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MSK/Rheum > Pharm-RA-NSAIDs > Flashcards

Pharm-RA-NSAIDs Flashcards

1
Q

Pt’s w/ RA taking NSAIDs should take the ________ dose for the _________ duration needed to _______?

A

Pt’s with RA taking NSAIDs should take the LOWEST EFFECTIVE DOSE for the SHORTEST DURATION needed to CONTROL SYMPTOMS.

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2
Q

What actions do NSAIDs possess? (3)

A

a. Analgesic
b. Antipyretic
c. Anti-inflammatory

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3
Q

Which NSAID does NOT have anti-inflammatory effects?

A

ACETAMINOPHEN

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4
Q

T/F: No oral NSAID is consistently more effective than any other. Some pt’s who do not respond to or tolerate one NSAID may respond to or tolerate another.

A

True

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5
Q

Compare Aspirin efficacy and toxicity in general to that of other NSAIDs.

A

Aspirin in high doses is as effective as any other NSAID, but may have more GI toxicity.

Non-acetylated salicylates have less GI toxicity than aspirin.

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6
Q

What are the NSAIDs use in Rx of RA? (11)

A
  1. Acetaminophen (Tylenol)
  2. Aspirin (ASA; Acetyl-salicylic acid)
  3. Diclofenac
  4. Ibuprofen (Motrin, Advil)
  5. Indomethacin
  6. Ketoprofen
  7. Ketorolac
  8. Naproxen
  9. Piroxicam
  10. Sulindac
  11. Celecoxib (Celebrex)
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7
Q

Highest selling NSAIDs globally?

A

Diclofenac and Ibuprofen

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8
Q

COX-2-selective?

A

Celecoxib (Celects Cox-2)

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9
Q

Which is also available formulated with misoprostol (synthetic PGE1 analog)? Why?

A

Diclofenac (MD coformulation); in order to prevent gastric or duodenal ulcers

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10
Q

Which also has a rectal preparation?

A

Indomethacin

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11
Q

Which also has a parenteral preparation?

A

Ketorolac

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12
Q

T/F: All are available orally; some are availabe in extended release preparations; they are also available as generic products.

A

True; they are readily available (prescription and OTC) and inexpensive

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13
Q

What are NSAIDs most commonly used to treat?

A

pain caused by inflammatory conditions, like arthritis and MSK injuries.

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14
Q

MoA/effect of NSAIDs?

A

Reversible inhibition of COX enzymes, resulting in amelioration of pain and inflammation (analgesic, antipyretic, anti-inflammatory)

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15
Q

How does the MoA of aspirin differ from that of the rest of the NSAIDs?

A

It IRREVERSIBLY inhibits the COX enzymes

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16
Q

How many COX isoforms are there and how do they differ?

A

Two Isoforms:

a. COX-1→constitutive expression
b. COX-2→inducible expression

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17
Q

What is responsible for many of the adverse effects associated with chronic NSAID use?

A

Unintended inhibition of COX

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18
Q

A pt’s relative risk factor for what two organ toxicities guide the physician choice of NSAID?

A

a. GI toxicity

b. CV toxicity

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19
Q

(T/F) NSAIDs are used so much because they don’t have a max does that affects escalation + daily dosing.

A

False, all NSAIDs have a maximum dose limit that affects dose escalation and daily dosing.

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20
Q

Metabolism/Elimination of NSAIDs?

A

a. All undergo extensive hepatic metabolism to a variety of products, sometimes involving conjugates
b. Ultimate elimination occurs predominantly in the urine w/ minor recovery in feces
c. Little parental drug recovered in excreta

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21
Q

What NSAID is differs from the others with regards to its metab/elim? How?

A

Ketorolac→58% is excreted unchanged in the urine

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22
Q

For each of the following, what is the COX isoform targeted and are they effects of traditional NSAIDS or COX2-selective NSAIDS, or Both?
Anti-inflammatory, Analgesic, and Antipyretic effects?

