18

C H A P T E R

The Eicosanoids:
Prostaglandins,
Thromboxanes,
Leukotrienes, & Related
Compounds
John Hwa, MD, PhD, & Kathleen Martin, PhD∗

C ASE STUDY

A 40-year-old woman presented to her doctor with pulmonary pressures, and right ventricular enlargement.
a 6-month history of increasing shortness of breath. Cardiac catheterization confirmed the severely elevated
This was associated with poor appetite and ankle swell- pulmonary pressures. She was commenced on appropri-
ing. On physical examination, she had elevated jugular ate therapies. Which of the eicosanoid agonists have been
venous distention, a soft tricuspid regurgitation murmur, demonstrated to reduce both morbidity and mortality in
clear lungs, and mild peripheral edema. An echocardio- patients with such a diagnosis? What are the modes of
gram revealed tricuspid regurgitation, severely elevated action?

The eicosanoids are oxygenation (oxidation) products of poly- ARACHIDONIC ACID & OTHER
unsaturated 20-carbon long-chain fatty acids (eicosa, Greek
for “twenty”). They are ubiquitous in the animal kingdom and
POLYUNSATURATED PRECURSORS
are also found—together with their precursors—in a variety of Arachidonic acid (AA), or 5,8,11,14-eicosatetraenoic acid, the
plants. They constitute a very large family of compounds that most abundant of the eicosanoid precursors, is a 20-carbon (C20)
are highly potent and display an extraordinarily wide spectrum fatty acid containing four double bonds (designated C20:4–6).
of important biologic activities. Thus, their specific receptors, The first double bond in AA occurs at 6 carbons from the methyl
receptor ligands, and enzyme inhibitors, and their plant and end, defining AA as an omega-6 fatty acid. AA must first be released
fish oil precursors, are therapeutic targets for a growing list of or mobilized from the sn-2 position of membrane phospholipids
conditions. by one or more lipases of the phospholipase A2 (PLA2) type
(Figure 18–1) for eicosanoid synthesis to occur. The phospho-
lipase A2 superfamily consists of 16 groups (over 30 isoforms),
∗
The authors thank Emer M. Smyth, PhD, and Garret A. FitzGerald, MD, with at least three classes of phospholipases contributing to ara-
for their contributions to previous editions of this chapter. chidonate release from membrane lipids: (1) cytosolic (c) PLA2,

321
322 SECTION IV Drugs with Important Actions on Smooth Muscle

Arachidonic acid esterified in

membrane phospholipids

Free radicals
Diverse physical, chemical,
inflammatory, and mitogenic stimuli Phospholipase A2
Isoprostanes
Epoxyeicosatrienoic acids
(EETs)
9 8 6 5 1
COOH
Cytochrome
P450 AA (20:4 cis D5,8,11,14)
20

11 12 14 15 19

Lipoxygenases Cyclooxygenases
(LOX) (COX)

HETEs Prostaglandins
Leukotrienes Prostacyclin Prostanoids
Lipoxins Thromboxane

FIGURE 18–1 Pathways of arachidonic acid (AA) release and metabolism.

and (2) secretory (s) PLA2, which are calcium-dependent; and of sustained or intense stimulation of AA production. AA can also
(3) calcium-independent (i) PLA2. Chemical and physical stimuli be released from phospholipase C-generated diacylglycerol esters
activate the Ca2+-dependent translocation of cPLA2, to the plasma by the action of diacylglycerol and monoacylglycerol lipases.
membrane, where it releases arachidonate for metabolism to eico- Following mobilization, AA is oxygenated by four separate
sanoids. In contrast, under nonstimulated conditions, AA liber- routes: enzymatically via the cyclooxygenase (COX), lipoxygen-
ated by iPLA2 is reincorporated into cell membranes, so there is ase, and P450 epoxygenase pathways; and nonenzymatically via
negligible eicosanoid biosynthesis. While cPLA2 dominates in the the isoeicosanoid pathway (Figure 18–1). Among factors deter-
acute release of AA, inducible sPLA2 contributes under conditions mining the type of eicosanoid synthesized are (1) the substrate
lipid species, (2) the cell type, and (3) the cell stimulus. Distinct
but related products can be formed from precursors other than
AA. For example, an omega-6 fatty acid such as homo-γ-linoleic
ACRONYMS acid (C20:3–6), in comparison to the omega-3 fatty acid eicosa-
AA Arachidonic acid pentaenoic acid (C20:5–3), yields products that differ quantita-
COX Cyclooxygenase tively and qualitatively from those derived from AA. This serves
DHET Dihydroxyeicosatrienoic acid
as the basis for dietary manipulation of eicosanoid generation
using fatty acids obtained from cold-water fish or from plants
EET Epoxyeicosatrienoic acid
as nutritional supplements. For example, thromboxane (TXA2),
HETE Hydroxyeicosatetraenoic acid a powerful vasoconstrictor and platelet agonist, is synthesized
HPETE Hydroxyperoxyeicosatetraenoic acid from AA via the COX pathway. COX metabolism of eicosa-
LTB, LTC Leukotriene B, C, etc pentaenoic acid (an omega-3 fatty acid) yields TXA3, which is
LOX Lipoxygenase relatively inactive. 3-Series prostaglandins, such as prostaglandin
LXA, LXB Lipoxin A, B
E3 (PGE3), can also act as partial agonists or antagonists, thereby
having reduced activity in comparison to their AA-derived
NSAID Nonsteroidal anti-inflammatory drug
2-series counterparts. The hypothesis that dietary eicosapentae-
PGE, PGF Prostaglandin E, F, etc noate (omega-3 fatty acid) substitution for arachidonate could
PLA, PLC Phospholipase A, C reduce the incidence of cardiovascular disease and cancer is an
TXA, TXB Thromboxane A, B area of intense study.
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 323

SYNTHESIS OF EICOSANOIDS F in PGE and PGF) and (2) in the number of double bonds in the
side chains (indicated by the subscript, eg, PGE1, PGE2). PGH2 is
Products of Prostaglandin Endoperoxide metabolized by prostacyclin, thromboxane, and PGF synthases
(PGIS, TXAS, and PGFS) to PGI2, TXA2, and PGF2α, respec-
Synthases (Cyclooxygenases) tively. Two additional enzymes, 9,11-endoperoxide reductase
Two unique COX isozymes convert AA into prostaglandin endo- and 9-ketoreductase, provide for PGF2α synthesis from PGH2
peroxides. PGH synthase-1 (COX-1) is expressed constitutively and PGE2, respectively. At least three PGE2 synthases have been
in most cells. In contrast, PGH synthase-2 (COX-2) is readily identified: microsomal (m) PGES-1, the more readily inducible
inducible, its expression levels being dependent on the stimu- mPGES-2, and cytosolic PGES. There are two distinct PGDS
lus. COX-2 is an immediate early-response gene product that isoforms, the lipocalin-type PGDS and the hematopoietic PGDS.
is markedly up-regulated by shear stress, growth factors, tumor Several products of the arachidonate series are of current clini-
promoters, and cytokines, consistent with the presence of multiple cal importance. Alprostadil (PGE1) may be used for its smooth
regulatory motifs in the promoter and 3′ untranslated regions of muscle relaxing effects to maintain the ductus arteriosus patent in
the COX-2 gene. Put simply, COX-1 generates prostanoids for some neonates awaiting cardiac surgery and in the treatment of
“housekeeping” functions, such as gastric epithelial cytoprotec- impotence. Misoprostol, a PGE1 derivative, is a cytoprotective
tion, whereas COX-2 is the major source of prostanoids in inflam- prostaglandin used in preventing peptic ulcer and in combination
mation and cancer. However, there are additional physiologic and with mifepristone (RU-486) for terminating early pregnancies.
pathophysiologic processes in which each enzyme is uniquely Dinoprostone (PGE2) and PGF2α are used in obstetrics to induce
involved, and others in which they function coordinately. For labor. Latanoprost and several similar compounds are topically
example, endothelial COX-2 is the primary source of vascular active PGF2α derivatives used in ophthalmology to reduce intra-
prostacyclin (PGI2), whereas renal COX-2-derived prostanoids ocular pressure in open-angle glaucoma or ocular hypertension.
are important for normal renal development and maintenance Prostacyclin (PGI2) is synthesized mainly by the vascular endo-
of function. Nonsteroidal anti-inflammatory drugs (NSAIDs; thelium and is a powerful vasodilator and inhibitor of platelet
see Chapter 36) exert their therapeutic effects through inhibition aggregation. Synthetic PGI2 (epoprostenol) and PGI2 analogs
of the COXs. Most older NSAIDs, like indomethacin, sulin- (iloprost, treprostinil) are used to treat pulmonary hypertension
dac, meclofenamate, and ibuprofen nonselectively inhibit both and portopulmonary hypertension. In contrast, thromboxane
COX-1 and COX-2, whereas the selective COX-2 inhibitors (TXA2) has undesirable properties (platelet aggregation, vaso-
follow the order celecoxib = diclofenac = meloxicam = etodolac < constriction). Therefore TXA2-receptor antagonists and synthesis
valdecoxib << rofecoxib < lumiracoxib = etoricoxib for increasing inhibitors have been developed for cardiovascular indications,
COX-2 selectivity. Aspirin acetylates and inhibits both enzymes although these (except for aspirin) have yet to establish a place in
covalently and hence irreversibly. Low doses (< 100 mg/d) inhibit clinical usage, and, in a recent large clinical trial, TXA2 receptor
preferentially, but not exclusively, platelet COX-1 (thus reducing antagonism failed to show superiority over low-dose aspirin for
thromboxane production), whereas higher doses inhibit both sys- secondary stroke protection.
temic COX-1 and COX-2. Genetic variations in human COX-2 All the naturally occurring COX products undergo rapid
variants have been linked with increased coronary heart disease metabolism to inactive products either by hydration (for PGI2
risk, increases in some cancers, and reduced pain perception. and TXA2) or by oxidation (of the 15-hydroxyl group to the cor-
Both COX-1 and COX-2 function as homodimers inserted responding ketone) by prostaglandin 15-hydroxy prostaglandin
into the membrane of the endoplasmic reticulum to promote dehydrogenase (15-PGDH) after cellular uptake via an organic
the uptake of two molecules of oxygen by cyclization of AA to anion transporter polypeptide (OATP 2A1). Further metabolism
yield a C9–C11 endoperoxide C15 hydroperoxide (Figure 18–2). is by ∆13 reduction, β-oxidation, and ω-oxidation. The inactive
This product is PGG2, which is then rapidly modified by the per- metabolites are chemically stable and can be quantified in blood
oxidase moiety of the COX enzyme to add a 15-hydroxyl group and urine by immunoassay or mass spectrometry as a measure of
that is essential for biologic activity. This product is PGH2. Both the in vivo synthesis of their parent compounds.
endoperoxides are highly unstable. Analogous families—PGH1
and PGH3 and their subsequent 1-series and 3-series products—
are derived from homo-γ-linolenic acid and eicosapentaenoic Products of Lipoxygenase
acid, respectively. In both COX-1 and COX-2 homodimers, one The metabolism of AA by the 5-, 12-, and 15-lipoxygenases
protomer acts as the catalytic unit binding AA for oxygenation, (LOX) results in production of hydroperoxyeicosatetraenoic
while the other acts as an allosteric modifier of catalytic activity. acids (HPETEs), which rapidly convert to hydroxy derivatives
The prostaglandins, thromboxane, and prostacyclin, collec- (HETEs). 5-LOX, the most actively investigated pathway, gives
tively termed the prostanoids, are generated from PGH2 through rise to the leukotrienes (Figure 18–3) and is present in leukocytes
the action of downstream isomerases and synthases. These ter- (neutrophils, basophils, eosinophils, and monocyte-macrophages)
minal enzymes are expressed in a relatively cell-specific fashion, and other inflammatory cells such as mast cells and dendritic
such that most cells make one or two dominant prostanoids. The cells. This pathway is of great interest because it is associated
prostaglandins differ from each other in two ways: (1) in the sub- with asthma, anaphylactic shock, and cardiovascular disease.
stituents of the pentane ring (indicated by the last letter, eg, E and Stimulation of these cells elevates intracellular Ca2+ and releases
324 SECTION IV Drugs with Important Actions on Smooth Muscle

COOH

Arachidonic acid

Cyclooxygenase COX-1
COX-2

O
COOH
O
PGG2
OOH

COX-1
Peroxidase
COX-2

O
COOH COOH
O
O
COOH OH PGH2 PGI2
O (prostacyclin)
O
TXA2
OH
(thromboxane) HO OH OH
PGF
O COOH
COOH
HO O
OH PGD2
HO OH PGE2 COOH

HO OH PGF COOH
2α

O 15-deoxy- 12,14
-PGJ2

FIGURE 18–2 Prostanoid biosynthesis. Compound names are enclosed in boxes.

arachidonate; incorporation of molecular oxygen by 5-LOX, inhibitors, cysteinyl leukotriene-receptor antagonists, inhibitors
in association with 5-LOX-activating protein (FLAP), yields of FLAP, and phospholipase A2 inhibitors. Variants in the human
5(S)-HPETE, which is then further converted by 5-LOX to 5-LOX gene (ALOX5) or the cysteinyl receptors (CYSLTR1
the unstable epoxide leukotriene A4 (LTA4). This intermediate or CYSLTR2) have been linked with asthma and with altered
is either converted to the dihydroxy leukotriene B4 (LTB4), via response to antileukotriene drugs.
the action of LTA4 hydrolase, or is conjugated with glutathione LTA4, the primary product of 5-LOX, can also be converted
to yield leukotriene C4 (LTC4), by LTC4 synthase. Sequential with appropriate stimulation via 12-LOX in platelets in
degradation of the glutathione moiety by peptidases yields LTD4 vitro to the lipoxins LXA4 and LXB4. These mediators can
and LTE4. These three products, LTC4, D4, and E4, are called also be generated through 5-LOX metabolism of 15(S)-
cysteinyl leukotrienes. Although leukotrienes are predominantly HETE, the product of 15-LOX-2 metabolism of arachi-
generated in leukocytes, nonleukocyte cells (eg, endothelial cells) donic acid. The stereochemical isomer, 15(R)-HETE, may
that express enzymes downstream of 5-LOX/FLAP can take up be derived from the action of aspirin-acetylated COX-2 and
and convert leukocyte-derived LTA4 in a process termed transcel- further transformed in leukocytes by 5-LOX to 15-epi-LXA4
lular biosynthesis. Transcellular formation of prostaglandins has or 15-epi-LXB4, the so-called aspirin-triggered lipoxins. The
also been shown; for example, endothelial cells can use platelet 15-LOX-1 isoform prefers linoleic acid as a substrate, forming
PGH2 to form PGI2. 13(S)-hydroxyoctadecadienoic acid, while the sequential action
LTC4 and LTD4 are potent bronchoconstrictors and are of 15-LOX-1 and 5-LOX can convert the omega-3 fatty acid
secreted in asthma and anaphylaxis. There are four current docosahexaenoic acid (DHA) to the resolvins, potentially anti-
approaches to antileukotriene drug development: 5-LOX enzyme inflammatory, pro-resolving lipids. Synthetic resolvins, lipoxins,
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 325

COOH

CYP2C, 2J COOH
Arachidonic acid

FLAP 5-LOX O
CYP3A, 4A, 4F
11,12-EET*
OOH
COOH COOH

CH2OH
20-HETE*
5(S)-HPETE
5-LOX

O
COOH

LTC4 synthase LTA4 hydrolase

LTA4 OH OH
OH
COOH
COOH

C5H11 S − Cys − Gly LTB4

LTC4 Glu
γ-GT
γ-GL
OH
COOH
Cysteinyl
leukotrienes C5H11 S − Cys − Gly
(CysLTs) OH
COOH
LTD4 Dipeptidase
C5H11 S − Cys
LTE4

FIGURE 18–3 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.

and epi-lipoxins exert anti-inflammatory actions when applied Epoxygenase Products

in vivo. Although these compounds can be formed from endog-
Specific isozymes of microsomal cytochrome P450 monooxygenases
enous substrates in vitro and when synthesized may have potent
convert AA to hydroxy- or epoxyeicosatrienoic acids (Figures 18–1
biologic effects, the importance of the endogenous compounds
and 18–3). The products are 20-HETE, generated by the CYP
in vivo in human biology remains ill defined. 12-HETE, a
hydroxylases (CYP3A, 4A, 4F) and the 5,6-, 8,9-, 11,12-, and
product of 12-LOX, can also undergo a catalyzed molecular rear-
14,15-epoxyeicosatrienoic acids (EETs), which arise from the CYP
rangement to epoxyhydroxyeicosatrienoic acids called hepoxil-
epoxygenase (2J, 2C). Their biosynthesis can be altered by pharma-
ins. Proinflammatory effects of synthetic hepoxilins have been
cologic, nutritional, and genetic factors that affect P450 expression.
reported although their biologic relevance is unclear.
The biologic actions of the EETs are reduced by their conversion to
The epidermal LOXs, 12(R)-LOX and LOX-3, are distinct
the corresponding, and biologically less active, dihydroxyeicosatri-
from “conventional” enzymes both in their natural substrates,
enoic acids (DHETs) through the action of soluble epoxide hydrolase
which appear to not be arachidonic acid and linoleic acid, and
(sEH). Unlike the prostaglandins, the EETs can be esterified into
in the products formed. Mutations in the genes for 12(R)-LOX
phospholipids, which then act as storage sites. Intracellular fatty
(ALOX12B) or LOX-3 (ALOXE3) are commonly associated with
acid-binding proteins promote EET uptake into cells, incorporation
autosomal recessive congenital ichthyosis, and epidermal accu-
into phospholipids, and availability to sEH. EETs are synthesized in
mulation of 12(R)-HETE is a feature of psoriasis and ichthyosis.
endothelial cells and cause vasodilation in a number of vascular beds
Inhibitors of 12(R)-LOX are under investigation for the treatment
by activating the smooth muscle large conductance Ca2+-activated
of these proliferative skin disorders.
326 SECTION IV Drugs with Important Actions on Smooth Muscle

