Anti-Inflammatory Agents

Front 1

Abbreviations:
AA, ASA, CNS, COX, coxibs, NSAID, PG, PGI2, PNS, PUFA, TxA2

Back 1

AA-arachidonic acid, ASA-acetylsalicylic acid (aspirin), CNS-central nervous system, COX-cyclooxygenase enzyme, NSAID-nonsteroidal antiinflammatory drug, PG-prostaglandin, PGI2-prostacyclin, PNS-peripheral nervous system, PUFA-polyunsaturated fat

Front 2

Pain control drugs: narcotics, nonnarcotics, anticonvulsants, and antidepressants: which ones?

Back 2

ONLY NARCOTICS ARE GOOD FOR ACUTE INJURY
Nonnarc: NSAIDs, salicylates, ibuprofen, naproxen, celecoxib

Narcotic: opioids (morphine, codeine)

Anticonvulsants: gabapentin

Antidepressants:amitryptilene, duloxetine

Front 3

PUFA and AA and their relation? Formation of PG: how is it done? What does PG do?

Back 3

Cell membranes have dietary PUFA in their bilayer: AA (AA eicosatetraenoic acid is major one (20c FA chain))

Stimuli free up the AA which is substrate for COX
COX will transform AA into a PGH2
PG binds to receptors and provides cell signaling
PGH2 is converted into other things needed for signaling via tissue specific isomerases

Front 4

What does an excess of PG in inflammed tissue do?

Back 4

Part of inflammation is due to too many PGs

Without treatment, excess PG will cause eventual loss of function

Front 5

Cardinal signs of inflammation seen by PG

Back 5

vasodilation, permeability, fever (temp), pain sensitization

Front 6

Cyclooxygenase: how many are there and which ones?

Back 6

COX 1 and COX2

Front 7

COX1 and 2 Similarities: what are they?

Back 7

Both use and make the same substrates (AA and PG respectively)
Both play an important role in inflammation
Both have a physiological role in renal function

Front 8

COX1: expression and roles?

Back 8

COX 1 is constitutive expression (expressed in all tissues at all times)
Plays a role in responding to physiological stimuli
Also plays a role in responding to any pathological stimuli that release AA
Contributes to forming PG

Front 9

Mechanism of COX 1 Action: what is it?

Back 9

AA + COX1 + O2 = PGH2

PGH2 travels to tissues and via tissue specific isomerases becomes tissue specific PGs

In uturus, helps during birthing. In gut, helps with mucosal integrity. In blood, helps with platelet aggregation, in blood platelets it stimulates activation of new platelets

Front 10

COX 2 and it's differences

Back 10

Has a pathological function
COX2 must be induced by cytokines (induced in SOME tissues at SOME times)-inflammation induces it and so does cancer
COX2 has a distinctive physiological role in kidney (complements role of COX1 in kidney)

Front 11

COX2 and COX1: roles in kidney

Back 11

They are expressed together in the kidney.

Their combined actions will make PGH2 and via tissue specific isomerases will make PGE2, PGI2 in the renal artery to help with sodium and water excretion

Front 12

COX1 and 2 in inflammation

Back 12

Inflammation stimulates AA release, COX 1 converts AA into PGE2 and PGE2 will cause symptoms.

With inflammation, COX2 expression will be induced and COX2 derived PGE2 will amplify symptoms

Front 13

NSAIDS: which drugs, traditional and nontrad?

Back 13

Traditional NSAIDS: ibuprofex, naproxen, Indomethacin

Coxibs: Celecoxib

Salicylates: Salicylate, Diflunisal, Aspirin

Acetaminophen is only an ANALGESIC

Front 14

Mechanism of Action of NSAID

Back 14

Anti-inflam, analgesic, and antipyretic actions of NSAID are though their inhibition of COX enzyme activity.

In doing this, they reduce PG formation and provide LOCAL reduction of edema, swelling, and pain sensitization

Front 15

Salicylates Traditional NSAIDs: what's their mechanism of action?

Back 15

Competitive, Reversible, Nonselective
These drugs occupy the active site of COX1 and COX2

Not every NSAID can get into all COX: ibuprofen is able to bind the AA site on BOTH COX1 and COX2

Front 16

tNSAIDs: length of action

Back 16

Ibuprofen has a half life of 2 hrs

Naproxen has a half life of 14 hours

Front 17

NSAID AntiInflammatory Indictions

Back 17

Osteoarthritis, bursitis, gout, ankylosing spondylitis, gout, dysmenorrhea, headaches

Front 18

tNSAIDs: what are complications?

