Eicosanoids

BYDr Md Ashraful Alam

Department of Pharmaceutical Sciences

North South University

Eicosanoids• Definition:• Prostaglandins and related compounds are collectively known

as eicosanoids. Most are produced from arachidonic acid, a 20-carbon polyunsaturated fatty acid 

• The eicosanoids are considered "local hormones." They have specific effects on target cells close to their site of formation. They are rapidly degraded, so they are not transported to distal sites within the body. But in addition to participating in intercellular signaling, there is evidence for

involvement of eicosanoids inintracellular signal cascades. • Classifications

a) Cyclooxygenase derivatives (prostaglandins and thromboxane)

b) Lipoxygenase products ( leukotriens)

Synthesis of eicosanoids and sites of inhibitory effects of anti-inflammatory drugs

Membrane lipidCorticosteroids

Arachidonic acid

NSAIDs

Hydroperoxides Endoperoxides (HPETES) (PGG, PGH)

Leukotrienes Prostacyclin Thromoxane(LTB, LTC ,LTD, LTE) (PGI) (TXA)

Prostaglandins(PGE, PGF)

-

-

Phospholipase A2

LipoxygenaseCycloxygenase

Physiological and Pharmacological Actions of Eicosanoids

Mechanisms and Receptors: Act on cell surface receptorsAll coupled to G-protein.PGI; PGE increases adenylate cyclase (decrease intracellular calcium) while TXA2 increases IP3 (increases intracellular calcium)

Pharmacological & Physiological Effects:A. Uterine ToneB. Blood pressure regulation (Dilatation and constriction)C. Inflammation D. Gastric Secretion and motility.E. Platelet aggregationF. Bronchial toneG. Effect on kidney H. CNS (Fever; Pain; Sleep)J. Eye

Table 1: Effects of some eicosanoids

EffectPGE2PGF2αPGI2 TXA2LTB4LTC4LTD4

Vascular tone

↓↑↓↓↑↑↑?,↑↓,↑↓

Bronchial tone

↓↓↑↓↑↑↑?↑↑↑↑↑↑↑↑

Uterine tone↑↑↑↑↑↓????

Platelete aggration

↑or ↓?↓↓↓↑↑↑???

Leukocyte chemotaxis

????↑↑↑↑??

↑= slight increase, ↑↑= moderate, ↑↑↑=high, ↑↑↑↑=very high, ↓= slight decrease, ↓↓= moderate and, ↓↓↓= marked; ?= unknown effects

Clinical Uses of Eicosanoids and Inhibitors:•

• A. Uses of Eicosanoids:• Oxytocis agents: (e.g.: Dinoprostone PGE2) vaginally or Misoprostol

(p.o)• _ - Impotance: Alprostadil PGE2• _ -Glaucoma: Latanoprost PGF2

– Pulmonary Hypertension ( PGI2 or prostacyclin, Epoprostenol)– Peptic Ulcer (PGE1 Misoprostol (Cytotec)

• B – uses of eicosanoids blockers:– Asthma: Leukotrien antagonists (Zafirleukast; Montelukast);

or Lipoxegenase inhibitor e.g. Zileuton•

– Anti-inflammatory and RA (NSAIDs)

– Antiplatelet action (Aspirin)

– Dysmenorrhea (NSAIDs)

Pulmonary Hypertension

C. Vasoactive Peptides

• A. Vasoconstrictors (angiotensin II;

vasopressin; endothelins and neuropeptide Y.

• B. Vasodilators (Bradykinin and related

Kinins; Natriuretic Pepties; Vasoactive Intestinal Peptide; substance P;

Neurotensin)

Kinins : (e.g. : Bradykinin & kallidin)• Polypeptides present in plasma and several

tissues including the kidneys, pancreas, intestine, sweat and salivary glands.

ACTIONS :

CVS : Very potent vasodilator (direct and via increase EDRF). Also, increases the body capillary permeability

• Bronchioles : Contraction of bronchial smooth muscles (cough).

• Inflammation : Kinins can produce all the symptoms of inflammation (pain and edema when injected to tissue).

• Pain : Intradermal injection of kinins elicited potent pain (Stimulate nociceptive nerve afferent fibers)

Natriuretic peptides:Locations: Atrial (ANB) and Brain (BNP) (Found in ventricle as well)

Clinical significant: (increase in heart failure; renal failure; SISADHActions: decrease the secretion of renin, aldosterone and vasopressin; decrease blood pressure and increase sodium excretion. Act via activation of guanalyl cyclase.

Calcitonin: from thyroid and the most potent vasodilators in the body.

Vasopressin (Antidiuretic hormone ADH)

Supstnace P: is an arteriolar vasodilator that is also pain-mediating neurotransmitter but causes venoconstriction and bronchoconstriction. Capsaisin releases substance P from nerve ending (used for arthritic joints and for postherpetic neuralgia).

The Natriuretic Peptide Family• Include atrial natriuretic peptide

(ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP)

• ANP derived from a 126 amino acids prohormone, secreted primarily from cardiac atria

• BNP, identified initially in brain, is secreted from both atria & ventricles

• CNP identified in brain & in vascular endothelial cells

• Stretch receptors in the atria and ventricles detect changes in cardiac chamber volume related to increased cardiac filling pressures, resulting in release of both ANP and BNP but not CNP

The Natriuretic Peptide Family• The actions of the natriuretic peptides are

mediated by natriuretic peptide receptors (NPRs), NPR-A/B/C

• NPR-A & NPR-B are coupled to membrane-bound GC, increases levels of cGMP

• NPRs are localized in vascular SM, endothelium, platelets, the adrenal glomerulosa, & the kidney

• ANP & BNP increase urine volume & sodium excretion, decrease vascular resistance, and inhibit release of renin and secretion of aldosterone & vasopressin

• Neutral endopeptidases (NEPs) inactivate NPs

2. Vasoconstrictor peptides:

Angiotensin II

1. the most potent vasoactive agent in the body (direct and vai NE)

2. release of aldosterone and renin as well.

3. Drinking and increase the secretion of vasopressin and ACTH.

Endothelins:• Widely distributed in the body (in endothelial cells of blood vessels)• ACTIONS: Dose-depen. Vasoconstriction in most vascular beds, Thus:

– Decrease GFR – Increase aldosterone, vasopressin and ANP– Potent bronchoconstriction

Endothelin Antagonists: Endothelin-converting enzyme inhibitors:(Bosentan) (4 pulmonary HTN)

KininsReceptors, Actions & Therapy

• The activate B1, B2, B3 receptors linked to PLC/A2

• Powerful Vasodilation→ decreased blood pressure via B2 receptor stimulation (NO-dependent)

• Increase in capillary permeability inducing edema.It produces inflammation & algesia (B2)

• Cardiac stimulation: Compensatory indirect & direct tachycardia & increase in cardiac output

• It produces coronary vasodilation

Bradykinin has a cardiac anti-ischemic effect, inhibited by B2 antagonists (NO & PI2 dependent)

KininsActions & Therapy

• Kinins produce broncho-constriction & itching in respiratory system (antagonized by ASA)

• Therapeutic Use: No current use of kinin analogues Increased bradykinin is possibly involved in the

therapeutic efficiency & cough produced by ACEIs Aprotinin (Trasylolol), a kallekrein inhibitor, used

in treatment of acute pancreatitis, carcinoid syndrome & hyperfibrinolysis