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Flashcards in NSAIDS Deck (34):
1

NSAIDS are useful in management of what?

Disorders in which pain is related to inflammation

2

What is the overall MOA of NSAIDs?

inhibition of Cyclooxygenase (COX)
--inhibition of production of prostaglandins and thromboxanes

3

First lets talk about COX1 what are some features?

Constitutive Enzyme
--expressed in blood platelets
Dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation

4

Next lets talk about COX2, what are some features?

Immediate early response gene product that is upregulated by
--stress, growth factors, tumor promoters and cytokines
Major source of prostanoids in inflammation and cancer

5

COX2 however is constitutive in what organs?

Kidneys and brain
--endothelial COX-2 is the primary source of vascular prostacyclin

6

The anti-inflammatory action of NSAIDs is mainly related to their inhibition of ?

COX2

7

Why are there selective COX2 inhibitors?

By inhibiting COX1 this leads to gastric damage
--by the inability to form protective prostaglandins

8

What are the nonselective COX inhibitors?

Aspirin
Diclofenac
Ibuprofen
Indomethacin
Ketorolac
Naproxen
Piroxicam

9

What are the COX2 selective inhibitors?

Celecoxib
Meloxicam

10

NSAIDs have three actions, each card will go through these associated actions. First action is anti-inflammatory action, what is the mechanism?

Diminished synthesis of prostaglandins
-so therefore aspects of inflammation is diminished

11

2nd action of NSAIDs is analgesic actions, what is the mechanism?

PGE2 (prostaglandin) sensitizes nerve endings to action of bradykinin, histamine, and other chemical mediators
--therefore by decreasing PGE2 synthesis NSAIDS repress the sensation of pain
--NSAIDs are always superior to opioids in regards to pain due to inflammation

12

3rd action of NSAIDs is antipyretic actions, what is the mechanism?

Inhibit fever by blocking PGE2 synthesis (fever occurs when the set point of the anterior hypothalamic thermoregulatory center is elevated, caused by PGE2)
--no effect on temp when it is due to exercise or ambient temperature

13

What are some of the therapeutic uses of NSAIDs?

1. Antipyretic, analgesic and antiinflammatory
2. Pain due to inflammation
3. Chronic post operative pain or pain from inflammation
4. Used for RA and osteoarthritis pain as well as gouty arthritis, anklyosing spondylitis and dysmenorrhea

14

In regards to gout what drugs are used in regards to NSAIDS?

Indomethacin
--gout
All other drugs except aspirin, salicylates and tolmentin can be used for gout

15

Why is aspirin not used for tx of gout?

Inhibits urate excretion at low doses
--therefore increases the risk of renal calculi at high doses
---also inhibition of uricosuric agents at high doses

16

How are NSAIDs used for colon cancer?

50% decrease in risk of colon cancer

17

Explain the connection between niacin and NSAIDS?

Niacin induces intense flushing mediated by release of PGD2 from the skin
--which can be inhibited by aspirin

18

Finally what is the drug of choice for PDA closures?

Indomethacin
-closure of ductus arteriosus in premature infants

19

Now lets talk about the adverse effects of NSAIDs, first are the GI effects. Gastric damage by NSAIDs can be brought about by at least two distinct mechanisms: what is the first?

Inhibition of COX1 = depression of mucosal cytoprotective prostaglandins, especially PGI2 and PGE2
These eicosanoids inhibit acid secretion by the stomach, enhance mucosal blood flow and promote the secretion of cytoprotective mucus in the intestine.

20

What is the second mechanism for gastric damage by NSAIDs?

Ulceration by local irritation from contact of orally administered drug with the gastric mucosa

21

What drugs reduce the risk of gastric ulcers and are used to protect the stomach to damage by NSAIDs?

Misoprostol, PPIs and H2 blockers

22

What is the order of relative risk of GI adverse effects from NSAIDs?

