the eicosanoids: prostaglandins, thromboxanes, leukotriens by s.bohlooli, phd ardabil university of...
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The eicosanoids: prostaglandins, thromboxanes, leukotriens
ByS.Bohlooli, PhD
Ardabil University of Medical Sciences
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 mechanismsOrgan effects
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Table 25-1. Eicosanoid ReceptorsRECEPTORPRIMARY
LIGANDSECONDARY LIGAND
PRIMARY COUPLING
MAJOR PHENOTYPE IN KNOCKOUT MICE
DP1PGD2 ↑ cAMP (Gs)
↓ Allergic asthma
DP2/CHRT2PGD215d-PGJ2?↑ Ca2+ i (Gi)?
EP1PGE2 GqDecreased response of colon to carcinogens
EP2PGE2 ↑ cAMPImpaired ovulation and fertilization; salt sensitive hypertension
EP3A-DPGE2 ↓ cAMP (Gi)
↑ cAMP (Gs)
↑ PLC (Gq)
Resistance to pyrogens
EP4PGE2 ↑ cAMP (Gs)
Patent ductus arteriosus
FPA,BPGF2αIsoP?GqFailure of parturitionArdabil University of Medical Sciences
IPPGI2PGE2↑ cAMP (Gs)↑ Thrombotic response, ↓ response to vascular injury
TPα,βTxA2IsoPs↑ PLC (Gq,
Gi, G12/13,
G16)
↑bleeding time, ↑ response to vascular injury
BLT1LTB4 G16, GiSome suppression of inflammatory response
BLT2LTB412(S)-HETE12(R)-HETE
Gq-like, Gi-
like, Gz-like
?
CysLT1LTD4LTC4/LTE4↑ PLC (Gq)↓ Innate and adaptive immune vascular permeability response, ↑ pulmonary inflammatory and fibrotic response
CysLT2LTC4/
LTD4
LTE4↑ 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 TXA2 mitogen PGF2
Vasodilators PGI2 PGE2
Gastrointestinal tract 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:
Neutrophils: LTB4, lipoxin A Eosinophils: LTC4, LTD4
Heart and Smooth Muscle Cardiovascular
Smooth Muscle Chemoattractant: 12(S)-HETE Gastrointestinal: LTB4 Airways: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 analogsEnzyme inhibitors and receptor antagonists
Dual Cox and Lipoxygenase inhibitorsDecreasing preexisting side effects
Dietary manipulationChange 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) Plasma t1/2: 2-2.5 min
Carboprost tromethamine (PGF2) Drawback: pulmonary hypertension
Facilitation of labor 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)
As intravenous infusion
Peripheral vascular diseases PGE , PGI
Patent Ductus Arteriosis PGE, PGI
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Blood TXA2, PGI2 involved in thrombosis
Respiratory System Peptidoleukotriens; LTC4, LTD4 synthesis
and receptor inhibitors Gastrointestinal System
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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