Nsaids drm

By:
D. R. Mali
Assistant Professor,
GES’s Sir Dr. M. S. Gosavi College of
Pharmaceutical Education and Research, Nashik

Inflammation
 The clinical features of inflammation have been
recognized since ancient times as swelling, redness,
pain, and heat.
 The underlying mechanisms which produce these
symptoms are complex, involving many different cells
and cell products.
 A normal inflammatory response is essential to fight
infections and is part of the repair mechanism and
removal of debris following tissue damage.

• Inflammation can also cause disease, due
to damage of healthy tissue.
• This may occur if the response is over-
vigorous, or persists longer than is
necessary.
• Additionally, some conditions have a
previously unrecognized inflammatory
component, e.g. Atherosclerosis.

• The inflammatory response
occurs in vascularised tissues in
response to injury.
• It is part of the innate nonspecific immune
response.
• Inflammatory responses require activation of
• leukocytes: neutrophils, eosinophils, basophils,
• mast cells, monocytes, and lymphocytes,
• although not all cell types need be involved in
an inflammatory episode. The cells migrate to
the area of tissue damage from the systemic
circulation and become activated

Inflammatory disease
Acute respiratory distress
syndrome
Bronchial asthma
Atherosclerosis
Glomerulonephritis
Inflammatory bowel disease
Osteoarthritis
Psoriasis
Rheumatoid arthritis
Sarcoidosis
Inflammatory cell infiltrate
Neutrophil
Eosinophil,T cell, monocyte,
basophil
T cell, monocyte
Monocyte,T cell, neutrophil
Monocyte, neutrophil,T cell,
eosinophil
Monocyte, neutrophil
T cell, neutrophil
Monocyte, neutrophil
T cell, monocyte
Diseases with a chronic inflammatory component

Inflammatory mediators
Activated leukocytes at a site of inflammation release
compounds which enhance the inflammatory response
mainly cytokines and eicosanoids (arachidonic acid
metabolites).
But the complexity of the response is indicated by the
range of many mediators: complement products,
 kinins (bradykinin) and
 the contact system (coagulation factors XI and XII,
pre-kallikrein, high molecular weight kininogen);
nitric oxide and vasoactive amines (histamine,
serotonin and adenosine); activated forms of oxygen;
platelet activating factor (PAF);
 metalloproteinases (collagenases, gelatinases, and
proteoglycanase), etc.

Cytokines (ILs, TNFs, IFNs, CSFs, etc.)
are peptides regulating cell growth,
differentiation, and activation, and some have
therapeutic value:
• IL-1 plays a part in the sepsis syndrome
and rheumatoid arthritis, and successful
blockade of its receptor offers a
therapeutic approach for these conditions.
• TNFα is similar to IL-1. Agents that block him,
e.g. etanercept, infliximab are finding their place
among Disease modifying antirheumatic drugs.

Eicosanoids (prostaglandins, thromboxanes,
leukotrienes, lipoxins)
 A group of 20-carbon unsaturated fatty
acids, derived principally from arachidonic
acid in cell walls.
 They are short-lived, extremely potent,
and formed in almost every tissue in the
body.
 Involved in most types of inflammation
 Most current antiinflammatory therapy is
based on manipulation of their biosynthesis

(+)
Phospholipase A2Phospholipids
Arachidonic acid
5-lipoxygenase
Leucotrienes
Cyclooxy genase (COX)
Endoperoxides
PGs TxA2
15-lipoxygenase
Lipoxins
Inflammatory stimulus
Ex
In

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
PROSTANOIDS (PGs & Txs)

PGE2 causes:
• inhibition of gastric acid secretion
•contraction of pregnant uterus
•contraction of GI smooth muscles
PGF2α – main effects:
•contraction of bronchi
•contraction of miometrium

Cyclooxygenase (COX) is found
bound to the endoplasmatic
reticulum. It exists in 3 isoforms:
• COX-1 (constitutive) acts
in physiological conditions.
• COX-2 (inducible) is
induced in inflammatory cells
by pathological stimulus.
• COX-3 (in brain).

Beneficial actions of NSAIDs due
to prostanoid synthesis inhibition
1. Analgesia
prevention of pain nerve ending sensitization
2. Antipyresis
connected with influence of thermoregulatory
centre in the hypothalamus
3. Antiinflammatory action
mainly antiexudative effect
4. Antithrombotic action
in very low daily doses
5. Closure of ductus arteriosus

Shared toxicities of NSAIDs due
to prostanoid synthesis inhibition
1. Gastric mucosal damage
Gastritis and peptic ulceration with
bleeding connected with PGE inhibition
2. Bleeding: inhibition of platelet
function (TxA2 synthesis)
3. Limitation of renal blood flow
Na+ and water retention, edema
Analgesic

4. Delay / prolongation of labour
 connected with PGF2α inhibition
 Prolongation of gestation and inhibition
of labor.
5. Asthma and anaphylactoid reactions
 connected with PGF2α inhibition
 Hypersenstivity (not immunologic)

Mechanisms by which NSAIDs may induce mucosal injury
Hypersenstivity (not immunologicHypersenstivity (not immunologic

Contraindications of Non-selective NSAIDs
 Peptic ulcer
 Pregnancy
 Hemophilic patients
 Patients taking anticoagulants drugs

Mechanism
of ActionNSAI
D
NSAIDS

 Inhibitor of
cyclooxygenase enzyme.
 (also known as
prostaglandin
endoperoxide synthase
or PGH synthase)
 The rate-limiting
enzyme responsible for
the biosynthesis of PGs.
Mechanism
of Action
 PGs are short-lived, lipidlike molecules.
 Play a vital role in modulating many important
physiological and pathophysiologicalfunctions including
pain, inflammation, gastric acid secretion, wound healing,
and renal function.

