NSAIDs (complete) Flashcards
What is arachidonic acid?
- a phospholipid, omega-6 fatty acid
- stored as an ester
- cleaved by esterases to become activated/processed into descendants
Describe the biosynthetic pathway for production of prostaglandins
Arachidonic acid —> endoperoxide – cyclic intermediate (using COX-1 and COX-2) —-> prostaglandins E2, D2, F2a (using endoperoxide isomerases)
Describe the biosynthetic pathway for production of prostacyclins
Arachidonic acid —> endoperoxide – cyclic intermediate (using COX-1 and COX-2) —-> prostacyclin I2 (prostacyclin synthase)
Describe the biosynthetic pathway for production of leukotrienes
Arachidonic acid —> leukotriene A4 (5-lipoxygenase) —> LTB4 and LTC C4/D4/E4
Compare cyclooxygenase 1 and 2
COX enzyme critical for prostaglandin and thromboxane production
Both catalyze synthesis of cyclic endoperoxide, PGH2 (unstable intermediate)
Where is COX-1 expressed?
Ubiquitously
1) GI tract
2) Platelets
3) Kidneys
4) Vascular smooth muscle
5) Bone
What is COX-1’s role in GI tract?
- Decreases gastric acid secretion
- Increases mucosal secretion (protects!)
- Promotes smooth muscle contraction
What is COX-1’s role in platelets?
Have a pro-aggregatory effect
What is COX-1’s role in the kidneys?
Promotes increased renal blood flow
Increased diuresis
What is COX-1’s role in vascular smooth muscle?
For prostaglandin/prostacyclin pathway: vasodilation
Tromboxane: vasoconstriction
What is COX-1’s role in the bone?
Stimulates formation/resorption
Where is COX-2 expressed?
When induced by cytokines, shear stress, GFs
When up-regulated as needed for specialized functions
Located in inflamed/activated tissues:
1) Areas of pain/inflammation
2) Hypothalamus
3) Kidneys
4) Endothelial cells
5) Uterine smooth muscle
6) Ductus arteriosus
What is COX-2’s role in areas of pain/inflammation?
Enhance edema formation
Enhance leukocyte infiltration via vasodilation
Increase bradykini pain-producing activity
What is COX-2’s role in the hypothalamus?
FEVER!
Increased heat generation
Decrease in heat loss
What is COX-2’s role in the kidneys?
Maintains renal blood flow (stresses can alter that)
Critical in elderly, when renal function deteriorates
What is COX-2’s role in endothelial cells?
Endos are upregulated by blood flow stress
Vasodilation and anti-aggregatory platelet effects
What is COX-2’s role in uterine smooth muscle?
Contributes to labor contractions near parturition
A COX inhibitor would cause a lot of problems in the third trimester
What is COX-2’s role in the ductus arteriosus?
Maintains patent ductus arteriosus via vasodilation
What are the effects of prostaglandins on vascular smooth muscle?
PGE2 causes vasodilation
What are the effects of prostaglandins on platelets?
No effect
What are the effects of prostaglandins on GI tract smooth muscle/secretory cells?
PGE2/PGI2 inhibit HCl secretion
Increase mucous secretion
What are the effects of prostaglandins on kidney cells?
PGE2/PGI2 increase renal blood flow
What are the effects of prostaglandins on uterine cells?
PGF2a induces contractions
What are the effects of prostaglandins on inflammatory cells?
PGE2/PGI2 potentiates …
1) pain
2) edema
3) fever
What are the effects of leukotrienes on inflammatory cell function?
LTB4 is chemoattractice for neutrophils
Induces endothelial cells and neutrophils to express adhesion proteins
What are the effects of leukotrienes on pulmonary cells?
Intense contraction in bronchial smooth muscle
ASTHMA!
What are the effects of leukotrienes on vascular smooth muscle?
Intense vasodilation —> edema
Promotes leukocyte margination/adhesion
Describe the functional interactions between prostacyclin and thromboxane on vascular smooth muscle and platelets.
Prost: vasodilation, disaggregation
Throm: vasoconstriction, aggregation
They are opposites!!!
What are the effects of aspirin on COX-1 and 2? (Therapeutic uses)
Irreversibly inactivates COX-1 and 2
Uses:
1) Analgesic
2) Antipyretic
3) Anti-inflammatory
4) Anti-platelet
What are the effects of NSAIDs on COX-1 and 2? (Therapeutic uses)
Reversibly inactivates COX-1 and 2
Uses:
1) Analgesic
2) Antipyretic
3) Anti-inflammatory
NOT ANTI-PLATELET
What are the effects of acetaminophen on COX-1 and 2? (Therapeutic uses)
CNS reversibly inactivates COX2
Uses:
1) Analgesic
2) Antipyretic
NOT ANTI-INFLAMMATORY or ANTI-PLATELET
What are the effects of COX-2 selective inhibitors on COX-1 and 2? (Therapeutic uses)
Inhibits only COX2 activity
Uses:
1) Analgesic
2) Antipyretic
3) Anti-Inflammatory
NOT ANTI-PLATELET
What are the adverse rxns from aspirin?
