05 NSAIDs Flashcards
Which of the following explains the GI complaints associated with aspirin use?
- inhibition of COX-2
- stimulation of COX-2
- increased production of PGs that increase gastric acid secretion
- decreased production of PGs that promote mucus secretion
- I don’t know
– decreased production of PGs that promote mucus secretion
COX-1 is in stomach
Choose the reason why aspirin increases bleeding time:
- -TXA2 production in platelet decreases
- TXA2 production in platelet increases
- PGI2 production in endothelial cells increases
- PGI2 production in endothelial cells decreases
- I don’t know
–TXA2 production in platelet decreases
Prevents platelet aggregation
The use of aspirin in pregnancy is contraindicated:
- yes
- no
- maybe
- i don’t know
Yes
PGs effect uterus
What is caused and what group of drugs are used to treat this property?
number of chemical mediators released at sites of inflammation release arachidonic acid which is metabolized to prostaglandins– prostaglandins directly cause vasodilation which can lead to edema formation
Anti-inflammatory
NSAIDs
What is caused and what group of drugs are used to treat this property?
chemical mediators, such as interleukin-1, can induce the synthesis of prostaglandins (PGE2) which act within hypothalamus to elevate body temperature
Anti-pyretic
NSAIDs
What is caused and what group of drugs are used to treat this property?
prostaglandins lower pain threshold by increasing sensitivity of pain receptors to chemical mediators, such as bradykinin and histamine
Analgesic
NSAIDs
What is the mechanism of action of all NSAIDs?
Inhibition of cyclooxygenase
COX-1 = constitutive COX-2 = inducible
What is special about the NSAIDs acetylsalicyclic acid (Aspirin)?
It is the only irreversible inhibitor of both COX-1 and COX-2
– acetylation of serine group of COXs
What drug is the only irreversible inhibitor of both COX-1 and COX-2?
Acetylsalicylic acid; Aspirin
What are the therapeutic implications of acetylsalicylic acid (Aspirin) on platelets vs endothelial cells?
Irreversible inhibition
Platelets: No nucleus, so no protein synthesis
Endothelial cells: nucleus, protein synthesis
What affects the absorption of aspirin?
- rapidly absorbed from stomach and small intestine
- limited by dissolution rate
- buffered vs. enteric coated:
- Buffered: coated with a substance to neutralize acid
- Enteric coated: pass thru stomach unaltered and dissolve in intestines
How is aspirin distributed?
- Highly bound to plasma proteins
- crosses BBB and placental barrier
How is acetylsalicylic acid (Aspirin) metabolized?
Aspirin hydrolyzed (deacetylated) by Phase I (CYP) in blood=> Salicylic Acid
Salicylic Acid => Less polar metabolites
- Phase I: Oxidation
- Phase II: Glucuronidation
- Phase II: Glycination (50%)
What does chewing aspirin do?
Increases rate of absorption
Who has a longer half-life: aspirin of salicylic acid?
Aspirin: 15 min
Salicylic acid: 2-3 hours
In overdose situations of Aspirin, half-life of salicylic acid becomes dependent on?
Dose/Zero order kinetics
What are unique effects of Aspirin/salicylates that are not related to inhibition of COX?
- Uric Acid Excretion
- CNS
- Respiration
At low doses of aspirin, what is the effect on uric acid excretion?
Decreased uric acid excretion:
at low doses, aspirin competes with uric acid for secretion by organic acid transport (OAT) system into renal tubules
At high doses of aspirin, what is the effect on uric acid excretion?
Increased uric acid excretion:
at high doses, aspirin competes with uric acid for both secretion and reabsorption and decreases serum uric acid
Block reabsorption via interaction with OAT
What is the role of PGs in uricosuric effects?
PGs have no effect on uric acid excretion
What is the effect of aspirin on the CNS at high doses?
Toxicity related effects
aspirin crosses the BBB:
- nausea and vomiting
- tinnitus, high-tone deafness, confusion, dizziness, delirium ,psychosis, coma
What are the GI AEs with NSAIDs?
gastric irritation which can lead to gastric ulcers and bleeding
mechanism: inhibition of COX-1 in GI prevents production of cytoprotective prostaglandins
What are the blood AEs with NSAIDs?
increased bleeding time
mechanism: inhibition of COX-1 in platelet blocks production of platelet thromboxane and decreases platelet aggregation
- Platelets lack nucleus
- new COX only with new platelets since ASA irreversible inhibition of COX
How can NSAIDs cause hypersensitivity?
