Ct-Ms - Pharm - 3-1 - Nsaids

Front 1

Acute inflammation

Back 1

The topic of this lecture

Precedes immune response and is mediated by release of autocoids (histamine, serotonin, bradykinin, PGs, LTs)

Front 2

Quickly review chart on slide 2

Back 2

adf

Front 3

Formation of PGs and Thromboxanes

Back 3

Membrane phospholipids to arachidonic acid via phospholipase A2. Then AAcid can go to LTs via lipoxygenase or PGs and thromboxanes via Cox-1 and Cox-2

Front 4

Cox-1 effects

Back 4

PGE2, I2 and thromboxane A2

GI protection, platelet function, regulation of blood flow, kidney function.

Front 5

Cox-2 effects

Back 5

PGE2, I2 and thromboxane A2

Inflammation, pain and fever.

Potently expressed and comes up really high very quickly in response to things.

Front 6

PGG2

Back 6

This is a precursor prostaglandin that is then turned into PGH2 which is then turned into J2, I2 or thromboxanes.

Front 7

COX and GI protection

Back 7

Dyspepsia occurs because PGE2 and I2 normally inhibits proton pumps in the gut.

Mainly COX-1 inhibition leads to GI toxicity.

Avoid these effects with PPIs.

Front 8

COX and platelet effects

Back 8

Only COX-1 is present in platelets. No COX-2.

COX-1 makes thromboxane A2 which initiates clotting.

Note that aspiriin irrev blocks platelets because it forms a covalent bond with COX1.

So using a COX-2 selective NSAID won't effect platelets.

Front 9

COX and renal effects

Back 9

COX1 - renal hemodynamics and GFR effects

COX2 - salt and water excretion (inflamm response)

Less E2 leads to sodium retention, HTN, water retention (high weight) and CHF.

Less I2 leads to hyperkalemia and acute renal failure.

Front 10

Inflammation process

Back 10

Leukocytes makes PGE2 which causes pain and vasodilation (redness, warmth, swelling)

Front 11

Pain process

Back 11

E2 does this.

E2 is constit synth by COX-1 and during acute inflamm COX-2 makes it as well.

Front 12

Fever process

Back 12

PG E2 and I2 - that's all we really know.

Front 13

COX continuum

Back 13

On the physiology side is COX-1 (ubiquitously expressed)

COX-2 is more inflammation and acute.

Front 14

Common themes for NSAIDs

Back 14

Time-dependent and reversible (other than aspirin) of the active site of COX.

Comp inhibit arachidonic acid from binding COX.

Most do not inhibit LT synthesis and can cause a type of anaphylaxis where more products are shunted to make leukotrienes. (this is different from actual NSAID allergy).

Front 15

Main difference between the NSAID agents

Back 15

The COX-1:2 selectivity ratio.

Front 16

Ketorolac

Back 16

NSAID for IV and IM

Front 17

Indomethacin

Back 17

For injection close to ductus arteriosus in neonates. (will close it).

Front 18

4 major uses of NSAIDs

Back 18

antipyretic (less PGE2 and IL-1)
Anti-inflammatory (COX inhibition and salicylates scavenge ROS)
Antithrombotic (inhib COX in platelets and endothelium)
Analgesic (less PGE2)

Front 19

Pharmacokin

Back 19

Well abs
Metab vy CYP3A or 2C

amt of biliary excretion and reabs correlates with degree of lower GI irritation.

Renal excretion.

Front 20

Toxicity

Back 20

safe for the most part.

GI toxicity, inc bleeding, CNS toxicity...

CONTRAINDICATED IN THIRD TRIMESTER OF PREG (inhibiting PGE2 and I2 will close DA) - but this is really just a guideline.

Front 21

Diff with acetominophen in indications?

Back 21

yes

Front 22

Drug interactions

Back 22

Reduces effectiveness of diuretics and antiHTN drugs.

Cimetidine makes them be metabolized quicker. (so use famotidine H2 blockers instead)

Steroids - has tons of interactions in general.

Just know that NSAIDs induce CYP3A and 2C

Front 23

COX-2 selectives

Back 23

May be good for cancer chemo (stops the stromal inflammation which is carcinogenic)

They don't block platelets and they do block prostacyclin (so it is thrombogenic)
Prostacyclin relaxes BVs and prevents sites of platelet clumping from forming.

Same amt of renal complications compared to non-selectives.

Front 24

Acetominophen and COX

Back 24

doesn't inhiibit it

Not very good for stopping inflammation.

Depletes glutathione which is hepatotoxic (so don't have this with alcohol)

Front 25

Ethanol and smoking on gut

Back 25

irritates it and enhances NSAID GI toxicity.

Front 26

When to use indomethacin (indol and indende acetic acid)

Back 26

Accel closure of patent DA

Tx of rheumatoid and osteoarthritis.

Oral, rectal or IV.

Front 27

When to use ibuprofen (arylproprionic acid)

Back 27

RA, OA and dysmenorrhea.

Half-life prolonged in pts with cirrhosis.

Front 28

Diclofenac (heteroaryl acetic acid)

Back 28

rapid release (pain and dysmen) or delayed release (RA, OA or ankylosing spond)

Ophthalmic activity. but does not affect intraocular pressure.

***dikes go both ways

Front 29

Salicylic acid deriv (aspirin)

Back 29

irrev cox inhib.

reduces risk of CV events adn colorectal cancer.

Front 30

para-aminophenol deriv (acetaminophen)

Back 30

fewer GI and renal side effects than NSAIDs.

used during preg and breast feeding if benefit to mother outweight risks to fetus/infant.

Front 31

anthranilic acids (meclofenamate)

Back 31

contraind in pts with gi or renal issues.

Front 32

enolic acids (piroxicam)

Back 32

long half life.

Front 33

Alkanones (nabumetone)

Back 33

prodrug

cox-2 selective at low doses.

long half-life

**picture mbNABb a PROfessional throwing down the cox-2 pathway

Front 34

cox-2 selective (celecoxib)

Back 34

less gastropathy and risk of GI bleeding.

adjuvant in pts with familial adenomatous polyposis.

Front 35

combo preparations

Back 35

combine opioid with aspirin or acetaminophen.

caffeine can enhance the analgesic actions of NSAIDs or aceteminophen.