THE EICOSANOIDS:

PROSTAGLANDINS,
THROMBOXANES,
LEUKOTRIENES, &
RELATED COMPOUNDS
Assistant Professor
Dr. Hayder B Sahib

November 30, 2020 1

 PROSTAGLANDINS
• The NSAIDs act by inhibiting the synthesis of
prostaglandins. Thus, an understanding of NSAIDs
requires comprehension of the actions and
biosynthesis of prostaglandins—

• unsaturated fatty acid derivatives containing 20

carbons that include a cyclic ring structure.

• [Note: These compounds are sometimes referred

to as eicosanoids; “eicosa” refers to the 20 carbon
atoms.]
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 A. Role of prostaglandins as local
mediators
• Prostaglandins and related compounds are produced in
minute quantities by nearly all tissues.

• They generally act locally on the tissues, and they are

rapidly metabolized to inactive products at their sites
of action.

• Therefore, the prostaglandins do not circulate in the

blood in significant concentrations.

• Thromboxanes and leukotrienes are related lipids that

are synthesized from the same precursors as the
prostaglandins.
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 B. Synthesis of prostaglandins
• Arachidonic acid is the primary precursor of the
prostaglandins and related compounds.
• Arachidonic acid is present as a component of
the phospholipids of cell membranes.
• Tissue phospholipids---PLA2---→arachidonic acid
• There are two major pathways in the synthesis
of the eicosanoids from arachidonic acid,
1)the cyclooxygenase
2)the lipoxygenase pathways.

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1. Cyclooxygenase pathway:
All eicosanoids are synthesized via the cyclooxygenase
pathway. Two related isoforms of the
cyclooxygenase enzymes have been described.

• Cyclooxygenase-1 (COX-1) is responsible for the

physiologic production of prostanoids, whereas
cyclooxygenase-2 (COX-2) causes the elevated
production of prostanoids that occurs in sites of
chronic disease and inflammation.

• COX-1 is a constitutive enzyme that regulates normal

cellular processes, such as gastric cytoprotection,
vascular homeostasis, platelet aggregation, and
reproductive and kidney functions.
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• COX-2 is constitutively expressed in tissues
such as the brain, kidney, and bone.

• Its expression at other sites is increased

during states of chronic inflammation.
• Differences in binding site shape have
permitted the development of selective COX-2
inhibitors.
• COX-2 expression is induced by inflammatory
mediators like TNF-α and IL-1 but can also be
pharmacologically inhibited by glucocorticoids.

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 2. Lipoxygenase pathway:
• several lipoxygenases can act on arachidonic
acid to form leukotrienes
• Antileukotriene drugs, such as zileuton,
zafirlukast, and montelukast, are treatment
options for asthma.

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C. Actions of prostaglandins
Vascular
•TXA2 and PGF2 are a potent vasoconstrictor.

•Vasodilator prostaglandins, especially PGI2

and PGE2, promote vasodilation by increasing
cAMP and decreasing smooth muscle
intracellular calcium.

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Gastrointestinal Tract
• Most of the prostaglandins and thromboxanes
activate gastrointestinal smooth muscle.

• Longitudinal muscle is contracted by PGE2 and

PGF2
• circular muscle is contracted strongly by PGF2
and weakly by PGI2, and relaxed by PGE2 .

• Administration of either PGE2 or PGF2 results in

colicky cramps .
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Airways
Respiratory smooth muscle is relaxed by PGE2
and PGI2 and contracted by PGD2, TXA2, and
PGF2.
The leukotrienes are bronchoconstrictors.
 PLATELETS
Both PGD2 and PGI2 inhibit aggregation.
TXA2 is the major product of platelet COX-1, is a
platelet aggregator, and amplifies the effects of
other more potent platelet agonists such as
thrombin.
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D. Therapeutic uses of prostaglandins
1. Prostaglandins have a major role in
modulating pain, inflammation, and fever.
2. They also control many physiological
functions, such as acid secretion and mucus
production in the gastrointestinal (GI) tract,
uterine contractions, and renal blood flow.
3. Prostaglandins are also among the chemical
mediators that are released in allergic and
inflammatory processes.

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 Alprostadil
• Alprostadil is a PGE1 that is naturally produced in
tissues such as
• 1- seminal vesicles
• 2- cavernous tissues
• 3- the placenta
• 4- the ductus arteriosus of the fetus.
• Therapeutically, alprostadil can be used to treat
erectile dysfunction , to keep the ductus arteriosus
open in neonates with congenital heart conditions
until surgery is possible.

• PGE1 maintains the patency of the ductus arteriosus

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 Lubiprostone
• Lubiprostone is a PGE1 derivative indicated
for the treatment of chronic idiopathic
constipation, opioid-induced constipation,
and irritable bowel syndrome with
constipation.
• It stimulates chloride channels in the luminal
cells of the intestinal epithelium, thereby
increasing intestinal fluid secretion.
• Nausea and diarrhea are the most common
side effects of lubiprostone
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 Misoprostol
• Misoprostol, a PGE1 analog, is used to protect
the mucosal lining of the stomach during chronic
NSAID treatment.
• Misoprostol interacts with prostaglandin
receptors on parietal cells within the stomach,
reducing gastric acid secretion. Furthermore,
misoprostol has a GI cytoprotective effect by
stimulating mucus and bicarbonate production.
• Misoprostol is also used off-label in obstetric
settings for labor induction, since it increases
uterine contractions by interacting with
prostaglandin receptors in the uterus.
Misoprostol has the potential risk to induce
abortion in pregnant women.
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Prostaglandin F2α analogs
• Bimatoprost, latanoprost , tafluprost , and travoprost
are PGF2α analogs
• indicated for the treatment of open-angle glaucoma.
By binding to prostaglandin receptors, they increase
uveoscleral outflow, reducing intraocular pressure.
They are administered as ophthalmic solutions once a
day and are as effective as timolol or better in
reducing intraocular pressure.
• Bimatoprost increases eyelash distinction, length, and
darkness and is approved for the treatment of
eyelash hypotrichosis. Ocular reactions include
blurred vision, iris color change, ocular irritation, and
foreign body sensation.

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Prostacyclin (PGI2) analogs
• Epoprostenol, the pharmaceutical form of
naturally occurring prostacyclin, and the
synthetic analogs of prostacyclin iloprost and
treprostinil are potent pulmonary
vasodilators that are used for the treatment
of pulmonary arterial hypertension.
• Dizziness, headache, flushing, and fainting
are the most common adverse effects.
• Bronchospasm and cough can also occur
after inhalation of iloprost.
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Female Reproductive Organs
• Uterine muscle is contracted by PGF2α,
TXA2, and low concentrations of PGE2; PGI2
and high concentrations of PGE2 cause
relaxation.
Male Reproductive Organs
• Smooth muscle–relaxing prostaglandins such
as PGE1 enhance penile erection by relaxing
the smooth muscle of the corpora cavernosa.

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