The Management of Phosphodiesterase-5 (PDE5) Inhibitor Failure
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.
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.
Keywords: PDE5 inhibitors; corpus cavernosum; erectile dysfunction; tachyphylaxis
Document Type: Research Article
Affiliations: Dept. of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College School of Medicine, University of London, Pond Street, London NW3 2QG, UK.
Publication date: 01 April 2006
- Vascular disease is the commonest cause of death in Westernized countries and its incidence is on the increase in developing countries. It follows that considerable research is directed at establishing effective treatment for acute vascular events. Long-term treatment has also received considerable attention (e.g. for symptomatic relief). Furthermore, effective prevention, whether primary or secondary, is backed by the findings of several landmark trials.
Vascular disease is a complex field with primary care physicians and nurse practitioners as well as several specialties involved. The latter include cardiology, vascular and cardio thoracic surgery, general medicine, radiology, clinical pharmacology and neurology (stroke units). Current Vascular Pharmacology will publish reviews to update all those concerned with the treatment of vascular disease. For example, reviews commenting on recently published trials or new drugs will be included. In addition to clinically relevant topics we will consider 'research-based' reviews dealing with future developments and potential drug targets. Therefore, another function of Current Vascular Pharmacology is to bridge the gap between clinical practice and ongoing research.
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