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Tadalafil

posted Nov 24, 2009, 1:01 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Erectile dysfunction, the inability to achieve and maintain an erection adequate for satisfactory sexual performance, has been reported to affect as many as 150 million men worldwide (1). Local treatments for erectile dysfunction include vacuum erection devices, penile prostheses and intracavernosal therapy. These treatment options may often limit patient satisfaction because of their invasiveness, unappealing technique or side effects (2). A more user friendly form of therapy for patients with erectile dysfunction is an orally active treatment. Sildenafil (Viagra) was the first oral agent to be launched in recent years. Its success was followed by the introduction of other new drugs into the market, including tadalafil (Cialis) and vardenafil (Levitra).

Mechanism of Action

Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by a PDE5-inhibitor such as tadalafil enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation (3).

Dosage and Administration

The recommended starting dose of tadalafil is 10mg. taken prior to sexual activity. The dose may be increased to 20mg or decreased to 5mg depending upon individual efficacy and tolerability. The maximum recommended dosing frequency is once daily. Dosage adjustment is only required in patients with severe renal insufficiency (creatinine clearance < 30ml/min). For patients with severe hepatic insufficiency, the use of taladafil is not recommended. For patients taking concomitant potent inhibitor of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 10mg, not to exceed once every 72 hours. Dosage adjustments are not required in patients greater than 65 years of age. Unlike sildenafil, the rate and extent of absorption of tadalafil are not influenced by food.

Contraindications and Precautions

Tadalafil is contraindicated in patients who are taking any form of organic nitrate. In clinical pharmacology studies, tadalafil was shown to potentiate the hypotensive effect of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Tadalafil is also contraindicated in patients for whom sexual intercourse is inadvisable due to unstable cardiovascular disease, for example: patients with myocardial infarction within the last 90 days, patients with unstable angina or angina occurring during sexual intercourse, patients with New York Heart Association Class 2 or greater heart failure in the last 6 months, patients with uncontrolled arrhythmias, hypotension (< 90/50 mmHg), or uncontrolled hypertension, patients with a stroke within the last 6 months.

Adverse effects most commonly reported are headache and dyspepsia. There may also be dizziness, flushing, nasal congestion, back pain and myalgia. The selectivity of tadalafil against PDE6 (found in retina) is insignificant, therefore visual side effects should be minimal (3).

Summary

The efficacy of tadalafil has been well proven in double-blind, placebo-controlled studies which demonstrated significant improvement in erectile function (4,5). These were in terms rigidity of erection, ability to penetrate, ability to maintain an erection during intercourse and percentage of intercourses with successful completion. Efficacy were uniformly reported for patients with mild, moderate or severe erectile dysfunction, and also in men with diabetes (5)

Tadalafil has been found to be effective from as early 16 minutes up to 36 hours following dosing. The claim is that this removes the time pressure for sexual performance and allow for a more natural, physiological response.

Tadalafil, sildenafil and vardenafil have all been proven effective against placebo. Direct comparison of these drugs will be required to clarify comparative efficacy and safety. At present, the choice between tadalafil, sildenafil and vardenafil is largely one of patient preference.

References

  1. Brock, B.B, McMahon, C.G., et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. The Journal of Urology. 2002;168:1332-1336
  2. Hellstrom W.J.G., Gittelman M., et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. Journal of Andrology. 2002;23:763-771
  3. Cialis product information, Eli Lilly and Company
  4. Porst H, Padma-Nathan H, Giuliano F et al: Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 2003; 62:121-126.
  5. Saenz de Tejada I, Anglin G, Knight JR et al: Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 2002; 25(12):2159-2164.
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