NSAIDs Flashcards
What are NSAIDs?
• The NSAIDs are a group of agents with
antipyretic, analgesic and anti-inflammatory
activities.
• Aspirin is the prototype.
MOA of NSAIDs?
• The mechanism of action of NSAIDs involves
inhibition of cyclooxygenase (COX).
• Inhibition of COX leads to inhibition of synthesis
of prostaglandins and thromboxanes.
Source of eicosanoids? Where is this source found?
• The main source of eicosanoids is arachidonic
acid, a 20-carbon unsaturated fatty acid
containing four double bonds.
• Arachidonic acid is found esterified in
phospholipids, usually in the 2 position
Describe Cox 1
• COX-1 is a constitutive enzyme involved in
tissue homeostasis.
• COX-1 is the dominant isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation.
Describe Cox-2
• COX-2 is induced by growth factors, tumor promoters and cytokines.
• COX-2 is the major source of eicosanoids in inflammation and cancer.
• COX-2 is constitutive in kidney and brain.
• Endothelial COX-2 is the primary source of
vascular prostacyclin.
Consequence of inhibition of cox 2 and cox 1 respectively?
- Most NSAIDs are inhibitors of both isozymes.
- The anti-inflammatory action of the NSAIDs is mainly related to their inhibition of COX-2.
- Gastric damage is due to inhibition of COX-1.
- This led to the search for selective COX-2 inhibitors.
List nonselective cox inhibitors?
- Aspirin
- Diclofenac
- Ibuprofen
- Indomethacin
- Ketorolac
- Naproxen
- Piroxicam
Cox-2 Selective inhibitors?
- Celecoxib
* Meloxicam
Actions of NSAIDs?
• ANTI-INFLAMMATORY • ANALGESIC • ANTIPYRETIC • Inhibition of PG synthesis mediates the antiinflammatory, analgesic and antipyretic actions of NSAIDs
Use of NSAIDs?
• NSAIDs are used for the treatment of mild to
moderate pain, especially the pain of inflammation.
• NSAIDs are useful in the treatment of
musculoskeletal disorders, such as rheumatoid
arthritis and osteoarthritis.
• Many NSAIDs are approved for the treatment of
rheumatoid arthritis, osteoarthritis, gout, ankylosing spondylitis, and dysmenorrhea.
• Frequent use of aspirin is associated with a 50%
decrease in the risk of colon cancer.
NSAID use in NIacin tolerability?
• Niacin lowers serum cholesterol levels.
• Niacin induces intense flushing.
• This flushing is mediated by a release of PGD2
from the skin.
• The flushing can be inhibited with aspirin.
DOC for closure of ductus arteriosus?
• Indomethacin is the drug of choice for closure of
ductus arteriosus in premature infants.
• Other NSAIDs have also been used
AE of NSAIDS?
- GI EFFECTS
- CARDIOVASCULAR EFFECTS
- RENAL EFFECTS
- NSAID-EXACERBATED RESPIRATORY DISEASE
GI adverse effects of NSAIDS?
• NSAIDs are associated with GI effects.
• Gastric damage by NSAIDs is due to two mechanisms:
• Inhibition of COX-1 in gastric epithelial cells.
• Ulceration by local irritation of the gastric mucosa.
• Misoprostol, proton pump inhibitors, and H2
blockers reduce the risk of gastric ulcer and are
used in the treatment of gastric damage induced
by NSAIDs
Relative risk of GI adverse effects?
Lowest Risk
• Celecoxib
Low Risk
• Ibuprofen
• Aspirin
• Diclofenac
Medium Risk
• Naproxen
• Indomethacin
High Risk
• Piroxicam
Cardiovascular AE?
• NSAIDs can increase the risk of CV events
(heart attack, stroke, death).
• Adverse CV events are thought to be caused by
NSAIDs upsetting the balance between TXA2
and PGI2.
• This may lead to vasoconstriction, platelet
aggregation, and thrombosis.
• NSAIDs that are more COX-2 selective have more CV risk. (induce prothrombotic state)
• Coxibs have fewer GI side effects.
• But their usefulness has been reduced by their
association with thrombotic events.
