Class autocoids 3 prostaglandins

THIS CLASS IS IN BRIEF FOR UNDERGRADUATE MEDICINE STUDENTS FOR UNDERSTANDING AND EXAMINATION

1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR, DEPT. OF PHARMACOLOGY
SSIMS & RC.
1

2. Prostaglandins and related compounds are collectively known
as eicosanoids. Eicosanoids are important regulatory
molecules
Mostare produced fromarachidonicacid, a20-carbon
polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid).
The eicosanoids are considered "local hormones."
They have specific effects on target cells close to their site
of formation.Theyare rapidly degraded, so they are not
transported to distal sites within the body.
Thereis evidence for involvement of eicosanoids in
intracellular signal cascades.

3. Twoclasses: Prostaglandins/thromboxanes, and
Leukotrienes
Prostaglandins–mediatepainsensitivity,
inflammation and swelling
Thromboxanes–involved in blood clotting,
constriction of arteries
Leukotrienes–attract white cells, involved
inflammatory diseases (asthma, arthritis, etc..)

5. Examples of eicosanoids:
prostaglandins,prostacyclins
thromboxanes, leukotrienes
epoxyeicosatrienoicacids.
They have roles in:
inflammation, fever
regulation of bloodpressure, bloodclotting
immune system modulation
control of reproductive processes & tissue growth
regulation of sleep/wake cycle.

6. Prostaglandins& related compounds are transported
out of the cells that synthesize them.
Most affect other cells by interacting with plasma
membrane G-protein coupled receptors.
Depending on the cell type, the activated G-
protein may stimulate or inhibit formation ofcAMP, or
may activate a phosphatidylinositol signal pathway
leading to intracellularCa
++
release.
Another prostaglandin receptor, designatedPPARg, is
related to a family of nuclear receptors with
transcription factor activity.

7. Prostaglandin H
2Synthaseproduction
of PGs, PGI
2& TXA
2
PGendoperoxides(PGG
2& PGH
2) are
more potent & long-acting than the
PGs to which they decompose
TXA
2formed mainly in platelets by TX
synthase mediating vasoconstriction &
platelet aggregation
PGI
2, formed mainly in endothelium
by PGI synthase opposes TXA
2
COOH
COOH
O
O
OH
COOH
O
O
OOH
2O
2
2e

arachidonic acid
PGG2
PGH2
Cyclooxygenase
Peroxidase

9. PGI
2/D
2/E
2→dilaon of arterioles, pre-capillary sphincters & post-
capillary veins → increased blood flow & cardiac output
TXA
2is a potent vasoconstrictor
TXA
2&PGI
2are potent platelet aggregation inducer & inhibitor
respectivelyVasoconstriction, Platelet aggregation, lymphocyte
proliferation, bronchoconstriction
PGI
2de-aggregate platelets clumps & reduces myocardial infarct size &
ischemic organ damage
PGI
2, PGE
2, & NOare simultaneously released from endothelium
PGE
2inhibits B-& T-lymphocyte activation & proliferation, inhibiting
antibodies &lymphokinesproduction

10. Smooth muscle:
Bronchial muscle relaxation by PGE
2& PGI
2, but
constriction by TXA
2, LTC
4& LTD
4
Human pregnant uterus is contracted by PGE
1/2, and PGF
2α
GIT:PGE
s& PGI
2inhibit gastric acid secretion & reduce
pepsin content
They increase bicarbonate, mucus & blood flow
Increased electrolyte/water movement into intestinal
lumen (diarrhea)
TXA
2is pro-ulcerogenic

12. Platelet Aggregation &
Thrombosis
PGI2:(InhibitAggregation)
Releasedbyendothelialcells
Responsiblefornon-adherence
ofplateletstohealthyblood
vessels
PGE2&TXA2:(PromoteClotting
Process)
Producedbyplatelets,accounts
forspontaneousaggregationof
plateletstothrombin,collagenat
thesiteofinjury

