The Eicosanoids:Prostaglandins, Thromboxanes,

LeukotrienesBy

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

The Eicosanoids:Prostaglandins, Thromboxanes, Leukotrienes

Introduction The COX pathway Leukotriene Synthesis Isoprostanes Inhibition of Eicosanoid Synthesis Organ effects Clinical Application Dietary Manipulation Drug Pictures

Introduction Eicosanoids (20 carbons) are found in the animal

kingdom and a variety of plants.

The eicosanoids are oxygenation products of acid arachidonic (AA) polyunsaturated fatty acid.

Acid arachidonic is released from membrane by phospholipase A2 (PLA2).

Introduction (Cont’d)

Arachidonic acid is oxygenated by 4 separate routes: The cyclooxygenase (COX) Lipoxygenase (LOX) Isoprostane pathways P450 epoxygenase

All of their receptors appear to be G protein-linked. The eicosanoids act in an autocrine & paracrine

fashion.

Pathways of arachidonic acid (AA) release and metabolism.

Prostanoid receptors and their signaling pathways. fMLP, formylated MetLeuPhe, a small peptide receptor; PLC-, phospholipase C-. All of the receptors shown are of the 7-transmembrane, G-protein coupled type. The terms "relaxant," "contractile," and "inhibitory" refer to the phylogenetic characterization of their primary effects. **All EP3 isoforms couple through Gi but some can also activate Gs or G12/13 pathways. RhoGEF, rho guanine nucleotide exchange factor. See text for additional details.

The COX Pathway

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 ). Renal COX-2 products are important for normal renal

function.

The COX Pathway (Cont’d)

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.

The mitogenic effect is potentiated by exposure of smooth muscle cells to testosterone.

Prostaglandins

Prostanoid biosynthesis. Compound names are enclosed in boxes.

Chemical structures of some prostaglandins and prostaglandin analogs currently in clinical use.

The COX Pathway (Cont’d)

PGF2α is also a vasoconstrictor but is not a smooth muscle

mitogen.

Vasodilator prostaglandins, (PGI2 & PGE2) increase cAMP and decrease smooth muscle intracellular calcium.

COX-2 inhibitors preserve the GI and renal functions by COX-1, thereby reducing toxicity.

COX-2 inhibition decreases PGI2 but not platelet COX-1-derived TXA2.

This increases cardiovascular events in patients taking selective COX-2 inhibitors.

Leukotriene Synthesis

The metabolism of AA by lipoxygenases (5-LOX) 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.

Leukotriene (LT) biosynthesis. LTC4, LTD4 and LTE4 are known collectively as the cysteinyl (Cys) LTs. FLAP, 5-LOX-activating protein; GT, glutamyl transpeptidase; GL, glutamyl leukotrienase. *Additional products include 5,6-; 8,9-; and 14,15-EET; and 19-, 18-, 17-, and 16-HETE.

Leukotriene Synthesis (Cont’d)

LTC4 and LTD4 are potent bronchoconstrictors involved in asthma and anaphylaxis.

There are four current approaches to antileukotriene drug development: 5-LOX inhibitors

Leukotriene-receptor antagonists

Inhibitors of FLAP (5-LOX-activating protein )

Phospholipase A2 inhibitors.

Isoprostanes

Isoprostanes are prostaglandin stereoisomers. Aspirin and other nonsteroidal inhibitors of COX do

not affect the isoprostane pathway. They have potent vasoconstrictor effects in the renal

and other vascular beds.

Inhibition of Eicosanoid Synthesis

NSAIDs exert their therapeutic effects through inhibition of the COXs.

Indomethacin is slightly selective for COX-1.

Ibuprofen is equipotent on COX-1 and COX-2.

For inhibition of COX-2: celecoxib = diclofenac < rofecoxib.

Selective COX-2 inhibitors vary in their degree of selectivity.

Inhibition of Eicosanoid Synthesis (Cont’d)

Aspirin acetylates and inhibits both enzymes covalently.

