1

(Analgesics-Antipyretics and Anti-Inflammatory Drugs)

Steroids Steroids NonSteroidal Anti-Inflammatory Drugs (NSAIDs) Paracetamol
Acetaminophen Paracetamol
NSAIDs

(GI Irritation)
,
( (Half Life) )
Cyclooxygenase type 2 COX-2
NSAIDs
(1) Nonselective COX Inhibitors

1.1) Salicylate Aspirin

Diflunisal Salsalate
1.2) Para-Aminophenol Acetaminophen (Paracetamol)
Phenacetin
1.3) Propionic acid derivatives Ibuprofen, Naproxen,
Fenoprofen, Tiaprofenic acid, Ketoprofen, Flurbiprofen, Caprofen
Suprofen
1.4) Acetic acid derivatives Indomethacin, Sulindac,
Diclofenac, Alcofenac, Tolmetin, Etodolac
1.5) Fenamic acid derivatives Flufenamic, Mefenamic

Meclofenamic
1.6) Pyrazolone

derivatives

Oxyphenbutazone,

Phenylbutazone Azapropazone
1.7) Oxicam Piroxicam, Tenoxicam, Sudoxicam,
Isoxicam, Meloxicam

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1.8) Alkanones Nabumetone

1: NSAIDs

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(2) Selective COX-2 Inhibitors

Cyclooxygenase Cyclooxygenase 2 Isoforms

COX-1 COX-2

Cyclooxygenase type 2 (COX-2)

2.1) Diaryl substituted furanones Rofecoxib

2.2) Diaryl substituted pyrazoles Celecoxib
2.3) Acetic acid derivatives Etodolac
NSAIDs

A) Mechanism of Action

Prostaglandins Chemical mediators
, , Kinin, Histamine, Lymphokines,
Neuropeptide, Leucotrienes, Platelet activating factor (PAF),
Oxygen free radical superoxide anion
Arachidonic acid Cyclic-endoperoxides (PGG2 PGH2)
Cyclooxygenase Prostaglandins PGE2,
Prostacyclin, Tromboxane A2

Cyclooxygenase
Isoforms COX-1 COX-2

Cyclooxygenase

COX-1

- Physiological COX (Constitutive Isoform)

Endothelium Cell
- Prostaglandins
Prostaglandins ,
Prostaglandins Prostacyclin (PGI2)
PGE2

-
Aggregation)

Tromboxane A2

(Platelet

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COX-2

-
(Inflammation),
- Inducible Isoform
- Macrophage
- (Inflammation)

Production and Actions of Prostaglandins and Thromboxane.

Arachidonic acid, a 20-carbon fatty acid containing four double bonds, is
liberated from the sn2 position in membrane phospholipids by phospholipase A2,
which is activated by diverse stimuli. Arachidonic acid is converted by cytosolic
prostaglandin G/H synthases, which have both cyclooxygenase (COX) and
hydroperoxidase (HOX) activity, to the unstable intermediate prostaglandin H2. The
synthases are colloquially termed cyclooxygenases and exist in two forms,
cyclooxygenase-1 and cyclooxygenase-2. Coxibs selectively inhibit cyclooxygenase2. Prostaglandin H2 is converted by tissue-specific isomerases to multiple
prostanoids. These bioactive lipids activate specific cell-membrane receptors of the
superfamily of G-proteincoupled receptors. Some of the tissues in which individual
prostanoids exert prominent effects are indicated. IP denotes prostacyclin receptor, TP
thromboxane receptor, DP prostaglandin D2 receptor, EP prostaglandin E2 receptor,
and FP prostaglandin F2a receptor.

