Nonsteroidal Antiinflammatory Drugs

(NSAIDs)
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 updated: November 23, 2022

CONTENTS

Pharmacodynamics
Classification
Indications
Adverse Effects
Aspirin Toxicity
Comparison of NSAIDs
References

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:
Thromboxanes:
Involved in platelet adhesion
Involved in vasoconstriction
Prostaglandins:
Mediate inflammation
Increase hypothalamic temperature set-point
Involved in anti-nociception
Trigger uterine contractions during menstruation
Prostacyclin (prostaglandin I2):
Inhibits platelet aggregation
Involved in vasodilation
There are 2 COX isoenzymes:
COX-1 is constitutively expressed in the body:
Involved in maintenance of GI mucosal lining
Involved in kidney vasoregulation
Involved in platelet aggregation
COX-2–induced expression occurs only during the inflammatory response
Non–COX-selective NSAIDs:
Irreversibly (aspirin) or reversibly (other NSAIDs) inhibit both COX-1 and COX-2
Decrease synthesis of:
Thromboxane A2 (TXA2)
Prostaglandins
Prostacyclins
Therapeutic and adverse effects are attributed to diminution of these
eicosanoids
COX-2–selective NSAIDs:
Selectively inhibit COX-2
Decrease prostaglandin synthesis
Spare COX-1 and, therefore, TXA2 synthesis
Have different side effect profiles from nonselective NSAIDs

Pharmacokinetics
NSAIDs are generally very similar:
 Lipid-soluble weak acids
Nearly complete absorption from GI tract
Topical formulations are available (e.g., diclofenac)
IV formulations are available (e.g., 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.
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.

Included in this category:
Aspirin
Diclofenac
Ibuprofen
Naproxen
Mefenamic acid
Indomethacin
Ketoprofen
Piroxicam
Sulindac
Selective NSAIDs inhibit only the COX-2 isoform.
Included in this category:
Celecoxib
Meloxicam (at doses < 7.5 mg/day)

Indications
 Aspirin:
Low dose (< 325 mg/day):
Antiplatelet effect to prevent atherosclerotic ischemic events (usually at
doses of 75–100 mg/day)
Note: per the USPSTF, initiation of daily low-dose aspirin is no longer
recommended for primary prevention of cardiovascular disease in people
> 60 yrs
Medium dose (325–4000 mg/day): analgesic and antipyretic effects
High dose (4000–8000 mg/day):
Antiinflammatory effect
The usual maximal dose is 4500 mg/day due to concern for toxicity (e.g.,
gastrointestinal bleeding and ulceration, hearing loss, tinnitus)
Note: These are not necessarily hard cutoffs, and there is some overlap
between these categories.
Reversible NSAIDs:
Analgesic
Antipyretic
Antiinflammatory
Closure of patent ductus arteriosus (indomethacin)
Celecoxib:
Rheumatoid arthritis
Osteoarthritis

Adverse Effects
GI tract effects
Prostaglandins inhibit gastric acid secretion and promote protective mucus
production.
NSAIDs block prostaglandins:
→ Dyspepsia
→ GI erosion
→ GI ulceration
→ GI bleeding

Cardiovascular effects
 Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation.
NSAIDs block prostacyclin:
→ Vasoconstriction
→ 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:
→ Vasoconstriction
→ Platelet aggregation
→ 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:
→ AKI
→ Interstitial nephritis
→ 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:
Nausea and vomiting
Tinnitus and vertigo (cranial nerve (CN) VIII overactivation)
Diaphoresis
Hyperventilation
Tachycardia
Hyperactivity
Symptoms of progressive toxicity:
Agitation
Delirium
Convulsions
Lethargy/stupor
Hyperthermia
Metabolic (acid–base) disturbance:
The early phase of respiratory alkalosis: due to the overactivation of the
medullary respiratory center
The middle phase of combined respiratory alkalosis and metabolic acidosis
The late phase of high anion gap metabolic acidosis: due to aspirin metabolite
(salicylate)
Treatment:
Aspirin toxicity treated with sodium bicarbonate (NaHCO3–): sodium bicarbonate
alkalinizes urine, facilitating salicylate excretion.
Dialysis may be needed if sodium bicarbonate treatment is unsuccessful.

Comparison of NSAIDs
Table: Comparison of NSAIDs

Class Mechanism of Clinical use Side effects

action

Reversible Reversibly Analgesic Gastric ulcers

NSAIDs (e.g., inhibit COX-1 Antipyretic and GI
ibuprofen, and COX-2 Antiinflammatory bleeding
ketorolac, Decreased Closure of patent AKI
indomethacin) prostaglandin ductus arteriosus Interstitial
and (PDA) nephritis
thromboxane Renal papillary
A2 (TXA2) necrosis
synthesis Aspirin:
Reye
syndrome
in children
Aspirin Irreversibly Low dose (< 300 with a viral
inhibits COX-1 mg/day): infection
and COX-2 antiplatelet Asthma-like
Decreased Medium dose symptoms
prostaglandin (300–2400 in patients
and TXA2 mg/day): with nasal
synthesis analgesic and polyps or
antipyretic atopy
High dose Tinnitus
(2400–4000 Mixed
mg/day): respiratory
antiinflammatory alkalosis–
metabolic
acidosis

COX-2 Selectively Rheumatoid Increased risk

inhibitors (e.g., inhibit COX-2 arthritis of thrombosis:
celecoxib) Decreased Osteoarthritis Deep
prostaglandin venous
synthesis thrombosis
Spared Pulmonary
platelets and embolism
TXA2 Acute MI
synthesis Sulfa allergy
References

1. Solomon, D.H. (2020). Nonselective NSAIDs: overview of adverse effects. UpToDate. Retrieved June 20, 2021,
from [Link]
2. Solomon, D.H. (2019). NSAIDs: pharmacology and mechanism of action. UpToDate. Retrieved June 20, 2021,
from [Link]
3. Solomon, D.H. (2021). Overview of COX-2 selective NSAIDs. UpToDate. Retrieved June 20, 2021, from
[Link]
4. Phillips, W.J., Currier, B.L. (2004). Analgesic pharmacology: II. Specific analgesics. J Am Acad Orthop Surg
12:221–233. [Link]
5. Dawood, M.Y. (2006). Primary dysmenorrhea: advances in pathogenesis and management. Obstet Gynecol
108:428–441. [Link]
6. Shekelle, P.G., et al. (2017). Management of gout: a systematic review in support of an American College of
Physicians clinical practice guideline. Ann Intern Med 166:37–51. [Link]
7. Oyler, D.R., et al. (2015). Nonopioid management of acute pain associated with trauma: Focus on
pharmacologic options. J Trauma Acute Care Surg 79:475–483. [Link]
8. Zacher, J., et al. (2008). Topical diclofenac and its role in pain and inflammation: an evidence-based review.
Curr Med Res Opin 24:925–950. [Link]
9. Van den Bekerom, M.P.J., et al. (2015). Non-steroidal anti-inflammatory drugs (NSAIDs) for treating acute ankle
sprains in adults: benefits outweigh adverse events. Knee Surg Sports Traumatol Arthrosc 23:2390–2399.
[Link]
10. May, J.J., Lovell, G., Hopkins, W.G. (2007). Effectiveness of 1% diclofenac gel in the treatment of wrist extensor
tenosynovitis in long distance kayakers. J Sci Med Sport 10:59–65. [Link]
11. Barkin, R.L. (2015). Topical nonsteroidal anti-inflammatory drugs: the importance of drug, delivery, and
therapeutic outcome. Am J Ther 22:388–407. [Link]
12. Vane, J.R. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New
Biol 231:232–235. [Link]
13. Chaiamnuay, S., Allison, J.J., Curtis, J.R. (2006). Risks versus benefits of cyclooxygenase-2-selective
nonsteroidal antiinflammatory drugs. Am J Health Syst Pharm 63:1837–1851.
[Link]
14. Day, R.O., Graham, G.G. (2013). Nonsteroidal anti-inflammatory drugs (NSAIDs). 346:f3195.
[Link]