PowerPoint Presentationjsmu.edu.pk/lectures/2018/Sem4/20180718 lecture 6...SYNTHESIS- SUBSTRATE 1. The dietary Essential fatty acids Linoleic (ш 6 , 18 C, dienoic fatty acid) and

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EICOSANOID METABOLISM

EICOSANOIDS

• C20 polyunsaturated fatty acids e.g. Arachidonic acid → Eicosanoids

→physiologically, pathologically and pharmacologically active compounds

• PG – Prostaglandins

• TX - Thromboxanes

• LT - Leukotrienes

• LX - Lipoxin

STRUCTURE

FUNCTIONS

• Physiologic:-

→ act as local hormones

through G protein linked receptors

→ biochemical effects

inflammatory response (calor, rubor, tumor, dolor)

gastric integrity

renal function

smooth muscle contraction (intestine / uterus / bronchus)

blood vessel diameter

platelet homeostasis

• Pathologic:-

→ hypersensitivity ( allergic reaction – may be fatal)

DIFFERENCE FROM HORMONES

• Produced in small amounts

• Produced by all tissues( not in glands)

• Act locally

• Not stored

• Short half life

SYNTHESIS- SUBSTRATE 1. The dietary Essential fatty acids Linoleic (ш 6 ,

18 C, dienoic fatty acid)

and Linolenic acids (ш 6 eicosa trienoic fatty acid)

→ Arachidonic acid

2. Arachidonic acid is found in the plasma membrane phospholipids at C2/ diet

3. Phospholipase A2 causes the hydrolytic release of Arachidonic acid

ARACHIDONIC ACID has 20 C and 4 double bonds 20:4 (5,8,11,14)

EICOSANOID SYNTHESIS

• Dietary precursor is the Essential Fatty acid, linoleic acid (ω6 fatty acid)

→desaturated →elongated

→ Arachidonic acid ( ω6 FA )

→ membrane bound phospholipids

→ released by Phospholipase A2

SYNTHESIS OF ARACHIDONIC ACID

EICOSANOID SYNTHESIS

EICOSANOID SYNTHESIS

2 PATHWAYS FOR ARACHIDONIC ACID 2 pathways compete for Arachidonic substrate:-

• Cyclo oxygenase → PG2 , TX2 (Prostanoids)

• Lipooxygenase → LT4, LX4

3 GROUPS OF EICOSANOIDS

CYCLOOXYGENASE PATHWAY • Prostaglandin H synthase enzyme (PGH synthase)

• Enzyme is bound to Endoplasmic reticulum

• Enzyme has 2 catalytic activities:-

(1) Fatty acid cyclooxygenase (COX)

requires 2 molecules of Oxygen

(2) Peroxidase – dependent on reduced

Glutathione

→oxidative cyclization of Arachidonic acid

→PGH2

→ variety of PG and TX(PGD, PGE2, PGF2, PGG2, TXA2, PGI2)

• Each cell type produces only 1 type of prostanoid

• Cyclooxygenase is a suicide enzyme (self catalyzed destruction→↓PG activity)

OXIDATION AND CYCLIZATION OF ARACHIDONIC ACID

CYCLOOXYGENASE PATHWAY

PGH SYNTHASE ISOZYMES • 2 isozymes :- COX 1 and COX 2

1. COX 1 – present in most tissues

required for healthy gastric tissue,

renal homeostasis

platelet aggregation

2. COX 2 - limited no. of tissues

induced by products of activated

immune cells

and inflammatory cells

→ Calor, Rubor, Tumor, Dolor of

Inflammation

INHIBITION OF PG SYNTHESIS • Steroidal anti inflammatory agent ( Cortisol):-

→↓Phospholipase A2 →↓Arachidonic acid

• Non steroidal anti inflammatory agents(NSAIDS)

(Aspirin, Indomethacin, Phenylbutazone, Ibuprofen):-

→↓Cyclooxygenase by competing with Arachidonate

→↓COX 1 and COX2 →↓PGH2

{ Aspirin toxicity →systemic inhibition of COX 1 and COX2

→damage to stomach and kidneys + ↓blood clotting }

{ Celecoxib (COX 2 inhibitor)→↓inflammatory process but COX 1 physiologic functions maintained→↑risk of heart attacks ( due to ↓PGI2) }

FUNCTIONS OF PROSTAGLANDINS • PGE2 (most tissues)→ vasodilation

relaxation of smooth muscle

↓acid secretion from stomach

↑release of Renin from JG cells

uterine contractions→ labor

FUNCTIONS OF PROSTAGLANDINS • PGF2α(most tissues)→

Vasoconstriction

Bronchoconstriction

Contraction of smooth muscle

↓Progesterone secretion + regression of Corpus Luteum →interrupts early pregnancy + onset of labor →termination of pregnancy / Labor

CLINICAL USES OF EICOSANOIDS • Induction of labor

• Prevention of conception

• Termination of pregnancy

• Relief of Asthma and nasal congestion

• Control BP in Hypertension

• ↓HCl formation in peptic ulcer

• PGD2 is sleep promoting substance

THROMBOXANES

• TXA2 is produced by COX-1 in activated platelets →

↑adherence+ aggregation of circulating platelets

contraction of vascular smooth muscle (vasoconstriction)

→formation of blood clots(thrombi)

• PGI2 (Prostacyclin) produced by COX2 in vascular endothelial cells →↓platelet aggregation

+ ↑vasodilation→↓ thrombogenesis

• Opposing effects of TXA2 and PGI2 →↓thrombi

(at site of injury only)

• Aspirin →↓COX1→↓TXA2 in platelets( inhibition cant be overcome because of lack of nuclei)

• →↓COX2→↓PGI2 in endothelial cells (inhibition can be overcome because of nuclei → can generate more enzyme)

• →↓thrombi

• →↓risk of stroke / heart attack (by low dose Aspirin)

•

SYNTHESIS OF THROMBOXANES AND PROSTACYCLINS

LIPOOXYGENASE PATHWAY • Lipooxygenases enzymes (LOXs)

→linear hydroperoxy acids (- OOH)

• 5 Lipooxygenase converts Arachidonic acid →

5-hydroperoxy-6,8,11,14 eicosa tetra enoic acid

(5-HPETE)→ Leucotrienes (4 double bonds)

(in leucocytes, platelets and macrophages)

→mediators of allergic response and inflammation

• NSAIDS do not affect their synthesis

• Inhibitors of 5- lipooxygenase and leucotriene receptor antagonists →treatment of Asthma

LIPOOXYGENASE PATHWAY

LIPOOXYGENASE PATHWAY

LIPOOXYGENASE PATHWAY

• Lipoxins:-

conjugated tetraenes

arising in leucocytes

PHYSIOLOGIC ACTIONS OF LEUKOTRIENES AND LIPOXINS

• Leukotrienes :-

Slow reaction g substance of anaphylaxis (SRS-A)

is mixture of Leukotrienes→

Bronchoconstriction,

Inflammatory/ hypersensitivity reaction

e.g. Asthma

• Lipoxins :-

Anti inflammatory role i.e. counter regulatory

compounds (Chalones) of immune response