K+ channels. This results in smooth muscle cell hyperpolarization and on the cell surface, with pharmacologic specificity determined by
vasodilation, leading to reduced blood pressure. Substantial evidence receptor density and type on different cells (Figure 18–4). A single
indicates that EETs may function as endothelium-derived hyper- gene product has been identified for each of the PGI2 (IP), PGF2α
polarizing factors, particularly in the coronary circulation. 15(S)- (FP), and TXA2 (TP) receptors, while four distinct PGE2 receptors
Hydroxy-11,12-EET, which arises from the 15-LOX pathway, is also (EPs 1–4) and two PGD2 receptors (DP1 and DP2) have been cloned.
an endothelium-derived hyperpolarizing factor and a substrate for Additional isoforms of the human TP (α and β), FP (A and B), and
sEH. Consequently, there is interest in inhibitors of soluble sEH as EP3 (Ia, Ib, Ic, II, III, IV, and e) receptors can arise through differen-
potential antithrombotic and antihypertensive drugs. An exception to tial mRNA splicing. Two receptors exist for LTB4 (BLT1 and BLT2)
the general response to EETs as vasodilators is the pulmonary vascu- and for LTC4/LTD4 (cysLT1 and cysLT2). It appears that LTE4 func-
lature where they cause vasoconstriction. It is unclear yet whether this tions through one or more receptors distinct from cysLT1/cysLT2,
activity of EETs may limit the potential clinical use of sEH inhibitors. with some evidence that the orphan receptor GPR99 and the ADP
Down-regulation of pulmonary sEH may contribute to pulmonary receptor P2Y12 may function as LTE4 receptors. The formyl peptide
hypertension. Anti-inflammatory, antiapoptotic, and proangiogenic (fMLP)-1 receptor can be activated by lipoxin A4 and consequently
actions of the EETs have also been reported. has been termed the ALX receptor. Receptor heterodimerization has
been reported for a number of the eicosanoid receptors, providing
Isoeicosanoids for additional receptor subtypes from the currently identified gene
The isoeicosanoids, a family of eicosanoid isomers, are formed non- products. All of these receptors are G protein-coupled; properties of
enzymatically by direct free radical-based action on AA and related the best-studied receptors are listed in Table 18–1.
lipid substrates. The isoprostanes thus formed are prostaglandin EP2, EP4, IP, and DP1 receptors activate adenylyl cyclase via Gs.
stereoisomers. Because prostaglandins have many asymmetric This leads to increased intracellular cAMP levels, which in turn
centers, they have a large number of potential stereoisomers. COX activate specific protein kinases (see Chapter 2). EP1, FP, and TP
is not needed for the formation of the isoprostanes, and its inhibi- activate phosphatidylinositol metabolism, leading to the forma-
tion with aspirin or other NSAIDs should not affect the isoprostane tion of inositol trisphosphate, with subsequent mobilization of
pathway. The primary epimerization mechanism is peroxidation Ca2+ stores and an increase of free intracellular Ca2+. TP also cou-
of arachidonate by free radicals. Peroxidation occurs while arachi- ples to multiple G proteins, including G12/13 and G16, to stimulate
donic acid is still esterified to the membrane phospholipids. Thus, small G protein signaling pathways, and may activate or inhibit
unlike prostaglandins, these stereoisomers are “stored” as part of adenylyl cyclase via Gs (TPα) or Gi (TPβ), respectively. EP3 iso-
the membrane. They are then cleaved by phospholipases, circulate, forms can couple to both increased intracellular calcium and to
and are excreted in urine. Isoprostanes are present in relatively large increased or decreased cAMP. The DP2 receptor (also known as
amounts (tenfold greater in blood and urine than the COX-derived the chemoattractant receptor-homologous molecule expressed on
prostaglandins). They have potent vasoconstrictor effects when Th2 cells, or CRTh2), which is unrelated to the other prostanoid
infused into renal and other vascular beds and may activate pros- receptors, is a member of the fMLP receptor superfamily. This
tanoid receptors. They also may modulate other aspects of vascular receptor couples through a Gi-type G protein and leads to inhibi-
function, including leukocyte and platelet adhesive interactions and tion of cAMP synthesis and increases in intracellular Ca2+ in a
angiogenesis. It has been speculated that they may contribute to the variety of cell types.
pathophysiology of inflammatory responses in a manner insensitive LTB4 also causes inositol trisphosphate release via the BLT1
to COX inhibitors. A particular difficulty in assessing the likely receptor, causing activation, degranulation, and superoxide anion
biologic functions of isoprostanes—several of which have been generation in leukocytes. The BLT2 receptor, a low-affinity recep-
shown to serve as incidental ligands at prostaglandin receptors—is tor for LTB4, is also bound with reasonable affinity by 12(S)- and
that while high concentrations of individual isoprostanes may be 12(R)-HETE, although the biologic relevance of this observation
necessary to elicit a response, multiple compounds are formed is not clear. CysLT1 and cysLT2 couple to Gq, leading to increased
coincidentally in vivo under conditions of oxidant stress. Analogous intracellular Ca2+. Studies have also placed Gi downstream of
leukotriene and EET isomers have been described. cysLT2. An orphan receptor, GPR17, binds cysLTs and may
negatively regulate the function of cysLT1, but its physiologic
role remains ill defined. As noted above, the EETs promote vaso-
■ BASIC PHARMACOLOGY OF dilation via paracrine activation of calcium-activated potassium
EICOSANOIDS channels on smooth muscle cells leading to hyperpolarization and
relaxation. This occurs in a manner consistent with activation of
MECHANISMS & EFFECTS OF a Gs-coupled receptor, although a specific EET receptor has yet to
be identified. EETs may also act in an autocrine manner directly
EICOSANOIDS activating endothelial transient receptor potential channels to
cause endothelial hyperpolarization, which is then transferred
Receptor Mechanisms to the smooth muscle cells by gap junctions or potassium ions.
As a result of their short half-lives, the eicosanoids act mainly in an Specific receptors for isoprostanes have not been identified, and
autocrine and a paracrine fashion, ie, close to the site of their synthe- the biologic importance of their capacity to act as incidental
sis, and not as circulating hormones. These ligands bind to receptors ligands at prostaglandin receptors remains to be established.
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 327

“relaxant” “contractile” “inhibitory” fMLP Receptor family

EP2 EP4 DP1 EP3 DP2/

IP TP FP EP11 CR H2

**
αs
β γ α12/13 αi
αq β γ
β γ β γ

α16
β γ +
RhoGEF
+
+
PLC-b
+
+
Rho activation Ca2+
–
Biologic Effects
Biological Effects

cAMP

+ Adenylyl –
Cyclase

FIGURE 18–4 Prostanoid receptors and their signaling pathways. fMLP, formylated MetLeuPhe, a small peptide receptor; PLC-β,
phospholipase C-β. All of the receptors shown are of the seven-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.

Although prostanoids can activate peroxisome proliferator- is potentiated by exposure of smooth muscle cells to testosterone,
activated receptors (PPARs) if added in sufficient concentration which up-regulates smooth muscle cell TP expression. PGF2α
in vitro, it remains questionable whether these compounds is also a vasoconstrictor but is not a smooth muscle mitogen.
ever attain concentrations sufficient to function as endogenous Another vasoconstrictor is the isoprostane 8-iso-PGF2α, also
nuclear-receptor ligands in vivo. known as iPF2αIII, which may act via the TP receptor.
Vasodilator prostaglandins, especially PGI2 and PGE2, pro-
mote vasodilation by increasing cAMP and decreasing smooth
Effects of Prostaglandins & Thromboxanes
muscle intracellular calcium, primarily via the IP and EP4 recep-
The prostaglandins and thromboxanes have major effects on tors. Vascular PGI2 is synthesized by both smooth muscle and
smooth muscle in the vasculature, airways, and gastrointesti- endothelial cells, with the COX-2 isoform in the latter cell type
nal and reproductive tracts. Contraction of smooth muscle is being the major contributor. In the microcirculation, PGE2 is a
mediated by the release of calcium, while relaxing effects are vasodilator produced by endothelial cells. PGI2 inhibits prolifera-
mediated by the generation of cAMP. Many of the eicosanoids’ tion of smooth muscle cells, an action that may be particularly
contractile effects on smooth muscle can be inhibited by relevant in pulmonary hypertension. PGD2 may also function
lowering extracellular calcium or by using calcium channel- as a vasodilator, in particular as a dominant mediator of flushing
blocking drugs. Other important targets include platelets and induced by the lipid-lowering drug niacin.
monocytes, kidneys, the central nervous system, autonomic
presynaptic nerve terminals, sensory nerve endings, endocrine 2. Gastrointestinal tract—Most of the prostaglandins and
organs, adipose tissue, and the eye (the effects on the eye may thromboxanes activate gastrointestinal smooth muscle. Longi-
involve smooth muscle). tudinal muscle is contracted by PGE2 (via EP3) and PGF2α (via
FP), whereas circular muscle is contracted strongly by PGF2α and
A. Smooth Muscle weakly by PGI2, and is relaxed by PGE2 (via EP4). Administration
1. Vascular—TXA2 is a potent vasoconstrictor. It is also a of either PGE2 or PGF2α results in colicky cramps (see Clinical
smooth muscle cell mitogen and is the only eicosanoid that has Pharmacology of Eicosanoids, below). The leukotrienes also have
convincingly been shown to have this effect. The mitogenic effect powerful contractile effects.
328 SECTION IV Drugs with Important Actions on Smooth Muscle

TABLE 18–1 Eicosanoid receptors.1

Receptor Endogenous Secondary G Protein; Second
(Human) Ligand Ligands Messenger Major Phenotype(s) in Knockout Mice

