NSAIDs (Week 2--Melega)

Question 1

3 broad classes of analgesics

Answer 1

Non-opioid

Opioid

Adjuvant analgesic (drugs with other indications but that are effective analgesics in certain circumstances)

Question 2

NSAIDs

Answer 2

Non-steroidal anti-inflammatory drugs that reduce inflammation but are not structurally related to corticosteroids

Inhibit peripheral “pain” pathway by inhibiting prostaglandin synthesis (by blocking COX1/2)

Aspirin

Salicylates

Non-selective COX inhibitors

Selective COX-2 inhibitors

Question 3

Acetaminophen

Answer 3

Non-opioid analgesic but not an NSAID because no anti-inflammatory activity

Question 4

What is the main adverse side effect of NSAIDs?

Answer 4

Gastrointestinal injury

(ulcers due to too much acid secretion)

Question 5

Physiologic and pathologic functions of prostaglandins

Answer 5

Physiologic: all cells can produce prostaglandins, they act locally; temperature homeostasis, bronchial tone, cytoprotection (gastric and renal mucosa), intestinal mobility, myometrial tone, semen viability (some, like PGE1 have anti-inflammatory effects), renin secretion

Pathologic: fever (aberrant hypothalamic thermoregulation), asthma (airway responsiveness and immune hyperreactivity), ulcers (loss of cytoprotection), diarrhea (intestinal mobility), dysmenorrhea (myometrial tone), inflammation, bone erosion, pain (thought to be caused by PGD2)

Question 6

PGE2

Answer 6

Pain, hyperalgesia, heat, vasodilation, bronchoconstriction; can synergistically act with other pro-inflammatory mediators (histamine, complement, LTB4)

Question 7

TxA2

Answer 7

Promotes platelet aggregation, vasoconstriction, bronchoconstriction

Pro-thrombotic

Question 8

PGI2

Answer 8

Inhibits platelet aggregation, vasodilation, vascular permeability

Anti-thrombotic

Question 9

Arachadonic acid as a precursor

Answer 9

Inflammatory stimuli –> phospholipase A2 cleaves AA from plasma membrane –> COX metabolizes AA to PGH2 –> PGD2, PGE2, PGF2alpha, PGI2, TxA2

Note: AA can also be metabolized to leukotrienes (LTB4, LTD4) by lipoxygenases, but only in neutrophils, eosinophils, monocytes, mast cells

Question 10

Where do corticosteroids act?

Answer 10

Corticosteroids interfere with phospholipase A2 so you can’t maky any AA (and thus can’t make its downstream products like prostaglandins OR leukotrienes)

Question 11

Where do NSAIDs act?

Answer 11

NSAIDs block cyclooxygenase (COX) so can’t make prostaglandins, TxA2, prostacyclin, but can still make leukotrienes

Question 12

Do glucocorticoids affect COX activity?

Answer 12

They don’t directly affect basal COX activity, but they prevent IL-1 induced increases in COX activity

Question 13

COX-1 vs COX-2

Answer 13

COX-1 and COX-2 catalyze same reaction but expression, functions, and properties are markedly different

COX-1: constitutive, found in platelets (converts AA –> TxA2), produces prostanoids that modulate physiologic functions (gastric cytoprotective, platelet aggregation, vascular homeostasis, renal function)

COX-2: inducible, NOT found in platelets, pro-inflammatory (produces prostanoids that result pain, fever, leukocyte proliferation, inducible by cytokines (IL-1, TNF-a), endotoxin, growth factors, reactive oxygen molecules

Question 14

Do NSAIDs want to block COX-1 or COX-2?

Answer 14

The point is to block COX-2 because that’s the only way you get anti-inflammatory effect!

However, NSAIDs inhibit COX-1 and COX-2 and inhibition of COX-1 results in significant side effects (GI, platelet, renal)

Question 15

NSAID pharmacodynamics

Answer 15

Aspirin covalently acetylates COX enzyme and irreversibly inhibits it

All other NSAIDs act as reversible, competitive COX inhibitors

Question 16

Inhibition of COX-2/inhibition of COX-1 Ratio

Answer 16

All NSAIDs have a ratio of (COX2:1 inhibition) and the higher the ratio, the more specific the therapeutic effect and fewer GI or platelet effects

NSAIDs with 100:1 or 1000:1 are COX-2 selective

Question 17

Do NSAIDs treat the problem?

Answer 17

No, NSAIDs usually do not treat the underlying pathophysioogy, they only provide symptomatic relief

Question 18

What are non-selective NSAIDs used for?

