Anti-inflammatory Drugs

• Anti-inflammatory process is a part of

normal defence mechanism that aids in
the repair of damaged tissues
• A large number of drugs are used in vet.
Practice to decrease the intensity of
inflammation and to alleviate pain
• These drugs are divided into steroidal and
non-steroidal anti-inflammatory drugs.
 Steroids/Corticosteroids
• Suppress all aspects of acute and chronic
inflammatory processes and are
extensively used for treatment of various
inflammatory conditions.
• They reduce release or synthesis of
several inflammatory mediators, almost all
cytokines, platelet activating factor,
eicosanoids (prostaglandins, leukotrienes
and thromboxane) and generation of free
radicals.
• One important biochemical pathway
blocked by corticosteroids is the
arachidonic acid cascade by inhibiting
activity of phospholipase A2 enzyme.
• Steroids are used in myositis, bursitis,
tendinitis, osteoarthritis, rheumatoid
arthritis etc.
• Also used in various allergic and non-
allergic inflammatory conditions of
respiratory system, skin, ear and eye.
• Ulcerative colitis and cerebral oedema.
Non-Steroidal Anti-inflammatory
Drugs
• NSAID’s
• Having weak or mild analgesic effect with
or without antipyretic and anti-
inflammatory actions
• These drugs have no affinity for opioid
receptors and don’t induce central
depressant and sedative activity.
• They don’t produce physical dependence
and no tolerance
• NSAID’s are among the most widely used
of all therapeutic drugs
 Classification:
• A. Non-selective COX inhibitors
I. Agents with analgesic and marked anti-
inflammatory activity
1. Salicyclic acid derivatives/Salicylates:
Aspirin, sodium salicylate, salicyclic acid
etc.
• 2. Pyrazolone derivatives:
Phenylbutazone, oxyphenbutazone,
antipyrine, aminopyrine etc.
• 3. Indole and indene acetic acid
derivatives: etodolac, indomethacin and
sulindac
• 4. Oxicam derivatives: Piroxicam,
meloxicam and tenoxicam
• 5. Amino-nicotinic acid derivatives:
Flunixin and clonixin
• 6. Hetero-aryl acetic acid derivatives:
Diclofenac, tolmetin, fenclofenac etc.
 II. Agents with analgesic and mild to
moderate anti-inflammatory activity:
• 1. Propionic acid derivatives: Carprofen,
naproxen, ketoprofen, ibuprofen,
oxaprozin etc.
• 2. Anthranilic acid derivatives/ Fenamates:
Meclofenamic acid, mefenamic acid,
tolfenamic acid, niflumic acid etc.
• 3. Sulphonalinide derivatives: Nimesulide
• 4. Alkalones: Nabumetone
 III. Agents with analgesic and poor anti-
inflammatory activity:
• 1. Para-aminophenol derivatives:
paracetamol, phenacetin etc.
• 2. Pyrazolone derivatives: Metamizole and
propiphenazone
• 3. Benzoxazocine derivatives: Nefopam
 B. Selective COX-2 inhibitors
• 1. Diaryl-substituted furanones: Rofecoxib
• 2. Diaryl-substituted pyrazoles: Celecoxib
 Important characteristics of NSAID’s

