By Dr. Vishal Pawar, MD pharmacology considering the complex nature of this topic, i am hereby providing a comprehensive review of prostaglandins and its various effects in the body, which after a through go through should be enough for simplifying the understanding of prostaglandins

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2. BY
DR. VISHAL PAWAR
JR II
DEPT. OF PHARMACOLOGY
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3.  Substrate is supplied by Membrane lipids
 Forming Eicosanoids and Platelet activating factor
 Essential fatty acid – Arachidonic Acid (AA)
 Eicosanoids
Prostaglandins (PGs)
Thromboxane (TxA 2)
Leukotrienes (LTs)
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4.  Contribute to
Inflammation
Smooth muscle tone
Hemostasis
Thrombosis
Parturition
GIT secretion
4

5.  “ eikosi “ means twenty (precursor FA has 20 carbon atoms)
 Biosynthesis
 Limited by availability of substrate
 Depends primarily on release of AA
 AA  5,8,11,14 – Eicosatetetraenoic acid
 Precursor Fatty Acid
5

6.  Esterified by acyl hydrolases
 Most notably by Phospholipase A 2 (PLA 2)
 Phospholipase are the enzymes responsible for releasing the
substrate from the cell membrane
 PLA 2 cleaves the ester bond of Membrane Phospholipids
releasing Arachidonate
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7. PLA 2 types AA Liberated
Calcium independent ( i PLA) Reincorporated
Cytosolic ( c PLA 2) Acute release
Secretory (s PLA 2) Sustained release
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8. AA
PG G2
PG H2
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PGF2α
PGE2
TxA2 PGI2
COX 1-2
COX 1-2
TP IP
EP 1,2,3,4 DP 1,2
FP
PGD2

9. Products of PG synthases (Cyclo-oxygenase  COX)
 Prostanoids  PG, PGI 2, TxA 2
 PG of E, D series  Hydroxy ketones
 PG of F series  1, 3 diols
 Single ring structure
 Double ring structure  PGI 2 (Prostacyclin)
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10. COX 1 :
 Expressed constitutively in most cells
 Considered dominant
 Not exclusive
 Source for normal functions for prostanoid formation
COX 2 :
 Up regulated by  Cytokines
Shear Stress
Growth factors
 Principal source of prostanoid formation in inflammation
and cancer
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11.  PG released from cell via PG transporter
 Cyclic endoperoxidases  PG G2 and PG H2
 Prostanoids are synthesized form PG H2 by their respective
synthase enzymes
 Eg. PGE 2 by PGE 2 synthase
 Which then act on their respective receptors
 Eg. PGE 2 on EP 1,2,3,4 receptors
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12.  Inhibition of PLA 2  in release of precursor FA
 Which in turn  in synthesis of all metabolites
 PLA 2 activated  Calcium and Calmodulin
 Inhibited by drugs by decreasing availability of calcium
 Glucocorticoids down regulate COX 2 expression
 Aspirin and other traditional NSAIDS (tNSAIDS) inhibit both
COX 1 and COX 2
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13. Selective COX 2 inhibitors
 Recent studies show CVS hazards (Myocardial Ischaemia,
Stroke, Pulmonary Hypertension, Congestive Hear Failure)
 Due to suppression of cardio protective PG derived from
COX 2 especially PGI 2
 Microsomal PGE synthatase 1 (mPGE S-1) has emerged as
target to decrease these CVS complications
 It converts PG H2  PG E2
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14. Catabolism
 Relative rapid initial step
 Oxidation of metabolites
 It’s similar for all prostanoids
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15. PGE 1 Misoprostol
Alprostadil
PGI 2 Epoprostenol
PGF 2α Latanoprost
Carboprost
PGE 2 Dinoprostone
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16.  Function: activation of specific cell surface receptors coupled to
intracellular 2nd messengers
PG receptors
 PG activate them locally near site of formation
 Receptors interact with Gs, Gi, Gq to modulate activities of
adenylyl cyclase and Phospholipase C
 Single gene products have been identified for receptors of PG1 2
(IP), PGF 2α (FP), TxA 2 (TP)
 4 PGE 2 receptors (EP 1,2,3,4) and 2 PGD 2 receptors (DP1,2) have
been cloned
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17. Prostanoid degradation
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Active Process Inactive
PGI 2 β Oxidation 2,3 keto PGF 2α
TxA2 β Oxidation TxB2
PGD 2 PG Dehydrogenase β Oxidation PGD-Metabolite (M)
PGE 2 PG Dehydrogenase β Oxidation PGE-M
PGF 2α PG Dehydrogenase β Oxidation PGF-M

