Nonsteroidal Antiinflammatory Drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) are a class of medications consisting of

aspirin, reversible NSAIDs, and selective NSAIDs. NSAIDs are used as antiplatelet,
analgesic, antipyretic, and antiinflammatory agents. Common side effects include GI
irritation, prolonged bleeding, and AKI.
Last update:

 July 13, 2021

 7:48 am

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents
 Pharmacodynamics
 Classification
 Indications
 Adverse Effects
 Aspirin Toxicity
 Comparison of NSAIDs
 References

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Pharmacodynamics

Mechanism of action
Nonsteroidal antiinflammatory drugs (NSAIDs) exert their therapeutic effects by
interrupting fatty acid metabolism, primarily the action of cyclooxygenase (COX) on
arachidonic acid (AA). 
  Arachidonic acid is a phospholipid found in cell membranes that is released
by a variety of stimuli to include cell membrane damage.
 COX converts arachidonic acid into: 
o Thromboxanes: 
  Involved in platelet adhesion
 Involved in vasoconstriction
o Prostaglandins:
 Mediate inflammation
 Increase hypothalamic temperature set-point
 Involved in anti-nociception
 Trigger uterine contractions during menstruation
o Prostacyclin (prostaglandin I2): 
 Inhibits platelet aggregation
 Involved in vasodilation
 There are 2 COX isoenzymes:
o COX-1 is constitutively expressed in the body:
 Involved in maintenance of GI mucosal lining
 Involved in kidney vasoregulation
 Involved in platelet aggregation
o COX-2–induced expression occurs only during the inflammatory
response 
 Non–COX-selective NSAIDs:
o Irreversibly (aspirin) or reversibly (other NSAIDs) inhibit both COX-
1 and COX-2 
o Decrease synthesis of: 
 Thromboxane A2 (TXA2)
 Prostaglandins
 Prostacyclins
o Therapeutic and adverse effects are attributed to diminution of
these eicosanoids
 COX-2–selective NSAIDs:
o Selectively inhibit COX-2
 o Decrease prostaglandin synthesis 
o Spare COX-1 and, therefore, TXA2 synthesis
o Have different side effect profiles from nonselective NSAIDs
Pharmacokinetics
NSAIDs are generally very similar:
 Lipid-soluble weak acids
 Nearly complete absorption from GI tract
o Topical formulations are available (diclofenac)
o IV formulations are available (ibuprofen)
 Minimal 1st-pass hepatic metabolism
 Highly protein-bound 
 Small volume of distribution
 Metabolized by CYP3A and CYP2C and /or glucuronidation.
 Half-lives vary from ＜ 2 to ＞ 8 hours.
 Excreted renally
Arachidonic acid pathway
HPETEs: hydroperoxyeicosatetraenoic acids
LOX: lipoxygenase
LT: leukotriene
Image by Lecturio. License: CC BY-NC-SA 4.0

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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Classification
NSAIDs can be divided into groups based on their ability to inhibit the isoforms of
cyclooxygenase (COX-1 and COX-2).
 Nonselective NSAIDs inhibit both COX-1 and COX-2.
o Included in this category: 
 Aspirin
 Diclofenac
 Ibuprofen
 Naproxen
 Mefenamic acid
 Indomethacin
 Ketoprofen
 Piroxicam
 Sulindac
 Selective NSAIDs inhibit only the COX-2 isoform.
o Included in this category:
 Celecoxib
 Meloxicam (at doses < 7.5 mg/day)
Indications

 Aspirin:
 o Low dose (< 300 mg/day): antiplatelet effect to prevent
atherosclerotic ischemic events
o Medium dose (300–2400 mg/day): analgesic and antipyretic effects
o High dose (2400–4000 mg/day): antiinflammatory effect
 Reversible NSAIDs:
o Analgesic
o Antipyretic
o Antiinflammatory
o Closure of patent ductus arteriosus (indomethacin)
 Celecoxib:
o Rheumatoid arthritis
o Osteoarthritis
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Aspirin (ASA)

