NSAID (non steroid anti

inflammation drugs) & opioid

analgesic drugs

Nur permatasari

Overview
Definition: NSAIDs are a chemically diverse class of
drugs (>70 NSAIDs in use) that have antiinflammatory, analgesic, and antipyretic properties.
-worldwide: 70 million people/day prescribed Ds
230 million people/day take OTC NS
-USA: 80 billion aspirin tablets consumed/year
constitute 4% of all prescriptions

2. Mechanism: inhibition of the inflammatory response

a. Normal inflammatory response
series of events that aid our survival in response to
injury
b. Mediated by a host of endogenous compounds
-histamine
-serotonin
-complement
-bradykinin
-prostaglandins **
-leukotrienes

Properties of Prostaglandins

Properties of Prostaglandins

Arachidonic acid metabolism

- released from lipid by phospholipases (PLA2)

- release stimulated by a variety of stimuli (physical, chemical,
hormonal,neurochemical, etc.)

Eicosanoids: protaglandins (PG), leukotrienes

- derived from arachidonic acid

- arachidonic acid is a 20 carbon essential fatty acid
- arachidonic acid is a component of membrane phospholipids

Prostaglandins

- released by all tissues

- type of prostaglandin released depends on cell type

Differential Actions of
Cyclooxygenases
Unwanted sideeffects
Constitutive

COX1
NSAIDs

Inducible
Inflammatory

COX2
Therapeutic antiinflammatory effects

PGI2
PGE2
TXA2
PGE2
PGF2
Proteases

Housekeeping
Endothelial integrity
Vascular patency
Gastric mucosal integrity
Bronchodilation
Renal function
Platelet function

Inflammation

Inhibition of Prostaglandin Synthesis

NSAID

Uses

Antiinflammatory
agent.
Analgesics.
Antipyretics.
Antithrombotic
s

Arthritis
Back pain
Soft tissue injuries
(sprains & strains)
Dental pain
Post-operative pain
Menstrual pain
Migraine
Delaying onset of
premature labour.

a. Anti-Inflammatory Actions

Inflammation is characterised by
redness, pain and swelling.
These are thought to be caused by
increased levels of prostaglandins.
NSAIDs reduce the prostaglandin levels
therefore reducing the symptoms of
inflammation.
They have varying degrees of antiinflammatory properties.

b. Antipyretic Actions

Pyrogens increase the body temperature by

activating macrophages & other cells to produce
cytokines.
These increase prostaglandin E 2 synthesis in the
hypothalmus (the bodys thermostat) which in
turn increases the body temperature.
NSAIDs inhibit prostaglandin E 2 synthesis and
lower the body temperature.
All NSAIDs have antipyretic properties. Aspirin,
ibuprofen and paracetamol are most commonly
used for this purpose.

c. Analgesic Actions

Prostaglandins cause sensitisation

of nerve cells to pain.
They sensitise nociceptor fibres to
bradykinins and 5HT.
The pain relieving properties of
NSAIDs are thought to be due to
the inhibition of prostaglandins,
particularly PGE2 & PGF2

d. Antithrombotic Actions

The body maintains a balance between

Thromboxane A2 (TXA2), produced by platelets &
Prostaglandin I2 (PGI2), produced by the vascular
endothelium.
This allows adequate platelet aggregation within
the body.
NSAIDs reduce both TXA2 & PGI2 levels.
Platelets cant synthesise cyclo-oxygenase enzymes
& so become inactive.
This causes the prostaglandin levels to increase &
reduces platelet aggregation.

Anti thrombotic effect of aspirin

e. Anti-cancer property

A number of studies in both animals and in

humans have
shown an up-regulation of COX-2 in colonic
cancers.
A large body of epidemiological evidence
points to an
inverse association between aspirin use and
colorectal cancer
risk.
The mechanism, the dose and duration
required for

Side effects

Gastric irritation and ulceration.

COX 1 produces prostaglandins that have a protective
effect on the stomach lining. NSAIDs inhibit this
enzyme & so it loses its function. Risk factors for
NSAID ulcers ??

Acute kidney failure.

The kidneys are rarely damaged in normal people.
Patients with heart failure, cirrhosis of the liver, renal
disease or who are taking diuretics should not take
NSAIDs as they cause kidney failure.

Side effects (cont)

Bleeding problems.
Bronchospasm can occur (may make
asthma worse).
Liver function abnormalities.
Headaches, Vertigo, Tinnitus, Dizziness
(Salicylism)
Metabolism.
Salt & Water Retention.

Hypersensitivity reaction

Classes of NSAIDs

Table showing the different classes of NSAIDs and some examples.

Prototype Non Steroidal Antiinflammatory Drugs

OH

OH
OH

O
Aspirin

Salicylic Acid

Modes of action
Irreversible Inhibition -- Aspirin only!
O

OH

OH
E Ser350

O
O

COX (active)

Aspirin

OH
OH

Salicyclic Acid

O
O
E Ser350
COX (inactive)

Reversible Inhibition -- All NSAIDS

HO

COX (active)

HO

COX (inactive)

Other Salicylates

NH2

OH

O
OH

Salicylamide

Mg

O
O
HO

Magnesium salicylate

OH O
O
O
Salsalate

OH

O
F
Diflunisal

OH

Aspirin - Pharmacokinetics

80-90% is bound to plasma proteins, mainly albumin

Can displace several other drugs from plasma protein
resulting in higher effective plasma concentrations

Aspirin - Dosage

Analgesic/antipyretic dose for adults is 325-650 mg every

4 hrs which results in a plasma concentration of
approximately 60 mg/ml. The half-life is 2-3 hours.
Anti-inflammatory dose is usually 4-6 g daily which results
in a plasma concentration of 150-300 mg/ml. The half-life
is usually 12 hours.
Fatal dose is 10-30 g resulting in plasma concentrations
exceeding 450 mg/ml. The half-life can be as long as
15-30 hours.