DP1 PGD2 Gs; ↑cAMP ↓Allergic asthma

↑Inflammatory cardiovascular disease, hypertension,
thrombosis
DP2 PGD2 15d-PGJ2 Gi; ↑Ca2+i, ↓cAMP ↑Allergic airway inflammation
↓Cutaneous inflammation
EP1 PGE2 PGI2 Gq; ↑Ca2+i ↓Colon carcinogenesis
EP2 PGE2 Gs; ↑cAMP Impaired fertilization
Salt-sensitive hypertension
↓Tumorgenesis
2+
EP3 I, II, III, IV, V, VI, e, f PGE2 Gi; ↓cAMP, ↑Ca i Resistance to pyrogens
Gs; ↑cAMP ↓Acute cutaneous inflammation
Gq; ↑PLC, ↑Ca2+i ↑Allergic airway inflammation
G12/13; Rho activation Obesity
EP4 PGE2 Gs; ↑cAMP ↑Myocardial infarction severity
↑Intestinal inflammatory/immune response
↓Colon carcinogenesis
Patent ductus arteriosus
2+
FPA,B PGF2α isoPs Gq; ↑PLC, ↑Ca i Parturition failure
G12/13; Rho activation ↓Basal blood pressure; ↑Vasopressor response
↓Atherosclerosis
IP PGl2 PGE2 Gs; ↑cAMP ↑Thrombotic response
↑Response to vascular injury
↑Atherosclerosis
↑Cardiac fibrosis
Salt-sensitive hypertension
TPα,β TXA2 isoPs Gq,G12/13,G16; ↑PLC, ↑Bleeding time
↑Ca2+i, Rho activation
↓Response to vascular injury
↓Atherosclerosis
↑Survival after cardiac allograft
2+
BLT1 LTB4 G16,Gi; ↑Ca i, ↓cAMP Inflammatory responses
↓Insulin resistance in obesity
BLT2 LTB4 12(S)-HETE Gq-like, Gi-like, G12-like, ↓inflammatory arthritis
↑Ca2+i
12(R)-HETE ↑Experimental colitis
CysLT1 LTD4 LTC4/LTE4 Gq; ↑PLC, ↑Ca2+i ↓Innate and adaptive immune vascular permeability
response
↑Pulmonary inflammatory and fibrotic response
2+
CysLT2 LTC4/LTD4 LTE4 Gq; ↑PLC, ↑Ca i ↓Pulmonary inflammatory and fibrotic response
1
Splice variants for the eicosanoid receptors are indicated where appropriate.
2+ 12,14
Ca i, intracellular calcium; cAMP, cyclic adenosine 3’,5’-monophosphate; PLC, phospholipase C; isoPs, isoprostanes; 15d-PGJ2, 15-deoxy-Δ -PGJ2.
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 329

3. Airways—Respiratory smooth muscle is relaxed by PGE2 and receptors), whereas higher concentrations inhibit (via IP recep-
PGI2 and contracted by PGD2, TXA2, and PGF2α. Studies of DP1 tors), platelet aggregation. PGD2 inhibits aggregation via DP1,
and DP2 receptor knockout mice suggest an important role of this leading to increased cAMP generation.
prostanoid in asthma, although the DP2 receptor appears more
relevant to allergic airway diseases. The cysteinyl leukotrienes are C. Kidney
also bronchoconstrictors. They act principally on smooth muscle Both the medulla and the cortex of the kidney synthesize prosta-
in peripheral airways and are a thousand times more potent than glandins, the medulla substantially more than the cortex. COX-1
histamine, both in vitro and in vivo. They also stimulate bron- is expressed mainly in cortical and medullary collecting ducts
chial mucus secretion and cause mucosal edema. Bronchospasm and mesangial cells, arteriolar endothelium, and epithelial cells
occurs in about 10% of people taking NSAIDs, possibly because of Bowman’s capsule. COX-2 is restricted to the renal medullary
of a shift in arachidonate metabolism from COX metabolism to interstitial cells, the macula densa, and the cortical thick ascend-
leukotriene formation. ing limb.
The major renal eicosanoid products are PGE2 and PGI2,
4. Reproductive—The actions of prostaglandins on reproduc- followed by PGF2α and TXA2. The kidney also synthesizes several
tive smooth muscle are discussed below under section D, Repro- hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 prod-
ductive Organs. ucts, and epoxides. Prostaglandins play important roles in maintain-
ing blood pressure and regulating renal function, particularly in
B. Platelets marginally functioning kidneys and volume-contracted states.
Platelet aggregation is markedly affected by eicosanoids. PGI2, a Under these circumstances, renal cortical COX-2-derived PGE2
major product of endothelial-derived COX-2, is a potent inhibitor and PGI2 maintain renal blood flow and glomerular filtration rate
of platelet aggregation. This inhibition occurs via an IP receptor- through their local vasodilating effects. These prostaglandins also
dependent elevation in Gs activity and cAMP. Dysfunctional modulate systemic blood pressure through regulation of water and
genetic variants in the human prostacyclin receptor as well as sodium excretion. Expression of medullary COX-2 and mPGES-1
drug inhibition of COX-2 (reducing prostacyclin signaling and is increased under conditions of high salt intake. COX-2-derived
production, respectively) lead to increased platelet activation and prostanoids increase medullary blood flow and inhibit tubular
aggregation. This has recently been demonstrated to have major sodium reabsorption, while COX-1-derived products promote salt
implications regarding adverse cardiovascular events, as described excretion in the collecting ducts. Increased water clearance probably
below (see Inhibition of Eicosanoid Synthesis). TXA2 is the major results from an attenuation of the action of antidiuretic hormone
product of platelet COX-1, the only COX isoform expressed (ADH) on adenylyl cyclase. Loss of these effects may underlie the
in mature platelets, with COX-1-derived PGD2 found in lesser systemic or salt-sensitive hypertension often associated with COX
amounts. TXA2 is a powerful inducer of platelet aggregation. inhibition. A common misperception—often articulated in discus-
TXA2 additionally amplifies the effects of other, more potent, sion of the cardiovascular toxicity of drugs such as rofecoxib—is
platelet agonists such as thrombin. The TP-Gq signaling pathway that hypertension secondary to NSAID administration is somehow
elevates intracellular Ca2+ and activates protein kinase C, facilitat- independent of the inhibition of prostaglandins. Loop diuretics,
ing platelet aggregation and TXA2 biosynthesis. Activation of G12/ eg, furosemide, produce some of their effect by stimulating COX
G13 induces Rho/Rho-kinase–dependent regulation of myosin activity. In the normal kidney, this increases the synthesis of the
light chain phosphorylation leading to platelet shape change. vasodilator prostaglandins. Therefore, patient response to a loop
Mutations in the human TP have been associated with mild diuretic is diminished if a COX inhibitor is administered concur-
bleeding disorders. The platelet actions of TXA2 are restrained in rently (see Chapter 15).
vivo by PGI2, which inhibits platelet aggregation by all recognized There is an additional layer of complexity associated with
agonists, and PGD2. Platelet COX-1-derived TXA2 biosynthesis the effects of renal prostaglandins. In contrast to the medullary
is increased during platelet activation and aggregation and is enzyme, cortical COX-2 expression is increased by low salt intake,
irreversibly inhibited by chronic administration of aspirin at low leading to increased renin release. This elevates glomerular filtra-
doses. Urinary metabolites of TXA2 increase in clinical syndromes tion rate and contributes to enhanced sodium reabsorption and a
of platelet activation, such as diabetes mellitus, and particularly rise in blood pressure. PGE2 is thought to stimulate renin release
in patients with myocardial infarction and stroke. Macrophage through activation of EP4 or EP2. PGI2 can also stimulate renin
COX-2 appears to contribute roughly 10% of the increment in release and this may be relevant to maintenance of blood pressure
TXA2 biosynthesis observed in smokers, while the rest is derived in volume-contracted conditions and to the pathogenesis of reno-
from platelet COX-1. A variable contribution, presumably from vascular hypertension. Inhibition of COX-2 may reduce blood
macrophage COX-2, may be insensitive to the effects of low-dose pressure in these settings.
aspirin. In a single trial comparing low- and high-dose aspirin, TXA2 causes intrarenal vasoconstriction (and perhaps an
no increase in benefit was associated with increased dose; in ADH-like effect), resulting in a decline in renal function. The
fact, this study, as well as indirect comparisons across placebo- normal kidney synthesizes only small amounts of TXA2. However,
controlled trials, suggests an inverse dose-response relationship, in renal conditions involving inflammatory cell infiltration (such
perhaps reflecting increasing inhibition of PGI2 synthesis at higher as glomerulonephritis and renal transplant rejection), the inflam-
doses of aspirin. Low concentrations of PGE2 enhance (via EP3 matory cells (monocyte-macrophages) release substantial amounts
330 SECTION IV Drugs with Important Actions on Smooth Muscle

