam preferentially inhibits COX-2 over COX-1. However, it is not as selective for COX-2 as the coxibs.

Question 17

Aspirin and Other Salicylates Actions and Uses

Answer 17

Salicylates include aspirin (acetyl salicylate), magnesium choline salicylate, sodium salicylate, and salicyl salicylate.

Aspirin is the prototype of NSAIDs. However, aspirin is unique among the NSAIDs in irreversibly acetylating (and thus inactivating) cyclooxygenase. The other salicylates, and all other NSAIDs are reversible inhibitors of cyclooxygenase.

Aspirin is rapidly deacetylated by esterases in the body, producing salicylate.

Some of the pharmacologic effects of aspirin are due to its salicylate metabolite.

RESPIRATORY ACTIONS

At therapeutic doses aspirin increases alveolar ventilation: Salicylates uncouple oxidative phosphorylation which leads to elevated CO2 and increased respiration. Higher doses work directly on the respiratory center in the medulla, resulting in hyperventilation and respiratory alkalosis that is usually adequately compensated by the kidney. At toxic levels central respiratory paralysis occurs and respiratory acidosis ensues.

EFFECT ON PLATELETS

Low-dose aspirin irreversibly inhibits TXA2 production in platelets. Since platelets lack nuclei, they cannot synthesize new enzyme, and the lack of TXA2 lasts for the lifetime of the platelet (7-10 days). Aspirin also inhibits COX in endothelial cells, but its action is not permanent because these cells are able to synthesize new COX molecules. Additionally, at low doses of aspirin the endothelial cell production of PGI2 is relatively unaffected. The decrease in TXA2 levels results in inhibition of platelet aggregation and a prolonged bleeding time.

USES

Anti-inflammatory, antipyretic and analgesic uses
Aspirin and related salicylates are used for the treatment of mild to moderate pain, such as that associated with headache, joint and muscle pain, and dysmenorrhea. At high doses aspirin is an effective analgesic for rheumatoid arthritis and other inflammatory joint conditions. Aspirin is also a potent antipyretic.

Cardiovascular applications
Aspirin is used to inhibit platelet aggregation. Low doses are used prophylactically to:

1. Reduce the risk of recurring transient ischemic attacks (TIAs) and stroke or death.
2. Reduce the risk of death in those having an acute MI.
3. Reduce the risk of recurrent nonfatal MI and/or death in patients with previous MI or unstable angina pectoris.
4. Reduce the risk of MI and sudden death in patients with chronic stable angina pectoris.

Colon Cancer
Frequent use of aspirin is associated with a 50% decrease in the risk of colon cancer.

Question 18

Dosage and Metabolism of Aspirin and Other Salicylates

Answer 18

DOSAGE

Salicylates are analgesic and antipyretic at low doses; they are anti-inflammatory at higher doses.

Low doses of aspirin (<100 mg daily) are used widely for their cardioprotective effects.

METABOLISM

Aspirin is hydrolyzed to salicylate and acetic acid by esterases in tissues and blood. At low doses, salicylate is mainly converted by the liver to hydrosoluble conjugates (with glycine and glucuronate) that are rapidly excreted by the kidney, resulting in elimination with first-order kinetics and a half-life of about 3.5 hours.

When doses of aspirin of 1g or more are administered, the conjugation enzymes become saturated and zero-order kinetics is observed; first-order kinetics is not observed until the amount of salicylate remaining in the body drops to the amount equivalent to about 300 mg of aspirin. Moreover, the time required to eliminate 50% of the salicylate in the body lengthens as the dose of aspirin increases.

Question 19

Adverse Effects of Aspirin and Salicylates

Answer 19

ADVERSE EFFECTS GI

Epigastric distress.

BLOOD

The irreversible acetylation of platelet cyclooxygenase reduces the level of platelet TXA2, resulting in inhibition of platelet aggregation and a prolonged bleeding time. A single 325-mg dose of aspirin approximately doubles the mean bleeding time of normal persons for a period of 4–7 days.

Patients with severe hepatic damage, hypoprothrombinemia, vitamin K deficiency, or hemophilia should avoid aspirin because of the risk of hemorrhage.

If possible, aspirin therapy should be stopped one week before surgery.

REYE’S SYNDROME

Reye’s syndrome is an often fatal, fulminating hepatitis with cerebral edema. Aspirin and other salicylates given during viral infections have been associated with an increased incidence of Reye’s syndrome. This is especially encountered in children.

