Oral Pharmacotherapies for ED
Erectile dysfunction (ED), the consistent or recurrent inability to attain or maintain a penile erection sufficient for sexual performance has a profound effect on a patient’s quality of life, including objectively measured decreases in physical satisfaction, emotional satisfaction, and general happiness. ED is associated with feelings of isolation, low self-esteem and depression. It is estimated that 20 to 30 million American men suffer from ED. Orally administered PDE 5 inhibitors have become a first-line treatment option for ED.
Sildenafil citrate was the first oral PDE 5 inhibitor for ED approved by the Food and Drug Administration in the United States in March 1998. Since the release, sildenafil has become the first-line therapy for ED with over 12,000 patient-years of experience with sildenafil demonstrating positive safety and efficacy data. Sildenafil use has markedly increased the number of men seeking treatment for ED and has shifted first line management from the urologist and psychologist to the primary care physician.
Patients who seek an alternatives will have other PDE 5 inhibitors with different chemical structures, pharmacokinetic and pharmacodynamic profiles. At present vardenafil is available by prescription. Tadalafil has been approved by the FDA and should be available shortly. It is further anticipated that over 7 PDE 5 inhibitors will be clinically available at the end of the decade. How will patients and physicians choose among the various PDE 5 inhibitors? Careful controlled head-to-head trials are needed to answer these critical issues. Until such data are available, there are distinguishing characteristics such as selectivity, onset and duration of action, safety and efficacy.
PDE 5 inhibitors enhance the effect of endogenous NO, one of the key mediators of penile erectile function. NO is locally released in the corpus cavernosum upon sexual stimulation from the parasympathetic nerves and from the vascular endothelium. NO activates soluble guanylyl cyclase within the cytoplasm of the erectile tissue smooth muscle and stimulates the production of cGMP. The second messenger cGMP acts to reduce calcium within the cell and promotes smooth muscle relaxation. Intracellular cGMP concentrations are tightly regulated, in part by synthesis via cyclase activity, but also by degradation via phosphodiesterase activity. Phosphodiesterase enzymes hydrolyze and inactivate cyclic nucleotides. Vardenafil has a more pronounced increase of cGMP in the presence of NO in intact cells compared to sildenafil at equivalent doses. The inhibitory effect of vardenafil is approximately 10 fold higher than sildenafil. Vardenafil is more selective to PDE 5 with a selectivity ratio of inhibitory effect on PDE 1/PDE 5 of approximately 130, PDE 6/PDE 1 of approximately 15, PDE 11/PDE 5 of approximately 300 and PDE 2, 3, 4, 7, 8, 9, 10/PDE 5 of approximately >1000. In a broad population of men with ED, vardenafil consistently improved all efficacy parameters of erectile function, improving erections in up to 85% of men treated with 20 mg vardenafil for 26 weeks. Safety pharmacological studies showed vasodilating cardiovascular effects of vardenafil as expected due to its pharmacodynamic properties.
Concerning selectivity, there are no pure PDE 5 inhibitors. Sildenafil produces modest PDE 6 inhibition at the upper limits of the dosage range, affecting retinal cones, resulting in “blue” vision. No chronic adverse retinal effects have been reported with sildenafil. These effects are likely absent with tadalafil and minimal with vardenafil based on selectivity ratios for PDE 6 by these selective agents. Tadalafil has definite PDE 11 effects at therapeutic doses. PDE 11 is present in the pituitary, pancreas, skeletal muscle, heart, testes, and corpus cavernosum. The effects on these tissues of chronic or intermittent PDE 11 inhibition by tadalafil are not known.
Concerning onset of action, none of the PDE 5 inhibitors have immediate effectiveness. Vardenafil has the lowest Tmax at 0.6 hours. The Tmax for tadalafil approaches 2 hours. In general, the speed of onset of a drug varies from person to person, determined in part by Tmax and by an individual’s internal chemistry. Patients should be advised to avoid taking PDE 5 inhibitors after a fatty meal which further delays gastric emptying and drug absorption. Tadalafil Tmax data, which is the most delayed, appears less adversely affected by fatty meals.
Concerning duration of action, sildenafil’s half-life is 4 hours, vardenafil’s half-life is slightly longer at 4 – 6 hours and tadalafil’s half-life is the longest at 17 – 21 hours. An oral erectogenic agent with a long duration of action provides some men with additional confidence, allowing them to take the drug long before they anticipate having sexual relations. However, the safety of long-term PDE 5 inhibition and the issue of taking a drug long before sexual relations may result in some waste of the medication as well as some blunting of response over time. It is clear that patients will, for the first time, have choice when selecting a PDE 5 inhibitor based on the issues of onset and duration. Considering the average frequency of sexual intercourse is 1 episode per week, the average time for foreplay is approximately 14 minutes and more than 70% of men have sex once in a 24-hour period, selection of a PDE 5 inhibitor to match a couple’s needs will be met by one of the three agents.
Concerning safety, a careful assessment of cardiovascular status before prescribing treatments for ED and/or advising the patient to resume sexual activity is recommended, since many men with ED also have cardiovascular disease. To date, there is no evidence that any of the PDE 5 inhibitors have any direct adverse cardiovascular effects. In fact, the reverse may be true, as recent studies suggest that PDE 5 inhibitors delay exercise-induced ischemia and angina. There will be safety issues specific to tadalafil because of the drug’s prolonged duration of action, approximately 17 hours in a healthy man and up to 21 hours in an elderly patient. It will take up to 4 days for tadalafil to be completely eliminated from the body. This could potentially extend the duration of adverse effects or delay intervention with nitroglycerin during a cardiac event. In addition, tadalafil inhibits PDE 11, thus additional studies examining the effects of tadalafil on spermatogenesis as well as on pituitary and cardiac function are also needed. Studies to date have demonstrated no long-term effects of sildenafil or vardenafil on sperm function. In general, the PDE 5 inhibitors are well tolerated and have similar mild to moderate adverse effects profiles. In clinical trials, the most commonly reported adverse events were vasodilation resulting in headache, nasal congestion, facial flushing, and dyspepsia. Tadalafil is associated with a greater incidence of myalgia and low back pain, in part due to the prolonged half-life. None of the PDE 5 inhibitors have any significant drug interactions except for an absolute contraindication for the concomitant use of organic nitrates. Sildenafil and all agents in this class potentiate nitrate-induced vasodilation. In addition, they are all metabolized by the cytochrome P450 3A4 isoenzyme system, and concomitant administration of inhibitors of this pathway (eg. ketoconazole, erythromycin, and protease inhibitors) will prolong duration of action and raise serum concentrations of the drugs.
In conclusion, new PDE 5 inhibitor treatments for ED are becoming available. How physicians will choose which drug to prescribe will be much the same as electing among other classes of drugs with multiple pharmacologic treatment options, such as NSAID’s for pain, alpha-blockers for obstructive voiding, or SSRI’s for depression. The selection process will take into account drug pharmacokinetic and pharmacodynamic profiles, physicians’ previous experiences, patient satisfaction and preferences as well as the recognition that similar drugs may have significantly different effects in the same individual.