1) GI upset
2) Bleeding
3) Decreased renal function
4) Decreased labor contractions
DOES NOT increase clotting
What are the adverse rxns from NSAIDs?
1) GI upset
2) Bleeding
3) Decreased renal function
4) Decreased labor contractions
DOES NOT increase clotting
What are the adverse rxns from acetaminophen?
Unlike NSAIDs/aspirin NO…
1) …GI upset
2) …Bleeding
3) …Decreased renal function
4) …Decreased labor contractions
5) …Increased clotting
Potential for hepatotoxicity
What are the adverse rxns from COX-2 inhibitors?
1) Decreased renal function
2) Decreased labor contractions
3) Increased clotting
4) Increase risk of cardio thrombotic events
NO GI UPSET or BLEEDING
Why is low dose aspirin able to exhibit anti-thrombotic/cardioprotective effect unlike high dose?
Aspirin inhibits platelet aggregation — low dose is COX-1 specific
B/c it’s irreversible platelets cannot produce COX-1 (no nucleus) —- TXA2 synthesis inhibited for life of platelet (>8 days)
At high dose, the aspirin no longer concentrates around just platelets, also endothelial cells — these have COX-2 (normally anti-thrombotic)
How is the low dose aspirin effect associated with COX-2 selective inhibitors?
COX-1 inhibition is favored over COX-2
Therefore the inhibition of pro-clotting is favored over that of anti-clotting
Again, what are the therapeutic uses of aspirin?
Low dose inhibits thrombus formation
Results from irreversible inhibition of COX-1&2
Analgesic, antipyretic, anti-inflammatory, anti-platelet
Describe the metabolism and excretion of aspirin
M: rapid absorption from stomach/sm intestine — ASA rapidly hydrolyzed to salicylate by esterases
E: Salicylate more slowly eliminated by glycine/glucuronide conj. — high dose = zero order kinetics
What are the side effects of aspirin?
1) Gastric irritation
2) Increased bleeding time
3) Renal dysfunction
What happens when a pt overdoses on aspirin?
Mild intox:
tinnitus, headache, dizziness, diarrhea, seeing probs, thirt
Acute intox-overdose:
uncoupling of oxidative phosphorylation, respiratory alkalosis, metabolic acidosis
What are the contraindications for aspirin?
1) pts w/ gastric ulcers
2) pts on oral anticoags
3) pregnant pts
4) pts w/ hypersensitivity (allergy)
5) children s syndrome
What drugs interact w/ aspirin?
1) Warfarin (inhibit platelet function)
2) Alcohol (add’l gastric irritation/bleeding)
What is a lethal dose of aspirin?
10-30 grams
Again, what are the therapeutic uses of traditional NSAIDs?
Anti-inflammatory, antipyretic, analgesic
Sometimes used for arthritis, dysmenorrhea
What are the side effects of NSAIDs?
1) gastric irritation if taken w/o food
2) platelets transient/reversible
What happens when you overdose on NSAIDs?
Rapid onset of renal failure, nausea, vomiting, GI pain/upset
Generally better tolerated and safer in overdose than aspirin
What are the contraindications for NSAIDs?
Safety for use in pregnancy not established
What are the therapeutic uses of acetaminophen?
- A Cox 2 inhibitor only in the CNS
- Analgesic, antipyretic, less anti-inflammatory
Compared w/ aspirin:
- Does not upset stomach
- Weak effect on platelets/clotting time
- Minimal renal effects
- no Reyes
- considered safe in pregnancy
Describe the metabolism and excretion of acetaminophen
- Absorbed in GI
- Metabolized to inactive sulfate and glucuronide (phase II conj)
- Large doses —» toxic product in liver
- t1/2 = 2-3 hrs
What are the side effects of acetaminophen?
- mild ^ in hepatic enzymes, reversible
- larger dose: dizziness, excitement, disorientation
- toxicity
What happens when you overdose on acetaminophen?
Glutathione stores are depleted —» can’t inactivate toxic metabolite —» liver damage (death if untreated)
t1/2 of Ac ^ 2-3 fold
What are the therapeutic uses for Celicoxib?
A COX-2 specific inhibitor
- Anti-inflammatory, antipyretic, analgesic
- Used for arthritis, menstrual pains, acute pain
Describe the metabolism and excretion of Celicoxib
M: well absorbed, metabolized by liver (CYP2C9)
E: renal — long half-life allows for 1/2 daily doses
What are the side effects of Celicoxib?
1) Renal
2) Increased risk of adverse CV event
What are the contraindications for Celicoxib?
Do not use in pregnant women (blocks uterine contractions)
Do not use in people who are prone to cardiovascular issues!! BADDD
A sulfa drug —» watch out for allergies
