The Effects of Chronic Phosphodiesterase-5 Inhibitor Use on Different Organ Systems

REVIEW The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

ER Schwarz1, V Kapur1, J Rodriguez, S Rastogi, and S Rosanio

Division of Cardiology, Cedars Sinai Medical Center, Los Angeles, CA, USA

Phosphodiesterase-5 (PDE-5) inhibitors selectively inhibit PDE-5 enzymes that are present in various tissues like penile tissue, platelets, vascular, and smooth muscle tissue. The drug’s actions on these tissues have lead to the successful therapeutic use in patients suffering from conditions such as erectile dysfunction (ED) and pulmonary hypertension. PDE-5 inhibitors (PDE-5i) act on the erectile tissue causing penile smooth muscle relaxation and vasodilatation leading to penile erection. In addition, in particular when used in conjunction with prostaglandin inhibitors, PDE-5i cause vasodilatation in pulmonary vasculature hence decreasing both the pulmonary arterial pressure and resistance. PDE-5i have also shown to mildly decrease blood pressure, increase cardiac index, and increase coronary blood flow in experimental animals as well as in human studies. The Food and Drug Administration (FDA) has approved three PDE-5i for the treatment of ED: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) and one for pulmonary hypertension: sildenafil (Revatio). These agents are highly selective for PDE-5 enzymes as compared to other subclasses of PDE enzymes and have the almost identical pharmacological action but slightly different pharmacokinetics. Only little data exist about long-term use of PDE-5i and their effects on different organ system. This paper reviews the current information available on chronic PDE-5 inhibitor use. International Journal of Impotence Research (2007) 19, 139–148. doi:10.1038/sj.ijir.3901491; published online 8 June 2006

Keywords: PDE-5 inhibitor; erectile dysfunction; heart disease; therapy; side effects

Introduction the close connection between endothelial dysfunction and ED as well as the potential signaling of ED Erectile dysfunction (ED) is a common medical as an early marker for cardiovascular conditions.18 condition linked both to endothelial dysfunction1–13 To date, PDE-5i are the most widely prescribed oral as well as multiple other comorbid conditions. 14–17 agents for ED treatment and Viagra is one of the most Historically, the treatment for ED has been limited to frequently sold drugs in the world. Specialists of all a selected group of specialists, namely urologists varieties are increasingly encountering patients and sexual therapists. In 1998, the Food and Drug seeking therapy for sexual dysfunction. As such, it Administration (FDA) approved the first phospho- is important that clinicians become proficient in the diesterase-5 inhibitors (PDE-5i) (sildenafil, Viagra) mechanisms and systemic effects of PDE-5i. for oral ED therapy. The ensuing avalanche of PDE-5i are considered first-line therapy for ED. research and interest in sexual dysfunction has been Sildenafil is the most commonly prescribed oral transferred this once ‘private condition’ from the agent for ED, and has earned a satisfactory efficacy exclusive domain of the urologist into the laps of safety profile in nearly all patient cohorts. Tadalafil numerous medical disciplines and demonstrated (Cialis) and vardenafil (Levitra) emerged in the European Union and in the US in 2003 and 2004, respectively. All three agents share many pharmacological and clinical characteristics, while still Correspondence: Dr ER Schwarz, Division of Cardiology, Cedars Sinai Medical Center and University of California, maintaining some unique features. Los Angeles (UCLA), 8700 Beverly Blvd, Suite 6215, Los Angeles, CA 90048, USA. E-mail: [email protected] 1These two authors contributed equally to the paper. Mechanism of action of PDE-5i Received 8 March 2006; revised 1 May 2006; accepted 7 PDE-5i act as selective inhibitors of cyclic guanosine May 2006; published online 8 June 2006 monophosphate (cGMP)-specific PDE-5 enzyme The effects of chronic PDE-5i ER Schwarz et al 140 which results in increased levels of cGMP and nitric Vardenafil (Levitra) was approved by FDA for the oxide (NO)19. Sexual stimulation causes local treatment of ED on 20 August 2003. Vardenafil release of NO and with the inhibition of PDE-5, appears to be as effective as sildenafil, as supported there is increased levels of cGMP in the corpus by a trial of 805 men aged 57–78 years with ED cavernosum. The increase levels of cGMP lead to of various etiologies. Vardenafil was more effective reduced intracellular calcium levels, thereby than placebo for improving penetration (64–80% producing smooth muscle relaxation in corpus versus 50%, respectively) and maintenance of cavernosum and an increase in blood flow in erections (50–67% versus 32%, respectively).27 erectile tissue.20 Studies in vitro have shown Tadalafil (Cialis) was approved by the FDA in that sildenafil is preferentially selective for PDE-5, November 2003 for the treatment of ED. Tadalafil 1 but not exclusive of other phosphodiesterase has a longer duration of action (t 2 17.5 h). This enzymes.1,21 distinguishes the drug clinically from sildenafil and The concomitant use of potent cytochrome P450 vardenafil, offering the theoretical advantage of 3A4 inhibitors (e.g., erythromycin, ketoconazole, more ‘spontaneity’ with sexual relations. Its efficacy itraconazole among several others) as well as the was proved by an integrated analysis of randomized nonspecific CYP inhibitor cimetidine can be trials in 1112 men with ED: 75% of intercourse associated with increased plasma levels of PDE- attempts were successful in the tadalafil patients 5i.22–26 Whether this is clinically relevant is con- compared with only 32% with placebo.28 troversial. While the three PDE-5i have similar mechanism of actions, differences exist in properties, especially in duration of action and bioavailability (Table 1). Effect of PDE-5i use on ED Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyra- Several clinical trials have established efficacy and zolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]- safety of PDE-5i in men with ED of all etiologies, 4-ethylpiperazine citrate. It was not originally ages and ethnic populations. Those with the most developed for the treatment of ED. Rather, sildenafil limited responses included patients with diabetes, was the result of a discovery program that began in ischemic heart disease, radical prostatectomy, and 1985 at Pfizer’s European Research headquarters in age over 65 years. Although onset of action can vary Sandwich, UK, aimed at developing a selective from 15 to 60 min, it is important to counsel patients inhibitor of PDE-5 to augment the NO/cGMP path- to expect optimal response at 60 min after adminis- way for the treatment of angina pectoris in patients tration.29 Since its introduction, PDE-5i have been with coronary artery disease (CAD). The drug was extensively studied, specially its effect on various patented in 1996, approved for use in ED by the FDA subgroups of patients such as diabetics, older men, on 27 March, 1998. and patients with CAD.

