PPT of Eicosanoids and PAF

S.RAMU13H61S0108M.PHARMACYDEPT OF PHARMACOLOGY

Overview

Eicosanoids are a large group of autocoids with potent effects on virtually every tissue in the body

these agents are derived from metabolism of 20-carbon, unsaturated fatty acids (eicosanoic acids).

.

The eicosanoids include:

1. the prostaglandins

2. thromboxanes

3. leukotrienes

4. hydroperoxyeicosatetraenoic acids (HPETEs)

5. hydroxyeicosatetraenoic acids (HETEs).

Biosynthesis

Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways:.

Biosynthesis

Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways:

1. Phospholipase A2-mediated production from membrane phospholipids; this pathway is inhibited by glucocorticoids.

Biosynthesis

Arachidonic acid, the most common precursor of the eicosanoids, is formed by two pathways:

1. Phospholipase A2-mediated production from membrane phospholipids; this pathway is inhibited by glucocorticoids.

2. Phospholipase C.

Eicosanoids are synthesized by two pathways:

1. The prostaglandin H synthase (COX, cyclooxygenase) pathway

produces: A. thromboxane B. the primary prostaglandins

prostaglandin E, or PGE prostaglandin F, or PGF prostaglandin D, or PGD)

C. prostacyclin (PGI2)

.2. The lipoxygenase pathway produces:

HPETEs HETEs leukotrienes

RECEPTORSPROSTAGLANDINS

PGE - EP1, EP2, EP3, EP4.

PGF - FP

PGD - DP

THROMBOXANE - TP

PROSTACYCLINS

PGI - IP

LEUKOTRIENES - LT1, LT2, LT3, LT4.

Actions:Vascular smooth muscle

○ PGE2 and PGI2 are potent vasodilators in most vascular beds.

○ Thromboxane is a potent vasoconstrictor.

.Inflammation

○PGE2 and PGI2 cause an increase in blood flow and promote, but do not cause, edema.

○HETEs (5-HETE, 12-HETE, 15-HETE) and leukotrienes cause chemotaxis of neutrophils and eosinophils.

. Bronchial smooth muscle PGFs cause smooth muscle

contraction.○PGEs cause smooth muscle

relaxation.

. Bronchial smooth muscle PGFs cause smooth muscle

contraction.○PGEs cause smooth muscle

relaxation.○Leukotrienes and thromboxane

are potent bronchoconstrictors and are the most likely candidates for mediating allergic bronchospasm.

. Uterine smooth muscle. PGE2 and PGF2a

cause contraction of uterine smooth muscle in pregnant women.

. Uterine smooth muscle. PGE2 and PGF2a

cause contraction of uterine smooth muscle in pregnant women.

The nonpregnant uterusnonpregnant uterus has a more variable response to prostaglandins PGF2a causes contraction

PGE2 causes relaxation.

Gastrointestinal tract ○ PGE2 and PGF2a

- increase the rate of longitudinal contraction in the gut and decrease transit time.

○ The leukotrienes - are potent stimulators of gastrointestinal

smooth muscle.

○ PGE2 and PGI2

- inhibit acid and pepsinogen secretion in the stomach.

Blood ○ TXA2

- is a potent inducer of platelet aggregation.○ PGI2 and PGE2

- inhibit platelet aggregation.○ PGEs

- induce erythropoiesis by stimulating the renal release of erythropoietin.

○ 5-HPETE - stimulates release of histamine

○ PGI2 and PGD - inhibit histamine release.

Therapeutic uses Induction of labor at term. Induction of labor is produced by:

infusion of PGF2 (carboprost tromethamine) [Hemabate] or

PGE2 (dinoprostone) [Prostin E].

Therapeutic abortion:

A.Inducing abortion in the second trimester: Infusion of carboprost tromethamine or Administration of vaginal suppositories

containing dinoprostone

B.inducing first-trimester abortion:○ these prostaglandins are combined with

mifepristone (RU486)

[[Maintenance of ductus

arteriosus

is produced by PGE1 [Prostin VR] infusion

PGE1 will maintain patency of the ductus arteriosus, which may be desirable before surgery.

Treatment of peptic ulcer.

Misoprostol [Cytotec] ○ a methylated derivative of PGE1

○ is approved for use in patients taking high doses of nonsteroidal antiinflammatory drugs (NSAIDs) to reduce gastric ulceration.

Treatment of Glaucoma

Latanoprost - 0.3% solution (Xalatan) Trovoprost (Travatan) Tefluprost (Zioptan)

Bimatoprost (Lumigan)

Adverse effects local pain and irritation bronchospasm gastrointestinal disturbances: nausea,

vomiting, cramping, and diarrhea.

MONTEUKAST

ZAFIRLEUKAST

PRANLEUKAST

ZILEUTON

NSAIDS

CORTICOSTEROIDS

MONTEUKAST

ZAFIRLEUKAST

PRANLEUKAST

ZILEUTON

NSAIDS

CORTICOSTEROIDS

PLATELET ACTIVATINGFACTOR

PAF also termed PAF- acether and AGEPC ( acetyl- glyceyl-ether-phosphorylcholine)

Biologically active phospholipid

BIOSYNTHESIS

Synthesized from acyl-PAF by two step process and under goes ACETYLATION DEACETYLATION

Phospholipid Arachidonic acid

acyl Co A Lys-PAF(INACTIVE)

PLA 2

acetyl hydrolase

PAF (ACTIVE) Lys-PAF (INACTIVE)

acetyl transferase

ACTIONS Vasodilatation Increased vascular permeability Chemotaxis Activation of leukocytes Aggregation of platelets Smooth muscle contraction

ANTAGONISTS

Rupatidine Lexipafant CV-3988 SM-12502 WEB-2086