PDE5 Inhibitors

Viagra, an oral drug taken one hour prior to sexual activity, improves erectile function in the majority of men with erectile dysfunction who receive it. It is not an aphrodisiac and therefore will not work without sexual stimulation. The drug is absolutely contraindicated in patients on organic nitrates, as this combination can lead to severe drops in blood pressure. Patients with heart disease, suspected heart disease and riskfactors for heart disease should discuss with their physicians the safety of resuming sexual activity. A cardiac work-up, including exercise treadmill testing, should be considered in appropriate patients.

Introduction

On March 27,1998, the FDA approved sildenafil (Viagra) as the first oral agent for the treatment of male erectile dysfunction. This new drug has received wide coverage in the media and on talk shows and has spurred an entire generation of new jokes; most importantly, however, it has awakened the public consciousness to the problem of erectile dysfunction (ED). This issue is now being discussed openly by patients, spouses and healthcare providers. The purpose of this article is to describe ED, and to discuss the various treatment options and the efficacy and warnings regarding this remarkable new drug.

What is ED?

A National Institutes of Health Consensus Conference defined ED as the inability of a man to achieve an erect penis as part of the overall multifaceted process of male sexual function. This process involves not only achieving an erection but maintaining it for satisfactory sexual intercourse. Prior to this report the term “impotence” usually was used, as can be seen throughout the literature. The NIH Consensus group suggested that this term be dropped because it had pejorative implications. Thus, in this article we will use the term ED.

How common is ED?

According to various estimates, 10 to 30 million men in the United States are affected. One study that examined the prevalence of ED was the Massachusetts Male Aging Study. It showed that among 1,290 men ages 40 to 70 years, 52% complained of some degree of ED. There are various grades of ED: “Complete” ED refers to the inability to ever achieve a satisfactory erection for sexual activity; “mild” implies only an occasional or rare difficulty; “moderate” is somewhere in between. In this study, complete ED was reported by 10% of the men enrolled; moderate ED by 25 %; and mild ED by 17%. Complete ED was present in 5% of men 40 years of age and in 15% of men 70 years of age. With the advent of Viagra, it is likely that many more men with ED will now come forward for treatment, causing an apparent increase in the prevalence rates of ED.

What causes ED?

There are numerous causes, and they can be broken down into several broad categories. Psychogenic, vascular and neurogenic are the major categories, followed by endocrine abnormalities, structural abnormalities, renal failure/ dialysis and the use of certain drugs. In the past, most cases of ED were labeled psychogenic, but we now know that this is usually not so. The vast majority of men over the age of 50 years experience ED as a result of vascular disease. It is especially prevalent in older men with diabetes because of a vascular as well as a neurogenic component.

Risk factors for atherosclerotic vascular disease are known contributors to ED. These include smoking, diabetes, low levels of high-density lipoprotein (HDL) cholesterol, high levels of total and low-density lipoprotein (LDL) cholesterol, and hypertension. Neurogenic causes of ED include neuropathies (such as diabetic or alcoholic neuropathy), multiple sclerosis, spinal cord injuries, nerve disruption associated with prostate surgery, and strokes.

Medications that have been associated with ED include antihypertensive drugs—especially the thiazide diuretics—and a host of others, such as P-blockers, reserpine, methyldopa and hydralazine. Alcohol, antidepressants, cancer chemotherapeutic agents and certain hormones also are associated with this condition. Endocrine abnormalities that can cause ED include hypogonadism (low testosterone levels), hyperprolactinemia (usually secondary to a pituitary tumor) and hypo- or hyperthyroidism.

Structural abnormalities leading to ED include Peyronie’s disease (fibrosis of the corpus cavemosum); priapism (painful, persistent erection associated with diseases such as sickle cell anemia, multiple myeloma and leukemia, which can ultimately damage the erectile tissue); and trauma.

Viagra: A Noninvasive Treatment Option

Viagra is the first FDA-approved oral agent specifically indicated for the treatment of ED. Prior to its availability, few desirable options for the treatment of ED existed. Until that time, treatment was limited to intracavernosal injections of vasodilators, such as alprostadil (prostaglandin E); intraurethral suppositories of alprostadil; vacuum tumescence devices; penile prostheses; counseling for psychogenic ED; alternative oral therapies (such as yohimbine); and vascular surgery. Additional oral forms of therapy for ED (e.g., oral phentolamine, apomorphine) are being studied, but as yet none has been approved by the EDA.

Efficacy

There is no question that Viagra works. Pfizer Pharmaceuticals reports that in a large series of men (n = 3,000), only 24% reported improved erections after receiving placebo, while 63% had improved erections after receiving 25 mg of Viagra; 75% had improvement at 50 mg; and 82% had improvement at the 100 mg dose. The drug was effective across ages, races and etiologies of ED. Its effectiveness was diminished in patients with diabetes and radical prostatectomies when compared with other groups of men with ED. The drug improved the frequency at which attempted sexual intercourse was successful and enhanced orgasmic function, intercourse satisfaction and overall satisfaction.

It is important to note that the drug does not increase sexual desire. Viagra is not an aphrodisiac. In order for it to work there must be sexual stimulation (visual, tactile, auditory, etc.).

Mechanisms of Action

Basically, Viagra works as a vasodilator. With sexual stimulation, nitric oxide (NO) is released by nerve cells and eridothelial cells within the corpus cavemosum (the spongy tissue within the penis that is responsible for erection). NO stimulates the formation of cyclic guanosine monophosphate (GMP), which causes dilation ofthe arteries, arterioles and sinusoids of the corpus cavemosum, causing it to fill with blood and stiffen. Cyclic GMP is then degraded by phosphodiesterase-5 (PDE-5), an enzyme that is highly concentrated in genital tissue. In men with ED, the problem is often that the cyclic GMP is not present in high enough concentrations to either develop or maintain an erection. Viagra’s mechanism of action is to inhibit PDE-5, resulting in higher concentrations of cyclic GMP, better vasodilation and, hence, erection.