 NSAIDs strongly inhibit PG synthesis in various tissues,
especially at the site of the tissue damage or inflammation.
 This inhibition occurs at the stage of oxidative cyclization
of AA,
cyclooxygenase (or PGH synthase),
AA hydroperoxy-endoperoxide ( PGG2)
 Its subsequent reduction to key intermediate, prostaglandin
H2 (PGH2) needed for all prostaglandin.
 Biosynthesis Blockade of PGH2 production, thus prevents its
further conversion, into different biologically active PGs
including PGE2, PGD2, PGF2, PGI2 (prostacyclin), and
thromboxane A2 (TXA2).
 PGI2 and PGE2 made at the site of injury (via COX-2
isozyme in the inflammatory cells such as monocytes and
macrophages) and also in the brain, are known to play a
dominant role in mediating inflammation and inducing
hyperanalgesia
 Newer “coxibs” are selective COX-2 inhibitors,

ENZYMATIC STRUCTURE OF CYCLOOXYGENASES (COX-1 & COX-2)
 Heme-containing, membrane-bound proteins .
 Share a high degree of sequence identity and also have very similar active
site topography.
 Despite their similarity, the active site for hCOX- 2 is approximately 20%
larger than the COX-1 binding site.
 Replacement of Ile-523 in COX-1 with a smaller Val-523 in hCOX-2 (Val-
509).
 There are 24 amino acid residues lining the largely hydrophobic AA binding
site with only one difference between the isozymes
 i.e., Ile-523 in COX-1 and Val-509 in hCOX-2.
 The hCOX-2 isozyme has an additional hydrophilic side pocket accessible
for drug binding, extended from the main binding pocket.
 The size and nature of this hydrophilic side pocket for binding in hCOX-2 is
a result of further substitutions Ile-434 and His-513 in COX-1 with a
smaller Val-434 (Val 420 in hCOX-2) and a more basic Arg-513 (Arg-499 in
hCOX-2).

 This basic amino acid residue in
hCOX-2 (Arg-499) may provide an
additional binding interaction for
selective COX-2 inhibitors such as celecoxib.
 Arg-120 (Arg-104 in hCOX-2) is the only
positively charged amino acid residue in the COX active site
 Responsible for binding, via an ionic interaction, with the
carboxylate anion of the substrate (AA) or the conventional
NSAIDs.
 Tyr-385 (Tyr-371 in hCOX-2) is located on the opposite end of
the COX active site and is believed to serve as the catalytic
residue for activating molecular oxygen and its initial addition
to the 11-double bond of the substrate to form PGG2.
 Ser-530 (Ser-516 in hCOX-2) is believed to be involved only in
the irreversible inactivation by aspirin and NSAID action but
not contributing to any substrate binding

 Most NSAIDs possess a free carboxylic acid (COOH) for an ionic
interaction with the positively charged arginine residue at the active site
of the cyclooxygenases (i.e., Arg- 120 in COX-1 or Arg-106 in COX-2
isozymes).
 This acidic moiety is further linked to an aromatic (or heteroaromatic)
ring for binding to either the 5-double-bond or 8-double-bond binding
regions, and an additional center of lipophilicity in the form of an alkyl
chain (e.g., ibuprofen) or an additional aromatic ring (e.g.,
indomethacin) for binding to the 11-double-bond binding region.
 Eg: indomethacin binding with COX
 Orientation and placement of the N-p-chlorobenzoyl group to the 11-
doublebond binding region and the indole ring to the 5- and 8- double-
bond binding regions is made from assuming that a preferred, lower-
energy conformation of indomethacin is essential for its binding to COX
isozymes.
 This orientation also allows correct positioning of the amide carbonyl
oxygen for possible binding interactions to Ser-530 and the 5-methoxy
group to Ser-355 at the active site of the enzymes.
BINDING OF NSAID TO CYCLOOXYGENASE

„Nonselective COX inhibitors(COX1&2)
(conventional)
1. SALICYLATES:Aspirin
2. PARA AMINOPHENOL DERIVATIVES:
Paracetamol (acetaminophen), phenacetin
3. PYRAZOLONE DERIVATIVES: Phenylbutazone,
oxyphenbutazone, metimazole,propiphenazone
4. ACETIC ACID DERIVATIVES: Indomethacin,
sulindac
5. PROPIONIC ACID DERIVATIVES: Ibuprofen,
naproxen, ketoprofen and flurbipropen
CLASSIFICATION OF NSAIDs

6. PHENYL ACETIC ACID DERVATIVES:
Diclofenac
7. FENAMATES: Flufenamic acid, mefenamic acid
8. OXICAM DERVATIEVS: Piroxicam, Tenoxicam,
9. HETERO ARYL ACETIC ACID DERIVATIVES:
Ketorolac
10.BENZOXAZOCINE: nefopam „
NON-Conventional
COX-2 selective – Nimeusulide, Etodolac,
Meloxicam, Nabumetone „
COX-2 Selective (absolute)- Celecoxib, Rofecoxib,
Valdecoxib

 Aspirin and the salicylates were among the first group of NSAIDs
introduced into medicine for their use as analgesics to relieve pain
and as antipyretics to reduce fever.
 History:
 The active ingredient of willow bark was isolated by Leroux, in 1827
and named salicin, which is a salicylic acid containing glycoside.
 After these discoveries, Cahours (1844) obtained salicylic acid from
oil of wintergreen (methyl salicylate), and Kolbe and Lautermann
 (1860) prepared it synthetically from phenol.
 Sodium salicylate was introduced in 1875 by Buss, followed by the
introduction of phenyl salicylate by Nencki in 1886.
 Aspirin, or acetylsalicylic acid, was first prepared in 1853 by Gerhardt
but remained obscure until Felix Hoffmann from Bayer discovered
its pharmacological activities in 1899.
 It was tested and introduced into medicine by Dreser (1899), who
named it aspirin by taking the a from acetyl and spirin, an old name
for salicylic or spiric acid, derived from its natural source of spirea
plants.
Salicylic Acid Derivatives

