Aspirin Flashcards
Prostaglandins are major mediators of
pain
fever
inflammation
COX leads to…
- Prostaglandins
- thromboxane
- prostacyclin
RLS in PG synthesis
COX
COX-1 is _____ expressed
constitutively
Where does COX1 work?
- CNS: fever/pain
- peripheral: pain
- stomach: protect mucosal lining
- platelets: increase platelet aggregation and blood clotting
- regulate kidney function
Prototype COX-1 inhibitor
aspirin
COX2 is ____ expressed ____
constitutively expressed isozyme
Where does COX2 work?
- CNS: pain
- stomach: protect mucosal lining
- endothelial cells: decrease platelet aggregation
- wound healing, bone repair
COX1 work in platelets or endothelial cells?
Platelets: increase platelet aggregation
COX2 work in platelets or endothelial cells?
endothelial cells: decreases platelet aggregation
COX2 has a ____ isozyme that is critical for inflammation
inducible
COX1 or COX2 key target for NSAID anti-inflammatory effects?
COX2
Prototype COX2 inhibitor
Celecoxib
Most NSAIDs inhibit both COX1 and COX2, usually stronger on ______. This makes them useful for treating what?
COX1
- pain (1 and constitutive 2)
- fever (1)
COX1 and COX2 suppression of inflammation
require high doses
COX 2 inhibitor drugs used for
- inflammation
- sometimes pain
- fewer unwanted COX1 adverse effects
Prototype of all NSAIDs and non-opioid analgesics
Aspirin
Aspirin is ____ ___
acetyl-salicylic acid
- rapidly hydrolyzed (de-acetylated) to salicylic acid
The anti-inflammatory and analgesic effects of aspirin are mediated by its ______ metabolite
salicylate
Salicylate are what type of inhibitors?
reversible
competitive
T/F salicylates are distributed throughout body
True
- including CNS for fever/pain
Aspirin is ____% protein bound in plasma
80%
- slow accumulation of free drug
- drug interactions from displacing warfarin, methotrexate, sulfonamides
At low to moderate doses, salicylate is metabolized where? what kinetics?
- liver by conjugation
- first order
- saturable
At higher doses, salicylate is metabolized where? what kinetics?
- unmetabolized by kidneys
- zero order
- OATs
- half-life increases with increasing dose
Lower doses of aspirin effects
analgesic
anti-pyretic
COX1 response
Higher doses of aspirin effects
- anti-inflammatory
- COX2 response
Low doses of aspirin how is it excreted?
glycine salts
glucuronide salts
Higher doses of aspirin how is it excreted?
free salicylate excretion
Aspirin amount for analgesia, anti=pyresis
2 tablets
650mg
Aspirin amount for anti inflammation
5 tablets
Aspirin t1/2 for low dose
2 hour
Aspirin t1/2 for moderate dose
10-12 hour
Aspirin t1/2 for high dose
15-30 hour
Is aspirin good for pain of inflammation?
yes!
inhibit pain and underlying inflammation
Unique use of aspirin
prevent thrombus formation (blood clotting)
prolong bleeding time
Aspirin can _____ inactivate COXs in some tissues by _____ acetylating enzyme
irreversible
covalently
____ near the site of GI absorption are the main cells exposed to acetyl-salicylic acid and covalent acetylation of COXs
platelets
Major current use of aspirin
prevent MI and stroke
lifetime of platelets
7 days
Why is MI and stroke a unique feature of aspirin?
- covalent acetylation of COX
- irreversible and prolonged action
- acetyl effect! not salicylate!
Side effects of aspirin
- bleeding (even at low doses)
CI aspirin
clotting deficiency
To ensure adequate clotting during and after surgery aspirin is stopped ____ days prior to surgery
7-10 days
Other possible uses of Aspirin
reduce GI cancer risk
AD
Platelets use ___ to make thromboxanes
COX1
- increase clotting and thrombosis risk
Endothelial cells use ____ to make prostacyclins
COX2
- decrease clotting and thrombosis risk
Low aspirin dose and thrombosis
- anti-thrombosis PGIs formation from endothelial cells
Prolonged inhibition of platelet COX1 causes _______
sustained reduction in Txs
Current aspirin recommendation for thrombosis prevention
75-81 mg
- if benefit outweighs risk of GI hemorrhage
Enteric coating to reduce ____
GI distress
Cautions of aspirin
- premature closure of ductus arterioles
- avoid 3rd trimester
- renal and hepatic toxicities (long term use, elderly)
Salicylism
mild toxicity
- from excess chronic use in older adults
- tinnitus, dizzy, HA, confusion, deafness
- drowsy, thirst, N/V
low dose aspirin toxicity
- increase O2 consumption, CO2 production
- stimulates respiration
- exces CO2 inhaled
high dose aspirin toxicity
- respiratory alkalosis
Adverse effects of aspirin
- GI irritation
- GI bleeding
- peptic ulcers
- CV effects
- induce asthma attacks
____ is responsible for 15,000 aspirin related deaths
GI hemorrhage
Reyes syndrome
- aspirin
- do not use <16
overdose aspirin
- children ingest large dose: >150 lethal
- GI disturbance
- CNS disturbance
- fever, dehydration, sweating
- skin eruptions
- metabolic acidosis, hypokalemia
- decrease blood flow
______ is eventual cause of death in aspirin OD
- respiratory failure
- respiratory depression: respiratory acidosis
Low dose aspirin acid base effect
- increased CO2
- acidosis
Low dose aspirin respiratory effect
compensation for acidosis by respiration
low dose aspirin serum pH
normal
higher dose aspirin acid base effect
- compensation for alkalosis by HCO3 excretion
higher dose aspirin respiratory effect
direct stimulation leads to alkalosis
higher dose aspirin serum pH
normal
toxic dose aspirin acid base effect
metabolic acidosis
renal + respiratory
toxic dose aspirin respiratory effect
central depression produces acidosis
toxic dose aspirin serum pH
acidic with organ failure
treating OD in aspirin
- hospitalize and maintain vital signs
- whole bowel irrigation
- activated charcoal
- hasten elimination
How to hasten elimination of aspirin
- volume repletion
- alkalization of urine with sodium bicarb
- ion trapping
