General Indications

Question 1

5 Main General Indications

Answer 1

FEVER REDUCTION-viral infection
REDUCE INFLAMMATION-chronic inflamm dz, RA/OA/gout
PAIN RELIEF-mild/moderate pain, muscle sprains/strains, headache/migraine, menstrual cramps/surgery

(ASPIRIN SPECIFIC)-stroke/MI prevention, inhibition of platelet activation
LESS COMMON INDICATIONs-promote closure of patent ductus arteriosus, cancer prevention

Question 2

NSAIDS by the numbers, widely used, but potentially toxic

Answer 2

1. > 1% Muricans use NSAIDS/day
2. 20-30% of hospitalizations of over 60s due to NSAID-associated adverse effects
3. ~33% hospitalizations for GI bleeds
4. 16.5 k deaths annually
5. > 80 million scripts/yr (~4.5% of total)
6. > 30 billion OTC sales (40k tons of aspirin)

Question 3

How do NSAIDS work?

Answer 3

By blocking COX-dependent PG synthesis. PG and cytokines cause Pain, Inflammation, and Fever

Question 4

What is special about aspirin MOA

Answer 4

IRREVERSIBLE NON-COMPETITIVE COX enzyme inhibitor. (all others are COMPETITIVE COX E inhibitors)

Question 5

PGs and pain responses

Answer 5

PG does NOT generate pain responses they themselves. PGs increase RESPONSES to painful stimuli, make you more sensitive.

Question 6

How is FEVER produced?

Answer 6

THERMOREGULATORY CENTER of HYPOTHALAMUS; median preoptic nucleus/organum vasculosom lamina terminalis.

Question 7

What is COX1 (the Housekeeper) involved in regulating?

Answer 7

1. Gi tract
2. CV system
3. kidney
4. female reproduction
5. ductus arteriosus

Question 8

What does PG do in the stomach?

Answer 8

PROTECTS THE STOMACH!

1. inhibit acid secretion
2. increase bicarb production
3. increase mucous production
4. increase vasoDILATION–> increase gastric blood flow

Question 9

Why is TXA2/PGI2 balance important?

Answer 9

It regulates systemic blood pressure and thrombogenesis.

Question 10

What happens when there is an imbalance of TXA2/PGI2?

Answer 10

incrase in vasoconstriction or an increase in latelet aggregation that will lead to INCREASED:

• hypertension (HTN)
• ischemia
• thrombosis
• MI & stroke

Question 11

What do PG do in the KIDNEY

Answer 11

1. increase GFR and water/Na retention
2. Increase VASODILATION
3. important in dz states (HF and renal failure) to counter the vasoCONSTRICTION (angiotensinII, vasopressin, catecholamines)

Question 12

NSAIDs and pregnancy

Answer 12

NSAID tx during pregnancy may prematurely close the ductus and adversely affect fetal circulation.

Question 13

NSAID and non closing ductus

Answer 13

When duct doesnt close spontaneously, NSAID therapy of newborn can be used topromote closure of a PATENT DUCTUS by inhibiting the synthesis of fetal PGs responsible for keeping the ductus open.

Question 14

What are the three types of NSAIDS?

Answer 14

1. aspirin and salicylates
2. traditional and non-selective NSAIDs
3. Coxibs: Selective COX-2 Inhibitors

Question 15

Aspirin-the prototypical NSAID

Answer 15

• Aspirin=acetylsalicylic acid, weak acid, pKa=3.5
  
  • in stomachs acid environment, aspiring will be mostly in its PROTONATED, neutral form that can readily cross the plasma membrane.
• rapidly absorbed in stomach and upper small intestine
• serum t1/2= ~15-20 mins

Question 16

How is aspirin metabolized?

Answer 16

rapidly metabolized by serum esterases to salicylic acid and acetic acid.

Question 17

How to Aspirin and salicylic acid exhibit anti-inflamm activity

Answer 17

inhibit COX1/COX2

Question 18

Apsiring COX1 action

Answer 18

Aspirin acetylates Ser530 in the active site which prevents access to arachidonic acid substrate. Aspirin acts as an IRREVERSIBLE INHIBITOR

Question 19

What is a unique indication for low dose aspirin?

Answer 19

prophylactic prevention of CV events, ie MI and stroke

Question 20

Why dont low levels of aspirin affect production of PGI2 (endothelium derived)

Answer 20

because endothelial cells can re-synthesize COX-1 (and express COX-2)

Question 21

How does an ANTI-THROMBOGENIC ENVIRONMENT form?

Answer 21

TXA2 production is inhibited and PGI2 synthesis is spared.

Question 22

Why cant platelets re-syn COX-1?

Answer 22

They have NO NUCLEI! So the acetylation of COX-1 is long-lasting for their 7-10 day lifetime.

Question 23

When would other NSAIDS be preferable over Aspirin?

Answer 23

In patients with:

• increased risk of GI COMPLICATIONS (gastric ulcer)
• increased risk of BLEEDING (hemophilics)

Question 24

What is a commonality for ALL salicylates?

Answer 24

they are 50-90% protein bound-high potential for drug interactions.

Question 25

What are the symptoms of salicylate Intoxication

Answer 25

-hyperventilation/metabolic acidosis/respiratory depression.
-hypoglycemia/confusion
-tremors/seizure
-cerebral edema/delerium
-hyperthermia
COMA and DEATH
Mortality: acute ~2%/Chronic ~25%

Question 26

Tx of Salicylate Toxicity/OD

Answer 26

Alkalinization of the urine with sodiu, bicarb…

• increases relative concentration of ionized form in urine
• prevents reabsorption of drug in the renal tubule
• increases rate of salicylate excretion

Question 27

Hypothesis for selective COX-2 inhibitors

Answer 27

they should exhibit potent anti-inflamm activity without the adverse effects associated with the inhibition of COX-1