Prostaglandins

• PG is generic name for group of closely related cyclic, oxygenated, 20C containing unsaturated fatty acids.(PG,TAX2,LT,PAF)

• Derived from prostanoic acid 20c fatty acid

• Discovered in semen in 1930by Ulf

• “prostaglandin” name form prostate gland where they were first thought to originate.

• The main inflammatory mediator derived from membrane phospholipids are eicosanoids

Phospholipids

Phospholipase A2

Arachidonic acid (Eicosa tetraenoic acid)

Eicosanoids (PGs,TAX2,LT,PAF)

prostanoids Eicosa=20carbon,tetra =4 double bond

Biosynthesis of eicosanoidsPhospholipids

Phospholipase A2Arachidonic acid (Eicosa tetraenoic acid)

LipoxygenaseCyc

looxy

genas

e

epo

xygen

ase

isoprostane

LT

PG EET

DHET

Esterified Arachidonic acid

EET=Epoxy eicosa trienoic acidsDHET= Dihydroxy eicosa trienoic acid

Biosynthesis of Prostanoids

Membrane phospholipidsPhospholipase A2

(or PLC)Arachidonic acid

Cyclooxygenase-IWidely present

Cyclooxygenase-IIInduced by cytokines during inflammation

PGG2PGH synthase

PGH2

PGI2 synthase

PGI2 (PC)Vascular endothelium

PGE2,PGF2α,PGD2

PGE synthase

TAX synthase

TXA2

In platelets

Corticosteriods

NSAIDS (aspirin)

COX1Constitutive

PGI2

PGE2

TXA2

HousekeepingEndothelial integrityVascular patencyGastric mucosal integrity

BronchodilationRenal

functionPlatelet function

COX2Inducible

Inflammatory

PGE2

PGF2a

Proteases

Inflammation

FeverPain

NSAIDs

COX-1: platelets, gastric, renal constitutively expressedCOX-2: vessel wall, renal, induced in inflammation and cancer. COX-3: controversial, thought to be a splice variant.

LT synthesis

• Leucko-trines first found in leucocytes, trines- conjugated “triene” system of double bond.

• Leuckotrines are products of lipoxygenase pathway

• Lipoxygenase enzyme present in cytosol.

Biosynthesis of LT(Lipoxygenase pathway)

Membrane phospholipidsPhospholipase A2

(or PLC)

Arachidonic acid5-Lipoygenase associated with protein FLAP

5HPETE

LTA4

LTB4,

LTC4

LTD4

LTE4

5-Hydroperoxy eicosatetraenoic acidFLAP:- 5-lipoxygenase activating protein

• Leukotriene Modulators: 5-Lipoxygenase Inhibitor : Zileuton LT – Receptor Antagonists :

Zafirlukast, Montelukast, Iralukast, Pranlukast

Platelet activating factor

Membrane phospholipidsPhospholipase A2

(or PLC)

Lyso-PAF Arachidonic acid

AcCoA

PAF

deacetylation

Acetyl transfera

se

Acyl PAF

• PAF- Gq-IP3/DA-Ca+2

Pharmacological actions of PAF:-• Vasodilatation• Vascular permeability • Chemotatic to eosinophils and neutrophils• Activation and aggregation of platelets• PAF produced by foetus at final term, involved in

progression of labour.• Most potent ulcerogen.• PAF synthesis inhibited by Glucocorticoids.

Prostanoid receptors:• Five main classesEndogenous Ligand Receptor type G protein II messenger

PGD2 DP GS cAMP

PGF2 FP Gq IP3,DAG

PGI2 IP GS cAMP

TAX2 TP Gq IP3,DAG

PGE2 EP1 Gq IP3,DAG

EP2 GS cAMP

EP3 GS,Gi OR cAMP

Gq IP3,DAG

EP4 GS cAMP

Pharmacological action of prostanoids:

• Eye: PGF2 and PGE2 IOP by uveoscleral pathway ( Drainage)

Respiratory system:

PGE2,PGI2- broncho dilatation

PGF2,TAX2, LT, PGD2-broncho constriction

broncho dilatation : broncho constriction LT are powerful constrictors.

