NON-STEROIDAL ANTI-

INFLAMMATORY DRUGS
(NSAIDS)

John Tiong
Inflammation
 Inflammation and the immune system are closely intertwined.

 Inflammation is a normal, protective response to tissue injury

caused by:
 physical trauma
 noxious chemicals
 microbiologic agents.

 Inflammation is the body’s effort to inactivate or destroy

invading organisms, remove irritants and set the stage for
tissue repair.

 A normal inflammatory response is an acute process that

resolves after removal of the inciting stimulus.
Inflammation
The cardinal signs of inflammation:
 Heat and redness:
 Due to increased local blood flow

 Swelling:
 Due to leakage of fluid (and proteins) from blood vessels
into surrounding inflamed tissues

 Pain:
 Stimulation of pain receptors and sensitization to pain by
lowering of pain threshold
Inflammatory response
 The cells and soluble mediators of the immune system
interact with one another to generate the
inflammatory response.

 This typically occurs in phases:

 Dilation of blood vessels
 Recruitment of cells

 Chemotaxis and phagocytosis

 Tissue repair
Dilation of blood vessels
 Injury to tissues causes the stimulation of pain receptors
which sends impulses along sensory nerves both towards
the CNS and also along branches towards nerve endings
causing these nerve endings to release substance P at
mast cells close to arterioles.

 Mast cells will be stimulated to release histamine while

damaged cell membrane will also stimulate the release of
arachidonic acid resulting in the formation of leukotrienes,
prostaglandins, thromboxane and prostacyclin.

 These inflammatory mediators will lead to vasodilation

resulting in increased blood flow to the site of injury
causing clinical signs of redness and warmth.
Dilation of blood vessels
 Inflammatory mediators also cause contraction of
vascular endothelial cells leading to increased capillary
permeability and to the development of an exudate
(interstitial fluid with a high protein content)  this
leads to clinical manifestation of swelling.

 Pain develops due to both increased tissue pressure and

stimulation of pain receptors and their sensitization (by
substance P and PGE2) leading to lowering of pain
threshold.
Inflammatory mediators will sensitize nociceptors

Lowering of pain threshold

Hyperalgesia:
Increase in pain sensation from a painful stimulus
Recruitment of cells
 Increased vascular permeability allows cells from the blood to
enter the interstitium.

 Leukocyte recruitment is orchestrated to optimize the clearing of

infection and local repair of the injured tissue.

 At the onset of an inflammatory response, the endothelial cells at

the site of injury are activated to express adhesion molecules that
bind specific receptors expressed by lecukocytes.

 P-selection, E-selection, Intercellular adhesion molecules

(ICAMs) or Vascular cell adhesion molecules (VCAMs) are
expressed by activated endothelial cells which bind leukocytes.
Their expressions are induced by thrombin, histamine, cytokines
(TNF-α, interferon gamma or interleukin-1) released by damaged
tissues, defense cells and mast cells
 Recruitment of cells
 This interaction causes leukocytes to bind tightly to the activated
endothelium at the site of injury which promotes transmigration
(diapedesis) from the vasculature into the interstitium.

 Specificity of the immune response is achieved according to the pattern

of adhesion molecules expressed by the activated endothelium and by
the various leukocytes. For example:
 P-selectin (expressed within minutes) binds neutrophil, monocytes and
activated T- cells
 E-selectin (expressed 3-6 hrs) binds neutrophils and monocytes
 VCAM-1 (expressed after 6-10hrs) binds lymphocyte, monocytes and
eosinophils ICAM-1 (expressed after 12-24 hrs) binds lymphocytes,
monocytes and neutrophils
Chemotaxis and phagocytosis
 Once the immune cells cross the endothelial barriers, they will
migrate through interstitium to the specific site of injury or infection

 Immune cells targeting is accomplished by the process of chemotaxis

or chemical signalling.