A

Enzyme Targeted: COX2

Both Traditional and COX2-selective have these effects

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23
Q

Increase BP?

A

Target Enzyme: COX2

Both Traditional and COX2-selective have this effect

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24
Q

Reduce Urinary PGI2 metabolites?

A

Target enzyme: COX2

both tradtional and COX2-selective have this effect

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25
Q

Reduce Urinary TXA2 metabolites?

A

Target enzyme: COX1

Only traditional NSAIDs have this effect

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26
Q

Inhibit Platelets?

A

Target enzyme: COX1

Only traditional NSAIDs have this effect

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27
Q

Increase bleeding time?

A

Target enzyme: COX1

Only traditional NSAIDs have this effect

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28
Q

GI toxicity?

A

Target enzyme: COX1 and possibly 2

Only Traditional NSAIDs have this effect

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29
Q

What are some effects that are common to both Traditional and COX2-selective NSAIDs? (5) Why?

A

They are common b/c they are mediated by inhibition of COX-2:

  1. Anti-inflammatory
  2. Analgesic
  3. Antipyretic
  4. Increase BP
  5. Reduce urinary PGI2 metabolites
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30
Q

What are some effects that only traditional NSAIDs have (not COX-2 selective NSAIDs)? (4) Why?

A

They only occur with traditional NSAIDs b/c they are mediated by inhibition of COX-1:

  1. Reduce urinary TXA2 metabolites
  2. Inhibit platelets
  3. Increase bleeding time
  4. GI toxicity (possibly associated w/ inhib of COX2 as well)
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31
Q

T/F: Within the class of known NSAIDs, all are structurally related.

A

False, some members are structurally related, others are not.

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32
Q

Which agent is the only COX2-selective agent? Why is that not completely true?

A

Celecoxib is THE COX2-selective NSAID; but some of the other traditional NSAIDS shows preference for COX1 or COX2

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33
Q

Which traditional NSAIDs shows some preference for COX2? Which has the highest preference for COX1? Which has pretty much no preference?

A

Some COX2:Diclofenac
COX1=COX2 for Ibuprofen
COX1: Ketorolac

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34
Q

Which NSAID has the shortest half-life? Which has the longest?

A

Shortest: Diclofenac
Longest: Piroxicam
Overall NSAIDs vary in t1/2; therefore, dose intervals vary considerably b/t the individual NSAIDs

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35
Q

(T/F) GI ADE with chronic NSAID use are limited usually to the upper GI tract.

A

False, upper GI may be more common, but the entire GI tract is at increased risk.

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36
Q

Risk factors for adverse GI events? (10)

A
  1. Older age (risk doubles every decade after 55)
  2. Males 2x more risk
  3. Hx of GI disorder (gastroduodenal ulcer, GI bleeding)
  4. Certain medications
  5. Comorbidities
  6. Prolonged NSAID use
  7. Use of maximum dose NSAID
  8. H pylori infection
  9. Excessive alcohol use
  10. Heavy smoking
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37
Q

What medications increase risk of adverse GI events with NSAIDs? (5)

A
  1. Aspirin
  2. Warfarin
  3. Oral corticosteroids
  4. SSRI’s
  5. SNRIs: Venlafaxine/Duloxetine
38
Q

What comorbidities increase the risk of adverse GI events w/ NSAIDs? (4)

A
  1. CV ds
  2. HTN
  3. DM
  4. Hepatic/Renal impairment
39
Q

What two factors contribute to relative risk of GI toxicity for the individual NSAIDs? Do all NSAIDs have risk of this?

A

a. COX Selectivity/Preference
b. Drug half-life
All NSAIDs carry risk, even celecoxib, though its risk is lower than that of traditional NSAIDs

40
Q

GI toxicity is mediated thru blockage of which COX enzyme?

A

COX-1 (TXA2, platelets, bleeding)

41
Q

Which traditional NSAID has the highest risk of GI toxicity?

A

Ketorolac (selectivity: COX1»>COX2)

42
Q

Which traditional NSAID has the lowest risk of GI toxicity?