CVS: PGE2 – Vasodilatation

Weak inotropic CO Capillary permeability Ductus arteriosus continually keep it

patent, maintain placental blood flow

PGI2- VasodilatorPeripheral, pulmonary and

coronary resistance

PGF2α , TAX2- Potent vasoconstrictor

GIT: PGE2 Mucous production

PGE2,PGI2 Mucosal blood flow Acid secretion

PGE2 water and electrolytic secretion (Diarrhoea)

Kidney: produced by renal medulla

PGE2,PGI2- NatriuresisRenal vasodilatationInhibit ADH actionStimulate renin release

PGE2 Cl- reabsorption

TAX2- Vasoconstriction ADH like action

Platelet:

PGE1,PGI2 inhibit platelet aggregation

TAX2 -Platelet aggregation-Low dose of aspirin acts an platelet (Inhibit

TAX2 production, platelets lack of nucleus so it can’t synthesis cox-1 but vascular produce cox-I) platelets

TX

PGHS-1: collagen, thrombin, ADP. PGI

PGHS-2: shear, bradykinin, acetylcholine

+

-

Uterus: PGE2,PGF2α • In vivo – Contraction• In vitroPGE2 – Pregnant- Contraction

Non pregnant – Relax

PGF2α- ContractionPG in low dose-Soften cervix

Male reproductive system: Enhance penile erection ( Smooth muscle

relaxation blood flow)

CNS: PGE1,PGE2- Pyrogenic

• Peripheral nerve ending: PGs are inflammatory mediators, sensitize pain receptors

• Endocrine: Facilitate release of GH,TSH, ACTH, FSH, LH and prolactin

• Bone metabolism: Stimulate bone resorption

Therapeutic uses of prostanoids and analogues:

• Obstetrics:- • PGE2, PGF2α used in terminate pregnancy

• First trimester:- Misoprostal PGE1, orally with mefepristone/ Methotrexate to induce abortion in first few weeks of pregnancy

• Second trimester:- Dinoprost(PGF2α) ,• Carboprost intra amniotic inj- abortion least use

due to side effects.• Dinoprostone(PGE2):- PGE2 –Vaginally for

inducing abortion, ripening of cervix for induction of labour at full term. side effect- prolong bleeding.

Facilitation of Labour, Cervical priming and postpartum haemorrhage:

• For induction of labour oxytocin is DOC.• PG is used for oxytocin CI i.e, renal failure,

pre-eclampsia, eclampsia. Advantage is PG is does not cause Na, water retention.

• Demeprost / Denoproste used viginally• Carboprost:- To control post- partum

haemorrhage.

Healing of peptic ulcer:- • PGE2,PGI2 Mucous production

Mucosal blood flow

Acid secretion (Anti ulcerogenic, cAMP)

Misoprostol-oral -200µg- QD.

Enoprostil- NSAIDs induced ulcer/chronic smokers

To prevent platelet aggregation:-

PGI2- inhibit platelet aggregation epoprostenol- renal dialysis.

To Treat Pulmonary Hypertension:- • PGI2 lower peripheral pulmonary and coronary

resistance. IV infusion Epoprostenol, Treprostinil

Peripheral vascular disease: Beraprost- oral PGI2 –thrice a day

Treating glaucoma:LatanoprostPGF2α - uveoscleral pathway (Drainage), Bimatoprost, travaprost, Unoprostone

For Patency of Ductus Arteriosus:- PGE2,PGI2 having vasodilators, inhibit platelet aggregation IV infusion – congenital heart disease, pulmonary artery stenosis. Alprostadil(PGE1), Epoprostenol(PGI2).

Male impotence:-Enhance penile erection

Bronchial asthma:- Bronchodilatation, but cough side effect.

Side effects of Prostanoids:- • PGs exhibit dose related adverse effects

bronchoconstriction, Hypotension, Vomiting, diarrhoea, fever, dizziness, and flushing.

• Carboprost:- Intra amniotic injection to induce second trimester abortions can cause anaphylactic shock and CVS collapse.

• Alprostadil – maintaining the patency of ductus arteriosus for long time leads ductus fragility and rupture.

• Misoprostol, Enprostil – GIT discomfort and diarrhoea.

• PGE (EP4) osteoclast and osteoblast activity, induce hypercalciuria.

Drug Preparation Use

Dinoprostone Vaginal tab/gel Induction labourMid term abortion

Dinoprost Intra amniotic inj Mid term abortion

Carboprost IM, Intra amniotic inj Mid term abortionControl of PPH

Gemeprost Vaginal pessary Cervical priming in early pregnancy

Alprostadil IV infusion, IV inj

Intra cavernosal inj

Maintenance of a patent ductus arteriosus in neonatesErectile dysfunction

MisoprostolEnoprostil

Oral Abortion & Peptic ulcerPeptic ulcer

Epoprostenol IV infusion Pulmonary hypertension

Latanoprostol Topical Glaucoma

iloprost IM Dec. infact size, when given IM after MI