NON-STEROIDAL

ANTI-INFLAMMATORY DRUGS
(NSAID’s)
 Eicosanoids
PGs, TXA2 LTs, prostacyclins, all
derived from precursor fatty acid,
arachidonic acid, are called eicosanoids.
( eikosi, Greek word, means twenty)
 Prostanoids
PGs, prostacyclins, TXA2 collectively
called as prostanoids.
 Scheme for Prostaglandin Biosynthesis with inhibitors
Stimulus

Disturbance of cell membrane

Phospholipids
Corticosteroids inhibit X Phospholipase – A2
Arachidonic Acid
Lipoxygenase Cyclooxygenase
X
Aspirin & NSAIDs
inhibit
Hydroperxides
PGG2
Endoperoxides
PGH2 Pr
sy osta

TX synthetase
e nth cy
e tase
as

er as eta clin
uc
er

Isom d se e
om

Re
Is

Leukotrienes PGE2 PGF2α PGD2 TXA2 Prostacycline

PROSTANOIDS (PGs & Txs)
PGI2 (prostacyclin) is located
predominantly in vascular
endothelium. Main effects:
•vasodilatation
•inhibition of platelet aggregation
TxA2 is found in the platelets.
Main effects:
•platelet aggregation
•vasoconstriction
PGE2 causes:
•inhibition of gastric acid secretion
•contraction of pregnant uterus
•contraction of GI smooth muscles

PGF2α – main effects:

•contraction of bronchi
•contraction of myometrium
 Classification
A- EFFECT BASED CLASSIFICATION
 Drugs with analgesic & marked
Anti-inflammatory Effect
a. Salicylic Acid derivatives
• Aspirin ( Acetyl salicylic Acid)
• Salicylic Acid
• Sodium Salicylate
• Methyl Salicylate
• Choline Salicylate
• Magnesium salicylate
• Diflunisal
b. Pyrazolone Derivatives
• Phenylbutazone
• Azapropazone
• Oxyphenbutazone
• Sulphinpyrazone
• Dipyron
[Link] Acid Derivatives
• Diclofenac Sulindac
• Indomethacin Etodolac
• Tolmetin
d. Oxicams
 Piroxicam Tenoxicam Meloxicam
II. Drugs with analgesic & moderate
Anti-inflammatory Effect

a. Propionic Acid Derivatives

• Ibuprofen Fenoprofen
• Ketoprofen Flurbiprofen
• Indoprofen Carprofen
• Naproxen Oxaprozin
b. Fenamic Acid Derivatives
(Fenamates)
• Mefenamic Acid
• Flufenamic Acid
• Meclofenamic Acid
• Tolfenamic acid
III. Drugs with analgesic & weak
Anti-inflammatory Effect:

 Aniline Derivative
Paracetamol / Acetaminophen

B- SELECTIVITY BASED
CLASSIFICATION

I- COX-2 Selective inhibitors

Celecoxib
Valdecoxcib
Rofecoxib
II- Non-Selective inhibitors :
Inhibiting both COX-1 & COX-2, includes all
gps. Mentioned under effect based
classification

III- COX-3 inhibitors

Paracetamol
 COX enzyme
 COX-1 “Constitutive enzyme”most tissues including
blood, platelets & GIT, serve as house keeping
functions, like cytoprotection of gastric epithelium.

 COX-2 is induced in the cells when they are stimulated

& is responsible for production of prostanoid mediators
of inflammation.
 Glucocorticoids inhibits PLA2 , also inhibits expression
of COX-2 but not of COX-1.
 COX-3 sufficiently similar to COX-1,the COX-3 enzyme
is without inflammatory action, found in CNS.
 ASPIRIN
 Prototype of traditional NSAIDs
 Willow bark & leaves- Salicin (glucoside)
 Synthesized in 1853
COOH
 Acetyl salicylic acid
 Organic acid OOCCH3

 pKa –3.5
 Aspirin- Pharmacokinetics
and metabolism

 Absorbed rapidly through stomach & [Link], it can

also be absorbed through rectal mucosa.
 Can cross both the BBB & placenta
 PPLs 1-2 hrs, t1/2 15 min
 Hydrolyzed to salicylate & acetic acid by esterases in
tissues and blood.
 Salicylate is 80-90-% PPB
 Salicylate is metabolized in liver into:
[Link] acid (glycine conjugate)
[Link] conjugate
[Link]-----Oxidized to--- Gentisic acid
Conjugated in liver and cleared by kidney
 When dose is small (600mg TDS)---- First order kinetics &
t1/2 is 3-5hrs
 When dose is large---- Zero order kinetics & t 1/2 is 12-16
hrs
 Excretion

