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ایکوزانوئیدها دکتر محمد ربانی گروه فارماکولوژی 94 آبان
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Introduction The COX pathway Eicosanoids properties: Prostanoids: PGs, TXs, Prostacycline Leukotrienes Isoprostanes COX inhibitors Clinical Application Dietary Manipulation Drug Pictures
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اهمیت ایکوزانوئیدها
Have you ever had pain and taken an “Aspirin” for relief?
Have you ever been feverish?
Have you seen patient suffering from asthma?
These common symptoms/ problems are related to a group of substances known as eicosanoids?
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هىرمىوهای لىکال که تصىرت اختصاصی تز روی سلىلهای مجاور اثز گذاری می کىد وقش مهمی در کىتزل تسیاری اس فزایىدهای فیشیىلىژیک مثل التهاب و ایمىی ایکىساوىئیدها تصىرت پیش ساخته،تز خالف هیستامیه در سلىل وجىد ودارود تعد اس1930 مطالعه تز روی ایکىساوىئیدها اس سال گشارشی که در آن یک ماده لیپیدی مىجة اوقثاض عضالت صاف رحم گزدید شزوع شد
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ساختار و نحوه ساخت Eicosanoids (20 carbons) are found in the animal kingdom and a variety of plants.
Arachidonic acid is oxygenated by 4 separate routes:
The eicosanoids are oxygenation products of acid arachidonic (AA) polyunsaturated fatty acid.
All of their receptors appear to be G protein-linked.
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Introduction (Cont’d)
CO2H
arachidonic acid C20:45,8,11,14
Acid arachidonic is released from membrane by phospholipase A2 (PLA2).
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Prostanoids effect
There are two isozymes for COX enzymes: COX1 and COX2.
COX-1 generates prostanoids for "housekeeping" such as gastric epithelial cytoprotection.
COX-2 is the major source of prostanoids in inflammation and cancer.
This distinction is overly simplistic: Endothelial COX-2 produces prostacyclin (PGI2 ).
Prostanoids: PGs, TXs, Prostacyclin
PGs have clinical importance.
Prostacyclin (PGI2 ) is synthesized by endothelium and is a powerful vasodilator and inhibitor of platelet aggregation.
TXA2 is a potent vasoconstrictor and activator of platelet aggregation.
It is also a smooth muscle cell mitogen and is the only eicosanoid to have this effect.
Renal COX-2 products are important for normal renal function.
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Leukotriene
The metabolism of AA by lipoxygenases (5LOX) results in the production of leukotrienes.
Leukotrienes are predominantly generated in leukocytes.
This pathway is important since it is associated with asthma, anaphylactic shock, and cardiovascular disease.
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Isoprostanes
COX inhibitors
Isoprostanes are prostaglandin stereoisomers.
NSAIDs exert their therapeutic effects through inhibition of the COXs.
Aspirin and other NSAIDs do not affect the isoprostane pathway.
Degree of COX-2 inhibition varies: celecoxib = diclofenac < rofecoxib.
They have potent vasoconstrictor effects in the renal and other vascular beds.
Indomethacin is slightly selective for COX-1.
Ibuprofen is equipotent on COX-1 and COX2.
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COX inhibitors
COX inhibitors
Aspirin acetylates and inhibits both enzymes covalently.
NSAIDs usually do not inhibit lipoxygenase activity at concentrations that inhibit COX activity.
In anuclear platelets, COX-1 cannot be restored via protein biosynthesis.
NSAIDs may cause more substrate to be metabolized through the lipoxygenase pathways.
This results in extended inhibition of TXA2 synthesis by aspirin.
This leads to an increased formation of the leukotrienes.
A 5-LOX inhibitor and antagonists of the leukotriene receptors are used clinically in asthma.
Corticosteroids also block all the known pathways of eicosanoid synthesis.
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Female Reproductive Organ
Clinical Application
Female Reproductive Organ
Male Reproductive System
Inflammation & Immunity
Gastrointestinal Tract
Respiratory System
Cardiovascular
Glaucoma
Kidney
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Uterine muscle is contracted by PGF2α, TXA2, and low concentrations of PGE2.
