Review Eicosanoids and Autocoids

Question 1

Do eicosanoids have a local or global hormonal effect?

Answer 1

local or on self (paracrine or autocrine)

Question 2

What are the main classes of eicosanoids?

Answer 2

prostaglandins, thromboxanes, and leuoktrienes

Question 3

What are the main functions of eicosanoids?

Answer 3

cell specific function! Thus, some cell eicosanoids behave differently than the same eicosanoids released from different cells

• participate in inflammatory response
• regulate smooth muscle contraction
• increase water and sodium excretion (i.e. involved in BP regulation)
• constriction/dilation of blood vessels
• bronchodilation/constriction

Question 4

What are eicosanoids derived from?

Answer 4

20C fatty acids like arachidonic acid

Question 5

How are arachidonic acids synthesized?

Answer 5

they start as essential fatty acids, of the omega-6 or omega-3 variety, that come in through diet where they are acted upon (i.e. if 18C linoleate came in, it would be acted upon by elongase and desaturase). However, note that arachidonic acid can be observed from diet. Once inside the body, arachidonic acid is activated by addition to CoA, and is incorporated into membrane phospholipids in the 2’ position. Upon signal, the membrane phospholipid is digested and phospholipase A2 (typically) releases arachidonic acid

Question 6

What inhibits the cleavage of arachidonic acid from the membrane phospholipid?

Answer 6

glucocortisoids. Thus, these can be given as an anti-inflammatory to decrease arachidonic acid release/synthesis

Question 7

How else can arachidonic acid be releases/synthesized beside releasing it from phospholipids via phospholipase A2?

Answer 7

DG lipase can release it from diacylglycerols (and so can MG subsequently)

Question 8

What can happen to arachidonic acid once released from diacylglycerol or phospholipids?

Answer 8

It can be acted upon by the enzymes in a specific cell in which it is released.

If the cell has lipoxygenases, it will go into the leukotriene pathway.

If the cell has prostaglandin synthase (cyclooxyrgenase activity to form PGG2 and peroxidase activity to form PGH2), it will become prostaglandin H2 (PGH2), a common precursor for synthesis of a variety of prostaglandin derivatives: namely, prostacyclin, thromboxanes, and other prostaglandins.

Arachidonic acid can also go to make epoxides of arachidonic acids (function unknown) via cytochrome P450

Question 9

How are the precursors of arachidonic acid stimulated to be released/acted upon to form arachidonic acid?

Answer 9

stimulus such as epinephrine, thrombin, or angiotension II can bind and cause either:

1) phospholipase A2 to cleave arachidonic acid from phosphotidylcholine or,
2a) phospholipase C to cleave 1,2 diacylglycerol from phosphatidylinositol bisphosphate, which can then be acted up by diacylglycerol lipase to form arachidonic acid
2b) the monoacylgylcerol that forms after the action of DG lipase can also release an arachidonic acid via MG lipase

Question 10

What is the mechanism of action of the prostaglandins PGD, PGI, and PGE?

Answer 10

work through adenyl cyclase, cAMP, and PKA

Question 11

What is the action of the prostaglandins PGF2, thromboxane A2 (TXA2), and leukotrienes in relation to calcium?

Answer 11

they increase Ca2+ in the cytosol

Question 12

Is the lifetime of eicosanoids long?

Answer 12

NO! only seconds to minutes at most

Significance: they must act nearby to the cell that synthesizes them (autocrine or paracrine)

Question 13

How are eicosanoids named?

Answer 13

the letter after PG (i.e. PGA) indicates the oxidation state (with A being the most oxidized and G being the most reduced) and the number (i.e. PGA2) indicating the number of double bonds in the structure

Question 14

What are some of the functions of PGD2, PGI2 (prostacyclin- produced by vascular enthotheial cells ), and PGE2?

Answer 14

they work through cAMP to:

1) increase vasodilation and edema in an affected region
2) decreases platelet aggregation, T-cell proliferation, lymphocyte migration, 1L-1/2, and leukocyte aggregation

Question 15

What does PGF2a?

Answer 15

increases vasoconstriction, bronchial constriction, and smooth muscle contraction

Question 16

How is thromboxane A2 made from PGH2?

Answer 16

acted upon by TXA synthase

Question 17

What does thromboxane A2 (TXA2) do? What are they produced by?

Answer 17

produced by platelets at wounds and stimulates bronchioconstriction, platelet aggregation and causes vasoconstriction to reduce blood flow to the affected area. No effect on COX-1 or COX-2

Question 18

What are the potential products of the lipooxygenase pathway?

Answer 18

HETE’s, leuoktrienes, and lipoxins

lipooxygenases incorporate an O2 molecule into arachidonic acid to make its derivative shown here

Question 19

What are some of the actions of different leukotrienes (which are made by leukocytes and have 3 double bonds)?

