5 Main General Indications
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
NSAIDS by the numbers, widely used, but potentially toxic
- > 1% Muricans use NSAIDS/day
- 20-30% of hospitalizations of over 60s due to NSAID-associated adverse effects
- ~33% hospitalizations for GI bleeds
- 16.5 k deaths annually
- > 80 million scripts/yr (~4.5% of total)
- > 30 billion OTC sales (40k tons of aspirin)
How do NSAIDS work?
By blocking COX-dependent PG synthesis. PG and cytokines cause Pain, Inflammation, and Fever
What is special about aspirin MOA
IRREVERSIBLE NON-COMPETITIVE COX enzyme inhibitor. (all others are COMPETITIVE COX E inhibitors)
PGs and pain responses
PG does NOT generate pain responses they themselves. PGs increase RESPONSES to painful stimuli, make you more sensitive.
How is FEVER produced?
THERMOREGULATORY CENTER of HYPOTHALAMUS; median preoptic nucleus/organum vasculosom lamina terminalis.
What is COX1 (the Housekeeper) involved in regulating?
- Gi tract
- CV system
- kidney
- female reproduction
- ductus arteriosus
What does PG do in the stomach?
PROTECTS THE STOMACH!
- inhibit acid secretion
- increase bicarb production
- increase mucous production
- increase vasoDILATION–> increase gastric blood flow
Why is TXA2/PGI2 balance important?
It regulates systemic blood pressure and thrombogenesis.
What happens when there is an imbalance of TXA2/PGI2?
incrase in vasoconstriction or an increase in latelet aggregation that will lead to INCREASED:
- hypertension (HTN)
- ischemia
- thrombosis
- MI & stroke
What do PG do in the KIDNEY
- increase GFR and water/Na retention
- Increase VASODILATION
- important in dz states (HF and renal failure) to counter the vasoCONSTRICTION (angiotensinII, vasopressin, catecholamines)
NSAIDs and pregnancy
NSAID tx during pregnancy may prematurely close the ductus and adversely affect fetal circulation.
NSAID and non closing ductus
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.
What are the three types of NSAIDS?
- aspirin and salicylates
- traditional and non-selective NSAIDs
- Coxibs: Selective COX-2 Inhibitors
Aspirin-the prototypical NSAID
- 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
How is aspirin metabolized?
rapidly metabolized by serum esterases to salicylic acid and acetic acid.
How to Aspirin and salicylic acid exhibit anti-inflamm activity
inhibit COX1/COX2
Apsiring COX1 action
Aspirin acetylates Ser530 in the active site which prevents access to arachidonic acid substrate. Aspirin acts as an IRREVERSIBLE INHIBITOR
What is a unique indication for low dose aspirin?
prophylactic prevention of CV events, ie MI and stroke
Why dont low levels of aspirin affect production of PGI2 (endothelium derived)
because endothelial cells can re-synthesize COX-1 (and express COX-2)
How does an ANTI-THROMBOGENIC ENVIRONMENT form?
TXA2 production is inhibited and PGI2 synthesis is spared.
Why cant platelets re-syn COX-1?
They have NO NUCLEI! So the acetylation of COX-1 is long-lasting for their 7-10 day lifetime.
When would other NSAIDS be preferable over Aspirin?
In patients with:
- increased risk of GI COMPLICATIONS (gastric ulcer)
- increased risk of BLEEDING (hemophilics)
What is a commonality for ALL salicylates?
they are 50-90% protein bound-high potential for drug interactions.
