Viagra and health: Beyond ED

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.

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 down cGMP.

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 responsibly.

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.

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 considered healthy).

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 high altitude.

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.

Perspectives

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 sexual function.

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.