1. AUTACOIDS
Mr.Manikanta
TMC

2. Autacoids- Local hormones
Means self remedies
Localized in tissue
Don't normally circulate
Has physio- pathological activities
Differ from hormones & N.T
Short duration of action
 Involved in response to injury
Site of action is restricted to the
synthesis area.
Sever as neuromodulators/ transmitters.

3. TYPES OF Autacoids
• Amines
-Histamine,
-Serotonin (5-HT)
• Lipid derived
- PG’s, TXA2, LT’s & PAF.
• Peptides
-Angiotensin &Bradykinin
- Cytokine, Gastrin, somatostatin & VIP etc.,

4. Lipid derived Autacoids
Prostaglandins, Thromboxanes,
Leukotrienes, Platelet Activating
Factor

5. History
 Prostaglandins were 1st discovered in human semen
by Ulf Von Euler.
 Bergstrom, Samuelsson & Vane- Noble prize.
 Prostaglandins derived from Prostanoic acid.
 Leukotrienes - obtained from leukocytes.
 P.G’s, LTs ,TXA2 & PAF - Eicosanoids.
 Eicosanoids are derived from Arachidonic acid.
 P.G’s & TXA2- Prostanoids.

6. Arachidonic acid
Membrane Phospholipids
Phospholipase A2
PG’S
TXA2
LT’S
COX
LOX
Cyt.P450
Epoxygenase pathway
Isoprostane pathway
Isoprotanes
19 & 20 HPETE’s
Cardiac
Cytosolic
Secretory
Physical, Chemical
Neurological or Hormonal,
Bradykinin
Synthesis:-
Synthesis of eicosanoids depend upon the release of arachidonic acid
from membrane lipids in response to stimuli.
Ca2+

7. Membrane Phospholipid
Arachidonic acid
5-HPETE
Leukotrienes
PGD2
PGE2
PGF2α
PGI2
TXA2 ---B2
Phospholipase A2Stimulus

8. Ring structure compounds
Open structure compounds
5,8,11,14-eicostetraenoic acid

9. Non selective &
Selective COX2
inhibitors
Non-Selective
COX inhibitor
COX2- Bacteria, Lipopolysaccharides, IL, TNF,
Epidermal / Platelet derived growth factors
Constitutive Inducible

10. COX-1 COX-2 COX-3
Constitutive
enzymes
(always present in
cells)
Constitutive in brain
endothelium & kidney
Recently isolated
from cerebral cortex
Serves as house
keeping function-
e.g.-
gastro protective,
Inducible-synthesis is
stimulated by endotoxins &
other inflammatory
mediators
Involved in pain
perception & fever
Haemostasis
Reno protective
Participates in inflammation Not involved in
inflammation
Pro-carcinogenic due to
inhibition of cell apoptosis,
stimulation of cell migration
angiogenesis,& invasiveness
Paracetamol targets
COX-3

11. Membrane
Phospholipid
Arachidonic acid
cyclooxygenase
PGG2
PGH2
TXA2 PGE2 PGF2α
PGI2PGD2
PGI Synthase
TXA Synthase
PGH Synthase
PG Synthase
Vascular
endothelium
Platelets GIT, LUNGs,
Uterus, B.V’s
Mast
cells
PLA2

12. PG’s & TXA2 Metabolism-
 PG’s are rapidly inactivated.
 Inactivation occurs through specific enzymes & oxidation.
 PGI & TXA2 are metabolised by non enzymatically.
 Short t ½ life.

13. Prostanoid receptors
 All are G-protein coupled receptors.
 IP3/DAG or CAMP transducer mechanism.
PGD2 PGF2α PGI2 TXA2 PGE2
TP EP1-4IPFPDP

14. PG Receptor Functions
PGD2, DP X P. aggregation, Vasodilatation, Relaxation of GIT
& uterus, regulates Sleep-wake cycle.
PGF2 FP Contractions Uterus & Bronchi.
PGI2 IP X platelet aggregation, Vasodilatation, Renin
release & Natriuresis
TXA2 TP P. aggregation, Vasoconstriction,
Bronchoconstriction.
PGE2
EP1
PEF2
Bronchonstrction, GIT motility, increases colon
cancer.
EP2 Br.dilation, Vasodilatation, GIT relaxation,
Intestinal fluid secretion, Ovulation & Fertilization
EP3 X gastric acid secretion, Cytoprotective action,
contraction of pregnant uterus & GIT muscle, X
lipolysis & ANS neurotransmitter release.
-Maintains patency of ductus arteriosus.EP4

15. Drugs inhibiting P.G & LT synthesis-
Membrane phospholipids
Arachidonic acid
PGG2/H2 LTA4
PGE2
PGF2α
PGD2
PGI2
TXA2
LTB4 LTC4
LTD4
LTE4
Act on Cys-LT receptors
Bronchoconstriction
NSAIDS
COX1,2 5-LOX Zileuton
Montelukast
zafirlukast
PLPA2Steroids