Back 18

Ulcers, preipheral edema (due to reduced excretion of NA and H20), bleeding

These risks will increase with prolonged usage and as age increases

Front 19

COXIBS selective inhibition of COX2: how does it do it?

Back 19

Competitive, Reversible, Selective
11 hr half life
COXIBS don't fit well on the active site of COX1...They fit great on COX2:
therefore, it will spare COX1 and select COX2

Front 20

Selectivity and Issues with COXIBS in the kidney

Back 20

Because COXIBS don't affect COX1 they are great at reducing inflammation while keeping all of the other side effects down.

However, due to their physiological function in the kidneys, there may still be an increase in peripheral edema and increase in BP due to reduced Na and H2O excretion

Selectivity might not be as black and white in kidneys

Front 21

Hypersensitivity to Sulfonamindes (CELECOXIB): what's going on here?

Back 21

Celecoxib (sulfonamide) can cause exfoliative dermatitis (SJS steven johnson syndrome) and toxic epidermal necrolysis (TEN) which could be fatal.

Celecoxibs have more tendency than other drugs to have this allergy

Allergies to sulfa drugs can be indicative to an allergy to celecoxib

This can occur without warning or prior sulfa allergies

Front 22

When not to use NSAIDS?

Back 22

Never use with asthma

Never use with gut inflammation: gastritis, colitis, pancreatitis, hepatitis
This is because gut healing relies on prostaglandins

Also never use with infectious inflammation:meningitis, endocarditis, sepsis, bronchitis, sinusitis, rhinorrhea
This is because fever is a mechanism of immunity and the fever is important to maintaining defense.

Front 23

Acetaminophen: how does it work?

Back 23

It inhibits COX in the CNS allowing analgesia
Doesn't work to reduce inflammation

Front 24

COX1 and 2 functions in endothelial and platelet cells

Back 24

Platelets have COX1 active, not COX2 because there is no nucleus (nno induction of COX2 and no regeneration of COX1). Decreased COX in platelets reduces TxA2 which is required for platelet aggregation
In endothelial cells, COX helps make PGI2 which is antithrobotic
Aspirin is an irreversible inhibitor of COX!: in endothelial cells it will stop antithrombotic factors and in the platelets it will stop TxA2 from forming

Front 25

Irreversible COX inhibition via aspirin: what happens

Back 25

Inhibition of COX via Aspirin will cause ceased production of thrombotic factors in endothelial cells and cause platelet cells not to release TxA2, req for platelet aggregation and activation.

This will persist DAYS after ASA metabolism and excretion

Platelets can't regenerate COX

Front 26

Advantage of Low Dose Aspirin?

Back 26

Low dose aspirin encounters every platelet through the presystemic circulation (liver).

This minimizes risk for toxicity, yet provides a great anti-thrombotic effect.

This dosage of aspirin will not produce antiinflammatory effects

Front 27

Aspirin Metabolism: what happens to it?

Back 27

Extensively metabolized in the liver into SALICYLATE via deacetylation.

Salicylate systemically circulates

Highdose ASA is a prodrug for anti-inflammatory doses of salicylate

Front 28

COX Independent Toxicities

Back 28

Salicylates and Aspirin can cause: acid base disturbances, tinnitus, hypersensitivity, and reye's syndrome (rash, vomitting, liver failure): The disease causes fatty liver with minimal inflammation and severe encephalopathy (with swelling of the brain). The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidneys. Jaundice is not usually present.

Front 29

Aspirin Dosage and salicylate effect

Back 29

Aspirin DOSE:
80-160 mg------------antiplatelet (aspirin effect)
325-1000 mg--------analgesic, antipyretic
325mg -6 grams----anti-inflamm/tinnitus
6-20 grams-----------early: Respiratory aklalosis; later-metabolic acidosis fever, dehydration
More than 20g-----above plus, shock, coma

Front 30

Aspirin/Salicylate toxicity: what happens? (in cns particularly which causes a cascade)

Back 30

Salicylates uncouple mitochondrial OX phosphorylation in CNS:
1. respiratory centers thinks reduced ATP production is from hypoxemia and responds by hyperventilation
2. hyperventilation blows off CO2
3. drop in CO2 causes respiratory alkalosis (which will prompt kidney to deplete bicarbonate)
4. Organic Acids accumulate b/c ATP isn't generating via Krebs Cycle
5. Metabolic Acidosis becomes life threatening

Front 31

Aspirin in children: when not to use?

Back 31

Shouldn't use aspiring by anyone under 19 with a fever: like treating symptoms of flu like illnesses, chicken pox, cold because of risk of Reyes syndrome (marked by rash, vomitting, liver failure)

Use acetaminophen or ibuprofen for this.