Immunology Block: Pharmacology 7 - Eicosanoids

Front 1

where do ecisanoids come from? what's the rate limiting step?

Back 1

linolenic acid - this is an essential fatty acid and has to come from the diet. it's found in the plasma membranes of cells, part of phospholipids.

the rate limiting step is the creation of arachadonic acid - done by PhosphoLipase A2

Front 2

What's cox? How do you get prostiglandins and thromboxanes?

Back 2

there are two kinds - Cox1 and Cox2. These convert arachadonic acid into PGH2 and PGG2 - these are unstable intermediates.

Then, thromboxane synthase or prostacyclin synthase take over and you get either TXA2 to clot and constrict, or PGI2 to dilate and make edema.

Front 3

what's the difference between the two cox's?

Back 3

just where they are. they both make the same product (PGH2 out of AA).

Cox1 is constitutively expressed most places, is the major one. Housekeeping.

Cox2 was thought to be produced only in sites of inflammation, making it a good target for drugs. Turns out it's constitutively expressed in the heart, kidneys, and vascular endothelium.

remember that one place that cox1 is made is in the stomach - it helps make mucous. if you kill off Cox1, you're going to get stomach problems.

Front 4

what are the general kinds of things covered under the heading of eicosanoids?

Back 4

remember that they're theoxygenated derivatives of arachidonic acid. could be leukotrienes, prostaglandins, or thromboxanes.

Front 5

how does aspirin work?

Back 5

only NSAID that binds irreversibly to COX and inactivates it. Note that if it's an endothelial cell, it's temporary because it can make more COX and continue along.

If it's a platelet, there's no nucleus - so any COX that's bound by asipirin and inactivated is permanently destroyed. Need to wait 2 weeks for the platelet to turn over to get more Cox working.

In the endothelial cells, it's going to inhibit the creation of prostilandins and prostacyclin (PGI2). In the platelets, it's going to stop the production of thromboxane - so you won't clot as easily and are more likely to bleed.

Front 6

If we're talking about ecosanoids but not about things made from COX, what are we talking about?

Back 6

Lipoxygenase pathway.

Here, arachadonic acid gets converted iby 5-Lipoxygenase into 5-HPETE.

I think all we need to know is that leukotrienes are involved in vasoconstriction, bronchospasm, and chemotaxis (B4 does chemotaxis, while A4, C4, D4, and E4 are what are in the lungs).

Front 7

what's meant by aspirin trails?

Back 7

lots of studies in europe and america have tried to balance the downsides of aspirin on the GI tract vs. its constant benefit when it comes to vascular disease.

Front 8

How do Eicosanoids get eaten up?

Back 8

#1 - there are specific enzymes for PG's, except PgI2 - so it lasts a little longer.

Also, general FA oxidizing enzymes.

These enzymes are mostly located in the lungs.

Note that the thromboxanes are relatively short lived and unstable.

Front 9

what's PAF?

Back 9

platelet activating factor. released by pro infalmatory signals, and it causes inflammation.

it vasodilates and broncho constricts. it can be made by most blood cells and platelets.

Front 10

which of these pathways do steroids stop?

Back 10

all of them - by knocking out the creation of AA (i guess in the phospholipase A part), end all of it.

Front 11

what can you do about leukotrienes?

Back 11

zileuton - this stops 5-lipoxygenase, which makes most of the lung-affecting leukotrienes.

monteleukast, zafirlukast - these are LT receptor antagonists.

also, corticosteroids.

Front 12

what can omega sixes and three have to do with anything?

Back 12

Omega sixes can be turned into AA pretty easy, which means you can get inflammation and athersclerosis.

much better off eating omega 3's, which can't be turned into AA. ALso, they displace normal Omega 6, which is a good thing - so you can lower your AA by eating lots o' fish.

Front 13

what's the effect of thromboxane and a prostiglandin on platelet aggreation? why does aspirin work?

Back 13

thromboxane promotes platelet aggregation (clots), PGI2 inhibits platelet aggregation (pro bleeding).

low dose aspirin works because taken in low doses, preferentially inhibit the thromboxane pathway

Front 14

how do NSAIDS bind to Cox 1 and Cox 2?

Back 14

irreversibly - note that aspirin is acetyl saliycilic acid, and the acetyl binds permanently to cox.
if you're in a platelet, no more ability to make cox.
if your'e an endothelial cell, still can make cox, so effect isn't as long lasting.

Front 15

if you don't make PGH2 from Cox, what else can we do? what do these do?

Back 15

make our leukotrienes.

first step is to use 5-lipoxygenase A2, which will make 5 HPETE.

one possible product from that it 5 HETE which will make leukotriene B2, which is a powerful chemoattractant.

Otherwise, make Leukotrienes A2, C2, D2, E2 : these are all causers of bronchospasm, vasoconstriction, and increased vessel permeability = edema, inflammation.

Front 16

how do corticosteroids work?

Back 16

2 methods of action:

1. Stop phospholipase A, so don't get any of the ecosanoids.

2. Activate the GRE's present in lots of cells, turning on NFkB's big antagnoist (IkB), which is required for all kinds of cytokine production.

So, you stop both eicosanoids and you stop cytokines.

Front 17

what drugs can we use to stop leukotrienes?

Back 17

of course you can use corticosteroids.

also, you can block lipoxygenase (Zileuton)

you can block leukotriene receptors (monteLUKAST, zafirLUKAST)

putting a "cast" on the receptors?

Front 18

breakdown of prrostaglandins/thromboxane?

Back 18

most PG's have specific enzymes in the lungs that kill them off. Exception is PGI2, which survives the fist past through the lungs, and eventually drops off later on.

there are general FA oxidizing enzymes that can be a 2nd step for all ecosanoids, if they don't get specifically chewed up.

Front 19

what's PAF?

Back 19

platelet activating factor.

Potent vasodilator and bronchoconstrictor (in contrast to the leukotrienes, which vasoconstrict and bronchospasm).

big time up regulator of inflammation.

made by most leukocytes, in addition to platelets.

it drops BP, can be a big deal in shock.

Front 20

ecosanoid receptors?

Back 20

all G-coupled.

Front 21

vasoconstriction vs. dilation - compare thromboxane and prostaglandins

Back 21

prostaglandins are all about inflammation, so they vasodilate. thromboxane is opposite, it constricts.