madman
Super Moderator
Considerations for Prescribing Pharmacotherapy for the Treatment of Erectile Dysfunction
Ahmed M. Bakr, Amro A. El-Sakka & Ahmed I. El-Sakka
Abstract:
Introduction: The effectiveness of phosphodiesterase type 5 inhibitors (PDE5i) in treating erectile dysfunction (ED) creates a new field of both medical practice and pharmaceutical manufacturing. Both paved the way for emerging minimally invasive therapies to restore male sexual function. However, what is the best drug to achieve the optimum outcome is still a challenging question to be answered.
Areas covered: The general viewpoint of matching the pharmacotherapeutic characteristics with the patient’s medical, social, and psychological variables, in order to balance between efficacy and safety. Several studies had investigated considerations for preference and long-term adherence for PDE5i. However, a thorough investigation of considerations for prescribing ED pharmacotherapy is still lacking in the literature. This is the aim of this manuscript.
Expert opinion: Several issues should be considered in the planning of ED management such as the patient’s and partner’s expectations, etiologic considerations, performance status, safety, adverse effects, ease of administration, compliance, bad experiences with previous treatment, availability, cost, social factors, satisfaction and finally, regimen considerations. Addressing the patient’s and partner’s individual needs help to tailoring treatment in order to minimize compromises and optimize gains.
1. Introduction:
ED is defined as the inability to initiate and/or maintain sufficient penile rigidity to have satisfactory sexual intercourse [1]. Though it can be secondary to other medical phenomena associated with other systemic diseases or a part of multi-organ dysfunctions [2], it can also be a primary complaint and reflect non-medical issues related to the social and psychological life of the patient [3, 4]
Since ED affects the personal, psychological and social aspects of life including self-image and relationship with the partner, therefore it is considered an important representative of the quality of life (QoL) [5, 6].
The most common organic causes of ED are vascular impairment and endothelial dysfunction that may result in the failure of vasodilation, which would cause blood to enter the corpus cavernosum and restrict venous output giving the penis rigidity [7, 8]. The first-line treatment of ED includes oral pharmacotherapy, vacuum device (VED), and topical or intra-urethral preparations. The second-line treatment is intra-cavernosal injections (ICI). A penile prosthesis is the third-line treatment and is characterized by irreversibility. The approach to be taken for the management of non-responding cases is to consider a plan of graduated interventions prioritized on the basis of patient’s characteristics and continuous re-assessment and participation in decision-making [9, 10]. The Selection of a suitable line of treatment needs an integrated approach of thinking that should be kept in parallel with the dynamic process of diagnosis, treatment, and monitoring of ED patients.
Preference and long-term adherence for oral PDE5i have been investigated in several studies using a longitudinal approach and discussed certain molecules and their features [5, 11-15]. In daily practice, it is of utmost importance to know how to select a particular drug across the whole range of available pharmacologic treatment. In the current article, we have addressed the basic rules of designing a therapeutic plan for ED patients. Furthermore, we have discussed the factors and considerations that affect this therapeutic plan.
2. What should be considered when treating ED? (Table 1, Figure: 1)
2.1. Physician versus Patient and Partner Prospect (Table 1, Figure: 2)
2.2. Performance:
2.2.1. Biological Efficacy:
2.2.2. Social Circumstances:
2.3. Therapeutic Regimen:
2.4. Compliance:
2.5. Previous Bad Experience:
2.6. Adverse effects:
3. Etiologic considerations
3.1. Curable causes of ED: the ED caused by testosterone deficiency, arterial injury, or psychological disorder can be managed with the intent of cure
3.1.1. Testosterone Deficiency (TD):
3.1.2. Arteriogenic ED:
3.1.3. Psycho-sexual issues
3.2. Non-curable causes of ED:
Microvascular and endothelial dysfunction associated with atherosclerosis plays an important role in the pathogenesis of non-curable ED [8]. Since the cure is not available, the pathogenic process that leads to ED is still in the action. The control of the associated molecular derangement and medical co-morbidities improves the outcomes of medical treatment in the short and long term [8]. Patients under chronic medications are liable for serious interaction with ED treatment [65]. The same occurs if the PDE5i levels are reduced by either hindering absorption or enhanced metabolism so that the false impression of non-response leads to escalating the dose, changing medication, or shifting to surgical management [65]. Accordingly, the atherosclerotic changes that start in a systematic manner all over the arterial system will progress at a similar pace and so occlude smaller arteries before larger ones [66]. With the contiguous exposure of harmful risk factors like obesity, smoking, and unhealthy diet, the ED can be an early sign of coronary artery disease [42].