• a. They are primarily weak organic acids

(carboxylic and enolic)
• b. Have anti-inflammatory, antipyretic and
analgesic effects
• c. Most NSAID’s mediate their primary
action th. Inhibition of COX enzymes.
• d. Provides only symptomatic relief from
inflammation and pain
• e. Against pain of low to moderate
intensity
• f. Pharmacokinetics varies b/w species
• g.Most NSAID’s are well absorbed after
oral admini9stration with bioavailibilty
ranging from 50 to 100%
• h. Highly bound to plasma proteins
• i. Many show prolonged duration
• j. All NSAIDs exert action on Git to varying
degree.
• k. Show interactions with drugs having
highly bound to plasma proteins
• l. Don’t show resp. depression, drug
dependence, tolerance or withdrawal
symptoms.
 Mechanism of Action:
• NSAIDs act primarily by inhibiting
synthesis of prostaglandins, the mediators
involved in nociception and pathogenesis
of inflammation and fever.
• These drugs block COX enzyme either
reversibly (most NSAIDs) or irreversibly
(Aspirin) causing inhibition of synthesis of
PGs, prostacyclin (PGI2) and thromboxane
A2 (TXA2)
 Cyclooxygenase Enzymes:
• Occurs in two isozymes:
1. COX-1
2. COX-2
• COX-1 is constitutive and is considered to
be necessary for normal homeostasis
• COX-2 is inducible and is considered to be
associated with inflammation and pain.
• Most NSAIDs inhibit both COX-1 and
COX-2 non-selectively
• Rofecoxib selectively inhibit COX-2
• GI irritation and renotoxicity are due to
inhibition of COX-1
• Desirable antiinflammatory and analgesic
actions are due to blockade of COX-2
• Inhibition of neutrophils function, inhibition
of oxygen radical production, stabilization
of lysosomal enzymes, antagonism of
bradykinin release, modulation of nictric
oxide synthesis, or inhibition of
metalloproteinase activity.
 Aspirin:
• Acetylsalicyclic acid.
• Most extensively used OTC drug
• Bayer first developed it in 1899
• Inhibits cyclooxygenase enzyme activity
and consequent reduction of PG’s
synthesis
• It irreversibly blocks both COX-1 and
COX-2 iso-enzymes
• It prevents binding of arachidonic acid to
the active site of the enzyme and thus the
ability of enzyme to form prostaglandins.
 Pharmacological effects:
• Aspirin acts both centrally and peripherally
to produce its pharmacological effects
 Analgesic effect:
• Weaker analgesic than morphine-like
drugs
• Relieves inflammatory, rheumatic, tissue
injury-related, connective tissue, muscular,
arthritic and integumental pain.
 Antipyretic effect:
• Marked antipyretic action
• It resets the hypothalamic thermostat and
rapidly reduces fever by increasing heat
loss as a result of peripheral vasodilation,
panting and sweating.
• Does not decrease heat production
 Anti-inflammatory effect:
• Shows this effect on higher doses
• It inhibits signs of inflammation such as
pain, tenderness, swelling, vasodilation
and leucocyte infiltration.
 GIT
• Normally prostacyclin (PGI2) inhibits
gastric acid secretion
• PGE2 and PGF2 stimulate synthesis of
protective mucus in both stomach and s.
intestine
• Aspirin, blocks the formation of these PGs
resulting in increased gastric acid
secretion and diminished mucus protection
• May cause epigastric distress, nausea and
vomiting.
• Aspirin produces dose-related gastric
ulceration and haemorrhage
 Pharmacokinetics:
• Easily absorbed from stomach and
proximal small intestine
• During absorption, most of aspirin is
hydrolysed to salicyclic acid (salicylate)
and acetic acid.
• Widely distributed in the body
• Readily crosses placental barrier
• Mostly metabolised in liver
• Excreted mainly through kidneys
 Drug interactions:
• It enhances action and toxicity of oral
anticoagulants and heparin by increasing
risk of bleeding.
• It decreases diuretic action of frusemide
and thiazides.
• Aspirin displaces warfarin, phenytoin,
naproxen, methotrexate, penicillins,
sulphonamides etc. from binding sites on
plasma proteins causing adverse
reactions and toxicity.
• Salicylates have hypoglycaemic action
and potentiate effects of insulin
• GI distress and bleeding is more
pronounced when aspirin is given with
other NSAID’s or steroids.
 Phenylbutazone:
• Introduced in 1949 as a synthetic
pyrazolone derivative, for rheumatoid
arthritis and other musculoskeletal
disorders.
• Weakly acidic and lipophilic
• Analgesic, antipyretic and anti-
inflammatory
• More toxic than aspirin
• MoA is similar to aspirin
• It scavenges toxic oxygen radicals
• Has more potent anti-inflammatory effect
than aspirin
• Analgesic and antipyretic effects are less
than that of salicylates
 Pharmacokinetics
• Well absorbed orally and s. intetine
• 99% bound to plasma proteins
• Metabolised mainly in liver
 Side effects:
• Produces oedema, ulceration of large
intestine, diarrhea, anorexia and necrosis
of hepatic vein in horses.
• Gastrointestinal ulceration, haemorrhage,
biliary stasis and proximal tubule damage
are reported in dogs
 Drug interaction:
• May displace warfarin, sulphonamides and
phenytoin.
 Piroxicam:
• Oxicam derivative
• Anti-inflammatory, analgesic and
antipyretic activity
• MoA is reversible inhibition of COX
enzymes.
• Its anti-inflammatory potency is equivalent
to aspirin
Inhibits platelet aggregation and prolongs
bleeding time, causes GI mucosal damage
and affects renal function.
 Pharmacokinetics:
• Well absorbed orally
• Highly bound to plasma proteins
• Largely metabolised in liver
• Excreted mainly in urine.
 Diclofenac:
• Hetero-aryl acetic acid derivative
• Analgesic, antipyretic and anti-
inflammatory activities
• Inhibitor of COX enzymes
• Used in rheumatoid and osteoarthritis,
bursitis, spondylitis, post-traumatic and
post-operative inflammatory conditions.
 Ibuprofen
• Introduced in 1969.
• Anti-inflammatory and analgesic agent
• Relatively low level of GI toxicity
• Overdose or intoxication gives rise to GI
irritation with enteritis, haemorrhage and
perforation.
• Renal failure and acidosis in dogs is also
seen
 Paracetamol:
• Acetaminophen
• Analgesic and antipyretic effects similar to
aspirin
• Not an anti-inflammatory agent
• Less side effects than aspirin
• More toxic in cats
• MoA: Inhibits COX enzymes in brain
• Poor inhibitor of COX enzymes and PGs in
peripheral tissues.
• It does not produce gastric irritation,
erosion, or bleeding
 Pharmacokinetics:
• In humans, well absorbed orally
• Bound to 35 % to plasma proteins
• Metabolised mainly in liver
 Rofecoxib:
• Diaryl substituted furanone non-steroidal
anti-inflammatory drug
• Introduced in 1999
• Anti-inflammatory, antipyretic and
analgesic effects
• Selective COX-2 inhibitor
• Recommended for the treatment of
osteoarthritis, acute pain in human
patients.