Prostaglandins

D r J o y c e M w a to n o k a
MMED PCH
 Introduction

Eicosanoids are metabolites of arachidonic acid or

other unsaturated fatty acids derived from the action
of the cyclooxygenase or lypoxygenase enzymatic
pathway
Cyclooxygenase – prostanoids
Lypoxygenase - leukotrienes
Eicosanoids are classified into 2 main groups;
 Cont…

1. Leukotrienes and lipoxins

2. Prostanoids
a) Prostaglandins (PGs)
b) Prostacyclins (PGI2)
c) Thromboxanes (TXs)
 Cont…

The key precursor fatty acid is arachidonic acid,

which is an essential fatty acid as it cannot be
synthesized de novo in animals
The primary precursor is obtained from the diet in
the form of linoleic acid (polyunsaturated omega-6
fatty acid). It typically occurs in nature as a
triglyceride ester
 Prostaglandins

PGs are extremely potent, biologically active lipid

mediators that are synthesized throughout the body
PGs have diverse hormone-like effects in animals
They are derived enzymatically from the fatty acid
arachidonic acid
 Biosynthesis of PGs

Involves the action of multiple enzymes, some of

which are rate limiting
1. The first step is production of free arachidonic acid
from membrane phospholipids upon stimulation of
the enzyme phospholipase A2
2. The COX pathway, accomplished by catalytic
activity of two distinct cyclooxygenase (COX-1
and COX-2) isozymes encoded by separate genes
-produces PGG2 and then PGH2
 Cont…

3. PGH2 is then converted into

-PGI2 by prostacyclin synthase
-TXA2 by thromboxane synthase, and
-PGE2, PGD2 and PGF2α by their respective synthase
enzymes
PGs are produced in the endoplasmic reticulum, exit
the cell and signal through G protein-linked
receptors at the cell surface
 Differences between COX-1 and COX-2

COX-1 COX-2

Constitutive  Inducible
Present in most tissues  Induced mainly at sites of
Synthesizes PGs that inflammation by cytokines
regulate physiologic  Synthesizes PGs that
processes mediate inflammation,
Especially important in pain, and fever
-gastric mucosa  Constitutive expression
-kidneys primarily in
-platelets -brain
-vascular endothelium -kidneys
 Cont…

Both COX iso-enzymes are inhibited by NSAIDs,

such as acetylsalicylic acid and ibuprofen
This prevents synthesis of endogenous PGs
Because of differences in the structures of the
binding sites, COX-1 is completely inhibited by
aspirin, whereas COX-2 is only partially inhibited
Synthesis of COX-2 is inhibited by steroidal anti-
inflammatory drugs at the level of transcription
 PG Receptors

PGs function close to the site of synthesis and are

deactivated to inactive metabolites before moving
into the circulation
They act locally in very low concentrations to
produce profound physiological changes through
receptor-mediated G-protein linked signaling
pathways
The immediate effect of the appearance of PGs is a
change in the rate of production of second
messengers such as cAMP or Ca2+ and a change in
the activation of a specific protein kinase
 Biological Functions of PGs

Maintenance of IOP (Intraocular Pressure)

Vasodilation/vasoconstriction
Cause aggregation or disaggregation of platelets
Regulate inflammation
Induce labor
Acts on parietal cells in the stomach wall to inhibit
acid secretion
Increase glomerular filtration rate
Sensitize spinal neurons to pain
 Inhibitors of PGs

NSAIDs (inhibit cyclooxygenase)

Corticosteroids (inhibit phospholipase
A2 production); used in allergic reaction and to
relive inflammation
COX-2 selective inhibitors or coxibs eg; Celecoxib,
used to treat arthritis pain and RA
 Clinical use of synthetic PG analogs

To induce labour or abortion

PGE1 analogue - misoprostol
PGE2 analogue - dinoprostol
PGF2 analogue – dinoprost
To prevent closure of patent ductus arteriosus in
newborns with particular CHD (PGE1)
As a vasodilator in severe Raynaud's
phenomenon or ischemia of a limb
 Cont…

In treatment of IOP and glaucoma, PGF2α analogs eg;

travoprost, latanoprost and bimatoprost
In pulmonary hypertension
To prevent and treat peptic ulcers (PGE)
To treat erectile dysfunction or in penile
rehabilitation following surgery (PGE1
as alprostadil)
 How PGs are different from true
hormones
Are formed in almost all tissues rather than in
specialized glands
Act locally rather than to distance sites
Act on their parent cells
Are not transported via blood
Are synthesized as per needed
Are not stored