Answer 19

LTB4- increase vascular permeability, T- cell proliferation, leukocytes aggregation, and IL1/2 regulation

LTC4 and LTD4- increase vascular permeability and bronchoconstriction

Question 20

What are the two ‘activities’ of prostaglandin synthase and what do they do?

Answer 20

cyclooxygenase and peroxidase. These work together to make prostaglandin H2

Question 21

What can inhibit the cyclooxygenase/peroxidase activity of prostaglandin synthase?

Answer 21

aspirin and other NSAIDS (non-steroidal anti-inflammatory drugs)

Aleve, tylenol, etc.

Question 22

What are the main points of the leukotriene synthesis pathway from arachidonic acid?

Answer 22

1) lipooxygenases introduce an unstable proxy oxygen into the arachidonic acid to make HPETE which rapidly reorganizes to form leukotrienes or HETE
2) Leukotrienes can be further converted from one form to another or they can be derivatives using glutathionine to LTA or LTE

Question 23

The epoxides formed from the action of cytochrome P450 on arachidonic acid do what?

Answer 23

these are active in ocular (vision), vascular, endocrine, and renal systems

Question 24

The action of the phospholipase used to cleave/synthesize arachidonic acid are inhibited by what?

Answer 24

corticosteroids

Question 25

Unesterified arachidonic acid is used as substrate for the cyclooxygenase, lipoxygenase, and epoxygenase pathways. The cyclooxygenase pathways produce what types of compounds?

Answer 25

cyclooxygenase pathways produce prostaglandins, prostacyclin, and thromboxane

Question 26

What inhibits the cyclooxyrgenase pathway from arachidonic acid?

Answer 26

This pathway is inhibited by the non-steroidal anti-inflammatory drug (NSAID) class

Question 27

The lipoxygenase pathways produce leukotrienes and lipoxins. This pathway is inhibited by what?

Answer 27

a synthesis inhibitor that is used for some asthma patients or the cellular targets of the leukotrienes can be blocked by antagonist drugs; these too are used for asthma

Question 28

What is the difference in the action of the COX 1 and COX 2 isoforms of cyclooxygenase (prostaglandin synthase)?

Answer 28

COX-1 has homeostatic roles (i..e ubiquitous expression and not typically inducible) whereas COX-2 is induced during inflammatory reactions.

Question 29

Overdose of NSAID drugs accounts for 30% of hospitalization over the age of 60. The primary toxicity of this class of drugs is what?

Answer 29

gastric erosion, ulceration and bleeding.

Question 30

How does overdose of NSAID cause gastric erosion, ulceration, and bleeding?

Answer 30

There are several issues. Firstly, we need to consider the inhospitable environment within the stomach where the pH lies in the region of 2; hardly conducive to cellular homeostasis! The pH is so low because of hydrogen ion secretion, a process that is stimulated via several mechanisms and regulated by PGs. The stomach maintains a degree of self-protection by secreting a bicarbonate “layer” that physically occludes the acid from reaching the cells lining the stomach. This is also regulated by PGs. Finally, PGs are involved in localized control of bloodflow within the tissue, both in increasing perfusion to bring buffers to control acidity in an eroded area, and in promoting the healing process following any damage.
 So PG inhibition via NSAIDs is bad in that context.

Question 31

What do drugs like a) Pepcid AC and b) Nexium do?

Answer 31

Anti-histamines (H2 receptor blockers) like famotidine [Pepcid AC] block the histamine-mediated acid stimulation in the stomach, whereas proton pump inhibitors like esomeparazole [Nexium] block the activity of the proton pump located in the wall of the parietal cell.


Question 32

T or F. COX-2 specific inhibitors are associated with a lower incidence of GI toxicity and bleeds

What are the roles of COX-1 and COX-2 in the GI?

Answer 32

T; this was part of the marketing appeal of the class. (That’s not to say that COX-2 doesn’t have ANY role in GI homeostasis)

roles of COX-1: increase platelet aggregation and increase bicarbonate flow and blood flow

roles of COX-2: increase leukocyte adherence and healing processes

Question 33

Why are selective COX drugs less likely to result in GI bleeding or mucosal erosion?

Answer 33

NSAIDs induce injury/bleeding via three key pathways: inhibition of COX-1, COX-2, or direct cytotoxic effect on the epithelium. Effects produced via only one of the these pathways are unlikely to produce significant damage

There are no absolutely COX-1 vs. COX-2 specific agents available clinically, each, to a greater or lesser degree, inhibits both isoforms.


Question 34

How does the ‘fever center’ work?

