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PT 1 > L18, 19 NSAIDs: Non-Steroidal Anti-Inflammatory Drugs > Flashcards

L18, 19 NSAIDs: Non-Steroidal Anti-Inflammatory Drugs Flashcards

1
Q

What are the general indications of NSAIDs?

A
  1. Reduce inflammation
  2. Pain relief
  3. Fever reduction
  4. Aspirin-specific: stroke/MI prevention by inhibition of platelet activation
  5. Promote closure of a patent ductus arteriosus
  6. Cancer prevention (experimental)
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2
Q

NSAIDs work by blocking production of ___. How?

A

Prostaglandins; Inhibition of COX enzymes

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3
Q

Prostaglandin synthesis is dependent upon ___.

A

Cyclooxgenase (COX) enzymes

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4
Q

Describe the process of prostaglandin synthesis.

A
  1. Cell activation
  2. Plasma membrane phospholipids are converted to arachidonic acid by phospholipase A2
  3. Arachidonic acid is converted to PGH2 by cyclooxgenases
  4. PGH2 is converted prostacyclins, prostaglandins, and/or thromboxane by PG/TX synthases
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5
Q

What is the general mechanism of action of NSAIDs?

A

Inhibition of COX enzymes by preventing the binding of the arachidonic acid substrate to the active site of the enzyme.

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6
Q

All NSAIDs except aspirin act as ___ COX enzyme inhibitors.

A

Competitive (Aspirin is irreversible non-competitive)

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7
Q

Compare and contrast COX-1 and COX-2 with respect to their activity.

A

They both catalyze the rate-limiting conversion of membrane-derived arachidonic acid into prostaglandins and thromboxane.

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8
Q

Compare and contrast COX-1 and COX-2 with respect to their expression.

A

COX-1: constitutive (no induction)

COX-2: inducible in response to pro-inflammatory/mitogenic stimuli

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9
Q

Compare and contrast COX-1 and COX-2 with respect to their tissue location.

A

COX-1: most tissue

COX-2: induced in macrophages, monocytes; low-level constitutive expression in kidney, endothelium

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10
Q

Compare and contrast COX-1 and COX-2 with respect to their physiological role.

A

COX-1: protection and maintenance of tissues (housekeeping)

COX-2: pro-inflammatory responses

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11
Q

Compare and contrast COX-1 and COX-2 with respect to their inhibitors.

A

COX-1: aspirin and tNSAIDs, NOT Celecoxib

COX-2: aspirin, tNSAIDs, and selective COX-2 inhibitors

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12
Q

Increased COX-2 activity promotes what three responses (mediated by prostaglandins)?

A
  1. Inflammation
  2. Pain
  3. Fever
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13
Q

Describe the process of inflammation after COX-2 increases in an inflammatory cell.

A
  1. Profound prostaglandin production
  2. PGE2/PGI2: increased blood vessel dilation, increased blood flow, redness
  3. PGE2: increased migration of phagocytes
  4. PGE2: increased vascular permeability, edema, swelling
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14
Q

Describe the process of pain after COX-2 increases in an inflammatory cell.

A
  1. Prostaglandin production; PGE2 > primary afferent neurons > decrease activation threshold for pain stimuli > peripheral pain sensitization
  2. Bradykinin production and cytokine secretion > dorsal horn neuronal increase of COX-2 > prostaglandin production (PGE2) > dorsal horn neurons > enhanced depolarization of secondary sensory neurons > central pain sensitization
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15
Q

Describe the process of fever after COX-2 increases in an inflammatory cell.

A

Inflammatory mediators produced in the periphery act on endothelial cells lining the hypothalamus to induce COX2. PGE2 is produced; this acts on the thermoregulatory center of the hypothalamus to cause fever

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16
Q

COX-1 activity is involved in regulating what 5 things?

A
  1. GI tract
  2. Cardiovascular system
  3. Kidney
  4. Female reproduction
  5. Ductus arteriosus
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17
Q

Describe the effects of constitutive production of PG by COX-1 on the GI tract.

A

PGs are cytoprotective and they limit damage:

  1. Decrease gastric acid secretion
  2. Increase bicarbonate production
  3. Increase mucous production
  4. Increase vasodilation and gastric blood flow
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18
Q

Describe the potential toxic effects of NSAIDs of the GI tract.

A

Block COX-1, decrease PG, decrease cytoprotection

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19
Q

What are the two components of the cardiovascular system controlled by PGs?

