Anti-inflammatory Drugs

INFLAMMATION
• Inflammation is a defense reaction caused by tissue damage
or injury.
• Can be elicited by numerous stimuli including:
• infectious agents
• Thermal injury
• Physical injury
• Noxious chemicals
• ischemia
Inflammatory responses occur in three distinct phases:

1. An acute transient phase, characterized by:

– local vasodilation and its resulting increased blood
flow causes the redness (rubor) and increased heat
(calor)
– Increased permeability of the blood vessels results in
an exudation (leakage) of plasma proteins and fluid
into the tissue (edema), which manifests itself as
swelling (tumor).

2. A delayed phase, most prominently characterized by:

– infiltration of leukocytes and phagocytic cells to
the injured /inflammed tissue
3. A chronic proliferative phase, in which:
– tissue degeneration and fibrosis occur
 Phases of inflammation
Stimulus of inflammation

Causes tissue injury

1)That causes release of chemical mediator

That results in dilation of blood vessels of injured area

That increases blood flow to injured area

[Symptoms: redness, increased heat generation]
The mediators also increase permeability of blood vessels

That causes exudation of plasma protein and fluid into the

tissue [Symptoms: Swelling and pain]

2)The chemical mediators also attract WBC to the injured

area
Which engulfs dead tissue and/or pathogen

3)Healing of tissue starts to restore normal structure and

function by two distinct process

degeneration Repair
 4 signs of inflammation
• Redness –
due to vasodilation of capillaries to increase blood flow.
• Heat - due to local vessel dilatation.
• Swelling –
due to Increased vascular permeability and influx of
plasma proteins and phagocytic cells into the tissue
spaces
• Pain – due to
-Hyperalgesia, sensitization of nociceptors
-local release of enzymes and
-increased tissue pressure
Mediators of the inflammatory response
i)Complement system- The complement system is a biochemical cascade that
helps, or “complements”, the ability of antibodies to clear pathogens from an
organism.

ii)histamine – Secreted from mast cell.

vasodilation
increases gap junction space
causes tissue to swell
causes bronchoconstriction
causes sneezing, watery eyes, itching
causes pressure & pain

iii) serotonin :Vasoconstrictor

iv)bradykinin -. A vasoactive protein which is able to induce vasodilation, increase

vascular permeability and induce pain
 v)leukotrienes
- increase vascular permeability and leakiness
- bronchoconstriction
- increase mobilization of endogenous mediators of inflammation

vi)Prostaglandins-Major mediators of inflammation

PGE2 - promote Vasodilation, Bronchodilation , leukocyte infiltration,
Directly Cause Pain and Induces Fever
PGI2 - increase vascular permeability, enhance pain producing
properties of bradykinin

vii) Thromboxane A2 (TXA2)- Thromboxane is a member of the family of

lipids known as eicosanoids. The two major thromboxanes are thromboxane
A2 and thromboxane B2.
cause platelets to aggregate
causes vasoconstriction
causes smooth muscle contraction
enhances function of inflammatory cells
 Prostaglandins
• Prostaglandins are unsaturated fatty acid
derivatives containing 20 carbons that include
a cyclic ring structure.
• Note: These compounds are sometimes
referred to as eicosanoids; which refers to the
20 carbon atoms.
 Synthesis of prostaglandins
• Arachidonic acid, a 20-carbon fatty acid, is the primary
precursor of the prostaglandins and related
compounds.
• Arachidonic acid is present as a component of the
phospholipids of cell membranes ,primarily
phosphatidylinositol and other complex lipids.
• Free arachidonic acid is released from tissue
phospholipids by the action of phospholipase A2 and
other acyl hydrolases via a process controlled by
hormones and other stimuli.
• There are two major pathways in the synthesis of the
eicosanoids from arachidonic acid.
 SYNTHESIS OF PROSTAGLANDIN
Stimulus of inflammation

Diacylglycerol/Essential fatty acid Disrupts cell membrane

Catalyzed by PLA2 Which causes release of phospholipid from cell

membrane
is converted into Arachidonic acid
Catalyzed by PLA2
Which is converted into arachidonic acid
Catalyzed by COX1 Catalyzed by COX2

Which is converted into prostaglandin H2 (PGH2)

Which is converted into Which is converted into

PGE2
PGE2 PGI2
•Impoves gastric - Decrease Produce pain,fever,
cytoprotection
•Dilation of renal platelet Inflammtion
artery
•Bronchodilation aggregation
-decrease HCl secretion
 Two main forms of Cyclooxygenases (COX)

