Download The eicosanoids

The eicosanoids: prostaglandins,
thromboxanes, leukotriens
By
S.Bohlooli, PhD
Ardabil University of Medical Sciences
Pathways of arachidonic acid
(AA) release and metabolism
Ardabil University of Medical Sciences
Cylcooxygenase pathway
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences
Lipoxygenase pathway
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences
Prostanoids Metabolism
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences
Basic pharmacology of
eicosanoids
Receptor mechanisms
Organ effects

Ardabil University of Medical Sciences
Table 25-1. Eicosanoid Receptors
RECEPTOR
PRIMARY
LIGAND
DP1
PGD2
DP2/CHRT2
PGD2
EP1
SECONDARY
LIGAND
PRIMARY
COUPLING
MAJOR PHENOTYPE IN
KNOCKOUT MICE
↑ cAMP
(Gs)
↓ Allergic asthma
↑ Ca2+ i (Gi)
?
PGE2
Gq
Decreased response of
colon to carcinogens
EP2
PGE2
↑ cAMP
Impaired ovulation and
fertilization; salt sensitive
hypertension
EP3A-D
PGE2
↓ cAMP (Gi) Resistance to pyrogens
↑ cAMP
(Gs)
↑ PLC (Gq)
EP4
PGE2
↑ cAMP
(Gs)
Patent ductus arteriosus
FPA,B
PGF2α
Gq
Failure of parturition
15d-PGJ2?
IsoP?
Ardabil University of Medical Sciences
IP
PGI2
PGE2
↑ cAMP (Gs) ↑ Thrombotic response, ↓ response to
vascular injury
TPα,β
TxA2
IsoPs
↑ PLC (Gq,
Gi, G12/13,
G16)
↑bleeding time, ↑ response to vascular
injury
BLT1
LTB4
G16, Gi
Some suppression of inflammatory
response
BLT2
LTB4
12(S)-HETE Gq-like, Gi12(R)like, Gz-like
HETE
CysLT1
LTD4
LTC4/LTE4
CysLT2
LTC4/LTD LTE4
4
?
↑ PLC (Gq)
↓ Innate and adaptive immune vascular
permeability response, ↑ pulmonary
inflammatory and fibrotic response
↑ PLC (Gq)
↓ Pulmonary inflammatory and fibrotic
response
Ardabil University of Medical Sciences
Prostanoid receptors and their signaling pathways
Ardabil University of Medical Sciences
Effect of prostaglandins and
thromboxanes
Ardabil University of Medical Sciences
Smooth muscle

Vascular:

vasocontrictors



Vasodilators



PGI2
PGE2
Gastrointestinal tract



TXA2  mitogen
PGF2
Longitudinal muscle: PGE2, PGF2
Circular muscle: PGF2, PGI2, relaxed by PGE2
Airways:


Relaxed: PGD2, PGE1, PGE2, PGI2
Contracted:PGF2, TXA2
Ardabil University of Medical Sciences
Platelets and Blood Cells

Aggregation:


Inhibtion:PGE1, PGI2
Aggregator: TXA2
Ardabil University of Medical Sciences
Kidney




Major one: PGE2, PGI2
GFR  (vasodilator effect)
Some effects of loop diuretics
TXA2: renal vasoconstrictor may play a
role in renal function? ( inflammatory
renal disease)
Ardabil University of Medical Sciences
Reproductive Organs


Female reproductive organ
Male reproductive organ


Fertility? PGE, PGF
Penile erection: PGE: alprostadil
Ardabil University of Medical Sciences
Central and Peripheral nervous
system



Fever
Sleep
Neurotransmission

Inhibition of Norepinephrine release
postganglionic sympathetic nerves
Ardabil University of Medical Sciences
Neuroendocrine organs

PGE:


GH, prolactin, TSH,ACTH, FSH, LH 
LTC4, LTD4:

LHRH, LH
Ardabil University of Medical Sciences
Bone metabolism

Increasing bone turnover

PGE2 ?
Ardabil University of Medical Sciences
EYE

PGE, PGF

Increasing outflow of aqueous humor
Ardabil University of Medical Sciences
Effect of Lipoxygenase & Cytochrome P450
derived Metabolites

Blood Cell and Inflammation

Chemoattractant:



Heart and Smooth Muscle

Cardiovascular



Smooth Muscle Chemoattractant: 12(S)-HETE
Gastrointestinal: LTB4
Airways:LTC4, LTD4


Neutrophils: LTB4, lipoxin A
Eosinophils: LTC4, LTD4
Increased vascular permeability, mucus secretion
Renal system


Speculative?
Product of free radical attack: 8-epi-PGF2
Ardabil University of Medical Sciences
Inhibition of Eicosanoid synthesis

Corticosteroids



By producing annexins, lipocortins
Inhibiting phospholipase A2
NSAIDs


Inhibition of COX activity
May increase the lipoxygenase activity?
Ardabil University of Medical Sciences
Clinical pharmacology of
Eicosanoids
Stable oral or long acting parenteral analogs
Enzyme inhibitors and receptor antagonists

Dual Cox and Lipoxygenase inhibitors
Decreasing preexisting side effects


Dietary manipulation

Change the polyunsaturated fatty acid
Ardabil University of Medical Sciences
Chemistry-1
Ardabil University of Medical Sciences
Chemistry-2
Ardabil University of Medical Sciences
Female reproductive system

Abortion


PGF2, PGE2: oxytocic and ripening and priming
of the cervix
Dinoprostone ( PGE2)


Carboprost tromethamine (PGF2)


Drawback: pulmonary hypertension
Facilitation of labor



Plasma t1/2: 2-2.5 min
Potency:PGE2 >> PGF2
Side effect: PGF2 >> PGE2
Dysmenorrhea
Ardabil University of Medical Sciences
Male Reproductive system

Erectile dysfunction:

Alprostadil (PGE1)


Intracavernosal injection
Urethral suppository
Ardabil University of Medical Sciences
Cardiovascular system

Pulmonary hypertension

Prostacylin (epoprostenol)


Peripheral vascular diseases


As intravenous infusion
PGE , PGI
Patent Ductus Arteriosis

PGE, PGI
Ardabil University of Medical Sciences

Blood


Respiratory System


Peptidoleukotriens; LTC4, LTD4 synthesis and
receptor inhibitors
Gastrointestinal System


TXA2, PGI2 involved in thrombosis
Cytoprotection: misoprostol (PGE1 analog)
Glaucoma

Latanoprost (PGF2), bimatoprost, unoprostone
Ardabil University of Medical Sciences
Immune system




Cell mediated organ transplant rejection
Inflammation
Rheumatoid arthritis
infection
Ardabil University of Medical Sciences
Ardabil University of Medical Sciences