25 % excreted unchanged & 75 % as metabolites in urine ,

enhanced by ALKLINIZATION
 MOA of Aspirin / NSAIDs
 Aspirin & NSAIDs inhibits biosynthesis of PGs, by
inactivating COX enzymes
 Aspirin is non selective COX inhibitor, causes
acetylation of COX-1 & COX-2, thus irreversibly inhibit
cyclooxygenase activity, while most of NSAIDs act as
reversible competitive inhibitor of COX activity.
 They do not inhibit lipooxygenase pathway of AA
metabolism so not suppress LT formation.
Various NSAIDs have additional mechanism of action,
including
 inhibition of chemotaxis

 Decrease proinflammatory cytokines (TNF-  , IL-1)

 Decrease production of free radicals & superoxides

 Induce apoptosis

 Interferes Ca-mediated intracellular events

 Mechanism of action

Cosrticosteroids Membrane phospholipids

Phospholipase
Arachidonic acid

Lipoxygenase COX NSAIDS

Leukotienes Prostaglandins Thromboxane Prostacyclin

Pharmacological
Actions of NSAIDs/
ASPIRIN
 Anti –inflammatory Effect

Inhibits PG synthesis at the periphery. This results in

• Inhibition of granulocytes adherence to damaged vasculature

• Stabilizes lysosomes
• Inhibit migration of polymorphs and macrophages at site of
inflammation.
• Interferes with chemical mediators of kalikrein system.

 Suppresses all manifestations of inflammation

 Analgesic Effect
 NSAIDs are classified as mild to moderate analgesics
 Bradykinins, histamine & cytokines (TNF-  , IL-1)
liberates PGs, after inflammation & tissue injury which
sensitizes pain receptors to mechanical & chemical
stimulation & decreases threshold of nociceptors of C
fibers.
 NSAIDs produces analgesia by inhibition of PGs
synthesis.
 They relieves pain by peripheral action, direct action on
CNS also involved.
 Antipyretic
 Hypothalamus regulates body temp. & maintains temp.
at a set point.
 Fever after infection & tissue injury, leads to formation of
cytokines (TNF- , IL-1) which ↑es synthesis of PGs
which triggers hypothalmus to raise body temp.
 NSAIDs & aspirin suppress this response by inhibiting
PGs synthesis.
 They do not inhibit fever by directly administered PGs,
rather inhibit fever caused by agents that promote
synthesis of IL-2 & other cytokines.
 Anti-platelet effect
 Aspirin in small doses (75-100mg) decreases platelet
aggregation by suppressing the synthesis of thromboxane
– A2.
 It irreversibly acetylates the COX so effect lasts for 8 – 10
days till new platelets are regenerated
 High doses suppress prostacyclins also and platelet
inhibitory effect is lost
 Effect on GIT
NSAIDs & aspirin produces anorexia, nausea, abd. pain,
diarrhea, gastric & intestinal ulcers, due to
 Inhibition of COX-1 in GIT mucosa depresses PGI 2
& PGE2 synthesis which inhibits acid secretion, es
mucus secretion, enhances  mucosal blood flow.
 They cause local irritation, which causes back
diffusion of acid into gastric mucosa & induces tissue
damage.
 Occurs more with aspirin b/c it irreversibly acetylates
COX enzymes
Uricosuric Effects
 Low doses(1-2g/day), es urate excretion & elevate plasma
urate concentration.
 In High doses (above 5 g/day) induce uricosuria & lower
plasma urate level.
 Intermediate doses (2-3g/day) do not alter urate excretion

CVS
 Low doses of aspirin(<100mg/daily) use for cardioprotective
effects.
 At high therapeutic doses(>3g/daily) it causes salt & water
retention, which increase circulating plasma volume
 Peripheral vasodilatation, due to direct effect on vascular
smooth muscles.
Renal Effects
 NSAIDs have little effect on renal function in normal

human subjects.
 COX inhibitors prevent synthesis of PGE & PGI which
2 2
are responsible for maintaining renal blood flow, water
& salt excretion.
 synthesis of PGs by NSAIDs results in salt & water

retention & may cause edema & hyperkalemia in some

pts.
Respiration
 At therapeutic doses, Salicylates es O consumption
2
&CO2 production as a result of uncoupling oxidative
phosphorylation,  CO2 production stimulates
respiration.
 Higher doses act directly on resp. center causing

hyperventilation & resp. alkalosis.

