Antiinflammatory agents ppt.pdf

1. Anti-Inflammatory Agents
MRS.REKHAAMIT BHALERAO
Department of Pharmaceutical Chemistry
PES MODERN COLLEGE OF PHARMACY, FOR
LADIES, Moshi- 412015

2. The non-steroidal antiinflammatory drugs (NSAIDs) are
widely used for the treatment of minor pain and for the
management of edema and tissue damage resulting from
inflammatory joint disease (arthritis). A number of these drugs
possess antipyretic activity in addition to having analgesic and
antiinflammatory actions, and thus have utility in the treatment
of fever.
Some of the primary indications for NSAID therapy include:
1. Rheumatoid arthritis,
2. Osteoarthritis (OA),
3. Acute gouty arthritis,
4. Ankylosing Spondylitis
Introduction

3. Cycloxygenase enzyme
 There are Two COX isoenzymes have been identified these are:
 COX-1 and COX-2.
 COX-1 constitutive enzyme is present in a wide variety of cell
types and influences the “housekeeping” functions of
prostaglandins. This activity is particularly important in the
gastrointestinal (GI) tract, the kidneys, and the circulatory
system.
 COX-2 is inducible enzyme, is found in only a few cell types,
especially macrophages and other leukocytes, fibroblasts, and
endothelial cells, including those of the vascular system. COX-
2 is involved in those aspects of the inflammatory process that
are mediated by prostaglandins.

4. Role of COX Enzyme
 Any Inflammatory stimulus activates COX-2 inducible
enzyme which synthesizes PGI2, PGE2, in Macrophages,
Leukocytes, Fibroblasts, Endothelial cells which causes
Inflammation.
 cyclooxygenases (Prostaglandin synthetase) the enzymes
that catalyze the synthesis of cyclic endoperoxides from
arachidonic acid to form prostaglandins.

5. Mechanism of Action
 The major mechanism by which the NSAIDs elicit their
therapeutic effects (antipyretic, analgesic, and antiinflammatory
activities) is inhibition of prostaglandin (PG) synthesis.
 Specifically NSAIDs competitively inhibit cyclooxygenases
also called Prostaglandin synthetase.
 Generally, the NSAIDs inhibit both COX-1 and COX-2. Most
NSAIDs are mainly inhibit COX-1 selective (e.g., aspirin,
ketoprofen, indomethacin, piroxicam, sulindac).
 Others are considered slightly selective for COX-1 (e.g.,
ibuprofen, naproxen, diclofenac) and others may be considered
slightly selective for COX-2 (e.g., etodolac, nabumetone, and
meloxicam).
 The mechanism of action of celecoxib and rofecoxib is primarily
selective inhibition of COX-2; at therapeutic concentrations, the
COX-1 isoenzyme is not inhibited thus GI toxicity is decreased.

6. Classification
The NSAIDs are classified on basis of chemical structure as follows:
1. Salicylates: Aspirin, Sodium Salicylate
2. Propionic acid derivatives (Profens): Ibuprofen
3. Arylacetic acids derivatives : Diclofenac,
4. Indolacetic acid derivatives: Indomethacin, Sulindac
5. Anthranilates (Fenamates): Mefenamic acid
6. Oxicams (“Enol Acids”): Piroxicam
7. Phenylpyrazolone derivatives: Phenyl butazone
8. Anilides derivatives: Paracetamol
9. Pyralopyralo Derivative: Ketorolac
II. Preferential COX2 Inhibitors

7. Salicylates
 The salicylates are derivatives of 2-hydroxybenzoic acid
(salicylic acid). They were discovered in 1838 following the
extraction of salicylic acid from willow bark. Salicylic acid was
used medicinally as the sodium salt but replaced therapeutically
in the late 1800s by acetylsalicylic acid (Aspirin).
 Mechanism of Action: The salicylates have potent
antiinflammatory activity with mild analgesic and antipyretic
activities. These compounds are mainly COX-1 selective—they
are bound with higher affinity to COX-1. The therapeutic and
some of the toxic actions (i.e. gut) of aspirin can be related to its
ability to inhibit COX-1 in various tissues and participate in
transacetylation reactions in vitro.
 Examples: Sodium Salicylate,, Acetyl Salicylic acid (Aspirin),
Phenyl salicylate

8. Sodium Salicylate
 Sodium salicylate is sodium 2-hydroxybenzenecarboxylate. It
occurs as a white, crystalline powder or small, colorless
crystals or shiny flakes, freely soluble in water, sparingly
soluble in alcohol and practically insoluble in ether. Sodium
salicylate is employed for the relief of pain, rheumatic fever
and symptomatic treatment of gout.
Sodium salicylate

9. Acetylsalicylic acid (Aspirin)
 Properties: Aspirin occurs as colorless crystals or powder. It is
slightly soluble in water and soluble in alcohol, chloroform,
ether and glycerin.
 Aspirin is stable in dry air but in presence of moisture, it
hydrolyses slowly into salicylic acid and acetic acid. Aspirin is
acidic and produces effervescence with carbonates and
bicarbonates.
 Use. Aspirin is used as an antipyretic, analgesic and
antirheumatic.

10. Phenyl Salicylate (Salol):
 Phenyl Salicylate is prepared by esterification of salicylic acid
with phenol.
 Phenyl Salicylate is available as white crystalline powder with
aromatic odor. It is insoluble in water but freely soluble in
alcohol, ether, chloroform, acetone and fixed oils.
Phenyl Salicylate

11. Propionic acid derivatives (Profens)
The arylpropionic acids are characterized by the general structure Ar—
CH(CH3)—COOH which conforms to the required general structure. These
compounds are referred to as the “profens” based on the suffix of the
prototype member, ibuprofen. These agents are strong organic acids (pKa =
3.0-5.0)and thus form water soluble salts with alkaline reagents.. All of
these compounds are predominantly ionized at physiologic pH and more
lipophilic than acetyl salicylic acid or salicylic acid.
The alpha -CH3 substitutent present in the profens increases
cyclooxygenase inhibitory activity and reduces toxicity of the profens. The
alpha-carbon in these compounds is chiral and the S-(+)-enantiomer of the
profens is the more potent cyclooxygenase inhibitor.
 Mechanism of Action: Generally the profens are considered to be slightly
“COX-1 selective”; They are used for rheumatoid arthritis, oesteoarthiritis
and as analgesics and antipyretics.
 Examples: Ibuprofen

12. Aryl acetic acid derivatives
2-[2-(2,6-dichloroanilino)phenyl]acetic acid is a
Diclofenac. Which is an example of aryl acetic acid
derivatives.

13. Indol acetic acid derivatives
 Indomethacin: Indomethacin contains a benzoylated indole nitrogen.
Indomenthacin was introduced in 1964 as a powerful anti-inflammatory,
analgesic agent. Chemically, indomethacin is 1-(p-chlorobenzoyl)-5-methoxy-
2-methylindole-3-acetic acid. Indomethacin is “COX-1” selective” and
produces primarily antiinflammatory actions with some analgesic and
antipyretic activity. It is used for rheumatoid arthritis, oesteo arthritis,
ankylosing spondylitis, to suppress uterine contraction, and to promote
closure of parent ductus artiosus in neonates (premature infants).
 Sulindac: In this agent the indole nitrogen has been eliminated which makes
the drug resemblance to 5-HT and therefore fewer CNS side effects are seen.
This compound has pharmacological actions similar to indomethacin (COX-1
selective and antiinflammatory primarily). It is used for rheumatoid arthritis,
osteoarthritis, ankylosing spondylytis, acute gout and to inhibit uterine
contractions.

14. Anthranilates (Fenamates)
 Anthranilates are N-aryl substituted derivatives of anthranilic acid or N-
anthranilic acid derivative. Which is a bioisostere of salicylic acid. These
agents retain the acidic properties that are characteristic of this class of
agents. 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). 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.

15. Mechanism of action: The anthranilates have primarily antiinflammatory with some
analgesic and antipyretic activity and are non-COX selective. The anthranilates are used
as mild analgesics.
Examples: Mefenamic Acid
.
Mefenamic Acid

16. Oxicam Derivatives (“Enol Acids”)
 Oxicams (Piroxicam and Meloxicam) are characterized by
the 4-hydroxybenzothiazine heterocycle. The acidity of the
oxicams is attributed to the 4-OH with the enolate anion
being stabilized by intramolecular hydrogen-bonding to the
amide NH group. These compounds are acidic (pKa = 6.3).
 Mechanism of Action: Selective COX-2 inhibitor
 These agents used in treatment of rheumatoid arthritis and
osteoarthritis.
 Examples: Piroxicam

17. Phenylpyrazolones
 This class of agents are characterized by the 1-aryl-3,5-
pyrazolidinedione structure. The presence of a proton
which is situated α to two electron with drawing carbonyl
groups renders these compounds acidic. The pKa for
phenylbutazone is 4.5. Oxyphenbutazone is a hydroxylated
metabolite of phenylbutazone.
 Example: Phenylbutazone

18. Anilides
 The anilides are simple acetamides of aniline,
which may or may not contain a 4-hydroxy or 4-
alkoxy group. Anilides do not possess the
carboxylic acid functionality and therefore they are
classified as neutral drugs and possess little
inhibitory activity against cyclooxygenase.
 Example: Acetoaminophen or Paracetamol

19. Pyrralo-Pyrrole derivatives
 Ketorolac is a potent analgesic and modest
antiinflammatory active drug. It inhibits Prostaglandine
synthesis.
 Ketorolac is frequently used in postoperative, dental and
acute musculoskeletal pain.
Ketorolac

20. Summary of NSAIDS:
 In general, NSAIDs structurally consist of an acidic moiety (carboxylic acid, enols)
attached to a planar, aromatic functionality. Some analgesics also contain a polar
linking group, which attaches the planar moiety to an additional lipophilic group.
 The NSAIDs are characterized by the following chemical/ pharmacologic
properties:
1. All are relatively strong organic acids with pKa in the 3.0–5.0 range.
2. Most, but not all, are carboxylic acids. Thus, salt forms can be generated upon
treatment with base and all of these compounds are extensively ionized at
physiologic pH. The acidic group is essential for COX inhibitory activity.
3. The NSAIDs differ in their lipophilicities based on the lipophilic character of their
aryl groups and additional lipophilic moieties and substituents.
4. The acidic group in these compounds serves a major binding group (ionic binding)
with plasma proteins. Thus all NSAIDs are highly bound by plasma proteins (drug
interactions).
5. The acidic group also serves as a major site of metabolism by conjugation. Thus a
major pathway of clearance for many NSAIDs is glucuronidation (and inactivation)
followed by renal elimination.