Prostaglanids Introduction Chemistry, Biosynthesis and Degradation Pharmacological properties Physiological and pathological effects Pharmacological effects Therapeutic uses Newer PGs and Recent Advances References

1. Presention by- Rizwan Ahamad
M. Pharma (Pharmacology)
Department of Pharmacology
SPER, Jamia Hamdard, New Delhi

2.  Introduction
 Chemistry, Biosynthesis and Degradation
 Pharmacological properties
 Physiological and pathological effects
 Pharmacological effects
 Therapeutic uses
 Newer PGs and Recent Advances
 References
1

3. Prostaglandins
 Any of a group of potent hormone like substances that are
produced in various mammalian tissues, derived from
arachidonic acid, and mediate a wide range of physiological
functions, such as control of BP, contraction of uterine, smooth
muscle, and modulation of inflammation.
 Prostaglandins (PGs) and related compounds (like as leukotriens)
collectively known as eicosanoids.
 Eicosanoids- Prostaglandins (PGs)
Thromboxane (TXA2)
Leukotrienes (LTs)
2

4. DISCOVERY OF PROSTAGLANDINS
 It was discovered by Ulf Von Euler (1930)
 He extracted from human semen
 It is secreted from prostate gland
 The understanding of PG grew in the 1960s and 1970s with the
pioneering research of Swedish biochemists Sune k. Bergstron and
Bengt I. Samuelsson and British biochemist Sir John Robert Vane
 The threesome shared the Nobel Prize for physiology or medicine in
1982 for their isolation, identification and analysis of numerous PGs
3

5. • Chemically prostaglandins may be considered as to be
derivatives of prostanoic acid.
• It have 5 member ring and two side chains.
• Most are produced from arachidonic acid, a 20 carbon
polyunsaturated fatty acid (5, 8, 11, 14-eicosatetraenoic
acid).
4

6. Biosynthesis of prostaglandins (PGs) and leukotrienes (LTs). Less active metabolites are shown in italics TX-
Thromboxane; PGI-Prostacyclin; HPETE-Hydroperoxy eicosatetraenoic acid (Hydroperoxy arachidonic acid);
HETE-Hydroxyeicosatetraenoic acid (Hydroxy arachidonic acid); SRS-A –Slow reacting substance of anaphylaxis
5

7. COX 1:
 Expressed constitutive in most cells
 Considered dominant
 Source of normal functions for prostanoid formation
COX 2:
 Up regulated by- Cytokines
Shear Stress
Growth factors
 Principal source of prostanoid formation in inflammation
and cancer
6

8. PGE 1 Misoprostol
Alprostadil
PGI 2 Epoprostenol
PGF 2 alpha Latanoprost
Carboprost
PGE 2 Dinoprostone
7

9.  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 PGI2 (IP),
PGF 2alpha (FP), TXA2 (TP)
 4PGE2 receptors (EP 1,2,3,4) and 2 PGD2 receptors (DP1,2) have been
cloned
8

10. Prostanoid degradation
Active Process Inactive
PGI2 Beta oxidation 2,3 keto PGF 2alpha
TXA2 Beta oxidation TXB2
PGD2 PG Dehydrogenase beta oxidation PGD-Metabolite (M)
PGE2 PG Dehydrogenase beta oxidation PGE-M
PGF 2alpha PG Dehydrogenase beta oxidation PGE-M
9

11.  3 sub clusters of PG receptors
Relaxant (Gs) Contractile Inhibitory
EP 2,4 EP 1 EP 3(Gi)
IP FP
DP 1 TP
Increase
cellular AMP
Increase
Ca++
Inhibit
Adenylyl cyclase
10

12. 11

13. Platelets
 Aggregation : activated by membrane phospholipases with release of AA-
Eicosanoid biosynthesis
 Major Eicosanoid formed- TXA2
 Total biosynthesis- determined by its urinary excretion
 PGI2 inhibits platelet aggregation
 TXA2 induce platelet aggregation
 Low PGI2 conc. Via EP3 receptors potentiates aggregation
12

14. Vascular tone
 PG half life – short
 Hence they locally modulate vascular tone
 PGI2 – major metabolite released from vascular endothelium
 Derived from primarily from COX2
 Regulated by shear stress, vaso constricor-dialator autocoids
13

15.  COX2 derived PGI2 via EP4 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 traditional Non – Steroidal Anti-
inflammatory Drugs (tNSAIDS) are used to induce
closure of patent ductus arteriosus in neonated
14

16. Lung
 PGE2 – Bronchodilator
 PGD2, TXA 2 and PGF 2alpha – Bronchoconstrictor
 Inhaled iloprost (PGI2 analog) – decrease cardinal features of
asthma in mice via inhalation of airway dendritic function
 Polymorphisms in genes for PGD2 synthase and TP receptor –
associated with asthma
 DP1,2 – associated with allergic responses
15

