What are oral therapies for ED— specifically, the phosphodiesterase type 5 (PDE-5) inhibitors?

Currently, three oral therapies are available for the treatment of ED. The first therapy to become available was sildenafil (Pfizer's Viagra), which was approved by the FDA in 1998. Vardenafil (Bayer's Levitra) and tadalafil (Lily Icos's Cialis) were approved for use years later. All three of these oral therapies are phosphodiesterase type 5 (PDE-5) inhibitors.

To understand how these therapies work, it is important to review the process involved in the normal erection. When aroused or stimulated sexually, the brain sends messages from nerves in the pelvis, resulting in the release of nitric oxide. The nitric oxide then stimulates the production of cGMP, which in turn tells the cavernosal muscle in the penis to relax, thereby allowing more blood to flow into the penis. cGMP is broken down in the penis by an enzyme, phosphodiesterase type 5 (PDE-5) (Figure 32). Thus, if PDE-5 is prevented from working by administration of a PDE-5 inhibitor, there will be more cGMP present and thus a greater stimulus for increased blood flow.

Critical to the success of all of the PDE-5 inhibitors is the need for sexual arousal (sexual stimulation) after taking the medication. That is, these medications will not cause an erection to occur without sexual stimulation. It is okay to have a glass of wine, a beer, or a mixed drink when using these therapies—such limited alcohol consumption should not interfere with their effectiveness. Too much alcohol, however, may have a negative effect on erectile function, so a man should limit his alcohol intake when taking any of these medications.

Figure 32 Neurologic mechanism of erectile function. Sexual stimulation leads to release of nitric oxide, which leads to an increase in cGMP, a neurotransmitter that causes smooth muscle relaxation and increased blood flow into the penis. Abbreviations within the figure are: cGMP, cyclic guanosine monophosphate; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NANC, nonadrenergic-noncholinergic neurons; CO, nitric oxide; PDES, phosphodiesterase type 5.

Reprinted with permission from Am J Cardiol 1999; 84(5B):11N—17N.

Who is a candidate for oral therapy with a PDE-5 inhibitor?

Most men can take PDE-5 inhibitors. Nevertheless, there are certain contraindications to the use of these therapies. If these limitations are ignored, serious or even life-threatening problems may occur.

Specific contraindications to the use of PDE-5 inhibitors include the use of products containing organic nitrates, such as sublingual nitroglycerin, amyl nitrates, nitro-glycerin patches, and long-acting nitrates such as Imdur (Table 20). Nitrates (e.g., nitroglycerin), which are a form of nitric acid that causes opening of the blood vessels to the heart, and nitrites should not be used for angina for at least 24 hours after a man has taken a PDE-5 inhibitor.

Table 20. Commonly Prescribed Nitrates

Source: Ellsworth, P. 100 Questions and Answers About Erectile Dysfunction, 2e. Jones and Bartlett Publishers, LLC, 2008.

When combined, nitrates and PDE-5 inhibitors may significantly lower blood pressure to a potentially life-threatening level. For this reason, a contradiction to the use of PDE-5 inhibitors is unstable angina requiring frequent use of short-acting or sublingual nitroglycerin.

Should you experience chest pain during intercourse, you should stop what you are doing. If the pain persists, you should go to the emergency room and notify the personnel there that you took a PDE-5 inhibitor so that they will know not to give you any form of nitrate.

The use of PDE-5 inhibitors has not been studied in patients with the following conditions, so caution should be used in treating such individuals with a PDE-5 inhibitor: congestive heart failure with a borderline low blood volume, recent heart attack (myocardial infarction), hypotension (low blood pressure), high blood pressure requiring 3 or more medications, retinitis pigmentosa (a congenital eye condition that causes blindness), severe arrhythmias (irregular heartbeat), and any condition that may make men prone to priapism such as sickle cell disease/trait, leukemia, and multiple myeloma.

If you are unsure of your cardiac status, you have a strong family history of cardiovascular disease, or you do not exercise regularly, then you should consider seeking further cardiac evaluation before you begin using a PDE-5 inhibitor. A cardiac stress test can help determine whether you have any significant cardiac risks associated with sex and the use of a PDE-5 inhibitor.

Males taking alpha-blockers, doxazosin (Cardura), terazosin (Hytrin), tamsulosin (Flowmax), and silodosin (Rapaflo) should be on stable doses of the alpha-blocker prior to starting PDE-5 therapy and should start at the lowest dose of the PDE-5 inhibitor. Although

PDE-5 inhibitors cause minimal effects on blood pressure, when used in conjunction with the alpha-blockers, which also may lower the blood pressure, the result may be clinically significant, so it is best to be cautious and follow the dosing guidelines.

How do I use PDE-5 inhibitors?

Use of PDE-5 inhibitors is on demand, meaning that in most cases, each time you want to have intercourse, you need to take a pill. These pills facilitate your body's response, rather than causing an erection on their own, so they require sexual stimulation or foreplay to work. Other medications that increase PDE-5 inhibitor levels include erythromycin (E-mycin), clarithromycin (Biaxin), ketoconazole (Nizoral), itraconazole (Sporanox), and cimetidine (Tagamet). Men taking protease inhibitors, such as indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir), or saquinavir (Fortovase), should start at a lower dose and take the PDE-5 inhibitor less frequently because the protease inhibitors (generally prescribed for HIV infection and AIDS) increase the blood levels of the PDE-5 inhibitors.

The three PDE-5 inhibitors vary somewhat in terms of how far in advance a man needs to take the medication for it to be effective and how long after taking the medication he can anticipate a response. Both sildenafil (Viagra) and vardenafil (Levitra) should be taken about 1 hour prior to intercourse, whereas tadalafil (Cialis) should be taken 2 hours prior to anticipated intercourse. Diet may affect the results with sildenafil— specifically, an individual should avoid consuming a high-fat meal prior to using this drug. Tadalafil has a long half-life (17-21 hours); thus, if this medication works for you, it may work for as long as 3 days after you initially take the medication. This is not the case for all men. Recently, a lower dose of tadalafil has been approved for daily use.

Multiple doses are available for each of these medications, but it is recommended that you start at the lowest dose and titrate the dose upward as needed. In certain patients, a lower dose and less frequent use of the medication are recommended. Your doctor will tell you which dose and dosing interval is appropriate for you. All of the PDE-5 inhibitors should be taken only once in a 24-hour period.