Pharmacology Eicosanoids Part 2

Front 1

What are the cardiovascular effects of PGI2?

Back 1

PGI2 is a potent vasodilator and induces hypotension. This lipid may play a role in modulating normal vascular tone. PGE2 is also a vasodilator but is much less potent than PGI2.

PGI2 (and PGE1) are both potent anti-aggregatory substances.

Front 2

what makes a good puppy

Back 2

a puppy who pets kitty lotzzz is a good puppy

Front 3

What are the cardiovascular effects of TXA2?

Back 3

TXA2 induces platelet aggregation and aggregating platelets release more TXA2 in a feed-forward cascade.

TXA2 is a powerful vasoconstrictor as are LTC4 and LTD4.

The opposing actions of PGI2 (generated by the endothelium) and TXA2 (from platelets) may play an important role in hemostasis.

Front 4

What are the cardiovascular effects of leukotrienes?

Back 4

The LT are particularly potent constrictors in the coronary and pulmonary circulations. The LT also induce hypotension in humans due to secondary effects induced by marked volume depletion (see below) and decreased coronary blood flow.

Front 5

What are the cardiovascular effects of LTC4, LTD4, and LTB4?

Back 5

LTC4, LTD4, and LTB4 induce plasma leakage from the postcapillary venules and thus may play a role in edema formation. The peptidoleukotriene effects are direct on the endothelium while LTB4 requires the presence of neutrophils. LTC4 and LTD4 are such potent vasoconstrictors that the decreased flow can overcome the leakage effect. As a consequence, the presence of vasodilator PG can enhance plasma leakage.

Front 6

What is transcellular biosynthesis? Give examples

Back 6

"Transcellular biosynthesis" of eicosanoids occurs in the cardiovascular system and among formed blood elements with pathophysical significance. For example, PGH2 can be shared between platelets and endothelium leading to production of PGI2 after platelet activation. In addition, endothelium, which cannot make LTA4, can metabolize LTA4 generated by activated neutrophils adherent to the vessel wall leading to the synthesis of significant amounts of LTC4. This may be of particular importance in segments of coronary artery distal to an occlusion where there LRC4 may intensify vasoconstriction further occluding flow.

Front 7

What are the medical complications of plateley aggregation?

Back 7

Platelet aggregates have been implicated as a cause of myocardial ischemia/infarction (MI), stroke and transient ischemic attacks (TIA). "Anti-platelet" therapies have been advocated.

Front 8

What anti-platelet therapy is the treatment of choice?

Back 8

Low dose aspirin

Front 9

What is low-dose aspirin effective for?

Back 9

It is likely effective for primary infarction and stroke. It is likely effective fro primary prevention of MI in men and stroke in women. Gender differences have been noted, but not explained.

Front 10

Describe thromboxane synthase inhibition

Back 10

It has not proved to be very effective since the substrate for this enzyme, PG endoperoxides interact at the same receptors as TXA2.

Front 11

Describe the results of the consumption of fish oil high in EPA

Back 11

It replaces some of the AA in hte membrane phospholipid pool. PG production may decrease.

Front 12

What are the platelet aggregation effects of NSAIDs?

Back 12

The inhibiton of platelet aggregation due to cyclooxygenase inhibition may be an unwanted side effect of nonsteroidal antiinflammatory drug (NSAID) therapy.

Front 13

Describe where PGI2 has been used in cardiovascular medicine

Back 13

PGI2 has been used in a variety of situations such as severe occlusion of a peripheral artery (to restore patency), severe congenital pulmonary hypertension (dilation of PA), in the extracorporeal circuit (to preserve platelets), etc.

Front 14

Which eicosanoids have GI effects?

Back 14

PGI2
PGE2
LTC4
LTD4

Front 15

What are the GI effects of PGI2 and PGE2?

Back 15

PGI2 and PGE2 inhibit gastric acid secretion and increase mucus secretion. PGE2 contracts smooth muscle (longitudinal) of the GI tract, causing cramps and diarrhea.

Front 16

What are the GI effects of LTC4 and LTD4?

Back 16

LTC4 and LTD4 induce smooth muscle contraction, causing cramps and diarrhea.

Front 17

How are PGI2 and PGE2 used in medicine?

Back 17

PGE2 protects the gastric mucosa via inhibition of gastic acid formation and increase in gastric blood flow. This underlies in part the ulcerogenic effects of cyclooxygenase inhibiton. Analogs of PGE1 (e.g. misoprestol) and PGE2 (e.g. enprostil) are used to suppress gastric ulceration.