A
  1. Platelets

2. Endothelial cells

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20
Q

Platelets express only ___ and produce principally ___. What are the effects of this product?

A

COX-1; TXA2 (thromboxane); vasoconstriction and platelet aggregation/activation

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21
Q

Endothelial cells express ___ and ___ but lack ___; thus, they primarily produce ___. What are the effects of this product?

A

COX-1; COX-2; TXA2 synthase; PGI2 (prostacyclin); vasodilation and inhibition of platelet aggregation

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22
Q

Of TXA2 and PGI2, which is pro-thrombotic and a vasoconstrictor?

A

TXA2

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23
Q

Of TXA2 and PGI2, which is anti-thrombotic and a vasodilator?

A

PGI2

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24
Q

What can happen if TXA2 and PGI2 are imbalanced?

A

Increased vasoconstriction and increased platelet aggregation –> increased hypertension, ischemia, thrombosis, MI, and stroke

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25
Q

Describe the effects of constitutive production of PG by COX-1 and COX-2 on the kidney.

A

Vasodilation (increase renal blood flow, prevent renal ischemia, increase GFR, increase water and sodium excretion

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26
Q

Why are PGs important in disease states (renal disease, heart failure)?

A

Vasoconstrictors are increased in these diseases; PG synthesis counteracts this to help maintain normal renal blood flow

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27
Q

Describe the effects of PG on female reproduction.

A

PGE2/PGF2-alpha production stimulates uterine contraction

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28
Q

How might NSAID use in labor affect the process?

A

It may delay labor by inhibition of uterine contraction

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29
Q

Describe the effects of PG on the ductus arteriosus, and the effects of treatment with NSAIDs during and after pregnancy.

A

The ductus is kept open during the fetal life via the actions of prostaglandins.

Treatment with NSAIDs during pregnancy may prematurely close the ductus.

Treatment with NSAIDs after birth can be used to promote closure of a patent ductus

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30
Q

What are the three categories of NSAIDs?

A
  1. Aspirin and salicylates (COX-1 and COX-2)
  2. Traditional non-selective NSAIDs (COX-1 and COX-2)
  3. Coxibs (COX-2)
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31
Q

What are the three types of aspirin/salicylic acids?

A
  1. Aspirin
  2. Diflusinal
  3. Salsalate
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32
Q

What are the 15 non-selective and traditional NSAIDs?

A
  1. Ibuprofen
  2. Naproxen
  3. Oxaprozin
  4. Ketoprofen
  5. Indomethacin
  6. Diclofenac
  7. Sulindac
  8. Keterolac
  9. Tolmetin
  10. Meloxicam
  11. Piroxicam
  12. Meclofenamate
  13. Mefenamic acid
  14. Nabumetone
  15. Etodalac
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33
Q

What are the 3 selective COX-2 inhibitors?

A
  1. Celecoxib
  2. Rofecoxib (withdrawn)
  3. Valdecoxib (withdrawn)
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34
Q

Aspirin (acetylsalicylic acid) is a weak acid with a pKa of 3.5. Describe what form it will take in the stomach.

A

In the acidic stomach, aspirin will be found in its protonated, neutral form; this can readiliy be absorbed.

35
Q

What metabolizes aspirin; what are the products?

A

Serum esterases; salicylic acid and acetic acid

36
Q

True or false - both aspirin and salicylic acid inhibit COX-1 and COX-2 and exhibit anti-inflammatory activity.

A

True

37
Q

Describe the unique mechanism of action of aspirin.

A

Aspirin is an irreversible inhibitor of COX1. It acetylates Ser530 in the active site and prevents access to arachidonic acid. Aspirin also acetylates COX-2, but it is a less potent inhibitor.

38
Q

What are the 5 indications of aspirin?

A
  1. Treatment of mild to moderate pain
  2. Inflammatory diseases
  3. Fever reduction
  4. Prophylactic prevention of cardiovascular events (low dose)
  5. Chemoprevention (experimental)
39
Q

Describe the unique indication of a low dose of aspirin (81 mg/day) in the treatment of CVD.

A
  1. Treatment in acute occlusive stroke
  2. Secondary prevention of CVD after a stroke, MI, or TIA
  3. Prophylactic treatment for prevention of stroke and MI in individuals at high risk
40
Q

Describe the mechanism of a low dose of aspirin (81 mg/day) in the treatment of CVD.

