NSAIDs

Dr Leonardo Dasso
Lecture 30
Fall Term 2016
1
 LEARNING OBJECTIVES

By the end of this session the student should be able to:

• Outline the main functions of COX-1 and COX-2.

• Describe the mechanism of action of the NSAIDs.
• Discuss the molecular basis of the analgesic, anti-inflammatory and
antipyretic actions of NSAIDs.
• Describe the therapeutic uses of NSAIDs.
• Discuss the adverse effects of NSAIDs, with particular reference to the
gastrointestinal, renal and cardiovascular effects.
• Discuss the differences in relative risk of gastrointestinal adverse effects
associated with NSAIDs.
• Explain why PPIs, H2 blockers, or misoprostol are sometimes co-
administered with NSAIDs.
• Describe the aspirin hypersensitivity syndrome.
• Describe drug interactions associated with the NSAIDs.
• Describe the main contraindications of the NSAIDs. Explain why aspirin is
contraindicated in patients <20 yo with fever associated with viral illness.
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 NSAIDs

• The NSAIDs are a group of agents with

antipyretic, analgesic and anti-inflammatory
activities.
• Aspirin is the prototype.

3
 MECHANISM OF ACTION 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.

4
 PLA2

Arachidonic acid

Lipoxygenases Cyclooxygenases

Leukotrienes Prostaglandins
Prostacyclin
Thromboxanes 5
 MECHANISM OF ACTION OF NSAIDS

• There are 2 types of COX: COX-1 & COX-2.

• 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.

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 MECHANISM OF ACTION OF NSAIDS

• COX-2 is induced by growth factors, tumor

promoters and cytokines.
• COX-2 is the major source of eicosanoids in
inflammation and cancer.

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MECHANISM OF ACTION OF NSAIDS

• COX-2 is constitutive in kidney and brain.

• Endothelial COX-2 is the primary source of
vascular prostacyclin.

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 MECHANISM OF ACTION OF NSAIDS

• 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.

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 NSAIDS

NONSELECTIVE COX-2 SELECTIVE

COX INHIBITORS INHIBITORS
• Aspirin • Celecoxib
• Diclofenac • Meloxicam
• Ibuprofen
• Indomethacin
• Ketorolac
• Naproxen
• Piroxicam

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 ACTIONS OF NSAIDS

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

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 USES OF NSAIDS

• NSAIDs are used for the treatment of mild to

moderate pain, especially the pain of inflammation.

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 USES: GOUT

• Indomethacin is commonly used in acute gout.

• All other NSAIDs can be used except aspirin,
and other salicylates.
• Aspirin is contraindicated in gout: It inhibits urate
excretion at low doses.

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 USES: COLON CANCER

• Frequent use of aspirin is associated with a 50%

decrease in the risk of colon cancer.

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 USES: 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.

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USES: CLOSURE OF DUCTUS ARTERIOSUS

• Indomethacin is the drug of choice for closure of

ductus arteriosus in premature infants.
• Other NSAIDs have also been used.

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 ADVERSE EFFECTS OF NSAIDS

• GI EFFECTS
• CARDIOVASCULAR EFFECTS
• RENAL EFFECTS
• ASPIRIN HYPERSENSITIVITY

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 GI ADVERSE EFFECTS

• 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.

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 GI ADVERSE EFFECTS

• 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.

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RELATIVE RISKS OF GI ADVERSE EFFECTS

Lowest Risk
• Celecoxib
Low Risk
• Ibuprofen
• Aspirin
• Diclofenac
Medium Risk
• Naproxen
• Indomethacin
High Risk
• Piroxicam

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CARDIOVASCULAR ADVERSE EFFECTS

• 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.

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CARDIOVASCULAR ADVERSE EFFECTS

• NSAIDs that are more COX-2 selective have

more CV risk.

