!
! aa are oxygenation products of polyunsaturated long-chainare oxygenation products of polyunsaturated long-chain fatty acids
fatty acids !
! are ubiquitous in the animal kingdom and are also found— are ubiquitous in the animal kingdom and are also found— together with their precursors—in a variety of plants. together with their precursors—in a variety of plants.
!
! 5,8,11,14-eicosatetraenoic acid5,8,11,14-eicosatetraenoic acid !
! the most abundant of the eicosanoid precursorsthe most abundant of the eicosanoid precursors !
! is a 20-carbon (C20) fatty acid containing four doubleis a 20-carbon (C20) fatty acid containing four double bonds (designated C20:4–6).
bonds (designated C20:4–6). !
! must first be released or mobilized from the sn-2 positionmust first be released or mobilized from the sn-2 position of membrane phospholipids by one or more lipases of the of membrane phospholipids by one or more lipases of the phospholipase A2 for eicosanoid synthesis to occur phospholipase A2 for eicosanoid synthesis to occur 3 classes of phospholipases mediate arachidonate release from 3 classes of phospholipases mediate arachidonate release from membrane lipids:
membrane lipids: 1.
1. cytosolic (c) PLA2- dominates the acute release of AAcytosolic (c) PLA2- dominates the acute release of AA 2.
2. secretory (s) PLA2- contributes under conditions ofsecretory (s) PLA2- contributes under conditions of sustained or intense stimulation of AA production sustained or intense stimulation of AA production 3.
3. calcium-independent (i) PLA2.calcium-independent (i) PLA2. !!
4 routes that oxygenate the AA 4 routes that oxygenate the AA
1.
1. the cyclooxygenase (COX)the cyclooxygenase (COX) 2.
2. lipoxygenaselipoxygenase 3.
3. P450 epoxygenaseP450 epoxygenase 4.
4. isoeicosanoiisoeicosanoid d pathwayspathways
Factors determining the type of eicosanoid synthesized: Factors determining the type of eicosanoid synthesized:
1.
1. the substrate lipid speciesthe substrate lipid species 2.
2. the type of cellthe type of cell 3.
3. the manner in which the cell is stimulatedthe manner in which the cell is stimulated
!
! Two unique COX isozymes convert AA into prostaglandinTwo unique COX isozymes convert AA into prostaglandin endoperoxides: endoperoxides: 1. 1. PGH synthase-1PGH synthase-1 most cells. most cells. 2. 2. PGH synthase-2PGH synthase-2
varies depending on the stimulus. varies depending on the stimulus.
!! An immediate early-respo An immediate early-respo nse gene produnse gene product that is ct that is markedly up-markedly up-regulated by shear stress, growth factors, tumor promoters, and regulated by shear stress, growth factors, tumor promoters, and cytokines.
cytokines.
the major source of the major source of prostanoids in prostanoids in inflammation and inflammation and cancer cancer
promote the uptake of promote the uptake of two molecules of two molecules of oxygen by cyclization oxygen by cyclization of arachidonic acid to of arachidonic acid to yield a C9–C11 yield a C9–C11 endoperoxide C15 endoperoxide C15 hydroperoxide hydroperoxide vascular vascular prostacyclin prostacyclin (PGI2) (PGI2) !! prostanoids are prostanoids are important for important for normal renal normal renal development development and and maintenance of maintenance of function function equipotent on COX-1 equipotent on COX-1 and COX-2 and COX-2
!! C9–C11 endoperoxide C15 hydroperoxide- rapidly modified byC9–C11 endoperoxide C15 hydroperoxide- rapidly modified by the peroxidase moiety of the COX enzyme to add a 15-hydroxyl the peroxidase moiety of the COX enzyme to add a 15-hydroxyl group that is essential for biologic activity
group that is essential for biologic activity !! TheThe
termed the termed the
action of downstream isomerases and synthases action of downstream isomerases and synthases !! The prostaglandins differ from each other in two ways:The prostaglandins differ from each other in two ways:
1.