Available Cox-2 inhibitors?
• Currently, celecoxib is the only selective COX-2
inhibitor available in the USA.
• Rofecoxib and valdecoxib were withdrawn due
to their association with thrombotic events.
• Meloxicam is not as selective for COX-2 as the
coxibs.
Renal Adverse Effects
• Decrease In Renal Blood Flow
• Analgesic Nephropathy
• NSAIDs have little effect on renal function or BP
pressure in normal human subjects.
• However, in patients with CHF, CKD, and
other situations in which there is reduced
renal perfusion, vasodilating PGs are crucial
in maintaining GFR.
Guideline for NSAID use with decreased renal blood flow?
• NSAIDs should be avoided in patients with HT,
HF, or CKD.
• In these patients NSAIDs can elevate BP,
reduce the action of anti-hypertensive agents,
cause fluid retention, and worsen kidney function.
• Alternatives to NSAIDs, such as acetaminophen,
tramadol, or opioids should be considered.
Discuss analgesic nephropathy in relation to NSAIDS?
• Chronic interstitial nephritis caused by prolonged
and excessive consumption of analgesics.
• The use of the NSAID phenacetin, which is no
longer available, was particularly associated with
analgesic nephropathy.
Renal effects of cox-2 inhibitors?
• COX-2 is constitutively active in the kidney.
• COX-2 inhibitors cause renal toxicities similar to
those caused by the non-selective NSAIDs
Describe NSAID-EXACERBATED RESPIRATORY DISEASE (NERD)?
• Certain individuals display hypersensitivity to aspirin and NSAIDs. • Symptoms: • Vasomotor rhinitis • Angioedema • Urticaria • Bronchial asthma • Laryngeal edema • Bronchoconstriction • Flushing • Hypotension • Shock
What causes NSAID-Exacerbated Respiratory Disease(NERD)?
• Caused by increase in biosynthesis of leukotrienes. • Due to diversion of arachidonate to lipoxygenase metabolism as a consequence of COX inhibition.
Celecoxib AE?
• Celecoxib is a sulfonamide and may cause hypersensitivity reactions (typically rashes).
Drug Interactions with NSAIDs?
- ACE-INHIBITORS
- CORTICOSTEROIDS
- WARFARIN
NSAID effect on ACE inhibitors?
ACE-inhibitors
ACE-inhibitors act partly by
preventing breakdown of kinins that stimulate prostaglandin production.
NSAIDs may diminish the
antihypertensive effect of ACEinhibitors by blocking the production of vasodilating prostaglandins.
What is Triple Whammy?
• The term refers to the risk of acute kidney injury
when an ACEI (or ARB) is combined with a
diuretic and a NSAID
How does Triple Whammy work? Consequences?
NSAIDs constrict the
afferent arteriole and
reduce GFR
ACEIs (and ARBs) dilate the
efferent arteriole and reduce GFR
Diuretics reduce plasma
volume and GFR
• This triple combination may lead to acute renal
failure.
• The combination should be avoided in the
elderly, in renal insufficiency or heart failure.
• Patients on the combination should be
monitored for creatinine and potassium levels
NSAID consequences with corticosteroids? Warfarin?
Corticosteroids
• NSAIDs may increase frequency or severity of
gastrointestinal ulceration when combined with
corticosteroids.
Warfarin
• NSAIDs may increase risk of bleeding in patients
receiving warfarin.
Contraindications of NSAIDS?
• Aspirin and other salicylates have been
associated with Reye’s syndrome.
• They are contraindicated in children and
young adults < 20 yo with fever associated
with viral illness.
• Acetaminophen is DOC for antipyresis in children
and teens.
• Ibuprofen is also appropriate.
• Pregnancy, especially close to term, is a
relative contraindication to the use of all
NSAIDs.
Salicylate include?
Salicylates include: • Aspirin (acetyl salicylate) • Magnesium choline salicylate • Sodium salicylate • Salicyl salicylate
Aspirin vs other salicylates in moa?
• Aspirin is unique among the NSAIDs in
irreversibly acetylating (and thus inactivating)
cyclooxygenase.