URICOSURIC EFFECTS

Uric acid uses the same transport system as anionic drugs such as aspirin, sulfinpyrazone and probenecid. Low doses of aspirin ( 1-2 g/day) compete with uric acid for secretion into the tubular fluid and thus reduce uric acid secretion. Large doses (>5 g/day) compete with uric acid for reabsorption and thus increase uric acid excretion in the urine. Because of its effect on uric acid secretion, aspirin is not recommended for treatment of gouty arthritis. Even small doses of aspirin can block the effects of probenecid and other uricosuric agents that decrease tubular reabsorption of uric acid.

HEPATIC EFFECTS

Salicylates can cause hepatic injury, usually in patients treated with high doses of salicylates. The onset occurs after several months of treatment. The injury usually is reversible upon discontinuation of salicylates. The use of salicylates is contraindicated in patients with chronic liver disease.

ASPIRIN IN PREGNANCY

Aspirin is classified as FDA pregnancy category C risk during Trimesters 1 and 2 and category D during Trimester 3.

SALICYLATE INTOXICATION

Salicylism

Mild chronic salicylate intoxication is called salicylism. The syndrome includes headache, dizziness, tinnitus, difficulty hearing, dimness of vision, mental confusion, lassitude, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting, and occasionally diarrhea.

Severe Intoxication

When large doses of salicylates are administered, severe intoxication may result. After an acute salicylate overdose patients typically present to the hospital with a mixed respiratory alkalosis and metabolic acidosis.

Prolonged exposure to high doses of salicylates leads to depression of the medulla, with central respiratory depression and circulatory collapse, secondary to vasomotor depression. Because enhanced CO2 production continues, respiratory acidosis ensues. Respiratory failure is the usual cause of death in fatal cases of salicylate poisoning.

Question 20

Acetaminophen

Answer 20

Acetaminophen is one of the most important drugs used for treatment of mild to moderate pain when an anti-inflammatory effect is not necessary.

Acetaminophen, although sometimes classified with the NSAIDs, is not an NSAID. Acetaminophen is a weak COX-1 and COX-2 inhibitor in peripheral tissues and has no significant antiinflammatory effects. The mechanism of action of analgesic action of acetaminophen is unclear.

Acetaminophen is an analgesic and antipyretic drug, lacking anti-inflammatory or antiplatelet effects. It does not affect uric acid levels. The drug is useful in mild to moderate pain such as headache, myalgia and postpartum pain.

Acetaminophen is the drug of choice for pain relief in osteoarthritis because of safety and effectiveness.

Acetaminophen has low GI risk.

Acetaminophen is preferable to aspirin in patients with hemophilia or a history of peptic ulcer and in those in whom bronchospasm is precipitated by aspirin.

Unlike aspirin, acetaminophen doesn’t antagonize the effects of uricosuric agents; it may be used concomitantly with probenecid in the treatment of gout.

Acetaminophen is the drug of choice for treating children with fever and flulike symptoms.

Acetaminophen is the drug of choice for short-term treatment of fever and minor pain during pregnancy.

Acetaminophen alone is an inadequate therapy for inflammatory conditions such as rheumatoid arthritis, though it may be used as an analgesic adjunct to anti-inflammatory therapy.

Question 21

Adverse Effects of Acetaminophen

Answer 21

Acetaminophen is considered a safe drug, especially because it lacks the GI, renal, and bleeding adverse effects seen with NSAIDs. However, hepatic injury as a result of acetaminophen use continues to be a serious health problem.

Acetaminophen is hepatically metabolized. More than 90% of the acetaminophen dose is metabolized to sulfate and glucuronide conjugates, which are hydrosoluble and eliminated in the urine. A small amount is metabolized by CYP2E1 to NAPQI, a metabolite which is hepatotoxic. Normally, NAPQI is conjugated with glutathione and the conjugate is excreted in the urine. However, with overdose, glutathione stores become depleted, and NAPQI is not detoxified and can cause hepatotoxicity. The antidote for acetaminophen overdose is N-acetylcysteine, a sulfhydryl donor.

Acetaminophen has a narrow therapeutic range, especially in certain populations. People who consume alcohol or have a pre-existing liver disease are at higher risk for acetaminophen hepatotoxicity, even at doses less than the currently recommended maximum daily dose of 4 g.

Acetaminophen overdoses are the most common cause of acute liver failure in the US; they account for about 50% of all cases of acute liver failure and carry a 30% mortality.