Msk Week 1 Objective10

Front 1

What does the flow diagram of the cyclooxygenase pathway look like?

Back 1

Front 2

What are the 3 main levels of pharmacological action of NSAIDs?

Back 2

1) Analgesic effects (pain-relief)
2) Antipyretic (fever relief)
3) Anti-inflammatory (at high doses)

Front 3

Why is acetaminophen (AKA Tylenol) not considered a NSAID?

Back 3

It has antipyretic and analgesic effects but it does not have an anti-inflammatory.

Front 4

Which pathway in the Arachidonic Acid cascade is targeted by NSAIDs?

Back 4

The cyclooxygenase (COX) pathway consisting of the COX-1, COX-2 and the newly discovered COX-3 enzymes
(Remember the other pathway? Lipoxygenase (LO) Pathway)

Front 5

Where does arachidonic acid come from?

Back 5

The breakdown of phospholipids on the membrane of cells.

Front 6

What are the three main products of the cyclooxygenase pathway?

Back 6

1) Prostacyclins
2) Prostaglandins
3) Thromboxane A2

Front 7

What enzyme(s) are necessary for prostacyclin a prostaglandin production?

Back 7

COX-1 and COX 2

Front 8

What enzyme(s) are necessary for TXA2 production?

Back 8

COX-1 only.

Front 9

What effect does prostaglandin production have on the body?

Back 9

Hyperalgesia
Fever
Pain
Inflammation
Vasodilation
Mucous production

Front 10

What effect does prostacyclin production have on the body?

Back 10

Inhibits platelet aggregation (thinning the blood)
Vasodilation

Front 11

What effects does thromboxane A2 have on the body?

Back 11

Stimulate platelet aggregation (thrombosis)
Vasoconstriction

Front 12

What is the location, expression, role and specific function(s) of the COX-1 enzyme?

Back 12

Constitutively expressed
Expressed in most tissues (including platelets)
Plays a role in housekeeping (protection and maintenance)
GI protection (prostalandins via mucous secretion)
Maintains renal blood flow via vasodilation (prostaglandins acting on the AA)

Front 13

What is the location, expression, role and specific function(s) of the COX-2 enzyme?

Back 13

Inducible via inflammatory mediators
Expressed in the KIDNEY, brain, bone and reproductive tissue (not platelets)
Pro-inflammatory and mitogenic role therefore function in inflammation and carcinogenesis

Front 14

What is the MOA of NSAIDs?

Back 14

Inhibit both the COX-1 and COX 2 enzymes of the cyclooxygenase pathway, thereby inhibiting prostacyclin, prostaglandin and TXA2 production.

Front 15

What is the overall affect of NSAIDs?

Back 15

Decreased pain and decreased platelet aggregation

Front 16

What does a COX-2 inhibitor block?

Back 16

Inhibits only prostaglandin and prostacyclin production via the cyclooxygenase pathway. TXA2 is still produced because it uses only COX-1 enzyme (therefore still have vasoconstriction and platelet aggregation occurring).

Front 17

What are some example drugs that are NSAIDs?

Back 17

Ibuprofen (Advil)
ASA
Naproxen
Diclofenac
Indomethacin

Front 18

What is the protype drug for COX-2 inhibitors?

Back 18

Celecoxib

Front 19

How do NSAIDs have an analgesic effect?

Back 19

By blocking COX-1&2, they block the production prostaglandins that sensitize nociceptors to inflammatory mediators (most sensitive against pain associated with inflammation or tissue damage).
Decreased prostaglandins = decreased vasodilation which may contribute to their effectiveness against headaches.

Front 20

How do NSAIDS cause an anti-inflammatory effect?

Back 20

Decreased prostaglandin production, decreases vasodilation thereby decrease edema

Front 21

Why is ASA not a good anti-inflammatory drug?

Back 21

Because of its side effects (GI upset, tinnitus (ringing of the ears))

Front 22

When is the use of ASA contraindicated?

Back 22

1) In children with a fever– causes Reye’s syndrome (potentially fatal liver and brain disease that can arise when ASA is given when children are infected with a viral infection; causes fatty liver and encephalopathy). Give Tyelonol instead.
2) Asthmatics – may result in brochospasms/bronchoconstriction
3) GI bleed – ASA binds irreversibly to platelets

Front 23

What are the side effects of NSAIDs?

Back 23

1) Gastrointestinal – nausea, heartburn, peptic ulcers, GI bleeds
2) Renal – prostacyclin causes vasodilation of the AA to the kidneys therefore NSAIDs decreased the ability to regulate renal flow
3) Increased chance of bleeding

Front 24

Biochemically, why do NSAIDs cause GI upset?

Back 24

- Local damage of the organic acid of the drug damaging the epithelial cells (minimal)
- Systemic reduction of mucosal secretions (due to prostaglandin inhibition) which decreases the mucous layer and HCO3- secretion on the surface of the GI epithelium. This reduces the protective layer for the epithelium against acid.

