Prostaglandins and leukotrienes are lipid-derived autacoids that play important roles in various physiological processes and in mediating inflammation. Prostaglandins were first identified in seminal fluid and named after the prostate gland. They are synthesized from arachidonic acid. Leukotrienes were initially identified as the "slow reacting substance of anaphylaxis". Prostaglandins and leukotrienes act through G-protein coupled receptors and are involved in cardiovascular, pulmonary, gastrointestinal, renal and ocular functions. They also mediate fertility, labor and abortion. Drugs targeting prostaglandin and leukotriene pathways are used to treat conditions like asthma, glaucoma and inflammation.

1. PROSTAGLANDINS &
LEUKOTRIENES
Dr Rushikesh Kulkarni
JR II, Department of Pharmacology,
GMC Aurangabad.

2. INTRODUCTION
 Autocoids - Greek Autos :- Self, akos :- Healing substance or
remedy
Amine autacoids :- Histamine, 5-Hydroxytryptamine (Serotonin)
Lipid derived autacoids :- Prostaglandins, Leukotrienes, Platelet
activating factor
Peptide autacoids :- Plasma kinins (Bradykinin, Kallidin),
Angiotensin

3. PROSTAGLANDINS

4. Human semen  to
contract uterine and
other smooth muscle
strips and fall in BP
in animals
Bergstrom,
Samuelsson
and Vane got
the Nobel prize
Identification
of Chemical
structure
Active principle
was termed
Prostaglandin',
thinking that it
was derived from
prostate
HISTORY

5. Basic outlines
 Fatty acids
 Saturated or Unsaturated
 UFA  MUFA or PUFA
 Animals can synthesize all FA except  Essential FA
Linoleic acid
Alpha Linolenic acid
PG3
PG1 PG2
 Gamma Linolenic acid  Dihomo gamma linolenic acid  Arachidonic acid
 Eicosapentanoic acid  Docosa hexanoic acid

6. Nomenclature
 Series A, B, C, depending on the ring structure and the
substituents
 Subscript 1,2,3 indicating the number of Double bonds in the
side chains
 Cyclization  Saturation of 2 double bonds  2 double bonds
remaining in side chain  importance of subscript 2 PGs in man,
e.g. PGE2, PGF2, PGI2, TXA2
 No cyclization or reduction of double bonds occurs during LT
synthesis, the LTs of biological importance are LTB4, LTC4, LTD4

8. Prostaglandin Receptors
GPCRs



Gi Gs Gq G12,13
cAMP cAMP DAG-IP3 Rho
DP2
DP1,
EP2,EP4
EP1, FP,
TP
Sm Relaxation
Inhibition of platelet aggregation
Sm Contraction
Platelet aggregation

9. Actions, Pathophysiological
Roles & Clinical Uses

10. Cardiovascular System
Vasodilators –
PGE2, PGI2 & PGD2
PGI2 more potent then PGE2 causes Reflex Tachycardia
Cardioprotective - PGE2 & PGI2
PGF2α
Action vary with species and vascular bed
Constricts many larger veins including pulmonary vein and artery
Little effect on BP in human
PGE2 & PGF2α
Vasodilatation in most , but not all vascular beds  Fall in BP
weak direct but more prominent reflex action  Increase CO
TXA2
Consistently produces vasoconstriction, role in HF

11. RA
RV LV
LA
BODY
LUNG
DA
Aspirin
Indomethacin
PGE1 (Alprostadil)

12. Platelet functioning
Inhibiting Aggegation PGI2
Enhancing Aggregation TXA2
Clinical Application
Epoprostenol
 Haemodialysis
 Cardiopulmonary Bypass
 Platelets For Transfusion
 Primary Pulmonary Hypertension
Clinical Application
Low dose Aspirin  Platelets in portal
circulation  Selective inhibition of
TXA2 synthesis

13. PGI2 in Pulmonary Hypertention
Generic
Name
Route of
Administration
Drug Class Indication
Epoprostenol IV Prostacyclin derivative Treatment of PAH to improve exercise capacity
Iloprost Inhaled Prostacyclin derivative
Treatment of PAH to improve a composite endpoint
consisting of exercise tolerance, symptoms (NYHA
Class), and lack of deterioration
Treprostinil IV or SC Prostacyclin derivative
Treatment of PAH to diminish symptoms associated
with exercise
Treprostinil Inhaled Prostacyclin derivative Treatment of PAH to improve exercise ability
Treprostinil Oral Prostacyclin derivative Treatment of PAH to improve exercise ability

14. UTERUS
In Vitro :- PGF2α
consistent contraction
PGE
Non Pregnant Strips Relaxation
Pregnant Human Uterine Strips Contraction
In Vio :- PGE2 & PGF2α uniformly contract human uterus
Pregnancy associated with Increased Sensitivity