1. in the substituents of the pentane ring (indicated by thein the substituents of the pentane ring (indicated by the last letter, eg, E and F in PGE and PGF)
last letter, eg, E and F in PGE and PGF) 2.
2. in the number of double bonds in the side chains (indicatedin the number of double bonds in the side chains (indicated by the subscript, eg, PGE1, PGE2).
by the subscript, eg, PGE1, PGE2). !! PGH2 is metabolized byPGH2 is metabolized by
synthases (PGIS, TXAS, and PGFS) to synthases (PGIS, TXAS, and PGFS) to respectively
respectively
EICOSANOIDS
EICOSANOIDS
ARACHIDONIC
ARACHIDONIC ACID ACID OTHER OTHER POLYUNSATURATEDPOLYUNSATURATED PRECURSORS
PRECURSORS
phospholipase C
phospholipase C and diglyceride lipaseand diglyceride lipase- can also release AA- can also release AA
SYNTHESIS OF
SYNTHESIS OF EICOSANOIDSEICOSANOIDS Products of Prostaglandin Endoperoxide Synthases Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases)
(Cyclooxygenases)
(COX-1)
(COX-1)is expressed constitutively inis expressed constitutively in (COX-2)
(COX-2)is inducible; its expressionis inducible; its expression
COX
COX 1 1 COX COX 2 2 BOTHBOTH
generates generates prostanoids for prostanoids for “housekeeping” such “housekeeping” such as gastric epithelial as gastric epithelial cytoprotection cytoprotection Indomethacin and Indomethacin and sulindac (slightly sulindac (slightly selective COX 1) selective COX 1) !! source of source of Meclofenamate and Meclofenamate and ibuprofen are ibuprofen are approximately approximately endothelial endothelial
COX- is the primary is the primary
renal renal COX-2-derived derived
prostaglandins, thromboxane, and
prostaglandins, thromboxane, and prostacyclprostacyclinin, collectively, collectively prostanoids
prostanoids, are generated from, are generated fromPGH2PGH2 through the through the
prostacycl
prostacyclin, thromboxane, and in, thromboxane, and PGFPGF
PGI2, TXA2, and PGF2 PGI2, TXA2, and PGF2!!,,
! 9,11-endoperoxide reductase and 9-ketoreductase- 2 additional enzymes that provide for PGF2" synthesis from PGH2 and
PGE2, respectively. ! At least
1. microsomal (m) PGES-1
2. mPGES-2- the more readily inducible 3. cytosolic PGES- the more readily inducible ! two distinct PGDS isoforms
1. lipocalin-type PGDS 2. hematopoietic PGDS
Several products of the arachidonate series with clinical importance: DRUG CLINICAL INDICATIONS
Alprostadil may be used for its smooth muscle relaxing effects to maintain the ductus arteriosus patent in some neonates awaiting cardiac surgery and in the treatment of impotence.
Misoprostol, cytoprotective prostaglandin used in preventing peptic ulcer and in combination with
mifepristone (RU-486) for terminating early pregnancies.
PGE2 used in obstetrics to induce labor
Latanoprost topically active PGF2" derivatives used in
ophthalmology to treat open-angle glaucoma. Prostacyclin (PGI2,
epoprostenol)
synthesized mainly by the vascular endothelium and is a powerful vasodilator and inhibitor of platelet aggregation. It is used clinically to treat pulmonary hypertension and portopulmonary hypertension.
!
of platelets, vasoconstriction ).
! All the naturally occurring COX products undergo rapid metabolism to inactive products either by:
A. B.
corresponding ketone by prostaglandin 15-hydroxy prostaglandin dehydrogenase (15-PGDH) after cellular uptake via an organic anion transporter polypeptide (OATP 2A1).
! Further metabolism is by , and"
! AA (metabolized by
hydroperoxyeicosatetraenoic acids (HPETEs)" derivatives (HETEs) and leukotrienes
!
recognized as the primary components of the anaphylaxis.
