21 - NSAIDs and Steroids

Question 1

What drugs are included in the class NSAIDs?

Answer 1

• Derivatives of salicylic acid (aspirin)
• Propionic acid (naprixen, ibuprofen)
• Acetic acid (indomethacin, ketorolac)
• Enolic acid (piroxicam)
• Alkanones (nabumetone
• Diaryl heterocyclic compounds (celecoxib)

Question 2

What is the therapeutic effects of NSAIDs derived from?

Answer 2

Their ability to inhibit prostaglandin (PG) production

Question 3

Describe the PG synthesis pathway?

Answer 3

Cyclooxygenase converts arachidonic acid (AA) to PGG2 and PGH2 and leads to the production of prostacyclin (PGI2), thromboxane (TXAs) and other PGs.

Question 4

What are the forms of cyclooxygenase (COX)? How do they differ?

Answer 4

COX1 and COX2

COX-1: expressed constitutively in most cells, is the dominant (but not exclusive) source of prostanoids for housekeeping functions, such as gastric epithelial cytoprotection and hemostasis.

COX-2: induced by cytokines, shear stress, and tumor promoters, is the more important source of prostanoid formation in inflammation and pain.

Question 5

How do NSAIDs work?

Answer 5

They inhibit the COX enzymes and thus PG productions; they do not inhibit the lipoxygenase pathway of AA metabolism and thus do not suppress leukotriene formation.

Question 6

How do glucocorticoids work?

Answer 6

Suppress the induced expression of COX-2, and thus COX-2– mediated PG production.

They also inhibit the action of phospholipase A2, which releases AA from the cell membrane.

These effects contribute to the antiinflammatory actions of glucocorticoids.

Question 7

What is the mechanism of action of aspirin? How does this distinguish it from other NSAIDs?

Answer 7

Covalently modifies COX-1 and COX-2, irreversibly inhibiting COX activity.

• the duration of aspirin’s effects is related to the turnover rate of COXs in different target tissues (have to make more COX)
• the duration of effect of nonaspirin NSAIDs, which inhibit the active sites of the COX enzymes competitively, r_elates to the time course of drug disposition_

Question 8

What is the therapeutic use of nonselective NSAIDs limited by?

Answer 8

Poor GI tolerability.

Chronic users are prone to experience GI irritation in 20% of cases.

Question 9

What was the basis for creating selective COX2 inhibitors?

Answer 9

Based on the hypothesis that they would afford efficacy similar to nonselective NSAIDs with better GI tolerability.

Believed that COX1 was the predominant source of cytoprotective PGs formed by the GI epithelium.

Question 10

What is correlated with an increasd probability of developing seroius adverse reactions to NSAIDs? What is an associated black box warning?

Answer 10

Age.

NSAIDs are labeled with a black box warning related to cardiovascular risks and are specifically contraindicated following coronary artery bypass graft (CABG) surgery

Question 11

How is aspirin metabolized? What is this pathway sensitive to?

Answer 11

To salicylic acid by esterases present in many tissues (especially the liver) and then to salicyluric acid and salicyl phenolic glucuronide.

These two pathways become saturated with the consequence that the renal excretion of salicylic acid increases after overdose; this excretion pathway is extremely sensitive to changes in urinary pH.

Question 12

What effects do salicylates (aspirin) have on uric acid excretion?

Answer 12

Dose dependent:

• Low doses (1 or 2 g/day) may decrease urate excretion and elevate plasma urate concentrations
• Intermediate doses (2 or 3 g/day) usually do not alter urate excretion.
• Large doses (>5 g/day) induce uricosuria and lower plasma urate levels; (however, such large doses are tolerated poorly.)

Question 13

What effects can salicylates (aspirin) have on probenecid and other uricosuric agents (drugs that increase the excretion of uric acid in urine)?

Answer 13

Even small doses of aspirin can block their effects (ie they can no longer decrease the tubular reabsorption of uric acid) - ie uric acid is retained instead of beign excreted.

Question 14

What effect can NSAIDs have on acute gout? How should they be given?

Answer 14

Effective in the treatment of acute gout, particularly if treatment is initiated within 24 hours of symptom onset.

When effective, NSAIDs should be given at relatively high doses for 3-4 days and then tapered for a total of 7-10 days.

Question 15

Which NSAIDs have all been found to alleviate inflammatory symptoms of gout?

Answer 15

Indomethacin, naproxen, and celecoxib.

Question 16

Why isn’t aspirin used to treat gout?

Answer 16

It can inhibit urate excretion at low doses, and through its uricosuric actions, can increase the risk of renal calculi at higher doses.

In addition, aspirin can inhibit the actions of uricosuric agents (drugs that increase uric acid excretion in the urine).

Question 17

Describe the tretment of osteoarthritis?

Answer 17

Osteoarthritis (OA) is a common cause of joint pain and disability.

Treatment is directed towards reduction of symptoms and the prevention of disability.

There are no pharmacologic therapies that have been proven to prevent the progression of joint damage due to OA.

Question 18

What should you do if you have a patient with OA (osteoarthritis) who lacks signs and symptoms of inflammation?

Answer 18

Initiate pharmacologic therapy with acetaminophen on an as-needed basis.

• If this is inadequate, use acetaminophen on a regular basis up to three to four times daily.

Question 19

When should NSAIDs be used to treat patients with OA (osteoarthritis)?

Answer 19

In patients with inadequate symptom relief with acetaminophen and those with evidence of inflammatory OA.

• NSAIDs may be used in addition to or in place of acetaminophen depending upon the degree of symptom relief.

Question 20

How should NSAIDs be given to a patient with OA?

Answer 20

Initiated in low doses on an as-needed basis to minimize risk of adverse events, but may be increased to regular daily antiinflammatory doses if required for symptom relief and permitted by the patient’s conditions.

Use the lowest dose required to control the patient’s symptoms.

Question 21

When should topical NSAIDs be used to treat a patient with OA?

Answer 21

As an alternative treatment in patients who cannot tolerate or have contraindications to oral agents, or who may be at increased risk of adverse effects with the use of oral NSAIDs, such as older adults (eg, patients 75 and older).