Adverse Effects

GI tract effects
 Prostaglandins inhibit gastric acid secretion and promote protective mucus
production. 
 NSAIDs block prostaglandins:
o → Dyspepsia
o → GI erosion
o → GI ulceration
o → GI bleeding
Cardiovascular effects
 Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation.
 NSAIDs block prostacyclin:
 o → Vasoconstriction
o → Platelet aggregation
 Platelets contain only COX-1, which produces TXA2.
 Thromboxane A2 is a potent vasoconstrictor and platelet aggregator and is
thrombogenic.
 Selective COX-2 inhibition results in unopposed COX-1 effects:
o → Vasoconstriction
o → Platelet aggregation
o → Prothrombotic state
 Long-term COX-2 inhibitor use is associated with increased risk of
cardiovascular complications. 
 Nonselective NSAIDs (except aspirin) also are associated with increased
risk (though less than with selective COX-2). 
 Safest NSAID/cardiovascular risk profile in this setting appears to be
naproxen.
Renal effects
 Prostaglandins are involved in renin release, regulation of vascular tone, and
control of tubular function in the kidneys.
 NSAIDs block prostaglandins:
o → AKI
o → Interstitial nephritis
o → Renal papillary necrosis
Miscellaneous effects
 NSAID-associated bleeding risk significant only in combination with
other anticoagulants.
 Diclofenac and sulindac have been associated with liver dysfunction and
failure.
Aspirin Toxicity
Salicylate toxicity is a series of symptoms and metabolic disturbances attributable to
excessive ingestion of salicylic acid (e.g., aspirin and other over-the-counter (OTC)
preparations). Accidental exposure is seen in pediatric patients, whereas purposeful
exposure is more commonly observed in adolescents and young adults
(i.e., suicide attempt).
 Initial symptoms:
o Nausea and vomiting
o Tinnitus and vertigo (cranial nerve (CN) VII overactivation)
o Diaphoresis
o Hyperventilation
o Tachycardia
o Hyperactivity 
 Symptoms of progressive toxicity:
o Agitation
o Delirium
o Convulsions
o Lethargy/stupor
o Hyperthermia
 Metabolic (acid–base) disturbance:
o The early phase of respiratory alkalosis: due to the overactivation of
the medullary respiratory center
o The middle phase of combined respiratory alkalosis and metabolic
acidosis
o The late phase of high anion gap metabolic acidosis: due to aspirin
metabolite (salicylate)
 Treatment:
o Aspirin toxicity treated with sodium bicarbonate (NaHCO3–): sodium
bicarbonate alkalinizes urine, facilitating salicylate excretion.
 o Dialysis may be needed if sodium bicarbonate treatment is
unsuccessful.
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Aspirin Toxicity

Comparison of NSAIDs

Table: Comparison of NSAIDs

Class Mechanism of Clinical use Side effects

action

Reversible
NSAIDs  Reversib  Analgesic  Gastric ulcers
(e.g., ly inhibit and GI bleeding
 Antipyretic
ibuprofen, COX-1
 AKI
ketorolac,  Antiinflam
and
indometh matory  Interstitial
acin) COX-2
nephritis
 Closure
 Decreas
of patent  Renal papillary
ed
ductus necrosis
prostagl
arteriosus (
andin  Aspirin:
PDA)
and
o Reye
thrombo
syndrom
xane
e in
A2 (TXA2)
children
synthesi
with a
s
viral
infection
Aspirin
 Irreversi  Low dose o Asthma-
bly (< 300 like
inhibits mg/day): symptom
COX-1 antiplatele s in
Table: Comparison of NSAIDs

Class Mechanism of Clinical use Side effects

action

and t
COX-2
 Medium
 Decreas dose (300–
ed 2400
prostagl mg/day):
andin analgesic
and and
TXA2 syn antipyretic
patients with
thesis
 High dose nasal polyps
(2400– or atopy
4000
o Tinnitus
mg/day):
antiinflam o Mixed respira
matory tory alkalosis–
metabolic

COX-2  Rheumatoi
inhibitors  Selectiv  Increased risk of
(e.g., d arthritis
ely thrombosis:
celecoxib)  Osteoarthr
inhibit
o Deep
itis
COX-2
venous
 Decreas thrombos
ed is
prostagl
o Pulmonar
andin
y
synthesi
embolism
s
 Acute MI
 Spared
 Table: Comparison of NSAIDs

Class Mechanism of Clinical use Side effects

action

platelets  Sulfa allergy

and
TXA2 syn
thesis

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3. Solomon, D.H. (2021). Overview of COX-2 selective NSAIDs. UpToDate. Retrieved June 20,
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