Most of the salicylic acid drugs (commonly referred to as the
salicylates) are either marketed as salts of salicylic acid
(sodium, magnesium, bismuth, choline, or triethanolamine)
or as ester or amide derivatives (aspirin, salsalate,
salicylamide).
Kinetics:
• Well absorbed from the stomach, more from upper small
intestine.
• Distributed all over the body, 50‐80% bound to plasma
protein (albumin).
• Excreted by the kidney.
•Low dose of aspirin 0.6 g is eliminated by 1st order kinetics
and its t 1/2 is 3‐5 h
• while high dose (more than 4 g/day) is eliminated by
zero‐order kinetics and its t ½ may increase up to 15 h.

Metabolism of Salicylates:
 Undergoes extensive
phase-II metabolism and
is excreted via the
kidneys.
 All salicyaltes are
converted to salicylic acid.
 Conjugated with Glycine
(watersoluble Glycine
conjugate)
 Uric acid as salicyluric
acid, with Glucuronides
 The major metabolite (75%) or as the corresponding
acyl glucuronides
 (i.e., the ester type, via the COOH) or O-glucuronides
 (i.e., the ether type, via the phenolic OH) (15%).
 Alkalinization of the urine increases the rate of
excretion of the free salicylates.

Effects of NSAIDs
1. Analgesic and antipyretic action
Aspirin is a weaker analgesic than morphine-type drugs
Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine
No sedation, tolerance, and dependence are produced.
Aspirin resets the hypothalamic thermostat and
rapidly reduces fever by promoting heat loss
(sweating, cutaneous vasodilation), but does not
decrease heat production.
2. Inhibition of platelet aggregation in low
doses (75–100 mg/24 h Aspirin).

3. Antiinflammatory action is exerted at high
daily doses of Aspirin (3 to 6 g). Clinical symptoms
of inflammation are suppressed, but prolongation
of the underlying disease in rheumatoid arthritis,
rheumatic fever, and osteoarthritis is not affect.
4. Metabolic effects –Cellular metabolism is
increased, especially in skeletal muscles, due to
uncoupling of oxidative phosphorylation as a result
of increased heat production. There is increased
utilization of glucose and blood sugar may
decrease (specially in diabetics) and liver glycogen
is depleted. However, hyperglycemia is often seen
at toxic doses.

5. Respirations. At antiinflammatory doses
respiration is stimulated by peripheral (increased
CO2 production) and central (increased sensitivity
of respiratory centre to CO2) action.
Hyperventilation is prominent in salicylate
poisoning. Further raise in the salicylate level causes
respiratory depression and failure, and death.
6. Acid-base and electrolyte balance.
Antiinflammatory doses produce significant
changes. Initially respiratory stimulation
predominates and tends to wash out CO2
despite increased production and the result is
respiratory alkalosis, which is compensated by
increased renal excretion of HCO3
- (with
accompanying Na+, K+, and water).

7. CVS. Larger doses of Aspirin increase cardiac output
to meet increased peripheral oxygen demand and cause
direct vasodilatation. Toxic doses depress vasomotor
centre: BP falls. Because of increased
cardiac work as well as sodium and water retention,
CHF my develop if the heart reserves are low.
8. GIT. Aspirin and its metabolite salicylic acid irritate
gastric mucosa and cause epigastralgia, nausea,
andvomiting. In higher doses it also stimulates CTZ.
Aspirin (pKa 3.5) remains unionized and diffusible inthe
acid gastric juice, but on entering the mucosal cell (pH
7.1) it ionizes and becomes indiffusible. This“ion
trapping” in the gastric mucosal cell enhances gastric
toxicity.
Alcohol increasis GI toxicity of NSAIDs.

Uses of Aspirin
As analgesic (300 to 600 mg during 6 to 8 h) for head-
ache, backache, pulled muscle, toothache, neuralgias.
As antipyretic in fever of any origin in the same doses as
for analglesia. However, paracetamol and metamizole are
safer, and generally preferred.
Acute rheumatic fever. Aspirin is the first drug of choice.
Other drugs substitute Aspirin only when it fails or in
severe cases. Antirheumatic doses are 75 to 100 mg/kg/24 h
(resp. 4–6 g daily) in the first weeks.
Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h
after meal is effective in most cases. Since large doses of
Aspirin are poorly tolerated for a long time, the new
NSAIDs in depot form are preferred.
Antiplatelet

Adverse effects
 CNS: Headache, Tinnitus, dizziness,blurred vision,
irritability, hyperventilation (Salicylism)
 Cardiovascular.: fluid retention, HT, edema, CHF(rarely)
 GIT upset: abd pain, nausea, vomiting, peptic ulceration
& bleeding
 Hypersensitivity: bronchial asthma, angioedema &
rashes,
 Thrombocytopenia, Hypoprothrombinemia and
bleeding tendency as aspirin competes with vitamin K, so
decreasing prothrombin synthesis.
 Renal effects: inhibition of PGE2 mediated vasodilation
in response to ATII : renal insufficiency, renal failure,
hyperkalemia, proteinuria. Analgesic nephropathy on
chronic use.
 Hepatic: Liver function abnormalities, rarely liver failure.

