NONSTEROIDAL

ANTI-INFLAMMATORY
DRUGS
( NSAIDs)

KUSWINARTI
DEPARTMENT OF PHARMACOLOGY AND THERAPY
MEDICAL SCHOOL
UNIVERSITAS PADJADJARAN
 INTRODUCTION
Inflammation is a normal, protective response
to tissue injury caused by physical trauma,
noxious chemicals, or microbiologic agents

Inflammation is triggered by the release of

chemical mediators from injured tissues and
migrating cells (such as histamine,
prostaglandins, bradykinin, interleukins-1)
The drugs act by interrupting the inflammatory
response through one mechanism or
another :

1. The salicylates (e.g.,acetosal / aspirin) and the newer

NSAIDs posses excellent anti-inflammatory activity due to
their inhibition of prostaglandins (PG) biosynthesis

2. Many of these drugs acetylate and irreversibly inactive

cyclooxygenase (COX). This blocks the synthesis of the
prostaglandins PGE2, PGI2, and PGF2, which are believed
to be involved in inflammation associated vasodilation,
pain, and edema

3. Additionally, acetosal inhibits the synthesis of thromboxane

A2 (TX2) due to blockade of platelet cyclooxygenase. This
results in increased bleeding time
 PHOSPHOLIPID (from cell membrane)

ARACHIDONIC ACID
NSAIDs - Cyclooxygenase

PGG2
Hydroperoxidase

PROSTACYCLINE (PGI2) PGH2 PGE2

PGF2

SYNTHESIS OF PROSTAGLANDINS
 INTRODUCTION (CONTINUED)
In contrast, acetaminophen (paracetamol),
although an excellent analgesic and antipyretic,
does not possess anti-inflammatory activity
In the treatment of rheumatoid arthritis, the
NSAIDs and the salicylates are the drugs of first
choice.
Besides their use in rheumatoid arthritis, many
of the NSAIDs are also useful in the treatment of
acute gout
Unlike narcotics, these agents have no
tolerance or addiction liability
 NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS (NSAIDs)

NSAIDs are group of chemically dissimilar

agents that differ in their antipyretic, analgesic
and anti-inflammatory activities

Prototype (standard) : ACETOSAL / aspirin

The newer NSAIDs are considerably more

expensive than aspirin, and some have proved
to be more toxic
ASPIRIN AND OTHER SALICYLATES
Aspirin is a weak organic acid that is unique
among the NSAIDs in irreversibly (and thus
inactivating) cyclooxygenase.
The other NSAIDs, including salicylate, are all
reversible inhibitors of cyclooxygenase
Diflunisal is not metabolized to salicylate can
not cause salicylate intoxication .
Diflunisal : 3-4 x more potent than aspirin as
analgesic and anti-inflammatory agent, but it has
no antipyretic properties ( enter the CNS
Can not relieve FEVER)
Mechanism of action :
The antipyretic and anti-inflammatory effects of the salicylates
are due to primary to the blockade of prostaglandin synthesis
at the thermoregulatory centers in the hypothalamus and at
peripheral target sites

Actions :
1. Anti-inflammatory actions :
Aspirin inhibits inflammation in arthritis
Acetaminophen, although a useful analgesic and antipyretic,
has weak anti-inflammatory activity rheumatoid arthritis

2. Analgesic action :
By decreasing Prostaglandin E2 (PGE2) synthesis, aspirin and
other NSAIDs repress the sensation of pain.
The salicylates are used mainly for the management of pain of
low to moderate
3. Antipyretic action :
The salicylates lower body temperature in patients with
fever by impeding PGE2 synthesis and release.
Aspirin resets the thermostat toward normal and
rapidly lowers the body temperature of febrile patients by
increasing heat dissipation as a result of peripheral
vasodilation and sweating. Aspirin has no effect on
normal body temperature

4. Respiratory actions :
At therapeutic doses, aspirin increases alveolar
ventilation
At higher doses hyperventilation
At toxic levels central respiratory paralysis
5. Gastrointestinal effects :
Aspirin increase gastric acid secretion and diminished
mucus protection may cause epigastric distress,
ulceration, and or/hemorrhage