- bronchoconstriction, edema
- cross-sensitivity with other NSAIDs
- more common in patients with asthma and nasal polyps
mechanism: may be due to action of leukotrienes because of shunting of AA pathway from COX to lipoxygenase
Tx: epinephrine
What are the renal AEs with NSAIDs?
decreased renal blood flow and glomerular filtration rate; salt and water retention
Mechanism: Inhibition of COX-1 (and 2?) -derived vasodilatory PGs
IMPORTANT: renal perfusion is more dependent on production of vasodilatory PGs in patients with congestive heart failure, chronic renal disease or liver disease compared to normal individuals (COX-2 may be upregulated in these diseases)
Effects elderly
Why are NSAIDs contraindicated in pregnancy?
Do NSAIDs affect the fetus?
What could happen to ductus arteriosus?
decreased uterine contractions, may prolong labor
Mechanism: prostaglandins stimulate uterine contraction. Production of prostaglandins increase before birth; therefore inhibition of COX prevents PG production.
- Intrauterine closure of patent ductus arteriosus
- low does not shown to cause fetal harm
- avoid 3rd trimester
Salicylism (Aspirin overdose)
initial effects: slight respiratory stimulation, nausea, vomiting, tinnitus, deafness
confusion with increased doses: fever, dehydration, electrolyte imbalance, metabolic acidosis
Mechanism: saturation of enzymes responsible for converting salicylic acid to inactive metabolites (these inactive metabolites are normally excreted) but instead have a build-up of salicylic acid. Salicylic acid is responsible for producing adverse symptoms.
treatment: gastric lavage
activated charcoal-to prevent absorption
replacement fluid and electrolytes alkalization of urine (iv bicarbonate)
Reye’s Syndrome
(unique to aspirin)
illness directly related to viral epidemics, can result in liver failure and death
in children there is a link between viral infections and taking aspirin
mechanism: mitochondrial damage?
What is the major limitation to long term therapy with NSAIDs, especially aspirin?
GI Side effects
What are the side effects associated with all non-selective (COX-1 and COX-2) NSAIDs?
- GI Irritation
- Inhibition of platelet aggregation/increased risk of bleeding
- decrease in RBF in patients dependent of vasodilatory PGs
- hypersensitivity
What drugs proprionic derivatives?
Ibuprofen (3-4/day) and Naproxen (1/day)
Reversible inhibition of COX1 and COX2
Less GI effects than aspirin
Indomethacin
Acetic Acid Derivative
Mech: reversible inhibitor of COX 1 and COX2
Plasma half-life: 3 hours
90% bound to plasma proteins
AEs/Toxicity:
- GI
- CNS: Severe frontal headache
Tx:
- Gout
- Pre-term labor
- To close patent ductus artteriosus
Not routinely used to treat pain or fever
What NSAID is used to treat gout or close patent ductus arteriosus in neonates but not used to treat pain and fever?
Indomethacin
Ketorolac
Pyrrole Derivative
Mech: reversible inhibitor of COX1 and COX2
Oral, IV, IM admin
- rapid onset, short duration
Tx: alternative for opioid analgesics for post-op pain
- more effective for pain than inflammation
What pyrrole derivative is used as an alternative for opioid analgesics for post-operative pain?
Ketorolac
What drugs are oxicam derivatives?
Piroxicam and Nabumetone (pro-drug)
Nabumetone
Pro drug Oxicam Derivative
Mech: active metabolite is reversible inhibitor of COX2 > COX1
Long half-life (1/day)
Tx:
- osteoarthritis
- rheumatoid arthritis
Piroxicam
Oxicam Derivative
Mech: reversible inhibitor of COX1 and COX2
Extremely long half-life (50 hours)
99% bound to plasma proteins
Metabolized by CYP2C9
Tx:
- symptomatic tx of acute and chronic rheumatoid arthritis and osteoarthritis
What drug is used to treat the symptoms of acute and chronic rheumatoid arthritis and osteoarthritis?
Prioxicam
What is the half-life of Piroxicam?
