NSAIDs

Question 1

In general the 4 therapeutic uses of NSAIDs are…

Answer 1

Analgesia, Antipyretic effect, Anti-inflammatory effect, and Antithrombogenesis

Question 2

Common side effects of NSAIDs

Answer 2

GI side effects: Ulceration, bleeding, nausea. Increased incidence of bleeding problems. Renal side effects: Acute renal failure and interstitial nephritis. Uterine side effects: Interference with uterine contractions in late-term pregnancy. Increased thrombotic events: Potential for increased cardiovascular events, including myocardial infarction and strokes

Question 3

How are the 4 main groups of NSAIDs distinguished?

Answer 3

Distinguished by selectivity for COX-1 vs COX-2 and reversible vs irreversible inhibition of COX.

Question 4

Defining characteristics of traditional NSAIDs

Answer 4

Reversible inhibition of COX-1 and COX-2

Question 5

Therapeutic uses of traditional NSAIDs

Answer 5

Analgesia, Antipyretic effect, Anti-inflammatory effect. Because they inhibit COX-1 and COX-2 reversibly.

Question 6

Name 3 traditional NSAIDs (that we need to know). Generic and brand name.

Answer 6

Ibuprofen [Advil, Motrin], Naproxen [Aleve, Naprosyn], Ketorolac [Toradol]

Question 7

How is Acetaminophen [Tylenol] different from other NSAIDs?

Answer 7

No inhibition of either COX-1 or COX-2 in periphery, it reversibly inhibits CNS COX-2. For this reason there is no anti-inflammatory effect and less GI side effects. It has analgesic and antipyretic effects.

Question 8

Selective CNS COX-2 inhibitor

Answer 8

Acetaminophen [Tylenol]

Question 9

Name a COX-2 selective inhibitor

Answer 9

Celecoxib [Celebrex]

Question 10

How does celecoxib [Celebrex] differ from other NSAIDs?

Answer 10

Selective reversible inhibition of COX-2 only. Analgesic, antipyretic, anti-inflammatory activities. Less GI side effects.

Question 11

Irreversible inhibitor of COX-1 and COX-2

Answer 11

acetylsalicylic acid aka Aspirin

Question 12

How does acetylsalicylic acid [Aspirin] differ from other NSAIDs?

Answer 12

Irreversible inhibition of COX-1 and COX-2]: Analgesic, antipyretic, anti-inflammatory, antithrombotic activities.

Question 13

Pharmacokinetics of traditional NSAIDs

Answer 13

Rapid, complete absorption; >90% protein-bound; renal excretion or liver metabolism

Question 14

How does ketorolac differ from ibuprofen and naproxen?

Answer 14

Ketorolac [Toradol] is given IM/IV while ibuprofen and naproxen are given orally. Ketorolac [Toradol] is available for treatment of post-surgical pain.

Question 15

Overdose with traditional NSAIDs vs aspirin

Answer 15

generally better tolerated and safer in overdose than aspirin

Question 16

Side effects of traditional NSAIDs on GI Tract

Answer 16

Interfere with gastric cytoprotection by inhibition of COX-1 PGE synthesis, leads to dyspepsia and gastric ulceration. Lowest risk with ibuprofen – highest with naproxen.

Question 17

Side effects of traditional NSAIDs on Platelets

Answer 17

Interfere with platelet aggregation by inhibition of COX-1 thromboxane A2 synthesis, leads to promotion of bleeding. Aspirin effect lasts 4-7 days (lifetime of a platelet, b/c irreversible inhibitor), whereas effect of other NSAIDs last about 2 days (dependent on half-life)

Question 18

Side effects of traditional NSAIDs on Kidneys

Answer 18

Cause renal vasoconstriction by inhibition of COX-1 and COX-2 PGE synthesis and loss of vasodilator actions, leads to reversible renal insufficiency. NSAIDs can cause fluid retention – caution advised for use in patients with risk of / or CVD.

Question 19

Compare cardiovascular risk of ibuprofen, celecoxib, and naproxen

Answer 19

Lowest cardiovascular risk with naproxen – highest with ibuprofen and celecoxib.

