Pharmacology 2: NSAIDs

Question 1

What is the significance of adverse effects?

Answer 1

-Severe and potentially fatal

Question 2

What is the arachidonic Acid pathway?

Answer 2

-Membrane phospholipids broken down into arachidonic acids by phospholipase A2
- Cycclooxygenase 1 and 2 break phospholipase in prostaglandin H2
- Lipoxygenase breaks arachindonic acid in leukotrienes
-Prostaglandins further break down into prostanoids

Question 3

How does an NSAID interact with the Arachidonic pathway?

Answer 3

Block Cyclooxgenase-1 and 2
- Only block the prostaglandin H2 arm of the pathway
- Does not block the leukotriene production

Question 4

Does blocking the prostaglandins increase the leukotrienes?

Answer 4

Yes
Leukotrienes common in lung - can activate asthma

Question 5

What are the prostanoids?

Answer 5

PGI2
TXA2
PGE2
PGF2a

Question 6

PGI2 function?

Answer 6

Anti-platelet
Vasodilatory

Question 7

TXA2 Function?

Answer 7

Pro-platelet
Vaconstriction

Question 8

PGE2 function

Answer 8

-Major prostaglandin for blocking inflammation
Pro-inflammatory
Pain
Vasodilation
GI motility

Question 9

PGF2A

Answer 9

Vasoconstriction
SmM constriction (uterus, GIT)
luteolysis
(No common concern for inflammation response)

Question 10

COX-1 effects?

Answer 10

• Constitutively expressed
• Cytoprotective to the GI Tract (decrease acid and increase mucus)

GOOD GUY

Question 11

COX-2 effects?

Answer 11

• Induced by inflammation
• Pro-inflammatory effect (Heat, pain, swelling, fever)

BAD GUY

Question 12

Theory behind COX-2 specific inhibitors

Answer 12

• COX-1 sparing
  Block the bad
  leave the good
  no adverse affects

Question 13

Why doesn’t the COX-1 sparing theory work?

Answer 13

• A lot of overlap
• COX-2 is needed regularly in the kidney
• COX-2 is NEEDED for muscosal healing
• Specificity of most drugs is overcome at high doses (overdose)

Question 14

COX selectivity characteristics? Example?

Answer 14

• Varies by drug and varies by species
• Carprofen is not selective in people
• But is selected in dogs

Question 15

When do we use NSAIDs?

Answer 15

• Fevers by infections that is so high it will cause destruction to tissue (NSAIDs are not immunosuppressive)

-Pain associated with inflammation

• Pain independent of inflammation
• Endotoxinemia/Sepsis
• Anticoagulant (platelet) activity

Question 16

Clinical uses of NSAIDs

Answer 16

Antipyresis
Analgesia

Question 17

Antipyresis NSAID action

Answer 17

Decrease of fever

Question 18

Analgesia NSAID action

Answer 18

Pain associated with inflammation (Effective)
Pain independent of inflammation (ineffective)

Question 19

Inappropriate clinical use of NSAIDs

Answer 19

• Immune-mediated disease (IMHA)
• Autoimmune disease (lupus)
• Allergy disease (atopy)
• Inflammatory respiratory disease (asthma, Chronic bronchitis)

** Use glucocorticoids instead for all!!

Question 20

PK of NSAIDs

Answer 20

• high bioavailability
• Small volume of distribution (0.15-0.3 L/Kg)
  -High protein binding (70-99%)

Question 21

Hepatic metabolism effects on PK of an NSAID?

Answer 21

Hepatic metabolism predominates:
- lIver can become overwhelmed in overdose and create REALLY long half life
–Capacity-limited (non-linear PK: toxic)
–Species differences: Dosing in one species is UNLIKELY correct for another species
–Neonates

Question 22

Choosing an NSAID Steps

Answer 22

• Many different NSAIDS
• Check species (BIG DIFFERENCES) and always dose if possible a drug that is labeled for that species
• Choices made related to pattern of use, experience and tradition

Question 23

In what cases is telling a client “Your pet will die a horrible death if you give it your NSAID” true?