Aspirin Toxicity - Salicylism

Mild intoxication with aspirin

Commonly experienced when the daily dose exceeds 4 g
Characterized by tinnitis, high frequency hearing loss,
headache, nausea, dimness of vision.
Symptoms are usually reversible within 2-3 days after
withdrawal of the drug.

Analgesia without Anti-inflammation

O
HO

N
H

Acetaminophen

O
O

N
H

Phenacetin

Acetaminophen (Tylenol)**
Does not have significant anti-inflammatory properties
and as a result is not considered a true NSAID.
Inhibits COX-3
Does not have the same degree of complications from
the development of ulcerations. One of the first
drugs of choicein the management of mild to moderate
chronic pain.
Conventional oral dose is 325 to 1000 mg.

Acetaminophen-Pharmacokinetics
A small percentage undergoes cytochrome P450
mediated
N-hydroxylation forming a highly reactive intermediate.
Associated with hepatoxicity when taken in large
doses
(10 to 15 g).
Neutralized with the sulphydryl reducing agent
N-acetylcysteine*

Side effects

Pharmacokinetics

COX-2 Hypothesis (1990s)

Normal Tissue

Inflammation Site
Arachidonic Acid

COX-1
Constitutive

Cytokines
Growth factors

COX-2
Inducible
COX-2
Inhibitors

NSAIDs
Physiolgical
Prostaglandin
Production

Normal Functions

Pathological
Prostaglandin
Production

Inflammation, pain, fever

COX-II Selective NSAIDS

N N
O
H2 N

CF3

celecoxib

O
O
O

rofecoxib

COX-II Selective NSAIDS

N
O

O
H2N

S
O

valdecoxib

N
Cl

S
O

etoricoxib

COX-2 Inhibitors - Do they meet

expectations?
Renal and cardiac complications at least as great
as conventional NSAIDS
No anti-thrombic activity
Gastrointestinal ulcerations reduced in short-term
studies (approximately 1-2 years)
-long-term benefit - results still are not clear

NSAID Cost/Convenience Comparison for

Arthritis
Drug

Cox1/
Cox2

Cost

Ibuprofen

10.48

Naproxen

43.61

Diclofenac

54.47

Etodolac

76.18

Nabumetone

76.23

Piroxicam

68.21

Meloxicam

59.40

Celecoxib

75.00

Rofecoxib

35

77.70

Valdecoxib

30

85.80

Gout
NH2
N

N
H
adenine
adenine
deaminase
OH
N
N
N

N
H
hypoxanthine
xanthine
oxidase
OH
N
N
N

OH
N

N
H2 N
N
guanine
N
H
H
deaminase
guanine
xanthine
xanthine
oxidase

HO

OH
N

N
HO
N
H
uric acid

OH

Gout Treatment Strategies

Treatment of Acute Gout:
indomethacin or other NSAID
corticosteroids (rarely used today)
colchicine second line therapy
Treatment of Chronic Gout:
1) Increase uric acid excretion
uricosuric agents - probenecid
2) Decrease uric acid production
metabolic inhibition - allopurinol
3) Decrease inflammatory response
colchicine (low dose)

Colchicine
O

O
O

NH
O

O
O

Functions by blocking polymerization of tubulin to microtubules

Blocks leukocyte migration and phagocytosis
Relieves pain in 12-24 h for acute attacks
Also used to prevent future attacks
Tox: diarrhea

Uricosuric Agents
O
N S
O

O
OH

Probenecid
O
S

O
O

Sulfinpyrazone

N
N

Benzbromarone

Allopurinol & Rasburicase

OH
N

N
N
N
H
allopurinol

xanthine
oxidase

OH
N

N
N
HO
N
H
alloxanthine

Rasburicase : catalizes the enzymatic oxidation

of uric acid into the soluble and inactive
metabolite allantoin

DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

The term DMARD is a latex concept that can be

stretched to cover a heterologous group of agents
with unrelated chemical structures and different
mechanisms of action. Included in this category are
methotrexate, sulfasalazine, gold compounds,
penicillamine and chloroquine
The DMARDs were often referred to as second-line
drugs, with the implication that they are only
resorted to when other therapies (e.g. NSAIDs)
failed. Today, however, DMARD therapy may be
initiated as soon as a definite diagnosis has been
reached.

Antirheumatoid drugs
These comprise non-steroidal anti-inflammatory drugs ,
disease-modifying antirheumatic drugs (DMARDs) and
anticytokine agents.
DMARDs:
include sulfasalazine, methotrexate (a folate
antagonist), gold compounds, chloroquine (an
antimalarial), penicillamine and azathioprine (an
immunosuppressant)
are slow-acting drugs and can improve symptoms
and reduce the inflammatory process
retard progress of the disease but do not halt it
entirely.
Anticytokine agents (e.g. infliximab, etanercept) are used
in Crohn's disease and psoriatic arthropathy, as well as in
rheumatoid arthritis.