A
  1. Aspirin acetylates COX-1 in platelets, permanently inhibiting its activity and preventing TXA2 production (pro-thrombic)
  2. Because these platelets cannot re-synthesize COX-1, this inhibition lasts for the 7-10 day lifespan of the platelet.
  3. Endothelial cells are able to re-synthesize COX-1, so this dose does not affect PGI2 production.
  4. By inhibiting TXA2 production, this treatment promotes a strong anti-thrombogenic environment.
41
Q

Describe the mechanism of action at high anti-inflammatory doses.

A

The anti-platelet effect of inhibiting TXA2 is offset by the increased inhibition of PGI2.

42
Q

Why is diflusinal an ineffective anti-pyretic?

A

Doe not cross the BBB

43
Q

What are 5 other salicylates (non-aspirin)?

A
  1. Salsalate
  2. Diflusinal
  3. Magnesium salicylate
  4. Sodium thiosalicylate
  5. Methyl salicylate
44
Q

How are other salicylates different from aspirin?

A

These are non-acetylated and are unable to irreversibly inhibit COX-1. They are less potent and have lower risk of adverse effects.

45
Q

When are other salicylates preferred compared to aspirin?

A

Patients with increased risk of GI complications and increased risk of bleeding

46
Q

All salicylates are 50-90% protein bound - why does this matter?

A

High potential for drug interactions

47
Q

Describe the pharmacokinetics of salicylates at a low dose.

A
  1. Metabolized in the liver, conjugated to glycine/glucuronic acid
  2. 1st order elimination
  3. Half life of ~3.5 hour
48
Q

Describe the pharmacokinetics of salicylates at a high dose.

A
  1. Limited capacity metabolic enzymes become saturated
  2. 0 order elimination
  3. Half life of >15-30 hours
49
Q

What are symptoms of salicylate intoxication?

A
  1. Hyperventilation
  2. Metabolic acidosis
  3. Hypoglycemia
  4. Confusion
  5. Tremors
  6. Seizure
  7. Cerebral edema
  8. Delirium
  9. Hyperthermia
  10. Respiratory depression
  11. Coma and death
50
Q

How is salicylate overdose treated?

A

Alkalinization of the urine with sodium bicarbonate; this increases the relative concentration of the ionized form in the urine and prevents reabsorption while also increasing excretion rate.

51
Q

All traditional NSAIDs are ___.

A

Non-selective inhibitors of both COX-1 and COX-2

52
Q

What are the indications of traditional NSAIDs?

A
  1. Mild to moderate pain
  2. Fever
  3. Inflammation associated with RA, OA, etc.
  4. Acute gout (not aspirin)
53
Q

Which traditional NSAID has a rapid onset of action of 15-30 minutes (ideal for fever and acute pain)?

A

Ibuprofen

54
Q

Which traditional NSAID has a rapid onset of action of 60 minutes (ideal for anti-pyretic use)?

A

Naproxen

55
Q

Compare the serum half lives of naproxen and oxaprozin.

A

Naproxen: long serum half life (14 hours, twice daily dosing)
Oxaprozin: very long serum half life (50-60 hours, once daily dosing)

56
Q

Describe the potency of indomethacin.

A

10-40x more potent than aspirin as an anti-inflammatory, but not tolerated as well due to toxicity

57
Q

Which traditional NSAID is used to promote closure of patent ductus arteriosus?

A

Indomethacin

58
Q

Which traditional NSAID is used mainly as an IV analgesic for post-surgical pain (can also replace opioid analgesics)?

A

Ketorolac

59
Q

Which traditional NSAID is relatively selective for COX-2 and shows increased heart/stroke risk similar to Coxibs?

A

Diclofenac

60
Q

What are the 8 adverse effects of aspirin and tNSAIDs (2 are aspirin-specific)?

A
  1. GI toxicity
  2. Kidney impairment
  3. Cardiovascular effects
  4. Anti-platelet effect/increased bleeding risk
  5. NSAID hypersensitivity
  6. Pregnancy-related adverse effets
  7. Reye’s syndrome (aspirin specific)
  8. Increased risk of gout (aspirin specific)
61
Q

What is the most common adverse effect of all NSAIDs (except celecoxib)?

A

GI toxicity (epigastric distress, nausea, vomiting, GI bleeding, aggravation/promotion of ulcers)

62
Q

What are the causes of NSAID-induced GI toxicity?

