Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat.
Phosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30-40% of men with ED do not respond to drug therapy. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors. Decreased expression or activity of neuronal or endothelial NO synthase (NOS), impaired NO release, or NO destruction will preclude sufficient cGMP formation to permit PDE5 inhibitor efficacy. This article discusses the possible reasons for unresponsiveness and strategies to overcome it. Therapeutic approaches proposed to increase available NO in penile tissue include facilitating NO release by using alpha-2 antagonists, enhancing NO synthesis by providing more substrate for the reaction, and using antioxidants to inhibit NO breakdown by reactive oxygen species.
de Tejada
I Sáenz
IS
Fundacion para la Investigacion y el Desarrollo en Andrologia (FI+DA) Madrid, Spain. fida@ibercom.com
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004351:Drug Resistance; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D010413:Penis / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D017382:Reactive Oxygen Species; D017211:Treatment Failure
D000975:Antioxidants; D010726:Phosphodiesterase Inhibitors; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C496320:NOS1 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP