Nsaids (Lecture Note)

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDs)
 A group of anti-inflammatory drugs that are not steroidal.
 They have anti-inflammatory, analgesic, and antipyretic properties
CLASSIFICATION
A. Nonselective COX inhibitors (traditional NSAIDs)
They inhibit both Cox-1 and Cox-2
1. Salicylates: Aspirin (acetylsalicylate), methylsalicylate
2. Indole derivative: Indomethacin.
3. Propionic acid derivatives: Ibuprofen,Naproxen,Ketoprofen
4. Oxicam derivatives: Piroxicam, Tenoxicam.
5. Anthranilic acid derivative: Mephenamic acid
6. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
7. Pyrrolo-pyrrole derivative: Ketorolac
8. Pyrazolone derivative: phenylbutazone, oxyphenbutazone
B. Preferential COX-2 inhibitors
• Nimesulide
• Meloxicam
• Nabumeton
C. Selective COX-2 inhibitors

• Celecoxib
• Etoricoxib
• Parecoxib
• Etodolac
PHARMACOKINETICS
Most NSAIDS are absorbed from the stomach and small intestines. Being
weak acids, their absorption is aided by acidic nature of the stomach
content
( Acidic drug in acidic medium poorly ionized) Easily
(Basic drug in basic medium poorly ionized) absorbed
(Acidic drug in basic drug highly ionized) Poorly

(Basic drug in acidic medium highly ionized) absorbed
Most NSAIDs are highly plasma protein bound, and undergo
enterohepatic circulation.
 Most are metabolized by CYP450 enzyme system and the

metabolite excreted via the kidney.
Aspirin (acetylsalicylate, acetylsalicylic acid) is rapidly deacetylated

in the gut wall, liver, plasma and other tissues to release salicylic
acid (salicylate) which is the major circulating and active form.
 The metabolite (salicylates) are excreted by glomerular filtration

after conjugation (in low, and moderate doses), as well as tubular
secretion (in high doses).
 D/4, they can inhibit tubular secretion of uric acid d/b increasing
plasma uric acid concentration (gout).
MECHANISM OF ACTION
 The mechanism of anti-inflammatory, antipyretic, analgesic,

and anti-platelet effects of NSAIDS can be traced to inhibition
of the enzyme cyclo-oxygenase (COX).
 COX exists in three isoforms: COX-1, COX-2, and COX -3.
a. COX-1 (constitutive) acts in physiological conditions.

Performs house-keeping functions. Inhibited by nonselective
COX inhibitors, but not by COX-2 selective inhibitors
b. COX-2 (inducible) is induced in inflammatory cells by
pathological stimulus. Inhibited by nonselective and COX-2
selective inhibitors
c. COX-3 (in brain). Inhibited by COX-3 inhibitor (paracetamol)
TRAUMA OR INFECTION DISRUPTING CELL MEMBRANES
MEMBRANE PHOSPHOLIPIDS
Lipocortin
Glucocorticoids
Phospholipase A2 + - +
ARACHIDONIC ACID
5-Lipoxygenase
+
+ COX -1, COX-2 - NSAIDs
Leukotrienes
Cyclic endoperoxides
Thromboxane Prostaglandin
Synthase + + synthase
Thromboxanes Prostaglandins
-TXA2 - PGD2
- PGE2
- PGF2
- PGI2
Arachidonic acid metabolism showing the role of cyclo-oxygenases in the production of
thromboxanes and prostaglandins (inflammatory mediators)
PGE2 is synthesized through the cyclooxygenase (COX) pathway,
mainly by COX-1 enzyme.
PGE2 has two roles in gastric mucosal protection:

(a) It acts on parietal cells to inhibit the activity of the proton pump,
thereby reducing secretion of gastric acid.
(b) It also stimulates secretion of mucin and bicarbonate which

increases gastric pH.
NSAIDs inhibit COX-1 enzymes, thus reducing the amount of PGE2

and subsequently reducing the amount of protective mucus in the
stomach.
Nonselective Cox inhibitors are thus implicated in damage to the

gastric mucosa. Therefore PGE1 analogue (misoprostol) may be given
as an adjunct in patients undergoing NSAID therapy
Pharmacological effects of NSAIDs
Anti-inflammatory effect
 Due to the inhibition of COX that converts arachidonic acid to
prostaglandins, TXA2, and prostacyclin.
 Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific
serine residue while other NSAIDs, reversibly inhibit COX-1 and COX-2.
 Anti-inflammatory action is exerted at high doses (3-6 g/ day,
100mg/kg/day ) by inhibiting the production of inflammatory mediators
like PG
Analgesic effect
 Due to the peripheral inhibition of PG production (PG stimulates pain
fibres) as well as the inhibition of pain stimuli at a subcortical site.
 Prevents potentiating action of PG on endogenous mediators of peripheral
nerve stimulation (e.g., bradykinin).
Antipyretic effect
Due to inhibition of PG production in the hypothalamus thereby
“resetting” the thermoregulatory centre.
Antiplatelet effect:
At low doses aspirin preferentially inhibits platelet COX d/b
↓TXA2 synthesis. Also, platelets lack nuclei and cannot
synthesize new COX enzyme once it is inhibited whereas
endothelium can regenerate COX enzyme to produce PGI2.
Hence the use of low dose aspirin for prevention of myocardial
infarction.
Note: The COX-2 selective NSAIDs (coxibs) preferentially inhibit

prostacyclin rather than thromboxane synthesis thereby reversing
the thromboxane/prostacyclin ratio. D/4, they are prothrombotic.
Effect on respiration: At high doses, respiration is stimulated by effect
on respiratory centre (respiratory alkalosis). Hyperventilation is
prominent in salicylate poisoning.
Higher doses (salicylate accumulation) causes respiratory acidosis
which results in respiratory depression.
Renal effects: PG modulates renal blood flow. In normally functioning

kidneys this regulation is not very significant. However, in renal
failure, CCF, AGN, the role of PG in maintaining adequate renal
perfusion becomes very significant. D/4 NSAIDs are contraindicated
in such conditions.
Gastric irritation: Aspirin and released salicylic acid irritate gastric mucosa
which can lead to ulcer. The mechanism of ulceration include
• Direct mucosal damage,
• Stimulation of HCL by ↓PGE2 production (PGE2 inhibits HCL production).
• Inhibition of mucus production by gastric epithelial cells
Note: Stomach ulcers can be prevented by co-administration of PG analog
(PGE2 analog, Misoprostol), use of enteric coated aspirin or nonacetylated
salicylates.
Metabolic effects: At high doses, cellular metabolism is increased. Due to

uncoupling of oxidative phosphorylation, there is ↑ heat production.
There is increased utilization of glucose, blood sugar may decrease
(especially in diabetics) and liver glycogen is depleted.
CLINICAL USES
1. Analgesic agents: Especially for the reduction of pain of trauma, inflammation,

arthritis, surgery. Useful in dysmenorrhoea b/c PG are implicated in the
pathogenesis of dysmenorrhoea.
2. Anti-inflammatory agents: Useful for reducing the swelling associated with

acute trauma. The 0.1% ophthalmic solution of diclofenac is used to prevent post
op ophthalmic inflammation. The anti-inflammatory effect is also employed in the
treatment of rheumatic fever and rheumatoid arthritis.
3. Antipyretic agents: Fever of any origin can be treated with NSAIDs
4. Prophylaxis against myocardial infarction: By preferentially inhibiting platelet

aggregation at low doses (inhibition of platelet COX) aspirin decreases the
incidence of MI.
5. Closure of PDA: Pharmacological closure of PDA in premature infants using
indomethacin or ibuprofen (Prostaglandins are involved in maintaining the patency
of ductus arteriosus in the fetus).
6. Prophylaxis against colon cancer:

ADVERSE EFFECTS
1.GI disturbances
 Nausea, vomiting, dyspepsia, and gastric ulceration. Gastric ulcers can be
prevented by co-administration of PG analog (PGE2 analog, Misoprostol),
use of enteric coated aspirin or nonacetylated salicylates.
2. Renal disturbances
Chronic NSAID administration can cause analgesic nephropathy, nephritis or
renal papillary necrosis. Normal doses can cause acute renal failure in patients
with impaired renal function.
This is b/c PG modulates renal blood flow. In normally functioning kidneys this
regulation is not very significant.
3. Respiratory disturbances
 NSAIDs worsen existing asthma and can worsen asthmatic attacks.
This is b/c NSAIDs inhibit COX thereby diverting arachidonic cid metabolism to
the 5-lipoxygenase pathway leading to ↑ production of leukotrienes ( leukotrienes
are bronchoconstrictors and mucus secretants.
4. Uterus
 NSAIDs inhibit labour b/c PGE2α and PGF2α are involved in cervical
ripening and uterine contraction
5. Coagulation disturbances
Aspirin is anti-platelet. This results from inhibition of TXA2 formation. There is
therefore increasing bleeding tendency especially in hemophiliacs.
6. Ductus arteriosus
When given to pregnant women NSAIDs can cause premature closure of ductus
arteriosus in the fetus. This is b/c prostaglandins are involved in maintaining the
patency of ductus arteriosus in the fetus.
7. Salicylism
This consists of vomiting , vertigo, tinnitus, and hearing loss. It is caused by high
doses of aspirin. Normal therapeutic doses of aspirin and other NSAIDs can cause
tinnitus in patients with auditory impairment.
8. Skin reactions
Skin rashes can also occur, especially with mefenamic acid and sulindac.
DRUG INTERACTIONS/CI
Anticoagulants: Aspirin increases the anticoagulant effect of heparin and warfarins

b/c it inhibits the formation of formation of thromboxanes.
Uricosuric agents: Uricosuric agents such as probenecid and sulfinpyrazone increase

tubular secretion of uric acid. Aspirin is excreted by tubular secretion at high
doses. D/4 aspirin causes competitive inhibition of tubular secretion of uric acid
thereby increasing plasma uric acid level.
Bleeding disorders: The use of salicylates is contraindicated in patients with bleeding

disorders.
Pregnancy: Salicylates are contraindicated in pregnancy; they may induce:

• postpartum hemorrhage.
• premature closure of the fetal ductus arteriosus
• Delayed induction of labour.

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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

C. Selective COX-2 inhibitors

(Acidic drug in basic drug highly ionized) Poorly

 Most are metabolized by CYP450 enzyme system and the

Aspirin (acetylsalicylate, acetylsalicylic acid) is rapidly deacetylated

 The metabolite (salicylates) are excreted by glomerular filtration

 The mechanism of anti-inflammatory, antipyretic, analgesic,

a. COX-1 (constitutive) acts in physiological conditions.

PGE2 has two roles in gastric mucosal protection:

(b) It also stimulates secretion of mucin and bicarbonate which

NSAIDs inhibit COX-1 enzymes, thus reducing the amount of PGE2

Nonselective Cox inhibitors are thus implicated in damage to the

Note: The COX-2 selective NSAIDs (coxibs) preferentially inhibit

Renal effects: PG modulates renal blood flow. In normally functioning

Metabolic effects: At high doses, cellular metabolism is increased. Due to

1. Analgesic agents: Especially for the reduction of pain of trauma, inflammation,

2. Anti-inflammatory agents: Useful for reducing the swelling associated with

3. Antipyretic agents: Fever of any origin can be treated with NSAIDs

4. Prophylaxis against myocardial infarction: By preferentially inhibiting platelet

6. Prophylaxis against colon cancer:

Anticoagulants: Aspirin increases the anticoagulant effect of heparin and warfarins

Uricosuric agents: Uricosuric agents such as probenecid and sulfinpyrazone increase

Bleeding disorders: The use of salicylates is contraindicated in patients with bleeding

Pregnancy: Salicylates are contraindicated in pregnancy; they may induce:

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