Answer 18

Analgesics for moderate pain of musculoskeletal and inflammatory origin (headaches, dysmenorrhea, osteoarthritis, rheumatoid arthritis, gout, surgical pain, tendonitis, bursitis)

Anti-inflammatory agents in conditions listed above and ulcerative colitis

Question 19

Aspirin vs. Advil vs. Tylenol

Answer 19

Aspirin: acetylsalicylic acid (salicylate NSAID)

Advil: ibuprofen (NSAID)

Tylenol: acetaminophen

Question 20

What drug is used for anti-platelet effects to prevent MI and stroke?

Answer 20

Aspirin, because it irreversibly inhibits COX in platelets, which do not have a nucleus and thus cannot synthesyze new COX molecules, thus TxA2 cannot be synthesized and you get less clotting activity

After administration of a single dose of aspirin, platelet aggregation is impaired for up to 4 days, until new platelets enter the circulation in sufficient numbers

All other NSAIDs inhibit COX competitively and thus their inhibitory effects on platelet aggregation depend on pharmacokinetics (half-life, etc)

Question 21

Are NSAIDS or opioids more effective for pain associated with inflammation?

Answer 21

NSAIDs!

Question 22

4 pharmacodynamic effects of NSAIDs

Answer 22

1) Antiplatelet: inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects (Aspirin dose of <300 mg/day)
2) Analgesic: relief of pain by mechanism other than reduction of inflammation (ex: headache); NSAIDs have ceiling effect for analgesia (Aspirin dose of 300-2400 mg/day)
3) Antipyretic: reduce fever by lowering elevated body temperature by acting on hypothalamus (normal body temp not reduced) (Aspirin dose of 300-2400 mg/day)
4) Anti-inflammatory: treat inflammatory diseases and injuries, contributes to analgesic effect (lower inflammation –> lower perception of pain) (Aspirin dose of 2400-4000 mg/day)

Question 23

How do NSAIDs reduce fever?

Answer 23

Fever occurs when set point in anterior hypothalamic regulatory center is elevated

Fever usually caused by increase in PGE2 due to bacterial endotoxins causing release of pyrogens (IL-1) which promote COX2 and production of PGE2

NSAIDs block COX so no more PGE2 produced

Question 24

How is prostacyclin (PGI2) production by vascular endothelial cells affected by aspirin?

Answer 24

PGI2 produced in vascular endothelial cells, which DO have a nucleus so can just synthesize more COX, so even though aspirin irreversibly inhibits COX activity, the entire effect lasts only for a short time and then PGI2 levels are restored

Question 25

Negative pharmacodynamic effects of NSAIDS

Answer 25

Remember, pharmacodynamic is what drug does to body **Gastric** **irritant**, **bleeding**, **decreased renal perfusion** (prostaglandins dilate afferent arteriole)

Question 26

Risk factors for NSAID induced GI toxicity

Answer 26

**Higher** NSAID doses **Older** age Concurrent **steroid** use History of **peptic ulcer disease**

Question 27

How do NSAIDs (including aspirin) damage GI cells?

Answer 27

NSAIDs and aspirin are **acidic** and exist in nonionized neutral **lipophilic** form in the gastric lumen which is at pH 2 (after you eat them) and can **diffuse across plasma membranes** into surface epithelial cells but when they get there and the pH gets to 7, they dissociate into ionized charged form and become **ion trapped** inside the cell

Question 28

NSAIDs and adverse GI effects

Answer 28

**Erosion** is a microscopic discontinuity in the epithelium No relationship between NSAID-associated dyspeptic symptoms and the presence of erosions 50% of patients taking nonselective NSAIDs have erosions Up to 100% have **subepithelial hemorrhage** **20%** have **ulceration** **Only 1-3%** of patients have **serious** GI side effects while taking NSAIDs

Question 29

How do you treat NSAID induced GI toxicity?

Answer 29

**Discontinue** NSAIDs Take medication with a **meal** Use other medicine: **H2 antagonists** (high doses of ranitidine), **PPIs** (omeprazole), **PGE1 analog** (misoprostol) to restore cytoprotective effect

Question 30

Other adverse effects associated with NSAIDs

Answer 30

**Cutaneous and hypersensitivity** (urticaria, bronchospasm, anaphylaxis, erythema multiforme, **skin reactions**) **NSAID-induced hyperreactivity** (in patients with aspirin allergy, NSAID exposure more likely to cause ocular and nasal congestion, severe bronchospasm and possible anaphylactic reaction, possibly bc AA shunted to lipoxygenase pathway and increases synthesis of bronchoconstrictor leukotrienes) **Samter's triad** (Aspirin allergy/hypersensitivity higher in patients with **nasal polyps, bronchial asthma and rhinitis** (sinusitis); occurs in 10% of asthmatics

Question 31

Do NSAIDs affect renal function?