! There are four current approaches to antileukotriene drug development:
1. 5-LOX enzyme inhibitors
2. leukotriene-receptor antagonists 3. inhibitors of FLAP
4. phospholipase A2 inhibitors.
!
appropriate stimulation via 12-LOX in platelets to the L
!
and ichthyosis
! Specific isozymes of microsomal cytochrome P450
monooxygenases convert AA to hydroxy- or epoxyeicosatrienoic acids
! The products are:
o 20-HETE- generated by the CYP hydroxylases (CYP3A,
4A, 4F)
o 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic
acids (EETs) - arise from the CYP epoxygenase (2J, 2C)
! EETs- have vasodilator effect except on pulmonary vasculature where they cause vasoconstriction.
! are family of eicosanoid isomers, are formed
nonenzymatically by on AA
and related lipid substrates. !
! have potent vasoconstrictor effects when infused into renal and other vascular beds and may activate prostanoid receptors
! may modulate other aspects of vascular function, including leukocyte and platelet adhesive interactions and
angiogenesis !
!
inhibition with aspirin or other NSAIDs should not affect the isoprostane pathway
! Peroxidation of arachidonate by free radicals- primary epimerization mechanism in the production of isoeicosanoids
! eicosanoids act mainly in an fashion
! PGI2 (IP), PGF2" (FP), and TXA2 (TP) receptors- has a single
gene product
! PGE2- have 4 receptors ! PGD2 – have 2 receptors
! LTB4 (BLT1 and BLT2) and the cysteinyl leukotrienes- both have 2 receptors
#
All of these receptors are G protein-coupled
! have major effects on smooth muscle in the vasculature, airways, and gastrointestinal and reproductive tracts. three PGE2 synthases have been identified:
(PGE1)
a PGE1 derivative
andPGF2
Thromboxane(TXA2)- has undesirable properties (aggregation
hydration(for PGI2 and TXA2)
oxidation of the key 15-hydroxyl group to the
13 reduction,!-oxidation oxidation
Products of Lipoxygenase
5-, 12-, and 15-lipoxygenases LOX) hydroxy LTC4andLTD4are potent bronchoconstrictors and are
slow-reacting substance of anaphylaxis (SRS-A)that is secreted in asthma and
LTA4- the primary product of 5-LOX, can be converted with lipoxins XA4 andLXB4 in vitro
Epidermal accumulation of 12( )-HETE is a feature of psoriasis
Epoxygenase Products
Isoeicosanoids
direct free radical-based action
Isoprostanes are prostaglandin stereoisomers
COX is not needed for the formation of the isoprostanes, and its
BASIC PHARMACOLOGY OF EICOSANOIDS
MECHANISMS EFFECTS OF EICOSANOIDS
autocrine and a p aracrine
!
, while relaxing effects are mediated by the generation of cAMP.
SMOOTH MUSCLE
Contraction of smooth muscle is mediated by the release of calcium
VASCULAR SMOOTH MUSCLES PROSTAGLANDINS
potent vasoconstrictor smooth muscle cell and is the
has convincingly been shown to have this effect.
PGE2 PGI2
PGD2
*
testosterone, which up-regulates smooth muscle cell TP expression
! Another vasoconstrictor is the
PROSTAGLANDINS PGE2 ( PGF2 ! PGE2 PGE2 or PGF2 ! PROSTAGLANDINS Contraction by TXA2
! - are also bronchodilators
! act principally on smooth muscle in peripheral airways and are a thousand times more potent than histamine, both in vitro and in vivo
! also stimulate bronchial mucus secretion and cause mucosal edema
PLATELET
! Low concentrations of PGE2 enhance platelet aggregation (via EP3), whereas higher concentrations inhibit (via IP) ! Both
! TXA2 is the major product of COX-1, the only COX isoform expressed in mature platelets. Itself a platelet aggregator, TXA2 amplifies the effects of other, more potent, platelet agonists such as thrombin.
