Pharm 26 Nsaids

Front 1

NSAIDS: Mechanisms of therapeutic action
1) Antiinflammatory

Back 1

1) Inhibits synthesis of PGs which leads to increased blood flow, permeability, and WBC recruitment (COX 2 most important here). NSAIDS reduce acute inflammation via COX but reduction of chronic inflammation not completely explained

Front 2

NSAIDS: Mechanisms of therapeutic action
2) Antipyretic

Back 2

2) Reduce production of PGE 2 which acts in preoptic hypothalamus to increase body temperature. Individuals without fever are not affected by NSAIDS

Front 3

NSAIDS: Mechanisms of therapeutic action
3) Analgesia

Back 3

3) Inhibit production of PG's which both sensitize pain receptors withing PNS as well as modulating perception of pain within the CNS. Mostly effective on low to moderate pain of integument structures. Not good for visceral pain.

Front 4

Aspirin: Low dose for thrombosis prevention
1) Mechanism of action

Back 4

1) Irreversible COX inhibitor. COX 1 - inhibition --> TXA decrease (TXA is potent platelet aggregator released by platelets) and COX -2 --> PG synthesis inhibitor (potent antiplatelet aggregator released by endothelial cells.) Endothelial cells can make new protein while platelets cannot, so --> increased ratio of PG: TXA --> prolonged anti platelet aggregation effect

Front 5

Aspirin: Low dose for thrombosis prevention
2) Recommended dosing? Why?
3) What to take for pain? Why?

Back 5

2) Low dose selectively inhibits COX-1 more than COX-2 --> greater PG:TXA ratio
3) Many other NSAIDs, like ibuprofin interfere with aspirins access to COX-1. So some recommendations are: acetaminophen, or coxib (which does not act at COX-1)
-increase aspirin to antiinflammatory dose
-take aspirin 2hrs before NSAID but 6-8 hrs after previous NSAID b/c while aspirin is irreversible other NSAIDs are reversible

Front 6

NSAIDS: dysmenorrhea

Back 6

PG --> uterine muscle contraction. Overproduction in uterus can --> bad cramping. ibufrofin, naproxen and NSAIDs other than aspiring are commonly used to treat pain

Front 7

NSAIDs: Bartter's Syndrome

Back 7

From overproduction of renal PGs. All but aspirin work

Front 8

NSAIDs: Patent ductus arteriosis

Back 8

PGs keep ductus open. NSAIDs are sometimes administered to neonates to close ductus. Conversely near term mothers must be careful about NSAID use.

Front 9

NSAID: Acute Gouty Arthritis

Back 9

can be used to treat gouty attacks, mechanism unclear

Front 10

NSAIDs: Familial Adenomatous Polypsis (FAP) and colorectal cancer
1) Hypotheses? Cox involvement? Other mediators?

Back 10

NSAID use has been found to decrease colon cancer especially in pts with FAP. They are found to decreased polyp formation. Mechanism: COX-2 inhibition b/c COX-2 is often induced in neoplastic tissue.
2) Regulation of gene expression outside COX inhibition: Found that PPARd (a member of ligand dependent activators of transcription) receptor expression is depressed in cells expressing APC (tumor suppressor). Sulindac was found to suppress PPAR via route other than COX inhibition

Front 11

NSAIDs: Gastric lesions
1) Mechanisms of harm?
2) Where?

Back 11

1) a) direct irritation of mucosa, especially aspirin b/c most are acidic
b) Inhibition of PGI2 and PGE2 --> decreased EP3 activation. EP3 typically reduces gastric acid secretion
c) mucus production decreased -bicarbonate production decreased -mucosal proliferation decreased -there is a loss of maintenance of normal endothelial integrity which normally participates in cytoprotection and HCO3 production
2) Throughout GI

Front 12

Misoprostal
1) What is it?
2) Function? Mechanism
3) Down falls

Back 12

1) PGE1 analog
2) Reduces NSAID induced duodenal and gastric ulcers
3) Causes diarrhea in 30% patients

Front 13

Strategies to minimize NSAID GI effects

Back 13

-use acetominophen instead
-use of COX-2 selective NSAIDs
-substitution of salsalid for other salicylates
-prophylaxis of ulcers with proton pump inhibitors
-Misoprostol or high dose H2 blockers (misoprostol are more effective than H2 blockers)

Front 14

NSAIDs: Renal complications

Back 14

Patients with decreased renal function should not be given NSAIDs. Although PGs normally play small role in blood flow to kidney, in many clinical settings PGs are required to maintain sufficient blood flow to kidney. (via angiotensin, to increase SNS, to NE, to AVP, to PG up). Can lead to renal failure

Front 15

NSAIDs: Common indicators of NSAID induces renal failure (sxs)

Back 15

-oliguria
-hyperkalemia out of proportion to renal failure
-low fractional excretion of sodium

Front 16

Aspirin sensitivity
1) In who?
2) Sxs
3) Sequelae?

