NSAIDs

Question 1

What are NSAIDs?

Answer 1

• The NSAIDs are a group of agents with
antipyretic, analgesic and anti-inflammatory
activities.
• Aspirin is the prototype.

Question 2

MOA of NSAIDs?

Answer 2

• The mechanism of action of NSAIDs involves
inhibition of cyclooxygenase (COX).
• Inhibition of COX leads to inhibition of synthesis
of prostaglandins and thromboxanes.

Question 3

Source of eicosanoids? Where is this source found?

Answer 3

• 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

Question 4

Describe Cox 1

Answer 4

• 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.

Question 5

Describe Cox-2

Answer 5

• 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.

Question 6

Consequence of inhibition of cox 2 and cox 1 respectively?

Answer 6

• 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.

Question 7

List nonselective cox inhibitors?

Answer 7

• Aspirin
• Diclofenac
• Ibuprofen
• Indomethacin
• Ketorolac
• Naproxen
• Piroxicam

Question 8

Cox-2 Selective inhibitors?

Answer 8

• Celecoxib

* Meloxicam

Question 9

Actions of NSAIDs?

Answer 9

• ANTI-INFLAMMATORY
• ANALGESIC
• ANTIPYRETIC
• Inhibition of PG synthesis mediates the antiinflammatory, analgesic and antipyretic actions
of NSAIDs

Question 10

Use of NSAIDs?

Answer 10

• 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.

Question 11

NSAID use in NIacin tolerability?

Answer 11

• 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.

Question 12

DOC for closure of ductus arteriosus?

Answer 12

• Indomethacin is the drug of choice for closure of
ductus arteriosus in premature infants.
• Other NSAIDs have also been used

Question 13

AE of NSAIDS?

Answer 13

• GI EFFECTS
• CARDIOVASCULAR EFFECTS
• RENAL EFFECTS
• NSAID-EXACERBATED RESPIRATORY DISEASE

Question 14

GI adverse effects of NSAIDS?

Answer 14

• 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

Question 15

Relative risk of GI adverse effects?

Answer 15

Lowest Risk
• Celecoxib

Low Risk
• Ibuprofen
• Aspirin
• Diclofenac

Medium Risk
• Naproxen
• Indomethacin

High Risk
• Piroxicam

Question 16

Cardiovascular AE?

Answer 16

• 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.

Question 17

Available Cox-2 inhibitors?

Answer 17

• 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.

Question 18

Renal Adverse Effects

Answer 18

• 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.

Question 19

Guideline for NSAID use with decreased renal blood flow?

Answer 19

• 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.

Question 20

Discuss analgesic nephropathy in relation to NSAIDS?

Answer 20

• 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.

Question 21

Renal effects of cox-2 inhibitors?

Answer 21

• COX-2 is constitutively active in the kidney.
• COX-2 inhibitors cause renal toxicities similar to
those caused by the non-selective NSAIDs

Question 22

Describe NSAID-EXACERBATED
RESPIRATORY DISEASE (NERD)?

Answer 22

• Certain individuals display hypersensitivity to
aspirin and NSAIDs.
• Symptoms:
• Vasomotor rhinitis
• Angioedema
• Urticaria
• Bronchial asthma
• Laryngeal edema
• Bronchoconstriction
• Flushing
• Hypotension
• Shock

Question 23

What causes NSAID-Exacerbated Respiratory Disease(NERD)?

Answer 23

• Caused by increase in biosynthesis of
leukotrienes.
• Due to diversion of arachidonate to
lipoxygenase metabolism as a consequence of
COX inhibition.

Question 24

Celecoxib AE?

Answer 24

• Celecoxib is a sulfonamide and may cause hypersensitivity reactions (typically rashes).

Question 25

Drug Interactions with NSAIDs?

Answer 25

* ACE-INHIBITORS * CORTICOSTEROIDS * WARFARIN

Question 26

NSAID effect on ACE inhibitors?

Answer 26

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.

Question 27

What is Triple Whammy?

Answer 27

• The term refers to the risk of acute kidney injury when an ACEI (or ARB) is combined with a diuretic and a NSAID

Question 28

How does Triple Whammy work? Consequences?

Answer 28

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

Question 29

NSAID consequences with corticosteroids? Warfarin?

Answer 29

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.

Question 30

Contraindications of NSAIDS?

Answer 30

• 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.

Question 31

Salicylate include?

Answer 31

``` Salicylates include: • Aspirin (acetyl salicylate) • Magnesium choline salicylate • Sodium salicylate • Salicyl salicylate ```

Question 32

Aspirin vs other salicylates in moa?

Answer 32

• 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.

Question 33

Respiratory actions of salicylates?

Answer 33

• 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.

Question 34

Effects of Aspirin on Platelets?

Answer 34

• 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.

Question 35

uses of aspirin ANTI-INFLAMMATORY, ANTIPYRETIC AND ANALGESIC actions? Cardiovascular uses?

Answer 35

``` • 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. ```

Question 36

DOSAGE of salicylates?

Answer 36

• 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.

Question 37

Correspond effect and dose of aspirin with given doses: 80-160mg: 650-1000mg: 3-6g: 6-10g: 10-20g: 20-30g:

Answer 37

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

Question 38

Metabolism of Aspirin?

Answer 38

• 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.

Question 39

AE of aspirin?

Answer 39

• 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

Question 40

Define salicylate intoxication?

Answer 40

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.

Question 41

Describe acetaminophen?

Answer 41

* Analgesic and antipyretic drug. * No anti-inflammatory or antiplatelet effects. * Technically it is not a NSAID.

Question 42

Uses of acetaminophen?

Answer 42

• 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.

Question 43

AE of Acetaminophen?

Answer 43

• 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