18. Cell signalling pathway and expression
 3 sub clusters of PG receptors
Increase Increase Inhibit
cellular AMP Ca++ Adenylyl cyclase
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Relaxant (Gs) Contractile Both
EP 2, 4 EP 1 EP 3 (Gi)
IP FP
DP 1 TP

19.  IP + Gs  increases adenylyl cyclase
 Expressed in
19
Kidney
Lung
Spine
Liver
Vasculature
Heart

20.  FP + Gq-PLC-IP3  mobilise Ca++, activate Rho Kinase
 Expressed in
20
Kidney
Lung
Stomach
Eye
Heart
Corpus Luteum  Most Abundantly

21. Platelets
 Aggregation : activated by membrane Phospholipases
with release of AA  Eicosanoid biosynthesis
 Major Eicosanoid formed  TxA2
 Total biosynthesis – determined by its urinary excretion
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22.  PGI 2 inhibits platelet aggregation
 It dis aggregated preformed clumps
 Limits TxA2 activated aggregation
 CVS events following selective COX 2 inhibitors has been
attributed to PGI 2 inhibition
 Low PGI 2 conc. via EP 3 receptors potentiates aggregation
22

23. Vascular tone
 PG half life – short
 Hence they locally modulate vascular tone
 PGI 2 – major metabolite released from vascular
endothelium
 Derived primarily from COX 2
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24.  Regulated by shear stress, vaso constrictor-dialator autocoids
 COX 2 derived PGI 2 via EP 4 receptors maintains the ductus
arteriosus patent until birth
 After which there’s increase in its metabolism  decrease in its
level
 Leads to closure of ductus arteriosus after birth
 Therefore tNSAIDS are used to induce closure of patent ductus
arteriosus in neonates
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25. Inflammatory vascular disease
 Studies in mice implicate prostanoids in development of
atherosclerosis, abdominal aortic aneurism
 Its been seen that Inhibition of TxA2  retards atherogenesis
 Deletion of FP receptor  decrease in blood pressure,
retardation of atherogenesis
Reproduction and Parturition
 PGF 2α  leucocytosis, consistent in delayed parturition in
mice deficient in COX and along with TxA 2  important in
final stages of parturition 25

26. Lung
 PGE 2  Bronchodialator
 PGF 2α, TxA 2, PGD 2  Bronchoconstrictor
 Inhaled iloprost (PGI 2 analog)  decreases cardinal features
of asthma in mice via inhibition of airway dendritic function
 Polymorphisms in genes for PGD 2 synthase and TP
receptor  associated with asthma
 DP 1,2  associated with allergic responses
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27. Kidney
 Long term use of all COX inhibitors is limited by
development of Hypertension, Edema, CHF
 PGE 2, PGI 2  play a critical role in maintaining renal
blood flow (RBF) and salt excretion
 Their synthesis is increased in response to factors which
decrease RBF
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28. Inflammation and Immune response
 Host of stimuli which elicit inflammation and immune
response lead to increased PG synthesis
 PGs play a significant role in this response
 Prostanoids promote acute inflammation
 Exception - PGE 2  inhibits mast cell activation, thereby
inhibiting inflammation
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29. Heart
 PGI 2, PGE 2 via IP / EP 3 receptors protect against oxidative
injury in cardiac tissue
 IP deletion  augments Myocardia ischaemia / reperfusion
injury
 mPGE S-1 and EP 4 deletion  increases in decline of
cardiac function
 TxA 2 contributes to oxidative stress
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30. Cancer
 Pharmacological inhibition or deletion of COX 2  restrains
tumor formation in models of colon, breast, lung
 Use of NSAID is associated with decreased risk for
development of these cancers
 PGE 2  primary oncogenic prostanoid (also TxA 2)
 Familial polyposis patients show decrease in polyps on
treatment with COX inhibitors
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31. Cardiovascular system
 Prostanoids do not circulate  hence do not directly impact
systemic vascular tone
 They modulate local vascular tone at site of formation
 Affect systemic blood pressure (BP) through renal actions
including changes to efferent arterioles
 PGE 2, PGI 2, PGD 2  elicit vasodilation and drop in BP
31