Back 16

1) 8-25% middle aged pts. with asthma, nasal polyps, or chronic urticaria
2) runny nose, bronchial asthma, hypotension, and shock (death)
3) x-reactivity of NSAIDs

Front 17

NSAIDs: Bronchoconstriction
1) Who?
2) Mechanisms?

Back 17

1) 10% asthmatics
2)a) PGE2 loss, via COX inhibition. PGE2 maintains dilator substances in bloodstream.
b) Substrate switching of 5-lipooxygenase to production of LTC and D4 --> bronchoconstriction

Front 18

NSAIDs: Prolonged bleeding time

Back 18

Inhibit platelet aggregation so typically advised against for pts undergoing surgery. However, found to reduce MI, thrombosis, stroke, renal failure, and bowel infarction post surgery.

Front 19

NSAIDs: Prolongation of gestation

Back 19

PGs E and F are uterotropic, so inhibition --> failure to deliver

Front 20

Aspirin and salicylates: NFkB hypothesis

Back 20

-Evidence supports idea that these drugs may inhibit IkB kinase activation that normally would phosphorylate inhibitor of NFkB, IkB, allow for NFkBs activation

Front 21

Salsalate
1) Drug class
2) Mechanism of action
3) Toxicity

Back 21

1) Salicylic acid
2) Reversible inhibitor of COX
3) Less GI toxicity than aspirin

Front 22

Reye's Syndrome

Back 22

Do not use aspirin in children because can lead to fatty deposition in liver and encephalopathy. May be due to viral infection

Front 23

Acetominophen
1) Drug class
2) Sites of action/effects
3) Uses
4) Toxicity

Back 23

1) NSAID
2) Weak Cox inhibition --> other action, mostly antipyretic and analgesic, not antiinflammatory
3) When aspiring counterindicated (peptic ulcer, or prolonged bleeding bad)
4) Metabolite depletes glutathione and then binds liver enzymes --> inactivation and hepatic toxity, txt with n-acetylcytein b/c repletes glutathione levels

Front 24

n-acetylcystein
1) What is it used for

Back 24

1) Acetominophen hepatotoxicity b/c repletes glutathione levels

Front 25

Celecoxib
1) Drug class
2) Mechanism
3) Possible problems

Back 25

1) NSAID
2) Selective Cox 2 inhibitor
3) Since TXA production not inhibited may lead to thrombosis.

Front 26

Diflusinol
1) Drug class
2) Mechanism/use

Back 26

1)NSAID
2) reversible nonselective cox inhibitor, used as analgesic

Front 27

ibuproben
1) Uses
2) Similar spectrum to what other drug

Back 27

1) RA, osteoarthritis, analgesia, temper, patent ductus, dysmenorrhea
2) naproxen

Front 28

naproxen
1) Uses
2) similar use spectrum to what other drug

Back 28

1) RA, osteoarthritis, analgesia, temper, patent ductus, dysmenorrhea
2) ibuprofen

Front 29

Indomethacin
1) Drug class
2) Uses
3) Toxicity

Back 29

Indocin
1) non-selective Cox inhibitor
2) RA, acute gouty arthritis, ankylosing spondylitis, patent ductus arteriosis, prevent preterm labor
3) CNS-Hd ache, dizziness, confusion, depression, psychosis, hallucinations
GI effects and platelet effects

Front 30

Ketorolac
1)Mechanism
2)Use
3)Administration
4) alternative to what
5) Toxicity

Back 30

1) Non-selective Cox inhibition
2) Analgesic only, post op
3) IV or IM, or orally <5days
4) Meperidine, and morphine
5) No resp depression, tolerance or withdrawal sxs. some GI and renal toxicity

Front 31

Mesalamine
1) Drug class
2) Administration
3) F, use

Back 31

1) NSAID, salicylate
2) Oral
3) Not absorbed from GI, used for IBS

Front 32

Rofecoxib
1) Drug class
2) Mechanism
3) Use

Back 32

Vioxx
1) NSAID
2) Selective Cox 2 inhibitor
3) No longer on market, b/c very selective for Cox 2 and led to thrombotic events

Front 33

Sodium salicylate
1) Drug class
2) Mechanism

Back 33

1) NSAID
2) Reversible Cox inhibition, also evidence for inhibition of NFkB via inhibition of IkB kinase

Front 34

Sulfasalazine
1) Drug class
2) Use

Back 34

1) NSAID, salicylate
2) IBS b/c not absorbed from gut but inhibits Cox

Front 35

Sulindac
1) Drug class
2) Mechanism
3) Use
4) Met, excretion, t1/2
5) Toxicity

Back 35

1) NSAID
2) COX inhibition plus inhibition of PPARd
3) osteoarthritis, RA, acute gouty arthritis, ankylosing spondylitis
4) Prodrug, eneterohepatic circulation --> 12-16 hr duration
5) Little GI toxicity, but otherwise the same as other NSAIDs