Eicosanoids Flashcards
phospholiapse A2 (PLA2)
Cleaves ester bond off the phospholipid core to free arachidonic acid (essential fatty acid)
1) Biosynthesis of eicosanoids is limited by the availability
of free arachidonic acid, which is released from membrane phospholipids by phospholipase A 2 (PLA 2 )
2) PLA 2 is activated by physical, hormonal, and chemical signals via Ca ++ and calmodulin
- also by mitogenic, inflammatory, and free radicals
Lipooxygenases (LOX)
Arachidonic Acid–> leukotrienes and lipoxins
Cyclooxygenases (COX)
Arachidonic Acid –> prostanoids:
prostaglandins, prostacyclin, thromboxane
Prostanoids (Slide 43)
AA–>PGG2–>PGH2
PGH2: mother of prostanoids
- PGI2-Prostacyclin
- TXA2-thromboxane
- PGE2
- PGFa
- PGD2
PGI2: Prostacyclin
Vasodilation
Inhibits Platelet Aggregation
*antagonist of thromboxane
Receptor: IP
TXA2-thromboxane
Vasoconstriction amd platelet aggregation
*antagonist of prostacylin PGI2
Receptor: TP
PGE2
Vasodilation Hyperalgesia Fever Diuresis Immunomodulation
Receptor: EP
Uterine Contractions
PGFa
Smooth Muscle contraction:
- bronchoconstriction
- uterine
- vasoconstrictions
Receptor: FP
PGD2
Smooth Muscle contraction
Inhibits Platelet Aggregation
Receptor: DP
prostanoids:
- Vasodilation
- Vasoconstriction
- Smooth Muscle Contraction
- inhibits platelet aggregation
- PGI2, PGE2
- PGFa, TXA2
- PGFa, PGD2
- PGI2, PGD2
Leukotrienes Synthesis
Common precursor: LTA4
1) LTA4 + LTC4 Synthase: The Cysteinyl Leukotrienes a. LTC4 (Cys-Gly-Glu) b. LTD4 (Cys-Gly) c. LTE4 (Cys) -as we go down list, each loses a component of glutathione
2) LTB4 made via LTA4 hydrolase
3) Lipoxins (not leukotrienes)
LTB4
Receptor: BLT
Source: Neutrophils
Action: Activates neutrophils, plasma exudation
Cysteinyl Leukotrienes
Receptors: CysLT
Source: mast cells, basophils, eosinophils
Action: Bronchoconstriction Vasoconstriction ↓ Coronary blood flow ↓ Cardiac contractility Plasma exudation
Initally increase in leukotrienes in beginning of inflammation, later replaced by lipoxins as the tissue heals
Lipoxins
LXA4 and LXB4
Antagonize effects of leukotrienes
As part of the inflammatory process, there is initially an increase in leukotrienes then as tissue heals, lipoxins are produced which lend to tissue repair and counteract the effects of the leukotrienes
Eicosanoid Receptors
- Prostanoid
- Leukotriene
- Lipoxin
G protein coupled
1. Prostanoids: DP-PGD2 EP-PGE2 FP-PGFa IP-PGI2 TP-TXA2
- Leukotriene
BLT-LTB4
CysLT-LTC4, :TD4, LTE4 - Lipoxin
ALX-activated
CysLT1 comp. inhibited
Relaxant Prostanoid Receptors
G-alpha S–>AC–cAMP
IP, EP2/4, DP1
Contractile prostanoid receptors
Via RhoGEF and Gq:PLC-Beta (increase Ca2+)
Tp, FP, EP1
inhibitory prostanoid receptors
Gi via AC inhibition and increasing Ca2+
EP
Corticosteroid Effects:
- Transactivation
- Transrepression
INCREASES:
a) Annexin 1 (Lipocortin 1)
-Annexin 1 binds to
Phospholipase A2 inhibiting
the synthesis of arachidonic
acid
b) Secretory leukoprotease inhibitor (SLPI)
c) Interleukin-10 (IL-10)-antiinflammatory
d) Inhibitor of nuclear factor-kB (IkB-a)
Corticosteroid Effects:
2. Transrepression
DECREASES:
Cytokines (Interleukins IL-1, IL-2, others)
Chemokines (e.g. IL-8)
Adhesion molecules (CAMs)
-decreases the ability
of some inflammatory cells to
migrate
Inflammatory enzymes, molecules, receptors
-COX expression is decreased!