16.  Pharmacological actions-
1.CVS:-
PGE2/PGI2
-Vasodilation- B.P, weak +ve inotropic, C.O slightly .
- Capillary permeability
- Maintains patent ducts arteriosus (D.A).
- NSAIDs - during labour & child with D.A ?
PGF2α- Vasoconstrictor.
- Mild effect on H.R/B.P/F.O.C/Capillary permeability.
TXA2- Vasoconstrictor, Smooth muscle mitogen-Testosterone.
PGF2α
PGE2/I2

17. 2.Platelets-
 PGI2/ PGD2- X Platelet aggregation.
 TXA2 - Platelet aggregation (P.A)
-both maintains integrity of vascular endothelium
-Prevents P.A & stick to arteriolar wall.
 Platelets- No nuclei(DNA), No COX-1 synthesis.
-limited amount of COX-1 & TXA2 persist.
-L.Dose Aspirin-prevention of coronary thrombosis.
-H.Dose NASID’s -X PGI2 & TXA2.
 Vascular endothelium-
-Has nuclei & continuous synthesis of COX-1—PGI2.

18. PGI
COX
Bloodvessel
COX
PGI2
TXA2
P.Aggregation
Vascular endothelium
Platelet
L.D-ASPIRIN
Aspirin antiplatelet effect persists till the life span of platelet 7 to 10days.
Aspirin- administered O.D/ alternative days.
Nuclei

19. 3.Uterus- (In vivo)
 PGE2 & PGF2α -contracts Pregnant/Non-pregnant uterus
In Vitro- PGE2 relax non.preg & contracts preg.uterus.
PGF2α - contracts both.
PG’s At term - soften cervix.
Foetus- involves initiation & progression of labour.
 Dysmenorrhoea- PGE2 & PGF2α during menstruation.
-Uterine contractions- ischaemic pain.
 Aspirin-effective in Rx dysmenorrhoea & to delay the labour.
 P.G’s analogues – Rx uterine inertia.

20. 4.Bronchial muscles
 PGE2 & PGI2 – Dilation.
 PGF2α , TXA2 & LTs - Contraction.
 Asthma-due to imbalance.
 Aspirin induced asthma due to shift to LOX pathway.
 LTs are powerful Br.constrictors.

21. 6.GIT - Anti-ulcerogenic.
 PGE2 & PGI2 - gastric acid & pepsin secretion.
- Mucous production & Blood flow.
 Aspirin- Cytoprotective action is lost.
 PGE2 & PGF2α - Contracts longitudinal muscle.
- H20 & Electrolyte secretions- Colic & diarrhoea as S/E.
 PGI2 - opposes propulsive movements.
 P.G’s - imp role in colonic cancer.
 Aspirin- risk of colon cancer & PGE2 induced diarrhoea.

22. 6.kidney-
 PGE2 & PGI2 – Natriuresis, Renal vasodilation & Cl-
ion.
- X ADH action to promote H20 clearance.
- β1+ R- Renin release.
 Bartter’s syndrome - Rx Indomethacin.
 TXA2 - Renal vasoconstriction (ADH like action)
 Furosemide - + COX activity to produce vasodilators PG’s.
 Indomethacin - X Furosemide diuretic action.

23. 7.CNS-
 PGE1,2 -pyrogenic. PGD2 & TXA2- n’t pyrogenic.
 Aspirin blocks P.G actions i.e. antipyretic
 PGD2- sleep.
 P.G’s X NE release.
 P’G’s – headache due to vasodilation.
8.Males-
 PGE1,2 - fertile semen , sperm motility, penile erection.
 Fertilization by coordinating uterine contractions.
 Testosterone promotes P.G synthesis.
 Aspirin the P.G content in semen.

24. 9.Pheripheral nerve endings-
 PGE2 & PGI2- sensitize the receptors to pain &
inflammatory mediators -amplify algesia.

25. 10. Endocrine-
 PGE2 promotes the release of GH/ACTH/FSH/LH &
Prolactin.
11.Bone metabolism-
 PGE2- Osteoporosis due + of bone resorption.
12.Eye- PGE2 , PGF2α - IOP by uveoscleral out flow
13.Cancer- PGE2 is a pro-carcinogen-colon cancer.

26. Uses of Prostaglandin analogues-
1.Abortion-
Dinoprostone - PGE2.
 Induction of mid-term abortion
 Cervical ripening & induction of labour at full term.
 Not used for menstrual regulation/early abortion.
Carboprost - PGF2α
 Used for mid-term abortion.
Misoprostol -PGE1
 used for abortion-200μg.BD/orally.
 along with mifepristone to induce abortion in 1
st
few wks of
pregnancy.

27. 2.Facilitation of labour, cervical priming & PPH-
1.Dinoprostone - PGE2.
 Orally - to augmenting labour & to check PPH.
 Vaginally- softens the cervix before labour induction.
 Preferred over oxytocin for labour induction in pre-
eclampsia, eclampsia, cardiac & renal disease.
 Intrauterine foetal deaths / along with oxytocin.
2. Carboprost - PGF2α - RX PPH-intra-amniotic inj.

