Eicosanoids

Eicosanoids precursor
• in mammals, arachidonic acid ,a 20 –carbon
un saturated fatty acid contain 4 double
bonds.
• The principal eicosanoids are;
• Prostaglandins
• Thromboxanes
• Leukotrienes
• lipoxins
Prostanoids mean
Prostaglandins+Thromboxane
• Eicosanoids synthesis
From Phospholipids--------------- arachidonic acid
(cell membrane)
Phospholipase A? enzyme(PLA?)
The activation of (PLA?) occur in
response to;
1-Thrombin action on platelets
2-C5a on neutrophil
3-Bradykinin on fibroblast
4-Ag –Ab reaction on mast cells
5- cell damage
Arachidonic acid metabolism
Arachidonic acid is metabolised by several
pathways;
1-by cyclooxygenase enzyme (COX1 and COX2)
To form prostaglandins and thromboxanes
2-by lipoxygenase enzyme
To form leukotrienes and lipoxin
Prostanoids
• COX1 present as constitutive enzyme in most
cells catalyze the conversion arachidonate to
thromboxaneA?
• Prostaglandin Synthase enzyme catalyze the
conversion arachidonate to PGI?, PGD?,PGF??.
Prostanoid receptors
5 main classes of receptors;
DP for ligand PGD?
FP for ligand PGF?
IP for ligand PGI?
Ep for ligand PGE?
TP for ligand TXA?
Action of prostanoids
PGD2 causes;
Vasodilatation
Inhibition of platalets aggregation
Relaxation of G.I.T and uterine muscles
Bronchospasm effect
PGF??
Causes myometerial contraction in human
PGI? causes
Vasodilatation
Inhibition of platelets aggregation
Renin release and natriuresis
TXA? causes
Vasoconstriction
Platelets aggregation
Bronchospasm
PGE? cauese
1- on EP? receptor
Brochospasm and contraction of G.I.T
2- on EP? receptor causes
Bronchodilator
Vasodilatation
Stimulation of intestinal secretion
Relaxation of G.I.T muscles
3- on EP? receptor causes
Contraction of intestinal muscles
Inhibition of gastric acid secretion
increase gastric mucous secretion
inhibition of lipolysis
Inhibition autonomic neurotransmitter release
Stimulation of contraction of pregnant uterus
Prostanoids analogue
Gemeprost or misoprostol (PG E analogue)
Used in termination of pregnancy.
Dinoprostone (PGE analogue)
Used to induction of labour.
Carboprost
Used in postpartum hemorrhage.
Misoprostol (PGE analogue)
To pevent ulcer of NSAID origin
Alprostadil ( PGE? analogue)
Used to maintain the patency of ductus
arteriosus .
Epoprostenol (PGI? analogue)
Used to inhibit platelets aggregation
Latanoprost
Used in treatment of glucoma
leukotrienes
Synthesised from arachidonic acid by
lipoxygenase pathway
Lipoxygynase found in lung ,platelets, mast cell
And WBC
The main enzyme is 5- lipoxygenase
The production by lipoxygenase is
Leukotriene A ?, this converted to leukotriene B?
And this a precursor for the cysteinyl leukotriene
LTC?
LTD?
LTE?
LTF?
Mixture of these called (SRS-A)
LTB? produced mainly in neutrophil
Cystienyl leukotriene produced in eosinophil,
mast cell ,basophil , macrophage
Leukotrienes receptors;
BLT. for LTB?
CYS LT. for CYS LTs
LTB? potent chemotactic agent
CYS LT. have action on respiratory system and
cardiovascular system
Small dose of LTC? or LTD? I.V causes
Rapid , short, drop in B .P.
And constriction of coronary B.Vs
Leukotriene antagonist
Zaferlukast , montelukast both are CYSLT.
Receptor antagonist ,used for treatment of
asthma .
Zileulton is drug used also for treament asthma
by inhibit 5- lipoygenase enzyme
bradykinin
Bradykinin are active peptide formed from
circulating protiens termed kininogen by
protease pathway
Synthesis of bradykinin
HMW kininogen -------------------- bradykinin
Kallikrien kininases
inactive peptide
prekallikrien
Source of bradykinin
Bradykinin formed from kininogen in the plasma
By action of kallikrien
Kallikrien also activate conversion plasminogen
to plasmin.
Metabolism of bradykinin
Kininases , are enzymes ,kininase II one of these
Are inactivate bradykinin .
Also ACE can inactivate bradykinin.
Role of bradykinin in inflammation
Bradykinin cause vasodilation (PGI2 and NO
release)
Also it pain producing agent
It contract the intestine ,uterus, and bronchial
smooth muscles.
It contributed to clinical picture of pancreatitis
Bradykinin receptors
2 Types of receptors
B1, B2
B1 normally expressed in inflammation
B2 present in many normal cells and are
activated by bradykinin
Icatibant = B2 antagonist .