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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.
2.
3.
4.

the prostaglandins
thromboxanes
leukotrienes
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 0.55


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-PGF1.

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 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.

transurethral suppository

injected directly into


the corpus cavernosum

Adverse effects of eicosanoids


local pain and irritation
bronchospasm
gastrointestinal disturbances:

nausea, vomiting, cramping, and


diarrhea.