Pharm Ii - Eicosanoids

Front 1

COX I

Back 1

Cyclooxygenase is a microsomal enzyme (in a vesicle of some form?)
COX I is ubiquitous and constitutively expressed. This enzyme is presumed to generate PG which play a role in homeostasis

Front 2

COX II

Back 2

Cyclooxygenase is a microsomal enzyme (in a vesicle of some form?)
COX II is an inducible form of the enzyme which is rapidly produced and rapidly degraded after cells are exposed to several cytokines or growth factors. PG generated by COX II are thought to play a role in inflammation.

Front 3

Break down of PGH2 in vascular tissue

Back 3

In vascular tissue, prostacyclin (PGI2) is formed by prostacyclin synthase. Causes vasodilation and inhibits platelet aggregation

Front 4

Break down of PGH2 in platelets and lung

Back 4

In platelets and lung, thromboxane A2 (TXA2) is formed by thromboxane synthase. Causes vasoconstriction and promotes platelet aggregation

Front 5

Break down of PGH2 in brain and mast cells

Back 5

in brain and in mast cells, PGD is formed by an isomerase. Causes vasodilation and increased vascular permeability

Front 6

Break down of PGH2 in most tissues

Back 6

in most tissues, PGE2 and/or PGF2α are formed enzymatically or nonenzymatically. Causes vasodilation and increased vascular permeability

Front 7

Lipooxygenase

Back 7

Cytosolic enzymes

Front 8

Prostaglandins and platelet aggregation

Back 8

TXA2 induces platelet aggregation and aggregating platelets release more TXA2 in a feed-forward cascade. PGI2 (and PGE1) are both potent anti-aggregatory substances. The opposing actions of PGI2 (generated by the endothelium) and TXA2 (from platelets) may play an important role in hemostasis.

Front 9

Eicosanoids and vascular tone

Back 9

PGI2 (and PGE2) is a potent vasodilator and induces hypotension.
TXA2 is a powerful vasoconstrictor as are LTC4 and LTD4. The LT are particularly potent constrictors in the coronary and pulmonary circulations.

Front 10

Eicosanoids and edema

Back 10

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 11

Eicosanoids and GI

Back 11

a. PGI2 and PGE2 inhibit gastric acid secretion and increase mucus secretion.
b. PGE2 contracts smooth muscle (longitudinal) of GI tract, causing cramps and diarrhea. LTC4 and LTD4 also induce smooth muscle contraction.

Front 12

Agents to suppress gastric ulceratoin

Back 12

Analogs of PGE1 (e.g., misoprostol) and PGE2 (e.g., enprostil) are used to suppress gastric ulceration.

Front 13

Eicosanoids and GU system

Back 13

a. PG are found in the ovary, myometrium and menstrual fluid. The physiological role of PG in menstruation and in conception remain unclear.
b. PGF2α required for the induction of labor. Concentration of PG in blood and amniotic fluid are elevated during labor.
c. Very high concentrations of PG are present in the seminal fluid. Their role in male sex function is not clearly understood.

Front 14

PGF2α

Back 14

required for the induction of labor. Concentration of PG in blood and amniotic fluid are elevated during labor.

Front 15

Use in midtrimester abortions

Back 15

PGE2, 15-methyl PGF2α

Front 16

Cylooxygenase effect on labor

Back 16

Cyclooxygenase inhibition prolongs gestation.

Front 17

Eicosanoids and Renal system

Back 17

a. Intrarenal synthesis of PG dilates renal blood vessels, counteracts the actions of AII; maintains renal blood flow.
b. PGI2 and PGE2 cause natriuresis and diuresis (renovascular and tubular effects.)
c. PG stimulate renin secretion (effect on JG cells).
d. All EP receptors play some role in renal function.

Front 18

Renal side effects of cyclooxygenase inhibition

Back 18

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

Front 19

Renal effect of PGI2 and PGE2

Back 19

PGI2 and PGE2 cause natriuresis and diuresis (renovascular and tubular effects.)

Front 20

Eicosanoids and Pulmonary

Back 20

a. PGE2 dilates while PGD2 and PGF2α constrict bronchial smooth muscle.
b. LTC4, LTD4 and TXA2 all are powerful bronchoconstrictors. In addition to their role in hypersensitivity reactions, they are no doubt playing a role in bronchospasm in asthma and COPD.

Front 21

Zileuton

Back 21

A 5-lipoxygenase inhibitor, zileuton, was approved in 1997. This inhibitor is beneficial in human allergic rhinitis and in asthma.

Front 22

cysLT1 receptor

Back 22

Are present in peripheral blood leukocytes, smooth muscle, especially in lungs.
Agonists are LTD4 and LTE4

Front 23

Antagonists for the cysLT1 receptor

Back 23

useful in asthma therapy and allow reductions in steroid or inhaled bronchodilator use. These drugs do not block activation of the cysLT2 receptor.

Front 24

Eicosanoids and Inflammatory and immune responses

Back 24

a. 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.
b. PGE2 inhibits the participation of lymphocytes in hypersensitivity reactions and inhibits the release of hydrolases and lysosomal enzymes from human neutrophils.
c. EP3 receptor is critical for the induction of fever.

Front 25

EP3 and Inflammatory and immune responses

Back 25

Induction of fever

Front 26

PGE2 and Inflammatory and immune responses

Back 26

ibits the participation of lymphocytes in hypersensitivity reactions and inhibits the release of hydrolases and lysosomal enzymes from human neutrophils.

Front 27

LTB4

Back 27

Potent neutrophil chemoattractant and promotes neutrophil adhesion and aggregation

Front 28

LTC4 and LTD4

Back 28

Promote edema formation

Front 29

Eicosanoids and Peripheral nerves

Back 29

a. PGE2 acts on the presynaptic membrane to inhibit the release of NE.
b. 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 30

PGE2 and Peripheral nerves

Back 30

PGE2 acts on the presynaptic membrane to inhibit the release of NE.

Front 31

NSAIDs and pain

Back 31

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

Front 32

Misoprostol

Back 32

PGE1 analog

Suppress gastric ulceration.
Induces labor, abortion drug