Answer 23

Tylenol: cats
Ibuprofen: Dogs, cats

Question 24

Overall idea of adverse effects of NSAIDs

Answer 24

Numerous and DANGEROUS

Question 25

What are the adverse effects?

Answer 25

- GI ulcers - Nephrotoxicity - Hemorrhage - Hepatotoxicity - IMHA - Blood dycrasias - Injection site rxn - Tissue necrosis - Clostridial myositis

Question 26

Characteristics of adverse effect: GI ulcers?

Answer 26

- Not just from oral admin, can happen with injectable too - PGE2 effects but PGE2 is needed for healing. Toxic loop.

Question 27

Characteristics of adverse effect: where are GI ulcers dog and cats?

Answer 27

Stomach and SI

Question 28

Characteristics of adverse effect: where are gi ulcers in horses?

Answer 28

Stomach and colon

Question 29

Characteristics of adverse effect: where are go ulcers in ruminants?

Answer 29

Abomasum

Question 30

Why do NSAIDS lead to GI ulcers?

Answer 30

Weak acids get trapped in the basic environment of the gastric epithelium resulting in cells death

Question 31

Characteristics of adverse effect: Nephrotoxicity

Answer 31

- Inhibition of PGE2 and PGI2 -- Vasoconstriction, decreased renal BF, possible toxicity -- Effects exacerbated in dehydrated patients (already compromised renal flow) -- COX-2 inhibitor not safer- PGE2 constitutively expressed in kidney and needs for healing.

Question 32

Characteristics of adverse effect: where are neurotoxicity lesions?

Answer 32

Medullary crest or papillary necrosis ** Less BF ** Is not fatal but animal can no longer concentrate urine

Question 33

Characteristics of adverse effect: Hemorrhage

Answer 33

- Effects platelets - Irreversibly binds to COX-1 -No longer activates thromboxane A2 activity. - Platelets do not clot appropriately - Lasts for life of platelet (7-10days)

Question 34

Characteristics of adverse effect: of selective COX-2 inhibitors

Answer 34

- Reduces PGI2 - little or no inhibition of prothrombotic thromboxane (COX-1)

Question 35

Characteristics of adverse effect: hepatotoxicity

Answer 35

- Form all NSAIDs in fairly low incidence - Idiosyncratic effect = unpredictable and no reproducible - Anorexia, Vomiting, icterus - hepatomegaly - increased bilirubin, ALT, ALP, AST

Question 36

Characteristics of adverse effect: IHMA

Answer 36

Up to 12% of human IHMA drug-induced causes are from NSAIDS - RARE in animals

Question 37

Characteristics of adverse effect: blood dyscrasias

Answer 37

- Pancytopenia marrow failure - Non-regenerative anemia and thrombocytopenia

Question 38

Characteristics of adverse effect: injection site reactions

Answer 38

- Heat, pain, swelling - abscess formation - tissue necrosis - clostridial myositis

Question 39

What drug can lead to clostridial myostitis?

Answer 39

Im Flunixin Meglumine in horse

Question 40

How to minimize adverse effects?

Answer 40

- injection site reactions - Dose appropriately (lowest effective dose at longest DI) - Right drug and formulation - GI Protection - Avoid co-administering other nephrotoxic drugs - Avoid co-administering other NSAID or GCS - Use extreme caution in those with preexisting conditions - Client education - Monitoring

Question 41

How to minimize adverse effects injection site reactions

Answer 41

Some can be given orally instead of IM - Mix with corn syrup to make less irritating and better tasting - Similar bioavailability

Question 42

How to minimize adverse effects with dosing appropriately?

Answer 42

- lowest effective dose at longest DI

Question 43

How to minimize adverse effects with GI protection

Answer 43

- PGE analog - Proton pump inhibitors

Question 44

How to minimize adverse effects in those with preexisting disease?

Answer 44

Watch for: - Renal disease - GI disease - Liver disease - Anorexia - Dehydration