A

Ibuprofen (COX1=COX2) (2nd is Diclofenac)

celecoxib has the lowest of all the NSAIDs though

43
Q

Which has the 2nd highest risk of GI toxicity? Why?

A

Piroxicam b/c it has the longest half-life

44
Q

Two general ways to reduce GI toxicity with NSAIDs?

A
  1. Take with food/milk

2. Take with ancillary drug

45
Q

Why may taking it with food and milk NOT be helpful (3)

A
  1. Depends on the type of food ingested
  2. Food may have differential effects on damage caused by NSAIDs in GI tract
  3. Studies don’t mimic what actually happens (far-removed from real-life events)
46
Q

Why do some people think it may be beneficial to take NSAIDs on an empty stomach?

A

Rapid absorption and onset of action/relief→pt’s dont take as much (avoid the extra dose)

47
Q

What ancillary drugs are recommended to take with NSAIDs to reduce GI toxicity (esp gastric ulcers)? Which is Best? Why?

A

Give NSAIDs in conjunction w/ gastroprotective Rx:
1. PPIs (BEST***)
2. H2 Receptor Antagonists
3. Misoprostol
PPI is more effective than H2R antag’s due to more complete gastric acid suppression.

48
Q

What are the two downsides to ancillary PPI Rx to reduce GI toxicity?

A
  1. Changing pH changes efficacy of concurrent drugs that depend on stomach acidity for absorption.
  2. Adverse CV effects are common in pt’s taking PPIs and Clopidogrel→increased comorbidity
49
Q

NSAIDs produce a __________ increased risk for adverse CV events?

A

treatment duration-dependent

50
Q

What are the CV ADEs associated with NSAIDs? (3)

A

MI, CHF, HTN

51
Q

Blocking which COX enzyme has traditionally been thought to mediate increased CV risk? Why?

A

COX2; inhibition of it leads to dysregulated COX2-mediated production of pro-aggregatory TXA2 in platelets and anti-aggregatory PGI2 in endothelial cells.

52
Q

What is the relative risk of adverse CV events with COX2-selective vs traditional NSAIDs?

A

COX2-selective inhibitors increase the risk, and traditional NSAIDs that possess COX2-inhibitory activity also increase the risk (diclofenac/ibuprofen)

53
Q

(T/F) The CV ADE associated with the NSAIDs have found that COX2 inhibitors have higher CV ADE; therefore this is based off of Cox-selectivity.

A

False, this is a HETEROGENEOUS PROCESS, and COX-selectivity is not the only variable.

54
Q

What is an NSAID that demonstrates the heterogeneity of the process leading to increased risk of CV events? Why?

A

Naproxen: it prefers COX1 but is associated with increased CV risks similar to the level of COX-2 selectives and greater than that of Ibuprofen or Diclofenac.

55
Q

What two general groups of NSAIDs have antiplatelet action (can inhibit platelets)? How?

A

a. Aspirin
b. Traditional NSAIDs
They both inhibit the thromboxane production via inhibition of COX1.

56
Q

How do the antiplatelet actions of Aspirin and traditional NSAIDs differ?

A

a. Traditional NSAIDs reversibly inhibit COX1, preventing thromboxane production.
b. Aspirin (ASA) IRREVERSIBLY ACETYLATES the COX1 on platelets, making the platelets functionally INERT. As the platelet is anuclear, it has no capacity for regeneration of new COX1, so platelet function does not return until new platelets are generated by the bone marrow. (this is why pt’s w/ CV risk take low dose aspirin)

57
Q

What is the potential ADE associated with pt’s taking both Aspirin and traditional NSAIDs? Do all NSAIDs have this effect?

A

NSAIDs can increase the relative CV risk in pt’s thru inhibition of the action of their concurrent aspirin regimen, thereby shifting the balance towards a pro-aggregatory condition with subsequent CV events.

58
Q

Specifically, which NSAIDs have been reported to inhibit Aspirin activity and increase CV risk? Which are compatible with concurrent aspirin use?