In anuclear platelets, COX-1 cannot be restored via protein biosynthesis.

This results in extended inhibition of TXA2 synthesis by aspirin.

Low doses (< 100 mg/day) inhibit preferentially platelet COX-1, but higher doses inhibit both enzymes.

Inhibition of Eicosanoid Synthesis (Cont’d)

NSAIDs usually do not inhibit lipoxygenase activity at concentrations that inhibit COX activity.

NSAIDs may cause more substrate to be metabolized through the lipoxygenase pathways.

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.

Organ Effects

The prostaglandins and thromboxanes have major effects on:

Smooth muscle in the vasculature, airways, and gastrointestinal and reproductive tracts

CNS, autonomic presynaptic nerve terminals, sensory nerve endings

Platelets and monocytes

Endocrine organs

Adipose tissue

Kidneys

Eye

Clinical Application Female Reproductive Organ

Male Reproductive System

Inflammation & Immunity

Gastrointestinal Tract

Respiratory System

Musculo skeletal

Cardiovascular

Glaucoma

Kidney

Cancer

Female Reproductive Organ

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 parturition.

Abortion

PGE2 and PGF2α have potent oxytocic actions.

The drugs are used for first- and second-trimester abortion and for ripening the cervix before abortion.

These PGs soften the cervix by increasing proteoglycan & changing the biophysical properties of collagen.

Dinoprostone, (PGE2), is approved for abortion in the second trimester and for induction of normal labor.

Abortion (Cont’d)

Dinoprostone is metabolized on the first pass through the lungs (about 95%).

For abortifacient purposes, the mean time to abortion is 17 hours.

In >25% of cases the abortion is incomplete and requires additional intervention.

PGE2 is also used for softening of the cervix, this fastens the onset and duration of delivery.

the vaginal route has been associated with an increased incidence of sepsis, so the oral route is now recommended.

Abortion (Cont’d)

Antiprogestins (mifepristone) have been combined with an oral PGE1 (misoprostol) to produce early abortion.

The major toxicities are cramping pain and diarrhea.

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.

Facilitation of Labor

PGE2 and PGF2α initiate and stimulate labor but PGF2 is one tenth as potent as PGE2.

There is no difference in the efficacy of PGE2 and PGF2α .

The most common usage is local application of PGE2 (dinoprostone) to promote labor through ripening of the cervix.

Facilitation of Labor (Cont’d)

These agents and oxytocin have similar success rates and induction-to-delivery intervals.

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.

Dysmenorrhea

Primary dysmenorrhea is attributable to increased endometrial synthesis of PGE2 and 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.

Inflammation & Immunity

PGE2 and PGI2 are the predominant prostanoids associated with inflammation.

PGE2 inhibits differentiation of B lymphocytes into plasma cells.

So it suppresses the humoral antibody response.

PGE2, PGF2α and PGI2 can induce fever.

Their synthesis is blocked by antipyretic compounds.

Inflammation and Immunity (Cont’d)

Some leukotrienes are potent chemoattractants.

They increase endothelial permeability thus promoting migration of inflammatory cells.

The leukotrienes are strongly implicated in the chronic diseases (asthma & IBD).

Gastrointestinal Tract

Most of the PGs, thromboxanes, and leukotrienes contract GI muscles.

Both longitudinal and circular muscles are activated.

Administration of either PGE2 or PGF2α results in colicky cramps.

The PGE compounds protect against peptic ulcers produced by either steroids or NSAIDs.

Gastrointestinal Tract (Cont’d)

Misoprostol is an orally active PGE1 for prevention of NSAID-induced peptic ulcers.

It causes abdominal discomfort and occasional diarrhea.

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.

Respiratory smooth muscle is relaxed by PGE2 and PGI2 and contracted by PGD2, TXA2, and PGF2.

The leukotrienes are also bronchoconstrictors (a thousand times more potent than histamine).

LTC4 and LTD4, are potent bronchoconstrictors.

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.

Respiratory System

Respiratory System (Cont’d)

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.

Musculo Skeletal

PGs mediate the effects of mechanical and inflammatory forces on bones.

COX inhibitors also slow skeletal muscle healing. They interfere with PG effects on myocytes in

response to injury.

Ductus Arteriosus

Patency of the fetal ductus arteriosus depends on PGE2.

At birth, increased PGE2 metabolism closes ductus arteriosus.

In certain types of congenital heart disease, ductus arteriosus should remain open before surgery.

They consist of: transposition of the great arteries, pulmonary atresia and pulmonary artery stenosis.

Alprostadil (PGE1) which is similar to PGE2 is used.

Prolonged treatment causes ductal fragility and rupture.

Ductus Arteriosus (Cont’d)

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.

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.

Pulmonary Hypertension (Cont’d)

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.

Blood Cells

low-dose aspirin (81 mg/d) selectively and irreversibly inhibits platelet COX-1 and TXA2 production.

It does not modify systemic COX-1 or COX-2.

Macrophage COX-2 contributes 10% of the increment in TXA2 in smokers (the rest is derived from platelets).

Cardioprotective actions of low- and high-dose aspirin suggest an inverse dose-response relationship.

This reflects increasing inhibition of PGI2 synthesis at higher doses of aspirin.

Blood Cells (Cont’d)

Low-dose aspirin reduces the secondary incidence of heart attack and stroke by 25%.

However, it elevates the low risk of serious GI bleeding twofold.

Low-dose aspirin also reduces the incidence of first myocardial infarction.

However, in this case, the benefit versus risk of GI bleeding is less clear.

Blood Cells (Cont’d)

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.

Glaucoma

PGE and PGF derivatives lower IOP but its mechanism is unclear.

Latanoprost, a PGF2α derivative, is used for glaucoma.

Similar drugs with ocular hypotensive effects are: bimatoprost, travoprost, and unoprostone.

Adverse effects include irreversible brown pigmentation of the iris and eyelashes, and conjunctivitis.

Kidney

The major renal eicosanoid products are PGE2 and PGI2 , followed by PGF2α and TXA2.

PGs play important roles in maintaining blood pressure and regulating renal function.

This is crucial in marginally functioning kidneys and volume-contracted states.

Renal COX-2-derived PGE2 and PGI2 maintain renal blood flow and GFR through their local vasodilating effects.

Kidney (Cont’d)

Loop diuretics, produce some of their effect by stimulating COX activity.

This increases the synthesis of the vasodilator PGs.

So, patient response to a loop diuretic is diminished if a COX inhibitor is administered.

Cancer

COX-2 expression is associated with markers of tumor progression in breast cancer.

Pharmacologic inhibition of COX-2 restrains tumor formation in colon, breast, and lung cancers.

The incidental use of NSAIDs is associated with significant reductions in risk of cancer.

In familial polyposis coli, COX inhibitors significantly decrease polyp formation.

Cancer (Cont’d)

NSAIDs have reduced the risk of breast cancer, especially for hormone receptor-positive tumors.

COX-1 as well as COX-2 is implicated in the production of pro-oncogenic prostanoids.

PGE2 is considered the principal pro-oncogenic prostanoid.

Dietary Manipulation

Linoleic acid or eicosapentaenoic acid yield products that differ quantitatively and qualitatively from those derived from AA.

This shift in product formation is the basis for using cold-water fish or plants as nutritional supplements.

Two approaches have been used: Adding corn, safflower, and sunflower oils, which contain

linoleic acid (C18:2), to the diet.

Adding omega-3 fatty acids from cold-water fish.

Dietary Manipulation (Cont’d)

Both types of diet change the cell membranes by replacing arachidonic acid with the dietary fatty acids.

Diets high in fish oils impact ex vivo indices of platelet and leukocyte function, blood pressure, and triglycerides.

Diets high in fatty fish reduce the incidence of MI & sudden cardiac death.

SummaryIn English

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