Answer 31

Not in people with normal kidneys, PGE2, and PGI2 But YES in people with **renal failure, CHF, volume depletion, liver disease, those receiving diuretics** --\> renal insufficiency, acute renal failure Prostaglandins vasodilate the afferent arteriole to increase renal blood flow and GFR

Question 32

Mechanism of action of Aspirin

Answer 32

Aspirin binds and **covalently** (acetylation) and **irreversibly** modifies COX so that AA can't bind it

Question 33

What is the half life of Aspirin?

Answer 33

Short, only **20 minutes**

Question 34

What is Aspirin broken down into?

Answer 34

Aspirin --\> **salicylate** --\> filtered, secreted and reabsorbed Salicylate is an **active metabolite**, can reversibly inhibit COX and **reduce inflammation** just as well as aspirin! Salicylate is less effective than aspirin for analgesia though Salicylate can build up and cause toxicity: first has first order kinetics with 3.5 hour half life but if \>600mg in body, get **zero order kinetics** and half life increases to \>15 hours (transporters in kidneys overwhelmed)

Question 35

Dose-dependent effects of aspirin

Answer 35

**Low**: \<300mg, **blocks platelet aggregation** for lifetime of platelet (10 days) **Intermediate**: 300-2400mg/day; **antipyretic** and **analgesic** **High**: 2400-4000mg/day; **anti-inflammatory** Salicylism (toxicity at high doses) only a problem at REALLY high concentrations

Question 36

Salicylism

Answer 36

**Toxicity** at **high doses of aspirin** due to **buildup of salicylate** Early warning signs: **tinnitus** (ringing in ears), **hyperventilation**, **dizziness**

Question 37

Reye's Syndrome

Answer 37

Rare form of acute encephalopathy and fatty infiltration of the liver that tends to **follow acute viral infection** and using **salicylates** during the illness **increases the risk of disease** Causal relationship hasn't been confirmed but just in case, if **kid** has fever, chickenpox, flu, etc just give them **Tylenol/acetaminophen instead!**

Question 38

Important NSAIDs and differences

Answer 38

**Ibuprofen**: 400mg; q 4-6h; half life 2h; available OTC **Naproxen**: 250-500mg; q 12h; half life 14h; more **potent** than ibuprofen, **long half-life** (delayed effects) **Fenoprofen**: 200mg; q 4-6h; contraindicated in renal disease **Indomethacin**: 25-50mg; q 8h; **GI side effects common**; more **potent** anti-inflammatory than aspirin **Ketorolac**: 15-60mg **IM** or **IV**; q 4-6h; available for parenteral use (IM, IV); short term management (**5 days**) of pain that requires analgesia at **opioid level** but not for minor or chronic painful conditions

Question 39

Do NSAIDS (fenoprofen, ibuprofen, naproxen, aspirin) inhibit COX1 or COX2 more?

Answer 39

**COX1**! Even though we take then in order to inhibit the pro-inflammatory COX2

Question 40

COX2 selective inhibitors

Answer 40

Only block COX2 because too **bulky** to access binding pocket of COX1 enzyme Better treatment of **arthritis** **Fewer GI effects** **Increased incidence of MI and stroke** compared to naproxen or aspirin **Celecoxib** is only COX2 inhibitor available in US

Question 41

Acetaminophen (APAP)

Answer 41

**Tylenol** Half life 2-4h **Analgesic**, **antipyretic** **NOT anti-inflammatory** (so not an NSAID) No gastric irritation, no platelet function interference, not contraindicated for asthma, not associated with Reye's syndrome **Selective inhibitor of COX2**, but different mechanism of COX binding from NSAIDs (maybe scavenge free radicals needed for COX activity) Note: weird that it is COX2 inhibitor and is NOT anti-inflammatory and does not have negative cardiovascular effects!

Question 42

N-acetylcysteine

Answer 42

**Give** this drug IV to someone who has **overdosed** on acetaminophen (Tylenol + alcohol)

Question 43

Aspirin compared to Tylenol

Answer 43

Aspirin and Tylenol (acetaminophen) have same potency for relieving **mild/moderate pain** and **reducing fever** Aspirin is anti-inflammatory but Tylenol is not Both used in **combination with opioid** analgesics for relief of severe pain Major concern with acetaminophen is high doses cause liver toxicity!