Question 20

Compare risk associated with aspirin, acetaminophen, ibuprofen, naproxen, ketorolac, celecoxib in pregnancy

Answer 20

Traditional NSAID (ibuprofen, naproxen, ketorolac) use during pregnancy not recommended (especially 3rd trimester), “safety not established”. Celecoxib: category C, but category D in 3rd trimester due to inhibitory effect on uterine prostaglandins necessary for labor contractions. Acetaminophen: considered safe in all stages of pregnancy (at therapeutic doses for short-term use). Aspirin: generally avoid use during pregnancy, especially 3rd trimester (can delay onset of labor).

Question 21

Therapeutic effect of Celecoxib and Pharmacodynamics

Answer 21

analgesic, antipyretic, and anti-inflammatory actions; Selectivity for reversible inhibition of COX-2 over COX-1 is 5-7 fold

Question 22

Selective COX-2 inhibitor is used for what diseases/conditions? Why?

Answer 22

Indicated for rheumatoid arthritis; osteoarthritis, dysmenorrhea, acute pain in adults. Better in long-term use because of less GI side effects.

Question 23

What is the advantage and disadvantage of COX-2 selective inhibitors with regards to platelets?

Answer 23

No inhibition of COX-1 mediated TXA2 synthesis in platelets, so no bleeding risk. But, Inhibition of endothelial COX-2 could reduce antithrombotic PGI2 activity relative to prothrombotic TXA2, so increases risk of ischemic CVD and HF.

Question 24

What patients may be allergic to Celecoxib?

Answer 24

Celecoxib [Celebrex] is sulfonamide i.e. patients with sulfa allergy.

Question 25

Possible side effects of COX-2 inhibitor on Kidneys

Answer 25

Similar to non-selective NSAIDs and can precipitate acute renal failure. Avoid use in at-risk patients.

Question 26

Pharmacodynamics of Acetaminophen [Tylenol]

Answer 26

Equivalent to aspirin as analgesic or antipyretic agent, but less anti-inflammatory properties (no inhibition of COX-1 or COX-2 at peripheral sites of inflammation, but possibly selective for inhibition of CNS prostaglandin synthesis [COX-2])

Question 27

Pharmacokinetics of Acetaminophen [Tylenol]

Answer 27

Absorption related to gastric emptying, peak levels in 30-60 min. Metabolized to inactive sulfate and glucuronide (phase II conjugation); in large doses metabolized to product toxic to liver. In overdose, glutathione stores are depleted and are no longer able to inactivate the toxic metabolite, leading to liver damage.

Question 28

Advantage of Acetaminophen [Tylenol] over other NSAIDs. Why does it have this advantage?

Answer 28

Little risk of GI dyspepsia-ulceration, bleeding, or renal dysfunction because no inhibition of COX-1 or COX-2 in the periphery–only in the CNS.

Question 29

Adverse effects of acetaminophen [Tylenol]

Answer 29

Hepatotoxicity. Most common cause of acute liver failure in US. Liver damage seen with as little as single 6 gm dose; also 5-8 g/day for several weeks or 3-4 g/day for 1 year (children appear less susceptible to liver toxicity). Alcohol induces the enzyme (CYP2E1) that produces hepatotoxic metabolite, thus liver damage may occur at lower doses with concomitant alcohol consumption

Question 30

Dose limits of Acetaminophen for safe use

Answer 30

Max dose at 4000 mg / 24 hrs - OTC recommended max dose of 3250 mg

Question 31

What is the maximal efficacious dose of acetaminophen [Tylenol]?

Answer 31

650 mg. 1000 mg dose does NOT provide more analgesic efficacy than 650 mg but it does increase risk of hepatotoxicity.

Question 32

Pharmacodynamics of acetylsalicylic acid [Aspirin]

Answer 32

Irreversible inhibition of cyclooxygenase (COX) 1 and 2

Question 33

What kind of pain is aspirin best for? Which is it worst for?

Answer 33

Best: Pain of inflammatory origin (pain of muscular / vascular origin, postpartum states, arthritis, bursitis, dental pain). Worst: Less effective for visceral pain (acute abdomen, renal colic, pericarditis, MI), i.e., pain that is caused by direct stimulation of sensory nerves (Aδ)

Question 34

What are the 2 mechanisms that allow for aspirin’s inhibition of platelet aggregation?

