Farmakodinamika

NSAIDs
Sony Eka Nugraha
Wahyudi

PROGRAM MAGISTER FARMASI USU

2016
 What is Nsaid ?
Nonsteroidal antiinflammatory drugs
(NSAIDs) block the COX enzymes and
reduce prostaglandins throughout the
body. As a consequence, ongoing
inflammation, pain, and fever are
reduced.
 Common Pharmacological Effects
to be covered below

Analgesic (CNS and peripheral effect) may involve

non-PG related effects
Antipyretic (CNS effect)
Anti-inflammatory (except acetaminophen) due
mainly to PG inhibition.
 Common Adverse Effects
Platelet Dysfunction
Gastritis and peptic ulceration with bleeding
(inhibition of PG + other effects)
Acute Renal Failure in susceptible
Sodium+ water retention and edema
Prolongation of gestation and inhibition of labor.
Hypersenstivity (not immunologic but due to PG
inhibition)
GIT bleeding and perforation
Metabolism of Arachidonic Acid (AA)
 Arachidonic acid
Many of the lipids that act as second messengers
in cell signaling pathways are derived from
arachidonic acid. Arachidonic acid is an omega 6
-unsaturated fatty acid that is a constituent of
cellular membranes, esterified to the sn-2
position of glycerophospholipids.
Arachidonic acid and its metabolites play
important roles in a variety of biological
processes, including signal transduction,
contraction, chemotaxis, cell proliferation and
differentiation, and apoptosis.
 Cyclooxygenase
An enzyme responsible for the production of
prostaglandins, prostacyclin and tromboxane.
Two forms, COX1 and COX2
Contains two separate active sites for
prostaglandin synthase
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).
Differing Functions of COX-1 & COX-
2
Arachidonic Acid

COX-1 COX-2
(constitutive) (inducible)

Homeostasis Pathophysiology
Stomach/GI protection Inflammation, Pain
Platelet aggregation Cancer
Renal blood flow
Prostaglandin Regulate Physiological Functions

Prostaglandins are
biologically active
phospholipid
molecules that
regulate many
physiological
functions

Proper balance of
prostaglandins are
critical for normal
homeostasis
 Most NSAIDs currently used today shows
no selectivity to COX1 and COX2 (ex Aspirin)

This non selectivity leads to various side effects

Aspirin and other similar NSAIDs lead to excessive
production of stomach acid as well as ulceration and
gastrointestinal bleeding
This is due to the inhibiting of COX1s house
keeping role as well as COX2s inflammatory
response
Resent research has been directed at the selectivity
of COX2 over COX1
 Aspirin effect on COX
Aspirin irreversibly acetylates the COX binding
site preventing formation of prostaglandins.
Binding to COX1 inhibits its prostaglandin
production responsible for assisting platelet
formation thus causing the blood to thin and
less clotting.
Binding COX2 lessens inflammatory response.
COX 1 and COX2 vary slightly in their structure
Finding drugs selective to COX2 requires the
utilization of the hydrophilic side pocket.
Since aspirin is nonselective to both COX1 and
COX2 it shows duel effects
CELECOXIB SELECTIVE TO COX2
Celecoxib shows selectivity to COX2 thus
inhibiting only the inflammatory
prostaglandins and not the COX1 house
keeping prostaglandins
 WHY IS CELECOXIB SELECTIVE TO
COX2?
Celecoxib effect on COX2
While aspirin can bind to COX1 and COX2,
celecoxib binds only to COX2 due to COX2s
hydrophilic side pocket.
 Future uses of selective NSAIDs
In addition of COX2 inhibiters to contr ol pain and
inflammation, research suggests that further uses
of these drugs can have beneficial effects.
Research has shown that there is a link to COX2
and cancer. Thus the effects of selective NSAID to
COX2 can reduce the occurrence of certain kinds
of cancer.
Other studies have also connected COX2
inhibiters to have reduced Alzheimer's disease
though the mechanism is unknown.
 COX2 selective
Celcoxib (celebrex)
Rofecoxib (Vioxx)
Valdecoxib (Bextra)
 COX3 selective
Acetaminophen
PAIN
Fever
Hypothalamus

Inflammation
Fever
 COX-3, a cyclooxygenase-1 variant

It is inhibited by acetaminophen
COX-3 and one of the PCOX-1 proteins (Partial-COX-1a=
PCOX-1) are made from the COX-1 gene but retain
intron 1 in their mRNAs
Acetaminophen is often categorized as a nonsteroidal
antiinflammatory drug (NSAID), even though in clinical
practice and in animal models it possesses little
antiinflammatory activity (1). Like NSAIDs, however,
acetaminophen inhibits pain and fever and is one of
the world's most popular analgesic/antipyretic drugs.
Inflammation and Cancer
The Significance of COX-2
Metabolites of arachidonic acid participate in
normal growth responses and in aberrant cellular
growth and proliferation, including carcinogenesis.
The key step in the conversion of free arachidonic
acid to prostaglandins is catalyzed by the
cyclooxygenase enzyme (COX). There are two COX
enzymes, COX-1 and COX-2. COX-1 is expressed
constitutively and is part of normal cell metabolic
functions. COX-2, on the other hand, is induced and
expressed in neoplastic growths.
Prostaglandin Signaling Mechanisms

Prostaglandins control
cellular function through
G-coupled membrane
receptors and nuclear
receptors
Prostaglandin Signaling
Promotes Cell Growth
 Increased PGE2 Promotes
Many Facets of Tumorigenesis
Metastasis
Vascular Invasion Reduced
Angiogenesis Apoptosis
MMP-2
VEGF MMP-9 BCL-2

IL-10
PGE2 PI3-K
IL-12 Activation

Immune Proliferation
Suppression Motility
COX-2/PGE2 Signaling: A Target for
Cancer
Structures of Cyclooxygenase (COX) Isoenzymes

COX-1 COX-2

Active site Active site

Hydrophobic Side
channel pocket
Hydrophobic
channel
Chemical Structures of Typical NSAIDs
Ibuprofen Naproxen Diclofenac

Fits into main cyclooxygenase

hydrophobic channel
Chemical Structure of Celecoxib

O
NH2
S

O
N
N
CF3
Fits into COX-2
side pocket

Fits into main

CH3
cyclooxygenase
hydrophobic channel
 MECHANISM OF NSAID INHIBITION
COX-1 COX-2

NSAID
Active site
Active site
Celecoxib

Arachidonic
acid N
N
Arachidonic
acid

Side
N pocket
N
Celecoxib
Terima kasih