• The other salicylates, and all other NSAIDs are
reversible inhibitors of cyclooxygenase.
• Aspirin is rapidly deacetylated by esterases in
the body, producing salicylate.
• Some of the pharmacologic effects of aspirin
are due to its salicylate metabolite.
Respiratory actions of salicylates?
• Salicylates uncouple oxidative phosphorylation
which leads to elevated CO2 and increased respiration.
• Higher doses stimulate the respiratory center resulting in hyperventilation.
• At toxic levels central respiratory paralysis occurs.
Effects of Aspirin on Platelets?
• TXA2 induces platelet aggregation.
• Aspirin irreversibly inhibits TXA2 production in
platelets.
• Platelets lack nuclei: they can’t synthesize new
enzyme, and the lack of TXA2 persists for the
lifetime of the platelet.
• Aspirin also inhibits COX in endothelial cells, but
these cells can synthesize new COX.
• Additionally, at low doses of aspirin
production of endothelial PGI2 is relatively
unaffected.
• The decrease in TXA2 levels results in prolonged
bleeding time.
uses of aspirin ANTI-INFLAMMATORY, ANTIPYRETIC AND
ANALGESIC actions?
Cardiovascular uses?
• Treatment of mild to moderate pain. • Effective analgesic for rheumatoid arthritis and other inflammatory joint conditions. • Potent antipyretic. CARDIOVASCULAR USES • Aspirin inhibits platelet aggregation. • Low doses are used for their cardioprotective effects.
DOSAGE of salicylates?
• Salicylates are analgesic and antipyretic at low
doses.
• They are anti-inflammatory at higher doses.
• Low doses of aspirin (<100 mg daily) are used
for their cardioprotective effects.
Correspond effect and dose of aspirin with given doses:
80-160mg:
650-1000mg:
3-6g:
6-10g:
10-20g:
20-30g:
80-160mg: Antiplatelet
effect
650-1000mg: Analgesic and
antipyretic effects
3-6g: Anti Inflammatory effect and tinnitus
6-10g: Hyperventilation
and respiratory alkalosis
10-20g: Fever, Dehydration,
metabolic acidosis
20-30g: Shock, coma,
respiratory and renal failure,
death
Metabolism of Aspirin?
• With doses of aspirin of 1g or more, the conjugation enzymes become saturated and zero-order kinetics are observed.
• The time required to eliminate 50% of the
salicylate lengthens as the dose of aspirin increases.
AE of aspirin?
• Epigastric distress
• Prolonged bleeding time
• Reye’s syndrome
• Hypersensitivity
ANTI-URICOSURIC EFFECTS
• Low doses of aspirin compete with uric acid for
secretion and thus reduce uric acid secretion.
HEPATIC EFFECTS
• Salicylates can cause hepatic injury in patients
treated with high doses of salicylates
Define salicylate intoxication?
Salicylism
• Mild chronic salicylate intoxication is called
salicylism.
• The syndrome includes headache, dizziness,
tinnitus, mental confusion and hyperventilation
• After an acute salicylate overdose patients
typically present to the hospital with a mixed
respiratory alkalosis and metabolic acidosis.
• Prolonged exposure to high doses of salicylates
leads to depression of the medulla, with central
respiratory depression and circulatory collapse.
• Respiratory failure is the usual cause of death.
Describe acetaminophen?
- Analgesic and antipyretic drug.
- No anti-inflammatory or antiplatelet effects.
- Technically it is not a NSAID.
Uses of acetaminophen?
• Useful in mild to moderate pain.
• DOC for pain relief in osteoarthritis.
• DOC for children with fever and flulike symptoms.
• DOC for short-term treatment of fever and minor
pain during pregnancy.
• Inadequate for inflammatory conditions such as rheumatoid arthritis.
• May be used as adjunct to antiinflammatory
therapy.
AE of Acetaminophen?
• In therapeutic doses, acetaminophen has
negligible toxicity in most individuals.
• When taken in overdose the drug is a hepatotoxin.
• Prompt administration of acetylcysteine, a sulfhydryl donor, may be lifesaving after an overdose