Answer 34

Endogenous pyrogens release interleukin-1 , which is turn promotes the synthesis and releases of PGE2. EP3 receptor expressed in specific part of the medial pre-optic area is primarily responsible for fever reopens. Fever is though to provide an optimal hyperthermia environment for hunting host defenses against invading bacteria and viruses while reducing pathogen viability

Question 35

What are antipyretics?

Answer 35

they reduce fever associated with infection (e.g. non-narcotic analgesics (NNAs) (i.e. aspirin and the salicylates, acetaminophen and the NSAIDs such as ibuprofen [Advil], naproxen sodium [Aleve], and indomethacin [Indocin]) combined with acetaminophen [Tylenol])

They do this by acting in the temperature-regulating centers found in the Pre-optic Area (the anterior portion of the hypothalamus) of the brain where PGE2 is involved in mediating the classical effects of a fever: non-shivering thermogenesis by the brown adipose tissue and cutaneous vasoconstriction.


Question 36

What is an important adverse effects of chronic NSAID consumption in older patients, who have age-related decline in renal function and the greatest likelihood of arthritis and general aches and pains?

What are the roles of COX-1 and COX-2 in the kidneys?

Answer 36

a further reduction in renal efficiency. Within the kidney, PGs are responsible for localized control of renal perfusion, maintaining the essential perfusion pressure and glomerular filtration, and in promoting sodium excretion in the collecting ducts. 


ROLES:
COX-1 kidney roles: maintain renal blood flow and filtration rate
COX-2 kidney roles: promote salt excretion
TXA2- renal vasocontrictor

Question 37

Why would chronic NSAID use be associated with increased BP?

Answer 37

due to reduced sodium excretion in the kidneys (mainly due to inhibition of COX-2). Since PG activity is involved in the final cellular actions of a variety of antihypertensive medications, the use of chronic NSAID consumption in hypertensive patients taking medications should not be encouraged.


Question 38

Why do COX-2 specific NSAIDS (e.g. Celebrex) run the risk of thrombosis?

What are the roles of COX-1 and COX-2 in the cardiovascular system?

Answer 38

Whereas COX-1 inhibition by an NSAID will inhibit platelet aggregation, a potential useful clinical action, drug inhibition of COX-2 removes the protective functions of this enzyme upon platelet function, including protection against oxidative injury, induction of epithelial cell surface thrombomodulin (this converts thrombin to an anticoagulant enzyme from a procoagulant enzyme), and vasodilation.

So, inhibition of these protective mechanisms can tip the pro-coagulant/anticoagulant “balance” in favor of thrombosis.


Question 39

Why are the effects of COX-1 inhibitors irreversible over the lifespan of a platelet?

Answer 39

COX-1 are the only PGs expressed in mature platelets (TXA2 is the major product here and promotes aggregation)

Platelets are anucleate, and as such they are incapable of generating fresh protein following drug-induced actions. Therefore, when COX-1 is inhibited (e..g. by NSAIDs) and TXA2 levels are reduced, this effect is permanent for the life of the platelet (8-9 days) if the inhibition is irreversible. Of the NSAIDs, acetaminophen, salicylates and aspirin, only aspirin is able to irreversibly inhibit COX-1

So, often aspirin is used as a prophalyxsis for MI.

Question 40

How do prostaglandins affect tumor growth?

Answer 40

They have a role in tumor growth and metastasis. PGs are ubiquitous in the growth of solid and hematologic malignancies through one or more of several mechanisms, including transcription, translation and degradation of critical genes and their products involved in tumor survival and growth.


So PGs may increase the severity/likelihood of a tumor forming

Question 41

What are the translational effects on tumor growth from PGs?

Answer 41

activation of transcriptional factors
tumor suppressor gene inactivation
inhibition of transcriptional silencing

Question 42

What are the transcriptional effects on tumor growth from PGs?

Answer 42

Increased mRNA stability, translational silencers, microRNAs

Question 43

What are the degradative effects on tumor growth from PGs?

Answer 43

suicide inactivation

Question 44

Notes on evidence about the use of aspirin in cancer treatment/prevention.

Answer 44

Some studies have seen a decrease in the instance of colon cancer prevalence related to daily aspirin use (>75mg/day). However, other studies have not seen any correlation and daily aspirin use runs the risk of GI bleeding due to PG inhibition

Question 45

Aspirin effects on PGH1 and PGH2.

Answer 45

Cyclic endoperoxides prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2) are produced by the sequential COX and HOX actions of prostaglandin H synthase-1 (PGHS-1) and then PGHS-2; these isoforms both have dual COX and hydroperoxidase (HOX) activity. Aspirin acts to inhibit PGHS-1 at both low-dose and high-doses or PGHS-2 only at high doses.

