When the history of men's health is written, 1998 will go down as a banner year. That's when sildenafil
(Viagra) was approved by the FDA to treat erectile dysfunction (ED).
But when the history of sildenafil is written, 2005 will also be
special. That's when the FDA approved the medication that revolutionized
male sexuality for a nonsexual condition. The illness is pulmonary hypertension, and sildenafil is prescribed for it under the brand name Revatio.
Sildenafil for ED
Sildenafil was the first effective oral medication for ED. In 2003 it was joined by vardenafil (Levitra) and tadalafil
(Cialis). Although there are some differences between these drugs
(vardenafil starts working sooner and tadalafil works longer), they all
act in exactly the same way to combat ED.
The three drugs are so similar because they share a common target, an enzyme called phosphodiesterase-5 (PDE-5). To understand why blocking PDE-5 improves sexual function, however, you have to know how erections develop.
Normal erections require a receptive state of mind, adequate levels
of testosterone, and healthy arteries, veins, and nerves. But they also
require a tiny chemical messenger called nitric oxide (NO). It
serves two crucial functions: transmitting the impulses of arousal
between nerves and relaxing the smooth muscle cells in the arteries,
allowing them to widen and admit more blood to the penis.
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Nitric oxide is essential because it signals the arterial cells to produce cyclic guanosine monophosphate
(cGMP), the chemical that increases the flow of blood to the penis. But
the tissues of the penis also produce PDE-5, the enzyme that breaks
In normal circumstances, the penis generates enough cGMP to produce a
rigid erection and enough PDE-5 to end the erection when ejaculation is
complete. In many men with ED, this intricate system is out of balance,
but one of the three oral medications can often make it right. By
inhibiting PDE-5, they increase the supply of cGMP, which for many men
will allow erections to develop.
In test tubes, vardenafil and tadalafil inhibit PDE-5 a bit more
effectively than sildenafil does. But laboratory potency doesn't
necessarily predict clinical activity. In this case, it means that lower
doses of the newer drugs will achieve comparable results to the older
drug's success rate. Vardenafil is marketed in 2.5-, 5-, 10-, and
20-milligram (mg) tablets; tadalafil in doses of 5, 10, and 20 mg; and
sildenafil, 25, 50, and 100 mg. Each produces better results at higher
doses, but the top doses are also more likely to cause side effects. And
all the drugs are more effective in men with mild ED than in those who
are severely impaired.
Doctors have had more clinical experience with sildenafil than its
newer rivals. Still, all three drugs seem to achieve similar results. In
broad terms, about 70% of men benefit. The response is best in men with
no identifiable organic cause of ED (about 90%), but it's less
favorable for diabetics (about 50%), and it's hard to predict for men
who have been treated for prostate cancer.
Other targets: Side effects
If PDE-5 were found exclusively in the penis, the side effects of
these drugs would be limited to that obdurate organ; in fact, a rare
side effect is priapism, painful prolonged erections that
require urgent treatment. But small amounts of PDE-5 are found in blood
vessels in other parts of the body. In addition, PDE-5 is just one of 11
enzymes in the phosphodiesterase family. The others are concentrated in
different parts of the body. While the ED pills have a much greater
affinity for PDE-5 than the other PDEs, they have some ability to
inhibit those closely related enzymes. Both factors explain why the ED
pills sometimes produce side effects in many parts of the body.
The most common side effects are headaches and facial flushing, which
occur in about 15% of men. Other reactions include nasal congestion,
indigestion, and back pain; blue-tinged vision is even less common. In
almost every case, these side effects are mild and transient. But new
information has added a rare eye disease to the list. Nonarteritic anterior ischemic optic neuropathy
(NAION) is a poorly understood disorder that can cause blindness. In
March 2005, doctors reported that seven men experienced visual
impairment within hours of using sildenafil. Since then, additional
cases have been reported to the FDA related to sildenafil, tadalafil,
and vardenafil. Fortunately, the number of cases is very small in
relation to the millions of men who have used ED pills successfully.
It's not clear that there is a cause-and-effect relationship between ED
pills and NAION. At present, the concern is not great enough to prevent
men from using these pills, but all men should use them carefully and
The most important worry about ED pills is their ability to widen
arteries enough to lower blood pressure. It's rarely a problem in
healthy men, but it explains a crucial precaution that applies to all
three medications. Nitrates are medications that temporarily
widen arteries by increasing their supply of nitric oxide. That's how
they widen partially blocked coronary arteries in patients with angina.