Pharmacologic Characteristics

Viagra is absorbed rapidly, reaching peak drug levels in 30 to 120 minutes. A high-fat meal can slow its rate of absorption, so patients should be wamed not to eat fatty meals prior to its use. Viagra is primarily cleared by hepatic enzymes. Inhibitors of liver isoenzymes involved in the drug’s breakdown can increase Viagra levels. Therefore, the dose of Viagra might need to be lowered when patients are on certain agents, such as cimetidine, erythromycin and certain antifungal agents, or in patients with liver disease.

Viagra, when taken alone, can cause small (usually clinically imperceptible) drops in systemic blood pressure; when given with common antihypertensive drugs (diuretics, angiotensin-converting enzyme [ACE] inhibitors, calcium blockers, P-blockers, or a-blockers), it resulted in the same small drops that would have been expected even if the patient had not been taking the antihypertensive drug. Thus, while it had a small additive effect on lowering blood pressure, it did not have a synergistic effect. It is likely that future studies will continue to examine the effect of Viagra on blood pressure. Other studies will be looking at potential interactions between Viagra and protease inhibitors. In patients with severe liver disease or renal disease the lowest dose should be used initially.

Dosage Recommendations

The current recommended dose is one 50 mg tablet one hour before sexual activity, but it can be administered from four hours to 30 minutes before sex. The drug is taken on an as-needed basis, only prior to sexual activity, and it therefore needn’t be taken chronically. If the 50 mg dose is ineffective and the patient does not experience severe side effects, the dose can be increased to 100 mg. In patients who develop severe side effects at 50 mg, reducing the dose to 25 mg may be considered, although efficacy is generally lower at this dose. The drug should not be taken more than once a day.

Contraindications and Side Effects

There is one major contraindication to taking Viagra: It absolutely must not be given to any patient taking organic nitrates. These include agents such as sublingual nitroglycerin tablets and sprays; long-acting nitrates such as isosorbide dinitrate and isosorbide mononitrate; nitroglycerin patches or pastes; and other forms. In most cases, patients will be receiving nitrates for angina pectoris.

Not all men taking organic nitrates are doing so for medical reasons. Prevalent in the gay community is the recreational use of^the drugs amyl nitrite and amyl nitrate (so-called “poppers”—alleged sexual enhancers). These are also organic nitrates and must not be taken concomitantly with Viagra. When the drug is administered in the presence of either of these organic nitrates (whicli are NO donors), there is a marked synergistic vasodilator effect, resulting in large drops in systemic blood pressure.

Side effects of Viagra ai”e primarily related to its effects as a vasodilator and include headache (16%), flushing (10%), dyspepsia (7%), nasal congestion (4%) and diarrhea (3%).’^ In addition, approximately 3% of men taking the drug may experience a transient visual disturbance reported as a blue-green color tinge, increased sensitivity to light, or blurred vision. It is important to note that priapism—as experienced with some of the other therapies, such as intracavemosal injections—is not a side effect of Viagra. The drug is not approved for use in women, and its effect on human pregnancy is not yet known.

Safety

As of three months after Viagra’s release, 30 deaths had occurred among approximately 2 million men using it.

Some of these deaths were associated with concomitant use of nitrates. Others occurred primarily in older men with histories of heart disease, hypertension, diabetes or other chronic diseases. It is conceivable that some of these men might have had cardiovascular events associated with sexual activity, and that these would have occurred regardless of whether they had used Viagra. It has been documented that there is a small, although finite, increase in the risk of myocardial infarction associated with sexual activity, arising from increased heart rate and elevated blood pressure, and hence, an increase in the cardiac workload.

For patients who have known coronary artery disease, heart disease or risk factors for coronary artery disease and want to try Viagra, consider performing a cardiac evaluation, including an exercise treadmill test, to help gauge the safety of a return to sexual activity. Ability to pass an exercise stress test without developing signs of ischemia would be reassuring to both the patient and spouse.

A preliminary statement of the American College of Cardiology/American Heart Association suggested that clinicians should exercise caution in using Viagra in patients with active coronary ischemia, patients with congestive heart failure and borderline low blood pressure and low volume status, patients on complicated drug regimens for the treatment of hypertension, and patients on drugs or with conditions that might prolong Viagra’s half-life.

Discussion

Although Viagra has only been available for approximately three months (at the time of this writing), it has already begun to change the sexual landscape in the United States, much as the birth control pill did in the 1960s. Eor the first time there is an orally administered drug that can be taken one hour before sexual activity, that can improve ED in most men and that has the potential to improve male-female relationships. Already, however, the drug is the subject of controversy. Obviously, there are concems about the number of deaths that have occurred, but epidemiologic studies have suggested that mortality associated with cardiovascular disease among men in the United States occurs with a frequency of 185 to 275 per million per month. Therefore, an incidence of 30 deaths per 2 million men taking Viagra in three months seems quite low.

The FDA has reviewed the data regarding these deaths and did not consequently change Viagra’s labeling. Nevertheless, it is likely that these cases will continue to be reviewed, as will the potential for drug-drug interactions, which are as yet unknown. In the meantime, the nitroglycerin-Viagra contraindication stands, so physicians should discuss this issue with their patients; and in those with a possible cardiac risk associated with sexual activity, they should consider a cardiac work-up. An additional area of controversy involves various HMOs’ unwillingness to pay for treatment with Viagra. Some HMOs have agreed to pay and others have not, primarily because of its cost and the view that Viagra is more of a “lifestyle” drug than one necessary for the treatment of a disease.