32.  PGE 2  vasoconstriction through EP 1, 3
 PGD 2  flushing, nasal stiffness, hypotension
 local subcutaneous release contributes to vasodilation
of skin
 PGI 2  relaxes vascular smooth muscle, causing hypotension
and reflex tachycardia in I.V administration
 TxA 2  potent vasoconstrictor and contracts smooth muscles
 Cardiac output increases on PGE, F infusion
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33. Platelets
 Low conc. PGE 2 via EP 3 increases platelet aggregation
 High conc. PGE 2 via IP/Gs – EP 2,4 decreases platelet
aggregation
 PGI 2, PGD 2 inhibit platelet aggregation
 Mature platelets express only COX 1
 Megakaryocytes, immature platelet turnover express COX 2
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34.  TxA 2 major product of COX 1 in platelets
 It induces platelet shape change and aggregation
 It amplifies signal for other more potent platelet agonists
eg. Thrombin
 Its actions are restrained by its short half life (30 secs), by
rapid TP desensitization, by endogenous inhibition of
platelet function by Nitric oxide
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35. Inflammation and Immunity
 COX 2- major source of prostanoids formed during and
after inflammatory response
 PGE 2, PGI 2  predominant as a result of increased
vascular permeability and blood flow in the inflamed
region
 TxA 2  increases platelet-leucocyte interaction
 PGD 2  contributes to resolution of inflammation
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36.  PGs generally inhibit lymphocyte function and proliferation
 Supress immune response
 PGE 2  depresses humoral antibody response by
inhibiting the differentiation of B lymphocyte into Antibody
secreting plasma cells
 It acts on T lymphocytes to inhibit their proliferation
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37.  PGD 2  major product of mast cells
 It’s a potent chemo-attractant, primarily through DP 1
 Activation of DP 1promotes chemotaxis, activation of T
helper Lymphocytes, eosinophils and basophils
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38. Smooth muscle
 PGs contract or relax smooth muscles outside of
vasculature
 For bronchial and tracheal muscles:
 TxA 2, PGF 2α, PGD 2  Contract
 PGE 2, PGI 2  Relax
 PGD 2  primary bronchoconstrictor
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39. Uterus
 TxA 2, PGF 2α  Contract
 PGE  Relax
 Sensitivity to contractile response is most prominent
before menstruation
 Relaxation is greatest in midcycle
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40.  Low conc. Of PGE 2 and PGF 2α  contracts uterus
 Low conc. Of PGE 2 and Oxytocin  essential for onset of
parturition
 High conc. Of PGE 2 and PGI 2  Relaxation
 PGEs and PGFs  used for Medical Termination of
Pregnancy
40

41. GIT muscle
 PGEs, PGFs  stimulate contraction of main longitudinal
muscle from stomach to colon and stimulate movement
of water and electrolytes into intestinal lumen
 PFI 2, TxA 2  also produce contraction (less active)
 PGE 2  relaxes circular muscle
 PGF 2α  contracts circular muscle
 Diarrhoea, cramps, reflux of bile – common side effects in
patients given PGs for abortion 41

42. Gastric and Intestinal secretions
 Stomach – PGE 2, PGI 2  increase mucus secretion
decrease acid secretion
decrease pepsin content
 These result from vasodialatory properties and direct effect
on secretory cells
 PGE 2 and analogs also inhibit gastric damage caused by
variety of ulcerogenic agents
 Also promotes duodenal and gastric ulcer healing
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43. Kidney
 Renal prostanoids perform complex, intricate functions
 Both medulla > cortex synthesize prostanoids
 COX 2 derived PGE 2, PGI 2  increase RBF and glomerular
filtration through their vasodialatory effects, also increases
medullary blood flow and inhibits tubular sodium reabsorption
 COX 1 derived PGs  promote salt excretion in collecting ducts
 TxA 2  potent vaso constrictor
 PGF 2α  Natriuresis, Diuresis
43

