Erectile dysfunction (ED) is a disorder that affects more than half of men >40 years of age.1 ED is defined as the inability to achieve an erection adequate for sexual intercourse. It is more likely to occur in the presence of increased age, diabetes mellitus, cigarette smoking, hyperlipidemia, hypertension, depression, and cardiovascular disease.2,3
ED is associated with a decreased quality of life. It often goes untreated because the sensitive nature of the issue leads to patient embarrassment and underreporting.4 With recent advances in oral therapy and public attention paid to the problem, however, more patients are now seeking help and using medications to treat ED.
Psychological, neurologic, hormonal, and vascular disorders all may contribute to ED. Nitric oxide (NO)-mediated smooth muscle relaxation of the cavernosal tissue and arterioles of the penis is required for penile erection.3 NO is released as a result of sexual stimulation. It then increases intracellular cyclic guanosine monophosphate (cGMP), decreases intracellular calcium in the smooth muscle, and causes relaxation of the cavernosal smooth muscle and penile arterioles.5 This action allows for increased blood flow to the corpora cavernosa, leading to tissue engorgement and penile erection. In ED, psychogenic and organic factors alter the release of NO, decrease smooth muscle relaxation, and diminish the ability of the penis to achieve erection.5
Before selecting a treatment for ED, a full medical workup and a medication history are necessary to determine the etiology of the disorder. Medications must be reviewed to ensure that the disorder is not druginduced before another treatment option is initiated. Some medications that inhibit sexual function are betablockers, calcium channel blockers, selective serotonin reuptake inhibitors, and antipsychotics.6
Several agents are used to treat ED, including trazodone, alprostadil, yohimbine, testosterone, bromocriptine, pergolide, papaverine, and phentolamine. Many have unwanted side effects, however, and their use may not be ideal for most patients.
Phosphodiesterase type 5 (PDE-5) inhibitors have become more favorable because of their efficacy and their availability in oral formulations. These medications work by blocking the degradation of cGMP by phosphodiesterase enzymes, therefore potentiating penile smooth muscle relaxation.7 Three of these agents are currently available by prescription: sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra).
Sildenafil was the first PDE-5 agent, released in 1998. It has a half-life of 4 hours and reaches peak concentrations in 1 hour. Administration with a highfat meal leads to decreased absorption and delayed onset of action.
Sildenafil is metabolized via the cytochrome (CYP) P450 3A4 isoenzyme, and it may interact with medications that also utilize that metabolic pathway. Therefore, lower doses are needed when it is given concomitantly with ketoconazole, erythromycin, and saquinivir, due to CYP 3A4 inhibition leading to increased plasma levels of sildenafil.8 Common side effects include headache, flushing, and dyspepsia. The use of sildenafil is contraindicated with the use of nitrates, and it should not be taken within 4 hours of an alpha-blocker.
A starting dose of 50 mg of sildenafil taken 1 hour prior to sexual activity is recommended for most patients, although a dose of 25 mg is recommended in patients >65 years of age.8,9 Sildenafil should not be taken more than once per day, with a maximum daily dose of 100 mg.8 Like all PDE-5 agents, the use of sildenafil alone will not produce an erection; sexual stimulation is needed for a therapeutic effect. Sildenafil is available in 25-, 50-, and 100-mg tablets.
Tadalafil is the most lipophilic of the 3 available PDE-5 inhibitors. It reaches peak concentrations in 2 hours and has a half-life of 17.5 hours.9,10 Unlike sildenafil or vardenafil, its absorption is not altered by food intake. One benefit that tadalafil has over the other agents is a duration of action of 36 hours, which may allow for more sexual spontaneity.5
Common side effects of tadalafil include headache, dyspepsia, and back pain.10 It is contraindicated with the concomitant use of nitrates, and it should be used with caution in patients taking alpha-blockers, with the exception of tamsulosin.10
A starting dose of 10 mg of tadalafil is needed for most patients, and no dosage adjustment is required for those >65 years of age. Patients with moderate renal impairment (creatinine clearance of 30-50 mL/min) should start with a 5-mg dose, with a maximum of 10 mg every 48 hours.9,10 Patients taking 3A4 inhibitors, such as ketoconazole or ritonavir, should not exceed 10 mg of tadalafil once every 3 days. Tadalafil is available in 5-, 10-, and 20- mg tablets.
Vardenafil is the most potent of the PDE-5 inhibitors.3 It reaches peak concentrations within 45 minutes and has a half-life of 4 hours. Vardenafil is only 15% bioavailable and has decreased absorption with a high-fat meal, which may cause patient variability with regard to efficacy.7,9
Like sildenafil, vardenafil is metabolized by CYP 3A4, and it interacts with drugs such as ketoconazole, erythromycin, and protease inhibitors.11 It is contraindicated with the use of nitrates and alpha-blockers due to hypotensive effects, and it is not recommended in patients with retinal degenerative disorders.9,11 Common side effects include headache, dyspepsia, and dizziness. No dosage adjustment is needed for renal impairment, although no information is available for dialysis patients.
A starting dose of 10 mg of vardenafil 1 hour prior to sexual activity is needed for most patients, although a dose of 5 mg is recommended for men >65 years of age and those with moderate hepatic impairment.9,11 Vardenafil is available in 2.5-, 5-, 10-, and 20-mg tablets.
Due to the vasodilatory properties of PDE-5 inhibitors, the risk of hypotension must be considered when they are prescribed. As stated above, all 3 agents are contraindicated with the use of nitrates, because nitrates also increase cGMP and potentiate smooth muscle relaxation. The concomitant use of PDE-5 inhibitors with nitrates can lead to excessive hypotension and possible syncope. It also can lead to myocardial ischemia in patients who suffer from coronary heart disease.2 Vardenafil is contraindicated and tadalafil must be used with caution when coadministered with alpha-blockers, because there may be additive hypotensive effects.9,11 Tadalafil also must be used with caution in patients with coronary heart disease because of its long duration of action.
ED is a common disorder that can have serious effects on the quality of life of the men it touches. PDE-5 inhibitors may be an option for patients who do not take nitrates on either a regular or intermittent basis and have no other contraindications to such therapy.
Pharmacists can assist patients with ED by screening their medication profiles to uncover any drug-induced reasons for ED. Pharmacists also can help by counseling patients on the importance of avoiding nitrates, and reminding them to report the use of PDE-5 inhibitors to all health care professionals to avoid any potential drug interactions. Patients should also be aware that sexual stimulation is needed for a therapeutic effect, and that if they get an erection lasting >4 hours they should seek medical help as soon as possible.
Dr. Hajjar is an assistant professor of clinical pharmacy at Philadelphia College of Pharmacy, University of the Sciences in Philadelphia.
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
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