But because the nitrates and ED pills all act on nitric oxide, they do
not mix. Men who are taking nitrates should never use any of the ED
pills. This ban includes all preparations of nitroglycerin (short-acting, under-the-tongue tablets or sprays); long-acting nitrates (isosorbide dinitrate, or Isordil, Sorbitrate, and others, and isosorbide mononitrate,
Imdur, ISMO, and others); nitroglycerin patches and pastes; and amyl
nitrite (so-called poppers, used for sexual stimulation by some men).
ED pills are quite safe for men with stable cardiovascular disease
who do not take nitrates. This group includes patients with stable
angina, previous heart attacks, mild congestive heart failure,
well-controlled hypertension, and previous strokes. But men with recent
heart attacks and strokes should wait until they have recovered fully,
and patients with unstable blood pressure, active angina, or any other
complex or unusual problem should hold off and get specific medical
guidance. And men who take alpha blockers (particularly terazosin, or Hytrin, and doxazosin, or Cardura) for hypertension or benign prostatic hyperplasia
(BPH) should use ED pills (particularly vardenafil or tadalafil) with
great caution, if at all. Studies also suggest that sildenafil may
increase respiratory distress in men with severe sleep apnea and that it slows gallbladder function, which might increase the risk of gallstones.
Jet lag, too?
Interest in Viagra is worldwide, but scientists in Argentina have
proposed the most unusual possibility. In a 2007 paper, they report that
Viagra may help decrease jet lag. It's not as farfetched as it seems,
since the drug inhibits PDE-5 in the part of the brain that controls the
body's internal clock. But before you request a prescription for your
next trip, you should know that the subjects in the Buenos Aires
experiments were hamsters.
Other targets: Therapeutic roles
Scientists who noticed that the ED pills can produce side effects in
many parts of the body are asking if they can also serve therapeutic
roles beyond male (or female) sexuality. Because of its seniority, most
of the research has used sildenafil, so it's not clear if the newer
medications will fill similar roles. But for sildenafil, at least, some
new uses appear promising.
Pulmonary hypertension. It's the only nonsexual condition
that has earned FDA approval for sildenafil. It's not common, and
sildenafil is far from a cure. But since it's a serious problem, any
benefit is most welcome.
When we think of blood pressure, we usually think of the systemic circulation, of the blood pumped from the heart's left ventricle to the aorta
and then to the smaller arteries that carry oxygen-rich blood
throughout the body. But to pick up vital oxygen, blood must first pass
from the less powerful right ventricle through the pulmonary artery
to the lungs, then back to the left side of the heart. The pressures in
the pulmonary artery are much lower (about 20/10 millimeters of
mercury, or mm Hg) than in the aorta (lower than 120/80 mm Hg is
Exercise is the most common cause of rising pulmonary artery
pressure, but the elevation is mild and subsides promptly with rest.
High altitudes are another cause, which can lead to mountain sickness
(see below). Far more serious are the large number of lung diseases,
vascular diseases, heart disorders, and miscellaneous conditions that
can cause pulmonary hypertension. And in primary pulmonary hypertension, no underlying cause is evident.
Pulmonary hypertension causes shortness of breath, first during
exertion but eventually at rest if the condition progresses. A variety
of treatments are available, depending on the underlying problem. And
the FDA has approved sildenafil (Revatio) in a dose of 20 mg three times
a day for men and women with pulmonary hypertension. Clinical trials
have demonstrated improved exercise tolerance with few side effects.
Mountain sickness. Pulmonary hypertension is a feature of
acute mountain sickness. High altitudes produce low blood-oxygen levels.
In turn, low oxygen produces a narrowing of the pulmonary arteries. The
heart must therefore work harder, reducing the capacity to exercise.
Sildenafil widens the pulmonary arteries. To find out if it might
improve exercise capacity in low oxygen conditions, scientists tested 14
healthy mountain climbers in a lab in Germany and again at a Mount
Everest base camp. In the lab, the volunteers breathed 10% oxygen
through a mask; on the mountain, they breathed natural air. Under both
conditions, a 50-mg sildenafil tablet decreased pressures in the lungs'
blood vessels and increased the maximum exercise capacity.