13. Renal System
PGs enhance urine
formation,natriuresis,
&kaliuresisvia action
on renal blood flow &
tubules
PGD
2, PGE
2, PGI
2
stimulate renin release
PGs inhibit water re-
absorption under ADH
effect

14. Nervous system
Hyperthermiaby PGE
2, relatedpyrogen-inducedfever
Antipyretic action of ASA & NSAIDs is via inhibition of
COX-1,-2&-3
Algesiainduction & pain sensitization to histamine, BK
or mechanical stimuli
Analgesic action of ASA & NSAIDs is via inhibition of
COXs

15. Eicosan
oid
Major Site(s) of
Synthesis
Major Biological Activities
PGD
2mast cells
inhibits platelet and leukocyte aggregation,
decreases T-cell proliferation and lymphocyte
migration and secretion of IL-1Α and
IL-2; inducesvasodilationand production of
cAMP
PGE
2
kidney, spleen,
heart
increasesvasodilationandcAMPproduction,
enhancement of the effects ofbradykinin
and histamine, induction of uterine
contractions and of platelet aggregation;
decreases T-cell proliferation and lymphocyte
migration and secretion of IL-1Α and
IL-2
PGF2α
kidney, spleen,
heart
increases vasoconstriction,
bronchoconstrictionand smooth muscle
contraction
.

16. PGI2, PGE2, PGD2
↑ Vasodilaon,cAMP
↓ Platelet and leukocyte aggregaon, IL1and IL2, T-
cell proliferation, lymphocyte migration
PGF2a
↑ Vasoconstricon, Bronchoconstricon, smooth
muscle contraction
TXA2
↑ Vasoconstricon, Platelet aggregaon, lymphocyte
proliferation, bronchoconstriction

17. Eicosa
noid
Major Site(s) of
Synthesis
Major Biological Activities
PGH
2many sites
a short-lived precursor tothromboxanesA
2
and B
2, induction of platelet aggregation
and vasoconstriction
PGI
2
heart, vascular
endothelial cells
inhibits platelet and leukocyte aggregation,
decreases T-cell proliferation and
lymphocyte migration and secretion of IL-
1Α and IL-2; inducesvasodilation
and production ofcAMP
.

18. Uterine Stimulation
Carboprost(15-methyl PGF
2α)
Used by IM route for induction of abortion between
12
th-
20
th
gestational weeks
Used at a dose of250μg every1-3hrs
Dinoprost(PGF
2α)
Injection form for intra-amniotic administration
Used to inducelabouror abortion

19. Misoprostol is a synthetic methyl ester analogue of PGE
1
Used to prevent drug-induced gastric ulceration during
NSAIDs, corticosteroid or anticoagulant therapy
It can be used alone or in combination with antacids for
duodenal ulcer treatment
Not used for pregnant women or whom are planning
pregnancy

20. Epoprostenol(PGI
2):
It is used as a heparin replacement in some
hemodialysis patients
Used to prevent platelet aggregation inextracorporal
circulation systems
Impotence
Alprostadil(PGE
1)was used by injectioninto corpora
cavernosato maintain erection
Replaced by PDE-V inhibitors

21. Eicosanoid
Major Site(s) of
Synthesis
Major Biological Activities
TXA
2 platelets
induces platelet aggregation,
vasoconstriction, lymphocyte proliferation
andbronchoconstriction
TXB
2 platelets induces vasoconstriction

22. LTB4
↑ Vascular permeability, T-cell proliferation,
leukocyte aggregation, IL-1, IL-2, IFN-g
LTC4and LTD4
↑ Bronchoconstricon, Vascular permeability, IFN-g

23. LTs have no therapeutic uses, but LTs antagonists have
Anti-asthma medications:
5-Lipoxygenase Inhibitors, e.g.,zileutin
Leukotriene-receptor antagonists;
montelukast, &zafirlukast