Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
36 Cards in this Set
- Front
- Back
504-2 PHARM: EICOSANOIDS as DRUG TARGETS
|
504-2 PHARM: EICOSANOIDS as DRUG TARGETS
|
|
What are eicosanoids?
|
Metabolites of arachodonic acids.
Can be synthesized or released from all cells. |
|
What are examples of eicosanoids?
|
Prostanoids:
1. prostacyclin 2. PG 3. thromboxanes Leukotrienes |
|
Eicosanoids are also known as?
|
Autacoids
|
|
Biosynthesis of eicosanoids
|
Xerox the Biosynthesis diagram
|
|
COX-2 hypothesis
|
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. |
|
Cellular mechanisms of action of eicosanoids
|
All eicosanoids act at G protein coupled receptors (GPCR)
|
|
Once GPCR is activated, what's next?
|
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. |
|
Clinically relevant patho/physiological actions of eicosanoids:
|
1. inflammation and pain
2. fever 3. bronchial smooth muscle, anaphalaxis, and asthma |
|
Role of eicosanoids in inflammation and pain:
|
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. |
|
Function of PGE2
|
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. |
|
Role of eicosanoids in causing bronchial smooth muscle, anaphalaxis, and asthma
|
Play important role in constriction of bronchial smooth muscle.
|
|
Which eicosanoids are the most potent and powerful stimulators of bronchospasm?
|
LTC4
LTD4 Likely responsible for anaphalactic type allergic rxn. |
|
Which eicosanoids play a role during pregnancy?
|
PGF-2a and low [ ] of PGE-2 cause contractions of the uterus.
|
|
Effects of eicosanoids in the CV system?
|
PGE2 and PGI2 are potent vasodilators.
Lead to hypotension |
|
Which eicosanoid play a role in platelet aggregation?
|
TXA2 is a potent stimulator of platelet aggregation--> promote clotting.
|
|
PLA2 Inhibitors
|
Example: glucocorticoids
|
|
Mechanism of glucocorticoids
|
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). |
|
What's a clinical use of glucocorticoids?
|
Very effective anti-inflammatory agents
|
|
Non-selective COX-1 and COX-2 inhibitors
|
Referred to as NSAIDs
1. aspirin 2. ibuprofen (motrin, advil) 3. alleve |
|
Aspirin
|
Acetylates COX-1 and COX-2 to irrev. block enzyme activity.
|
|
Clinical uses of aspirin
|
1. Very effective as anti-inflammatory agent, antipyretic, and mild analgesic agent.
|
|
Side effect of aspirin
|
Breakdown of GI epithelium leading to ulceration and bleeding.
|
|
Ibuprofen and naproxen
|
Reversibly binds to COX-1 and COX-2 to inactivate enzyme activity.
|
|
Clinical uses of ibuprofen and naproxen?
|
Anti-inflammatory agents
Analgesia Antipyretic |
|
Side effects of ibuprofen and naproxen?
|
Breakdown of GI epithelium
Leads to ulceration and bleeding of GI. |
|
Acetaminophen (tylenol) mechanism of action
|
Weak inhibitor of COX-1 and COX-2
|
|
Clinical uses of tylenol?
|
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. |
|
Side effects of tylenol?
|
No negative GI effects or disruption of platelet function.
Liver damage at high doses |
|
Celebrex
|
Binds reversibly and with high affinity to COX-2 and blocks its activity.
|
|
Clinical uses of celebrex
|
Effective anti-inflammatory actions
|
|
5'-Lipoxygenase (5-LO) inhibitors
|
Example: zyleuton (zyflo)
|
|
Clinical uses of Zyleuton
|
Tx of asthma
|
|
Side effects of zyleuton
|
Mild GI upset, heartburn, headache.
|
|
Misoprostol (cytotec)
|
Agonist for EP receptor
Prevents negative GI ulceration due to chronic use of NSAIDs |
|
Side effect of cytotec?
|
Contraindicated in women of childbearing age due to its effects on the uterus.
|