Hepatic Effects
High doses of salicylates cause reversible hepatic injury
Metabolic Effects
Oxidative phosphorylation
 Uncoupling of oxidative phosphorylation by salicylates

Carbohydrate metabolism
 Large doses of salicylates cause hyperglycemia

glycosuria & deplete liver & muscle glycogen

Local Irritant Effects
Saicylic acid is irritant to skin & mucosa & destroy
epithelial cells, this action is used for treatment of
warts, corns, fungal infections & eczematous
dermatitis.
Methyl salicylate used as counter-irritant.
 Salicylates & Pregnancy :

Long period use of salicylates during pregnancy, results in delivery

of low birth wt. babies
When given during third trimester, there is increase perinatal
mortality, anemia, antepartum & postpartum hemorrhages,
prolonged gestation , premature closure of ductus arteriosus &
complicated deliveries.
 Therapeutics Uses of Aspirin
1- Analgesia
Aspirin is one of the most frequently used analgesic
For mild to moderate pain especially arising from
integumental origin is better relieved than of visceral
origin
Severe pain is not controlled by aspirin
used in pain like.
 Toothache, Headache, Myalgia, Arthralgia, Neuralgia
 Dysmenorrhea
2- Anti Inflammatory

NSAIDs & aspirin are used in treatment of

musculoskeletal disorders, they relief pain &
inflammation associated with diseases, such as
Rheumatoid arthritis
Osteoarthritis
Ankylosing spondylitis
Gout
3. Anti pyretic
NSAIDs & aspirin reduce all fevers but not effective in
raised body temperature due exercise induced.

4. Anti platelet
Low doses 80 – 100mg/day are used prophylactically
 For transient ischemic attacks & Cerebrovascular
stroke.
 Prophylaxis of Unstable angina, MI
 Thrombosis after coronary artery by pass grafting.
5- Systemic Mastocytosis
A condition associated with excessive formation of mast
cells in bone marrow, RES, GIT, bones & skin. Large
amount of PGD2 released from mast cells which causes
severe episodes of vasodilatation & [Link]
PGD2 effect is resistant to antihistamines.
Aspirin & ketoprofen are useful in this condition.
4- Bartter´s Syndrome
 Rare disorder characterized by

hypokalemia, hypochloremic metabolic

alkalosis with normal B.P & hyperplasia
of JG [Link] is functional
mutation in Na-K-2Cl cotransporter in
ascending limb of LOH.
 Renal COX-2 is induced, synthesis of

PGE2 is increased.
 Treatment with NSAIDs along with
spironolactone is useful.
5- Cancer Chemoprevention
Frequent use of aspirin associated with
50% decrease in risk of colon cancer.

6- Niacin Tolerability
Large doses of niacin used to reduce
serum cholesterol, however it induces
intense flushing by release of PGD2
from skin, which can be inhibited by use
with aspirin.
7- Closure of PDA
PGs implicated in maintenance of patency of ductus
arteriosus & indomethacin & other NSAIDs have been
used in neonates to close inappropriately patent
ductus.

8- Topical uses
 Saicylic is used for treatment of warts, corns, fungal

infections & eczematous dermatitis.

 Methyl salicylate (oil of wintergreen) used as counter-

irritant for relief of mild musculoskeletal pain.