of TXA2. Theoretically, TXA2 synthase inhibitors or receptor with COX inhibitors may be due, in part, to increased release of
antagonists should improve renal function in these patients, but norepinephrine as well as to inhibition of the endothelial synthesis
no such drug is clinically available. Hypertension is associated of the vasodilators PGE2 and PGI2. PGE2 and PGI2 sensitize the
with increased TXA2 and decreased PGE2 and PGI2 synthesis in peripheral nerve endings to painful stimuli. PGE2 acts via EP1
some animal models, eg, the Goldblatt kidney model. It is not and EP4 receptors to potentiate excitatory cation channel activity
known whether these changes are primary contributing factors and inhibit hyperpolarizing K+ channel activity, thereby increas-
or secondary responses. PGF2α may elevate blood pressure by ing membrane excitability. Prostaglandins also modulate pain
regulating renin release in the kidney. Although more research is centrally. Both COX-1 and COX-2 are expressed in the spinal
necessary, FP antagonists have potential as novel antihypertensive cord and release prostaglandins in response to peripheral pain
drugs. stimuli. PGE2, and perhaps also PGD2, PGI2, and PGF2α, con-
tribute to so-called central sensitization, an increase in excitability
D. Reproductive Organs of spinal dorsal horn neurons, that augments pain intensity, wid-
1. Female reproductive organs—Animal studies demonstrate ens the area of pain perception, and results in pain from normally
a role for PGE2 and PGF2α in early reproductive processes such as innocuous stimuli. PGE2 acts on the EP2 receptor to facilitate pre-
ovulation, luteolysis, and fertilization. Uterine muscle is contracted synaptic release of excitatory neurotransmitters and block inhibi-
by PGF2α, TXA2, and low concentrations of PGE2; PGI2 and high tory glycinergic neurotransmission as well as postsynaptically to
concentrations of PGE2 cause relaxation. PGF2α, together with enhance excitatory neurotransmitter receptor activity.
oxytocin, is essential for the onset of parturition. PGI2 also assists
in promoting uterine smooth muscle cell maturation. The effects F. Inflammation and Immunity
of prostaglandins on uterine function are discussed below (see PGE2 and PGI2 are the predominant prostanoids associated with
Clinical Pharmacology of Eicosanoids). inflammation. Both markedly enhance edema formation and
leukocyte infiltration by promoting blood flow in the inflamed
2. Male reproductive organs—Despite the discovery of pros- region. PGE2 and PGI2, through activation of EP2 and IP, respec-
taglandins in seminal fluid, the role of prostaglandins in semen is tively, increase vascular permeability and leukocyte infiltration.
still conjectural. The major source of these prostaglandins is the Through its action as a platelet agonist, TXA2 can also increase
seminal vesicle; the prostate, despite the name “prostaglandin,” platelet-leukocyte interactions. Although probably not made by
and the testes synthesize only small amounts. The factors that lymphocytes, prostaglandins may potently regulate lymphocyte
regulate the concentration of prostaglandins in human seminal function. PGE2 and TXA2 may play a role in T-lymphocyte devel-
plasma are not known in detail, but testosterone does promote opment by regulating apoptosis of immature thymocytes. PGI2
prostaglandin production. Thromboxane and leukotrienes have contributes to immune suppression by interfering with dendritic
not been found in seminal fluid. Men with a low seminal fluid cell maturation and antigen uptake for presentation to immune
concentration of prostaglandins are relatively infertile. cells. PGE2 suppresses the immunologic response by inhibiting
Smooth muscle-relaxing prostaglandins such as PGE1 enhance differentiation of B lymphocytes into antibody-secreting plasma
penile erection by relaxing the smooth muscle of the corpora cells, thus depressing the humoral antibody response. It also inhib-
cavernosa (see Clinical Pharmacology of Eicosanoids). its cytotoxic T-cell function, mitogen-stimulated proliferation of
T lymphocytes, and maturation and function of Th1 lympho-
E. Central and Peripheral Nervous Systems
cytes. PGE2 can modify myeloid cell differentiation, promoting
1. Fever—PGE2 increases body temperature, predominantly via type 2 immune-suppressive macrophage and myeloid suppressor
EP3, although EP1 also plays a role, especially when administered cell phenotypes. These effects likely contribute to immune escape
directly into the cerebral ventricles. Exogenous PGF2α and PGI2 in tumors where infiltrating myeloid-derived cells predominantly
induce fever, whereas PGD2 and TXA2 do not. Endogenous pyro- display type 2 phenotypes. PGD2, a major product of mast cells, is
gens release interleukin-1, which in turn promotes the synthesis a potent chemoattractant for eosinophils in which it also induces
and release of PGE2. This synthesis is blocked by aspirin, other degranulation and leukotriene biosynthesis. PGD2 also induces
antipyretic NSAIDs, and acetaminophen. chemotaxis and migration of Th2 lymphocytes, mainly via activa-
tion of DP2, although a role for DP1 has also been established. It
2. Sleep—When infused into the cerebral ventricles, PGD2
remains unclear how these two receptors coordinate the actions of
induces natural sleep (as determined by electroencephalographic
PGD2 in inflammation and immunity. A degradation product of
analysis) via activation of DP1 receptors and secondary release of
PGD2, 15d-PGJ2, at concentrations actually formed in vivo, may
adenosine. PGE2 infusion into the posterior hypothalamus causes
also activate eosinophils via the DP2 (CRTh2) receptor.
wakefulness.

3. Neurotransmission—PGE compounds inhibit the release G. Bone Metabolism

of norepinephrine from postganglionic sympathetic nerve end- Prostaglandins are abundant in skeletal tissue and are produced by
ings. Moreover, NSAIDs increase norepinephrine release in vivo, osteoblasts and adjacent hematopoietic cells. The major effect of
suggesting that the prostaglandins play a physiologic role in prostaglandins (especially PGE2, acting on EP4) in vivo is to increase
this process. Thus, vasoconstriction observed during treatment bone turnover, ie, stimulation of bone resorption and formation.
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 331

EP4 receptor deletion in mice results in an imbalance between mPGES-1 is evident in tumors, and preclinical studies support the
bone resorption and formation, leading to a negative balance potential use of mPGES-1 inhibitors in chemoprevention or treat-
of bone mass and density in older animals. Prostaglandins may ment. In tumors, reduced levels of OATP2A1 and 15-PGDH,
mediate the effects of mechanical forces on bones and changes which mediate cellular uptake and metabolic inactivation of
in bone during inflammation. EP4-receptor deletion and inhibi- PGE2, respectively, likely contribute to sustained PGE2 activity.
tion of prostaglandin biosynthesis have both been associated with The pro- and anti-oncogenic roles of other prostanoids remain
impaired fracture healing in animal models. COX inhibitors can under investigation, with TXA2 emerging as another likely procar-
also slow skeletal muscle healing by interfering with prostaglandin cinogenic mediator, deriving either from macrophage COX-2 or
effects on myocyte proliferation, differentiation, and fibrosis in platelet COX-1. Studies in mice lacking EP1, EP2, or EP4 recep-
response to injury. Prostaglandins may contribute to the bone loss tors confirm reduced disease in multiple carcinogenesis models.
that occurs at menopause; it has been speculated that NSAIDs EP3, in contrast, plays no role or may even play a protective role
may be of therapeutic value in osteoporosis and bone loss pre- in some cancers. Transactivation of epidermal growth factor recep-
vention in older women. However, controlled evaluation of such tor (EGFR) has been linked with the oncogenic activity of PGE2.
therapeutic interventions has not been carried out. NSAIDs, espe- PGD2, acting on the DP1 receptor, may reduce angiogenesis,
cially those specific for inhibition of COX-2, delay bone healing thereby reducing tumor progression.
in experimental models of fracture.

H. Eye
Effects of Lipoxygenase & Cytochrome
PGE, PGF, and PGD derivatives lower intraocular pressure. The P450-Derived Metabolites
mechanism of this action is unclear but probably involves increased Lipoxygenases generate compounds that can regulate specific cel-
outflow of aqueous humor from the anterior chamber via the uveo- lular responses that are important in inflammation and immunity.
scleral pathway (see Clinical Pharmacology of Eicosanoids). Cytochrome P450-derived metabolites affect nephron transport
functions either directly or via metabolism to active compounds
I. Cancer (see below). The biologic functions of the various forms of
hydroxy- and hydroperoxyeicosaenoic acids are largely unknown,
There has been considerable interest in the role of prostaglandins,
but their pharmacologic potency is impressive.
and in particular the COX-2 pathway, in the development of malig-
nancies. Pharmacologic inhibition or genetic deletion of COX-2
A. Blood Cells and Inflammation
restrains tumor formation in models of colon, breast, lung, and
other cancers. Large human epidemiologic studies have found that LTB4, acting at the BLT1 receptor, is a potent chemoattractant
the incidental use of NSAIDs is associated with significant reduc- for T lymphocytes, neutrophils, eosinophils, monocytes, and pos-
tions in relative risk for developing these and other cancers. Chronic sibly mast cells. LTB4 also contributes to activation of neutrophils
low-dose aspirin does not appear to have a substantial impact on and eosinophils, and to monocyte-endothelial adhesion. The
cancer incidence; however, it is associated with reduced cancer death cysteinyl leukotrienes are potent chemoattractants for eosinophils
in a number of studies. The anticancer efficacy of aspirin in humans and T lymphocytes. Cysteinyl leukotrienes may also generate dis-
may be related to hyperactivity of the PI3 kinase/Akt pathway in tinct sets of cytokines through activation of mast cell cysLT1 and
tumor cells. In patients with familial polyposis coli, COX inhibitors cysLT2. At higher concentrations, these leukotrienes also promote
significantly decrease polyp formation. Polymorphisms in COX-2 eosinophil adherence, degranulation, cytokine or chemokine
have been associated with increased risk of some cancers. Several release, and oxygen radical formation. Cysteinyl leukotrienes also
studies have suggested that COX-2 expression is associated with contribute to inflammation by increasing endothelial permeabil-
markers of tumor progression in breast cancer. In mouse mammary ity, thus promoting migration of inflammatory cells to the site of
tissue, COX-2 is oncogenic whereas NSAID use is associated with inflammation. The leukotrienes have been strongly implicated in
a reduced risk of breast cancer in women, especially for hormone the pathogenesis of inflammation, especially in chronic diseases
receptor-positive tumors. Despite the support for COX-2 as the such as asthma and inflammatory bowel disease.
predominant source of oncogenic prostaglandins, randomized clini- Lipoxins have diverse effects on leukocytes, including activa-
cal trials have not been performed to determine whether superior tion of monocytes and macrophages and inhibition of neutrophil,
anti-oncogenic effects occur with selective inhibition of COX-2, eosinophil, and lymphocyte activation. Both lipoxin A and lipoxin
compared with nonselective NSAIDs. Indeed data from animal B inhibit natural killer cell cytotoxicity.
models and epidemiologic studies in humans are consistent with a
role for COX-1 as well as COX-2 in the production of oncogenic B. Heart and Smooth Muscle
prostanoids. 1. Cardiovascular—12(S)-HETE promotes vascular smooth
PGE2, which is considered the principal oncogenic prostanoid, muscle cell proliferation and migration at low concentrations; it
facilitates tumor initiation, progression, and metastasis through may play a role in myointimal proliferation that occurs after vas-
multiple biologic effects, increasing proliferation and angio- cular injury such as that caused by angioplasty. Its stereoisomer,
genesis, inhibiting apoptosis, augmenting cellular invasiveness, 12(R)-HETE, is not a chemoattractant, but is a potent inhibitor
and modulating immunosuppression. Augmented expression of of the Na+/K+-ATPase in the cornea. In vascular smooth muscle
332 SECTION IV Drugs with Important Actions on Smooth Muscle