Table 1 Comparison of the available PDE-5i

Sildenafil Vardenafil Tadalafil

Onset of action (min) 15–30 15–45 15–30 Duration of action (h) 4 4 36 1 T 2 (h) 3–4 4–5 17.5 Bioavailability (%) 40 15 25 Active metabolite Yes Yes No Excretion Feces – 80% Feces – 90% Feces – 60% Urine – 20% Urine – 5% Urine – 35% Active metabolite Yes Yes No Headache 12% 6% 8% Contraindications Hypersenstivity to drug, Hypersenstivity to drug, Hypersenstivity to drug, concomitant use of nitrates and concomitant use of nitrates concomitant use of nitrates a-blockers Warnings/precautions Recent stroke, myocardial Hepatic and renal insufficiency, Hepatic impairment, renal infarction (within 6 months), prolonged QT interval, left insufficiency. resting hypotension (BPo90/ ventricular outflow obstruction, 50), Unstable angina, retinitis hypotension. pigmentosa Recommended doses 50 mg 10 mg 10 mg Cost (US $) (approximately) $10/tablet $10/tablet $13/tablet Medicare approved (for ED) Yes Yes Yes

Abbreviations: BP, blood pressure; ED, erectile dysfunction; PDE-5i, phosphodiesterase-5 inhibitors.