6. Effects on platelets :
Aspirin platelet aggregation is reduced
anticoagulant effects prolonged bleeding time

7. Actions on the kidney :

Decreased synthesis of prostaglandins can result in
retention of sodium and water and may cause edema
and hyperkalemia
 Acetaminophen
Anti-inflammatory
weak

NSAIDs
STRONG

Analgesic Antipyretic

ACTIONS OF NSAIDs AND ACETAMINOPHEN

 THERAPEUTIC USES

a. Antipyretics and analgesics :

Gout, rheumatic fever, rheumatoid arthritis, headache, arthralgia,
myalgia

b. External applications :
Salicylic acid To treat corns, epidermophytosis
Methyl salicylate is used externally as a cutaneous counterirritant in liniment

c. Cardiovascular applications :
Low doses of aspirin are used prophylactically to decrease the
incidence of ischemic attack ,unstable angina , coronary artery
thrombosis

d. Colon cancer
Chronic use of aspirin reduces the incidence of colorectal cancer
 PHARMACOKINETICS
ADMINISTRATION AND DISTRIBUTION :
Salicylates, especially Methyl salicylate are absorbed through intact
skin.
After oral adm : salicylates absorbed from the stomach and the
small intestine.
Rectal absorption slow and unreliable
Salicylates (except for diflunisal) cross both the BBB and the
placenta

DOSAGE :
The salicylates exhibit analgesic activity at low doses, only at higher
doses do these drugs show anti-inflammatory activity
PHARMACOKINETICS (CONTINUED)

FATE :
Aspirin (low doses) salicylate + acetic acid
Salicylate is converted by the liver to watersoluble conjugates that
are rapidly cleared by the kidney (serum half life of 3,5 hours)
At anti-inflammatory dosages ( > 4 g/day) T1/2 : >15 hours
At low doses of aspirin uric acid secretion
At high doses uric acid secretion
(Alkalinization of the urine promotes excretion)
 ADVERSE EFFECTS
GI : epigastric distress, nausea, vomiting

Blood : a prolonged bleeding time

Respiration : In toxic doses respiratory

depression

Hypersensitivity : urticaria, bronchoconstriction

Reyes Syndrome
 DRUGS INTERACTING WITH SALICYLATES

Antacids Reduced rate of aspirin absorption

Heparin or oral anticoagulants Hemorrhage
Probenecid, Sulfinpirazone Decreased urate
excretion (contraindicated in patients with gout)
Bilirubin, Phenytoin, Naproxen, Sulfinpirazone,
Thiopental Increased plasma concentration
leading to prolonged half-lives, therapeutic
effects, and toxicity
 PROPIONIC ACID DERIVATES
Ibuprofen, Naproxen, Fenoprofen, Ketoprofen,
Flurbiprofen, Oxaprozin
Anti-inflammatory, analgesic and antipyretic
activity The chronic treatment of rheumatoid
and osteoarthritis
Gastrointestinal effects < than aspirin
Well absorbed on oral adm. hepatic
metabolism excreted : kidney
Side effects : dyspepsia, bleeding, headache,
tinnitus, dizziness
 INDOLEACETIC ACIDS

DRUGS :
INDOMETHACIN
SULINDAC
ETODOLAC
All have anti-inflammatory, analgesic,
antipyretic activity
They act by reversibly inhibiting
cyclooxygenase
 INDOMETHACIN

More potent than aspirin as an anti-

inflammatory agent

Therapeutic uses :
- control of pain associated with uveitis and
postoperative opthalmic procedures
- antipyretic for Hodgkins disease
- like aspirin, indomethacin can delay labor
by suppressing uterine contractions
 PHARMACOKINETICS :
- rapidly and almost completely absorbed from the upper
GI tract after oral adm. metabolized by the liver
excreted in bile and urine (unchanged drug and
metabolites)

ADVERSE EFFECTS :
-GI complaints : nausea, vomiting, anorexia, diarrhea, abdominal
pain, ulceration / hemorrhage
-CNS : Headache, dizziness, vertigo, mental confusion
-Hematopoietic reactions : neutropenia, thrombocytopenia, aplastic
anemia
-Hypersensitivity reactions : rashes, urticaria, itching, acute attacks
of asthma.
-Others : acute pancreatitis, hepatic effects
 DRUGS INTERACTION

