DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

aqueous humor outflow of the eye via the uveoscleral
and trabecular meshwork pathway. A variety of FP
receptor agonists have proven effective in the treatment
of open-angle glaucoma, a condition associated with
the loss of COX-2 expression in the pigmented epithelium
of the ciliary body (see Chapter 64).
CNS. Although effects have been reported following
injection of several PGs into discrete brain areas, the
best established biologically active mediators are PGE 2
and PGD 2
. The induction of fever by a range of endogenous
and exogenous pyrogens appears to be mediated
by PGE 2
(Smyth and FitzGerald, 2009). The hypothalamus
regulates the body temperature set point, which is
elevated by endogenous pyrogens such as interleukin
(IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and
interferons. The initial phase of the thermoregulatory
response to pyrogens is thought to be mediated by
ceramide release in neurons of the preoptic area in the
anterior hypothalamus, while the late response is mediated
by coordinate induction of COX-2 and mPGES-1
in the endothelium of blood vessels in the preoptic
hypothalamic area to form PGE 2
. PGE 2
can cross the
blood-brain barrier and acts on EP 3
, and perhaps EP 1
,
on thermosensitive neurons. This triggers the hypothalamus
to elevate body temperature by promoting an
increase in heat generation and a decrease in heat loss.
Exogenous PGF 2α
and PGI 2
induce fever but do not
contribute to the pyretic response. PGD 2
and TxA 2
do
not induce fever. PGD 2
also appears to act on arachnoid
trabecular cells in the basal forebrain to mediate an
increase in extracellular adenosine that, in turn, facilitates
induction of sleep.
COX-2-derived prostanoids also have been implicated in several
CNS degenerative disorders (e.g, Alzheimer’s disease, Parkinson
disease; see Chapter 22), although the therapeutic efficacy of blocking
their synthesis or action remains to be established.
Pain. Inflammatory mediators, including LTs and PGs,
increase the sensitivity of nociceptors and potentiate
pain perception. Both PGE 2
, through the EP 1
and EP 4
,
and PGI 2
, via the IP, reduce the threshold to stimulation
of nociceptors, causing “peripheral sensitization”.
Centrally, both COX-1 and COX-2 are expressed in the
spinal cord under basal conditions and release PGs in
response to peripheral pain stimuli. PGE 2
, and perhaps
also PGD 2
, PGI 2
, and PGF 2α
, can increase excitability
in pain transmission neuronal pathways in the spinal
cord, causing hyperalgesia and allodynia. Hyperalgesia
also is produced by LTB 4
. The release of these
eicosanoids during the inflammatory process thus
serves as an amplification system for the pain mechanism.
The role of PGE 2
and PGI 2
in inflammatory pain is discussed
in more detail in Chapter 34.
Endocrine System. A number of endocrine tissues
respond to PGs. In several species, the systemic administration
of PGE 2
increases circulating concentrations
of adrenocorticotropic hormone (ACTH), growth
hormone, prolactin, and gonadotropins. Other effects
include stimulation of steroid production by the adrenals,
stimulation of insulin release, and thyrotropin-like
effects on the thyroid. The critical role of PGF 2α
in
parturition relies on its ability to induce an oxytocindependent
decline in progesterone levels. PGE 2
works as
part of a positive-feedback loop to induce oocyte maturation
required for fertilization during and after ovulation.
LOX metabolites also have endocrine effects. 12-HETE stimulates
the release of aldosterone from the adrenal cortex and mediates
a portion of the aldosterone release stimulated by AngII, but not
that which occurs in response to ACTH.
Bone. PGs are strong modulators of bone metabolism.
COX-1 is expressed in normal bone, while COX-2 is
upregulated in certain settings, such as inflammation
and during mechanical stress. PGE 2
stimulates bone
formation by increasing osteoblastogenesis. Bone
resorption also is mediated via PGE 2
, through activation
of osteoclasts.
Therapeutic Uses
Inhibitors and Antagonists. As a consequence of the
important and diverse physiological roles of
eicosanoids, mimicking their effects with stable agonists,
inhibiting eicosanoid formation, and antagonizing
eicosanoid receptors produce therapeutically useful
responses. As outlined earlier in “Inhibitors of
Eicosanoid Biosynthesis” and in Chapter 34, the
nonselective tNSAIDs, and those with selective
COX-2 inhibition, are used widely as anti-inflammatory
drugs, whereas low-dose aspirin is employed frequently
for cardioprotection. LT antagonists are useful
clinically in the treatment of asthma, and FP agonists
are used in the treatment of open-angle glaucoma
(Chapter 64). EP agonists are used to induce labor and
to ameliorate gastric irritation owing to tNSAIDs.
There are as of yet no potent selective antagonists
of prostanoid receptors in clinical use. TP antagonists
were abandoned as antiplatelet agents when it seemed
like they would confer nothing superior to aspirin. Now
that the clinical implications of suppressing PGI 2
are
recognized, the partial suppression by even low doses
of aspirin may confer an advantage on TP antagonists,
as may blockade of receptor activation by unconventional
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CHAPTER 33
LIPID-DERIVED AUTACOIDS: EICOSANOIDS AND PLATELET-ACTIVATING FACTOR