504-2 Pharm: Eicosanoids As Drug Targets

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504-2 PHARM: EICOSANOIDS as DRUG TARGETS

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504-2 PHARM: EICOSANOIDS as DRUG TARGETS

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What are eicosanoids?

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Metabolites of arachodonic acids.

Can be synthesized or released from all cells.

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What are examples of eicosanoids?

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Prostanoids:
1. prostacyclin
2. PG
3. thromboxanes

Leukotrienes

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Eicosanoids are also known as?

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Autacoids

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Biosynthesis of eicosanoids

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Xerox the Biosynthesis diagram

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COX-2 hypothesis

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Not normally present in cells

Upregulated only in response to stimuli that initiate inflammatory responses.

States that COX-2 mediates most, if not all, of the pathological effects of eicosanoids (pain, inflammation, etc...)

Deleterious side-effects (eg. GI bleeding, ulcers) associated with drugs that block both COX-1 and COX-2 are mediated by COX-1.

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Cellular mechanisms of action of eicosanoids

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All eicosanoids act at G protein coupled receptors (GPCR)

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Once GPCR is activated, what's next?

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1. Couple to G protein Gs which stimulates adenylyl cyclases and raises intracellular cAMP.

2. or couple with Gq which activates isoforms of PLC to increase Ca.


NOTE: both Ca and PLC are 2nd messengers to activate various kinase driven signaling cascades.

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Clinically relevant patho/physiological actions of eicosanoids:

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1. inflammation and pain
2. fever
3. bronchial smooth muscle, anaphalaxis, and asthma

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Role of eicosanoids in inflammation and pain:

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1. causes vasoconstriction (TXA, LTC, LTD, LTE)
2. causes vasodilation (PGI, PGE, PGD)
3. increased vascular permeability (LTC, LTD, LTE)
4. chemotaxis and leukocyte adhesion.

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Function of PGE2

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At site of inflammation, it can stimulate efferent pathways that sense long lasting pain.

Induces fever

Reset the temperature "set point" by facilitating vasoconstriction and a decrease in heat dissipation.

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Role of eicosanoids in causing bronchial smooth muscle, anaphalaxis, and asthma

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Play important role in constriction of bronchial smooth muscle.

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Which eicosanoids are the most potent and powerful stimulators of bronchospasm?

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LTC4

LTD4

Likely responsible for anaphalactic type allergic rxn.

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Which eicosanoids play a role during pregnancy?

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PGF-2a and low [ ] of PGE-2 cause contractions of the uterus.

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Effects of eicosanoids in the CV system?

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PGE2 and PGI2 are potent vasodilators.

Lead to hypotension

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Which eicosanoid play a role in platelet aggregation?

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TXA2 is a potent stimulator of platelet aggregation--> promote clotting.

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PLA2 Inhibitors

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Example: glucocorticoids

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Mechanism of glucocorticoids

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INDIRECTLY inhibit PLA2 in two ways:

1. causes expression of lipocortin which binds to PLA2 to inhibit its actions.
2. decreasing expression of COX-1 and COX-2. Net effect is to block synthesis of all eicosanoids (prstanoids and leukotrienes).

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What's a clinical use of glucocorticoids?

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Very effective anti-inflammatory agents

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Non-selective COX-1 and COX-2 inhibitors

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Referred to as NSAIDs

1. aspirin
2. ibuprofen (motrin, advil)
3. alleve

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Aspirin

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Acetylates COX-1 and COX-2 to irrev. block enzyme activity.

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Clinical uses of aspirin

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1. Very effective as anti-inflammatory agent, antipyretic, and mild analgesic agent.

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Side effect of aspirin

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Breakdown of GI epithelium leading to ulceration and bleeding.

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Ibuprofen and naproxen

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Reversibly binds to COX-1 and COX-2 to inactivate enzyme activity.

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Clinical uses of ibuprofen and naproxen?

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Anti-inflammatory agents

Analgesia

Antipyretic

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Side effects of ibuprofen and naproxen?

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Breakdown of GI epithelium

Leads to ulceration and bleeding of GI.

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Acetaminophen (tylenol) mechanism of action

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Weak inhibitor of COX-1 and COX-2

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Clinical uses of tylenol?

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CNS effects only

Excellent as antipyretic (anti-fever) and mild analgesic for CNS.

NOTE: no anti-inflammatory activity and not useful for reducing clot formation.

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Side effects of tylenol?

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No negative GI effects or disruption of platelet function.

Liver damage at high doses

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Celebrex

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Binds reversibly and with high affinity to COX-2 and blocks its activity.

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Clinical uses of celebrex

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Effective anti-inflammatory actions

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5'-Lipoxygenase (5-LO) inhibitors

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Example: zyleuton (zyflo)

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Clinical uses of Zyleuton

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Tx of asthma

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Side effects of zyleuton

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Mild GI upset, heartburn, headache.

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Misoprostol (cytotec)

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Agonist for EP receptor

Prevents negative GI ulceration due to chronic use of NSAIDs

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Side effect of cytotec?

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Contraindicated in women of childbearing age due to its effects on the uterus.