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 COX-2 SELECTIVE INHIBITION & CV RISK

Platelet Endothelial cell

COX-1 COX-1 COX-2

⊗ Non selective ⊗
NSAID ⊗

TXA2 PGI2
Promotes platelet aggregation Inhibits platelet aggregation
Vasoconstrictor Vasodilator
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 COX-2 SELECTIVE INHIBITION & CV RISK

Platelet Endothelial cell

COX-1 COX-1 COX-2

⊗
Prothrombotic state

TXA2 Coxib
PGI2
Promotes platelet aggregation Inhibits platelet aggregation
Vasoconstrictor Vasodilator
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COX-2 SELECTIVE INHIBITION & CV RISK

• Coxibs have fewer GI side effects.

• But their usefulness has been reduced by their
association with thrombotic events.

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GI & CV RISK OF COX INHIBITORS

Cardiovascular risk Gastrointestinal risk

COX-2 COX-1
Degree of selectivity
 COX-2 SELECTIVE INHIBITORS

• Currently, celecoxib is the only selective COX-2

inhibitor available in the USA.

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 COX-2 SELECTIVE INHIBITORS

• Rofecoxib and valdecoxib were withdrawn due

to their association with thrombotic events.

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 COX-2 SELECTIVE INHIBITORS

• Meloxicam is not as selective for COX-2 as the

coxibs.

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 RENAL ADVERSE EFFECTS

• Decrease In Renal Blood Flow

• Analgesic Nephropathy

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 Decrease In Renal Blood Flow

• 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.

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 Decrease In 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.

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 Decrease In Renal Blood Flow

• Normal individual

PGs

Ang II

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 Decrease In Renal Blood Flow

• CHF

PGs

Ang II

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 Decrease In Renal Blood Flow

• CHF

PGs

Ang II

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 Decrease In Renal Blood Flow

• CHF
NSAID

PGs X

Ang II

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 Decrease In Renal Blood Flow

• CHF
NSAID

PGs X

Ang II

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 Analgesic Nephropathy

• 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.

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 RENAL EFFECTS: 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.

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 ASPIRIN HYPERSENSITIVITY

• Certain individuals display hypersensitivity to

aspirin and NSAIDs.
• Symptoms:
• Vasomotor rhinitis
• Angioedema
• Urticaria
• Bronchial asthma
• Laryngeal edema
• Bronchoconstriction
• Flushing
• Hypotension
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• Shock
 ASPIRIN HYPERSENSITIVITY

• Caused by increase in biosynthesis of

leukotrienes.
• Due to diversion of arachidonate to
lipoxygenase metabolism as a consequence of
COX inhibition.

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 PLA2

Arachidonic acid NSAIDs

Lipoxygenases
 Cyclooxygenases

Leukotrienes Prostaglandins
Prostacyclin
Thromboxane 42
 OTHER ADVERSE EFFECTS

• Celecoxib is a sulfonamide and may cause

hypersensitivity reactions (typically rashes).

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 DRUG INTERACTIONS

• ACE-INHIBITORS
• CORTICOSTEROIDS
• WARFARIN

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 DRUG INTERACTIONS

ACE-inhibitors
• ACE-inhibitors act partly by preventing
breakdown of kinins that stimulate prostaglandin
production.

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 DRUG INTERACTIONS

Decreased BP

Vasodilation

Vasodilatory PGs NO

Angiotensin I Bradykinin

X ACE X
Angiotensin II Bradykinin inactive
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 DRUG INTERACTIONS

ACE-inhibitors
• NSAIDs may diminish the antihypertensive effect
of ACE-inhibitors by blocking the production of
vasodilating prostaglandins.

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 DRUG INTERACTIONS

Decreased BP

Vasodilation

Vasodilatory PGs NO

Angiotensin I
XBradykinin
X ACE X
Angiotensin II Bradykinin inactive
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DRUG INTERACTIONS: The 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.

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 The Triple Whammy

NSAIDs constrict the

afferent arteriole and
reduce GFR

Diuretics reduce plasma

ACEIs dilate the volume and GFR
efferent arteriole
and reduce GFR

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 The Triple Whammy

• 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

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 DRUG INTERACTIONS

Corticosteroids
• NSAIDs may increase frequency or severity of
gastrointestinal ulceration when combined with
corticosteroids.

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 DRUG INTERACTIONS

Warfarin
• NSAIDs may increase risk of bleeding in patients
receiving warfarin.

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 CONTRAINDICATIONS

• 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.