44. Eye
 PGF 2α  overall effect is decreasing IOP by increasing
Aqueous humor outflow via uveoscleral and trabecular
pathway
 Variety of FP receptor agonists have proven effective in
Open angle glaucoma
 It’s a condition associated with loss of COX 2 expression in
pigmented epithelium of ciliary body
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45. CNS
 PGE 2  induction of fever, PGD 2  induction of sleep
 Hypothalamus regulates body temperature set point
 Which is elevated by endogenous pyrogens like IL-1β, IL-6, TNFα
and interferons
 Thermoregulatory response is mediated by induction of COX 2
and mPGE S-1 in endothelium of preoptic hypothalamic area to
form PGE 2
 PGE 2 crosses BBB and acts on EP 1,3 on thermosensory neurons,
triggering hypothalamus to increase body temperature by
increasing heat generation and decreasing heat loss
45

46. Pain
 PGs increase sensitivity of noci receptors and potentiate
pain perception
 PGE 2via EP 1,4 and PGI 2via IP reduce threshold to
stimulation of noci receptors, causing peripheral
sensitization
 Both COX are expressed in spinal cord, releasing PGs
upon peripheral pain stimulation
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47. Endocrine
 PGE 2
 PGF 2α  induces oxytocin dependent decline in
progesterone levels in parturition
47
Increases ACTH, GH, Prolactin, Gonadotropins levels
Increases steroid production
Stimulates insulin release
Helps in induction of oocyte maturation

48. Bone
 PGs are strong modulators of bone metabolism
 COX 1 is dominant in normal bone
 COX 2 is dominant in inflammation and mechanical stress
 PGE 2  stimulates bone formation by increasing
osteoblastogenesis
 Also mediates resorption via osteoclast activation
48

49. Inhibitors, antagonists and agonists
 Non selective tNSAIDS and selective COX 2 inhibitors
used as anti inflammatory drugs
 Low dose aspirin used as cardioprotective agent
 FP agonists used for treatment of open angle glaucoma
 EP agonists used for induction of labor
49

50. Therapeutic abortion
 PGs are valued in missed abortion and molar gestation
 Used widely in mid trimester abortion
 Misoprostol (PGE 1 analog) + Mifepristone is effective in
termination of early pregnancy
 Dinoprostone ( PGE 2 synthetic preparation) approved for
50
inducing abortion in 2nd trimester
missed abortion
cervical ripening
managing benign hydatiform mole

51.  Gastric cytoprotection – several PG analogs decrease
gastric ulceration
 Misoprostol is approved for prevention of NSAID induced
gastric ulcers
 Impotence – PGE 1 (Alprostadil)  2nd line of treatment for
erectile dysfunction
 Maintenance of ductus arteriosus – highly sensitive to
vasodialation by PGE 1 (Alprostadil)
51

52.  Pulmonary hypertension (PH) – primary PH : long term
therapy with PGI 2 (prostacyclin) improves symptoms
 Also used are synthetic PGI 1(Epoprostenol) and PGI 1
analogs (iloprost)
 Glaucoma – Latanoprost  stable, long acting derivative of
PGF 2α, first prostanoid used
 Bimatoprost, Travoprost are now available
 Act as agonist of FP receptor and administered as drops 52

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54. Zioptan (Tafluprost ophthalmic solution)
 Approved February 2012
 Fluorinated analog of PGF 2α
 Acts on same receptors in eye as natural prostaglandins
 Specifically approved for reducing elevated intraocular
pressure in patients with open-angle glaucoma or ocular
hypertension
54

55. Duexis (ibuprofen and famotidine)
 Approved April 2011
 Specifically indicated for the relief of signs and
symptoms of rheumatoid arthritis and osteoarthritis
 And to decrease the risk of developing upper GIT ulcers
in patients taking ibuprofen for those indications
 Oral administration
55

56. Omidria (phenylephrine and ketorolac injection)
 Approved June 2014
 Specifically indicated for use during cataract surgery or
intraocular lens replacement
 For maintaining pupil size by preventing intraoperative
miosis and reducing postoperative ocular pain
 Supplied as a solution for intraocular administration
56