 Inflammatory mediators released at the site of injury such as N-

formyl peptides (derived from bacterial proteins) or complement
system C5a and leukotriene B4 (LTB4) will attract leukocytes to the
site of the inflammatory reaction.

 Upon arrival at the site, leukocytes will be stimulated for killing by

foreign particles which are coated by opsonins such as complement
proteins, antibodies and collectins (plasma proteins that bind to
microbial carbohydrates).
 Chemotaxis and phagocytosis
 The interaction between phagocytic cells with the opsonized particles will
initiate engulfment and the destruction of the invading particles.

 Neutrophils also secretes phospholipases A2 which further releases

arachidonic acid from cell membranes resulting in the formation of more
inflammatory mediators potentiating pain, vasodilation, chemotaxis.
Bradykinin is also released from local tissues causing vasodilation.

 Prolonged presence of neutrophils at the inflamed site (such as in chronic

inflammation) will cause major destruction of surrounding tissues.
 Tissue repair
 Tissue repair and re-establishment of homeostasis are the final events in
the acute inflammatory response.

 The same mediators that activate inflammation also initiate a cascade

of tissue repair; this process is mediated by the release of growth
factors and cytokines, including:
 epidermal growth factor (EGF)
 platelet-derived growth factor (PDGF)
 basic fibroblast growth factor-2 (bFGF-2)
 transforming growth factor- 1 (TGF- β1), IL-1 and TNF-α.

 These factors act as mitogens for endothelial cells and fibroblasts and
ultimately stimulate healing and scar formation through angiogenesis
(formation of new blood vessels) and the formation of granulation
tissue.
 Chronic inflammation
 Diseases of inflammation and immunity can occur when the normal
inflammatory response progresses to chronic inflammation, either
because of a long-term inappropriate response to a stimulus (for
example allergies) or because the offending agent is not removed (for
example, chronic infection, transplantation, and autoimmunity).

 Prolonged action of the mechanisms for killing infecting organisms and

for destroying, removing and repairing of damaged tissues ultimately
results in the death and destruction of body’s own tissue and the
deposition of new tissue at sites where it is not needed.

 The outcome of chronic inflammation is thus progressive tissue damage,

scar tissue formation in organs, joint damage and erosions, functional
disability, significant pain and reduction in quality of life.
Arachidonic acid
 Arachidonic acid is the primary precursor of the prostaglandins and
related compounds.

 Arachidonic acid is present as a component of the phospholipids of

cell membranes.

 Free arachidonic acid is released from tissue phospholipids by the

action of phospholipase A2 via a process controlled by hormones
and other stimuli e.g. tissue injury

 There are two major pathways in the synthesis of the eicosanoids

from arachidonic acid, the cyclooxygenase and the lipoxygenase
pathways.
 Cyclooxygenases
 All eicosanoids with ring structures (prostaglandins, thromboxanes, and
prostacyclin) are synthesized via the cyclooxygenase pathway  called
the prostanoids

 COX-1 is a constitutive enzyme that regulates normal cellular processes,

such as gastric cytoprotection, vascular homeostasis, platelet
aggregation, as well as reproductive and kidney functions.

 COX-2 is constitutively expressed in tissues such as the brain, kidney,

and bone. Its expression at other sites is increased during states of
chronic inflammation.

 The expression of COX-2 is induced by inflammatory mediators like

TNF-α and IL-1.
NSAIDs
 The NSAIDs are a group of chemically dissimilar agents that differ
in their antipyretic, analgesic, and anti-inflammatory activities.

 They act primarily by inhibiting the cyclooxygenase enzymes that

catalyze the first step in prostanoid biosynthesis.

 This leads to decreased prostaglandin synthesis with both beneficial

and unwanted effects.

 Differences in safety and efficacy of the NSAIDs may be explained

by relative selectivity for the COX-1 or COX-2 enzyme. Inhibition of
COX-2 is thought to lead to the anti- inflammatory and analgesic
actions of NSAIDs, while inhibition of COX-1 is responsible for
prevention of cardiovascular events and most adverse events. I
NSAIDs
 Aspirin irreversibly acetylates and blocks platelet
cyclooxygenase, while most non-Cox-selective NSAIDs are
reversible inhibitors.