Aspirin therapy in children with rheumatoid arthritis has
been found to raise serum concentration transaminases,
indicating liver damage. Most cases are asymptomatic but
it is potentially dangerous.
An association between salicylate therapy and “Reye’s
syndrome”, a rare form of hepatic encephalopathy seen in
children, having viral infection (varicella, influenza), has
been noted.
Aspirin should not be given to children under 15 years
unless specifically indicated, e.g. for juvenile arthritis
(paracetamol is preferred).
Postmyocardial infarction and poststroke patients.
By inhibiting platelet aggregation in low doses (100 mg
daily) Aspirin decreases the incidence of reinfarction.

Drugs Result
Diuretics Decrease diuresis
Beta-blockers Decrease antihypertensive effect
ACE inhibitors Decrease antihypertensive effect
Anticoagulants Increase of GI bleeding
Sulfonylurea Increase hypoglycemic risk
Cyclosporine Increase nephrotoxicity
GCS Increase of GI bleeding
Alcohol Increase of GI bleeding
Drug interactions with NSAIDs

Salsalate
 salicylsalicylic acid (Amigesic,
Disalcid, Salflex), is the ester formed
between two salicylic acid
molecules.
 It is rapidly hydrolyzed to salicylic
acid following its absorption.
 It reportedly causes less gastric
irritation
 than aspirin, because it is relatively
insoluble in the stomach and is not
absorbed until it reaches the small
intestine.

Diflunisal
 longer acting and more potent drug
than aspirin because of its
hydrophobic, 2,4-difluorophenyl
group attached to the 5-position of
the salicyclic acid.
 Better tolerated with less GI complications than aspirin.
 Marketed in tablet form for treating mild to moderate
postoperative pain as well as RA and OA.
 Highly protein bound.
 Its metabolism is subject to a dose-dependent, saturable,
and capacity-limited glucuronide formation.
 An enterohepatic circulation and the reabsorption of 65%
of the drug and its glucuronides, followed by cleavage of
its unstable, acyl glucuronide back to the active drug.
 Thus, diflunisal usage in patients with renal impairment
should be closely monitored.

Sodium salicylate
 Prepared by the reaction, in aqueous solution,
by adding equal molar ratio of salicylic acid and
sodium bicarbonate; evaporating to dryness
yields the white salt.
 In solution, particularly in the presence of
sodium bicarbonate, the salt will darken on
standing. This is the salt of choice for salicylate
medication and usually is administered with
sodium bicarbonate to lessen gastric distress, or
it is administered in enteric coated tablets. .
 However, the use of sodium bicarbonate is ill advised,
because it decreases the plasma levels of salicylate and
increases the excretion of free salicylate in the urine.
 Sodium salicylate, even though not as potent as aspirin for
pain relief, also has less GI irritation and is useful for patients
who are hypersensitive to aspirin

OTHER SALTS OF SALICYLIC ACID
 Sodium thiosalicylate (Rexolate) is the sulfur or thio analog
of sodium salicylate.
It is more soluble and better absorbed, thus allowing lower
dosages. It is recommended for gout, rheumatic fever, and
muscular pains, but it is available only for injection.
 Magnesium salicylate (Mobidin, Magan) is a sodiumfree
salicylate preparation for use when sodium intake is
restricted. It is claimed to produce less GI irritation.
 Choline salicylate (Arthropan) is extremely soluble in water
and is available as a flavored liquid. It is claimed to be
absorbed more rapidly than aspirin, giving faster peak blood
levels. It is used when salicylates are indicated. It is also
available in combination with magnesium salicylate (Trilisate,
Tricosal, Trisalcid, CMT) for the relief of minor to moderate
pains and fever associated with arthritis, bursitis, tendinitis,
menstrual cramps, and others.

Salicylamide
 o-hydroxybenzamide, is a derivative of salicylic acid
that is fairly stable to heat, light, and moisture.
 Reportedly exerts a moderately quicker and deeper
analgesic effect than aspirin because of quicker CNS
penetration.
 Its metabolism differs from aspirin, because it is not
metabolized to salicylic acid but rather excreted
exclusively as the ether glucuronide or sulfate.
 As a result of lack of contribution from salicylic acid,
it has a lower analgesic and antipyretic efficacy than
that of aspirin.

 Can be used for patients with a demonstrated
sensitivity to salicylates.
 It is also excreted much more rapidly than
other salicylates, which accounts for its lower
toxicity.
 It is available in several nonprescription
products, in combination with acetaminophen
and phenyltoloxamine (e.g., Rid-A Pain
compound, Cetazone T, Dolorex, Ed-Flex,
Lobac)
 or with aspirin, acetaminophen, and caffeine
(e.g., Saleto, BC Powder).

Propionic Acid Derivatives (Propionates)
Aryl and heteroaryl derivatives
 These compounds are often referred to as the
“profens” based on the suffix of the prototype
member, ibuprofen. Like the salicylates these
agents are all strong organic acids (pKa = 3-5)and
thus form water soluble salts with alkaline reagents.
 The arylpropionic acids are characterized by the
general structure Ar-CH(CH3)-COOH which
conforms to the required general structure.
 All of these compounds are predominantly ionized
at physiologic pH and more lipophilic than ASA or
salicylic acid.

 All of the members of this class (except oxaprozin) contain a chiral
carbon in the α-position of the acetic acid side chain.
 Even though most are marketed as racemates, only the (S)-
enantiomer was found to have any inhibitory activity against the
COX isozymes.
 Thus, the (S)-enantiomer is believed to be solely responsible for the
observed therapeutic action as well as the drug-induced GI side
effects and nephrotoxicity.
 Furthermore, in
most cases, the
inactive (R)-
enantiomer is
epimerized in vivo,
via the 2-
arylpropionyl
coenzyme-A
epimerase to its
active (S)-
enantiomer.

