Presentation on Eicosanoids AND Cyclooxygenase enzymes.

Sultan Ullah Vardag Mphil Ph.chemistry 2nd semester RIPS Islamabad.

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Introduction
Eicosanoids (20 carbons) are found in the animal kingdom and a variety of plants.
The eicosanoids are oxygenation products of acid

arachidonic (AA) polyunsaturated fatty acid.

Acid arachidonic is released from membrane by phospholipase A2 (PLA2).

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Introduction (Contd)
Arachidonic acid is oxygenated by 4 separate routes: The cyclooxygenase (COX) Lipoxygenase (LOX) Isoprostane pathways P450 epoxygenase All of their receptors appear to be G protein-linked.
The eicosanoids act in an autocrine & paracrine

fashion.

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Eicosanoids- Classification

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Prostanoids

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Characteristic features of Structure of prostaglandins

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Series of prostaglandins

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Characteristic features of prostaglandins

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Functions of Prostaglandins

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Prostacyclins and ThromboxanesChemistry and Functions

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Functions of Prostcyclins

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Functions of Thromboxanes

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Catabolism of Prostaglandins

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Leukotrienes

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Lipoxins

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Functions of Leukotrienes

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Pharmacological applications of Eicosanoids

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Pharmacological applications of Eicosanoids(Contd.)

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Pharmacological applications of Eicosanoids(Contd.)

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CYCLOOXYGENASE ENZYMES (COX-1 and COX-2)

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The COX Pathway

There are two isozymes for COX enzymes: COX1 and

COX2. COX-1 generates prostanoids for "housekeeping" such as gastric epithelial cytoprotection. COX-2 is the major source of prostanoids in inflammation and cancer. This distinction is overly simplistic:
Endothelial COX-2 produces prostacyclin (PGI2 ).
Renal COX-2 products are important for normal renal

function.
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The COX Pathway (Contd)

PGs have clinical importance.
Prostacyclin (PGI2 ) is synthesized by endothelium and is

a powerful vasodilator and inhibitor of platelet aggregation.

TXA2 is a potent vasoconstrictor and activator of platelet

aggregation.

It is also a smooth muscle cell mitogen and is the only

eicosanoid to have this effect.

The mitogenic effect is potentiated by exposure of smooth

muscle cells to testosterone.

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Prostanoid biosynthesis. Compound names are enclosed in boxes.

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The COX Pathway (Contd)

PGF2 is also a vasoconstrictor but is not a smooth muscle

mitogen.

Vasodilator prostaglandins, (PGI2 & PGE2) increase cAMP

and decrease smooth muscle intracellular calcium.

COX-2 inhibitors preserve the GI and renal functions by

COX-1, thereby reducing toxicity.

COX-2 inhibition decreases PGI2 but not platelet COX-1-

derived TXA2.

This increases cardiovascular events in patients taking

selective COX-2 inhibitors.

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COX-I and COX-2 Inhibiters

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Mechanism(s) of Action
Inhibition of prostaglandin synthesis
Inhibition of Cox-1 Inhibition of Cox-2

Cox-2 is induced 10-80 fold in inflammation

Inhibition of Cox-2 is the main mechanism for the anti-

pyretic, analgesic and anti-inflammatory actions

Inhibition of Cox-1 leads to side effects

Most NSAIDS are non-selective but there are

selective Cox-2 inhibitors

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Indications

Pain and inflammation in rheumatic diseases Musculoskeletal disorders Post-operative analgesia Acute Gout Migraine Dysmenorrhoea Fever and pain in children (including post-immunization pyrexia) Pyrexia Dental pain Less well-defined conditions of back pain and soft-tissue disorders

Patients NOT responsive to one NSAID may well respond to

another need to tailor treatment to the individual patient. Full analgesic effect may take up to three weeks

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Non-selective Cox or Cox-2?

Non-selective Ibuprofen, Diclofenac, Indometacin, naproxen, Piroxicam, ketoprofen, azapropazone Cox-2 Newer Provides protection against gastrointestinal side effects of NSAIDS Celecoxib, Rofecoxib, Etoricoxib, Lumiracoxib, Parecoxib, Valdecoxib

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Nonselective Cox or Cox-2?

Action of NSAIDs due to inhibition of Cox-2
Side effects usually due to inhibition of Cox-1 Extensive experience with Non-selective Cox

Inhibitors Cox-2 expensive Evidence for cost-effectiveness of Cox-2

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Side-Effects
Most notorious side effect adverse gastrointestinal events including gastric or intestinal ulceration 2 mechanisms responsible for GI side effects Local erosion of orally administered agents

(THEREFORE they are to be taken with or after meals)

Inhibition of biosynthesis of cytoprotective prostaglandins PGI2

and PGE2

Hence NSAIDs still do cause GI side effects despite the ROUTE of administration Administration of cytoprotectants e.g. misoprostol [AVOID IN PREMENOPAUSAL WOMEN] for GI protection May be given with proton pump inhibitors e.g. omeprazole, esomeprazole, rabeprazole, lansoprazole for GI protection

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Caution/Contraindication
Avoid ALL NSAIDs in patients with active peptic

ulceration Caution in those with peptic ulceration (risk/benefit) Asthma any worsening of asthma should be investigated Pregnancy; Breastfeeding ; allergic conditions

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Any question?

References
University of Kansas Medical Center (2004). "Eicosanoids and Inflammation" (PDF). http://classes.kumc.edu/som/bioc801/small_group/eicos noids/eicosanoids-2004.pdf. Retrieved 2007-01-05. P. N. Praveen Rao and Edward E. Knaus. Evolution of Nonsteroidal AntiInflammatory Drugs

NSAIDs): Cyclooxygenase (COX) Inhibition and Beyond Funk, Colin D. (30 November 2001). "Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology". Science 294 (5548): 18711875. doi:10.1126/science.294.5548.1871. PMID 11729303. http://www.sciencemag.org/cgi/content/full/294/5548/1871. Retrieved 200701-08.

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