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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Ardabil University of Medical Sciences