eicosanoid general
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
Creation of eicosanoids
draw out with enzymes
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
how do cells use prostanoids
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
leukotrienes
-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
where are each made and what they affect
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)
degradation
short 1/2 life or 15-hydroxyprostaglandin dehydrogenase
-high levels in pulmnonary cap bed
Cox1 Vs Cox2
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
Cox inhibitors
NSAIDS
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
Cox inhibitors non nsaids
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