Chemical structures of the propionic acid
derivatives (propionates)

Ibuprofen
 Derivative of phenylpropionic acid.
 IUPAC: 2-(4-isobutylphenyl)propionic acid
 Potency: Aspirin < Ibuprofen < Indomethacin
 In doses of 2.4 g daily it is is equivalent to 4 g of
Aspirin in anti-inflammatory effect.
 Oral ibuprofen is often prescribed in lower doses (< 2.4 g/d), at
which it has analgesic but not antiinflammatory efficacy.
 It is available in low dose forms under several trade names .
 A topical cream preparation is absorbed into fascia and muscle.
 A liquid gel preparation of ibuprofen provides prompt relief in
postsurgical dental pain.
 In comparison with indometacin, ibuprofen decreases urine
output less and also causes less fluid retention.
 It is effective in closing ductus arteriosus in preterm infants, with
much the same efficacy as indometacin.

ADME:
 Peak plasma level:2 hr.
 DOA: less than 6 hr.
 Plasma binding : 99%
 Metabolism occurs
rapidly
 Excretion: Urine
 Metabolism through
CYP system involves ω -
,ω1-,ω2- oxidation of p-
isobutyl side chain. All
metabolite are inactive.

 It appears to have comparable efficacy to aspirin in the
treatment of RA, but with a lower incidence of side
effects.
 It has also been approved for use in the treatment of
primary dysmenorrhea, which is thought to be caused
by an excessive concentration of PGs and
endoperoxides.
 Concurrent use of ibuprofen and aspirin may actually
interfere with the cardioprotective effects of aspirin, at
least in patients with established cardiovascular disease.
 This is because ibuprofen can reversibly bind to the
platelet COX-1 isozymes, thereby blocking aspirin’s
ability to inhibit TXA2 synthesis in platelets.

Clinical uses
A) Analgesic
B) Antipyretic
C) Anti-inflammatory
D)Acute gouty arthritis
E) Patent ductus arteriosus
 Oral preparations.
 Topical cream for
osteoarthritis.
 A liquid gel for rapid
relief of postsurgical
dental pain.
 Intravenous route as
In patent ductus
arteriosus
Preparations of Ibuprofen

Adverse effects
1. Gastric upset ( less
frequent than aspirin ).
2. Fluid retention
3.Hypersensetivity
reactions
4. Ocular disturbances
5. Rare hematologic
effects(agranulocytosis &
aplastic anaemia ).
1. Peptic ulcer
2. Allergic patients to
aspirin
3. Kidney impairment
4.Liver diseases
5.Pregnancy
6.Haemophilic patients
(antagonizes the
irrevesible platelet
inhibition of aspirin).
Contraindications

Fenoprofen Calcium
 The calcium and sodium salts of
fenoprofen possess similar Pharmacokinetic.
 Calcium salt that is marketed (less hygroscopic).
 Less potent in anti –inflammatory than ibuprofen,
indomethacin.
 Aspirin<Fenoprofen= ibuprofen <<indomethacin.
(PG inhibition)
 Possesses analgesic and antipyretic activity.
 Also inhibition of phagocytic and complement
functions and stabilization of lysosomal
membranes.

 Marketed as a racemic mixture (no differences in in
vivo & also enantiomer conversion).
 Absorption and Metabolism:
 Readily absorbed (85%) on oral administration
 Highly bound (99%) to plasma proteins.
 Peak plasma levels : within 2 hours.
 The free acid has a pKa of 4.5
 Extensively metabolized, primarily through
glucuronide conjugation and hydroxy metabolite.
 Uses:
 Rheumatoid arthritis
 Osteoarthritis
 Relief of mild to moderate pain.

Flurbiprofen
 Propionic acid derivative
 Possibly more complex mechanism of action
than other NSAIDs.
 Its (S)(-) enantiomer inhibits COX nonselectively,
 but it has been shown in rat tissue to also affect TNF-α and
NO synthesis.
 Hepatic metabolism is extensive.
 It does demonstrate enterohepatic circulation.
 The efficacy of flurbiprofen at dosages of 200–400 mg/d is
comparable to that of Aspirin and other NSAIDs for
patients with rheumatoid arthritis.
 Flurbiprofen synthesis was original y reported in 1974 .
 It was not marketed until 1987

 When it was introduced as the sodium salt as Ocufen, the
first topical NSAID indicated for ophthalmic use. The
indication for Ocufen to inhibit intraoperative miosis
induced by prostaglandins in cataract surgery.
 Thus, flurbiprofen is an inhibitor of prostaglandin
synthesis. The oral form was introduced in 1988 as Ansaid
(another non-steroidal anti-inflammatory drug) and gained
immediate acceptance.
 In acute inflammation assays in adrenalectomized rats,
 Flurbiprofen = 536-fold more potent than aspirin and 100-
fold more potent than phenylbutazone.
 Orally, it was half as potent as methylprednisolone.
 As an antipyretic, it was 403 times as potent as aspirin in the
yeastinduced fever assay in rats and was 26 times more
potent than ibuprofen as an antinociceptive

 Well absorbed after oral administration
 Peak plasma levels - within 1.5 hours.
 Food alters the rate of absorption but not the
bioavailability.
 Plasma proteins Binding (99%)
 Plasma half-life of 2 to 4 hours.
 Metabolism is extensive, with 60 to 70% of flurbiprofen and
its metabolites being excreted as sulfate and glucuronide
conjugates.
Shows interesting metabolic
patterns, with 40 to 47% as the
4′-hydroxy metabolite, 5% as the
3′,4′-dihydroxy metabolite, 20 to
30% as the 3′-hydroxy- 4′-
methoxy metaboli te, and the
remaining 20 to 25% of the drug
being excreted unchanged.