15. Fertilization
Labour
Dysmennorhoea
PGs in semen  rapidly absorbed when lodged in the
vagina during coitus  They coordinate movements of
the female genital tract & transport of sperms 
fertilization is facilitated
Increased PG synthesis by the endometrium during
menses  Uncoordinated uterine contractions 
compress blood vessels  uterine ischaemia  pain(
Dysmennorhoea)
Foetal tissues  PGs and
Maternal blood(at term)  PGF2α
PGs mediate initiation & progression of labour
ROLE

16. Upto 7 weeks
• Alternative in patients
unresponsive to
Ergometrine/Oxytocine
• Carboprost(PGF2a) 0.25mg
im every 30 – 120 min
• Delayed erratic action and incomplete
abortion
• Converts oxytocin resistant midterm uterus 
oxytocin responsive
• Single extra-amniotic injection (PGE2) followed
by i.v. infusion of oxytocin or intraamniotic
PGF2α with hypertonic solution
• Pretreatment with mifepristone improves the
efficacy of PGE as abortifacient
• By transcervical suction
• Intravaginal PGE2 pessary
inserted 3 hours before
attempting dilatation
• Reduces resistance to
dilatation
• Minimize trauma
• Mifepristone 600mg orally f/b
Misoprostol 400mcg after 2
days
• Precautions – Ectopic, confirm
complete expulsion
• s/e uterine cramps, vaginal
bleeding, nausea, vomiting
• Methotrexate + Misoprostol
Induction/Augumentation of LabourPost partum haemorrhage
Low dose PGE2(Dinoprostone)
intravaginally/cervical canal
Oxytocin after 12 hours
Unfavourable Cervix Cervical Priming/Augumentation
• Cervical gel (0.5 mg in 2.5 ml prefilled
syringe)
• Vaginal gel (1 mg in 2.5 ml) inserted into
posterior fornix, followed by 1-2 mg after
6 hour, if required
Induction
• PG offers no advantage over oxytocin
• No fluid retention
Clinical applications
• Mephenamic acid/Aspirin in Dysmenorrhoea
• Aspirin known to delay the initiation of labourNSAIDS
ABORTION
During 1st
trimenster
Midterm , missed, molar

17. GIT
COX 1 PGE2
Acid secretion
Mucus secretion
Blood flow
Antiulcer
Propulsive
Selective COX 2 Inhibitor
• Less Ulcerogenic
• However Delays Healing
Circular Muscle
Longitudinal
Muscle
Ulcer T/t
• Stop NSAIDS, Smoking
• PGE2  Misoprostol
• Toxin induced increased fluid
movement in secretory dirrhoea
• Growth of colonic polyps and
cancer
• Regular aspirin intake  Low risk of
Colon Cancer
• NSAIDS  Relief in FAP by reducing
polyp formation

18. KIDNEY
Important Substances
Na+, Urea
Na+, K+, 2Cl-
Na+, Cl-
H+
H+
Na+
CD
DC
T
Thick ALOH
Thin
ALOH
DLOH
PCT
P cell
I cell
BC
K+ Aldosterone
Angiotensin Renin
High Salt Intake
Sympathetic
Stimulation
COX 2
PGE2, PGI2
Vasoconstriction
Increase in BP
Osmotic D
CAase Inhibitor
Loop Diuretics
Thiazide
K+ Sparring
Diuresis
COX 1
TXA2
Vasodilatation

19. EYE
PGF2α
 induces ocular inflammation
 lowers i.o.t. by enhancing uveoscleral & trabecular outflow
COX-2 expression in the ciliary body has been found to be deficient in wide angle
glaucoma patients
Non irritating congeners like Iatanoprost, Travoprost, Bimatoprost are now first line drugs
in wide angle glaucoma

20. (1) Site of action of miotics in angle closure
glaucoma: contraction of sphincter pupillae
removes pupillary block and reverses
obliteration of iridocorneal angle
(2) Site of action of miotics in open angle
glaucoma: contraction of ciliary muscle pulls
on scleral spur and improves trabecular
patency
(3) Site of action of (a)  blockers (b) 1 agonists
(c) 2 agonists (d) carbonic anhydrase
inhibitors: all reduce aqueous secretion by
ciliary body
(4) Site of action of prostaglandins and adrenaline
( agonist action): increase uveoscleral
outflow by altering permeability and/or
pressure gradients
(5) Site of action of adrenaline (2 agonist
action): possibly increases aqueous
conductivity of trabecular filtering cells