Steroids
- general mechanism
- Drugs
main uses: antiinflammatory: COX2 repression
Anti-inflammatory: represses COX-2 expression; ↓ cytokine production, decreased formation and release of endogenous inflammatory mediators; causes apoptosis of eosinophils
- Hydrocortisone (Cortizone-10)
- Prednsione (Sterapred, generic)
- Fluticasone (Cutivate, Flovent)
Steroids
General Adverse Rxns and Precautions
- Cushing’s syndrome
- High doses and long-term therapy can suppress hypothalamic-pituitary-adrenal system; avoid abrupt DC of prolonged therapy
- Preexisting bacterial, viral, fungal infections
- Patients receiving corticosteroids chronically should be periodically assessed for cataracts
Dexamethasone
Decadron
30x more potent in anti-inflammation than hydrocortisone
Long duration
Fludrocortisone
Used to replace aldosterone due to its 250 mineralocorticoid potency
Only a 10 for anti-inflammatory
Intermediate duration
Nonsteroidal Anti- Inflammatory Drugs and Acetaminophen
Properties and Indications
Properties:
a) Anti-inflammatory (but not acetaminophen)
b) Antipyretic
c) Analgesic
–Not effective for neurogenic pain
ex) phantom limb pain, herpes, diabetic neuropathy
Major indications:
-Mild-to-moderate pain (headache, dental pain, common cold, backache, joint pain, muscle ache)
-Rheumatoid arthritis, osteoarthritis
-Fever
-Dysmenorrhea
-Gout
-Prophylaxis of thrombosis (aspirin only)
-Prophylaxis of polyps and colon cancer inhibitng COX enzymes may help
NSAIDs
- General Mechanism of Action
- Inhibition of cyclooxygenase (COX) enzymes involved in
prostaglandin biosynthesis → ↓ prostaglandins
Two isoforms exist, COX-1 and COX-2
1. COX-1 is constitutively expressed in almost all tissues
2. COX-2 is constitutively expressed only in brain, kidney, and bone but is
inducible in response to certain mediators of inflammation
All are competitive inhibitors except aspirin which is irreversible*
NSAIDs
- . Black Box Warning
- How are NSAIDs differentiated?
- Increased risk of CV and GI adverse effects
- All equally efficacious: differences are in toxicity and cost-effectiveness
- NSAIDs that more likely inhibit COX1 can cause more intense GI issues like bleeding
- most blunt ACE inhibitors
NSAIDs and GI Bleeding
COX1 Inhibition
- PGE2 binding EP3 receptor in superficial epithelial cell in GI mucosa secretes mucous and HCO3- to protect against gastric acid
- Inhibiting COX1 means we can’t make PGE2
NSAID Drugs (8)
Aspirin (ASA, Bayer, generic) Ketolorac (Toradol) Indomethacin (Indocin) Naproxen (Aleve, Anaprox) Ibuprofen (Advil) Meloxicam (Mobic) Celecoxib (Celebrex) Diclofenac (generic)
Aspirin Triad
Correlation of aspirin hypersensitivity, asthma, and nasal polyps
*Aspirin can trigger asthma attacks because by blocking COX, we shunt more towards LOX and the product leukotrienes are proinflammatory
Reye’s Syndrome
Results from giving aspirin to children
NSAIDs
- Common Precautions
- General Adverse Reactions
- Precautions
Salicylate sensitivity
Aspirin triad
Heart disease
Hepatic disease
Prior history of GI bleeding or perforation
Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency - Adverse Reactions
GI: NVD, damage to mucosa, gastric bleeding, abdominal pain
NSAIDs:
- COX 1
- COX 2
- COX1: KAN i i?
- Ketolorac: 100x
- Aspirin: 5x
- Naproxen: 3-5x
- Indomethacin: 3-5x
- Ibuprofen: 2x - Mexico City and DC are in 2 different countries-CYP2C9
- Meloxicam (Mobic): 10x
- Diclofenac: 10-20x
- Celecoxib (Celebrex): 10-20x
Acetominophen and hepatotocixity
- metabolism by CYP1A2, CYP2E1, CYP34A
- toxic: NAPQi+sulfhydryl protein
*in acute overdose, 2-3 days pass before maximum liver damage becomes
apparent
- antidote is IV N-acetyl cysteine
- reacts w/NAPDQI b/c it has a sulfhydryl group and will shift synthesis towards mercapturic acid formation
Prostanoid Agonists
Alprostadil (Caverject)
Latanoprost (Xatalan)
Misoprostol (Cytotec)
-H2 inhibitor in parietal cells
Leukotriene Inhibitors
- General usage
- Precautions
- Generally for prophylaxis and chronic treatment of asthma. Not Acute!
Zileuton (Zyflow)
Zafirlukast (Accolate)
- Not a bronchodilator, not used for acute episodes of asthma
- Liver disease: cirrhosis, acute hepatitis, cholestasis, alcoholism, smoking, age
Oleocanthal
From EVOO
- has ibuprofen like activity
- could be a new lead compound