Since endothelial dysfunction plays a key role in the pathogenesis of the atherosclerotic process, growing interest in the effects of PDE5-i in preven
Erectile dysfunction (ED) is the persistent inability to achieve and maintain an erection adequate for satisfactory sexual performance 1 Its prevalence is underestimated because the patients treated (less than 20% out of total) are considered as only the ‘tip of the iceberg' 2 The probability of ED increases with ageing and the presence of diabetes mellitus, hypertension, hypercholesterolemia, ischemic cardiac disease, depression and obesity. They selectively inhibit intrapenile PDE5 isoenzyme which in turn increases intracellular cyclic guanosine monophosphate levels, thus resulting in prolonged relaxation of cavernosum smooth muscle cells and facilitating the erectile process. Systemic and metabolic effects of PDE5-inhibitor drugs.
Pending the publication of further studies detailing interactions with PDE5 agents, pharmacists will have to use their knowledge of drug metabolism and drug interactions to infer the risk to their patients of potentially interacting drugs. Since more vardenafil normally is metabolized prior to reaching the systemic circulation, a greater increase in systemic exposure can occur when the first-pass metabolic pathways are inhibited by CYP3A4 inhibitors. All 3 drugs should be used with caution in patients receiving any substance known to inhibit CYP3A4 (eg, amprenavir, ritonavir, indinavir, saquinavir, nelfinavir, clarithromycin, erythromycin, itraconazole, ketoconazole, fluconazole, voriconazole, diltiazem, verapamil, telithromycin, nefazodone, fluvoxamine, and grapefruit juice), because increased side effects may occur.
The data in the Table also show that the only exactly comparable interaction study that has been done involves ketoconazole (200 mg/day) with Fildena and vardenafil. The Table shows mean percentage changes in maximal concentrations (Cmax) and areas under the concentration time curve (AUC) for the PDE5 agents when coadministered with precipitant drugs (CYP3A4 inhibitors) that were studied in more than one PDE5. Fildena, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro.
Is clearance of PDE5 inhibitors from smooth muscle cells delayed by the tight binding of these inhibitors to PDE5 in the cells? Does inhibitor binding to the PDE5 molecule increase when cGMP binds to its allosteric sites? Since they raise the level of cGMP, PDE5 inhibitors potentiate their own actions since cGMP binding to the allosteric site stimulates further PDE5 inhibitor binding to the catalytic site.
In rat aorta and human smooth muscle cells, activation of PKG by 8-Br-cGMP leads to phosphorylation and activation of PDE5, whereas 8-Br-cAMP has no effect.