• Cyclooxygenase-1 (COX-1) • Cyclooxygenase-2 (COX-2)

• Produces prostaglandins that • Produces prostaglandins that

mediate homeostatic functions mediate inflammation, pain, and
• Constitutively expressed fever.
• Induced mainly in sites of
• Homeostatic inflammation by cytokines
Protection of gastric
mucosa • Pathologic
Inflammation
Renal functions
Pain
Decrease platelet aggregation over the
endothelium
Fever
 NSAID
• The NSAIDs are a group of chemically
dissimilar agents that have similar
pharmacological activities such as antipyretic,
analgesic, and anti-inflammatory activities.
ASPIRIN
Pharmacologic properties of Aspirin

– Aspirin is a weak organic acids;

– These agents are rapidly absorbed from the intestine as

well as from the stomach, where the low pH favors
absorption.
Mechanism of action of Aspirin as
Anti-inflammatory agent
– NSAID inhibits the enzymes cyclooxygenase,
(COX1 and COX2), which converts arachidonic
acid to prostaglandinE2(PGE2), and to
prostaglandinI2(PGI2)/prostacyclin.

– Aspirin irreversibly inactivates COX-1 and COX-2 by

acetylation of a specific serine residue.

– This distinguishes it from other NSAIDs, which

reversibly inhibit COX-1 and COX-2.
 SYNTHESIS OF PROSTAGLANDIN
Stimulus of inflammation

Diacylglycerol/Essential fatty acid Disrupts cell membrane

Catalyzed by PLA2 Which causes release of phospholipid from cell

membrane
is converted into Arachidonic acid
Catalyzed by PLA2
Aspirin Which is converted into arachidonic acid
X
Catalyzed by COX1 X Catalyzed by COX2

Which is converted into prostaglandin H2 (PGH2)

Which is converted into Which is converted into

PGE2
PGE2 PGI2
•Impoves gastric - Decrease
cytoprotection
Produce pain,fever,
•Dilation of renal platelet
artery Inflammtion
aggregation
-decrease HCl secretion
2.Mechanism of action of Aspirin as
Analgesic

The analgesic effect of Aspirin is thought to be related to:

– the peripheral inhibition of prostaglandin
production

– may also be due to the inhibition of pain stimuli at

a subcortical site.
 SYNTHESIS OF PROSTAGLANDIN
Stimulus of inflammation

Diacylglycerol/Essential fatty acid Disrupts cell membrane

Catalyzed by PLA2 Which causes release of phospholipid from cell

membrane
is converted into Arachidonic acid
Catalyzed by PLA2
Aspirin Which is converted into arachidonic acid
X
Catalyzed by COX1 X Catalyzed by COX2

Which is converted into prostaglandin H2 (PGH2)

Which is converted into Which is converted into

PGE2 TXA2
PGE2 PGI2
•Impoves gastric - Decrease
cytoprotection
Produce pain,fever, Increase
•Dilation of renal platelet
artery Inflammtion platelet
•Bronchodilation aggregation aggregation
-decrease HCl secretion
 Mechanism of formation of fever
Infection or other stimulus of inflammation

Activate WBC to mobilize to infected or inflamed area

Where they release cytokines

Through blood, cytokines move to hypothalamaus of brain

And induce hypothalamus to produce PGE2 by COX2 enzyme

PGE2 elevates set point of thermoregulatory centre of hypothalamus

That increase heat production and decreases heat loss

3.Mechanism of action of Aspirin as
Antipyretic
The antipyretic effect of Apirin is believed to be related to:

• inhibition of production of prostaglandins induced by

cytokines such as interleukin-1 (IL-1) and interleukin-
6 (IL-6) in the hypothalamus

• the “resetting” of the thermoregulatory system,

leading to vasodilatation and increased heat loss.
Metabolism
– Aspirin is hydrolyzed rapidly by plasma and tissue
esterases to acetic acid and the active metabolite
salicylic acid.

esterases
– If the urine pH is raised above 8, clearance is
increased approximately fourfold as a result of
decreased reabsorption of the ionized salicylate
from the tubules.
 Clinical Use
Aspirin is the first-line drugs used to arrest inflammation and
the accompanying pain of-
1) rheumatoid arthritis,
2)juvenile arthritis,
3)osteoarthritis,
4) psoriatic arthritis,
5) ankylosing spondylitis,
6) Reiter syndrome,
7) bursitis and
8) dysmenorrhea.
9)Dental pain