17. Kidney
 Long term use of all COX inhibitors is limited by
development of Hypertension, Edema, CHF
 PGE2, PGI2 – play a critical role in maintaining renal blood
flow (RBF) and salt excretion
 It has diuretic impact
 There synthesis is increased in response to factors which
decrease RBF
16

18. 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 promotes acute inflammation
 Exception: PGE2 – inhibits mast cell activation, thereby
inhibiting inflammation
17

19. Heart
 PGI2, PGE2 via IP / EP3 receptors protect against oxidative
injury in cardiac tissue
 IP deletion – augments Myocardial ischemia / reperfusion
injury
 mPGE S-1 and EP4 deletion – increase in decline of cardiac
function
 TXA2 contributes to oxidative stress
18

20. Cancer
 Pharmacological inhibition or deletion of of COX2 –
restrains tumor formation in models of colon, breast and
lung.
 Use of NSAID is associated with decreased risk for
development of these cancers.
 PGE2 – primary oncogenic prostanoid (also TXA2)
 Familial polyposis patients show decrease in polyps on
treatment with COX inhibitors
19

21. 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
 PGE2, PGI2, PGD2 – elicit vasodialation and drop in BP
20

22.  PGE2 – Vasoconstriction through EP 1,3
 PGD2 – flushing, nasal stiffness, hypotension
- local subcutaneous release contributes to vasodilation
of skin
 PGI2 – relax vascular smooth muscle, causing hypotension
and reflex tachycardia in I.V. administration
 TXA2 – potent vasoconstrictor and contracts smooth
muscles
21

23. Platelets
 Low conc. PGE2 via EP3 increases platelet aggregation
 High conc. PGE2 via IP/Gs – EP2,4 decrease platelet
aggregation
 PGI2, PGD2 inhibit platelet aggregation
 Mature platelets express only COX1
 Megakaryocytes, immature platelet turnover express COX2
22

24.  TXA2 major product of COX1 in platelets
 It induces platelet shape change and aggregation
 It amplifies signal for other more potent platelet
agonists e.g., 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
23

25. Inflammation and Immunity
 COX2 – major source of prostanoids formed during and
after inflammatory response
 PGE2, PGI2 – predominant as a result of increased vascular
permeability and blood flow in the inflamed region
 TXA2 – increases platelet- leucocyte interaction
 PGD2 – contributes to resolution of inflammation
24

26.  PGs generally inhibit lymphocyte function and
proliferation
 Suppress immune response
 PGE2 – depress humoral antibody response by
inhibiting the differentiation of B lymphocyte into
Antibody secreting plasma cells
 It acts on T lymphocyte to inhibit their proliferation
25

27. Smooth muscle
 PGs contract or relax smooth muscles outside of
vasculature
 For bronchial and tracheal muscles:
o TXA2, PGF 2alpha, PGD2 – Contract
o PGE2, PGI2 – Relax
o PGD2 – primary bronchoconstrictor
26

28. Uterus
 TXA2, PGF 2alpha – contract
 PGE – Relax
 Sensitivity to contractile response is most prominent before menstruation
 Low conc. Of PGE2 and PGF 2alpha – contract uterus
 Low conc. Of PGE2 and Oxytocin - essential for onset of parturition
 High conc. Of PGE2 and PGI2 – Relaxation
 PGEs and PGFs – used for Medical Termination of Pregnancy
27

29. GIT muscle
 PGEs, PGFs – stimulate contraction of main longitudinal muscle
from stomach to colon and stimulate movement of water and
electrolytes into intestinal lumen
 PFI2, TXA2 – also produce contraction (less active)
 PGE2 – relaxes circular muscle
 PGF 2alpha – contracts circular muscle
 Diarrhoea, cramps, reflux of bile – common side effects in
patients given PGs for abortion
28

30. Gastric and Intestinal secretions
 Stomach – PGE2, PGI2 – increase mucus secretion
-decrease acid secretion
-decrease pepsin content
 These result from vasodilatory properties and direct effect on
secretor cells
 PGE2 and analogs also inhibit gastric damage caused by variety
of ulcerogenic agents
 Also promotes duodenal and gastric ulcer healing
29

31. Kidney
 Renal prostanoids perform complex, intricate function
 COX2 derived PGE2, PGI2 – increase RBF and glomerular
filtration through their vasodilatory effects, also increases
modularly blood flow and inhibits tubular reabsorption
 COX1 derived PGs – promote salt excretion in collecting ducts
 TXA2 – potent vasoconstrictor
 PGF 2alpha – Natriuresis, diuresis
30