Answer 34

Low-dose aspirin is essentially platelet COX-1 selective. (1) Platelets cannot synthesize new COX-1 enzyme, thus TXA2 synthesis is inhibited for life of platelet (> 8 days). (2) Largest concentration of acetylsalicylic acid is presystemic in portal vein (prior to hepatic metabolism by esterases), thus greater effect on circulating platelet COX-1 (TXA2 synthesis) relative to tissue endothelial cell COX-2 (prostacyclin synthesis) resulting in a decreased tendency for clotting.

Question 35

Side effects of Aspirin

Answer 35

Gastric irritation, increased bleeding time, renal dysfunction, avoid in pregnancy (can delay onset of labor–like other peripherally-acting NSAIDs), Reye’s syndrome

Question 36

What is Reye’s syndrome? What are its signs and symptoms? How do you prevent it?

Answer 36

Occurs in salicylate use only. Liver damage encephalopathy unexpected vomiting, sleepiness. Avoid use if flu or other viral infections present (esp., Varicella/chicken pox).

Question 37

What are the signs and symptoms of Aspirin poisoning–mild and acute? What is a lethal dose?

Answer 37

Mild intoxication: Headache, dizziness, tinnitus, visual disturbances, mental confusion, drowsiness, sweating, thirst, hyperventilation, n/v, diarrhea. Acute intoxication (lethal dose: 10-30 grams): Vomiting, fever, and sweating (uncouples oxidative phosphorylation) leading to respiratory alkalosis followed by respiratory and metabolic acidosis. Death usually due to severe acidosis / electrolyte imbalance.

Question 38

What are the 2 most important/common drug-drug interactions of Acetylsalicylic acid [Aspirin]?

Answer 38

Warfarin, heparin. Inhibit platelet function hemorrhage. Avoid concomitant use. Alcohol. Additive gastric irritation internal bleeding. Avoid concomitant use.

Question 39

What reaction does Cyclooxygenase catalyze? What is the product of the reaction converted to?

Answer 39

Arachidonic acid to PGH2, which in turn is converted to either PGD2, PGE2, PGF2, PGI2 (prostacyclin), or TXA2.

Question 40

What are the main locations of the constitutively expressed COX-1? What are the effects at these sites?

Answer 40

GI tract: [PGE2/PGI2/PGF2]: Secretions: acid/pepsin secretion, mucous/bicarbonate production (cytoprotective effects); Smooth muscle [PGE2/PGF2]: contractions; Platelets [TXA2]: Pro-aggregatory effect; Kidneys [PGE2/PGI2]: Renal blood flow, promotion of diuresis; Vascular smooth muscle: PGI2/PGE2: vasodilation; TXA2: vasoconstriction; Bone [PGE2]: Stimulates bone formation and resorption.

Question 41

Where is the inducible COX-2 expressed? What are its effects at these sites?

Answer 41

Areas of pain/inflammation [PGE2 / PGI2]: Enhance edema formation and leukocyte infiltration via vasodilation; potentiation of bradykinin pain-producing activity; Hypothalamus/Fever [PGE2]: Increase in heat generation and decrease in heat loss; Kidneys [PGE2/PGI2]: Renal adaptation to stresses via maintenance of renal blood flow, most critical in elderly and when renal function deteriorates; Endothelial cells [PGI2]: Vasodilation and anti-aggregatory platelet effects; Uterine smooth muscle [PGE2/PGF2]: Contributes to labor contractions near parturition; Ductus arteriosus [PGE2]: Maintenance of patent ductus arteriosus via vasodilatory effects

Question 42

What reaction does 5-Lipoxygenase catalyze? What is the product converted to and where?

Answer 42

Arachidonic acid to Leukotriene A4, which is converted to leukotriene B4 (LTB4) in neutrophils, LTB4 diffuses into mast cells, eosinophils, basophils, and macrophages for conversion into the cysteinyl leukotrienes (CysLTs) LTC4, LTD4, and LTE4.

Question 43

What are the biologic effects of LTB4, LTC4, LTD4, and LTE4?

Answer 43

LTB4: Neutrophil chemotaxis, aggregation, and transmigration through endothelium. LTC4 / LTD4 / LTE4: Increased vascular permeability, bronchoconstriction, vasoconstriction. Important role in pathophysiology of asthma, psoriasis, and various arthritic/allergic/hypersensitivity processes.

Question 44

Can you draw the pathways that arachidonic acid is involved in and the effects of its products?

Answer 44

Question 45

Can you draw the pathways that COX-1 and COX-2 are involved in?

Answer 45