A

Bad interaction/increased CV risk: Ibuprofen

Compatible/no bad interaction: Celecoxib, Sulindac, Naproxen

59
Q

Why is chronic NSAID use associated with increasing/worsening arterial BP?

A

NSAIDs that inhibit COX2 on endothelial cells reduce PG synthesis, and this autocoid is very important in regulating renal blood flow.

60
Q

Concurrent use of _________ (2 NSAIDs) significantly increased the risk of treatment intensification in pt’s taking ________***(2)?

A

Concurrent PIROXICAM or DICLOFENAC significantly increases risk for Rx intensification ONLY for pt’s taking ACEi’s or ARBs!!! (NOT alpha/beta blockers, CCBs, diuretics, or other antihypertensives)

61
Q

About 10% of drug-induced _______ damage is attributable to NSAIDs, reflecting what?

A

About 10% of drug-induced LIVER DAMAGE/HEPATOTOXICITY is ascribed to NSAIDs, reflecting their widespread use.

62
Q

What are some NSAIDs are associated with liver damage (Low yield)? (7) Which is most common?

A 
Pretty much all
SAD COIN lesion on liver
1. Sulindac (5-10x more often than other NSAIDs)
2. Aspirin
3. Diclofenac
4. Coxibs (celecoxib)
5. Oxicams (piroxicam)
6. Ibuprofen
7. Naproxen
63
Q

What is the general incidence of hepatotoxicity with most NSAIDs?

A

low

64
Q

***Which NSAID is the only one associated with significant liver damage at normal clinical doses?

A

SULINDAC

65
Q

***Which NSAID has the highest liver safety profile?

A

IBUPROFEN; it has showed no severe liver injury in larger studies

66
Q

What should be monitored in pt’s with increased risk of hepatotoxicity (ie Hx of hepatitis) taking NSAIDs?

A

LFTs; stop the drug if signs of liver damage appear

67
Q

Why do NSAIDs cause Acute Renal Toxicity?

A

They inhibit the production of vasodilatory PGs (PGI2, PGE2), which are important for maintaining RBF and GFR in various disease conditions.

68
Q

What type of kidney damage results from inhibition of PGs by chronic NSAID use? (2)

A

a. Reversible renal ischemia

b. Reduced glomerular hydraulic pressure and reduced GFR→Acute Renal Failure

69
Q

When is the risk of acute renal failure highest? Lowest? Which NSAIDs have highest risk?

A

Acute failure is most likely UPON INITIATING THERAPY with NSAIDs, and risk declines after the 1st 30 days.

The relative risk is comparable among all NSAIDs, including celecoxib.

70
Q

Occasionally, NSAID pt’s may present with what renal symptoms?

A

Hematuria, pyuria, white cell casts, proteinuria, ARI associated with minimal change disease (MCD)

71
Q

In addition to inhibiting PGs, how else can NSAIDs cause renal toxicity?

A

They decrease renal clearance of LITHIUM and METHOTREXATE, potentially leading to toxicity

72
Q

** ALL adults on chronic NSAID Rx should have what four things monitored? Why?

A
  1. LFTs
  2. SrCr/BUN
  3. Stool Guaiac
  4. CBC
    a. 1,2, and 3 reflect the PRIMARY TOXICITIES OF NSAIDs: GI, HEPATIC, RENAL
    b. CBC b/c NSAIDs can occasionally cause blood dyscrasias
73
Q

What are some of the blood dyscrasias occasionally cause by NSAIDs?

A

Hemolytic anemia, aplastic anemia, pancytopenia, agranulocytosis, thrombocytopenia

74
Q

The BEER criteria for PIM states what about geriatric use of NSAIDs?

A

Avoid chronic use of all NSAIDs (unless alternatives are ineffective or pt can take gastro-protective agent) b/c of risk of GI bleed/PUD in this high risk group.

75
Q

The BEER criterial for PIM states geriatric pt’s should ABSOLUTELY NOT TAKE which 2 NSAIDs why?

