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Eicosanoids Flashcards

1
Q

phospholiapse A2 (PLA2)

A

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

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2
Q

Lipooxygenases (LOX)

A

Arachidonic Acid–> leukotrienes and lipoxins

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3
Q

Cyclooxygenases (COX)

A

Arachidonic Acid –> prostanoids:

prostaglandins, prostacyclin, thromboxane

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4
Q

Prostanoids (Slide 43)

A

AA–>PGG2–>PGH2

PGH2: mother of prostanoids

  1. PGI2-Prostacyclin
  2. TXA2-thromboxane
  3. PGE2
  4. PGFa
  5. PGD2
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5
Q

PGI2: Prostacyclin

A

Vasodilation
Inhibits Platelet Aggregation

*antagonist of thromboxane

Receptor: IP

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6
Q

TXA2-thromboxane

A

Vasoconstriction amd platelet aggregation

*antagonist of prostacylin PGI2

Receptor: TP

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7
Q

PGE2

A 
Vasodilation 
Hyperalgesia 
Fever
Diuresis 
Immunomodulation

Receptor: EP

Uterine Contractions

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8
Q

PGFa

A

Smooth Muscle contraction:

  • bronchoconstriction
  • uterine
  • vasoconstrictions

Receptor: FP

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9
Q

PGD2

A

Smooth Muscle contraction
Inhibits Platelet Aggregation

Receptor: DP

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10
Q

prostanoids:

  1. Vasodilation
  2. Vasoconstriction
  3. Smooth Muscle Contraction
  4. inhibits platelet aggregation
A
  1. PGI2, PGE2
  2. PGFa, TXA2
  3. PGFa, PGD2
  4. PGI2, PGD2
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11
Q

Leukotrienes Synthesis

A

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)

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12
Q

LTB4

A

Receptor: BLT

Source: Neutrophils

Action: Activates neutrophils, plasma exudation

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13
Q

Cysteinyl Leukotrienes

A

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

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14
Q

Lipoxins

A

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
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15
Q

Eicosanoid Receptors

  1. Prostanoid
  2. Leukotriene
  3. Lipoxin
A

G protein coupled

1. Prostanoids: 
DP-PGD2
EP-PGE2
FP-PGFa
IP-PGI2
TP-TXA2
  1. Leukotriene
    BLT-LTB4
    CysLT-LTC4, :TD4, LTE4
  2. Lipoxin
    ALX-activated
    CysLT1 comp. inhibited
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16
Q

Relaxant Prostanoid Receptors

A

G-alpha S–>AC–cAMP

IP, EP2/4, DP1

17
Q

Contractile prostanoid receptors

A

Via RhoGEF and Gq:PLC-Beta (increase Ca2+)

Tp, FP, EP1

18
Q

inhibitory prostanoid receptors

A

Gi via AC inhibition and increasing Ca2+

EP

19
Q

Corticosteroid Effects:

  1. Transactivation
  2. Transrepression
A

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)

20
Q

Corticosteroid Effects:

2. Transrepression

A

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!

21
Q

Steroids

  1. general mechanism
  2. Drugs
A

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

  1. Hydrocortisone (Cortizone-10)
  2. Prednsione (Sterapred, generic)
  3. Fluticasone (Cutivate, Flovent)
22
Q

Steroids

General Adverse Rxns and Precautions

A
  • 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
23
Q

Dexamethasone

A

Decadron

30x more potent in anti-inflammation than hydrocortisone

Long duration

24
Q

Fludrocortisone

A

Used to replace aldosterone due to its 250 mineralocorticoid potency

Only a 10 for anti-inflammatory

Intermediate duration

25
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
26
NSAIDs 1. General Mechanism of Action
1. 􏰀 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****
27
NSAIDs 1. . Black Box Warning 2. How are NSAIDs differentiated?
1. Increased risk of CV and GI adverse effects 2. 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
28
NSAIDs and GI Bleeding
COX1 Inhibition 1. PGE2 binding EP3 receptor in superficial epithelial cell in GI mucosa secretes mucous and HCO3- to protect against gastric acid 2. Inhibiting COX1 means we can't make PGE2
29
NSAID Drugs (8)
``` Aspirin (ASA, Bayer, generic) Ketolorac (Toradol) Indomethacin (Indocin) Naproxen (Aleve, Anaprox) Ibuprofen (Advil) Meloxicam (Mobic) Celecoxib (Celebrex) Diclofenac (generic) ```
30
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
31
Reye's Syndrome
Results from giving aspirin to children
32
NSAIDs 1. Common Precautions 2. General Adverse Reactions
1. Precautions 􏰀 ***Salicylate sensitivity*** 􏰀 ***Aspirin triad*** 􏰀 Heart disease 􏰀 Hepatic disease 􏰀 Prior history of GI bleeding or perforation 􏰀 Bleeding disorders: hemophilia, thrombocytopenia, vitamin K deficiency 2. Adverse Reactions GI: NVD, damage to mucosa, gastric bleeding, abdominal pain
33
NSAIDs: 1. COX 1 2. COX 2
1. COX1: KAN i i? - Ketolorac: 100x - Aspirin: 5x - Naproxen: 3-5x - Indomethacin: 3-5x - Ibuprofen: 2x 2. Mexico City and DC are in 2 different countries-CYP2C9 - Meloxicam (Mobic): 10x - Diclofenac: 10-20x - Celecoxib (Celebrex): 10-20x
34
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
35
Prostanoid Agonists
Alprostadil (Caverject) Latanoprost (Xatalan) Misoprostol (Cytotec) -H2 inhibitor in parietal cells
36
Leukotriene Inhibitors 1. General usage 2. Precautions
1. Generally for prophylaxis and chronic treatment of asthma. Not Acute! Zileuton (Zyflow) Zafirlukast (Accolate) 2. Not a bronchodilator, not used for acute episodes of asthma - Liver disease: cirrhosis, acute hepatitis, cholestasis, alcoholism, smoking, age
37
Oleocanthal
From EVOO - has ibuprofen like activity - could be a new lead compound

Pharmacology (12 decks)

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