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inhibiting secretion of hydrochloric acid in
because these cells have no nuclei and, therefore, cannot synthesize new
the mucosal cells of the stomach. Analogs of
mRNA. Thus, the inhibition of cyclooxygenase by aspirin persists for the lifespan of
PGE1 are used in the treatment of sexual
the platelet (7 10 days). When aspirin is taken daily at doses between 81 and 325 mg,
impotence. Men with certain forms of sexual
new platelets are affected as they are generated. Higher doses do not improve efficacy
impotence can self-inject this agent into the
but do increase side effects, such as gastrointestinal bleeding and easy bruisability.
corpus cavernosum of the penis to induce
Patients with established or suspected atherosclerotic coronary disease, such as
immediate but temporary penile tumes-
Ann Jeina, Cora Nari, and Ivan Applebod, benefit from the action of low-dose
cence. The erection lasts for 1 to 3 hours.
aspirin (approximately 162 mg/day), which produces a mild defect in hemostasis.
The stimulatory action of PGE2 and PGF2 on
This action of aspirin helps to prevent thrombus formation in the area of an athero-
uterine muscle contraction has led to the use
sclerotic plaque at critical sites in the vascular tree. of these prostaglandins to induce labor and
to control postpartum bleeding. PGE1 is also
used as palliative therapy in neonates with
Corticosteroids reduce inflammation, in part, through their inhibitory effect
congenital heart defects to maintain patency
on phospholipase A2. In addition, suppression of COX-2 induction is now
of the ductus arteriosus until surgery can be
thought to be a primary anti-inflammatory mechanism of action for gluco-
performed. Analogs of PGI2 have been
corticoids. Despite the unquestionable value of glucocorticoid therapy in a variety of
shown to be effective in the treatment of pri-
diseases associated with acute inflammation of tissues, the suppression of the inflam-
mary pulmonary hypertension.
matory response with pharmacologic doses of corticosteroids is potentially haz-
ardous. The sudden appearance of temporary glucose intolerance when Emma
Wheezer was treated with large doses of dexamethasone, a gluconeogenic steroid
(glucocorticoid), is just one of the many potential adverse effects of this class of
drugs when given systemically in pharmacologic doses over an extended period. The
inhaled steroids, conversely, have far fewer systemic side effects because their
absorption across the bronchial mucosa into the circulation is very limited. This
property allows them to be used over prolonged periods in the treatment of asthma.
The fact that inhalation allows direct delivery of the agent to the primary site of
inflammation adds to their effectiveness in the treatment of these patients.
BIOCHEMICAL COMMENTS
Inflammation is the response of the body to infection or injury, directed at
destroying the infectious agents and repairing the damaged areas. It
involves an increase of the blood supply to the affected region by means of
666 SECTION SIX / LIPID METABOLISM
Although uncomfortable, the pain,
vasodilation. The capillaries become more permeable so that fluid, large molecules,
swelling, and fever that are part of
and white blood cells can cross, leaving the blood and entering the tissue. White
the inflammatory response serve
blood cells (particularly neutrophils and monocytes) move by chemotaxis to the
as an important warning sign that the host is
injured site. Redness (rubor), heat (calor), swelling (tumor), and pain (dolor) are
threatened and that some specific counter-
associated with the inflammatory process. Redness and heat are caused by the
actions must be taken against the offending
increased blood flow. Swelling is the result of the increased movement of fluid and
agent or process. Although the use of anti-
white blood cells into the area of inflammation. Pain is caused by the release of
inflammatory drugs may bring welcome
chemical compounds and the compression of nerves in the vicinity of the inflam-
symptomatic relief, their use may, in part,
matory process.
diminish the effectiveness of the host s
The chemical mediators of inflammation usually are produced by activation of
response to the inciting agent.
complement (a family of blood proteins that are cleaved to form active fragments)
or of the blood clotting cascade (see Chapter 45). These processes cause the release
of histamine from mast cells, and the production of kinins by cleavage of kinino-
gens. Among their other effects, both histamine and kinins increase vascular per-
meability. They stimulate the synthesis of eicosanoids that act on the motility and
metabolism of white blood cells and cause the aggregation of platelets to arrest
bleeding. Some of the prostaglandins act on thermoregulatory centers of the brain,
producing fever. Cytokines are also released that stimulate the proliferation of cells
involved in the immune response.
Suggested References
Brash AR. Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem
1999;274:23679 23682.
Dimarzo V, Bisogno T, and DePetrocellis L. Anandamide: some like it hot. Trends Pharm Sci
2001;22:346 349.
Halushka PV. Prostaglandins and related compounds. In: Goldman L and Bennett JC, eds. Cecil Text-
book of Medicine. Philadelphia: WB Saunders, 2000:1189 1194.
Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA. Arachidonic acid oxygenation
by COX-1 and COX-2: Mechanisms of catalysis and inhibition. J Biol Chem 1999;274:
22903 22906.
Morrow JD, Roberts LJ II. Lipid-derived autacoids. In: Hardman JG, Limbird LE, eds. Goodman
and Gilman s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 2001:
669 680.
REVIEW QUESTIONS CHAPTER 35
1. In humans, prostaglandins are primarily derived from which of the following?
(A) Glucose
(B) Acetyl CoA
(C) Arachidonic acid
(D) Oleic acid
(E) Leukotrienes
2. Aspirin will inhibit which of the following reaction pathways?
(A) Arachidonic acid S thromboxanes
(B) Arachidonic acid S leukotrienes
(C) Arachidonic acid S phospholipids
(D) Linoleic acid S arachidonic acid
(E) Acetyl CoA S linoleic acid
CHAPTER 35 / METABOLISM OF THE EICOSANOIDS 667
3. Which of the following drugs leads to the covalent modification, and inactivation, of both the COX-1 and COX-2 enzymes?
(A) Aspirin
(B) Tylenol
(C) Celebrex
(D) Vioxx
(E) Advil
4. Thromboxane A2, which is found in high levels in platelets, aids in wound repair through induction of which of the follow-
ing activities?
(A) Inhibits COX-2 gene expression
(B) Inhibits COX-1 gene expression
(C) Vasoconstriction
(D) Vasodilation
(E) Bronchodilation
5. Certain prostaglandins, when binding to their receptor, induce an increase in intracellular calcium levels. The signal that leads
to the elevation of intracellular calcium is initiated by which of the following enzymes?
(A) Protein kinase A
(B) Phospholipase C
(C) Phospholipase A2
(D) Protein kinase C
(E) Cyclooxygenase [ Pobierz całość w formacie PDF ]