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Erectile Dysfunction: Medical Therapy and Rehabilitation (2022)
Alessandro Palmieri, Marco Capece, Angelo di Giovanni, and Carlo D’Alterio
4.1 Introduction
Medical treatment for erectile dysfunction (ED) has dramatically evolved in the last decades. However, to set realistic expectations with the patient, correct counseling is fundamental. Every kind of medical treatment must be discussed with the patient regarding risk factors, prognostic factors, treatment alternatives, correct drug use, and adverse reactions [1]
4.1.1 Oral Pharmacotherapy: PDE-5Is Phosphodiesterase 5 inhibitor
(PDE-5I) drugs are the most common drugs for the management of erectile dysfunction.
The four molecules synthesized and approved by the European Medicines Agency (EMA) are as follows:
• Sildenafil citrate, the first drug approved for the management of erectile dysfunction in 1998 by the FDA
• Vardenafl approved in 2003
• Tadalafil also approved by the FDA in 2003
• Avanafil approved in 2012
However, they are not initiators of erection and adequate sexual stimulation is required [2].
PDE5-Is are actually effective in about 65% of patients; the effectiveness of this type of drug is defined as the patient’s ability to undertake sufficient sexual intercourse [3].
The choice of the molecule must be personalized; adequate counseling is essential in order to investigate patients’ comorbidities, the frequency of intercourses, and expectations [4].
4.1.1.1 Pharmacokinetic and Pharmacodynamic Features
The endothelial cells of the corpora cavernosa release nitric oxide (NO), which activates guanylate cyclase, further enhancing the synthesis of cyclic guanosine monophosphate (cGMP).
cGMP is an intracellular second messenger molecule that causes relaxation and vasodilatory effects in smooth muscle cells. It is degraded and inactivated by the enzyme phosphodiesterases. At least 11 different subtypes are currently known.
In the human corpus cavernosum, there is a greater percentage of PDE-2, PDE-3, PDE-4, and PDE-5. The latter phosphodiesterase is the most widely expressed form within the corpus cavernosum. The drugs used for erectile dysfunction are competitive inhibitors of PDE-5; therefore, they enhance the releasing effect of nitric oxide. Inhibiting the activity of the enzyme responsible for the degradation of GMPc, they allow an accumulation of the cyclic nucleotide in response to nitrergic stimulation. The end result is calcium sequestration from the cytoplasm to the endoplasmic reticulum with arteriolar and trabecular smooth muscle relaxation and venous vasoconstriction [5].
Sildenafil
Sildenafil was the first erectile dysfunction drug that hits the world market in 1998 [6]. His discovery was accidental; in fact, originally, the drug was to be used for the treatment of hypertension and angina pectoris. The drug did not prove effective for this purpose, but patients reported unexpected penile erections [7].
Sildenafil takes effect 30–60 min after its administration with a half-life of 4–8 h [8]. Its action can last up to 12 h after the drug intake. Its effectiveness is reduced after a large meal or with the ingestion of fatty foods [9].
The dosages available on the market are 25 mg, 50 mg, 75 mg, and 100 mg.
A placebo-controlled study evaluated the improvement of erection in 465 patients using different dosages of sildenafil. After 24 weeks of treatment in the dose-response study, improved erections are reported in 56%, 77%, and 84% of the men taking 25, 50, and 100 mg of sildenafil, respectively [10].
The most common side effects are headache (16%), flushing (10%), and dyspepsia (7%). Other side effects include nasal congestion, diarrhea, and changes in vision [7].
Vardenafil
Vardenafl was introduced in 2003. It is effective 30 min after the intake. Most patients report satisfactory erections within 15 min [11]
It is available in the market in doses of 5 mg, 10 mg, and 20 mg. The starting dose is 10 mg, and it can be modified according to the patient’s response [12]. A 10 mg orodispersible dose was also recently introduced to the market.
The absorption of vardenafil is reduced after a fatty meal [9].
The most frequent side effects include facial flushing and nasal congestion (9–11%) [13].
After 12 weeks of treatment with vardenafil, a placebo control study showed a statistically significant improvement in erections in 66%, 76%, and 80% of patients taking 5 mg, 10 mg, and 20 mg formulations, respectively [14].
Tadalafil
Tadalafil was approved in the United States in November 2003 [15]. It has particular pharmacokinetic properties. Absorption does not appear to be influenced by the intake of fatty meals or alcohol [16]. The peak of the serum concentration is reached about 2 h after the ingestion different from sildenafil, vardenafil, and avanafil which require 1 h. In addition, the half-life of the molecule (t½) is around 17.5 h [17, 18]. Therefore, a chronic administration of tadalafil enhances erectile function for up to 36 h and may restore more physiological sexual intercourse [19, 20]. However, tadalafil's prolonged half-life has a higher risk of long-lasting adverse effects than other PDE5-Is. Indeed up to 30% of men taking tadalafil report side effects lasting longer than 1–2 h [21]
Avanafil
Avanafil is the latest d approved. It was launched on the market in 2013 [22]. The available formulations are 50 mg, 100 mg, and 200 mg, and the recommended starting dose is 100 mg [17].
Avanafil is rapidly absorbed and quickly eliminated after an oral administration.
Avanafil has the highest selectivity for phosphodiesterase 5 among PDE5-Is, thus side effects are minimized. Adverse effects are generally consistent with the known pharmacology of PDE5-Is, and the most commonly reported adverse events are headaches, flushing, back pain, nausea, muscle cramps, and fatigue. Besides most of these events are mild and self-resolving [18].
The active ingredient is effective 15 min after the intake. The absorption of avanafil is reduced from fatty meals, and its duration is approximately 6 h [23].
Hellstrom et al. showed successful attempts within 15 min in 64%, 67%, and 71% after avanafil dosages of 50 mg, 100 mg, and 200 mg, respectively [23].
Patients suffering from chronic renal failure or hepatic insufficiency do not require a dosage modification [24].
4.1.1.2 The Right Molecule for the Right Patient
4.1.1.3 Pharmacological Interactions
4.1.1.4 Cardiovascular Safety
4.1.1.5 Non-responders
4.1.1.6 On-Demand Vs Daily Treatment
4.1.1.7 PDE5-I in Penile Rehabilitation
4.1.2 Vacuum Erection Devices
The vacuum device is a manual or electric pump used to obtain a mechanical erection in a vacuum chamber.
4.1.3 Alprostadil
Prostaglandine E-1 and its synthetic formulation known as alprostadil is the only intracavernous and transurethral therapy, approved by FDA, to treat ED. The drug is absorbed by the urethra to the corpus spongiosum and then to the corpus cavernosum.
Alprostadil operates by stimulating adenyl cyclase. The latter increases the cAMP level and decreases the intracellular calcium involving the subsequent relaxation of arterial and trabecular smooth muscle [53]
4.1.3.1 Topical Route
The topical route (200 and 300 μg VITAROS) is less invasive than the other formulations. It is a cream with a permeation enhancer that facilitates the urethral absorption
4.1.3.2 Intraurethral Route
The intraurethral route (125–1000 μg MUSE, medicated urethral system for erection) consists of small semisolid pellets managed into the distal urethra using an adequate device.
4.1.3.3 Intracavernous Injection
Intracavernous injection (ICI) allows the chemical erection of the corpora cavernosa.
It is considered the most effective non-surgical treatment for PDE5-I non-responders (approximately 25% of patients [61]) or those that cannot tolerate the side effects of oral agents [62, 63].
4.1.4 Extracorporeal Shockwave Therapy
4.1.4.1 Introduction
The shockwaves (SW) are acoustic waves that deliver energy when focused on an anatomical target. The focused SW simulates a microtrauma in the tissues that eventually stimulate the release of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and proliferating nuclear cell antigen (PCNA) [66]. Thus neo-angiogenesis and subsequent improvement of the bloodstream are facilitated [67, 68].
4.1.4.2 ESWT and Vascularization
4.1.4.3 ESWT and Stem Cells
4.1.4.4 ESWT and Erectile Dysfunction
4.1.4.5 ESWT Protocol
4.1.4.6 ESWT Adverse Effects
Alessandro Palmieri, Marco Capece, Angelo di Giovanni, and Carlo D’Alterio
4.1 Introduction
Medical treatment for erectile dysfunction (ED) has dramatically evolved in the last decades. However, to set realistic expectations with the patient, correct counseling is fundamental. Every kind of medical treatment must be discussed with the patient regarding risk factors, prognostic factors, treatment alternatives, correct drug use, and adverse reactions [1]
4.1.1 Oral Pharmacotherapy: PDE-5Is Phosphodiesterase 5 inhibitor
(PDE-5I) drugs are the most common drugs for the management of erectile dysfunction.
The four molecules synthesized and approved by the European Medicines Agency (EMA) are as follows:
• Sildenafil citrate, the first drug approved for the management of erectile dysfunction in 1998 by the FDA
• Vardenafl approved in 2003
• Tadalafil also approved by the FDA in 2003
• Avanafil approved in 2012
However, they are not initiators of erection and adequate sexual stimulation is required [2].
PDE5-Is are actually effective in about 65% of patients; the effectiveness of this type of drug is defined as the patient’s ability to undertake sufficient sexual intercourse [3].
The choice of the molecule must be personalized; adequate counseling is essential in order to investigate patients’ comorbidities, the frequency of intercourses, and expectations [4].
4.1.1.1 Pharmacokinetic and Pharmacodynamic Features
The endothelial cells of the corpora cavernosa release nitric oxide (NO), which activates guanylate cyclase, further enhancing the synthesis of cyclic guanosine monophosphate (cGMP).
cGMP is an intracellular second messenger molecule that causes relaxation and vasodilatory effects in smooth muscle cells. It is degraded and inactivated by the enzyme phosphodiesterases. At least 11 different subtypes are currently known.
In the human corpus cavernosum, there is a greater percentage of PDE-2, PDE-3, PDE-4, and PDE-5. The latter phosphodiesterase is the most widely expressed form within the corpus cavernosum. The drugs used for erectile dysfunction are competitive inhibitors of PDE-5; therefore, they enhance the releasing effect of nitric oxide. Inhibiting the activity of the enzyme responsible for the degradation of GMPc, they allow an accumulation of the cyclic nucleotide in response to nitrergic stimulation. The end result is calcium sequestration from the cytoplasm to the endoplasmic reticulum with arteriolar and trabecular smooth muscle relaxation and venous vasoconstriction [5].
Sildenafil
Sildenafil was the first erectile dysfunction drug that hits the world market in 1998 [6]. His discovery was accidental; in fact, originally, the drug was to be used for the treatment of hypertension and angina pectoris. The drug did not prove effective for this purpose, but patients reported unexpected penile erections [7].
Sildenafil takes effect 30–60 min after its administration with a half-life of 4–8 h [8]. Its action can last up to 12 h after the drug intake. Its effectiveness is reduced after a large meal or with the ingestion of fatty foods [9].
The dosages available on the market are 25 mg, 50 mg, 75 mg, and 100 mg.
A placebo-controlled study evaluated the improvement of erection in 465 patients using different dosages of sildenafil. After 24 weeks of treatment in the dose-response study, improved erections are reported in 56%, 77%, and 84% of the men taking 25, 50, and 100 mg of sildenafil, respectively [10].
The most common side effects are headache (16%), flushing (10%), and dyspepsia (7%). Other side effects include nasal congestion, diarrhea, and changes in vision [7].
Vardenafil
Vardenafl was introduced in 2003. It is effective 30 min after the intake. Most patients report satisfactory erections within 15 min [11]
It is available in the market in doses of 5 mg, 10 mg, and 20 mg. The starting dose is 10 mg, and it can be modified according to the patient’s response [12]. A 10 mg orodispersible dose was also recently introduced to the market.
The absorption of vardenafil is reduced after a fatty meal [9].
The most frequent side effects include facial flushing and nasal congestion (9–11%) [13].
After 12 weeks of treatment with vardenafil, a placebo control study showed a statistically significant improvement in erections in 66%, 76%, and 80% of patients taking 5 mg, 10 mg, and 20 mg formulations, respectively [14].
Tadalafil
Tadalafil was approved in the United States in November 2003 [15]. It has particular pharmacokinetic properties. Absorption does not appear to be influenced by the intake of fatty meals or alcohol [16]. The peak of the serum concentration is reached about 2 h after the ingestion different from sildenafil, vardenafil, and avanafil which require 1 h. In addition, the half-life of the molecule (t½) is around 17.5 h [17, 18]. Therefore, a chronic administration of tadalafil enhances erectile function for up to 36 h and may restore more physiological sexual intercourse [19, 20]. However, tadalafil's prolonged half-life has a higher risk of long-lasting adverse effects than other PDE5-Is. Indeed up to 30% of men taking tadalafil report side effects lasting longer than 1–2 h [21]
Avanafil
Avanafil is the latest d approved. It was launched on the market in 2013 [22]. The available formulations are 50 mg, 100 mg, and 200 mg, and the recommended starting dose is 100 mg [17].
Avanafil is rapidly absorbed and quickly eliminated after an oral administration.
Avanafil has the highest selectivity for phosphodiesterase 5 among PDE5-Is, thus side effects are minimized. Adverse effects are generally consistent with the known pharmacology of PDE5-Is, and the most commonly reported adverse events are headaches, flushing, back pain, nausea, muscle cramps, and fatigue. Besides most of these events are mild and self-resolving [18].
The active ingredient is effective 15 min after the intake. The absorption of avanafil is reduced from fatty meals, and its duration is approximately 6 h [23].
Hellstrom et al. showed successful attempts within 15 min in 64%, 67%, and 71% after avanafil dosages of 50 mg, 100 mg, and 200 mg, respectively [23].
Patients suffering from chronic renal failure or hepatic insufficiency do not require a dosage modification [24].
4.1.1.2 The Right Molecule for the Right Patient
4.1.1.3 Pharmacological Interactions
4.1.1.4 Cardiovascular Safety
4.1.1.5 Non-responders
4.1.1.6 On-Demand Vs Daily Treatment
4.1.1.7 PDE5-I in Penile Rehabilitation
4.1.2 Vacuum Erection Devices
The vacuum device is a manual or electric pump used to obtain a mechanical erection in a vacuum chamber.
4.1.3 Alprostadil
Prostaglandine E-1 and its synthetic formulation known as alprostadil is the only intracavernous and transurethral therapy, approved by FDA, to treat ED. The drug is absorbed by the urethra to the corpus spongiosum and then to the corpus cavernosum.
Alprostadil operates by stimulating adenyl cyclase. The latter increases the cAMP level and decreases the intracellular calcium involving the subsequent relaxation of arterial and trabecular smooth muscle [53]
4.1.3.1 Topical Route
The topical route (200 and 300 μg VITAROS) is less invasive than the other formulations. It is a cream with a permeation enhancer that facilitates the urethral absorption
4.1.3.2 Intraurethral Route
The intraurethral route (125–1000 μg MUSE, medicated urethral system for erection) consists of small semisolid pellets managed into the distal urethra using an adequate device.
4.1.3.3 Intracavernous Injection
Intracavernous injection (ICI) allows the chemical erection of the corpora cavernosa.
It is considered the most effective non-surgical treatment for PDE5-I non-responders (approximately 25% of patients [61]) or those that cannot tolerate the side effects of oral agents [62, 63].
4.1.4 Extracorporeal Shockwave Therapy
4.1.4.1 Introduction
The shockwaves (SW) are acoustic waves that deliver energy when focused on an anatomical target. The focused SW simulates a microtrauma in the tissues that eventually stimulate the release of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and proliferating nuclear cell antigen (PCNA) [66]. Thus neo-angiogenesis and subsequent improvement of the bloodstream are facilitated [67, 68].
4.1.4.2 ESWT and Vascularization
4.1.4.3 ESWT and Stem Cells
4.1.4.4 ESWT and Erectile Dysfunction
4.1.4.5 ESWT Protocol
4.1.4.6 ESWT Adverse Effects
