Eicosanoids

BY
Dr 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 lipid
Corticosteroids

Phospholipase A2
Arachidonic acid

Hydroperoxides
(HPETES)

Leukotrienes
(LTB, LTC ,LTD, LTE)

Lipoxygenase

Cycloxygenase
NSAIDs

Endoperoxides
(PGG, PGH)

Prostacyclin
(PGI)

Thromoxane
(TXA)
Prostaglandins
(PGE, PGF)

Physiological and Pharmacological Actions of Eicosanoids

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

Pharmacological & Physiological Effects:

A.
B.
C.
D.
E.
F.
G.
H.
J.

Uterine Tone
Blood pressure regulation (Dilatation and constriction)
Inflammation
Gastric Secretion and motility.
Platelet aggregation
Bronchial tone
Effect on kidney
CNS (Fever; Pain; Sleep)
Eye

Table 1: Effects of some eicosanoids

Effect

PGE2

PGF2

PGI2

TXA2

LTB4

LTC4

LTD4

Vascular
tone

Bronchial
tone

Uterine tone

or

Platelete
aggration
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; SISADH
Actions: 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)

Kinins
Receptors, 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)

Kinins
Actions & 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