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Pharmacology of Male Sexual Function
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Andrei Kozan, Weida Lau, Oliver Kayes
Sildenafil and vardenafil cross-react with PDE6.PDE6 predominates in the retina → visual disturbancesTadalafil and avanafil have the lowest incidence of visual disturbances.
Phosphodiesterase 5 inhibitors: preclinical and early-phase breakthroughs for impotence treatments
Published in Expert Opinion on Investigational Drugs, 2023
Zachary Melchiode, Tivoli Nguyen, Omar Dawood, Graham A. Bobo, Wayne J.G. Hellstrom
Detrimental effects on auditory, cardiovascular, ocular, and reproductive systems are among the more serious side effects of PDE inhibitors. For example, there have been multiple documented cases linking sensorineural hearing loss with sildenafil [4]. Skeith et al. demonstrated that the risk of ototoxicity was greatest in combination with loop diuretics and CYP3A4 inhibitors [4]. Due to the lack of selectivity of current PDE inhibitors, the expression of PDE6 in the retina can lead to short-term ophthalmologic adverse effects, such as blurred vision, disturbed color vision, and photophobia. Regarding reproductive safety, tadalafil’s increased selectivity for PDE11, which is highly expressed in the testes, was a concern for detrimental effects on the structure and function of testes in a rat model [5]. Fortunately, this has not been observed in human trials [5].
Tadalafil for the treatment of benign prostatic hyperplasia
Published in Expert Opinion on Pharmacotherapy, 2019
Fabiola Zakia Mónica, Gilberto De Nucci
While PDE5 is expressed in several organs including prostate [23], bladder [24], testis [25], corpus cavernosum [26], vascular smooth muscle [24,27] and platelets [28], and others, the PDE6 isoform is mainly found in the mammalian eye to control phototransduction in the rod and cone segments of retina [29]. Due to the amino acid sequence homology between PDE5 and PDE6 and the similarity of their catalytic domains, the first generation of PDE5 inhibitors (sildenafil and vardenafil) can also inhibit PDE6 [30]. On the other hand, the PDE5/PDE6 ratio (780) makes tadalafil [31] a more selective PDE5 inhibitor than sildenafil and vardenafil. Visual disturbances such as functional blindness, blurred vision, and greater light sensitivity have been linked to PDE6 inhibition [32]. With respect to the cross-reactivity with the isoform PDE11, in cells overexpressing human PDE11, the PDE5/PDE11 ratios for tadalafil, vardenafil, and sildenafil are 40, 9300 and 1000-fold [33]. However, the physiological role of PDE11 is poorly studied. To date, there are no studies that evaluated whether sildenafil, vardenafil or tadalafil interfere with PDE9 activity, an enzyme that preferentially degrades cGMP.
Treatment of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction
Published in The Aging Male, 2018
Aldo E. Calogero, Giovanni Burgio, Rosita A. Condorelli, Rossella Cannarella, Sandro La Vignera
Avanafil, a new-generation PDE5i, is highly selective for PDE5. It has also relatively little cross-reactivity with other PDE isoenzymes. In an in vitro receptor-binding study comparing the inhibitory effects of avanafil on 11 PDE isoenzymes with those of tadalafil, sildenafil, and vardenafil, avanafil potently inhibited PDE5 activity without significant inhibition of the other PDE isoenzymes. In contrast, tadalafil, sildenafil, and vardenafil inhibited the activity of other PDE isoenzymes (PDE1, PDE6, and PDE11). These differences in PDE isoenzyme activity are important, given that greater selectivity for the PDE5 isoenzyme may diminish the potential for adverse effects (caused by the inhibition of other PDE isoenzymes; e.g. inhibition of PDE6 by other PDE5 inhibitors may lead to visual disturbances) [46].