32. Eye
 PGF 2alpha – 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 COX2
expression in pigmented epithellim of ciliary body
31

33. CNS
 PGE2 – induction of fever, PGD2 – induction of sleep
 Hypothalamus regulates body temperature set point
 Which is elevated by endogenous pyrogens like IL-1beta, IL-6, TNF
alpha and interferons
 Thermoregulatory response is mediated by induction of COX2 and
mPGE S-1 in endothelium of preoptic hypothalamic area to from PGE2
 PGE2 crosses BBB and acts on EP 1,3 on thermosensory neurons,
triggering hypothalamus to increase body temp. by increasing heat
generation and decreasing heat loss
32

34. Pain
 PGs increase sensitivity of nociceptors and potentiate
pain perception
 PGE2 via EP 1,4 and PGI2 via IP reduce threshold to
stimulation of nociceptors, causing peripheral
sensitization
 Both COX are expressed in spinal cord, releasing PGs
upon peripheral pain stimulation
33

35. Bone
 PGs are strong modulators of bone metabolism
 COX1 is dominant in normal bone
 COX2 is dominant in inflammation and mechanical stress
 PGE2 – stimulates bone formation by increasing
osteoblastogenesis
 Also mediates resorption via osteoclast activation
34

36. Inhibitors, antagonists and agonists
I. Non selective tNSAIDs and selective COX2 inhibitors
used as anti inflammatory drugs
II. Low dose aspirin used as cardio-protective agent
III. FP agonists used for treatment of open angle glaucoma
IV. EP agonists used for induction of labor
35

37. Therapeutic abortion
I. PGs are valued in missed abortion and molar
gestation
II. Used widely in mid trimester abortion
III. Misoprostol (PGE1 analog) + Mifepristone is
effective in termination of early pregnancy
IV. Dinoprostone (PGE2 synthetic prepration) approved
for: Including abortion in 2nd trimester
Missed abortion
Cervical ripening
Managing benign hydatiform mole
36

38. Gastric cytoprotection – several PG analogs decrease
gastric ulceration
o Misoprostol is approved for prevention of NSAID
induced gastric ulcers
Impotence – PGE1 (Alprostadil) – 2nd line of treatment
for erectile dysfunction
Maintenance of ductus arteriosus –highly sensitive to
vasodialation of by PGE1 (Alprostadil)
37

39.  Pulmonary hypertension (PH) – primary PH: long term
therapy with PGI2 (prostacyclin) improves symptoms
 Also used are synthetic PGI1(Epoprostenol) and PGI1
analogs (iloprost)
 Glaucoma – Latanoprost- stable, long acting derivative of
PGF 2alpha, first prostanoid used
 Bimaprost, Travorost are now available
 Act as agonist of FP receptor and administered as drops
38

40. Newer PGs
and
Recent Advances
39

41. Duexis (ibuprofen & famotidine)
 Approved April 2011
 Specifically indicated for the relief of sign and
symptoms of rheumatoid arthritis and osteoarthritis.
 And to decrease the risk of developing upper GIT
ulcers in patients taking ibuprofen for those
indication.
 Oral medication
 Manufacturer – Horizon Pharma
40

42. Zioptan (Tafluprost ophthalmic solution)
 Aprroved February 2012
 Fluorinated analog of PGF 2alpha
 Acts on same receptors in eye as natural PGs
 Specifically approved for reducing elevated intraocular
pressure in patients with open-angle glaucoma or
ocular hypertension
 Manufacturer – Santen Pharma Co. Ltd.
41

43. Vimovo (naproxen and esomeprazole)
 Approved April 2010
 Specifically indicated for the relief of sign 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
ulcer
 Supplied as a tablet for oral administration
 Manufacturer – Horizone Pharma
42

44. 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
 Manufacturer – Aralez Pharma R&D Inc.
43

45.  Latanoprost- can induce skin pigmentation, a side
effect discovered through its use in glaucoma therapy
 It 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
44

46. 1. Tripathi KD. Essentials of Medical Pharmacology. 8th
edition. Jaypee Brothers Medical Publishers (P)
Limited; 2019:197-208
2. Goodman and Gilman’s, The Pharmacological Basis
of Therapeutics, 12th edition, Pg no.- 937-958
3. Udaykumar P. Textbook of Medical Pharmacology.
2nd edition. CBS Publishers & Distributors PVT.LTD;
2010:274-277
45

47. 4. http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/1143/duexis-ibuprofen-and-famotidine
5. http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/1189/zioptan-tafluprost-ophthalmic-solution
6. http://www.centerwatch.com/drug-information/fda-approved-
drugs/drug/100165/yosprala-aspirin-and-omeprazole
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300730/
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48. Thank You