A
  1. Ketorolac

2. Indomethacin (has the most adverse effects)

76
Q

MoA of Aspirin?

A

It irreversibly acetylates both isoforms of COX (1 on platelets, 2 on endothelial cells) and inhibits platelet aggregation.

77
Q

Low dose “baby” aspirin is often used for prevention of CV events. Why? How long does it take for the effect to wear off?

A

B/c of its PERSISTENT antiplatelet activity; regeneration of functional platelets take 7-10 days

78
Q

T/F: Aspirin is the NSAID of choice for anti-inflammatory uses.

A

False, while it is equally effective w/ other NSAIDs when used for this purpose, it seems to produce more GI toxicity than other NSAIDs when used in anti-inflammatory doses.

79
Q

What are the 4 potential ADEs of aspirin?

A
  1. GI toxicity
  2. Hepatotoxicity
  3. Renal Toxicity
  4. Salicylate Poisoning
80
Q

Incidence of GI tox in pt’s taking .3.6g/day of aspirin? What are the GI toxicities?

A

a. 1/3; this incidence increases substantially if pt has pre-existing GI disease
b. Nausea/dyspepsia/abd pain/heartburn (pyrosis)/gastritis and also Gastric Ulceration

81
Q

What can be done to reduce the GI symptoms caused by aspirin?

A

a. Taking it with food reduces the symptoms (nausea/dyspepsia/etc) but does NOT REDUCE the incidence of gastric ulcers
b. H2 antagonists and PPIs can reduce GI ADEs

82
Q

What are the potential complications of aspirin-induced GI ulcers? How is the incidence reduced?

A

a. Pt’s w/ gastric ulcers may be asymptomatic, but occult blood is evident in stool→can cause IRON DEFICIENCY ANEMIA
b. ENTERIC-COATED preparations reduce incidence of GI ulcers (taking with food doesnt help)

83
Q

What types of liver damage can aspirin cause? (3) What is the incidence of aspirin-induced hepatotoxicity associated with?

A

a. Reversible mild focal necrosis, portal HTN, elevated liver enzymes
b. Incidence is dose and duration related

84
Q

Aspirin-induced renal toxicity: In who? What are they? (2) Drug interaction?

A

a. Salicylates rarely cause renal toxicity in pt’s with normal renal function.
b. Reduced Cr clearance, papillary necrosis, interstitial nephritis, tubular necrosis w/ renal failure
c. Also, HYPERURICEMIA with high doses, so salicylates can antagonize the beneficial effects of uricosuric drugs (probenecid???)

85
Q

What is salicylate poisoning? (just read)

A

Salicylates alter acid/base balance→respiratory alkalosis; under normal circumstances, there is compensation and no significant ADE.
At supratherapeutic doses: severe a/b imbalance→ hyperventilation (via stimulated medullary respiratory center)→ respiratory alkalosis and metabolic acidosis→ultimately, central respiratory depression and CV collapse

86
Q

***What parameters need to be monitored in pt’s taking aspirin? (4)

A
  1. LFTs
  2. SrCr/BUN
  3. Serum salicylate concentrations
  4. Stool Guaiac
87
Q

How does acetaminophen differ from other NSAIDs? Why?

A

It possesses NO ANTI-INFLAMMATORY ACTION because it has no clinical action in peripheral tissues

88
Q

MoA of Acetaminophen?

A

Inhibition of COX1 and 2 within the CNS (CENTRALLY, not peripherally), producing analgesic and anti-pyretic actions.

89
Q

Most common ADE caused by Acetaminophen? Why?

A

HEPATIC failure due to metabolic production of a highly reactive adduct with ensuing immunologic response.

90
Q

Characterize GI and Renal toxicity associated with Acetaminophen.

A

a. Oral therapy usually does not give rise to adverse GI effects; N/V/D/Constipation are encountered with IV dosing
b. Renal toxicity is also rare

MSK/Rheum (7 decks)

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