PGI2 and high concentrations of PGE2 cause relaxation.
PGF2α, together with oxytocin, is essential for the onset of childbirth.
PGE2 and PGF2α have potent oxytocic actions.
Cancer
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Abortion-PGE2
Abortion-PGE1
Dinoprostone, (PGE2), is approved for abortion in the second trimester and for induction of normal labor (softens the cervis and fastens the onset and duration of delivery.
Antiprogestins (mifepristone) have been combined with an oral PGE1 (misoprostol) to produce early abortion.
Dinoprostone is metabolized on the first pass (about 95%).
The major toxicities are cramping pain and diarrhea.
In >25% of cases the abortion is incomplete and requires additional intervention.
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PGE1 - Gemeprost
Abortion- PGF2α
An analogue of PGE1.
It is used as a treatment for obstetric bleeding.
Administered vaginally, used with mifepristone as an abortifacient
It is safe but expensive, and requires specific conditions for storage and transportation.
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A PGF2α, carboprost tromethamine is used for abortions and to control PPH that is not responding to other methods.
The success rate is 80%. Vomiting and diarrhea is common, because of GI smooth muscle stimulation.
Transient bronchoconstriction may also occur.
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Facilitation of Labor
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Facilitation of Labor (Cont’d)
PGE2 and PGF2α initiate and stimulate labor but PGF2 is one tenth as potent as PGE2.
These agents and oxytocin have similar success rates and induction-to-delivery intervals.
The most common usage is local application of PGE2 (dinoprostone) to promote labor through ripening of the cervix.
PGF2α is a bronchoconstrictor and should be used with caution in women with asthma.
Oral PGE2 is superior to the oral oxytocin and in most studies is as efficient as IV oxytocin.
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Dysmenorrhea
Primary dysmenorrhea is attributable to increased endometrial synthesis of PGE2 & PGF2α.
This causes contractions of the uterus that lead to ischemic pain. NSAIDs successfully inhibit the formation of these PGs and relieve dysmenorrhea in 75–85% of cases.
Aspirin is also effective in dysmenorrhea, but may increase the amount of menstrual bleeding.
Male Reproductive System
Intracavernosal injection or urethral suppository of alprostadil (PGE1) is a second-line treatment for erectile dysfunction.
Penile pain is a frequent side effect, which may be related to the algesic effects of PGE.
Prolonged erection and priapism are side effects that occur in less than 4% of patients.
When injected, alprostadil is used alone or in combination with either papaverine or phentolamine.
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Inflammation & Immunity
Inflammation and Immunity (Cont’d)
Some leukotrienes are potent chemoattractants.
PGE2 inhibits differentiation of B lymphocytes into plasma cells.
They increase endothelial permeability thus promoting migration of inflammatory cells.
So it suppresses the humoral antibody response.
The leukotrienes are strongly implicated in the chronic diseases (asthma & IBD).
PGE2, PGF2α and PGI2 can induce fever.
Their synthesis is blocked by antipyretic compounds.
PGE2 and PGI2 are the predominant prostanoids associated with inflammation.
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Gastrointestinal Tract
Gastrointestinal Tract (Cont’d)
Most of the PGs, thromboxanes, and leukotrienes contract GI muscles.
Misoprostol is an orally active PGE1 for prevention of NSAID-induced peptic ulcers.
Both longitudinal and circular muscles are activated.
It causes abdominal discomfort and occasional diarrhea.
Administration of either PGE2 or PGF2α results in colicky cramps.
Selective COX-2 inhibitors were developed in an effort to spare gastric COX-1.
In this way, cytoprotection by locally synthesized PGE2 and PGI2 is undisturbed.
This benefit is seen only with highly selective inhibitors and may be offset by increased cardiovascular toxicity.
The PGE compounds protect against peptic ulcers produced by either steroids or NSAIDs.
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Respiratory System (Cont’d)
Respiratory System
Respiratory smooth muscle is relaxed by PGE2 and PGI2 and contracted by PGD2, TXA2, and PGF2.
The leukotrienes (LTC4 and LTD4) are also bronchoconstrictors (a thousand times more potent than histamine).