International Journal of Impotence Research The effects of chronic PDE-5i ER Schwarz et al 141 Effect of PDE-5i for ED in patients with diabetes may reflect an increase in left heart filling pressure mellitus in the presence of normal pulmonary vascular A multicenter, double-blind, placebo-controlled resistance, pulmonary vascular or parenchymal study assessed the effectiveness and safety of disease with an elevation in pulmonary vascular tadalafil (10 or 20 mg) in 216 men with mild to resistance, or a combination of these initiating severe ED and type 1 or type 2 diabetes. The study factors. The majority of data available in patients showed tadalafil improved erectile function in men with primary pulmonary hypertension implicates an with diabetes regardless of diabetes type, current imbalance between endothelial-derived vasodilating diabetic therapy and initial level of glycemic control factors such as prostaglandin I2 (PGI2), NO, and or the presence of microvascular complications.30 vasoconstricting mediators such as endothelin-1 Another study assessing efficacy and patient satis- and thromboxane A2, producing a net effect of faction on sildenafil in diabetic patients with ED precapillary pulmonary hypertension. Secondary showed a significant improvement of ED. Hence, pulmonary hypertension in most cases is attributed both studies suggested the efficacy of PDE-5i in to various causes such as heart failure (HF), acute patients with coexistent diabetes.31 respiratory distress syndrome (ARDS), postlung transplantation, and pulmonary embolism. Recent studies demonstrated promising therapeutic potential of PDE-5i in pulmonary hypertension, Effect of PDE-5i for ED in older patients which is due to the fact that the gene encoding PDE- PDE-5i has been proven to be beneficial in the 5 is highly expressed in the lung.36 Guazzi et al.37 elderly population (465 years) with ED. This has showed a reduction in pulmonary systolic (21.8%) been successfully demonstrated in a study involving and diastolic (20.7%) arterial pressures and in patients more than 70 years of age. Sildenafil arteriolar resistance (45.1%) after sildenafil admin- demonstrated 69% of successful intercourse as 32 istration in patients with stable HF (in NYHA compared to 22% with placebo. Analysis of data classes II–III), without significant changes in cardiac from a phase 2 vardenafil trial (to assess the index and wedge pulmonary pressure. In all but one differences in erectile response to vardenafil patient, there was an increase in diffusion capacity. between younger patients (o45 years) and older The authors concluded that PDE-5 inhibition atte- patients (465 years)) suggested improvement in nuated (secondary) pulmonary hypertension by erectile function in both groups, suggesting PDE-5i lowering arteriolar resistance, facilitating alveolar as representing an effective ED therapy also in the 33 gas exchange, and improving overall exercise per- elderly, with similar side effects when compared formance and ventilation efficiency in patients with to younger men. HF. Lepore et al.38 studied the hemodynamic effects of 50 mg of sildenafil alone and in combination with inhaled NO in nine patients with severe pulmonary Effect in patients with ischemic heart disease hypertension and showed shown that the combina- Patients with ED and coexisting ischemic heart tion of oxygen and NO with sildenafil reduced disease have shown significant improvement in pulmonary vascular resistance more than oxygen erectile function by using PDE-5i. This has been and NO alone. Michelakis et al.39 also showed a shown by a meta-analysis of 357 patients with decrease in pulmonary vascular resistance with the ischemic heart disease enrolled in 11 randomized combined use of PDE-5i and NO in 13 patients with double-blind, placebo-controlled trials on sildenafil. pulmonary hypertension. To date, there is only few In these patients mean scores on ability to achieve data available on the effects of vardenafil and and maintain erection were significantly higher for tadalafil on pulmonary vasculature. A case report sildenafil-treated patients than for the placebo by Palmieri et al.40 described a 72-year-old woman group. Mean scores for all five International Index with pulmonary hypertension who showed marked for Erectile Function (IIEF) domains were also 34 improvement in functional status (NYHA classifica- significantly higher. tion), arterial oxygenation and a decrease in systolic pulmonary hypertension after using tadalafil for 6 months. The reduction of pulmonary arteriolar Effect of PDE-5i use on the lung resistance and pressure in HF patients by concomitant use of NO and PDE-5i is expected, moreover In a normal human lung, NO secretion by pulmon- since a defective NO release can be found in ary endothelium plays an important role in lung pulmonary hypertension that facilitates pulmonary physiology.31 It is involved in the special capacity of vasoconstriction. Interestingly, in these patients the vasculature to adapt to local changes in blood sildenafil also significantly improved brachial artery flow, maintenance of normal pulmonary vascular flow-mediated endothelial function, which was not tone, permeability,35 and the modulation of tissue observed in controls. Overall, PDE-5i also promoted resistance to oxygen transfer (from the alveolus to its a favorable reduction of the alveolar-capillary uptake by hemoglobin). Pulmonary hypertension membrane resistance to gas exchange. Hence