 Common Adverse Effects
1- CNS: headaches, tinnitus, vertigo, confusion & dizziness
2- CVS: Fluid retention, HT, edema, rarely CCF
3. GIT: abd. pain, anorexia, N, V, D ulcers & bleeding
4. Hematologic: Rarely thrombocytopenia, neutropenia or even
aplastic anemia
5- Hepatic : abnormal LFTs, rarely liver failure
6- Pulmonary: Asthma in sensitive individuals
7- Rashes: pruritis, urticaria, flushing
8- Renal: renal insufficiency, renal failure, hyperkalemia, salt &
water retention, edema & proteinuria
Reye´s Sndrome
 Associated with use of aspirin & other salicylates
 occurs when aspirin is given in children & young adults
less than 20years with fever associated with viral illness.
 Characterized by acute onset of encephalopathy, liver
dysfunction, fatty infilteration of liver & other viscera
 Acetaminophen not associated with Reye´s syndrome,
drug of choice for antipyresis in children & teens.
 Aspirin Toxicity - Salicylism
 Headache - tinnitus - dizziness – hearing impairment – dim
vision
 Confusion and drowsiness
 Sweating and hyperventilation
 Nausea, vomiting
 Marked acid-base disturbances
 Hyperpyrexia
 Dehydration
 Cardiovascular and respiratory collapse,
 Coma convulsions and death
 Management of Aspirin / Salicylate
Overdose toxicity / Poisoning
1. Gastric Lavage
2. Activated Charcoal
3. Correct electrolyte, fluid & acid base balance
4. Aggressive volume repletion with I/V fluids
5. Keep airway patent
6.  Body temp. by cold sponging
7. Vit. K I/V to correct hypoprothrombinemia
8. Diazepam I/V - convulsions.
9. Promote excretion of salicycates by NaHCO 3 I/V to
alkalinize urine, maintain pH at 8.0
10. Hemodialysis in pt. with severe acidosis & coma.
Contraindications
APD
Children with viral infections
Pregnancy
Hypersensitive pts
Paracetamol / Acetoaminophen
 Aniline derivative
 Chemically is N-acetyl-p-aminophenol
 It is the active metabolite of phenacetin
 Unlike aspirin, acetaminophen is primarily centrally
acting.
 COX-3, found in the brain and spinal cord, which is
selectively inhibited by paracetamol.
 Selective inhibition of the enzyme COX-3 in the
brain and spinal cord explains the effectiveness of
paracetamol in relieving pain and reducing fever
 Paracetamol has no significant action on COX-1
and COX-2, so lack of anti-inflammatory action &
GIT side effects.
Ph. Actions
• Analgesic , antipyretic effects similar to aspirin
• No or weak anti-inflammatory
• Do not produce gastric irritation, erosion or bleeding
• No effect on CVS & respiratory system
• No effect on platelet aggregation or coagulation
• No effect on uric acid excretion
• No effect on acid-base balance
Therapeutic Uses
 Used as analgesic & antipyretic particularly for pts. in

whom aspirin is contraindicated

 Pharmacokinetics
 Given orally
 PPL---30-60min, t-1/2—2hrs

 PPB---25%

 Metabolized in liver

 Excreted by kidneys in urine

Toxicity & Common Adverse Affects

 Well tolerated

 Most serious acute adverse effect of overdosage of

acetaminophen is fatal hepatic necrosis

At therapeutic doses(1.2g/d) -- Mild increase in hepatic enzymes
Doses above 4g may be toxic, 15G may be fatal.
 Paracetamol is metabolized primarily in the liver, into non-
toxic products by glucuronidation, sulfation & N-
hydroxylation(95%) & remaining 5% by P450 dependent
GSH conjugation forming toxic metabolite known as
NAPQI (N-acetyl-p-benzoquinoneimine). At toxic doses
glucuronidation & sulfation pathways are saturated & drug
is metabolized by P450 dependent pathway to form
NAPQI, no hepatotoxicity occurs as long as GSH is
available for conjugation.
 But when hepatic GSH depleted, highly reactive NAPQI,
reacts with hepatic cellular proteins, causing
hepatotoxicity.
Management of toxicity
 Stop the drug
 Induce vomiting
 Gastric Lavage generally not recommended
 Activated Charcoal – to prevent further absorption
 Correct electrolyte, fluid & acid base balance
 Antidote--N-Acetylcysteine (NAC) replete GSH stores, &
conjugate directly with NAPQI & serve as GSH
substitute
 COX II Inhibitors
1) Selective COX-2inhibitors (Coxibs)
Celecoxib
Rofecoxib
Etoricoxib
Valdecoxib
Parecoxib
Lumaricoxib
2) Preferential COX-2 inhibitors
Meloxicam
Nimesulide
Nabumetone
 COX-2 expression
 It is expressed primarily in the brain, kidneys, female
reproductive system and bone, & induced by
inflammatory cytokines in other tissues, such as
endothelial cells.
 COX-2 is not found in platelets, but COX-2 in
endothelial cells induces prostacyclin synthesis, which
prevents platelet aggregation and promotes
vasodilatation.
 COX-2 inhibitors block endothelial prostacyclin
synthesis, which leads to platelet aggregation and
vasoconstriction.
Celecoxib
 10-20 times more selective for COX-2 than for COX-1
 Is as effective as other NSAIDs in the treatment of
rheumatoid arthritis and osteoarthritis.
 It causes fewer endoscopic ulcers than most other
NSAIDs.
 It is a sulfonamide, so cause rashes.
 It does not affect platelet aggregation at usual doses.
 It inhibit COX-2 mediated prostacyclin synthesis in
vascular endothelium so do not offer cardioprotective
effects.
Meloxicam
 Preferentially inhibit COX-2 than COX-1, particularly at
its lowest therapeutic dose. It is not as selective as the
other coxibs and may be considered “preferentially"
selective rather than “highly” selective.
 Use for treatment of osteoarthritis and rheumatoid
arthritis.
 It is associated with fewer clinical GI symptoms &
complications than piroxicam, diclofenac,& naproxen.
 Other toxicities are similar to those of other NSAIDs.
 Aspirin Paracetamol
1-Source:
Willow bark & leaves  Semi-synthetic
2- Chemistry:  Analine derivative
Acetyl-salicylic acid  active metabolite of
Phenacetin
2-
 N-acetyl-p-aminophenol
3- Pharmacokinetics: 3- Pharmacokinetics:
 Absorption pH dependent
 Mainly absorbed from
 Partly absorbed from
small intestine
stomach, mainly absorbed  PPL : 30- 60 min
from [Link]  t-1/2 : 2hrs
 PPL :1 hr
 PPB : 25%
 t-1/2 : 15min
 Metabolism :Hepatic
 PPB : 80-90 %