They also stimulate mucus secretion, and increase microvascular permeability and plasma exudation.
Bronchospasm occurs in 10% of people taking NSAIDs, because of a shift from COX to LOX.
Leukotriene-receptor inhibitors (zafirlukast, montelukast) are effective in asthma.
A LOX inhibitor (zileuton) has also been used in asthma but is not as popular as the receptor inhibitors.
Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release.
Cromolyn inhibits the release of eicosanoids, histamine and platelet-activating factor from mast cells.
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Ductus Arteriosus
The ductus arteriosus is a passage between two major blood vessels, the pulmonary artery aorta.
The ductus arteriosus usually closes one or two days after birth, but sometimes it remains open (patent) after birth. If the ductus arteriosus remains open, it's called a patent ductus arteriosus (PDA).
Patency of the fetal ductus arteriosus depends on PGE2.
At birth, increased PGE2 metabolism closes ductus arteriosus but sometimes it remains open (patent) after birth
In certain types of congenital heart disease, ductus arteriosus should remain open before surgery.
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Ductus Arteriosus (Cont’d)
Alprostadil (PGE1) which is similar to PGE2 is used in PDA (Patency Ductus Arteriosus)
Prolonged treatment causes ductal fragility and rupture.
In PDA, COX inhibitors inhibit synthesis of PGE2 and close the ductus.
In premature infants, failure of ductus closure causes respiratory distress.
They are treated efficiently with indomethacin.
This treatment often precludes cardiac surgery.
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Pulmonary Hypertension
PGI2 lowers peripheral, pulmonary, and coronary resistance.
It has been used to treat pulmonary and also portopulmonary hypertension.
Epoprostenol a preparation of PGI2 is used for primary pulmonary hypertension.
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Pulmonary Hypertension…
Epoprostenol has a short half-life (3–5 min.) so continuous prolonged IV infusion through a central line is necessary.
Several drugs with longer half-lives are used clinically.
Iloprost (half-life about 30 minutes), & Treprostinil (half-life about 4 hours) are some examples.
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Blood Cells
low-dose aspirin (81 mg/d) selectively and irreversibly inhibits platelet COX-1 and TXA2 production.
Low-dose aspirin reduces the secondary incidence of heart attack, stroke & MI.
However, it elevates the low risk of serious GI bleeding twofold.
However, in this case, the benefit versus risk of GI bleeding is less clear.
Blood Cells …
Reversible nonselective NSAIDs (ibuprofen) do not have this effect.
Selective COX-2 inhibitors do not alter platelet TXA2 and are not platelet inhibitors.
However, COX-2-derived PGI2 generation is suppressed during selective COX-2 inhibition.
This removes a restraint on the cardiovascular action of TXA2.
It is highly likely that selective COX-2 inhibition contributes to the increased thrombotic events in humans.
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Glaucoma
Kidney
The major renal eicosanoid products are PGE2 and PGI2 , followed by PGF2α and TXA2.
Latanoprost, a PGF2α derivative, is used for glaucoma.
PGs play important roles in maintaining blood pressure and regulating renal function.
Similar drugs with ocular hypotensive effects are: bimatoprost, travoprost, and unoprostone.
This is crucial in marginally functioning kidneys and volume-contracted states.
Adverse effects include irreversible brown pigmentation of the iris and eyelashes, and conjunctivitis.
Renal COX-2-derived PGE2 and PGI2 maintain renal blood flow and GFR through their local vasodilating effects.
PGE and PGF derivatives lower IOP but its mechanism is unclear.
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Kidney …
Cancer
Loop diuretics, produce some of their effect by stimulating COX activity.
COX-2 expression is associated with markers of tumor progression in breast cancer.
This increases the synthesis of the vasodilator PGs.
Pharmacologic inhibition of COX-2 restrains tumor formation in colon, breast, and lung cancers.
So, patient response to a loop diuretic is diminished if a COX inhibitor is administered.
The incidental use of NSAIDs is associated with significant reductions in risk of cancer.
In familial polyposis coli, COX inhibitors significantly decrease polyp formation.
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