LTB4 may cause vasoconstriction as well as smooth muscle cell luteinizing hormone (LH) and LH-releasing hormone release
migration and proliferation, possibly contributing to athero- from isolated rat anterior pituitary cells.
sclerosis and injury-induced neointimal proliferation. LTC4 and
LTD4 reduce myocardial contractility and coronary blood flow,
leading to depression of cardiac output. Lipoxin A and lipoxin B INHIBITION OF EICOSANOID
exert coronary vasoconstrictor effects in vitro. In addition to their SYNTHESIS
vasodilatory action, EETs may reduce cardiac hypertrophy as well
as systemic and pulmonary vascular smooth muscle proliferation Corticosteroids block all the known pathways of eicosanoid
and migration. synthesis, perhaps in part by stimulating the synthesis of several
inhibitory proteins collectively called annexins or lipocortins.
2. Gastrointestinal—Human colonic epithelial cells synthesize They inhibit phospholipase A2 activity, probably by interfering
LTB4, a chemoattractant for neutrophils. The colonic mucosa of with phospholipid binding, thus preventing the release of arachi-
patients with inflammatory bowel disease contains substantially donic acid.
increased amounts of LTB4. It appears that activation of the BLT2 The NSAIDs (eg, indomethacin, ibuprofen; see Chapter 36)
receptor, possibly by agonists other than LTB4, is protective in block both prostaglandin and thromboxane formation by revers-
colonic epithelium and contributes to maintenance of barrier ibly inhibiting COX activity. The traditional NSAIDs are not
function. selective for COX-1 or COX-2. The more recent, purposefully
designed selective COX-2 inhibitors vary—as do the older
3. Airways—The cysteinyl leukotrienes, particularly LTC4 and drugs—in their degree of selectivity. Indeed, there is consider-
LTD4, are potent bronchoconstrictors and cause increased micro- able variability between (and within) individuals in the selectivity
vascular permeability, plasma exudation, and mucus secretion attained by the same dose of the same NSAID. Aspirin is an
in the airways. Controversies exist over whether the pattern and irreversible COX inhibitor. In platelets, which lack nuclei, COX-1
specificity of the leukotriene receptors differ in animal models and (the only isoform expressed in mature platelets) cannot be restored
humans. LTC4-specific receptors have not been found in human via protein biosynthesis, resulting in extended inhibition of TXA2
lung tissue, whereas both high- and low-affinity LTD4 receptors biosynthesis.
are present. EP-receptor agonists and antagonists are under evaluation
in the treatment of bone fracture and osteoporosis, whereas
C. Renal System TP-receptor antagonists are being investigated for usefulness in
the treatment of cardiovascular syndromes. Direct inhibition of
There is substantial evidence for a role of the epoxygenase prod-
PGE2 biosynthesis through selective inhibition of the inducible
ucts in regulating renal function, although their exact role in the
mPGES-1 isoform is also under examination for potential thera-
human kidney remains unclear. Both 20-HETE and the EETs
peutic efficacy in pain and inflammation, cardiovascular disease,
are generated in renal tissue. 20-HETE, which potently blocks
and chemoprevention of cancer.
the smooth muscle cell Ca2+-activated K+ channel and leads to
Although they remain less effective than inhaled corticosteroids,
vasoconstriction of the renal arteries, has been implicated in the
a 5-LOX inhibitor (zileuton) and selective antagonists of the
pathogenesis of hypertension. In contrast, studies support an
CysLT1 receptor for leukotrienes (zafirlukast, montelukast, and
antihypertensive effect of the EETs because of their vasodilating
pranlukast; see Chapter 20) are used clinically in mild to moderate
and natriuretic actions. EETs increase renal blood flow and may
asthma. Growing evidence for a role of the leukotrienes in cardio-
protect against inflammatory renal damage by limiting glomerular
vascular disease has expanded the potential clinical applications of
macrophage infiltration. Inhibitors of soluble epoxide hydrolase,
leukotriene modifiers. Conflicting data have been reported in ani-
which prolong the biologic activities of the EETs, are being devel-
mal studies depending on the disease model used and the molecular
oped as potential new antihypertensive drugs. In vitro studies,
target (5-LOX versus FLAP). Human genetic studies demonstrate
and work in animal models, support targeting soluble epoxide
a link between cardiovascular disease and polymorphisms in the
hydrolase for blood pressure control, although the potential for
leukotriene biosynthetic enzymes, and indicate an interaction
pulmonary vasoconstriction and tumor promotion through anti-
between the 5-LOX and COX-2 pathways, in some populations.
apoptotic actions require careful investigation.
NSAIDs usually do not inhibit lipoxygenase activity at con-
centrations attained clinically that inhibit COX activity. In fact,
D. Miscellaneous by preventing arachidonic acid conversion via the COX pathway,
The effects of these products on the reproductive organs have not NSAIDs may cause more substrate to be metabolized through
been elucidated. the lipoxygenase pathways, leading to an increased formation of
Similarly, actions on the nervous system have been suggested the inflammatory and proliferative leukotrienes. Even among the
but not confirmed. 12-HETE stimulates the release of aldosterone COX-dependent pathways, inhibiting the synthesis of one deriva-
from the adrenal cortex and mediates a portion of the aldosterone tive may increase the synthesis of an enzymatically related prod-
release stimulated by angiotensin II but not that by adrenocorti- uct. Therefore, drugs that inhibit both COX and lipoxygenase are
cotropic hormone. Very low concentrations of LTC4 increase and being developed. One such drug, the COX-2/5-LOX inhibitor
higher concentrations of arachidonate-derived epoxides augment darbufelone, has shown promise in studies of cancer cells and in
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 333

O HO
COOH
COOH

HO
HO
OH OH
Alprostadil Prostaglandin F2`
(prostaglandin E1) (PGF2` )

OH

COOH
O
COOCH3
HO
CH3
H3C OH
OH Carboprost tromethamine
HO
(prostaglandin F2` analog)
Misoprostol
(prostaglandin E1 analog)

COOH
O O

COOH

HO HO
OH OH
Dinoprostone Epoprostenol
(prostaglandin E2, PGE2) (prostacyclin, PGI2)

OH COOH
H

OH Iloprost

CH3
H
OCH2CO–
2 Na
+

Treprostinil sodium OH OH

FIGURE 18–5 Chemical structures of some prostaglandins and prostaglandin analogs currently in clinical use.

mouse tumor models. These mechanistic studies, paired with the (Figure 18–5). Second, enzyme inhibitors and receptor antago-
observed up-regulation of both COX-2 and 5-LOX in multiple nists have been developed to interfere with the synthesis or effects
human tumors, including pancreatic cancer, suggest that this may of the eicosanoids. The discovery of COX-2 as a major source
be an important avenue for further investigations. of inflammatory prostanoids led to the development of selective
COX-2 inhibitors in an effort to preserve the gastrointestinal
and renal functions directed through COX-1, thereby reducing
■ CLINICAL PHARMACOLOGY OF toxicity. However, it is apparent that the marked decrease in
EICOSANOIDS biosynthesis of PGI2 that follows COX-2 inhibition occurring
without a concurrent inhibition of platelet COX-1-derived TXA2
Several approaches have been used in the clinical application of removes a protective constraint on endogenous mediators of car-
eicosanoids. First, stable oral or parenteral long-acting analogs diovascular dysfunction and leads to an increase in cardiovascular
of the naturally occurring prostaglandins have been developed events in patients taking selective COX-2 inhibitors. Third, efforts
334 SECTION IV Drugs with Important Actions on Smooth Muscle

