Eicosanoids- Chemistry and function

Eicosanoids- Chemistry and
Functions
Professor (Dr.) Namrata Chhabra
29-Apr-18 Namrata Chhabra 1

Eicosanoids
• Prostaglandins and related compounds are collectively known as
Eicosanoids.
• Most are produced from Arachidonic acid, a 20-carbon
polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid).

Eicosanoids- Classification
Eicosanoids
Prostanoids
Prostaglandins Prostacyclins Thromboxanes
Leukotrienes Lipoxins

Characteristic structural features of prostaglandins
1) A trans double bond is present between 13th and 14th carbon atom
2) An alpha oriented -OH group is present at 15th position
3) Differences in the main groups are due to difference in structure of
cyclopentane ring.

Prostaglandins(PGs)
Prostaglandins
(PGs)
PG- F PG- A PG- B PG-C and DPG-E
PG- G and H

Series of prostaglandins
• There are 3 series of prostaglandins:
• Series-1 contain one double bond at 13-14 position (Trans)
• Series-2 have two double bonds at 13-14 (trans) and 5-6 (Cis)
• Series-3 – have three double bonds at 13-14 (trans) , 5-6 (Cis) and
17-18 (Cis) positions.

Series of prostaglandins

Types of Prostaglandins
• PG-E: PGE1,PGE2 and PGE3
• PG-F: PGF1α,PGF2αand PGF3α
• PG-A: PGA1,PGA2 and PGA3
• PG-B: PGB1,PGB2 ,19-OH-PGB1and 19-OH-PGEB2

Synthesis of Eicosanoids

Sources of Arachidonic acid

Release of Arachidonic acid
Release of
Arachidonic
acid
Activation of
phospholipase
A2
Binding of
ligand to cell
surface

Steps of synthesis of Prostanoids
• Pathway is also called Cyclo-
oxygenase pathway or cyclic
pathway.
• The type of prostanoid
produced is determined by
which downstream enzyme is
present
• Usually one downstream
enzyme predominates in a
given cell.

PGH synthase Isoforms
• Each PGHS isoform catalyzes two separate
reactions.
1) The first reaction (Arachidonate to PGG2)
involves insertion of two molecules of oxygen
and Cyclization of the fatty acid backbone.
• This step is catalyzed by the cyclo-oxygenase
activity of PGHS-1 or -2; it is these cyclo-
oxygenase activities (also called COX-1 and
COX-2) that are inhibited by nonsteroidal anti-
inflammatory drugs (NSAIDs).

PGH synthase Isoforms
2) The second step (PGG2 to PGH2)
involves the reduction of the hydro
peroxide on C15 to an alcohol and is
catalyzed by the peroxidase activity of
PGHS-1 or -2.

Significance of PGH synthase isoforms
There are two isoforms- PGH Synthase 1 and 2
PGH Synthase 1 – Basal form(constitutive)
Many cells, including platelets and gastric mucosal cells, have moderate levels of
the “basal” isoform, PGHS-1.
Functions attributed to PGHS-1 include:
• Regulating hemostasis and vascular tone,
• Renal function, and Maintaining gastric mucosal integrity.

Significance of PGH synthase isoforms
• PGH Synthase 2- Inducible form
Present in a smaller number of cells, such as macrophages, vascular
endothelial cells, and fibroblasts.
• Participate in cell proliferation, inflammation, carcinogenesis, and
parturition.
PGHS-2 are induced in response to cytokines or mitogens.

Catabolism of Prostaglandins
• All Arachidonic acid derivatives are quickly
inactivated in the body by :
• Self-catalyzed destruction of
cyclooxygenase ("suicide enzyme”).
• 15-hydroxyprostaglandin dehydrogenase.
The OH group present at 15th position is
changed to a keto group.

Characteristic features of prostaglandins
1) Act as local hormones.
2)Show the effects near the site of
synthesis(autocrine and Paracrine
effects)
3) Are not stored in the body
4) Have a very short life span and are
destroyed within seconds or few
minutes.

Characteristic features of prostaglandins (contd.)
5) Production increases or
decreases in response to diverse
stimuli or drugs.
6) Are very potent in action. Even in
minute (nanogram concentration),
biological effects are observed.
PGs
Local
hormones
Not stored
Short
lifespan
Stimulus
based
production
Potent
Required
in small
amounts

Physiological roles of Prostaglandins
1) Inflammation
i) Fever- PGs induce fever by stimulating the
thermoregulatory center in the brain.
ii) Pain- PGs sensitize pain receptors to
stimulation, as a result increase pain
perception.
iii) Swelling-There is vasodilatation and
increased capillary permeability induced by
PGS which is responsible for swelling of the
inflamed tissue.
iv Erythema, wheal and Flare is also induced
by PGs like PGE and PGD2.
v) PGD2 is considered an important
mediator of anaphylaxis

Effect on smooth muscle
Intestinal Bronchial Vascular Uterine
PGE and PGF produce
contraction of the
longitudinal smooth
muscles producing
diarrhea, cramps and
reflux of bile.
Clinical significance-
Diarrhea and abdominal
cramps are the
commonly observed as
side effects of PGs.
PGFs contract and
PGEs relax bronchial
smooth muscles.
PGE1 and PGE2 are
therapeutically used as
bronchodilators.
PGEs cause vasodilatation.
PGF2 α , and PG A2 cause
vasoconstriction.
Systemic blood pressure
falls in response to PGEs and
PGAs
PGE1, PGE2 and PGF2α
cause uterine contractions.
• PGE2 is used for the
induction of labor at or
near term.
• In higher dosage PGEs
are used as
abortifacients in first
and second trimester of
pregnancy.
• They are also
responsible for causing
dysmenorrhea.

Effect on platelets
• PGE1 cause inhibition of platelet
aggregation.
• Clinical significance- PGE1 has
been used for harvesting and
storage of blood platelets for
therapeutic transfusion.

Effect on Kidney
• PGEs cause:
• ↑ in renal plasma flow,
• ↑GFR,
• ↑diuresis,
• Natriuresis, and
• kaliuresis is also induced by the
action of PGE2

Effect on Gastrointestinal secretions
• PGE1and E2 inhibit gastric secretions and
are required for maintaining the integrity of
gastric mucosa.
• The effect is opposite on the pancreatic and
intestinal secretions. There is increase in the
volume, enzyme and electrolyte content of
the pancreatic and intestinal secretions in
response to PGE1.
• Watery diarrhea results in response to
administration of PGE1.

Effect on Endocrine glands
• PGEs have insulin like effects, They inhibit lipolysis and the effects on
carbohydrate metabolism are same as insulin
• PTH(Parathormone) like effects are also seen on bone metabolism by
PGs. They mobilize calcium from bones producing hypercalcemia.
• Thyrotropin like effects-are seen on thyroid gland.
• Steroidogenic effects are seen on the adrenal tissue.es

Immunological Response
• PGEs secreted by macrophages :
• modulate or decrease the
functions of
• T and B lymphocytes .

Clinical role of PGs
Tissue growth
Inflammation
And fever
Regulation of
sleep wake
cycles
Regulation of
blood
pressure
Blood clotting
Immune
system
modulation
Reproductive
processes

Prostacyclins and Thromboxanes
1)Prostacyclins(PGI) contain another
ring between 6 th and 9th carbon
atoms.
2) Thromboxanes (TX) have a six
membered Oxane ring.
There are three series for
Thromboxanes as well as for
Prostacyclins.

Functions of Prostacyclins
• Synthesized in heart and vascular endothelial cells.
• Inhibit platelet and leukocyte aggregation
• Decrease T-cell proliferation ,lymphocyte migration and secretion of
IL-1α and IL-2
• Induce vasodilatation and production of cAMP
• Prevent clot formation.

Functions of Thromboxanes
• Synthesized by platelets,
• Induce platelet aggregation,
• Promote vasoconstriction,
• Lymphocyte proliferation
• Bronchoconstriction and
• Promote clot formation

Inhibitors of Prostanoids synthesis
1) Corticosteroids act as
anti-inflammatory agents
because they inhibit
Phospholipase A2 expression,
reducing arachidonate
release.

2)Non-steroidal anti-inflammatory drugs
(NSAIDs), such as aspirin and derivatives
of ibuprofen inhibit :
• Cyclooxygenase activity of PGH Synthase.
• Formation of prostaglandins involved in
fever, pain, & inflammation.
• Blood clotting by blocking thromboxane
formation in platelets.
• Most NSAIDs inhibit both COX I & COX II.

3)Selective COX-2 inhibitors -
Celecoxib and Rofecoxib.
• coxibs very useful for anti-
inflammatory and antiproliferative
therapy with reduced
gastrointestinal side effects,
• it also makes them ineffective as
antiplatelet agents and
consequently can increase
cardiovascular risks.

Leukotrienes
• Identified as LTs.
• A family of conjugated trienes formed in
leukocytes, platelets, and macrophages
by the lipoxygenase pathway in
response to both immunologic and
nonimmunologic stimuli.

Lipoxins
• Lipoxins are a family of
conjugated tetraenes also arising
in leukocytes.
• They are formed by the combined
action of more than one
lipoxygenase.

Steps of synthesis of Leukotrienes

Steps of Synthesis of Lipoxins

Functions of Leukotrienes
• Leukotrienes have roles in inflammation.
• They are also implicated in asthmatic constriction of the bronchioles.
• The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of
slow-reacting substance of anaphylaxis (SRSA).
(The subscript 4 in each molecule refers to the number of carbon-
carbon double bonds presen.

Slow-reacting substance of anaphylaxis (SRS-A)
• Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of
leukotrienes C4, D4, and E4.
• This mixture is a potent constrictor of the bronchial airway
musculature.
• These leukotrienes together with leukotriene B4 also cause vascular
permeability,
• Chemotaxis and activation of leukocytes and
• are important regulators in many diseases involving inflammatory or
immediate hypersensitivity reactions, such as asthma.

Reason for Aspirin induced Asthma
• Aspirin inhibits the COX pathway and diverts arachidonic acid
metabolites to the LO pathway.
• This also leads to a decrease in the levels of PGE2, the anti-
inflammatory PG.
• LTC4 synthase overexpression further increases the number of
cysteinyl LTs, tilting the balance toward inflammation and broncho
constriction

Reason for Aspirin induced Asthma

Pharmacological applications of Eicosanoids
1)Cardiovascular uses:
• Pulmonary arterial hypertension,
• Peripheral vascular disease
• Patency of ductus arteriosus until surgery in neonates with cardiac
malformations and
• Platelet anti-aggregating agents.

2) Digestive Uses- indicated in the treatment of :
• Gastro duodenal ulcer and
• Prevention of NSAID-induced ulcers.

3) Gynecological and obstetrical uses –
• Induce cervical dilatation
• Induce uterine contractions, particularly in late pregnancy.
• Used for medical termination of pregnancy and induction of labor.

6) Ulcerative Colitis
Mesalamine also called mesalazine or 5 aminosalicyclic acid has anti
inflammatory properties in the colon and is used in the treatment of
ulcerative colitis (Crohn's disease). In addition to cyclo-oxygenases, it
also inhibits lipoxygenases.
7)Bronchial Asthma- PGE2 agonists and leukotrienes receptor
antagonists are used for the treatment of bronchial asthma.

Summary

Thank you

Eicosanoids- Chemistry and function

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