L49 Eicosanoids

Question 1

eicosanoid general

Answer 1

mediate physiologic and pathalogic repsonses

made everywhere except blood

short 1/2 life, function autocrine and paracrine signalling

Prostanoids

• prostaglandins
• prostacyclins (PGI2) glandins with an extra ring
• thromboxane

Leukotrienes
Expoxides

3rd letter is ring structure, number is number of double bonds 1,2,3

Question 2

Creation of eicosanoids

draw out with enzymes

Answer 2

activation of Gq protein couples receptor
-increased Ca

Membrane phospholipid
-Phospholipase A2 (LR)
Arachodonic Acid, DGLA(linoleic), EPA(linelenic)
(linoleic-both less and more inflammatory)

TWO PATHS

-5-lipoxygenase
Leukotrienes
Cysteinyl Leukotrienes

OR

-Cyclooxygenase 1or2
-Peroxidase
(PGH Synthase-1st com step) requires 2 O2 (cyclization)
PGH2
-PGH a substrate for prostanoid synthssis

Question 3

how do cells use prostanoids

Answer 3

platelets can use them to recruit eachother

• AA used -> TXA2 & PGI2
• STRONGER PLATELET RESPONSE

endothelial cells can release different ones to inhibit platelet aggregation or the other

• EPA used -> TXA3 and PGI3
• WEAKER AGGREGATION RESPONSE
• lower risk of heart attack

Question 4

leukotrienes

Answer 4

-5 lipoxygenase (ZYFLO INHIBITS)-prevent asthma
Leukotrienes
cysteinyl leukotrienes
-act at cell surface receptors (SINGLULAIR INHIBITS)-treat asthma
-contract bronchial and vascular smooth muscle
-enhance mucus secresion in airway and gut
-recruit leukocytes
-increase cap perm

Question 5

where are each made and what they affect

Answer 5

endothelial cells make PGI2

platelets produce TXA2

PG and TX-GPCRs- IP3/DAG increase Ca and increase PKC
PGI (cyclin) PGE2 PGD2 - Gs linked receptors (adenylate cyclase increase cAMP)

Question 6

degradation

Answer 6

short 1/2 life or 15-hydroxyprostaglandin dehydrogenase

-high levels in pulmnonary cap bed

Question 7

Cox1 Vs Cox2

Answer 7

Cox 1 smaller substrate binding site

• constitutively expressed most tissues
• inhibition problematic due to essential role in gastic mucosa
• hemostasis

Cox 2 larger binding site (can design drugs that bind only to Cox2)

• expressed in limited tissues (role in infl and pain)
• mediation of pain/inflammation/fever
• inducible in some, const in lunch, brain kindey, ep , bone

gastric damage occurs when both inhibited

Question 8

Cox inhibitors

NSAIDS

Answer 8

Aspirin (NSAID) COX1 and COX2 inhibition

• acetylates serine in both active sites
• Antiinflam, Analgesic, Antipyretic (fever)

ibuprofen/naproxen COX1 and COX2
-competetive inhibitor of 1/2
A, A, A

Celebrex: COX 2 ONLY
-substrate channel cox2 INFLAMMATION ONLY

Question 9

Cox inhibitors non nsaids

Answer 9

Tylenol: NEITHER COX

• acts on CNS (block PG in CNS cox ind manner)
• Analgesia, antipyretic (NOT INFLAM)

Glucocorticoids: decrease PLA2 activity, decrease COX2 synthesis

• REDUCE INFLAMMATION, SUPRESS IMMUNITY
• stimulate synth Annexin 1 (binds PLA2-inhibits hydrolyzation)
• shuts down COX2 gene transcription