Transcript The eicosanoids

The eicosanoids: prostaglandins,
thromboxanes, leukotriens
By
S.Bohlooli, PhD
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Pathways of arachidonic acid
(AA) release and metabolism
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Cylcooxygenase pathway
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Lipoxygenase pathway
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Prostanoids Metabolism
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Basic pharmacology of
eicosanoids
Receptor mechanisms
Organ effects

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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?
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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
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Prostanoid receptors and their signaling pathways
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Effect of prostaglandins and
thromboxanes
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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
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Platelets and Blood Cells

Aggregation:


Inhibtion:PGE1, PGI2
Aggregator: TXA2
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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)
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Reproductive Organs


Female reproductive organ
Male reproductive organ


Fertility? PGE, PGF
Penile erection: PGE: alprostadil
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Central and Peripheral nervous
system



Fever
Sleep
Neurotransmission

Inhibition of Norepinephrine release
postganglionic sympathetic nerves
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Neuroendocrine organs

PGE:


GH, prolactin, TSH,ACTH, FSH, LH 
LTC4, LTD4:

LHRH, LH
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Bone metabolism

Increasing bone turnover

PGE2 ?
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EYE

PGE, PGF

Increasing outflow of aqueous humor
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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
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Inhibition of Eicosanoid synthesis

Corticosteroids



By producing annexins, lipocortins
Inhibiting phospholipase A2
NSAIDs


Inhibition of COX activity
May increase the lipoxygenase activity?
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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
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Chemistry-1
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Chemistry-2
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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
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Male Reproductive system

Erectile dysfunction:

Alprostadil (PGE1)


Intracavernosal injection
Urethral suppository
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Cardiovascular system

Pulmonary hypertension

Prostacylin (epoprostenol)


Peripheral vascular diseases


As intravenous infusion
PGE , PGI
Patent Ductus Arteriosis

PGE, PGI
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
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
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Immune system




Cell mediated organ transplant rejection
Inflammation
Rheumatoid arthritis
infection
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