 Metabolism: Hepatic
4- Metabolites: 4- Metabolites:
mainly Metabolites form by
 Salicyluric acid  Sulphation, glucuronidation
 Glycine conjugates  5% oxidised to N-acetyl – para
 Gentistic acid benzo quinonimine which is
buffered with reduced
Glutathion
5- Elimination: 5- Elimination:
 only first order kinetics
 First order kinetics with
 with higher doses NAPQI
smaller doses, Zero order
kinetics with higher doses formed depleting glutathion
stores, & causes
hepatotoxicity
 Renal elimination is increased  No effect of alkalinization of
by alkalinization of urine
urine on elimination
6- MOA 6- MOA
 Non-selective irreversible
 Selective COX-3 inhibitor
COX inhibitor mainly at the
periphery mainly in the brain
7-Pharmacological
actions:
 Marked anti- inflammatory  Very weak anti-
action inflammatory action
 Analgesic
 Analgesic
 Anti-pyretic

 Anti- platelet effect

 Anti-pyretic
 No Anti-platelet effect
8- Uses Mainly use as
 Analgesic
 Analgesic
 Anti-inflammatory  Anti-pyretic

 Anti-pyretic  In Reye’s Syndrome

 Uricosuric in high doses

 Anti-platelet
 PDA
 Colon cancer (prevention)
 Familial polyposis coli
 Bartter’s Syndrome
 Niacin induced flushing due
to PGD2
 Systemic mastocytosis
9- Reye’s syndrome if given 9- Safely used in children
as antipyretic during viral
infections in children.

10- Cause complication during

10- Safe during pregnancy
pregnancy, if given for long
period
 Acetic Acid Derivatives

 Indomethacin
 Diclofenac
 Sulnidac
 Tolmetin
 Etodolac
Indomethacin :
 Marked anti-inflammatory, analgesic-antipyretic properties
like salicylates
 More potent COX inhibitor than aspirin
 Patient’s intolerance limits its use, so not commonly used
as analgesic or antipyretic unless fever is refractory to other
agents (e.g., Hodgkin’s disease)
 When tolerated, more effective than aspirin in relieving joint
pain, ankylosing spondylitis, & osteoarthritis
 Not uricosuric but effective in Gout
 Approved drug for closure of patent ductus arteriosus
 Mechanism of Action of NSAIDs

CO2H

Arachidonic acid
COX-1 Non-specific COX-2
“Constitutive” NSAIDs “Inducible”
COX-2 NSAIDs

GI Mucosa Platelet
Prostaglandins
Prostaglandins Thromboxane

Mediate pain,
GI mucosal
Hemostasis inflammation, and fever
Protection