COX inhibits Flashcards
What enzymes to prostaglandins activate
COX-1
COX-2
What drugs counteract activity of COX-1 and 2
Aspiring
Ibuprofen
Celebrex
Acetaminophen
COX -1 effects on the body
(3)
Always active - housekeeping chores
- Gastric protection (mucus production)
- Promoting Platelet aggregation
- Maintain Renal Vasodilation
COX-2 effects on the body
(4)
Activated by tissue damage
- vasodilation
- inflammation/ pain
- fever
- colorectal cancer promotion
COX-1 inhibition drugs
Beneficial and Adverse
Beneficial Effect:
- decrease platelet aggregation
- protects against MI and stroke
Adverse:
- bleeding
- gastric ulceration
COX 2 inhibition drugs
Beneficial and Adverse effects
Beneficial:
- decreases inflammation, pain, fever
- protection against collateral cancer
Adverse:
- renal impairment
- vasoconstriction
COX inhibitors: 2 groups
1) Anti-inflammatory properties
- NSAIDs (aspirin, ibuprofen, celecoxib)
2) Acetaminophen
- reduce pain and fever
- CANT SUPPRESS INFLAMMATION
NSAIDs 2 groups
1) first generation
- inhibit both COX 1 and COX2
- suppress pain and inflammation but SERIOUS SIDE EFFECTS
2) second generation
- inhibit only COX 2
- in theory can suppress pain and inflammation
-FEWER adverse effects than first
Chemistry of Aspirin
belongs to chemical family of salicylic acids
produced by substituting an acetyl group into salicylic acid
–> acetylsalicylic acid (ASA)
Mechanism of aspririn
inhibits COX-1 and COX-2
aspirin inhibition of COX-1
Positive and negative
Positive: protection against MI and stroke
Negative: gastric ulceration, bleeding and renal impairment
Inhibition of COX-2
Positive:
- decrease inflammation, pain, and fever
- vasoconstriction
- protection against colorectal cancer
Is aspirin a reversible or irreversible inhibitor of COX
irreversible inhibitor
Aspririn Pharmacokinetics
A: PO
D: ++ bound to albumin/ 20% delivered to body tissues and CNS
M: ASA reduced to salicylic acid in liver
E: salicylic acid excreted by the kidney
Plasma therapeutic and toxicity levels
low- 100 mcg/ml
therapeutic- 150-300 mcg/ml
severe toxicity- 400 mcg/ml
therapeutic uses aspirin (4)
1) mild moderate analgesia
2) fever reducer
3) rheumatoid arthritis and Osteoarthritis ** drug of choice
4) Suppression of platelet aggregation
- aspirin binds to cox 1 = suppresses platelt aggregation
- irreversible effect requires 8 days for platelets to reach normal levels
- daily aspirin recommended for ischemic stroke, acute MI, chronic angina
aspirin adverse effects
Short term
Long term
Salicylism
Pregnancy
short term- low AE
long-term high doses- toxicity
Salicylism- tinnitus, sweating, dizziness
- symptoms stop once aspirin stopped
pregnancy
- anemia from GI blood loss
- postpartum hemorrhage
acute poisoning of aspirin
respiratory depression
adults lethal dose: 20-25 gm
children 4 gm
dose/ administration of aspirin
always PO
- dose with food/water
Non-aspirin first-generation NSAIDS
ibuprofen *prototype
Non-aspirin First generation NSAIDS mechanism
Reversible?
inhibit COX 1 and COX 2
BUT REVERSIBLE INHIBITION
Non-aspirin First generation NSAIDS therapeutic uses
similar to aspirin
- decreased inflammation, pain, fever
Ibuprofen compared to Aspirin
- less gastric bleeding
- less inhibition of platelet aggregation = greater risk MI and stroke
Non-aspirin First generation NSAIDS drug interaction
similar to aspirin
Reye Syndrome
rare, serious, swelling of liver and brain
-affects children after viral infection
- aspirin puts children at risk of these
Second-Generation NSAIDs
COX-2 inhibitors
- aka COXIBS
why were COX 2 inhibitors developed
hypothesis that
- selective inhibition of COX-2 should be able to suppress pain/inflammation but no risk gastric ulcertaion
Selective COX-2 Inhibitors drug
Celecoxib
Selective COX-2 Inhibitors mech
selective inhibition of COX-2
- primarily reduces painand inflammation
Selective COX-2 Inhibitors pharmacokinetics
A, D, Half life
PO- peaks in 3hours
Extensive (97%) binding to plasma proteins
Half-life 11 hours
Selective COX-2 Inhibitors Adverse effects
well tolerated
dyspepsia (upset stomach) and stomach pain
pregnancy: don’t use third trimester
Cardiovasuvlar events
how does celecoxib have increased risk MI and stroke?
1) does not inhibit COX-1
= does not inhibit platelet aggregation
2) does inhibit COX02 in blood vessels
- increased risk of vasoconstriction
Together = risk of vessel blockage, development of thrombis
Second-Generation NSAIDs therapeutic uses
first selective COX-2 inhibitor to market
reduce pain and inflammation
indicated for RA, OA, juvenile idiopathic arthritis, pain and dysmenorrhea
doesn’t decrease aggregation = does not promote bleeding
Acetaminophen
- similar to aspirin
- aceta has analgesic, antipyretic like aspirin
–> doesnt have anti-inflammatory
Mechanism of Action acetaminophen
- limited to prostaglandin CNS inhibition of COX-1 and 2
–> can reduce fever and pain but not inflammation
acetaminophen pharmacokinetics
A,D, half life
PO/ peak in 3 hours
extensive plasma binding
Half-life 11 hours
Drug interaction acetaminophen
Alcohol: regular alcohol consumption combined
= greater risk liver damage
Warfarin: increased bleeding
Vaccines: blunt immune response to childhood vaccines
Acture Toxicity: Liver Damage with acetaminophen
overdose is leading cause of acute liver failure
low risk in normal therapeutic doses
- except for ppl who drink alcohol or have liver disease
therapeutic uses acetaminophen
relief of pain and fever
Preferred to NSAIDs for children who have chickenpox or influenzas