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 Reye’s syndrome

Belay et al, NEJM 340(18): 1377, 1999

 CONTRAINDICATIONS

• Pregnancy, especially close to term, is a

relative contraindication to the use of all
NSAIDs.

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ASPIRIN & OTHER SALICYLATES

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 ASPIRIN & OTHER SALICYLATES

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

Aspirin 58
 ASPIRIN & OTHER SALICYLATES

• 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.

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 ASPIRIN & OTHER SALICYLATES

• Aspirin is rapidly deacetylated by esterases in

the body, producing salicylate.
• Some of the pharmacologic effects of aspirin
are due to its salicylate metabolite.

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ASPIRIN & OTHER SALICYLATES:
ACTIONS

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 RESPIRATORY ACTIONS

• 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.

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 EFFECT 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.

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 EFFECT ON PLATELETS

• 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.

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 ASPIRIN/NSAIDs/COXIBs

PGI2 TXA2

Low-Dose
aspirin

Conventional
NSAIDs

COX-2
inhibitors

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ASPIRIN: USES

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 ANTI-INFLAMMATORY, ANTIPYRETIC AND
ANALGESIC USES

• Treatment of mild to moderate pain.

• Effective analgesic for rheumatoid arthritis and
other inflammatory joint conditions.
• Potent antipyretic.

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 CARDIOVASCULAR USES

• Aspirin inhibits platelet aggregation.

• Low doses are used for their cardioprotective
effects.

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 DOSAGE

• 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.

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RELATIONSHIP BETWEEN ASPIRIN DAILY DOSE
AND EFFECTS
Shock, coma,
Fever, respiratory and
Dehydration, renal failure,
metabolic death
acidosis
Hyperventilation
and respiratory
alkalosis 20 – 30 g

Antiinflammatory 10 – 20 g
effect
Analgesic and tinnitus
and
6 - 10 g
antipyretic
effects
Antiplatelet 3-6g
effect
650 -1000
80 -160
80 mg mg

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 METABOLISM

• Aspirin is hydrolyzed to salicylate and acetic acid

by esterases in tissues and blood.
• At low doses salicylate is converted by the liver
into hydrosoluble conjugates that are rapidly
excreted by the kidney.
• Elimination follows first-order kinetics with a half-
life of about 3.5 hours.

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 METABOLISM

Aspirin

Salicylic
acid

Minor Salicylic Salicyluric

metabolites glucuronides acid

Excreted in urine
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 METABOLISM

• 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.

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METABOLISM

Beginning of
first-order
kinetics

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 ADVERSE EFFECTS

• Epigastric distress
• Prolonged bleeding time
• Reye’s syndrome
• Hypersensitivity

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 ADVERSE EFFECTS

URICOSURIC EFFECTS
• Low doses of aspirin compete with uric acid for
secretion and thus reduce uric acid secretion.

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 ADVERSE EFFECTS

HEPATIC EFFECTS
• Salicylates can cause hepatic injury in patients
treated with high doses of salicylates.
• The onset occurs after several months of
treatment.
• Reversible upon discontinuation of salicylates.
• Salicylates are contraindicated in patients with
chronic liver disease.

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 ASPIRIN IN PREGNANCY

• Category C risk during Trimesters 1 and 2

• Category D during Trimester 3.

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 SALICYLATE INTOXICATION

Salicylism
• Mild chronic salicylate intoxication is called
salicylism.
• The syndrome includes headache, dizziness,
tinnitus, mental confusion and hyperventilation.

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 SALICYLATE INTOXICATION

• 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.

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 ACETAMINOPHEN

• Analgesic and antipyretic drug.

• No anti-inflammatory or antiplatelet effects.
• Technically it is not a NSAID.

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 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. 82
 ADVERSE EFFECTS

• In therapeutic doses, acetaminophen has

negligible toxicity in most individuals.
• When taken in overdose, or by patients with
severe liver impairment, the drug is a dangerous
hepatotoxin.
• Prompt administration of acetylcysteine, a
sulfhydryl donor, may be lifesaving after an
overdose.

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 Acute liver failure cases
attributed to acetaminophen

84
 Etiologies of acute liver failure in the US

Acetaminophen
% of cases

85
THE END

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