Pharmacology: NSAIDs

What is an NSAID?

The NSAIDs are a group of chemically dissimilar agents with antipyretic, analgesic and anti-inflammatory activities.

What is the mechanism of action of NSAIDs?

The mechanism of action of NSAIDs involves inhibition of cyclooxygenase (COX), and thus inhibition of the production of prostaglandins and thromboxanes.

What is COX-1?

COX-1 is a constitutive enzyme expressed in most tissues, including blood platelets, and is involved in cell-cell signaling and in tissue homeostasis. COX-1 is the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytop

What is COX-2?

COX-2 is inducible and an immediate early-response gene product that is markedly up-regulated by shear stress, growth factors, tumor promoters and cytokines. COX-2 is the major source of prostanoids in inflammation and cancer. It is constitutive in the ki

Inhibition of which COX leads to the anti-inflammatory effect of NSAIDs?

The anti-inflammatory action of the NSAIDs is mainly related to their inhibition of COX-2.

Inhibition of which COX leads to the gastric adverse effects of NSAIDs?

Their adverse effect of causing gastric damage is due to inhibition of COX-1, resulting in an inability to form protective prostaglandins.

Which NSAIDs are selective COX-2 inhibitors?

� Celecoxib
� Meloxicam

Which NSAIDs are nonselective COX inhibitors?

� Aspirin
� Diclofenac
� Ibuprofen
� Indomethacin
� Ketorolac
� Naproxen
� Piroxicam

How do NSAIDs elicit anti-inflammatory action?

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

How do NSAIDs act as analgesics?

PGE2 sensitizes nerve endings to bradykinin, histamine, and other local chemical mediators of inflammation. By decreasing PGE2 synthesis, NSAIDs repress the sensation of pain.

Are NSAIDs or opioids better an managing 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.

How do NSAIDs cure headaches?

The ability of NSAIDs to relieve headache may be related to the abrogation of the vasodilatory effect of prostaglandins in the cerebral vasculature.

How do NSAIDs alleviate fever?

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.

Can NSAIDs alleviate rises in body temperature associated with warm weather or exercise?

No. NSAIDs do not influence body temperature when it is elevated by factors such as exercise or in response to ambient temperature.

What is the cause of fever?

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 o

What kinds of pain are alleviated by NSAIDs?

NSAIDs are useful for mild to moderate pain of inflammation and chronic postoperative pain:
� Pain arising from hollow viscera usually is not relieved; an exception is menstrual pain.
� Symptomatic relief of rheumatoid and osteoarthritis.
� Acute gouty ar

Which NSAID is commonly used to treat gout initially?

Indomethacin is commonly used in the initial treatment of gout.
The others, except aspirin, salicylates, and tolmetin, have been successfully used to treat acute gouty episodes.

Why isn't aspirin used to treat gout?

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.

Why isn't tolmetin used to treat gout?

Tolmetin is ineffective in gouty arthritis for unknown reasons.

How does aspirin affect the incidence of 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.

Why is aspirin sometimes administered after niacin?

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 wit

Which NSAID is indicated for closure of a patent ductus arteriosus?

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

Describe two mechanisms by which NSAIDs result in gastrointestinal damage.

� Inhibition of gastric epithelial COX-1 depresses mucosal cytoprotective prostaglandins (PGI2 and PGE2). Inhibition of PGI2 and PGE2 synthesis may render the stomach more susceptible to damage and can occur with oral, parenteral, or transdermal administr

Which drugs are indicated to reduce the gastric damage caused by NSAIDs?

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.

Which has less gastric side effects, nonselective or COX-2 inhibitors?

COX-2 selective NSAIDs have fewer gastrointestinal side effects.

Which NSAIDs have the highest risk of gastric mucosal damage?

Lowest Risk: Celecoxib
Low Risk: Ibuprofen; Aspirin; Diclofenac
Medium Risk: Naproxen; Indomethacin
High Risk:

What adverse effects do NSAIDs have on the cardiovascular system?

NSAIDs can increase the risk of cardiovascular events due to upsetting the balance thromboxane A2 and prostacyclin. This may lead to vasoconstriction, platelet aggregation, and thrombosis.

Which NSAIDs have a higher cardiovascular risk?

NSAIDs that tend to be
more COX-2 selective
could 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. The usefulness of the
has been re

Why do NSAIDs cause a reduction in renal blood flow?

In persons with compromised renal hemodynamics the kidney synthesizes vasodilating prostaglandins (PGE2 and PGI2) to offset the effects of vasoconstricting mediators (angiotensin II and epinephrine) and maintain renal perfusion. These prostaglandins becom

Why do NSAIDs cause interstitial nephritis?

Current evidence points to a type I hypersensitivity reaction. Almost any drug can cause acute interstitial nephritis, but the most common offenders are antibiotics and NSAIDs.

What is 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. After many years of exposure to damaging analgesics, renal papillar

What happens in aspirin hypersensitivity?