 Flurbiprofen is indicated as an oral formulation for the
acute or long-term treatment of
 Rheumatoid arthritis and
 Osteoarthritis
 Ankylosing spondylitis,
 Gout
 As an ophthalmic solution for the inhibition of
intraoperative miosis.
 Flurbiprofen i.v. is effective for perioperative analgesia
in minor ear, neck, and nose surgery and in lozenge
form for sore throat.
 Its adverse effect profile is similar to other NSAIDs.

Ketoprofen
 Propionic acid derivative
 inhibits both COX (nonselectively) and
lipoxygenase.
 Concurrent administration of probenecid
elevates ketoprofen levels and prolongs its
plasma half-life.
The effectiveness of ketoprofen at dosages of
100–300 mg/d is equivalent to that of other
NSAIDs
 Antibradykinin activity also has been
observed.
 Its major adverse effects are on the GIT and
the CNS.

 ADME:
 Rapidly and nearly completely absorbed on oral administration
 Peak plasma levels -within 0.5 to 2 hours.
 Highly plasma protein bound (99%)
 Despite a lower acidity (pKa = 5.9) than some other NSAIDs.
 It is metabolized by glucuronidation of the carboxylic acid,
hydroxylation of the benzoyl ring, and reduction of the keto
function.
 USES:
 in the treatment of rheumatoid arthritis,
 osteoarthritis,
 Gout,
 Dysmenorrhea,
 and other painful conditions.
 In spite of its dual effect on prostaglandins and
leukotrienes, ketoprofen is not superior to other NSAIDs.

 Synthesized from 2-methoxynaphthalene
 It is marketed as the S-(+)-enantiomer, but interestingly,
the sodium salt of the (–)-isomer also is on the market as
Anaprox.
 PG inhibition- Naproxen more Potent < 12 times
aspirin, 10 times Phenylbutazone, 3-4 times ibuprofen,
and 4 times fenoprofen,
 but it is approx 300 times less potent than
indomethacin.
 The order of gastric ulcerogenic activity is sulindac <
naproxen < aspirin, indomethacin, ketoprofen, and
tolmetin.
 Naproxen is the only arylalkanoic acid NSAID currently
marketed as optically active isomers.
 It is also available OTC as 200-mg tablets (Aleve).
Naproxen

ADME:
Almost completely absorbed following oral administration.
Peak plasma levels in 2 to 4 hours
A half-life of 13 hours.
The pKa = 4.2, it is highly bound (99.6%) to plasma proteins.
Approx 70% of dose is eliminated as either unchanged drug
(60%) or as conjugates of unchanged drug (10%).
 The remainder is converted to the 6-O-desmethyl metabolite
and, further, to the glucuronide conjugate.
 Rheumatoid arthritis,
 osteoarthritis,
 juvenile arthritis,
 ankylosing spondylitis,
 tendinitis, bursitis,
 acute gout,
 primary dysmenorrhea
 for the relief of mi ld to moderate pain.
USES:

Suprofen
 Was introduced in 1985 for the
treatment of dysmenorrhea and as an
analgetic for mild to moderate pain.
 Reports of severe flank pain and transient renal fai lure
appeared, however, with the syndrome being noted
abruptly within several hours after one or two doses of
the drug; therefore, suprofen was removed in 1987.
 Suprofen was reintroduced in 1990 as a 1% ophthalmic
solution for the prevention of surgically induced miosis
during cataract extraction.

Oxaprozin
 Oxaprozin, 4,5-diphenyl-2-oxazolepropionic
acid (Daypro),
 differs from the other members of this group in being an
arylpropionic acid derivative.
 Well absorbed (100%) following oral administration, but
Plasma concentrations - 3 to 5 hours following ingestion.
 A rapid onset of action and a prolonged duration of action.
 Highly bound to plasma proteins (99%),
 Highly lipophilic, & undergoes little first-pass metabolism.
 Metabolism is via hepatic microsomal oxidation and
glucuronidation.
 long elimination half-life of 59 hours (range, 26–92 hours),
 short- and long-term management of OA and RA,
administered as a once-daily dose of 600- to 1,200-mg dose

Aryl- And Heteroaryl Acetic Acids
 As a group, they show high analgesic potency in
addition to their potent anti-inflammatory activity,
needed for treating inflammatory diseases.
 Ketorolac, Indomethacin, and Tolmetin have the
highest risk of GI complications because of their
higher affinity for the COX-1 isozymes, whereas
etodolac has the lowest risk because of its COX-2
selective inhibitory action.
 Both Sulindac and Nabumetone are prodrugs that
require activation, and therefore have lower risk of
causing GI irritation than indomethacin

A. Indene and Indole Acetic Acids:
1. Indometacin
 is a potent nonselective COX inhibitor and may also inhibit
phospholipase A and C, reduce neutrophil migration, and
decrease T cell and B cell proliferation.
 IUPAC: 2-{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methyl-
1H-indol-3-yl}acetic acid
ADME:
 Following oral administration, rapidly absorbed
 90% protein bound at therapeutic Conc.
 biological half-life - 5 to 10 hours
 Plasma clearance of 1 to 2.5 ml/kg per min.

