Erectile Dysfunction Drugs Failure- How do we manage it?

[Nelson Vergel]

[h=3]The Management of Phosphodiesterase-5 (PDE5) Inhibitor Failure


Authors: Lau, David H.W.; Kommu, Sashi; Mumtaz, Faiz H.; Morgan, Robert J.; Thompson, Cecil S.; Mikhailidis, Dimitri P.
Source: Current Vascular Pharmacology, Volume 4, Number 2, April 2006, pp. 89-93(5)


Abstract:[/b]The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the treatment of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, PDE5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of PDE5 inhibitor failure. Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug.

Treatment failure may cause considerable distress. If dose titration, more attempts and continuous dosing of PDE5 inhibitors (taken on a daily basis) fail to resolve the initial PDE5 inhibitor failure, clinicians need to consider alternative treatments. These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery.

Combination therapy like prostaglandin E1 (PGE1) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT2 antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/ losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide (NO) donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low.

The early use of PDE5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of PDE5 inhibitors may be maintained.

Targeting the risk factors of ED (similar to those for arteriosclerosis) in the early stages of the disease may prevent the development or decrease the severity of ED.

 

[Nelson Vergel]

Note from Nelson: NEVER use PDE5 inhibitors with penile injections as shown in the above diagram. You can have priaprism and penile damage.


Three potent selective PDE5 inhibitors (sildenafil (Viagra; Pfizer), tadalafil (Cialis; Lilly), and vardenafil (Levitra; Bayer)) are currently available. Although large multicentre clinical trials have shown the efficacy and tolerability of these drugs in erectile dysfunction with various aetiologies and a broad range of severity, 30-35% of patients fail to respond. The reported 62% prescription renewal rate at three to four months of follow-up, which dropped to around 30% by 6-12 months, suggests that patients stop taking the drug for reasons other than failure of treatment.

Practice pointer: Treating erectile dysfunction when PDE5 inhibitors fail

 

[CoastWatcher]

... Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug.

This is is something that I am concerned about. Daily administration has helped dramatically; but for how long? Now that my test protocol is on track, I wonder if I should consider a taper of Cialis?

 

[Nelson Vergel]

Does reduced response happen after long term use of daily PDE5 inhibitors (Tachyphylaxis)?

View attachment 1377

PDE5 gene expression in the penis may be modulated by influences including PDE5-regulated NO/cGMP molecular signalling and the androgen milieu [61], [65], [66], [67], and [68]. Although it has been suggested that tachyphylaxis may occur with extended use, this hypothesis remains unproven on the basis of existing clinical trial data [50] and [68].
Daily dose PDE5-I therapy and excessive cGMP accumulation may upregulate PDE5 expression [69] and [70]. The clinical sequelae of tachyphylaxis secondary to these mechanisms should include increased dosage requirements for efficacy. However, a review of more than 1000 men using sildenafil for ED demonstrated low tachyphylaxis potential and dropout rates; subsequent studies have corroborated these findings [9] and [71]. Nonurological applications for daily PDE5-I use have also reported longer-term (up to 20 mo) satisfactory safety, efficacy, and tolerability data [27], [57], [72], [73], [74], and [75]. Several animal studies have shown no evidence of tachyphylaxis [21], [67], [76], [77], and [78].


Daily Administration of Phosphodiesterase Type 5 Inhibitors for Urological and Nonurological Indications

 

[Nelson Vergel]

Penis Injections for Hard Erections: TRIMIX

 

[CoastWatcher]

Does reduced response happen after long term use of daily PDE5 inhibitors (Tachyphylaxis)?

Although it has been suggested that tachyphylaxis may occur with extended use, this hypothesis remains unproven on the basis of existing clinical trial data [50] and [68
[/QUOTE


Great catch. You answered my question, Nelson. Thank you.