57. Vimovo (naproxen + esomeprazole)
 Approved April 2010
 Specifically indicated for the relief of signs and
symptoms of osteoarthritis, rheumatoid arthritis and
ankylosing spondylitis
 To decrease the risk of developing gastric ulcers in
patients at risk of developing NSAID associated gastric
ulcers
 Supplied as a tablet for oral administration
57

58. Yosprala (aspirin and omeprazole)
 Approved September 2016
 Specifically indicated for patients who require aspirin for
secondary prevention of cardiovascular and
cerebrovascular events
 And who are at risk of developing aspirin associated
gastric ulcers
 Supplied as delayed-release tablets for oral administration
58

59.  Latanoprost  can induce skin pigmentation, a side
effect discovered through its use in glaucoma therapy
 It up regulates tyrosinase and promotes melanocyte
proliferation
 ONO-9054 is a novel compound that aims to enhance
mechanism of prostaglandin analogs by targeting both
the FP receptor as well as the prostanoid EP3 receptors
in open angle glaucoma
59

60.  Goodman and Gilman’s, lipid derived autocoids: eicosanoids and
platelet activating factor, the pharmacological basis of therapeutics,
12th edition, chapter 35, 937-958
 Katung, trevor, the eicosanoids: prostaglandins, thromboaxne,
leucotrienes, basic and clinical pharmacology, 13th edition, chapter
18, 428
 Louise J. Lu, J. (2017). Focus: Drug Development: Novel Pharmacologic
Candidates for Treatment of Primary Open-Angle Glaucoma. [online]
PubMed Central (PMC). Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369028/ [Accessed
13 Oct. 2017]
60

61.  Peinhaupt M, Sturm EM, Heinemann A. Prostaglandins and Their
Receptors in Eosinophil Function and As Therapeutic Targets. Frontiers
in Medicine. 2017;4:104.
 AlSaad D, Alobaidly S, Abdulrouf P, Thomas B, Ahmed A, AlHail M.
Misoprostol for miscarriage management in a woman with previous five
cesarean deliveries: a case report and literature review. Therapeutics and
Clinical Risk Management. 2017;13:625-627
 Zhu H, Xu X, Ding Y, Zhou L, Huang J. Effects of prostaglandin E1 on
reperfusion injury patients: A meta-analysis of randomized controlled
trials. Zhang. Y-J, ed. Medicine. 2017;96(15):e6591
 Chin K-Y. A Review on the Relationship between Aspirin and Bone
Health. Journal of Osteoporosis. 2017;2017:3710959 61

62.  Cuzin B. Alprostadil cream in the treatment of erectile dysfunction:
clinical evidence and experience. Therapeutic Advances in Urology.
2016;8(4):249-256
 Zioptan New FDA Drug Approval | CenterWatch [Internet].
Centerwatch.com. 2017 [cited 12 October 2017]. Available from:
http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/1189/zioptan-tafluprost-ophthalmic-solution
 Duexis New FDA Drug Approval | CenterWatch [Internet].
Centerwatch.com. 2017 [cited 12 October 2017]. Available from:
http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/1143/duexis-ibuprofen-and-famotidine
 Yosprala New FDA Drug Approval | CenterWatch [Internet].
Centerwatch.com. 2017 [cited 12 October 2017]. Available from:
http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/100165/yosprala-aspirin-and-omeprazole
62

63.  Omidria New FDA Drug Approval | CenterWatch [Internet]. Centerwatch.com.
2017 [cited 12 October 2017]. Available from:
http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/100008/omidria-phenylephrine-and-ketorolac-injection
 Vimovo New FDA Drug Approval | CenterWatch [Internet]. Centerwatch.com.
2017 [cited 12 October 2017]. Available from:
http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/1101/vimovo-naproxen--esomeprazole
 Vicente A, Prud'homme S, Ferreira J, Abegão Pinto L, Stalmans I, Open-Angle
Glaucoma: Drug Development Pipeline during the Last 20 Years (1995-2015).
Ophthalmic Res 2017;57:201-207
 Anon, (2017). [online] Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300730/ [Accessed 13 Oct.
2017]
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