NONSTEROIDAL

ANTI-INFLAMMATORY
DRUGS
INTRODUCTION
Inflammation → 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 (Hist, PG, Brad, IL-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) → block the synthesis of the
prostaglandins PGE2, PGI2, and PGF2α α, 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 → bleeding time ↑
 PHOSPHOLIPID (cell membrane)

ARACHIDONIC ACID
NSAIDs Cyclooxygenase
-

PGG2
Hydroperoxidase

PROSTACYCLINE (PGI2) PGH2 PGE2

PGF2α

SYNTHESIS OF PROSTAGLANDINS
INTRODUCTION

Acetaminophen (PCT) although an excellent analgesic
and antipyretic, does not possess anti-inflammatory
activity

The NSAIDs and the salicylates are the drugs of first
choice for RA

And 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-
ANTI-INFLAMMATORY DRUGS
(NSAIDs)

I. Aspirin & Other Salicylates

II. Propionic Acid Derivates
III. Indoleacetic Acids
IV. Oxicam Derivates
V. Fenamates
VI. Phenylbutazone
VII.Other Agents
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 à can not cause salicylate
intoxication
- 3-4 x more potent than aspirin as analgesic and anti-
inflammatory agent
- no antipyretic properties (≠ enter the CNS à 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 à ≠ 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 :
§ impending PGE2 synthesis and release.
§ 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
§ no effect on normal body temperature

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

6. Effects on platelets :
Aspirin à platelet aggregation is reduced à
anticoagulant effects à prolonged bleeding time
7. Actions on the kidney :
↓ synthesis of PG à result in retention of sodium
and water and à edema and hyperkalemia
 THERAPEUTIC USES

a. Antipyretics and analgesics :

Gout, RF, RA, headache, arthralgia, myalgia
b. External applications :
Salicylic acid à To treat calluses, 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, esp Methyl salicylate are absorbed through intact
skin.
Oral adm : salicylates à absorbed from the stomach and the
small intestine.
Rectal absorption à slow and unreliable
Salicylates (except for diflunisal) cross both the BBB and
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 water–soluble
conjugates that are rapidly cleared by the kidney
(serum half life of 3,5 hours)
At anti-inflammatory dosages ( > 4 g/day) à T1/2 : >15
hours
At low doses of aspirin à uric acid secretion ↓
At high doses à 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 à respiratory depression

Hypersensitivity : urticaria, bronchoconstriction

Reye’s Syndrome
DRUGS INTERACTING WITH SALICYLATES

Antacids à Reduced rate of aspirin absorption

Heparin or oral anticoagulants à Hemorrhage

Probenecid, Sulfinpirazone à Decreased urate
excretion (contraindicated in patients with gout)

Bilirubin, Phenytoin, Naproxen, Sulfinpirazone,
Thiopental à 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 à
The chronic treatment of RA + OA

GI effects < than aspirin

Well absorbed on oral adm. à hepatic metabolismà
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 Hodgkin’s 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. à metabolized by the liver à 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 :
RA, ankylosing spondylitis, OA, 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 :
↑ the serum levels and thus raise the risk of adverse
reactions caused by digoxin, lithium, methotrexate
enhance the nephrotoxicity of cyclosporine

OXICAM DERIVATES :
PIROXICAM

Therapeutic uses :

RA, ankylosing spondylitis, OA

Half-life : 50 hours à 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 RA (toxicity à short-term therapy)

Use : up to 1 week only

Pharmacokinetics :

PO / rectal à rapidly and completely absorbed

Active Metabolite : oxyphenbutazone

Interaction : warfarin, oral hypoglycemic agents, sulfonamides
(Bound to PP à displacement à 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 : RA, OA, Ankylosing spondilitis

KETOROLAC

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

TOLMETIN AND NABUMETONE

Potency = aspirin for adult or juvenile RA or OA

SE < aspirin
 NON-
NON-NARCOTIC ANALGESICS
ACETAMINOPHEN
PHENACETIN

Have little or no anti-inflammatory activity

Do not cause physical dependence or tolerance
ACETAMINOPHEN & PHENACETIN

Act by inhibiting PG synthesis in CNS à Antipyretic and
Analgesic properties

Less effect on COX in peripheral tissues à weak anti-
inflammatory activity

Do not affect platelet function or increase blood clotting time

SE < Aspirin

Phenacetin à 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 à Acetaminophen à conjugated with glucoronic or sulfat /
hydroxylated à Excreted in urine

ADVERSE EFFECTS :

Infrequently : skin rash , minor allergic reactions

Large doses : Hepatic necrosis & renal tubular necrosis à 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
No antipyretic effect Pyrazoles :
than aspirin
Phenylbutazone
Indoleacetic acids :
Indomethacin
Long half-life permits
Sulindac daily or twice daily dosing
Very potent : should be
Tolmetin
used only after less toxic
Propionic acids :
agents have proven
ineffective Ibuprofen Lower toxicity and
Naproxen better acceptance
CNS disturbances Ketoprofen in some patients
common
Fenoprofen
Oxicam :
Piroxicam
Fenamates :
Mefenamic acid
Meclofenamic acid
TERIMA
KASIH