Front 18

What are the pharmacological effects of NSAIDs on the GI tract?

Back 18

Antiinflammatory effects of NSAIDs are mainly obtained by inhibiting COXII which the PG which protect the gastric mucosa are derived from COXI. Thus, the pharmaceutical industry has identified compounts that inhibit COX II but not COX I and thereby remove the GI side effects of NSAIDs. Some of the members of this drug class have been linked with increased cardiovascular risk.

Front 19

What limits the oral use of PG compounds?

Back 19

GI side effects

Front 20

Where in the GU system is PG found? What is its role?

Back 20

PG are found in the ovary, myometrium and menstrual fluid. The physiological role of PG in menstruation and in conception remains unclear.

In men, very high concentrations of PG are present in hte seminal fluid. Their role in male sex function is not clearly understood.

Front 21

Describe the natural levels of eicosanoids during labor

Back 21

PGF2alpha is required for the induction of labor. Concentrations of PG in blood and amniotic fluod are eleveated during labor.

Front 22

What are the pharmacological implications of eicosanoids on the GU system?

Back 22

-PGE2, 15-methyl PGF2alpha, misoprostol are currently approved for midtrimester abortions.
-Cyclooxygenase inhibition prolongs gestation.

Front 23

What are the renal effects of eicosanoids?

Back 23

-Intrarenal syntehsis of PG dilates renal blood vessels, conteracts the actions of AII; maintains renal blood flow.
-PGI2 and PGE2 cause natriuresis and diuresis (renovacular and tubular effects)
-PG stimulates renin secretion (effect of JG cells).
-All EP receptors play some role in renal function.

Front 24

What are the pharacological implications of eicosanoids on the kidneys?

Back 24

Cyclooxygenase inhibition may leave the vasoconstricting effect of AII unopposed, and, in patients with compromised renal function, may precipitate renal failure.

Front 25

What are the pulmonary effects of eicosanoids?

Back 25

a. PGE2 dilates while PGD2 and PGF2alpha constrict bronchial smooth muscle.
b. LTC4, LTD4, and TXA2 all are powerful bronchoconstrictors. In addition to thair role in hypersensitivity reactions, they are no doubt playing a role in bronchospasm in asthma and COPD.

Front 26

What are the pharmacological implications of eicosanoinds on the pulmonary system?

Back 26

-A 5-lipoxygenase inhibitor, zileuton, was approved in 1997. This inhibitor is beneficial in human allergic rhinitis and in asthma.
-Several antagonists for the cysLT1 receptor and on the market. These compounds are useful in asthma therapy and allow reductions in steroid or inhaled bronchodilator use. These drugs do not block activation of the cysTL2 receptor.

Front 27

What are the effects on eicosanoids on the inflammatory and immune responses?

Back 27

-PG and LT make an important contribution to the development of inflammation. LTB4 is a potent neutrophil chemoattractant and promotes neutrophil adhesion and aggregation. This leads to enhanced plasma exudation. LTC4 and LTD4 also promote edema formation through a direct effect. Vasodilating PG increase blood flow and enhance edema formation.
-PGE2 inhibits the articipation of lymphocytes in hypersensitivity reactions nad inhibits the release of hydrolases and lysosomal enzymes from human neutrophils.

Front 28

What is the EP3 receptor important for?

Back 28

It is critical from the induction of fever.

Front 29

What are the pharmacological implications of the effects of eicosanoids on the inflammatory and immune responses?

Back 29

NSAID (cyclooxygenase inhibition) and steroids (inhibition of the induction of COX II and inhibiton of PLA2) are widlely uised as antiinflammatory and antiarthritic drugs. It should be noted here that the prodution of leukotrienes would not be affects with the inhibiton of cyclooxygenase alone, and therefore the symptoims and signs of inflammation may not be totally alleviated.

Some COXII-selective inhibitors are available for clinical use.

Front 30

What are the effects of eicosanoids on peripheral nerves?

Back 30

-PGE2 acts on the presynaptic membrane to inhibit the release of NE.
-PGE2, PGI2, and LTB4 lower the threshold of nociceptors, causing hyperalgesia. PGE2 and PGI2 sensitize the afferent nerve endings to pain due to chemical and mechanical stimuli.

Front 31

What are the pharmacological implications of eicosanoids on peripheral nerves?

Back 31

Inhibition of production of PG after therapy with NSAIDs underlie part of the analgesic effects of these drugs.