21. Latanoprost
 PGF2α derivative
 Efficacy similar to timolol (i.o.t. reduction by 25–35%)
 Effect is well sustained over long-term
 Reduces i.o.t. in normal pressure glaucoma also
 Ocular irritation and pain are relatively frequent
 No systemic side effects
 Blurring of vision, increased iris pigmentation, thickening and darkening of eyelashes
 Macular edema especially in aphakic patients
 Good efficacy, once daily application and absence of systemic complications
 The first choice drugs for open angle glaucoma
 High cost is a disadvantage
 LACOMA, XALATAN, LATOPROST, 0.005% eyedrops (To be stored in cold)

22. Travoprost
• Effect starts within2 hours, peaks at 12 hours and lasts for 24
hours or more
• TRAVATAN 0.004% eyedrops
• Refrigeration of the eyedrop is not required
Bimatoprost
• A synthetic prostamide derivative
• LUMIGAN, CAREPROST 0.3% eyedrops
• Need not be stored in refrigerator

23. Bronchial muscle
PGF2α, PGD, and TXA2  Potent bronchoconstrictors
(more potent than histamine)
PGE2  powerful bronchodilator
PGI  produces mild dilatation
Inhibit Histamine release
Irritation

24. CNS
 PGE2
 injected i.v. penetrate brain poorly  no central effects
 injected intracerebroventricularly  sedation, rigidity,
behavioral changes & rise in body temperature(PGI2 also)
 COX-2 is the major isoenzyme involved
 Aspirin and other inhibitors of PG synthesis are antipyretic
PNS sensitize afferent nerve endings to painful stimuli
ANS modulate sympathetic neuro-transmission in the periphery

25. PGE2
Endocrine system
 Facilitates the release of anterior pituitary hormones, insulin &
adrenal steroids
 TSH like effect on thyroid
Metabolism
 Anti lipolytic
 Insulin like effect on carbohydrate Metabolism
 Mobilize Ca2+ from bone

26. Other Suggested Uses Of PG
Peripheral vascular diseases
lmpotence
Organ Transplant Rejection
PGI2 Renal transplant patients
PGE2 and PGI2 Attenuation of T-cell proliferation and rejection
PGE1
 Organ procurement
 Organ preservations
 Primary graft failure

27. LEUKOTRIENES

28. Lung, WBCs &
Platelets
‘Slow Reacting
Substance Of
Anaphylaxis’ (
SRS-A)

29. LT Receptors
All LT receptors couple with Gq protein & function through
IP3/DAG transducer mechanism
For LTB4
 BLT receptors expressed in leucocytes & spleen
 Chemotactic
 Subtypes :- BLT1 & BLT2
For Cysteinyl LTs (LTC4 & LTD4)
 CysLT receptors
 Subtypes :- cysLT1 & cysLT2
 cysLT1 Bronchial & Intestinal receptors
 cys LT2leucocytes & spleen

30. CVS and blood
• LTC4 and LTD4 injected i.v.  rise in BP followed by
prolonged fall
• These LTs markedly increase capillary permeability
Inflammation mediation
• LTB4 is highly chemotactic for neutrophils and monocytes
• The LTC4 & LTD4 are chemotactic for eosinophils
Actions

31. Smooth muscle
 LTC4 & D4 contract most smooth muscles
 potent BRONCHOCONSTRICTORS
 induce spastic contraction of g.i.t. at low concentrations
 increase MUCUS SECRETION in the airways
 Mediator of Human Allergic ASTHMA
 In Lungs :- AG : AB reaction  LTs are released ( more slowly metabolize)
Long Action
 Abdominal Colics during systemic anaphylaxis

32. Clinical application in Bronchial
Asthma

33. The cysLT1 receptor antagonist :- Montelukast & Zafirlukast &
Pranlukast
Pharmacokinetics :-
Well absorbed orally , highly plasma protein bound
Metabolized by CYP2C9
T1/2 : Montelukast 3-6 hours while Zafirlukast :- 8-12 hours
Side effects :-
Both montelukast and zafirlukast are very safe drugs
Produce few side effects like headache, rashes
Eosinophilia and neuropathy are infrequent
Few cases of Churg-Strauss syndrome ( Vasculitis with eosinophilia)

34. Ziluton :-
 A 5-LOX inhibitor, blocks LTC4/D4 as well LTB4 synthesis
 Potential to prevent all LT induced responses
 Clinical efficacy in asthma is similar to montelukast
 The duration of action is short
 hepato-toxic Potential
 These limitations have restricted its use

35. Eicosanoids are not preformed in cells but are generated from
phospholipid precursors on demand
They are implicated in the control of many physiological
processes, and are among the most important mediators and
modulators of the inflammatory reaction and are a very
significant target for drug action
Over the past 40 years they have been among the most
intensely investigated substances