A
  1. Direct damage to gastric epithelial cells caused by ion-trapping of aspirin/NSAIDs
  2. Inhibition of COX1 blocks the gastric protective effect of PGs
63
Q

How can GI toxicity caused by NSAIDs be ameliorated?

A
  1. Misprostol (PGE1 analog)

2. Omeprazole (Proton pump inhibitor)

64
Q

What causes the NSAID-related adverse effect of acute renal failure?

A

NSAIDs block production of vasodilatory PGs, leads to ischemia in people with underlying kidney disease or volume depletion (reversible)

65
Q

What causes the NSAID-related adverse effects of acute interstitial nephritis and nephrotic syndrome?

A

Associated with inflammatory cell infiltration; more common in elderly/women

66
Q

What causes the NSAID-related adverse effect of analgesic nephropathy/chronic interstitial neprhitis?

A

Associated with chronic daily overuse over many years; slow progressive renal failure leads to end-stage renal disease caused by prolonged renal ischemia

67
Q

What are the two adverse effects of NSAIDs on the cardiovascular system?

A
  1. Increased risk of heart attack and stroke

2. Exacerbation of pre-existing hypertension and heart failure

68
Q

What is the mechanism of the anti-platelet effect of NSAIDs?

A

Inhibit platelet COX-1 production of TXA2, leading to decreased clotting and increased risk of bleeding

69
Q

What are the platelet-related contraindications of NSAIDs?

A
  1. Patients with pre-existing platelet deficiency

2. Prior to surgery

70
Q

What is the likely cause of NSAID hypersensitivity?

A

Increased production of leukotrienes due to a build-up of arachidonic acid

71
Q

What is Reye’s Syndrome?

A

A rare, often fatal liver degenerative disease with associated encephalitis

72
Q

Reye’s syndrome is associated with what?

A

Aspirin given to young children and adolescents during a febrile viral infection (chickenpox or influenza); use NSAID or acetaminophen

73
Q

How can aspirin and the salicylates increase risk of gout?

A

Inhibit renal anion transporter responsible for uric acid excretion

74
Q

What are three other NSAID-induced adverse effects?

A
  1. Skin reactions (rare)
  2. Photosensitivity
  3. CNS effects (tinnitus, aspetic meningitis, psychosis/cognitive dysfunction)
75
Q

Why are aspirin and tNSAIDs associated with significant adverse effects?

A

Non-selective inhibition of COX-1

76
Q

What is the mechanism of action of Celecoxib?

A

Selective competitive inhibitor of COX-2 with minimal effects on COX-1

77
Q

What are the indications of Celecoxib?

A
  1. RA, OA
  2. Patients w/increased risk of GI complications
  3. Patients with increased risk of bleeding
78
Q

What are the adverse effects of Celecoxib? Why?

A

Increased risk of cardiovascular events; tips the scales in favor of PGI2 (vasodilator, anti-thrombotic)

79
Q

What are the general NSAID contraindications?

A
  1. History of GI ulcers (not celecoxib)
  2. Renal disorders
  3. Bleeding disorders/on anti-coagulants (not celecoxib)
  4. History of CVD/hypertension/HF (especially celecoxib)
  5. NSAID Hypersensitivity
  6. Delay onset of labor, increase risk of post-partum hemorrhage, premature closure of ductus arteriosus
  7. History of gout (aspirin)
  8. Children w/febrile viral infections (aspirin)
80
Q

How does lithium interact with NSAIDs?

A

NSAIDs impair renal function, decrease renal clearance of lithium, increase lithium toxicity

81
Q

How does methotrexate interact with NSAIDs?

A

NSAIDs impair renal clearance of MTX, displace it from serum proteins, increase toxicity

82
Q

How does aminoglycosides interact with NSAIDs?

A

NSAIDs impair renal clearance of aminoglycosides, increase aminoglycoside toxicity

83
Q

What is acetaminophen used for?

A

Pain and fever (no anti-inflammatory activity, no anti-platelet activity)

84
Q

What is the mechanism of action of acetaminophen?

A
  1. Weak inhibitor of COX1/2 in periphery
  2. Inhibits COX1/2 in the CNS
  3. Metabolized to active AM404, which can inhibit COX-2 in the brain and act on the cannabinoid system to decrease pain/fever

PT 1 (34 decks)

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