Lowest Risk: Celecoxib (makes sense COX2 inhibitor)
Low Risk: Ibuprofen, aspirin, diclofenac
Medium Risk: Naproxen and Indomethacin
High Risk: Piroxicam

23

Moving on to CVS risks associated with NSAIDs. Why are these adverse effects thought to happen?

NSAIDs upset the balance between vasoconstricting, platelet-aggregating thromboxane A2 (produced by COX-1) and vasodilating, platelet-inhibiting prostacyclin (produced by both COX-1 and COX-2)
--this may lead to vasoconstriction, platelet aggregation and thrombosis

24

What NSAID is therefore associated with more CVS symptoms?

COX2 selective
--due to the inhibition of prostacyclin and not thromboxane A2
(MI and thrombotic cardiovascular events)

25

NSAIDS have a potent effect on the kidneys, explain the decrease of renal blood flow.

Applies to patients with CHF, CKD, and other situations in which there is reduced renal perfusion
--synthesis of vasodilating PGs (PGE2 and PGI2) is critical for maintaining GFR
However NSAIDs decrease PGs therefore vasoconstriction of the afferent arteriole and therefore reduced GFR
--reduced GFR leads to Na and H20 retention, edema, increased BP, hyperkalemia and acute renal failure

26

Moving on to the next side effect of NSAIDs is aspirin hypersensitivity. What are some features of this?

Manifestations:
--vasomotor rhinitis with profuse watery secretions, angioedema, generalized urticaria, and bronchial asthma to laryngeal edema, bronchoconstricition, flushing, hypotension and shock
MOA:
--due to an increase in biosythesis of leukotrienes, reflecting diversion of arachidonate to lipooxygenase metabolism

27

Lets move on to drug interactions with NSAIDs. Explain the drug interaction with ACEI.

ACEI: act by preventing breakdown of kinins which stimulate PG production
NSAIDs: act by inhibiting vasodilator and natriuretic PGs
--therefore NSAIDs have been associated with a decrease in antihypertensive effects of the ACEI
Additionally ACEIs dilate the efferent arteriole and reduce GFR while NSAIDs constrict the afferent arteriole and reduce GFR
---patients may have sodium and water retention and edema and worsening of HTN

28

Explain the drug interaction of NSAIDs with diuretics

NSAIDs reduce the diuretic effects
--the effects of diuretics depends on renal prostaglandin production

29

What is the triple whammy in regards to NSAIDs, diuretics and ACEI?

Acute Renal Injury
--NSAIDs: constrict the afferent arteriole and reduce GFR
--ACEI: dilate the efferent arteriole and reduce GFR
--Diuretics: reduce plasma volume and GFR
therefore when used in combo acute renal failure can occur

30

Finally what are the drug interactions of NSAIDs with corticosteriods and warfarin?

Corticosteriods: NSAIDs may increase frequency or severity of GI ulceration when combinted
Warfarin: NSAIDs may increase risk of bleeding in patients receiving warfarin

31

What are the contraindications of NSAIDs?

1. Reye's Syndrome: aspirin and other salicylates are contraindicated in kids with fever due to viral illness. Use either acetaminophen or ibuprofen
2. Pregnancy: esp the closer the patient gets to term

32

Lastly lets talk about COX2 selective inhibitors (Coxibs). These drugs have analgesic, antipyretic and antiinflammatory effects similar to nonselective NSAIDs, however what is the difference?

Fewer GI side effects
--spares COX1 which helps maintain gastric mucosa

33

COX2 inhibitors due seem to be associated with increased risk of cardiovascular thrombotic events, why?

COX-1 mediates synthesis of thromboxane A2 -- this promotes platelet aggregation and vasoconstriction in endothelial cells
COX-1 and COX-2 mediates synthesis of prostacyclin (PGI2) -- this inhibits platelet aggregation and causes vasodilation
--therefore COX2 inhibitors selectively inhibit synthesis of PGI2 without inhibiting TXA2 resulting in prothrombotic state.

34

Meloxicam is the other COX2 inhibitor, however, how is this drug different than Celecoxib?

not as selective for COX2

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