 Metabolized to its
inactive, O-desmethyl, N-
deschlorobenzoyl-, and
O-desmethyl, N-
deschlorobenzoylindomet
hacin metabolites.
 approximately 50% of a
single dose is 5-O-
demethylated by
CYP2C9
 10% conjugated with
glucuronic acid

Structure–Activity Relationships
 Replacement of the COOH- decreases activity.
 Anti-inflammatory activity generally increases as the acidity of
the carboxyl group increases and decreases as the acidity is
decreased.
 N-Benzoyl derivatives substituted in the para-position with
fluoro, chloro, trifluoromethyl, or thiomethyl groups are the
most active.
 The 5-position of the indole ring is most flexible with regard to
the nature of substituents that enhance activity.
 Substituents such as methoxy, fluoro, dimethylamino, methyl,
allyloxy, and acetyl are more active than the unsubstituted indole
ring.
 The presence of an indole ring nitrogen is not essential for
activity, corresponding 1-benzylidenyl indene analogues (e.g.,
sulindac) are active. Alkyl groups, especially methyl, at the α-
position are more active than aryl substituents.

 Anti-inflammatory activity is displayed only by the S-(+)-
enantiomer.
 The conformation of indomethacin appears to play a crucial role in
its anti-inflammatory actions.
 The acetic acid side chain is flexible and can assume a large number
of different conformations.
 The preferred and lower-energy conformation of the N-p-
chlorobenzoyl group is one in which the chlorophenyl ring is
oriented away from the 2-methyl group (or cis to the methoxyphenyl
ring of the indole nucleus) and is noncoplanar with the indole ring
because of steric hindrance produced by the 2-methyl group and
the hydrogen atom at the 7-position. These conformations are
represented as follows

 Probenecid prolongs indometacin's half-life by inhibiting
both renal and biliary clearance.
 A high incidence (up to 50%) of GI and CNS side effects is
produced: GI bleeding, diarrhoea, frontal headache, mental
confusion, etc.
Uses:
 Juvenile rheumatoid arthritis,
 Gout
 Ankylosing spondylitis,
 Postepisiotomy pain.
 Treat patent ductus arteriosus.
 Efficacious for conjunctival inflammation and to reduce
pain after traumatic corneal abrasion (ophthalmic sol.)
 Because of supression of uterine activity , also has an
unlabeled use to prevent premature labor.

Sulindac
 IUPAC:(Z)-5-fluoro-2-methyl-1-([p-(methylsulfinyl)
 phenyl]methylene)-1H-indene-3-acetic acid
 Sulindac is a pro-drug and is converted to a metabolite that
appears to inhibit the cyclooxygenase system approx 8-fold as
effectively as aspirin.
 Undergoes in vivo reduction by the hepatic enzymes into its
achiral, active metabolite, methyl sulfide that exhibits potent
and nonselective COX inhibition similar to indomethacin.
 The parent sulfoxide has a plasma half-life of 8 hours,
 Active methyl sulfide metabolite is 16.4 hours.
 highly bound to serum proteins (93%).

 Long half-life of sulindac is caused by the extensive
enterohepatic circulation and reactivation of the
inactive sulfoxide excreted.
 Coadministration of aspirin is contraindicated
 Because it considerably reduces the sulfide blood
levels.
 Gastric bleeding, nausea, diarrhea, dizziness, and
other adverse effects have been noted with sulindac,
but with a lower frequency than with aspirin.
 Sulindac is recommended for RA, OA, and
ankylosing spondylitis.

Etodolac
 a chiral
 COX-2 selective NSAID drug
that is marketed as a racemate,
 possesses an indole ring as the
aryl portion of this group of
NSAID drugs.
 Approx 50 times more active than aspirin, 3 times
sulindac, and one-third as active as indomethacin.
 Elimination half life of 6 to 8 hours
 Rapidly absorbed following oral administration,
 Peak plasma conc.-within 1 to 2 hours
 highly bound to plasma proteins (99%) with pKa 4.7.

 Etodolac is extensively metabolized into three major
inactive metabolites,
 6-hydroxy etodolac (via aromatic hydroxylation),
 7-hydroxy-etodolac (via aromatic hydroxylation),
 8-(1-hydroxylethyl) etodolac (via benzylic
hydroxylation), which are eliminated as the
corresponding ether glucuronides.
 Indicated for short- and long-term management of
pain
 Used for RA, OA and as a post-operative analgesic

B. Arylacetic Acids: The Pyrrole Acetic Acids
Tolmetin
 Tolmetin sodium (Tolectin), is an arylacetic
acid derivative with a pyrrole as the aryl
group.,
 Short plasma half-life (1 hour).
 absorbed with peak plasma levels occurring
2 to 4 hours after oral administration.
 It undergoes hepatic benzylic hydroxylation of its 3-
methyl group regioselectively into two inactive
metabolites, 3-hydroxymethylmefenamic acid and the
3carboxylate metabolite (via further oxidation of the
benzylic alcohol group).
 The parent drugs and these metabolites are conjugated
with glucuronic acid and excreted primarily in the urine.

 Common side effects - diarrhea, drowsiness,
and headache.
 The possibility of blood disorders has also
prompted limitation of its administration to 7
days.
 Not recommended for children or during
pregnancy.
Use: for the treatment of
Rheumatoid arthritis,
Juvenile rheumatoid arthritis,
Osteoarthritis.

Ketorolac
 which lacks this benzylic methyl group
 Not susceptible to the type of oxidation
observed for tolmetin and as a result its half-
life is longer (4-6 hours).
Good oral activity with primarily analgesic activity, but
also has antiiflammatory activity and antipyretic actions.
Use
management of post-operative pain
for the treatment of moderately severe, acute pain.

 It should be noted that the pharmacokinetic
disposition of ketorolac in humans is subject to
marked enantioselectivity.
 Thus, it is important to monitor the individual
blood levels so an accurate assessment of its
therapeutic action can be made correctly.
 One of the conventional NSAIDs with highest
risk of GI complications.
 Administration should not exceed 5 days.