International Journal of Impotence Research The effects of chronic PDE-5i ER Schwarz et al 142 because of the vasodilator properties of PDE-5i in pressure (À8/À5 mm Hg in supine position) oc- pulmonary vasculature, it has proven to be bene- curred 1–2 h after oral sildenafil (congruent with ficial also when used in conjunction with prosta- the time to peak serum concentration). Interestingly, glandin inhibitors in the treatment of pulmonary the decreases in blood pressure were neither age- hypertension.41–43 nor dose-related. The lack of a clear dose–response might be explained by the degree of inhibition of PDE-5.8 No consistent orthostatic effects and no Effect of PDE-5i use on the heart significant differences in blood pressure response between the young and elderly were found. Silde- ED shares several modifiable risk factors with nafil’s blood pressure-lowering effect is only modest cardiovascular disease including atherosclerosis, and therefore unlikely to trigger a reflex heart rate hypertension, dyslipidemia, diabetes mellitus, response. Indeed, a mild sympathetic response smoking, obesity, and sedentary lifestyle.15–18 As directly to the vasculature may be responsible for the maintenance of blood pressure without trigger- PDE-5 is found in smooth muscles of the systemic 47 arteries and veins throughout the body, use of PDE- ing a reflex tachycardia. Mahmud et al. showed 5i has been associated with various cardiovascular a decrease in both systolic and diastolic blood effects. pressure with no significant changes in heart rate in patients on current antihypertensive medications (either monotherapy or dual therapy using amlodi- pine, diuretics, angiotensin converting enzyme Effect on cardiac contractility inhibitors, and/or diltiazem) following sildenafil There is no conclusive evidence of the effects 44 administration. Similar effects have been shown in of PDE-5i on cardiac contractility. Corbin et al. patients taking tadalafil and vardenafil for ED. In demonstrated that sildenafil does not have any a study involving the use of 10 or 20 mg tadalafil direct inotropic effect on segments from dog (or in healthy patients there was a small but statistically human) heart. Similarly, in patients with severe significant reduction in systolic and diastolic pres- CAD or stable ischemic heart disease, no or only sure without adverse effects on hemodynamics.48 small decreases in cardiac output were observed In a crossover study comparing sildenafil (50 mg) after either oral or intravenous (i.v.) sildenafil 45 and vardenafil (10 mg) both agents caused a drop administration. Similar results were shown in in systolic (sildenafil: 4.774.2 mm Hg, vardenafil: in vitro studies. In humans, however, in a rando- 5.475.5 mm Hg) and diastolic blood pressures (sil- mized double-blinded placebo-controlled study 7 7 46 denafil: 4 4.1 mm Hg, vardenafil: 5.0 5.3 mm Hg), by Borlaug et al. involving 35 healthy volunteers, with a slight increase in heart rate (sildenafil: it has been shown that sildenafil suppressed 1.270.9 beats per minute (b.p.m), vardenafil: b-adrenergic stimulated systolic function (but had 2.472.3 beats per minute).49 only little effects under resting conditions). In PDE-5i have been shown to be tolerated with a summary, more studies are needed to assess the wide range of concomitant antihypertensive drugs, effects of PDE-5i on cardiac contractility, since in such as b-adrenergic receptor blockers, calcium particular the effects of vardenafil and tadalafil on channel blockers, and angiotensin converting en- cardiac contractility are unclear, yet. zyme inhibitors (ACEi). However, PDE-5i should be used with caution in patients receiving a blocking agents since the combination of both might lead to Effects on central hemodynamics and peripheral excessive vasodilatation and hypotension. For tada- vasculature lafil and vardenafil, the combination with a-blockers Sildenafil is known to have both arterio-dilating and has been considered as a precaution. On the other veno-dilating properties on the peripheral vascula- hand, the combination with nitrates or any NO ture. This can be explained by increased cGMP donating agents (such as nitroprusside among a few levels in vascular smooth muscle. In a randomized others) can cause cumulative hypotension that can controlled study in patients with known CAD (or at be life threatening, in particular in patients with high risk for CAD), the use of sildenafil had no effect CAD and critical stenoses, and therefore is the main on heart rate, cardiac index or exercise-induced wall contraindication for PDE-5i use. motion score index.45 In another study involving eight CAD patients with stable angina, i.v. sildenafil reduced systemic and pulmonary arterial pressures and cardiac output by 8, 25, and 7%, respectively, Effect on coronary vasculature consistent with mixed arterial and venous vaso- Sildenafil has been shown to selectively increase dilating effects.47 cGMP in vascular smooth muscles of isolated canine A number of studies have assessed the effects of coronary arteries. Concentrations of 10–100 nM PDE-5i on blood pressure and heart rate. Small, demonstrated a dose response, however, further transient decreases in systolic and diastolic blood increases in concentration had no effects on cGMP