28. 3.Ulcer healing-
 Misoprostol -PGE1
 Ulcer protective agent-200μg orally QID
 Enprostil - PGE2.
 Used in NSAID’s induced P.U & Chronic smokers.
4) To prevent platelet aggregation-
 Epoprostenol-
 PGI2- Haemodialysis & Cardiopulmonary bypass.
 PGE2 & PGI2- used to store platelets for transfusion.

29. 5.To treat pulmonary HTN-
 Epoprostenol (PGI2)-I.V - pulmonary & coronary resistance.
 Treprostinil -longer acting.
6.Patency of Ductus arteriosus-
 Epoprostenol (PGI2) or Alprostadil (PGE1)- I.V infusion.
7.P.V.D-
 Beraprost (PGI2)-orally ,T.I.D.
8.Glaucoma-
 Latanoprost (PGF2α) - Reduces I.O.P.

30. 9.Male impotence- Alprostadil to RX E.D.
-2.5-25mcg intracavernosal inj.
10.To reduce infract size- iloprost- in post-MI. Period.
11.Asthma- areosolised PGE2- Rx A/C attacks.

31. A patient come to you complaining that when ever he takes
aspirin for headache, he develops sever shortness of breath.
What might be the reason?

32. A lady with 2 children and history of amenorrhea for 35
days went to a doctor for termination of pregnancy. The
obstetrician advised her Misoprostol 400μg stat
1. Comment on prescription?
2. Which analogue is used for midterm abortion?
3. Name one non-obstetric use of Misoprostol?

33. MCQ’s
A new born baby was diagnosed as having a congenital
abnormality that result in transportation of great vessels. While
preparing for the surgery, the medical team needed to keep the
ducts arteriosus open. They did this by infusion ?
A ) Corticsol b) Indomethacin
c) Alprostadil d) Tacrolimus

34. S/E-
 Hypotension, Syncope & Flushing
 Carboprost-mid term abortion- Anaphylactic shock & CVS
collapse.
 Alprostadil- Ductus fragility & rupture.
 PGF2-GIT toxicity & Bronchoconstriction.
 Misoprostol/Enprostil-Diarrhoea.
 Long term use-PGE2-EP4 R mediated increase in osteoclast
& osteoblast activity.
 Renal Ca2+ oxalate stone- hypercalciuria.

35. LEUKOTRIENES

36. Zileuton
Arachidonic acid
5HPETE
LTA4
LTC4
LTD4
LTE4
LTB4
5-Lipooxygenase
5-Lipooxygenase
LTB4 SynthaseLTC4 Synthase
Glutanyl Transpetidase,
Glutanyl Leucotrienase
Dipeptidase
SRS-A
FLAP
Zafirlukast

37.  Blood-
 LTB4 – Neutrophil chemotaxis, lymphocyte proliferation.
 LTC4 & LTD4 -Eosinophils chemotaxis , Degranulation &
O2 radical formation.
 Heart & B.V-
 LTC4 & LTD4 - contractility & coronary blood flow.
 Play imp role in myointimal proliferation-angioplasty.
 GIT smooth muscles-
 LTB4- causes neutrophil chemotaxis - IBD’s.

38.  Bronchial smooth muscle-
 LTC4, LTD4 & LTE4
 Bronchoconstriction
 Increased permeability
 Increased mucus secretion.
 Inflammation –LTB4
- Imp mediator of all types of inflammations like R.A,
Psoriasis & Ulcerative colitis.

39.  LT receptors- (LT.R)
 LTB4- BLT receptors
 LTC4/LTD4/LTE4- cyst LT receptors.
 LT R are G-protein coupled & function through IP3/DAG
transduction mechanism.
LT inhibitor-
 Zileuton LOX inhibitor, X LT induced responses.
LT receptor antagonists-
 Zafirlukast, Montelukast & Iralukast.
 Antiasthmatic & Anti-inflammatory agent.

41. Platelet Activating Factor (PAF)
Membrane Acyl-Glycero phosphocholine
Lyso PAF
PAF
PAF-Acetyl transferase
PL A2Fatty acid
Acetyl CoA
Acetyl hydroxylase
Lyso PAF
Acyl-Glycero phosphocholine
Acetate
Fatty acid
Synthesis
Degradation

42. Pharmacological actions-
 Vasodilation, vascular permeability
 Chemotactic to neutrophil & eosinophils.
 Activation of leucocytes
 Promotes platelet aggregation
 Involved in inflammation & bronchial hyper-responsiveness
 Foetus- involved in progression labour at term
 Potent peptic ulcerogen.
M.O.A- G-ptn R - IP3/DAG---Ca2+ pathway.
 Some of it actions are mediated through the release of P/G’s,
TXA2 & LT’s.

43. PAF antagonist-
 Ginkgolide -B & structural analogues of PAF.
 Alprazolam & Triazolam antagonize PAF actions.
 Used in Rx of shock, M.I, P.U, intermittent claudication,
asthma, sepsis & contraceptives.
Thank U