4. When the PDE5i should be considered as the first line of management? (Figure 3) (Dynamic interactive approach)
4.1. How could the ED be treated dynamically and interactively?
4.2. What should be considered while approaching ED patients? (Figure 3)
4.2.1. Patient’s preference:
4.2.2. Invasiveness:
4.2.3. Ease of administration:
4.2.4. Re-assessment:
4.2.5. Reversibility:
4.2.6. Availability:
4.2.7. Cost affects compliance:
4.3. Why are PDE5is most commonly used as a first-line?
4.4. What kind of PDE5is should be started with?
4.5. When to bypass this approach?
4.6. What are the other lines and combination therapy?
4.6.1. Herbal supplementation
5. Regimen considerations:
5.1. Considering the interval between pill intake and sexual act:
5.2. Dose adjustment with food:
5.3. Considerations regarding the duration of action:
5.3.1. The importance of duration:
5.3.2. What is the duration of action of each drug?
Sildenafil and vardenafil have a half-life of about 4 hours duration. Sildenafil and vardenafil have an effective window of 6 – 8 hours [102]. Tadalafil has an effective window of 36 hours, as its half-life is as long as 17 hours. Avanafil has a half-life of 5 – 10 hours [93, 94, 95], and has a similar window as sildenafil [102]. The consideration in this context is mainly to educate the patient about the timing profile of each drug so that he can adjust his social and relationship contexts accordingly.
5.4. Dose-response relationship:
5.5. Daily dose vs on-demand dose:
5.5.1. Rationale:
5.5.2. Advantage:
5.5.3. The biologic evidence of advantage: Tadalafil is the first PDE5i molecule approved for daily dosing. Tadalafil has a dose-dependent effect, in which the erectogenic effect increases with the increase in oral dose and plasma levels. The long-term effects of Tadalafil on the erectile tissue persist even after the cessation of the therapeutic regimen [94].
The long-term advantages of Tadalafil are related to its biologic effects on vascular and cavernosal functions. It has been shown that the chronic use of PDE5i reduces the vascular stress caused by endothelial injury associated with aging and diabetes as proved by Sildenafil [108] and Tadalafil [109]. Tadalafil also causes remodeling of the vascular bed. These changes have positive effects on the erectile function that persists after the stoppage of the daily dose [93, 94, 95].
5.5.4. The clinical evidence of advantage:
5.6. Generic vs brand products:
6. Considering comorbidities
6.1. Why should comorbidities be considered?
6.2. What is the importance of cardiovascular disease considerations? [2]
6.2.1. The intimate relationship:
6.2.2. The predictive value of ED:
6.2.3. Recommendations for screening and treatment:
6.2.4. Safety of PDE5i in heart diseases:
7. Follow-up Considerations
7.1. Monitoring (physician prospect)
7.1.1. Patient education:
7.1.2. Indices of success/failure:
7.1.3. Adverse effects:
7.1.3.1. Why should the adverse effects be considered?
7.1.3.2. What adverse effects should be followed?
7.2. Tolerability (patient prospect):
8. Social considerations:
8.1. Partner issues:
8.2. The pattern of sexual life:
8.3. Cultural issues:
9. Conclusion
Although several studies had investigated some considerations for preference and long-term adherence for oral treatment as PDE5i, however; thorough addressing of considerations for prescribing pharmacotherapy for ED treatment are still lacking in the literature. This prompted us to address the considerations for prescribing pharmacotherapy for the treatment of ED. Several issues had been addressed in the current review paper such as patient and partner expectations, etiologic considerations, performance status, safety, adverse effects, ease of administration, compliance, a bad experience with previous treatment, availability, cost, satisfaction, regimen considerations, and finally social factors.
10. Expert Opinion
Over the past 50 years, the treatment of ED has quickly promoted and endures to vary with new types of treatment. Intracavernosal therapy was emerged in the eighties of the last century and followed by intraurethral therapy. The actual advancement in the non-surgical ED treatment was with the institution of oral PDE5i in 1998 which rapidly became the primary monotherapy. Nowadays, four PDE5i are existing in the market, i.e., sildenafil, vardenafil, tadalafil, and avanafil. New PDE5Is, including udenafil, and mirodenafil are presently available in several countries, and other molecules are in process.
One effective model of thinking regarding ED problems is to consider patients with ED as having a complex medical and non-medical condition that should be targeted in assessment and modification of risk factors to properly manage ED. For example; a triad of ED, cardiovascular disease, and depression has shown in multiple investigative efforts, a significant correlation and association in both directions of occurrence and recovery. Currently, several forms for ED pharmacotherapy are accessible. With the determination of the factors that should be considered in the planning of pharmacotherapy, sexual function can be successful in most patients. Physicians should offer their patients a safe and effective drug for the disease of concern and also for the other conditions. In summary, the current mainstay treatments for ED comprise of oral PDE5Is, VEDs, penile ICI or intraurethral suppositories, and vascular surgery or penile prosthesis. In spite of the available progress and advancement in drug development, the sustainable ideal ED treatment is still far lagging behind.
In the near future, we will witness more progress in the field of ED treatment with the immerging of molecules with better safety profiles as well as long-term efficacy. With the appearance of new ED pharmacotherapies more concerns regarding their adverse events, efficacy, tolerability, and of course their cost will continue to be an important consideration in this context. In this review, we have emphasized the issues that should be considered in the planning of pharmacotherapy of ED such as, patients and partner expectations, etiologic considerations, performance status, safety, adverse effects, ease of administration, compliance, a bad experience with previous treatment, availability, cost, satisfaction, regimen considerations, and finally social factors.