! Platelet COX-1-derived TXA2 biosynthesis is increased during platelet activation and aggregation and is irreversibly inhibited by chronic administration of aspirin at low doses
KIDNEY
! medulla and the cortex of the kidney synthesize prostaglandins, the medulla substantially more than the cortex
! COX-1 is expressed mainly in cortical and medullary collecting ducts and mesangial cells, arteriolar endothelium, and epithelial cells of Bowman’s capsule.
! COX-2 is restricted to the renal medullary interstitial cells, the macula densa, and the cortical thick ascending limb. ! major renal eicosanoid products are
followed by PGF2" and TXA2
! also synthesizes several hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 products, and epoxides !
pressure and regulating renal function, particularly in marginally functioning kidneys and volume-contracted states.
! renal cortical COX-2-derived PGE2 and PGI2 maintain renal blood flow and glomerular filtration rate through their local vasodilating effects
!
inhibit tubular sodium reabsorption, while products promote salt excretion in the collecting ducts.
! Loop diuretics, eg, furosemide, produce some of their effect by stimulating COX activity.
o patient response to a loop diuretic is diminished if a COX
inhibitor is administered concurrently
! TXA2 causes intrarenal vasoconstriction (and perhaps an ADH-like effect), resulting in a decline in renal function.
! Hypertension is associated with increased TXA2 and decreased PGE2 and PGI2 synthesis
o increased TXA2 formation has been reported in
nephrotoxicity TXA
vasoconstrictor (PGF2!
not a smooth muscle mitogen mitogen*
only eicosanoid that
Vasodilator (especially PGI2 and PGE2)- promote
vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium, primarily via the IP and EP4 receptors.
is a vasodilator produced by endothelial cells.
inhibits proliferation of smooth muscle cells, an action that may be particularly relevant in pulmonary hypertension.
may also function as a vasodilator—in particular as a dominant mediator of flushing induced by the lipid-lowering drug niacin
mitogenic effect is potentiated by exposure of smooth muscle cells to
isoprostane 8-iso-PGF2!
SMOOTH MUSCLES of the GIT
TXA Most of the prostaglandins and thromboxanes activate gastrointestinal smooth muscle
via EP3) andPGF2 ! (via
FP)-contract the longitudinal smooth muscle and weakly byPGI2- contract the circular muscle
(via EP4)- relaxes the circular smooth muscle
results in colicky cramps AIRWAY SMOOTH MUSCLES
TXA PGE2 and PGI2 RELAXATION
PGD2 and PGF2! CONTRACTION
cysteinyl leukotrienes
PGD2 and PGI2 inhibit aggregation
PGE2 and PGI2,
Prostaglandins play important roles in maintaining blood
COX- 2-derived prostanoids increase medullary blood flow and COX-1-derived
REPRODUCTIVE ORGANS
(FEMALE)
! Uterine muscle is
! .
! PGF2", together with oxytocin, is essential for the onset of parturition.
REPRODUCTIVE ORGANS
(MALE)
! A major source of these prostaglandins is the seminal vesicle; the prostate, despite the name “prostaglandin,” and the testes synthesize only small amounts.
! Smooth muscle-relaxing prostaglandins such as PGE1 enhance penile erection by relaxing the smooth muscle of the corpora cavernosa
CNS and PNS
1. FEVER
! PGE2 increases body temperature, predominantly via EP3
!
PGD2 and TXA2 do not
! Endogenous pyrogens release interleukin-1, which in turn promotes the synthesis and release of PGE2
! synthesis is blocked by aspirin and other antipyretic compounds.
2. SLEEP ! !
3. NEUROTRANSMISSION
! PGE compounds inhibit the release of norepinephrine from postganglionic sympathetic nerve endings
! Both COX-1 and COX-2 are expressed in the spinal cord and release prostaglandins in response to peripheral pain stimuli
INFLAMMATORY AND
IMMUNITY
! PGE2 and PGI2 are the predominant prostanoids associated with inflammation
• enhance edema formation and leukocyte infiltration
! PGE2 and PGI2, through activation of EP2 and IP, respectively, increase vascular permeability and leukocyte infiltration.