 Selectivity for COX-1 versus COX-2 is variable for the older

NSAIDs, but many selective COX-2 inhibitors have been
synthesized.

 In testing using human whole blood, aspirin, ibuprofen,

indomethacin, piroxicam, and sulindac are somewhat more
effective in inhibiting COX-1.
NSAIDs
 The efficacy of COX-2-selective drugs equals that of the
older NSAIDs, while gastrointestinal safety may be improved.

 On the other hand, selective COX-2 inhibitors may increase

the incidence of cardiovascular risks.

 As of December 2008, celecoxib and the less selective

meloxicam are the only COX-2 inhibitors marketed in the
USA.

 Rofecoxib and valdecoxib, two previously marketed,

selective COX-2 inhibitors, have been withdrawn from the
market due to their association with increased cardiovascular
thrombotic events.
 MOA & Therapeutic uses:
Anti-inflammatory actions:
 Cyclooxygenase inhibition diminishes the formation of prostaglandins and, thus,
modulates aspects of inflammation in which prostaglandins act as mediators.
 NSAIDs inhibit inflammation such as in in arthritis, but they neither arrest the
progression of the disease nor induce remission

 Analgesic action:
 PGE2 is thought to sensitize nerve endings to the action of bradykinin,
histamine, and other chemical mediators released locally by the inflammatory
process.
 Thus, by decreasing PGE2 synthesis, the sensation of pain can be decreased. As
COX-2 is expressed during times of inflammation and injury, it is thought that
inhibition of this enzyme is responsible for the analgesic activity of NSAIDs. No
single NSAID has demonstrated superior efficacy over another, and all agents
are generally considered to have equivalent efficacy.
 The NSAIDs are used mainly for the management of mild to moderate pain
arising from musculoskeletal disorders. One exception is ketorolac, which can
be used for more severe pain but for only a short duration.
MOA & Therapeutic uses:
Antipyretic action:
 Fever occurs when the set-point of the anterior hypothalamic
thermoregulatory center is elevated.
 This can be caused by PGE2 synthesis, which is stimulated during
infection, hypersensitivity, malignancy, or inflammation).
 The NSAIDs lower body temperature in patients with fever by
impeding PGE2 synthesis and release. These agents essentially reset
the “thermostat” toward normal.
 This rapidly lowers the body temperature of febrile patients by
increasing heat dissipation as a result of peripheral vasodilation and
sweating.
 NSAIDs have no effect on normal body temperature
MOA & Therapeutic uses:
Cardiovascular applications:
 Aspirin is used to inhibit platelet aggregation.
 Low-dose aspirin inhibits COX-1–mediated production of TXA2,
thereby reducing TXA2-mediated vasoconstriction and platelet
aggregation and the subsequent risk of cardiovascular events.
 Low doses of aspirin irreversibly inhibits COX-1and the antiplatelet
effects persist for the life of the platelet.
 Chronic use of low doses allows for continued inhibition as new
platelets are generated.
MOA & Therapeutic uses:
External applications:
 Salicylic acid is used topically to treat acne, corns, calluses, and
warts.
 Methyl salicylate (“oil of wintergreen”) is used externally as a
cutaneous counterirritant in liniments, such as arthritis creams and
sports rubs.
Celecoxib
 A selective COX-2 inhibitor that is significantly more selective
for inhibition of COX-2 than COX-1.

 The inhibition is also reversible.

