Compounded PDE-5 inhibitor BasicsNelson Vergel
Phosphodiesterase-Type 5 Inhibitors Mechanism:
During sexual arousal, nitric oxide (NO) is released from nerve terminals and endothelial cells in the corpus cavernosum. NO activates guanylate cyclase to convert guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP), triggering a cGMP-dependent cascade of events. The accumulation of cGMP leads to smooth-muscle relaxation in the corpus cavernosum and increased blood flow to the penis. PDE5 is an enzyme found primarily in the smooth muscle of the corpus cavernosum that selectively cleaves and degrades cGMP to 5′-GMP. PDE5 inhibitors are similar in structure to cGMP; they competitively bind to PDE5 and inhibit cGMP hydrolysis, thus enhancing the effects of NO. This increase in cGMP in the smooth muscle cells is responsible for prolonging an erection. PDE5 inhibitors lack a direct effect on corpus cavernosum smooth-muscle relaxation. Therefore, after administration, adequate sexual stimulation is necessary for an erection to occur.
PDE-5 Inhibitor Products:
Sildenafil was the first PDE5 inhibitor to arrive on the market, in 1998. The usual dose of sildenafil is 50 mg (25 to 100 mg) taken one hour before sexual activity. The effects of sildenafil last for approximately four hours, and patients should be instructed to use no more than one dose within 24 hours. Fatty meals reduce the absorption of sildenafil; therefore, the drug should be taken on an empty stomach.
Vardenafil (Levitra), the first second-generation PDE5 inhibitor to be developed, is given at a usual dose of 10 mg (2.5 to 20 mg) one hour before sexual activity. Elderly patients and those with moderate liver dysfunction should receive a lower initial dose of 5 mg. Vardenafil begins working within 30 to 45 minutes after administration and lasts for about four hours. As with sildenafil, patients taking vardenafil should not use more than one dose within a 24-hour period. Patients should not take vardenafil within three hours of fatty meals, due to a reduction in absorption.
The newest PDE5 inhibitor is tadalafil (Cialis), which has a longer duration of action–approximately 36 hours–than sildenafil or vardenafil. In addition, the usual dose of 10 mg (5 to 20 mg) should be taken about 30 minutes before sexual activity–possibly allowing patients more opportunity for spontaneity. Food intake does not appear to affect the absorption of tadalafil; thus, the drug may be taken without regard to meals.
Though considered generally safe for most patients, including those taking multiple antihypertensives, PDE5 inhibitors are not a viable treatment option for every man with ED. Patients with a cardiovascular history that includes a recent myocardial infarction or stroke (within the past two weeks), cerebral vascular accident, life-threatening arrhythmia, hypertension (blood pressure >170/100 mmHg), hypotension (blood pressure <90/50 mmHg), unstable angina, and/or moderate to severe heart failure (New York Heart Association class III or IV) should not receive therapy with these agents. The risks and benefits associated with PDE5 inhibitor therapy and the patient’s medical history must be assessed.
Because PDE5 is inhibited in penile tissue as well as extragenital tissue, patients treated with PDE5 inhibitors may experience headache, facial flushing, nasal congestion, dyspepsia, and dizziness. Sildenafil also inhibits PDE type 6 in the retina. Therefore, patients treated with sildenafil may experience sensitivity to light, blurred vision, and loss of blue-green color discrimination, all of which are generally considered reversible. Tadalafil also inhibits PDE type 11 in skeletal tissue, possibly leading to back and muscle pain. Priapism, or painful, prolonged erections, is an extremely rare adverse effect, especially with shorter-acting agents, such as sildenafil and vardenafil. However, patients should be counseled to seek immediate medical attention if they experience erections lasting longer than four hours. PDE5 inhibitors may also cause various cardiovascular effects, including ventricular arrhythmias, cerebrovascular hemorrhages, myocardial infarctions, transient ischemic attacks, hypertension, and even sudden cardiac death. These adverse cardiac effects confirm the importance of a thorough cardiology evaluation in patients with a significant cardiovascular history.
PDE5 inhibitors should never be used in patients who are receiving scheduled or intermittent nitrates, due to a risk for severe hypotension. Organic nitrates supply additional NO, which increases cGMP levels and can lead to hypotension. Interestingly, dietary sources of nitrates and nitrites do not interact with the PDE5 inhibitors, as they do not increase circulating levels of NO. The PDE5 inhibitors are metabolized through the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Therefore, inhibitors of CYP3A4 (e.g., cimetidine, ketoconazole, ritonavir) may prolong the effects of PDE5 inhibitors. Patients receiving such agents may need a lower dose of the PDE5 inhibitor. Alpha-adrenergic antagonists (e.g., terazosin, doxazosin, prazosin) commonly used in the management of benign prostatic hyperplasia (BPH)can cause hypotension, especially when given in combination with PDE5 inhibitors. For patients receiving more than 25 mg of sildenafil, the dose of the alpha-antagonist and sildenafil should be separated by at least four hours. Both tadalafil and vardenafil are labeled for precautious use with alpha-antagonists. However, tadalafil may be given concomitantly with tamsulosin 0.4 mg.
1. Brown, Dana. The Management of Erectile Dysfunction and Identification of Barriers to Treatment. US Pharm. 2006;8:53-64.
2. Huang et al. Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Dysfunction. Pharmacy and Therapeutics. 013 Jul; 38(7): 407, 414-419.