! TXA2 can also increase platelet-leukocyte interactions. ! PGE2 suppresses the immunologic response by inhibiting
differentiation of B lymphocytes into antibody-secreting plasma cells
! PGD2, a major product of mast cells, is a potent chemoattractant for eosinophils
• also induces chemotaxis and migration of TH2
lymphocytes
BONE METABOLISM
!
produced by osteoblasts and adjacent hematopoietic cells
o increase bone turnover
EYE
! PGE and PGF derivatives lower intraocular pressure
CANCER
! In familial polyposis coli, COX inhibitors significantly decrease polyp formation
!
prostanoid, facilitates tumor initiation, progression, and metastasis through multiple biologic effects, increasing proliferation and angiogenesis, inhibiting apoptosis, augmenting cellular invasiveness, and modulating immunosuppression
Blood Cells and Inflammation ! LTB4 ! cysteinyl leukotrienes -! Heart and
Smooth Muscle vascular smooth muscle cell proliferation and migration at low concentrations
! reduce myocardial
contractility and coronary blood flow, leading to cardiac depression. cells synthesize
neutrophils. The
bronchoconstrictors and cause increased micro- vascular permeability, plasma
exudation, and mucus secretion in the airways Renal System ! 20-HETE, which potently blocks the
smooth muscle cell Ca2+-activated K+ channel and leads to vasoconstriction of the renal arteries" HPN
contracted by PGF2#, TXA2, and low concentrations of PGE2
PGI2 and high concentrations of PGE2 causerelaxation
Exogenous PGF2# and PGI2 induce fever, whereas
PGD2 induces natural sleep
PGE2 infusion into the posterior hypothalamus causes wakefulness.
Prostaglandins are abundant in skeletal tissue and are
PGE2, which is considered the principal oncogenic
Effects of Lipoxygenase Cytochrome
P450-Derived Metabolites
, acting at the BLT1 receptor, is a potentchemoattractant for T
lymphocytes, eosinophils, monocytes, are potent chemoattractants for eosinophils and T lymphocytes.
also contribute to inflammation by increasing endothelial permeability, thus promoting migration of
inflammatory cells to the site of inflammation
Bothlipoxin A and lipoxin B inhibit natural killer cell cytotoxicity.
Cardiovascular—12( )- HETE promotes
LTC4 and LTD4
Gastrointestinal Human colonic epithelial LTB4, a chemoattractant for Airways— cysteinyl leukotrienes,
! block all the known pathways of eicosanoid synthesis.
- They inhibit phospholipase A2 activity, probably by interfering with phospholipid binding, thus preventing the release of arachidonic acid.
! NSAIDs (eg,
- block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity.
!
! 5-LOX inhibitor (
receptor for leukotrienes ( and
FEMALE REPRODUCTIVE ORGANS
! PGE2 and PGF2" have potent oxytocic actions.
! by promoting uterine contractions
!
vaginally for oxytocic use.
! it is approved for
induction of labor in patients at or near term.
! A stimulates the contraction of the uterus through- out
pregnancy.
! also directly affects the collagenase of the cervix,
resulting in softening.
• Excreted in urine • T" is 2.5- 5 mins.
• 20-mg dinoprostone vaginal suppository repeated at
3-to 5-hour intervals – recommended dose for abortifacient purposes
• mean time to abortion is 17 hours,
! Antiprogestins (eg,
oral oxytocic synthetic analog of PGE1 ( early abortion.
!
! used to induce second-trimester abortions and to
control postpartum hemorrhage that is not responding to conventional methods of management.