International Journal of Impotence Research The effects of chronic PDE-5i ER Schwarz et al 143 levels. Traverse et al.9 studied the effects of involving 35 men with HF and ED over a 12-week sildenafil on coronary blood flow at rest and during period. Sildenafil use was also associated with exercise in chronically instrumented dogs and improved quality-of-life scores and amelioration of found that sildenafil caused an increase in coronary symptoms of depression when compared with blood flow, suggesting a modest vasodilator activity placebo. Katz52 described a study to investigate the in coronary resistance vessels. Myocardial hypoper- safety and efficacy of sildenafil in patients with ED fusion, induced by exercise in the presence of a left and stable HF and observed a significant improve- anterior descending coronary artery stenosis, was ment in erections (74%) and the ability to have improved by increased coronary blood flow after intercourse (68%) if compared to a placebo group sildenafil administration. This was achieved at the (18 and 16%, respectively). There is yet no data, same distal coronary pressure before and after however, on the effects of vardenafil and tadalafil in treatment with sildenafil, suggesting a direct effect patients with HF.53 Hence sildenafil has proven to be on the coronary microvasculature. In a study in efficacious and safe in patients with ED and stable HF. humans, Herrmann et al.45 demonstrated no change in coronary blood flow but a significant increase in coronary flow reserve in both stenosed and non- Effect of PDE-5i use on other organ system stenosed coronary arteries. Sildenafil, in contrast to nitrates, is therefore unlikely to cause a coronary Besides erectile tissue, the lung and the heart, PDE- steal phenomenon. 5i have also been known to exert physiological effects on other systems such as platelets and the eyes. Effects on patients with HF Chronic HF is an increasingly common cardiovascular disease with approximately 75% of Effects on platelets patients reporting associated ED. The efficacy and Human platelets contain PDE-5 -2, -3, and -5 safety of PDE-5i in men with HF has been reported (Table 2). Initial data suggested that sildenafil has by several groups. Bocchi et al.50 studied the effects no direct effects on platelet function, but that it did of sildenafil in HF patients and reported an modestly potentiate the inhibitory effect of the NO- improvement in the Erectile Dysfunction Inventory donor sodium nitroprusside on adenosine diphos- of Treatment Satisfaction (EDITS) score and the phate-induced platelet aggregation ex vivo. This is scores for questions regarding the frequency of consistent with the requirement for an NO drive for penetration and the frequency of maintained erec- sildenafil to produce its pharmacologic effects.44 In tions after penetration (IIEF Questionaire) when a recent study by Dunkern et al.54 it was shown that compared with baseline. Webster et al.51 showed a sildenafil potentiated antiplatelet aggregatory effect significant improvement in IIEF results in a single- of NO donors in vitro. The authors also illustrated center placebo-controlled fixed-dose crossover trial that sildenafil plus sodium-nitroprusside in low

Table 2 Tissue distribution and physiological effects of the different PDEs

Class of PDE Tissue localization Physiological effects

1 Brain, heart, kidney, liver, skeletal muscle, vascular and Vascular and smooth muscle proliferation, gestation smooth muscle 2 Adrenal cortex, heart, kidney, liver, corpus cavernosum, Corticosteroid production visceral smooth muscle, brain 3 Corpus cavernosum, heart, platelets, vascular and visceral Insulin secretion, lipolysis, cardiac contractility, hepatic smooth muscle, adipose tissue, liver, kidney glucose production 4 Kidney, lung, mast cells, brain, skeletal muscle, heart, Smooth muscle relaxation, thyroid hormone secretion, thyroid, testis, neural tissue, vascular and visceral smooth inflammation muscle 5 Corpus cavernosum, platelets, vascular and visceral Penile erection, smooth muscle relaxation, antiplatelet smooth muscle aggregation 6 Retina Visual transduction 7 Skeletal muscle, lymphocytes, heart T-cell activation 8 Wide distribution, mainly in testis, ovaries, small intestine, T-cell activation colon 9 Wide distribution, mainly in spleen, brain, small intestine Unknown 10 Putamen and caudate nucleus, testis, thyroid Dopamine neural signaling 11 Corpus cavernosum, vascular smooth muscle, testis, Unknown pituitary, liver, skeletal muscle, liver, kidney

Abbreviation: PDE, phosphodiesterases.

