NSAIDS

Question 1

NSAIDS

Answer 1

NONSELECTIVE COX INHIBITORS

• Aspirin
• Diclofenac
• Ibuprofen
• Indomethacin
• Ketorolac
• Naproxen
• Piroxicam: Highest risk of GI adverse effects

COX-2 SELECTIVE INHIBITORS

• Celecoxib
• Meloxicam
• Rofecoxib: Withdrawn due to CV adverse effects.

Question 2

USES OF NSAIDS

Answer 2

Many NSAIDs are approved for the treatment of:

• Rheumatoid arthritis
• Osteoarthritis
• Acute gouty arthritis
• Colon cancer: Frequent use of aspirin is associated with a 50% decrease in the risk of colon cancer.

Question 3

NSAID USES: GOUT

Answer 3

• Indomethacin is commonly used in acute gout.
• All other NSAIDs except aspirin, salicylates, and tolmetin can be used to treat acute gout.
• Aspirin is not used for gout:
• It inhibits urate excretion at low doses.
• May increase risk of renal calculi at high doses.
• Tolmetin is ineffective in gouty arthritis for unknown reasons.

Question 4

NSAID USES: NIACIN TOLERABILITY

Answer 4

• Niacin lowers serum cholesterol levels.
• Niacin induces intense flushing.
• This flushing is mediated by a release of PGD2 from the skin.
• The flushing can be inhibited with aspirin.

Question 5

ADVERSE EFFECTS OF NSAIDS

Answer 5

• GI EFFECTS
• CARDIOVASCULAR EFFECTS
• RENAL EFFECTS
• ASPIRIN HYPERSENSITIVITY

Question 6

NSAID: GI Adverse

Answer 6

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.

Question 7

NSAID: CVS Adverse

Answer 7

• Adverse CV events are thought to be caused by NSAIDs upsetting the balance between TXA2 and PGI2.
• This may lead to vasoconstriction, platelet aggregation, and thrombosis.

Question 8

COX-2 SELECTIVE INHIBITION & CV RISK

Answer 8

• Coxibs have fewer GI side effects.
• But their usefulness has been reduced by their association with thrombotic events.

Question 9

NSAID: RENAL Adverse EFFECTS

Answer 9

Decrease In Renal Blood Flow

• NSAIDs have little effect on renal function or BP pressure in normal human subjects.
• However, in patients with CHF, CKD, and other situations in which there is reduced renal perfusion, vasodilating PGs are crucial in maintaining GFR.
• NSAID-induced decreases in PGs may lead to sodium and water retention, edema, increased BP, hyperkalemia, and acute renal failure.

Analgesic Nephropathy

• Chronicinterstitialnephritiscausedbyprolonged and excessive consumption of analgesics.
• The use of the NSAID phenacetin, which is no longer available, was particularly associated with analgesic nephropathy.

Question 10

ASPIRIN HYPERSENSITIVITY

Answer 10

Certain individuals display hypersensitivity to aspirin and NSAIDs.

• Symptoms:
• Vasomotor rhinitis
• Angioedema
• Urticaria
• Bronchial asthma
• Laryngeal edema
• Bronchoconstriction
• Flushing
• Hypotension
• Shock
• Caused by increase in biosynthesis of leukotrienes.
• Due to diversion of arachidonate to lipoxygenase metabolism as a consequence of COX inhibition.
• Celecoxib is a sulfonamide and may cause hypersensitivity reactions (typically rashes), i.e. sulfa drug allergies

Question 11

NSAID DRUG INTERACTIONS

Answer 11

• ACE-INHIBITORS: NSAIDs may diminish the antihypertensive effect of ACE-inhibitors by blocking the production of vasodilating prostaglandins.
• CORTICOSTEROIDS: NSAIDs may increase frequency or severityof GI ulceration when combined with corticosteroids.
• WARFARIN: NSAIDs may increase risk of bleeding in patients receiving warfarin.

Question 12

ASPIRIN & OTHER SALICYLATES

Answer 12

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.

Aspirinis rapidly deacetylated by esterases in the body, producing salicylate.

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

Question 13

ASPIRIN & OTHER SALICYLATES: RESPIRATORY ACTIONS

Answer 13

• Salicylates uncouple oxidative phosphorylation which leads to elevated CO2 and increased respiration.
• Higher doses stimulate the respiratory center resulting in hyperventilation.
• At toxic levels central respiratory paralysis occurs.

Question 14

ASPIRIN & OTHER SALICYLATES: EFFECT ON PLATELETS

Answer 14

• TXA2 induces platelet aggregation.
• Aspirin irreversibly inhibits TXA2 production in platelets.
• Platelets lack nuclei: they can’t synthesize new enzyme, and the lack of TXA2 persists for the lifetime of the platelet.
• Aspirin also inhibits COX in endothelial cells,but these cells can synthesize new COX.
• Additionally, at low doses of aspirin production of endothelial PGI2 is relatively unaffected.
• The decrease in TXA2 levels results in prolonged bleeding time.

Adverse

URICOSURIC EFFECTS

• Low doses of aspirin compete with uric acid for secretion and thus reduce uric acid secretion.
• Large doses compete with uric acid for reabsorption and thus increase uric acid excretion in the urine.

HEPATIC EFFECTS

• Salicylates can cause hepatic injury in patients treated with high doses of salicylates.
• The onset occurs after several months of treatment.
• Reversible upon discontinuation of salicylates.
• Salicylates are contraindicated in patients with chronic liver disease.

SALICYLATE INTOXICATION (> 2 to 3 g)

• Mild chronic salicylate intoxication is called salicylism.
• The syndrome includes headache, dizziness, tinnitus, mental confusion and hyperventilation.
• Afteranacutesalicylateoverdosepatients 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.
• Respiratory failure is the usual cause of death.

Question 15

RELATIONSHIP BETWEEN ASPIRIN DAILY DOSE AND EFFECTS

Answer 15

• antiplatelet effect: 80 - 160 mg
• Analgesic and antipyretic effects: 650 -1000 mg ]
• Antiinflammatory effect and tinnitus: 3 to 6 mg
• Hyperventilation and respiratory alkalosis: 6 to 10 g
• Fever, Dehydration, metabolic acidosis: 10 – 20 g
• Shock, coma, respiratory and renal failure, death: 20 – 30 g

Question 16

Aspirin Metabolism

Answer 16

• Aspirin is hydrolyzed to salicylate and acetic acid by esterases in tissues and blood.
• At low doses salicylate is converted by the liver into hydrosoluble conjugates that are rapidly excreted by the kidney.
• Elimination follows first-order kinetics with a half- life of about 3.5 hours.
• With doses of aspirin of 1g or more, the conjugation enzymes become saturated and zero-order kinetics are observed.

Question 17

ACETAMINOPHEN

Answer 17

• Analgesic and antipyretic drug.
• No anti-inflammatory or antiplatelet effects.
• Technically it is not a NSAID.
• Useful in mild to moderate pain.
• DOC for pain relief in osteoarthritis.
• DOC for children with fever and flulike symptoms.
• DOC for short-term treatment of fever and minor pain during pregnancy.
• Inadequate for inflammatory conditions such as rheumatoid arthritis but may be used as adjunct to antiinflammatory therapy.

Adverse

• In therapeutic doses, acetaminophen has negligible toxicity in most individuals.
• Whentakeninoverdose,orbypatientswith severe liver impairment, the drug is a dangerous hepatotoxin.
• Prompt administration of acetylcysteine, a sulfhydryl donor, may be lifesaving after an overdose.