Prostaglandin H2 is converted into a range of prostanoids by tissue-specific isomerases; therefore, the inhibition of this pathway prevents (or reduces) the downstream activation of a superfamily of context specific G‑protein-coupled receptors.


Question 46

How does Aspirin act?

Answer 46

As I noted previously, aspirin has a unique action amongst the NSAIDS with respect to the ability to irreversibly inhibit COX-1. Aspirin, or acetyl-salicylic acid, is a pro-drug that is rapidly hydrolyzed in the stomach, intestines blood and predominantly in the liver to produce the active salicylate metabolite that is responsible for the majority of anti-inflammatory and analgesic effects. This conversion liberates the acetyl moiety which has important cellular actions of its own. COX-1 in platelets is irreversibly inhibited by aspirin and platelet aggregation inhibited. What is actually happening is that the COX-1 enzyme is acetylated by the liberated acetyl moiety. 
So if one considers the intracellular actions of the aspirin, these must clearly involve actions of the acetyl function.. Although one would immediately identify COX enzymes as important cellular targets, there are also non-COX effects, and separately the effects of the acetyl function on critical cellular targets. This diversity of action may explain why aspirin, of all the NSAIDs, seems to have prophylactic and antiproliferative actions against tumors.


Question 47

How are specific PGs involved in uterine function?

Answer 47

PGF2a, TXA2, and low conc. of PGE2- Cause uterine contraction as pregnancy progresses

General- increased cervix collegians causing ‘softening/ripening’

PGI2 and PGE2- relaxation

PGF2a w/ oxytocin- initiate birth

PGE2 and PGF2a- primary dysmenorrhea

Question 48

What drug can help relieve some of the painful contractions during pregnancy?

Answer 48

a short course (2-3 days) of indomethacin is particularly effective in the second and early third trimesters, in preventing preterm labor in women who continue to have contractions after being given magnesium sulfate (smooth muscle relaxant).


In the context of pregnancy, NSAIDs like indomethacin should be avoided during the third trimester due to the potential for such drugs to cause in utero constriction of the fetal ductus arteriosus.


Question 49

How is endometriosis caused by PGs?

Answer 49

PGs are also involved in the painful condition of endometriosis. In this context, the upregulation of COX-2 by the hormone, estrogen, leads to increased inflammatory mediators, and through a positive feedback loop, to increased production of estrogen and a ”wind up” phenomenon occurs. In this disease process, treatment is best afforded by preventing estrogen production rather than by inhibiting PGs. We will talk more about the modulation of estrogen when we get to the GU module, next year.


Question 50

How are PGs involved in male reproductive systems?

Answer 50

PGs were first discovered in seminal fluid; despite this, the role of PGs in male reproduction, other than vasodilation in the penis (enhancing erection), remains unclear.

men with low seminal PG are typically infertile


Question 51

How are PGs involved in neurotransmission?

Answer 51

PGs play an important modulatory role in the vascular tone, perhaps by increasing alpha-1 adrenergic activity upon the smooth muscle, but also by inhibiting the direct vasodilatory effects of the PGs themselves. PGs also play an important modulatory role in pain pathways both on peripheral nerve endings and in the brain and in the spinal cord. Thus drugs that possess only a central action, e.g., acetaminophen (this drug has NO anti-inflammatory activity) can provide analgesia though these central mechanisms.


augment pain sensibility, widens the area of pain perception, inhibit the release of norepinephrine, vasodilator, increase sensitively of neural terminals

Question 52

How are PGs involved in bone metabolism?

Answer 52

PGs also play an as yet undefined role in bone health, though their presence in skeletal tissue is well established. PGE4 receptor deletion in genetic mouse models leads to decreased bone mass and density. There has also been discussion regarding the deleterious effects of long-term NSAID use for pain relief following fractures, but nothing definitive has been established. 
At the present time the consensus is that the NSAID, ibuprofen is a better choice for pain relief than morphine for children with broken bones. Although both medications are effective in easing the pain associated with these injuries, oral morphine carries more risk for negative side effects.

increased bone resorption and formation, so chronic inhibition is bad in that context

Question 53

What does Dinoprostone do?

Answer 53

administered vaginally for inducing labor by mimicking the effects of PGE2, increase collegians activity in the cervix (aka ripening of the cervix) for induction of labor or inducing abortion in the second trimester

Question 54

What does Alprostadil do?

Answer 54

works in the penis similar to PGE1 to induce vasodilation for erection and,

Alprostadil is also used for the treatment of neonates with congenital heart defects to maintain the patency of the ductus arteriosus (ductus arteriosus maintenance) until palliative or corrective surgery can be performed. Thus, NSAIDs can be used to help close a patent duct.