It's a small study, and it's too soon to say if sildenafil will help
prevent or treat acute mountain sickness. Still, a study of 29 climbers
reported that tadalafil can also reduce pulmonary artery pressure at a
Raynaud's phenomenon. In affected individuals, exposure to
the cold triggers spasm of the small arteries that supply blood to the
fingers, toes, or both. Temporarily deprived of adequate blood flow, the
involved digits become pale, cold, and very painful. It's a common
condition, affecting up to 8% of men and 17% of women. In the vast
majority, there are no underlying diseases (primary Raynaud's), and patients do well simply by minimizing their exposure to cold. But secondary Raynaud's can complicate collagen-vascular diseases
or certain other conditions. It's not common, but secondary Raynaud's
can be very painful and difficult to treat. Many medications have been
used without consistent success. But a 2005 study of 16 patients with
severe Raynaud's phenomenon that had not responded to other medications
reported benefit from sildenafil in a dose of 50 mg twice a day. And a
2006 study of 40 Raynaud's patients reported similar benefits from
vardenafil in a dose of 10 mg twice a day.
Heart disease. Sildenafil was discovered by scientists
looking for a new medication to dilate coronary arteries. It does that,
but because it widens healthy coronary arteries more than diseased
vessels, it has not been successful in treating angina. But it may have
other benefits for cardiac patients.
In the first years of the Viagra era, research on sildenafil and the
heart was devoted to making sure the drug was safe for the circulation.
In most men with heart disease, it is. But several studies of patients
with congestive heart failure also reported that the medication
improves oxygen consumption, pulmonary artery pressure, and exercise
capacity in these patients. Research shows that sildenafil helps the
heart muscle relax properly, which could help patients with heart
failure due to diastolic dysfunction. Another interesting
property is sildenafil's ability to protect the heart from excessive
stimulation by adrenaline. Clinical trials will be needed to see which
patients might benefit.
Stroke. It's the most speculative use for sildenafil, and
it's far from clinical application. Still, it's an interesting area of
new research. A European study of 25 men who had erectile dysfunction
but no other circulatory disorders found that blood vessels in the brain
responded to stress better after a 50-mg dose of sildenafil. More
interesting results were reported by scientists in Michigan, who
produced ischemic strokes in rats by temporarily blocking blood vessels.
During their recovery, the animals were divided into three groups. One
received no treatment, another low-dose sildenafil, and the third
high-dose sildenafil. The animals who got sildenafil recovered better,
with the highest doses producing the best results. The scientists
concluded that the medication actually stimulated the growth of new
nerve cells in the brain tissue next to the stroke damage.
It's far too early to know whether sildenafil may someday help people with strokes. Stay tuned.
ED pills for BPH?
Although erectile dysfunction and benign prostatic hyperplasia are
both common in older men, they are separate conditions. But three 2007
studies report that all of the ED pills may ease lower urinary tract
symptoms in men with BPH. This potential benefit appears to depend on
inhibiting PDE-5 in the bladder, not the prostate, and it may require
daily use of these expensive drugs. More research is under way.
Meanwhile, men who use popular and effective alpha blockers for BPH
symptoms should get medical clearance before they use ED pills. In
particular, the newest ED pills may reduce blood pressure in men taking
the older, nonselective alpha blockers.
If you get your information about sildenafil from Super Bowl
commercials or e-mail spam, you might dismiss it as a lifestyle drug of
little real medical importance. In fact, it's a serious prescription
medication that has helped millions of men who are distressed by an
entirely legitimate medical problem. Because the drug acts on arteries
beyond the penis, it can produce various side effects. That means it
should only be prescribed by a personal physician who really knows you.
And it also means that scientists are investigating uses for the drug in
patients with an array of vascular disorders having nothing to do with
Vardenafil and tadalafil are very similar to sildenafil. They have
nearly identical effects on ED as well as similar side effects. Because
they are newer drugs, scientists are just beginning to study them for
problems that don't involve sexuality.
Sildenafil has already been licensed to treat men and women with
pulmonary hypertension. Time will tell if any of these drugs will fill
other potentials beyond promoting potency.
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