Overview Eicosanoids are a large group of autocoids with potent effects on virtually every tissue...

Overview

Eicosanoids are a large group of autocoids with potent effects on virtually every tissue in the body

these agents are derived from metabolism of 20-carbon, unsaturated fatty acids (eicosanoic acids).

The eicosanoids include: 1. the prostaglandins 2. thromboxanes 3. leukotrienes 4. hydroperoxyeicosatetraenoic

acids (HPETEs)5. hydroxyeicosatetraenoic acids

(HETEs).

Biosynthesis

Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways:1. Phospholipase A2-mediated

production from membrane phospholipids; this pathway is inhibited by glucocorticoids.

2. Phospholipase C.

Eicosanoids are synthesized by two pathways:

1. The prostaglandin H synthase (COX, cyclooxygenase) pathway

produces: A. thromboxane B. the primary prostaglandins

prostaglandin E, or PGE prostaglandin F, or PGF prostaglandin D, or PGD)

C. prostacyclin (PGI2)

2. The lipoxygenase pathway produces:

HPETEs HETEs leukotrienes

The eicosanoids all have short plasma half-lives (typically 0.5—5 min).

Most catabolism occurs in the lung. Metabolites are excreted in the

urine. Thromboxane A2 (TXA2) is rapidly

hydrated to the less active TXB2. PGI2 is hydrolyzed to 6-keto-PGF1α.

Various eicosanoids are synthesized throughout the body

synthesis can be very tissue specific: PGI2 is synthesized in endothelial and

vascular smooth muscle cells. Thromboxane synthesis occurs

primarily in platelets. HPETEs, HETEs, and the leukotrienes

are synthesized predominantly in mast cells, white blood cells, airway epithelium, and platelets.

Actions:

Vascular smooth muscle PGE2 and PGI2 are potent

vasodilators in most vascular beds. Thromboxane is a potent

vasoconstrictor.

Inflammation PGE2 and PGI2 cause an increase in

blood flow and promote, but do not cause, edema.

HETEs (5-HETE, 12-HETE, 15-HETE) and leukotrienes cause chemotaxis of neutrophils and eosinophils.

Bronchial smooth muscle PGFs cause smooth muscle

contraction. PGEs cause smooth muscle

relaxation. Leukotrienes and thromboxane

are potent bronchoconstrictors and are the most likely candidates for mediating allergic bronchospasm.

Uterine smooth muscle. PGE2 and PGF2a

cause contraction of uterine smooth muscle in pregnant women.

The nonpregnant uterusnonpregnant uterus has a more variable response to prostaglandins PGF2a causes contraction

PGE2 causes relaxation.

Gastrointestinal tract PGE2 and PGF2a

increase the rate of longitudinal contraction in the gut and decrease transit time.

The leukotrienes are potent stimulators of gastrointestinal smooth

muscle.

PGE2 and PGI2 inhibit acid and pepsinogen secretion in the

stomach.

Prostaglandins increase mucus, water, and electrolyte secretion in

the stomach and the intestine.

Blood TXA2

is a potent inducer of platelet aggregation.

PGI2 and PGE2 inhibit platelet aggregation.

PGEs induce erythropoiesis by stimulating the renal

release of erythropoietin.

5-HPETE stimulates release of histamine

PGI2 and PGD inhibit histamine release.

Therapeutic uses

Induction of labor at term. Induction of labor is produced by:

infusion of PGF2 (carboprost tromethamine) [Hemabate] or

PGE2 (dinoprostone) [Prostin E].

Therapeutic abortion:A.Inducing abortion in the second

trimester: Infusion of carboprost tromethamine

or Administration of vaginal suppositories

containing dinoprostone

B.inducing first-trimester abortion: these prostaglandins are combined with

mifepristone (RU486)

Maintenance of ductus arteriosus

is produced by PGE1 [Prostin VR] infusion

PGE1 will maintain patency of the ductus arteriosus, which may be desirable before surgery.

Treatment of peptic ulcer.

Misoprostol [Cytotec] a methylated derivative of PGE1

is approved for use in patients taking high doses of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce gastric ulceration.

Erectile dysfunction: Alprostadil (PGE1) can be injected directly

into the corpus cavernosum or administered as a transurethral suppository to cause vasodilation and enhance tumescence.

injected directly into the corpus cavernosum

transurethral suppository

Adverse effects of eicosanoids

local pain and irritation bronchospasm gastrointestinal disturbances:

nausea, vomiting, cramping, and diarrhea.