Neutrophil function
Neutrophil Neutrophil Lysosomal enzyme
Superoxide radicals Neutrophil Macrophage,
Granulocyte, Basophil Mast Cell


PGE2 Prostacyclin
Gastric mucosal microcirculation Prostaglandins
(Mucosal blood flow )

Tromboxane A2 Tromboxane A2
(Prolong bleeding time) Prostaglandins
PGF2
Prostaglandin Prostaglandin
Acute renal
failure
Cyclooxygenase Lipoxygenase
Leucotrienes

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(B)

Paracetamol

(C)

Nabumetone
Prodrug
Albumin
98 Phase I Phase II Metabolism
CYP3A CYP2C

(D)
1)

Prostacycline PGE2

,

- Enteric Coated Tablet

- (Antacid), H2-Receptor Antagonists
( Cimetidine, Ranitidine ), Prostaglandin Analogues
Misoprostal , Proton Pump Inhibitors Omeprazole,
Lanzoprazole, Rabiprazole
-
Selective COX-2 Inhibitors

2)
Prostaglandin

Antidiuretic Hormone Na

Renin-Angiotensin

Aldosterone

3)
NSAIDs
,
NSAIDs ,

4)
Aspirin
Pyrazolone
Oxyphenbutazone, Phenylbutazone Azapropazone
Agranulocytosis
5)
NSAIDs Indomethacin
Aseptic
Meningitis Ibuprofen
6) (Hypersensitivity Reaction)
Prostaglandin
Leucotrienes Lipooxygenase Pathway
NSAIDs Cross
sensitivity
(E) Indications
-Analgesia

(Inflammation) ,
CNS Opioids
-Antipyretics Aspirin, Ibuprofen
-Anti-Inflammation (Inflammation)
Rheumatoid arthritis, Osteoarthritis, Acute gout
Musculoskeletal symptoms

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NSAIDs
(A) Nonselective COX Inhibitor

(1) Salicylate
Acetyl salicylic acid (ASA) Aspirin
Salicylic acid, Choline salicylate, Methyl salicylate ()
Aspirin Antipyretic

1.1) Mechanism of Action

- Prostaglandins

(Inflammation)
- Plasmin Bradykinin

COX

COOH

COOCH3

OH

OH

Salicylic acid

Methyl salicylate

COOH

OCOCH3
Acetyl salicylic acid (Aspirin)

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1.2) Pharmacokinetics
-

Hydrolyze Acetic acid

- Aspirin

Salicylate

1.3) Pharmacology
CNS Peripheral Hypothalamus

Opioid Narcotic Analgesic Peripheral
-Analgesia:

Prostaglandins
-Antipyretics:

-Anti-Inflammation:
4-6
-Antiplatelet Aggregation: Aspirin 81

1.4) Adverse drug reaction

-

Prostacycline Aspirin
Gastitis, GI Bleeding, Gastric
ulcer
-

Metabolism
Metabolic acidosis
-
Tromboxane A2
Oral anticoagulant, Hemophilia, , Viral
Infection (, ) Aspirin

-Reyes Syndrome
Acute encephalopathy Fatty
degenaeration 50%
Aspirin

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Aspirin acute viral infection Reyes

syndrome Aspirin 14

-
Bronchoconstriction
1.5) Drug interaction
Warfarin Warfarin Plasma protein
Tromboxane A2
- Probenecid Probenecid

-Aspirin

1.6) Dosage
(1)
- 325 650 mg 4
(2)
- 50 75 mg/ kg/ day 6
(2) Ibuprofen

(3) Indomethacin
(4) Mefenamic acid
(5) Diclofenac
(6) Piroxicam

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(B) Selective COX-2 Inhibitor

- COX-2

- Celecoxib, Rofecoxib
- Cardiovascular adverse
events Rofecoxib
VIOXX (18
)
Rofecoxib
NSAIDs
(1) ( Nonselective COX Inhibitors)

(2)

(3)

(4)
(5) Drug Interaction
Paracetamol

-
Aspirin

-
-

- 10-15
Paracetamol NAcetylcysteine Toxic Metabolite
Loading dose 140 mg/ kg 70 mg/ kg 4 17

-: Tablet 325, 500 mg, Syrup 125 mg/ 5 ml, 250 mg/ 5 ml,
Paracetamol Drop 60 mg/ 0.6 ml, Paracetamol Injection 300 mg

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-:

325-1,000 mg/ 4-6 (

4 ) 5 10 mg/ kg/ 4-6
5 5