50 hours
What enzyme metabolizes piroxicam?
CYP2C9
Sulfasalazine
5-ASA linked to sulfapyridine by an azo bond (N=N)
Mech:
- effect independent of COX inhibition
- inhibition of cytokine production (IL-1 and TNF-alpha)
- inhibition of lipoxygenase
- free radical scavenger
Azo bond prevents absorption in upper GI tract
Local effect in GI to inhibit inflammatory response
AE: sulfa moiety
Tx:
- ulcerative colitis (5-ASA)
- RA and ankylosing spondylitis (sulfapyridine)
What drug is linked by an azo bond?
Sulfasalazine
What drug, independent of COX inhibition, inhibits cytokine production, lipoxygenase, and is a free radical scavenger?
Sulfasalazine
What prevents sulfasalazine absorption in upper GI tract?
Azo bond (N=N)
What drug causes AEs usually due to the sulfa moiety?
Sulfasalazine
What drug is treatment of ulcerative colitis and RA?
Sulfasalazine
- ulcerative colitis (5-ASA)
- RA and ankylosing spondylitis (sulfapyridine)
Why use COX-2 selective inhibitors?
COX-1 responsible for synthesis of cytoprotective PGs
If only block COX-2, can treat inflammation without risk of GI side effects
Celecoxib
Selective COX-2 inhibitor
- contains sulfonamide side chain
Mech: inhibition of COX2
- binds tightly to distinct hydrophilic side pocket of COX2 (close to active site–not present in COX1)
Oral (peak conc at 3 hrs)
Highly protein bound
Metabolized by CYP2C9
AEs:
- inc risk of GI irritation, ulceration, bleed ***
- hypersensitivity
- inc risk of CV thrombotic events (MI/stroke)
- anemia (rare)
Contraindications:
- patients with sulfonamide toxicity
- prior NSAID hypersensitivity
- pre-existing CV risk factors
- use with caution if any history of GI bleeding ***
- after coronary artery bypass graft surgery
- CYP2C9 deficiency
Tx:
- signs/symptoms of RA and osteoarthritis
- primary dysmenorrhea
- acute pain
- reduce number of intestinal polyps in familial adenomatous polyposis
What drug is a selective COX-2 inhibitor?
Celecoxib
What is important about the structure of Celecoxib?
Has sulfonamide side chain
How is Celecoxib specific for COX2?
Binds a distinct hydrophilic side pocket on present only on COX2
What AE can Celecoxib cause that does not make sense to its mechanism of action?
Inc risk of GI irritation, ulceration, and bleeding
Does Celecoxib have greater CV risk than non-selective NSAIDs?
Yes
What does Celecoxib treat?
Tx:
- signs/symptoms of RA and osteoarthritis
- primary dysmenorrhea
- acute pain
- reduce number of intestinal (colorectal) polyps in familial adenomatous polyposis
Acetaminophen
Para-aminophenol Derivative
Mech: not well understood
- no affinity for COX 1 or 2 active site
- but does inhibit the reduction of COX to peroxidase form
(necessary for production of PGs)
- more selective for COX in brain ?
- COX-3 ?
Pharmacokinetics:
- effective absorb in GI
- half life = 2 hrs
- little plasma protein binding
- major metabolism via phase II (glucuronidation and sulfation) then renal excretion
- minor metabolism via phase I (CYP2E1–toxicity)
NOT anti-inflammatory
AEs:
- hepatic toxicity after large doses (NAPQI depletes glutathione)–elevated liver enzymes (aminotransferase)
- Treat with N-acetylcysteine to replenish glutathione stores
Tx:
- mild to moderate pain and fever
- no antirheumatic or anti-inflammatory effects?
What drug inhibits the reduction of COX to peroxidase form (important for PGs synthesis)?
Acetaminophen
What drug may have increased selectivity for brain COX? COX3?
Acetaminophen
What drug is normally well tolerated, but with over dose, leads to hepatotoxicity?
Acetaminophen
How is Acetaminophen metabolized?
Phase II glucuronidation and sulfation (major)
Phase I (CYP2E1) minor–adverse effects
Can Acetaminophen be used to treat rheumatoid arthritis?
No, it is only analgesic and antipyretic
No anti-inflammatory effects