SIDE EFFECTS:
! Prostaglandins have moderate AE, with a slightly higher incidence of nausea, vomiting, and diarrhea than that produced by oxytocin ! PGF2" has more gastrointestinal toxicity than PGE2
! PGF2" is a bronchoconstrictor and should be used with caution in women with asthma
! both PGE2 and PGF2" pass the fetoplacental barrier, fetal toxicity is uncommon
"
labor in women with preeclampsia-eclampsia or cardiac and renal
diseases because, unlike oxytocin, they have no antidiuretic effect.
Dysmenorrhea
!
in patients with primary dysmenorrhea !
potency and is quickly hydrolyzed,
MALE REPRODUCTIVE ORGANS
! (PGE1) is a second-line treatment for erectile dysfunction
o
related to the algesic effects of PGE derivatives
RENAL SYSTEM
! Bartter’s syndrome – results when synthesis of prostaglandins is increased.
! characterized by low-to-normal blood pressure,
decreased sensitivity to angiotensin, hyperreninemia, hyperaldosteronism, and excessive loss of K+
CARDIOVASCULAR SYSTEM
! !
vascular resistance ! PGI2 (
• side effects include flushing, headache,
hypotension, nausea, and diarrhea. !
! may be delivered by subcutaneous or intravenous infusion.
!
! use of PGE1 and PGI2 compounds in Raynaud’s phenomenon and peripheral arterial disease
!
! COX inhibitors are often used to inhibit synthesis of PGE2 and so close the ductus.
BLOOD
! Chronic administration of low-dose aspirin" selectively and irreversibly inhibits platelet COX-1 without modifying the activity of systemic COX-1 or COX-2
RESPIRATORY SYSTEM
!
form " promotes !
were once thought to be primary mediators in ! leukotriene-receptor inhibitors (eg,
are effective in asthma.
! Corticosteroids and cromolyn are also useful in asthma
INHIBITION OF EICOSANOID SYNTHESIS
Corticosteroids
indomethacin, ibuprofen)
Aspirin is an irreversible COX inhibitor.
zileuton) and selective antagonists of the CysLT1 zafirlukast, montelukast, pranlukast-used clinically in mild to moderate asthma.
CLINICALPHARMACOLOGYOF EICOSANOIDS
Dinoprostone,a synthetic preparation of PGE2, is administered inducing abortion in the second trimester of pregnancy, formissed abortion, for benign hydatidiform mole, and for ripening of the cervix for
mifepristone) have been combined with an misoprostol) to produce Arboprost tromethamine –analog of PGF2"
PGE2 and PGF2# should be superior to oxytocin for inducing
NSAIDs successfully inhibit the formation of these prostaglandins Aspirin is also effective in dysmenorrhea, but because it has low
Alprostadil
Penile pain is a frequent side effect, which may be
Pulmonary HPN
PGI2 lowers peripheral, pulmonary, and coronary epoprostenol)
Iloprost-prostacyclin analogs used also for pHPN
Treprostinil-Peripheral Vascular Disease
PDA
PGE2 is a powerful bronchodilator when given in aerosol COUGHING
PGF2! and TXA2 are both strong bronchoconstrictors and
ASTHMA. zafirlukast, montelukast)
GASTROINTESTINAL SYSTEM
!
- approved indication is for prevention of NSAID-induced peptic ulcers
IMMUNE SYSTEM
! !
rejection process
! TXA2 increases during acute rejection !
of acute rejection because of their lymphotoxic effects, inhibit both phospholipase and COX-2 activity.
! Inflammation
! Aspirin has been used to treat arthritis ! Rheumatoid Arthritis
! Eicosanoids- amplify the inflammatory response
GLAUCOMA
!
first prostanoid used for glaucoma
o Other drugs are: and
o Adverse effects include irreversible brown
pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis
Misoprostol-orally active synthetic analog of PGE1
Cell- Mediated Organ Transplant Rejection
PGI2 to renal transplant patients has reversed the
Corticosteroids- the first- line drugs used for treatment
Latanoprost-a stable long-acting PGF2" derivative, was the
bimatoprost, travoprost, unoprostone