C. Arylacetic Acids: Oxazole Acetic Acids
 A recent addition (1993) to this class of
agents
 another nonseelective COX inhibitor.
 It differs slightly in that substitution of
the propionic moiety is at the 3
position rather that at the 2 position as
in other agents of this class.
 It is metabolized by glucuronidation
and uncharacterized oxidation
products.
Oxaprozin (DayproTM)

Nabumetone
 A nonacidic NSAID prodrug,
 classified as an arylacetic acid, because it
undergoes rapid hepatic metabolism to its
active metabolite, 6-methoxy-2-
naphthylacetic acid.
 Being nonacidic, it does not produce significant primary
insult to the GI mucosa lining and also has no effect on
prostaglandin synthesis in gastric mucosa, thus
producing minimum secondary GI damage when
compared with other conventional NSAIDs.
Use- short- or long-term management of RA and OA.

is the result of the application of classical medicinal
chemistry bio-isosteric drug design concepts,
because these derivatives are nitrogen isosteres of salicylic
acid.
N-ARYLANTHRANILIC ACIDS (FENAMATES)
Substitution on the anthrani lic acid ring
generally reduces activity, whereas
substitution of the N-aryl ring can lead to
conflicting results. In the ultraviolet
erythema assay for anti-inflammatory
activity, the order of activity general ly 3′ >
2′ ≫ 4′ for monosubstitution, with the 3′-
CF3 derivative (flufenamic acid) being
particularly potent.

These agents are considered to be N-aryl substituted derivatives
of anthranilic acid which is itself a bioisostere of salicylic acid.
These agents retain the acidic properties that are characteristic
of this class of agents; however, note that while mefenamic
acid and meclofenamic acid are derivatives of anthranilic acid,
diclofenac is derived from 2- arylacetic acid. The most active
fenamates have small alkyl or halogen substituents at the
2’,3’ and/or 6’ position of the N-aryl moiety (meclofenamate is
25 times more potent than mefenamate- see below). Among the
disubstituted N-aryl fenamates the 2’,3’-derivatives are
most active suggesting that the substituents at the 2’,3’-positions
serve to force the N-aryl
ring out of coplanarity with the anthranilic acid. Hence this
steric effect is proposed to be
important in the effective interaction of the fenamates at their
inhibitory site on
cyclooxygenase.

Oxicam derivatives
 Piroxicam
 Tenoxicam

Piroxicam
 Mechanism of actions
 A) Non-selective inhibitors to Cox1 & Cox2
 B) Traps free radicals
 C) Inhibits polymorphonuclear leukocytes migration
 D) Inhibits lymphocyte function.

Pharmacokinetics
 Well absorbed orally
 Half- Life 45 hours
 Given once daily

Adverse effects
 Less frequent gastric upset (20%) .
 Dizziness
 Tinnitus
 Headache
 Allergy

Acetic acid derivatives
 1. Diclofenac
 Mechanism of action
 A) As aspirin ,but non-selective inhibitor to cox1 &
Cox2.
 More potent as anti-inflammatory than analgesic and
antipyretics
 Accumulates in synovial Fluid

Clinical uses
 A) Any inflammatory conditions
 B) Musculoskeletal pain
 in treatment of rheumatoid arthritis , osteoarthritis &
ankylosing spondylitis
 C) Dysmenorrhoea
 D)Acute gouty arthritis
 E) Fever
 F) Locally to prevent or treat post opthalmic
inflammation
 G) A topical gel for solar keratoses

Adverse effects
 Gastric upset
 Renal impairment
 Elevation of serum aminotransferase
 Salt & water retention

Preparations of Diclofenac
 Oral preparation
 Diclofenac with misoprostol decreases upper
gastrointestinal ulceration ,but result in diarrhea.
 Diclofenac with omeprazole to prevent recurrent
bleeding.
 .1% opthalmic preparation for postoperative
opthalmic inflammation.
 A topical gel 3% for solar keratoses.
 Rectal suppository as analgesic or for postoperative
nausea.

Selective Cox2 inhibitors
 Advantages :
 1. Highly selective inhibitors to cox2 enzyme.
 2. Potent anti-inflammatory.
 3. Have analgesic& antipyretic
 4. Highly bound to plasma proteins.

Selective Cox2 inhibitors
 5. Lower incidence of gastric upset
 6. No effect on platelet aggregation (cox1 )
 7. Renal toxicities ( they are not recommended for
patients with severe renal insufficiency)
 8. High incidence of cardiovascular thrombotic
events with some of them as rofecoxib.

CELECOXIB
 first selective COX-2 inhibitor drug
introduced in market
 use in the treatment of RA, OA, acute pain, and menstrual
pain.
 fewer GI complications over conventional NSAIDs.
 well absorbed and undergoes rapid oxidative metabolism.
 potential drug interaction exists between celecoxib and
warfarin because the active isomer of warfarin is primarily
degraded by CYP2C9.
 Probably because it is a sulfonamide, celecoxib may
cause rashes.
 It does not affect platelet aggregation at usual doses.

Etoricoxib
 is a second-generation COX-2-selective
 inhibitor with the highest selectivity ratio of any coxibs.
 It is extensively metabolized by hepatic CYP450 enzymes
followed by renal excretion and has an elimination
 t1/2 of 22 h.
 Use for the treatment of the symptoms of osteoarthritis (60
mg once daily) and rheumatoid arthritis (90 mg once
daily), acute gouty arthritis (120 mg once daily), and for the
relief of acute musculoskeletal pain (60 mg once daily).
 has similar efficacy to traditional NSAIDs for osteoarthritis,
acute gouty arthritis, and primary dysmenorrhea and has a
 GI safety profile similar to other coxibs.

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