Front 25

What are five factors that increase risk of getting ulcers when taking NSAIDs?

Back 25

1) Previous ulcers/bleed
2) Eldery
3) Concomitant steroids
4) Cardiac disease
5) Choice of NSAID

Front 26

How would you manage someone that had GI effects from NSAIDs?

Back 26

1) Gastroprotectants (antacids, H2-receptor antagonists, H+ pump inhibitors, prostaglandin analogs)
2) Choose agents with less GI side effects (Ibuprofen)
3) Administration of food
4) Avoid concomitant steroids
5) Consider COX-2 inhibitors

Front 27

What are some gastroprotectants you can use to help subside GI effects of NSAIDs?

Back 27

Antacids
H2-receptor antagonists (Ranitidine)
Misoprostol (prostaglandin analog)
Omeprazole (H+ pump inhibitor)
* Note – all of them will be effective for dyspepsia but only Misoprostol and Omeprazole will be gastroproctectant against ulcers.

Front 28

How do PPI decreased dyspepsia side effects of NSAIDs?

Back 28

They inhibit the H+/K pump on the apical side of parietal cells thereby decreasing H+ (acid) secretion into the gastric lumen

Front 29

What type of drug is Misoprostol?

Back 29

Prostaglandin analog – will replace the prostaglandins being inhibited by the NSAIDs

Front 30

What compounds regulate H+ release into the stomach?

Back 30

1) ACh
2) Gastrin
3) Histamine

Front 31

In someone with a previous bleeding ulcer, is it better to treat with COX-2 specific inhibitors or Diclofenac + omeprazole?

Back 31

No significant different in GI bleeds comparably.

Front 32

Why should you never give someone with renal dysfunction, a NSAID or a COX-2 inhibitor?

Back 32

Prostacyclins mediate vasodilation in renal medulla and glomerulus therefore, if you inhibit prostacylcins, you decrease the ability to regulate blood flow to the kidney. In someone with a failing kidney or on sodium depletion, this decrease in blood flow (and therefore GFR) can send them into renal failure.

Front 33

Which NSAID(s) has the highest rate of toxicity?

Back 33

Indomethacin

Front 34

Which NSAID(s) have longer half lives and therefore less frequent dosing schedules?

Back 34

Naproxen
Piroxicam

Front 35

What drugs interact with NSAIDs?

Back 35

1) Lithium – due to decreased renal clearance
2) Warfarin – excessive thinning of already thin blood; bleeding risk
3) ACEi – reduces the anti-HTN effects

Front 36

Why do COX-2 inhibitors have an increased cardiovascular risks then NSAIDs?

Back 36

Although NSAIDs affect all pathways of the cyclooxygenase pathway, the net platelet effect is decreased platelet aggregation.
With COX-2 inhibitors, TXA2 is still produces (via COX-1) whereas prostacylcins are reduced. This shifts the net effect towards the TXA2 effects which includes platelet aggregation. COX-2i therefore increases your risk of a thrombotic effect increasing your risk of MI.

Front 37

Why are NSAIDs not used as the 1st line of defense in OA therapy?

Back 37

Because OA is considered a non-inflammatory process.
NSAIDs have more side effects then tylenol.

Front 38

What is the order of treatment for someone with OA?

Back 38

1) Education - obesity, exercise, supports
2) Non-medical - PT and/or OT
3) Pharmacological
a) Tyelonol (Acetominophen)
b) NSAIDs
c) Corticosteroid injection
d) Viscosupplementation - glucosamine sulfate, chondroitin sulfate, Synvisc (HA injection)
e) Surgery - arthroscopy or partial/total joint replacement/arthroplasty

Front 39

What are the two subtypes of corticosteroids and what physiological role do they play?

Back 39

a) Glucocorticoids (cortisol) - control CHO, fat, protein metabolism and anti-inflammatory,
b) Mineralocorticoids (aldosterone) - control water and electrolyte level via the kidneys.

Front 40

Where in the cell do steroids exert their action?

Back 40

Steroids bind a cytosolic receptor and translocate into the nucleus where they alter gene expression.

Front 41

Why are steroids used for treating OA?

Back 41

Steroids have a potent anti-inflammatory effect that if injected can be localized.

Front 42

What is the anti-inflammatory MOA of steroids (glucocorticoids)?

Back 42

1) Glucorticoids prevent Phospholipase A2 of cell membranes from coming into contact with its arachodonic acid substrate. This diminished eicosanoid production, decreasing leukotriene production
2) Cyclooxygenase expression is suppressed decreasing prostaglandin production
Leukotriene and PG are the two main products in inflammation
3) Steroids also inhibits various inflammatory events such as, epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators.