PDE5 inhibitors have been considered as the standard ED treatment since FDA approval of sildenafil citrate in 1998, subsequently; other agents such as vardenafil, tadalafil, and avanafil emerged and gained popularity as an effective oral treatment for ED [25].

PDE5 inhibitors facilitate cavernous smooth muscle relaxation via blockade of cGMP, the catalytic enzyme that involves degradation of nitric oxide (NO). These agents are only effective under the effect of sexual stimulation as their effect is to augment rather than to start penile erection through the release of NO first [26]. Overall, the satisfaction rate of PDE5 inhibitors is approximately 70% [27].

Drug efficacy is enhanced by reduction of food intake that may lag drug absorption. Drug dose escalation and repetition (9–10 times) might be necessary to judge efficacy [28]. Glycemic control, androgen replacement, and dyslipidemic control are also important to potentiate drug efficacy [29].

To avoid PDE5–nitrite interaction, it is absolutely contraindicated to use any form of nitric oxide donors in combination with PDE5I. Hypotension may occur when using PDE5 inhibitors simultaneously with alpha blockers, as they both are vasodilators. Other side effects include headache, dyspepsia, flushing, myalgia, back pain, nasal congestion, and visual disturbances

PDE5 inhibitors have similar modes of action but differ in their pharmacokinetics and pharmacodynamics (Tables 13-2, 13-3, and 13-4).

Sildenafil (Viagra^®, Pfizer) 50 mg is the recommended starting dose, taken 1 h before sexual activity. The maximum recommended frequency is once daily. Drug absorption is impaired by high-fat diet. Sildenafil efficacy has been investigated with other coexisting conditions (e.g., hypertension, spinal cord injury, depression, prostate surgery, diabetes, and the elderly) [32] with no significant difference in response rates compared to normal cohorts [33–38]. Response rate to sildenafil is significantly diminished in patients who underwent non-nerve sparing radical prostatectomy [36].

Vardenafil (Levitra, Bayer) is a highly selective and potent PDE5 inhibitor. Despite being similar in chemical structure, it is more potent and selective than sildenafil. The recommended starting dose is either 10 or 20 mg oral (Levitra^®) or 10 mg sublingual (Staxyn^®). Vardenafil has a faster onset of action if compared to other PDE5 inhibitors. Fifty-three percent of patients can obtain erection sufficient for penetration at 25 min. As well as sildenafil, vardenafil absorption is impaired if the drug is taken after a fat meal [39]. Dose-dependent side effects include headache (21%), flushing (13%), and dyspepsia (6%) [40].

Tadalafil (Cialis^®, Eli Lilly) has a distinct chemical structure that differs from other PDE5 inhibitors. Recommended on-demand doses are 5, 10, and 20 mg. It is also available at 2,5 and 5 mg as a daily dose medication. Onset of action is within 30–45 min that may last for 24–48 h. Visual side effects encountered with other PDE5 inhibitors are less evident with tadalafil as it has a little inhibitory effect on PDE-6 and it has milder side effects but low back pain is a reported side effect of tadalafil. Drug absorption is not affected by meal or alcohol intake with a unique half-life of 17.5 h, peak plasma concentration of 2, and 36 h duration of action [41].

Avanafil (stendra^®, Vivus) has a different chemical structure, fast onset of action and 5–10 h half-life [42]. It shares other PDE5 inhibitors the same side effects [43].

TPN729MA is an under-development selective PDE5 inhibitor that has a potent and balanced selectivity for ED treatment. It has a longer duration of action than conventional PDE5 inhibitors in the studied animal models [45].

Preclinical pharmacokinetics of TPN729MA showed promising results that predict its future human application [46].

Udenafil is another new PDE5 inhibitor that acts by modulation of cNOS expression, thus inhibiting cGMP degradation. It compensates diabetes-associated corpus cavernosum changes. Compared to conventional PDE5 inhibitors, udenafil has a comparable safety profile [47].

Mirodenafil is a second generation PDE5 inhibitor that has high affinity and selectivity for PDE5 enzyme compared to conventional PDE5Is with better efficacy for ED treatment. The drug is given in two doses, 50 or 100 mg. Men with ED, hypertension or LUTS due to benign prostatic hyperplasia have adequately tolerated mirodenafil. Similar to other PDE5Is, mirodenafil has mild to moderate side effects (53.7%), commonly flushing (6.7–24.1%) and headache (1.8–14.8%) [48].

Tadalafil once daily regimen is available alternative to on-demand PDE5 inhibitor therapy in ED patients [49]. However, satisfaction and compliance rates are not affected by patient’s characteristics or associated comorbidities [50]. More than 68% of men on tadalafil 5 mg once-daily regimen were able to continue this plan for 6 months if they were involved in treatment plan [51]. On the other hand, amelioration of the effect of diabetes on erectile function was achieved by chronic low-dose PDE5 inhibitor administration combined by tight glycemic control [52]. Similarly, endothelial function and insulin sensitivity are enhanced on a 3-months PDE5 inhibitor regimen [18].

Melanocortin analogues have a central action on melanocortin-4 receptors that modulates erectile function, sexual behavior, food intake and energy. These molecules have shown to improve erectile function in clinical trials [53, 54]. Bremelanotide intranasal administration improved erectile function compared to placebo in both control and PDE5I nonresponders. Side effects include flushing and nausea [95, 96]. Nevertheless, melanocortin analogues have not been FDA approved for the treatment of ED due to limited safety profile.

Trazodone (Desyrel) is an antidepressant drug that may cause priapism. This off-label effect promoted trazodone as a possible ED treatment [55]. Its active metabolite acts as an agonist to 5-HT2C receptors promoting erectile function [11]. This drug has limited role in ED treatment given its limited safety profile. Side effects include nausea, vomiting, drowsiness, urine retention, and priapism [56].

Yohimbine is an alpha 2-blocker that is not indicated in patients with organic ED as it has a marginal effect on erectile function. Studies on non-organic ED patients have shown some response over placebo. Side effects include anxiety, tremors, palpitation and hypertension [57].

Apomorphine (Uprima^®) is a dopaminergic (D1/D2 receptors) agonist that is given in a sublingual route. It is a potent emetic drug. It acts as a pro-erectile drug when given in a subcutaneous route in rats and humans. Side effects especially nausea limited its clinical application. Sublingual route is available in Europe, but not FDA approved yet [58].

Phentolamine (Vasomax^®) is an oral drug that has been reported to improve erectile function. Its side effects include facial flushing, headache and nasal congestion. It has not been FDA approved yet. [59, 60].

Additional oral drugs have been proposed including l-arginine (nitric oxide precursor amino acid), Limaprost (prostaglandin E1), l-dopa, and Naltrexone (opioid antagonist) [61]. However, role of these drugs remain unclear because they are not thoroughly investigated [25].

Most patients on ICI are former PDE5I nonresponders. ICI could be offered as a sole second-line treatment or in combination with PDE5I. Satisfactory penile rigidity is restored in 60.2% of patients. Discontinuation of ICI therapy is mainly due to insufficient response (43.1%), poor compliance (18.3%), shift to other treatment (10.7%), loss of desire (6.7%), side effects (5.5%), and return of normal spontaneous erection (2.8%) [80]. Drug withdrawal occurs mainly due to pain. On the other hand, injection anxiety decreases the use of ICI, especially if ‘high’ injection anxiety is reported, which may be as high as 42% at 4 months [81]. Satisfaction rate seems to be higher in patients who alternate the use of PDE5I and ICI [82]. Some ED patients prefer ICI even though if they were responding to PDE5I possibly due to better erection quality [83]. Despite being reliable, self-injection is associated with higher rate of penile fibrosis compared to office program [84].

Androgen replacement encompasses monitoring of testosterone level before and after starting treatment. However, clinical response is more important than having a normal androgen level. It is recommended to complete 3-month course of androgen replacement before judging to discontinue the drug [90].

Several testosterone preparations are available for the treatment of hypogonadism, shown in Table 13-6.

Dihydrotestosterone (DHT) gel (125–250 mg/day): pure androgen that has no estrogenic effect (not aromatized to estradiol) on the prostate. It produces DHT plasma level that is similar to physiologic testosterone level [92].

Dehydroepiandrosterone (DHEA) has androgen/estrogen-like effects. It has a limited evidence of improving sexual function [93].

Human chorionic gonadotropin (HCG) increases testosterone level by 50%. It would be beneficial to hypogonadal men in a similar manner to testosterone replacement. However, it has no documented improvement on sexual function [94].

Aromatase inhibitors and selective androgen modulators increase testosterone level but they are still investigational. Their therapeutic value and safety profile are still unclear [95].

Treatment of hyperprolactinemia is necessary as regard to insufficiency of testosterone-replacement therapy to ameliorate erectile function. Underlying cause of hyperprolactinemia must be initially identified.

Prolactin-secreting adenoma should be treated medically or surgically if necessary. Bromocriptine (dopamine agonist) reduces prolactin and normalizes testosterone level. It facilitates reduction of adenoma size [96]. Recovery of erectile function is achieved after normalization of serum prolactin elevations [97].

These are new class of molecules that initiate and promote vasodilatation when response to nitric oxide donors and sGC stimulators is attenuated. BAY 60-2770 is an effective molecule in ED treatment in the lack of NO after pelvic nerve injury [72]. These molecules are more effective than sGC stimulators or PDE5 inhibitors when ED is associated with extensive endothelial damage [98]

BAY 41-2272 acts by direct stimulation of sGC. It increases enzymatic sensitivity to NO and upregulates cGMP by sGC activation independent of NO availability. These mechanisms produce anti-aggregatory, vasodilatory, and antiproliferative effects [99]. Chronically exposed rats to L-NAME showed improved relaxation of corpus cavernosum following 4-week therapy with BAY 41-2272 , this indicates the pro-erectile effect of cGMP accumulation into corpus cavernosum [100].

The acute effect of BAY 60-4552, the soluble guanylate cyclase (sGC) stimulator, and vardenafil was evaluated alone or in combination on erectile responses to electrical stimulation of the cavernous nerve (ES CN) in rats with cavernous nerve (CN) crush injury-induced ED. It was found that combined BAY 60-4552, and vardenafil provides synergistic beneficial effects and might therefore salvage patients who experience treatment failures with PDE5 inhibitors after RP [101].

Stem cell is now an evolving tool to be added to ED treatment armamentarium. SC ability to ameliorate cavernous nerve injury is currently being thoroughly investigated by different researchers. SC is a potential treatment and ultimately a cure to ED [79].

Intracavernosal injection of placental matrix-derived MSCs was investigated on a limited number of patients who failed previous oral therapies. Follow-up for 3 months showed the ability of one patient to achieve spontaneous erection. Further studies on a larger number of patients are needed in this perspective. [102]. On the other hand, ICI of ADSCs produced substantial recovery of erectile function induced by cryoablation of cavernous nerve. This effect thought to be achieved by the increased levels of cavernous tissue neurotrophic factors and the resultant neuroregenerative effects [103]. Patients undergoing radical prostatectomy who develop ED can be treated by ICI of bone marrow mononuclear cells. They show improved cavernous tissue revascularization with no serious side effects [104]. In another setting, structural penile deformity and reduction of Peyronie’s-like changes might be corrected by local injection of interferon-labelled ADSC. This effect is thought to be due to decreased expression of metalloproteinases tissue inhibitors [105].

Mesenchymal stem cells (MSCs) and ADSCs showed positive effects on erectile function in animal models of ED. [79] similarly, in another study, human umbilical cord blood MSCs (hUCB-MSCs) showed the ability to ameliorate erectile dysfunction in rat models of cavernous nerve injury [106]. Hepatocyte growth factor-modified ADSCs could potentiate the effect of ADSCs on erection in diabetic rats; this effect may be related to TGFb1down-regulation in the cavernous tissue [107]. Furthermore, Combination of SC and low-intensity extracorporeal shockwave therapy (LI-ESWT) induce cavernous nerve recovery and enhance endothelial function in a rat model of cavernous nerve cryoablation [108].