vardenafil-dihydrochloride and Tachycardia

Phosphodiesterases (PDEs) play a decisive role in cyclic nucleotide-mediated intracellular signaling. As PDEs are expressed in a variety of tissues, selectivity is a prerequisite for a therapeutically applicable PDE inhibitor. Sildenafil, vardenafil, and tadalafil are selective for PDE5, with vardenafil exhibiting the highest potency and minimal inhibition of other PDEs, with the exception of PDE6. Tadalafil is extremely selective for PDE5, but also potently inhibits PDE11, an enzyme with unknown physiological function. As PDE1 is expressed in the brain, myocardium, and vascular smooth muscle cells, nonselectivity with respect to this enzyme (selectivity: tadalafil>vardenafil>sildenafil) may result in vasodilation and tachycardia. Inhibition of PDE6 (selectivity: tadalafil>vardenafil congruent with sildenafil), which is expressed only in retina and functions in visual transduction, can transiently disturb vision. PDE5 inhibitors may also indirectly inhibit PDE3 by increasing cyclic guanosine monophospate levels, thereby elevating heart rate and vasodilation while inhibiting platelet aggregation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Rate; Humans; Imidazoles; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Substrate Specificity; Sulfones; Tachycardia; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilation; Vision, Ocular

QT correction factors (QTc) can cause errors in the interpretation of drug effects on cardiac repolarization because they do not adequately differentiate changes when heart rate or autonomic state deviates from the baseline QT/RR interval relationship. The purpose of our study was to determine whether the new method of QT interval dynamic beat-to-beat (QTbtb) analysis could better discriminate between impaired repolarization caused by moxifloxacin and normal autonomic changes induced by subtle reflex tachycardia after vardenafil. Moxifloxacin produced maximum mean increases of 13-14 ms in QTbtb, QTcF, and QTcI after 4 h. After vardenafil administration, a 10-ms effect could be excluded at all time points with QTbtb but not with QTcF or QTcI. Subset analysis of the vardenafil upper pharmacokinetic quartile showed that the upper bound of QTcF and QTcI was >10 ms, whereas that of QTbtb was <8 ms. This study demonstrated that newer methods of electrocardiogram (ECG) analysis can differentiate changes in the QT interval to improve identification of proarrhythmia risk.

Topics: Anti-Infective Agents; Arrhythmias, Cardiac; Autonomic Nervous System; Aza Compounds; Cross-Over Studies; Electrocardiography; Female; Fluoroquinolones; Heart; Heart Rate; Humans; Imidazoles; Long QT Syndrome; Male; Moxifloxacin; Phosphodiesterase 5 Inhibitors; Piperazines; Placebos; Quinolines; Sulfones; Tachycardia; Triazines; Vardenafil Dihydrochloride