at dietary manipulation—to change the polyunsaturated fatty acid group prolongs the duration of action) is used to induce second-
precursors in the cell membrane phospholipids and so change trimester abortions and to control postpartum hemorrhage that
eicosanoid synthesis—is used extensively in over-the-counter is not responding to conventional methods of management. The
products and in diets emphasizing increased consumption of success rate is approximately 80%. It is administered as a single
cold-water fish. 250-mcg intramuscular injection, repeated if necessary. Vomiting
and diarrhea occur commonly, probably because of gastrointesti-
Female Reproductive System nal smooth muscle stimulation. In some patients transient bron-
choconstriction can occur. Transient elevations in temperature are
Studies with knockout mice have confirmed a role for prosta- seen in approximately one eighth of patients.
glandins in reproduction and parturition. COX-1-derived PGF2α
appears important for luteolysis, consistent with delayed parturition
in COX-1-deficient mice. A complex interplay between PGF2α and B. Facilitation of Labor
oxytocin is critical to the onset of labor. EP2 receptor-deficient mice Numerous studies have shown that PGE2, PGF2α, and their analogs
demonstrate a preimplantation defect, which underlies some of the effectively initiate and stimulate labor, but PGF2α is one tenth as
breeding difficulties seen in COX-2 knockouts. PGI2 production potent as PGE2. There appears to be no difference in the efficacy
leads to maturation of uterine smooth muscle cell prior to labor. of PGE2 and PGF2α when they are administered intravenously;
however, the most common usage is local application of PGE2
A. Abortion analogs (dinoprostone) to promote labor through ripening of the
cervix. These agents and oxytocin have similar success rates and
PGE2 and PGF2α have potent oxytocic actions. The ability of the
comparable induction-to-delivery intervals. The adverse effects of
E and F prostaglandins and their analogs to terminate pregnancy
the prostaglandins are moderate, with a slightly higher incidence
at any stage by promoting uterine contractions has been adapted
of nausea, vomiting, and diarrhea than that produced by oxytocin.
to common clinical use. Many studies worldwide have established
PGF2α has more gastrointestinal toxicity than PGE2. Neither drug
that prostaglandin administration efficiently terminates preg-
has significant maternal cardiovascular toxicity in the recommended
nancy. The drugs are used for first- and second-trimester abortion
doses. In fact, PGE2 must be infused at a rate about 20 times faster
and for priming or ripening the cervix before abortion. These
than that used for induction of labor to decrease blood pressure
prostaglandins appear to soften the cervix by increasing proteogly-
and increase heart rate. PGF2α is a bronchoconstrictor and should
can content and changing the biophysical properties of collagen.
be used with caution in women with asthma; however, neither
Dinoprostone, a synthetic preparation of PGE2, is admin-
asthma attacks nor bronchoconstriction have been observed during
istered vaginally for oxytocic use. In the USA, it is approved
the induction of labor. Although both PGE2 and PGF2α pass the
for inducing abortion in the second trimester of pregnancy, for
fetoplacental barrier, fetal toxicity is uncommon.
missed abortion, for benign hydatidiform mole, and for ripening
For the induction of labor or softening of the cervix, dinopros-
of the cervix for induction of labor in patients at or near term (see
tone is used either as a gel (0.5 mg PGE2 every 6 hours; maximum
below). Dinoprostone stimulates the contraction of the uterus
24-hour cumulative dose of 1.5 mg) or as a controlled-release
throughout pregnancy. As the pregnancy progresses, the uterus
vaginal insert (10 mg PGE2) that releases PGE2 over 12 hours. The
increases its contractile response, and the contractile effect of oxy-
softening of the cervix for induction of labor substantially shortens
tocin is potentiated as well. Dinoprostone also directly affects the
the time to onset of labor and the delivery time. An advantage of
collagenase of the cervix, resulting in softening. Dinoprostone is
the controlled-release formulation is a lower incidence of gastroin-
metabolized in local tissues and on the first pass through the lungs
testinal effects (<1% versus 5.7%).
(about 95%). The metabolites are mainly excreted in the urine.
The effects of oral PGE2 administration (0.5–1.5 mg/h) have
The plasma half-life is 2.5–5 minutes.
been compared with those of intravenous oxytocin and oral
For abortifacient purposes, the recommended dosage is a
demoxytocin, an oxytocin derivative, in the induction of labor.
20-mg dinoprostone vaginal suppository repeated at 3- to 5-hour
Oral PGE2 is superior to the oral oxytocin derivative and in most
intervals depending on the response of the uterus. The mean
studies is as efficient as intravenous oxytocin. Oral PGF2α causes
time to abortion is 17 hours, but in more than 25% of cases, the
too much gastrointestinal toxicity to be useful by this route.
abortion is incomplete and requires additional intervention.
Theoretically, PGE2 and PGF2α should be superior to oxy-
Antiprogestins (eg, mifepristone) have been combined with an
tocin for inducing labor in women with preeclampsia-eclampsia
oral oxytocic synthetic analog of PGE1 (misoprostol) to produce
or cardiac and renal diseases because, unlike oxytocin, they have
early abortion. This regimen is available in the USA and Europe
no antidiuretic effect. In addition, PGE2 has natriuretic effects.
(see Chapter 40). The ease of use and the effectiveness of the com-
However, the clinical benefits of these effects have not been docu-
bination have aroused considerable opposition in some quarters.
mented. In cases of intrauterine fetal death, the prostaglandins
The major toxicities are cramping pain and diarrhea. The oral
alone or with oxytocin seem to cause delivery effectively.
and vaginal routes of administration are equally effective, but the
vaginal route has been associated with an increased incidence of
sepsis, so the oral route is now recommended. C. Dysmenorrhea
An analog of PGF2α is also used in obstetrics. This drug, Primary dysmenorrhea is attributable to increased endome-
carboprost tromethamine (15-methyl-PGF2α; the 15-methyl trial synthesis of PGE2 and PGF2α during menstruation, with
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 335

contractions of the uterus that lead to ischemic pain. NSAIDs increased in a graded dose-dependent manner, based on recur-
successfully inhibit the formation of these prostaglandins (see rence, persistence, or worsening of symptoms. Several prostacy-
Chapter 36) and so relieve dysmenorrhea in 75–85% of cases. clin analogs with longer half-lives have been developed and used
Some of these drugs are available over the counter. Aspirin is also clinically. Iloprost (half-life about 30 minutes) is usually inhaled
effective in dysmenorrhea, but because it has low potency and is six to nine times per day (2.5–5 mcg/dose), although it has
quickly hydrolyzed, large doses and frequent administration are been delivered by intravenous administration outside the USA.
necessary. In addition, the acetylation of platelet COX, causing Treprostinil (half-life about 4 hours) may be delivered by subcu-
irreversible inhibition of platelet TXA2 synthesis, may increase the taneous or intravenous infusion or by inhalation. Recently, two
amount of menstrual bleeding. oral prostacyclin receptor agonists were approved by the US Food
and Drug Administration (FDA): selexipag (a prodrug rapidly
Male Reproductive System converted to active prostacyclin agonist) and an oral preparation
of treprostinil. Other drugs used in pulmonary hypertension are
Intracavernosal injection or transurethral suppository therapy discussed in Chapter 17.
with alprostadil (PGE1) is a second-line treatment for erectile
dysfunction. Injected doses are 2.5–25 mcg; suppositories are B. Peripheral Vascular Disease
recommended to start at 125 mcg or 250 mcg, up to 1000 mcg.
A number of studies have investigated the use of PGE1 and PGI2
Penile pain is a frequent side effect, which may be related to the
compounds in Raynaud’s phenomenon and peripheral arterial
algesic effects of PGE derivatives; however, only a few patients
disease. However, these studies are mostly small and uncontrolled.
discontinue the use because of pain. Prolonged erection and pria-
Currently, these therapies do not have an established place in the
pism are side effects that occur in less than 4% of patients and
treatment of peripheral vascular disease.
are minimized by careful titration to the minimal effective dose.
When given by injection, alprostadil may be used as monotherapy C. Patent Ductus Arteriosus
or in combination with either papaverine or phentolamine.
Patency of the fetal ductus arteriosus depends on COX-2-derived
PGE2 acting on the EP4 receptor. At birth, reduced PGE2 levels,
Renal System a consequence of increased PGE2 metabolism, allow ductus arte-
Increased biosynthesis of prostaglandins has been associated with riosus closure. In certain types of congenital heart disease (eg,
one form of Bartter’s syndrome. This is a rare disease character- transposition of the great arteries, pulmonary atresia, pulmonary
ized by low-to-normal blood pressure, decreased sensitivity to artery stenosis), it is important to maintain the patency of the
angiotensin, hyperreninemia, hyperaldosteronism, and excessive neonate’s ductus arteriosus until corrective surgery can be carried
loss of K+. There also is an increased excretion of prostaglandins, out. This can be achieved with alprostadil (PGE1). Like PGE2,
especially PGE metabolites, in the urine. After long-term adminis- PGE1 is a vasodilator and an inhibitor of platelet aggregation,
tration of COX inhibitors, sensitivity to angiotensin, plasma renin and it contracts uterine and intestinal smooth muscle. Adverse
values, and the concentration of aldosterone in plasma return to effects include apnea, bradycardia, hypotension, and hyperpy-
normal. Although plasma K+ rises, it remains low, and urinary rexia. Because of rapid pulmonary clearance (the half-life is about
wasting of K+ persists. Whether an increase in prostaglandin 5–10 minutes in healthy adults and neonates), the drug must be
biosynthesis is the cause of Bartter’s syndrome or a reflection of a continuously infused at an initial rate of 0.05–0.1 mcg/kg/min,
more basic physiologic defect is not yet known. which may be increased to 0.4 mcg/kg/min. Prolonged treatment
has been associated with ductal fragility and rupture.
Cardiovascular System In delayed closure of the ductus arteriosus, COX inhibitors are
often used to inhibit synthesis of PGE2 and so close the ductus.
A. Pulmonary Hypertension Premature infants in whom respiratory distress develops due to
PGI2 lowers peripheral, pulmonary, and coronary vascular resis- failure of ductus closure can be treated with a high degree of suc-
tance. Pulmonary hypertension is characterized by an increase cess with indomethacin. This treatment often precludes the need
in vascular resistance in the pulmonary blood vessels. PGI2 has for surgical closure of the ductus.
been used to treat pulmonary hypertension arising from primary
lung disease and that arising from heart or systemic diseases.
In addition, prostacyclin has been used successfully to treat Blood
portopulmonary hypertension, which arises secondary to liver As noted above, TXA2 promotes platelet aggregation while PGI2,
disease. The first commercial preparation of PGI2 approved for and perhaps also PGE2 and PGD2, inhibit aggregation. Chronic
treatment of pulmonary hypertension (epoprostenol) improves administration of low-dose aspirin (81 mg/d) selectively and irre-
symptoms, prolongs survival, and delays or prevents the need versibly inhibits platelet COX-1, and its dominant product TXA2,
for lung or lung-heart transplantation. Side effects include flush- without modifying the activity of nonplatelet COX-1 or COX-2
ing, headache, hypotension, nausea, and diarrhea. The extremely (see Chapter 34). TXA2, in addition to activating platelets, ampli-
short plasma half-life (3–5 minutes) of epoprostenol necessitates fies the response to other platelet agonists; hence, inhibition of its
continuous intravenous infusion through a central line for long- synthesis inhibits secondary aggregation of platelets induced by
term treatment. Intravenous infusion dosage of epoprostenol is adenosine diphosphate, by low concentrations of thrombin and
336 SECTION IV Drugs with Important Actions on Smooth Muscle