 Therapeutic uses:
 Celecoxib is approved for the treatment of RA, osteoarthritis, and acute
mild to moderate pain.
 Celecoxib has similar efficacy to NSAIDs in the treatment of pain.
 Adverse effects
Gastrointestinal:
 The most common adverse effects of NSAIDs are GI related,
ranging from dyspepsia to bleeding.
 Normally, production of prostacyclin (PGI2) inhibits gastric acid
secretion, and PGE2 and PGF2α stimulate synthesis of protective
mucus in both the stomach and small intestine.
 Agents that inhibit COX-1 reduce beneficial levels of these
prostaglandins, resulting in increased gastric acid secretion,
diminished mucus protection, and increased risk for GI bleeding
and ulceration.
 Agents with a higher relative selectivity for COX-1 may have a
higher risk for GI events compared to those with a lower
relative selectivity for COX-1 (that is, higher COX-2 selectivity).
 NSAIDs should be taken with food or fluids to diminish GI upset
Adverse effects
Increased risk of bleeding (antiplatelet effect):
 TXA2 enhances platelet aggregation whereas PGI2 decreases
it.
 Aspirin irreversibly inhibits COX-1–mediated TXA2 formation,
while other NSAIDs reversibly inhibit the production of TXA2.
 Because of the decrease in TXA2 production, platelet
aggregation (the first step in thrombus formation) is reduced,
producing an antiplatelet effect with a prolonged bleeding
time. For this reason, aspirin is often held, or not given, at least
1 week prior to surgery.
 NSAIDs other than aspirin are not utilized for their antiplatelet
effect but can still prolong bleeding time.
Adverse effects
Actions on the kidney:
 NSAIDs prevent the synthesis of PGE2 and PGI2,
prostaglandins that are responsible for maintaining renal
blood flow
 Decreased synthesis of prostaglandins can result in retention of

sodium and water and may cause edema in some patients.

 Patients with a history of heart failure or kidney disease are at

particularly high risk.

Adverse effects
Cardiac effects:
 Agents such as aspirin, with a very high degree of COX-1 selectivity,
have shown a cardiovascular protective effect thought to be due to
a reduction in the production of TXA2.
 Agents with higher relative COX-2 selectivity have been associated
with an increased risk for cardiovascular events, possibly by
decreasing PGI2 (it prevents platelet activation and is an effective
vasodilator) production mediated by COX-2.
 An increased risk for cardiovascular events, including MI and stroke,
has been associated with all NSAIDs except aspirin.
 Use of NSAIDs, other than aspirin, is discouraged in patients with
established cardiovascular disease.
Adverse effects
Other side effects:
 NSAIDs are inhibitors of cyclooxygenases and, therefore,
inhibit the synthesis of prostaglandins but not of leukotrienes.
For this reason, NSAIDs should be used with caution in patients
with asthma, as inhibition of prostaglandin synthesis can cause
a shift toward leukotriene (which can cause bronchoconstriction)
production  increase the risk of exacerbations of asthma.
 Approximately 15% of patients taking aspirin experience
hypersensitivity reactions. Symptoms of true allergy include
urticaria, bronchoconstriction, and angioedema.
 Fatal anaphylactic shock is rare. Patients with severe

hypersensitivity to aspirin should avoid using NSAIDs.

Paracetamol (acetaminophen)
 It inhibits prostaglandin synthesis in the CNS. This explains its
antipyretic and analgesic properties.

 Acetaminophen has less effect on cyclooxygenase in peripheral

tissues (due to peripheral inactivation), which accounts for its
weak anti-inflammatory activity.

 Acetaminophen does not affect platelet function or increase

bleeding time.

 It is not considered to be an NSAID.

Paracetamol (acetaminophen)
 Paracetamol is a suitable substitute for the analgesic and
antipyretic effects of NSAIDs for those patients with gastric
complaints/ risks, in those whom a prolongation of bleeding
time is not desirable, as well as those who do not require the
anti-inflammatory action of NSAIDs.

 At normal therapeutic doses, paracetamol is virtually free of

significant adverse effects. High doses can cause hepatic
necrosis, a very serious and potentially life threatening
condition  N-acetylcysteine is given as antidotes.

 Paracetamol should be avoided in patients with severe hepatic

impairment.
WHO Analgesic Ladder
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