International Journal of Impotence Research The effects of chronic PDE-5i ER Schwarz et al 144 concentrations partially inhibited thrombin- CAD.60 Some animal studies showed beneficial induced release of serotonin, hence eliciting the effects of PDE-5i use on the endothelium function antisecretory activity of sildenafil. However, in diabetics. For example, Ahn et al.61 studied the because the effects of sildenafil have not been effect of DA-8159 (PDE-5i) on diabetic rats and evaluated in patients with bleeding disorders or demonstrated that chronic administration of PDE-5i in patients taking antiplatelet agents such as attenuated the development of ED. This effect was ticlopidine, clopidogrel, or dipyridamole, caution associated with an improvement in endothelial should be taken if the drug is administered with dysfunction. Interestingly, human studies have also this concomitant medication.55 The effect of varde- demonstrated that administration of sildenafil might nafil and tadalafil specifically on platelets has not limit myocardial damage induced by prolonged been well defined. It is suggested, however, that ischemia-reperfusion-induced endothelial dysfunc- PDE-5i have antiaggregatory effects on platelets, the tion,62 which has been attributed to the opening clinical potential of which has yet to be explored. of ATP-dependant potassium channels. Moreover, tadalafil improved endothelial function in patients with increased cardiovascular risk, an effect that was sustained for at least 2 weeks after discontinua- Effect on the gastrointestinal tract tion of the drug.63 On the other hand, there are There is only rare data on the effects of PDE-5i use conflicting data on PDE-5i effects in smoking-induced on the gastrointestinal tract. Studies carried out in endothelial dysfunction. Dishy et al.64 showed that animal models have shown an inhibitory effect of there was no significant change in flow-mediated PDE-5i on smooth muscles in the gastrointestinal dilatation of the brachial artery (and in forearm tract. Araujo et al.56 showed that sildenafil had postischemic reactive hyperemia) by PDE-5i in an inhibitory effect on rat duodenal contractility smokers. However, a study by Vlachopoulos et al.65 in vitro, which was thought to be caused by a myo- demonstrated that PDE-5i (sildenafil) abrogates the relaxant and antispasmodic effect on rat duodenal smoking-induced acute decrease in flow-mediated tissue, most likely secondary to intracellular cGMP dilatation of the brachial artery. Endothelial dys- accumulation. Almost similar results were shown function with impaired endothelium-dependent by Zhang et al.57 in the esophagus of cats by flow-mediated vasodilatation in patients with HF studying the effects of sildenafil propagation of is partly attributed to hyporesponsiveness of cGMP- esophageal contractions and lower esophageal mediated vasorelaxation mechanisms in vascular sphincter relaxation. The authors concluded that smooth muscle. In a study by Katz et al.,66 PDE-5i sildenafil caused a reduced amplitude of esophageal increased endothelium-dependent, flow-mediated contractions. Additionally, the time period from vasodilatation in patients with chronic HF when swallowing to distal esophageal contractions was compared to placebo. significantly prolonged in associated with a reduction in lower esophageal sphincter pressure. More- over, Sarnelli et al.58 assessed the role of sildenafil Effect on visual function on gastric sensorimotor function and demonstrated Sildenafil is approximately 10-fold as potent that sildenafil increased postprandial gastric vo- for PDE-5 compared to PDE-6,5,22 an enzyme found lume (and slowed time required to empty liquids), in the retina; this lower selectivity is thought to be which was thought to be attributed to NO-induced the basis for abnormalities related to color vision smooth muscle relaxation. observed with higher doses or plasma levels. In vitro studies of PDE-5i on human anal sphincter Transient visual abnormalities67 such as color- have shown myogenic effects associated with re- tinged (blue-green) vision, increased perception of laxation of the internal anal sphincter.59 Altogether, light, and blurred vision have been reported in PDE-5 inhibition has been shown to induce smooth patients taking sildenafil, particularly at high oral muscle relaxation and inhibition of peristalsis by doses (4100 mg). In patients with inherited dis- NO-mediated cGMP pathways. orders of retinal PDE-6, such as retinitis pigmentosa, sildenafil should be administered with extreme caution. Several case reports published between Effect on the endothelium 2000 and 2005 suggest a temporal association It has been suggested that endothelial dysfunction between PDE-5i and nonarteritic anterior ischemic results in decreased endothelial-derived NO pro- optic neuropathy (NAION) and the obstruction of duction. This may be attributed to a downregulation the cilioretinal artery,68 and pupil-sparing third of the mRNA production for the endothelial nerve palsy,69 associated with the intake of high enzymes NO synthase and cyclooxygenase, both of dosages of sildenafil. Moreover, in May and July which are required for vasodilator properties of the 2005, the media reported about individuals who endothelium. Endothelial function has been shown have decided to sue Pfizer because of vision loss to be altered in patients with HF (ischemic or caused by NAION that occurred in association with nonischemic in nature), diabetes mellitus and PDE-5i.

