Lecture 24 - Nsaids

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS )NSAIDs( Definition Drugs that inhibit inflammation by preventing the synthesis of prostanoids. Mechanism of Action Inhibit prostanoids synthesis by inhibiting cyclo-oxygenase )COX-1 and COX-2( enzymes. Aspirin inhibits the enzyme irreversibly (acetylation of serine residue)

Additional mechanism of Action of Aspirin 

Induction of the generation of antiinflammatory lipoxins (aspirin-triggered lipoxins or ATLs)

PHARMACOLOGICAL ACTIONS OF NSAIDs  Analgesic  Anti-inflammatory  Antipyretic  Anti-platelet )aspirin(

CLASSIFICATION OF NSAIDs Non-selective )COX-1/COX-2( inhibitors Group

Examples

Salicylates

 Aspirin

Aniline derivatives

 Paracetamol (acetaminophen)

Indol derivatives

 Indomethacin

Propionic acids

 Ibuprofen

Oxicams

 Piroxicam

CLASSIFICATION OF NSAIDs )cont’d( Selective COX-2 inhibitors

Group

Examples

Pyrazole derivatives

Celecoxib

Furanone derivative

Rofecoxib

CLINICAL USES OF NSAIDs Aspirin/salicylates

-

thromboembolism stroke myocardia infaction fever and pain

Paracetamol

-

fever and pain )no effect on inflammation(

CLINICAL USES OF NSAIDs )cont’d( Indomethacin

Others: )ibuprofen, naproxen, piroxicam, mefenamic acid(

-

rheumatoid arithritis gout malignancy-associated fever

-

as alternatives

ADVERSE EFFECTS OF NSAIDs GIT Gastric erosion, ulceration and bleeding Skin Skin reactions )rashes, urticaria or photosensitivity( Renal Acute renal failure: (patients with high vasoconstrictor catecholamine and angiotensin II (e.g., liver cirrhosis, congestive heart failure, etc).

Aspirin-specific adverse effects  Salicylism )dizziness, deafness and tinnitus(  Asthma in aspirin-sensitive asthmatics  Reye’s syndrome )hepatic encephalitis(  Bleeding disorders )esp. with warfarin(  Respiratory and metabolic acidosis )poisoning(

GOUT Definition A metabolic disease of purine overproduction leading to deposition of urate crystals in joints which in turn evokes acute inflammatory joint pain.

Drug treatment a. Inhibition of uric acid synthesis – allopurinol )drug of choice( b. Enhancement of uric acid excretion – probenecid and sulphinpyrazone )uricosuric agents( c. Inhibition of leukocyte accumulation in the joint – colchicine d. General inhibition of inflammation and pain – NSAIDs )except aspirin(

MECHANISM OF ANTI-GOUT ACTION OF ALLOPURINOL O Hypoxanthine O Allopurinol

HN

HN1 6 5 2 3 4

N N

N

N H

Xanthine oxidase

Xanthine oxidase

O N O

N H

N H

O

7

8

9

N H

O N

HN

HN

N

N H

Xanthine

N H

Xanthine oxidase O

Alloxanthine Uric acid

HN O

H N O

N H

N H

LEARNING OBJECTIVES Describe the mechanism of action of NSAID .1 Contrast the actions of aspirin with other NSAIDs .2 Understand the adverse effects of NSAIDs and the role .3 of COX inhibition .List aspirin-specific adverse effects .4 .(Describe the clinical uses of NSAID (with drugs if choice .5 .Describe the mechanisms by which anti-gout drugs act .6