collagen, and by epinephrine. Because their effects are reversible numerous experimental and clinical investigations have shown that
within the typical dosing interval, nonselective NSAIDs (eg, ibu- the PGE compounds and their analogs protect against peptic ulcers
profen) do not reproduce this effect, although naproxen, because produced by either steroids or NSAIDs. Misoprostol is an orally
of its variably prolonged half-life, may provide antiplatelet benefit active synthetic analog of PGE1. The FDA-approved indication
in some individuals. Not surprisingly, given the absence of COX-2 is for prevention of NSAID-induced peptic ulcers. This and other
in platelets, selective COX-2 inhibitors do not alter platelet TXA2 PGE analogs (eg, enprostil) are cytoprotective at low doses and
biosynthesis and are not platelet inhibitors. However, COX- inhibit gastric acid secretion at higher doses. Because it is also an
2-derived PGI2 generation is substantially suppressed during selec- abortifacient, misoprostol is a pregnancy category X drug. Miso-
tive COX-2 inhibition, removing a restraint on the cardiovascular prostol use is low, probably because of its adverse effects including
action of TXA2, and other platelet agonists. It is highly likely that abdominal discomfort and occasional diarrhea. Dose-dependent
selective depression of PGI2 generation explains the increase in bone pain and hyperostosis have been described in patients with
vascular events, particularly major coronary events, in humans liver disease who were given long-term PGE treatment.
treated with a coxib or nonselective NSAID. High-dose ibuprofen Selective COX-2 inhibitors were developed in an effort to spare
may confer a similar risk, whereas high-dose naproxen appears to gastric COX-1 so that the natural cytoprotection by locally synthe-
be neutral with respect to thrombotic risk. All NSAIDs appear to sized PGE2 and PGI2 is undisturbed (see Chapter 36). However,
increase the risk of heart failure. this benefit is seen only with highly selective inhibitors and is offset,
Large clinical studies have now clearly demonstrated secondary at least at a population level, by increased cardiovascular toxicity.
prevention of adverse cardiovascular events (ie, preventing a sec-
ond event after an initial event) by low-dose aspirin. There is also Immune System
some evidence that low-dose aspirin can confer primary cardiovas-
Cells of the immune system contribute substantially to eicosanoid
cular protection (protection from an initial cardiovascular event),
biosynthesis during an immune reaction. T and B lymphocytes are
particularly in high cardiovascular risk populations. However,
not primary synthetic sources; however, they may supply arachi-
low-dose aspirin also elevates the low risk of serious gastrointes-
donic acid to monocyte-macrophages for eicosanoid synthesis. In
tinal bleeding about twofold over placebo. The effects of aspirin
addition, there is evidence for eicosanoid-mediated cell-cell inter-
on platelet function are discussed in greater detail in Chapter 34.
action by platelets, erythrocytes, leukocytes, and endothelial cells.
PGE2 and PGI2 limit T-lymphocyte proliferation in vitro, as do
Respiratory System corticosteroids. PGE2 also inhibits B-lymphocyte differentiation
PGE2 is a powerful bronchodilator when given in aerosol form. and the antigen-presenting function of myeloid-derived cells, sup-
Unfortunately, it also promotes coughing, and an analog that pressing the immune response. T-cell clonal expansion is attenuated
possesses only the bronchodilator properties has been difficult to through inhibition of interleukin-1 and interleukin-2 and class II
obtain. antigen expression by macrophages or other antigen-presenting
PGF2α and TXA2 are both strong bronchoconstrictors and cells. The leukotrienes, TXA2, and platelet-activating factor stimu-
were once thought to be primary mediators in asthma. Polymor- late T-cell clonal expansion. These compounds stimulate the forma-
phisms in the genes for PGD2 synthase, both DP receptors, and tion of interleukin-1 and interleukin-2 as well as the expression of
the TP receptor have been linked with asthma in humans. DP interleukin-2 receptors. The leukotrienes also promote interferon-γ
antagonists, particularly those directed against DP2, are being release and can replace interleukin-2 as a stimulator of interferon-γ.
investigated as potential treatments for allergic diseases includ- PGD2 induces chemotaxis and migration of Th2 lymphocytes.
ing asthma. However, the cysteinyl leukotrienes—LTC4, LTD4, These in vitro effects of the eicosanoids agree with in vivo findings
and LTE4—probably dominate during asthmatic constriction of in animals with acute organ transplant rejection.
the airways. As described in Chapter 20, leukotriene-receptor
inhibitors (eg, zafirlukast, montelukast) are effective in asthma. A. Inflammation
A lipoxygenase inhibitor (zileuton) has also been used in asthma Aspirin has been used to treat arthritis of all types for approxi-
but is not as popular as the receptor inhibitors. It remains unclear mately 100 years, but its mechanism of action—inhibition of
whether leukotrienes are partially responsible for acute respiratory COX activity—was not discovered until 1971. COX-2 appears
distress syndrome. to be the form of the enzyme most associated with cells involved
Corticosteroids and cromolyn are also useful in asthma. Corti- in the inflammatory process, although, as outlined above, COX-1
costeroids inhibit eicosanoid synthesis and thus limit the amounts also contributes significantly to prostaglandin biosynthesis during
of eicosanoid mediator available for release. Cromolyn appears inflammation. Aspirin and other anti-inflammatory agents that
to inhibit the release of eicosanoids and other mediators such as inhibit COX are discussed in Chapter 36.
histamine and platelet-activating factor from mast cells.
B. Rheumatoid Arthritis
Gastrointestinal System In rheumatoid arthritis, immune complexes are deposited in the
The word “cytoprotection” was coined to signify the remarkable affected joints, causing an inflammatory response that is amplified
protective effect of the E prostaglandins against peptic ulcers in by eicosanoids. Lymphocytes and macrophages accumulate in the
animals at doses that do not reduce acid secretion. Since then, synovium, whereas leukocytes localize mainly in the synovial fluid.
 CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 337

The major eicosanoids produced by leukocytes are leukotrienes, P R E P A R A T I O N S

which facilitate T-cell proliferation and act as chemoattractants. A V A I L A B L E
Human macrophages synthesize the COX products PGE2 and
TXA2 and large amounts of leukotrienes.
GENERIC NAME AVAILABLE AS
NONSTEROIDAL ANTI-INFLAMMATORY
Glaucoma DRUGS ARE LISTED IN CHAPTER 36.
Latanoprost, a stable long-acting PGF2α derivative, was the first Alprostadil
prostanoid used for glaucoma. The success of latanoprost has Penile injection, mini-suppository Caverject, Edex, Muse
stimulated development of similar prostanoids with ocular hypo- Parenteral Generic, Prostin VR Pediatric
tensive effects, and bimatoprost, and travoprost are now avail- Bimatoprost Lumigan, Latisse
able. These drugs act at the FP receptor and are administered as Carboprost tromethamine Hemabate
drops into the conjunctival sac once or twice daily. Adverse effects Dinoprostone [prostaglandin E2] Prostin E2, Prepidil, Cervidil
include irreversible brown pigmentation of the iris and eyelashes, Epoprostenol [prostacyclin] Generic, Flolan, Veletri
drying of the eyes, and conjunctivitis. Iloprost Ventavis
Latanoprost Generic, Xalatan
Misoprostol Generic, Cytotec
Hypotrichosis Montelukast Generic, Singulair
Bimatoprost is FDA approved for treatment of eyelash hypotri- Selexipag Uptravi
chosis and has shown efficacy in enhancing eyelash growth after Travoprost Generic, Travatan, Travatan-Z
chemotherapy. The drug is applied in a 0.03% solution to the skin Treprostinil Remodulin, Tyvaso,
at the base of the upper lashes. A common but minor adverse effect Orenitram
is darkening of eyelid skin due to increased melanin production Zafirlukast Generic, Accolate
that is reversible with discontinuation. Recent trials have also dem- Zileuton Zyflo, Zyflo CR
onstrated efficacy in eyebrow hypotrichosis, and emerging studies
have suggested that this drug may have utility for treating alopecia.

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