352 Chapter 11
- Reproductive system. Prostaglandins may play a role in
ovulation and corpus luteum function in the ovaries and in
contraction of the uterus. Excessive production of PGE 2
and PGI 2 may be involved in premature labor, endometrio-
sis, dysmenorrhea (painful menstrual cramps), and other
gynecological disorders. - Digestive system. The stomach and intestines produce
prostaglandins, which are believed to inhibit gastric secre-
tions and influence intestinal motility and fluid absorption.
Because prostaglandins inhibit gastric secretion, drugs
that suppress prostaglandin production may make a person
more susceptible to peptic ulcers. - Respiratory system. Some prostaglandins cause constric-
tion whereas others cause dilation of blood vessels in the
lungs and of bronchiolar smooth muscle. The leukotrienes
are potent bronchoconstrictors, and these compounds,
together with PGF 2 a , may cause respiratory distress and
contribute to bronchoconstriction in asthma. - Circulatory system. Some prostaglandins are vasocon-
strictors and others are vasodilators. Thromboxane A 2 , a
vasoconstrictor, and prostacyclin, a vasodilator, play a role
in blood clotting, as previously described. In a fetus, PGE 2
is believed to promote dilation of the ductus arteriosus —
a short vessel that connects the pulmonary artery with the
aorta. After birth, the ductus arteriosus normally closes as a
result of a rise in blood oxygen when the baby breathes. If
the ductus remains patent (open), however, it can be closed
by the administration of drugs that inhibit prostaglandin
synthesis. - Urinary system. Prostaglandins are produced in the renal
medulla and cause vasodilation, resulting in increased
renal blood flow and increased excretion of water and
electrolytes in the urine.
Inhibitors of Prostaglandin Synthesis
Aspirin is the most widely used member of a class of drugs known
as nonsteroidal anti-inflammatory drugs (NSAIDs). Other
members of this class are indomethacin and ibuprofen. These
drugs produce their effects because they specifically inhibit the
cyclooxygenase enzyme that is needed for prostaglandin syn-
thesis. Through this action, the drugs inhibit inflammation but
produce some unwanted side effects, including gastric bleeding,
possible kidney problems, and prolonged clotting time.
It is now known that there are two major isoenzyme forms
of cyclooxygenase. The type I isoform ( COX-1 ) is produced
constitutively (that is, in a constant fashion) by cells of the
stomach and kidneys and by blood platelets, which are cell
fragments involved in blood clotting (chapter 13, section 13.2).
The type II isoform of the enzyme ( COX-2 ) is induced in a num-
ber of cells in response to cytokines involved in inflammation,
and the prostaglandins produced by this isoenzyme promote
the inflammatory condition.
When aspirin and indomethacin inhibit the COX-1 isoen-
zyme, they reduce the synthesis of prostacyclin (PGI 2 ) and PGE 2
in the gastric mucosa. This is believed to result in the stomach
irritation caused by these NSAIDs. Indeed, inhibition of the
COX-1 isoenzyme may cause serious gastrointestinal and renal
toxicity in long-term use. This has spurred research into the
development of next-generation NSAIDs that more selectively
inhibit the COX-2 isoenzyme. These newer COX-2-selective
drugs, including celecoxib and rofecoxib (for example, Celebrex
and Vioxx), thus inhibit inflammation while producing fewer
negative side effects in the gastric mucosa.
However, studies indicated that the COX-2 selective inhib-
itors produced a significant increase in the risk of myocardial
infarction (heart attack) and thrombotic stroke after a year or
more of treatment. This has been explained by the observa-
tion that the selective COX-2 inhibitors reduce the ability of
the vascular endothelium to produce prostaglandin I 2 (which
inhibits clotting and promotes vasodilation) while not inhibit-
ing the ability of blood platelets to produce thromboxane A 2
(which promotes clotting and vasoconstriction). At the time
of this writing, most of the selective COX-2 inhibitors have
been withdrawn from the market. The benefits of the selective
COX-2 inhibitors for gastrointestinal protection may outweigh
the increased risk of cardiovascular disease in some patients,
so this is a complex issue that physicians and patients may best
weigh on an individual basis.
Also, inhibition of the specific COX-1 isoenzyme by aspi-
rin can provide an important benefit. This is the isoenzyme
present in blood platelets that catalyzes the production of
thromboxane A 2. As mentioned previously, thromboxane A 2 is
the prostaglandin produced by blood platelets that promotes
platelet aggregation in the process of blood clotting (chapter 13;
see fig. 13.7). While inhibition of platelet aggregation can be
detrimental in certain situations, such aspirin-induced inhibi-
tion has been shown to reduce the risk of heart attacks and
strokes. It should be noted that this protective effect is pro-
duced by daily doses of “baby aspirin” (81 mg), which are sig-
nificantly lower than the doses used to reduce inflammation.
Acetaminophen (e.g., Tylenol) does not greatly inhibit either
COX-1 or COX-2, and is not an effective anti-inflammatory
drug. Yet it does reduce fever and relieve pain. It has recently
been shown to work by inhibiting a newly discovered isoenzy-
matic form, designated COX-3, which is found in large amounts
in the brain.
Drugs that are anti-leukotrienes have recently become
available. Some (such as Zyflo) work by inhibiting the enzyme
5-lipoxygenase that forms the leukotrienes; others (such as
Singulair) block the leukotriene receptors. These drugs are
used for the treatment of asthma.