Symptoms range from vasomotor rhinitis with profuse watery secretions, angioedema, generalized urticaria, and bronchial asthma to laryngeal edema, bronchoconstriction, flushing, hypotension, and shock. Aspirin hypersensitivity is associated with an increa

What serious adverse reaction is associated with indomethacin and ibuprofen?

Serious hematologic reactions
have been observed with indomethacin and ibuprofen.

What adverse reaction is associated with celecoxib?

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

How do NSAIDs interact with ACE inhibitors?

ACE-inhibitors act partly by preventing breakdown of kinins that stimulate prostaglandin production. NSAIDs may diminish the antihypertensive effect of ACE- inhibitors by blocking the production of vasodilator and natriuretic prostaglandins.

How do NSAIDs interact with glucocorticoids?

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

How do NSAIDs affect warfarin administration?

NSAIDs may increase risk of bleeding in patients receiving warfarin.

In which patients are NSAIDs contraindicated?

� Due to Reye's syndrome, aspirin and other salicylates are contraindicated in
children and young adults less than 20 years old
d* with fever associated with viral illness.
� Pregnancy, especially close to term, is a relative contraindication to the use o

Which NSAID is appropriate for children with viral fever?

Acetaminophen is the drug of choice for antipyresis in children and teens. Ibuprofen is also appropriate.

Which group of NSAIDs are particularly effective at selective COX-2 blocking?

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

What is the mechanism of meloxicam?

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

Are rofecoxib and valdecoxib available for use in the USA?

No. Rofecoxib and valdecoxib were withdrawn due to their association with thrombotic events.

What is the only selective COX-2 inhibitor approved for use in the USA?

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

What are some general facts about COX-2 selective inhibitors?

� Analgesic, antipyretic and anti-inflammatory effects; fewer gastrointestinal side effects.
� They cause renal toxicities similar to non-selective NSAIDs.

Why are coxibs particularly risky for cardiovascular events?

It's related to the balance between the biological effects of COX-1 and COX-2. In platelets, COX-1 mediates the synthesis of TXA2, which promotes platelet aggregation and vasoconstriction; in endothelial cells, both COX-1 and COX-2 mediate synthesis of pr

What makes aspirin unique among other NSAIDs?

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

How does salicylate compare to aspirin?

Aspirin is rapidly deacetylated by esterases in the body, producing salicylate, which has no acetylating capacity; it is a weak, reversible, competitive inhibitor of COX. It has the same effects, but less efficacy.

When are salicylate NSAIDs preferred to aspirin?

The lower efficacy and lack of platelet aggregation inhibition makes nonacetylated salicylates preferable
when COX inhibition is undesirable: asthma, bleeding tendencies, and even (under close supervision) with renal dysfunction

How does aspirin affect the respiratory system?

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 hyperventi

How does aspirin affect 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, b

What is aspirin used prophylactically for?

1) reduce the risk of recurring transient ischemic attacks (TIAs) and stroke or death in those who have had single or multiple episodes of TIA or stroke; 2) reduce the risk of death in those having an acute myocardial infarction; 3) reduce the risk of rec

How does dosage affect the action of aspirin and salicylates?

� 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.

How is aspirin metabolized?

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 i

How long does a 325-mg dose of aspirin last?

A single 325-mg dose of aspirin approximately doubles the mean bleeding time of normal persons for a period of 4-7 days.

In which patients is aspirin contraindicated?

� Severe hepatic damage, hypoprothrombinemia, vitamin K deficiency, or hemophilia (risk of hemorrhage).
� One week before surgery.
� Children younger than 20 years
� Gouty arthritis
� Chronic liver disease
� Pregnancy

How does aspirin affect uric acid clearance?

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/

Why are salicylates contraindicated in chronic liver disease?

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.

Why is aspirin contraindicated in pregnancy?

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

What is 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 occas

What happens in severe salicylate toxicity?

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 depressio

What is acetaminophen?

Acetaminophen is a weak COX-1 and COX-2 inhibitor in peripheral tissues and has no significant anti-inflammatory effects. The mechanism of action of analgesic action of acetaminophen is unclear.

What effects does acetaminophen have?

It's an analgesic and antipyretic drug, lacking anti-inflammatory or antiplatelet effects. It does not affect uric acid levels and has low GIT risk.

What are the clinical uses of acetaminophen?

The drug is useful in mild to moderate pain such as headache, myalgia and postpartum pain. Unlike aspirin, acetaminophen may be used concomitantly with probenecid in the treatment of gout. Acetaminophen alone is an inadequate therapy for inflammatory cond

What are the adverse effects of acetaminophen?

Hepatic injury
as a result of acetaminophen use continues to be a serious health problem. In the liver, more than 90% of the dose is metabolized to sulfate and glucuronide conjugates, which are hydrosoluble and eliminated in the urine.
A small amount is m

What is the antidote for acetaminophen overdose?

The antidote for acetaminophen overdose is N-acetylcysteine, a sulfhydryl donor.

Who is at risk for acetaminophen overdose?

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. Overdoses are the most common cause of acute liver failure in