Concurrent administration of indomethacin may

decrease the antihypertensive effects of :

Furosemide
Thiazide diuretics
Beta-blocking drugs
ACE inhibitors
 SULINDAC
- Inactive pro-drug active form
Hepatic microsomal enzymes of the drug

Long duration of action

Less potent than indomethacin
Adverse effects are similar to but less severe
than indomethacin

Therapeutic uses :
- rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis, acute gout
 ETODOLAC

- Has effects similar to those of the other NSAIDs

- Gastrointestinal problems <
- Adverse effects : fluid retention, abnormal kidney and
liver function

DRUGS INTERACTION :
May increase the serum levels and thus raise the risk of
adverse reactions caused by digoxin, lithium,
methotrexate, and enhance the nephrotoxicity of
cyclosporine
 OXICAM DERIVATES :
PIROXICAM
Therapeutic uses :
Rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis
Half-life : 50 hours adm : once a day

FENAMATES
Mefenamic acid & Meclofenamate
Have no advantages over the other NSAIDs
SE : diarrhea, hemolytic anemia
 PHENYLBUTAZONE
Has powerful anti-inflammatory effect but weak analgesic and
antipyretic activities
Therapeutic uses :
Acute gout & acute rheumatoid arthritis (toxicity short-term
therapy)
Use : up to 1 week only
Pharmacokinetics :
PO / rectal rapidly and completely absorbed
Active Metabolite : oxyphenbutazone
Interaction : warfarin, oral hypoglycemic agents,
sulfonamides (Bound to PP displacement free drugs )
SE :
Agranulocytosis, aplastic anemia, nausea, vomiting, skin
rashes, epigastric discomfort, fluid and electrolyte retention,
diarrhea, vertigo, insomnia, blurred vision, euphoria,
nervousness, hematuria
 OTHER AGENTS
DICLOFENAC :
More potent than indomethacin or naproxen
Therapeutic uses : Rheumatoid arthritis, Osteoarthritis,
Ankylosing spondilitis

KETOROLAC
Route of drug adm : PO, IM (Post operative pain), Topically
(allergic conjunctivitis)

TOLMETIN AND NABUMETONE

Potency = aspirin for adult or juvenile rheumatoid arthritis or
osteoarthritis
SE < aspirin
 NON-NARCOTIC ANALGESICS

ACETAMINOPHEN
PHENACETIN

Have little or no anti-inflammatory activity

Do not cause physical dependence or tolerance
 ACETAMINOPHEN & PHENACETIN

Act by inhibiting prostaglandin synthesis in CNS

Antipyretic and Analgesic properties
Less effect on cyclooxygenase in peripheral
tissues weak anti-inflammatory activity
Do not affect platelet function or increase blood
clotting time
SE < Aspirin
Phenacetin potential renal toxicity
 THERAPEUTIC USES :
Analgesic-antipyretic of choice for children with viral
infections or chicken pox
Gastric complaints

PHARMACOKINETICS :
Rapidly absorbed from GIT
First pass metabolism in intestine & hepatocytes
Phenacetin Acetaminophen conjugated with
glucoronic or sulfat / hydroxylated Excreted in urine
 ADVERSE EFFECTS :

Normal therapeutic doses : free of any

significant adverse effects

Infrequently : skin rash , minor allergic

reactions

Large doses : Hepatic necrosis & renal

tubular necrosis Treatment : N-
acetylcystein
THERAPEUTIC DISADVANTAGES OF THERAPEUTIC ADVANTAGES OF
SELECTED NSAIDs SELECTED NSAIDs

Salycylates :
Upper GI disturbances Aspirin
Low cost ; long
history of safety
Salicylate salts
Diflunisal
Less GI irritation
Pyrazoles :
No antipyretic effect than aspirin
Phenylbutazone
Indoleacetic acids :
Indomethacin
Sulindac Long half-life permits daily
Tolmetin or twice daily dosing
Very potent : should be
V only after less toxic
used Propionic acids :
e
agents have proven Ibuprofen
Lower toxicity and
r
ineffective Naproxen
better acceptance
y Ketoprofen
CNS disturbances
Fenoprofen
in some patients
common
Oxicam :
Piroxicam
Fenamates :
Mefenamic acid
Meclofenamic acid