International Journal of Impotence Research The effects of chronic PDE-5i ER Schwarz et al 145 NAION is a frequent cause of untreatable, sudden, 5i use. In an animal model Schermuly et al.74 irreversible vision loss in individuals older than 40 studied the chronic effects of sildenafil in mono- years. The condition is characterized by optic disc crotaline (MCT)-induced pulmonary hypertension edema, frequently associated with nerve fiber layer in rats. At 4 weeks after a single subcutaneous hemorrhages, an afferent papillary defect and visual injection of MCT, the animals displayed nearly field loss that has been reported rarely in men after threefold elevated pulmonary artery pressure and taking sildenafil or other PDE-5i for ED. An analysis vascular resistance with a concomitant decline in of clinical trial data in more than 13 000 men and on central venous oxygen saturation and arterial oxy- more than 35 000 patient-years of observation in genation. Sildenafil, when chronically administered epidemiologic studies, an estimated incidence of 2.8 from days 14 to 28, significantly increased plasma cases of NAION per 100 000 patient-years of silde- cGMP and inhibited the development of pulmonary nafil exposure was recognized, which is similar to hypertension and right heart hypertrophy, with estimates reported in general US population sam- preservation of gas exchange and systemic arterial ples (2.52 and 11.8 cases per 100 000 men aged X50 pressure. Moreover, the death rate significantly years).70 Even though individual cases have been decreased in animals treated with sildenafil. Hence, reported for all PDE-5i, these recently published the authors concluded that sildenafil attenuates data do not suggest an increased incidence of MCT-induced pulmonary hypertension and cor NAION in men who took PDE-5i for ED. pulmonale in rats. In an another animal study75 involving long-term sildenafil use for approximately 8 weeks on the effect of doxorubicin-induced cardiomyopathy and cardiotoxicity, it was shown Effect on cerebral blood flow that treatment with clinically relevant doses of PDE-5 has also recently been reported to be present sildenafil (0.7 mg/kg) 1 h before doxorubicin admin- in brain tissue, predominantly in the cerebellum, istration resulted in cardioprotection from doxo- hippocampus and superior cervical ganglion.71 rubicin-induced cardiotoxicity. These data also PDE-5 has also been shown to be present and illustrated the capacity of sildenafil in attenuation active in the guinea-pig basilar artery72 and in of cardiomyocyte apoptosis, preservation of myo- human cerebral arteries. Kruuse et al.72 showed that fibrillar integrity, prevention of left ventricular sildenafil had no vasodilator effects on cerebral dysfunction, and prevention of ST prolongation arteries, with no effect on cerebral blood flow or consistent with chronic doxorubicin toxicity 8 blood flow velocity. This fact has been reinforced weeks after the treatments. In a unique study by in a pilot study by Arnavaz et al.73 who showed that Takimoto et al.,76 the authors showed that blocking there was no significant change in blood flow the intrinsic catabolism of cGMP with chronic use velocity changes of the middle cerebral artery before of oral PDE-5i for 9 weeks (sildenafil) suppressed and after administration of sildenafil. The lack of chamber and myocyte hypertrophy, and improved a dilatory response to sildenafil in cerebral arteries in vivo cardiac function in mice exposed to chronic and arterioles in healthy subjects may indicate that pressure overload induced by transverse aortic cGMP is not accumulated in cerebral smooth muscle constriction. The authors also postulated that or that a compensatory regulatory mechanism sildenafil reversed pre-established hypertrophy. effectively decreases cGMP. Another explanation However, sildenafil had no effect on hypertrophy may be that the PDE-5 in smooth muscle cells is if induced by overexpression of calcineurin in vitro a splice variant, which inhibits sildenafil only to a or Akt gene in vivo. Based on these interesting minor degree, but not enough to elicit vasodilata- findings, PDE-5i might provide new treatment tion. No studies have been carried out to assess strategies for cardiac hypertrophy and remodeling the effects of vardenafil and tadalafil on cerebral in the future. blood flow. In a study involving the effect of long-term vardenafil treatment on development of fibrotic plaques in a rat model of Peyronie’s disease (PD), Effects of chronic PDE-5i use vardenafil slowed and reversed the early stages of an experimental PD-like plaque in rat, and might There is a paucity of data on the long-term effects of have ameliorated a more advanced plaque.77 These chronic PDE-5i use. There is no consensus on the effects were noted after giving vardenafil for 45 definition of long-term or chronic use, with studies days. No data were found looking at long-term stating it from 4 weeks to 1 year. Few studies in both effects of tadalafil in animal models. animal models and in human subjects have assessed A number of studies have been published in the long-term effects of PDE-5i use, mainly indicat- human subjects to assess long-term effects of PDE-5i ing long-term beneficial effects with minimal side use. A study by Stiebellehner et al.78 evaluated long- effects. term sildenafil therapy in patients with pulmonary Some animal studies have shown beneficial hypertension in addition to continuous i.v. epopros- pulmonary and cardiac effects with long-term PDE- tenol. The authors demonstrated that chronic use of

International Journal of Impotence Research The effects of chronic PDE-5i ER Schwarz et al 146 sildenafil (for 5 months) improved pulmonary Hemodynamic effects of PDE-5i (tadalafil) admi- hemodynamics and quality-of-life, without major nistered daily for 26 weeks was assessed in another adverse events such as systemic hypotension or randomized placebo-controlled study.82 At the end decreased arterial oxygenation. In another small of 26 weeks, the mean change in systolic and study79 of 14 patients, with pulmonary hyperten- diastolic blood pressure was similar between two sion of various etiologies treated with sildenafil, 1 groups suggesting no significant hemodynamic year follow-up was associated with increased ex- deterioration after chronic use of PDE-5i. ercise tolerance and pulmonary blood flow without changes in pulmonary pressures. Again, no major adverse effects were noted, suggesting clinical safety Conclusions on chronic use of sildenafil. PDE-5i have also been shown to have favorable effects on chronic throm- The role of PDE-5i as a treatment modality has been boembolic pulmonary hypertension that occurs ever expanding since its first approval in 1998. From secondary to a progressive increase in lung vascular the initial use in patients with ED, PDE-5i are now resistance after remodeling following emboli. This 41 indicated for the use in patients with pulmonary was shown by Ghofrani et al. in a study of 12 hypertension, thereby highlighting its multiorgan patients with nonoperable, progressive, chronic beneficial effects. Being a relatively newer drug and thromboembolic pulmonary hypertension despite associated apprehension on its usage, PDE-5i are not sufficient long-term anticoagulation. Significant im- used to their utmost potential and there exists provements in exercise capacity and pulmonary a large realm of the disease world where this drug hemodyanmics after 6 months of therapy with oral can prove beneficial. In particular, owing to well- sildenafil were seen. In a recently published case 80 studied effects on vasculature and hemodynamics report, sildenafil was safely used for 323 days in by PDE-5i, several data exist from experimental a 14-month-old child who had undergone cardiac as well as human studies regarding efficacy and surgery for d-transposition of the great arteries, tolerability. There is, however, lack of data on long- ventricular septal defect and pulmonary hyperten- term, chronic PDE-5i use in patients with under- sion. The patient was weaned off NO postsurgery lying cardiovascular disorders. So far, long-term and had normal pulmonary pressure postsildenafil PDE-5i in stable patients with or without cardio- use. There were no observed side effects with long- vascular or pulmonary disorders are promising and term drug usage. have not shown unwanted chronic side effects. Only few data are available on cardiac effects of Further studies, especially in patients considered at long-term PDE-5i use. In a recently published study high risk, are warranted. by Preston et al.,81 10 HF patients in NYHA classes III–IV were followed after an average course of 1271.6 months of sildenafil therapy. Six of the 10 patients reported improvement in NYHA functional Conflict of Interest score by at least one class and nine patients reported improvement in exertional dyspnea. Echocardio- The authors have no conflict of interest. grams obtained after two 8 months of initiation of sildenafil therapy showed no change in peak systolic pulmonary artery pressures or right ventri- References cular function. A 6 min walk test improved from 191746 to 250750 m (Po0.05). 1 Beavo JA. Cyclic nucleotide phosphodiesterases: functional Chornic tadalafil therapy, on the other hand, has implications of multiple isoforms. 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