Ahmed M. Bakr, Amro A. El-Sakka & Ahmed I. El-Sakka
Abstract:
Introduction: The effectiveness of phosphodiesterase type 5 inhibitors (PDE5i) in treating erectile dysfunction (ED) creates a new field of both medical practice and pharmaceutical manufacturing. Both paved the way for emerging minimally invasive therapies to restore male sexual function. However, what is the best drug to achieve the optimum outcome is still a challenging question to be answered.
Areas covered: The general viewpoint of matching the pharmacotherapeutic characteristics with the patient’s medical, social, and psychological variables, in order to balance between efficacy and safety. Several studies had investigated considerations for preference and long-term adherence for PDE5i. However, a thorough investigation of considerations for prescribing ED pharmacotherapy is still lacking in the literature. This is the aim of this manuscript.
Expert opinion: Several issues should be considered in the planning of ED management such as the patient’s and partner’s expectations, etiologic considerations, performance status, safety, adverse effects, ease of administration, compliance, bad experiences with previous treatment, availability, cost, social factors, satisfaction and finally, regimen considerations. Addressing the patient’s and partner’s individual needs help to tailoring treatment in order to minimize compromises and optimize gains.
1. Introduction:
ED is defined as the inability to initiate and/or maintain sufficient penile rigidity to have satisfactory sexual intercourse [1]. Though it can be secondary to other medical phenomena associated with other systemic diseases or a part of multi-organ dysfunctions [2], it can also be a primary complaint and reflect non-medical issues related to the social and psychological life of the patient [3, 4]
Since ED affects the personal, psychological and social aspects of life including self-image and relationship with the partner, therefore it is considered an important representative of the quality of life (QoL) [5, 6].
The most common organic causes of ED are vascular impairment and endothelial dysfunction that may result in the failure of vasodilation, which would cause blood to enter the corpus cavernosum and restrict venous output giving the penis rigidity [7, 8]. The first-line treatment of ED includes oral pharmacotherapy, vacuum device (VED), and topical or intra-urethral preparations. The second-line treatment is intra-cavernosal injections (ICI). A penile prosthesis is the third-line treatment and is characterized by irreversibility. The approach to be taken for the management of non-responding cases is to consider a plan of graduated interventions prioritized on the basis of patient’s characteristics and continuous re-assessment and participation in decision-making [9, 10]. The Selection of a suitable line of treatment needs an integrated approach of thinking that should be kept in parallel with the dynamic process of diagnosis, treatment, and monitoring of ED patients.
Preference and long-term adherence for oral PDE5i have been investigated in several studies using a longitudinal approach and discussed certain molecules and their features [5, 11-15]. In daily practice, it is of utmost importance to know how to select a particular drug across the whole range of available pharmacologic treatment. In the current article, we have addressed the basic rules of designing a therapeutic plan for ED patients. Furthermore, we have discussed the factors and considerations that affect this therapeutic plan.
2. What should be considered when treating ED? (Table 1, Figure: 1)
2.1. Physician versus Patient and Partner Prospect (Table 1, Figure: 2)
2.2. Performance:
2.2.1. Biological Efficacy:
2.2.2. Social Circumstances:
2.3. Therapeutic Regimen:
2.4. Compliance:
2.5. Previous Bad Experience:
2.6. Adverse effects:
3. Etiologic considerations
3.1. Curable causes of ED: the ED caused by testosterone deficiency, arterial injury, or psychological disorder can be managed with the intent of cure
3.1.1. Testosterone Deficiency (TD):
3.1.2. Arteriogenic ED:
3.1.3. Psycho-sexual issues
3.2. Non-curable causes of ED:
Microvascular and endothelial dysfunction associated with atherosclerosis plays an important role in the pathogenesis of non-curable ED [8]. Since the cure is not available, the pathogenic process that leads to ED is still in the action. The control of the associated molecular derangement and medical co-morbidities improves the outcomes of medical treatment in the short and long term [8]. Patients under chronic medications are liable for serious interaction with ED treatment [65]. The same occurs if the PDE5i levels are reduced by either hindering absorption or enhanced metabolism so that the false impression of non-response leads to escalating the dose, changing medication, or shifting to surgical management [65]. Accordingly, the atherosclerotic changes that start in a systematic manner all over the arterial system will progress at a similar pace and so occlude smaller arteries before larger ones [66]. With the contiguous exposure of harmful risk factors like obesity, smoking, and unhealthy diet, the ED can be an early sign of coronary artery disease [42].
4. When the PDE5i should be considered as the first line of management? (Figure 3) (Dynamic interactive approach)
4.1. How could the ED be treated dynamically and interactively?
4.2. What should be considered while approaching ED patients? (Figure 3)
4.2.1. Patient’s preference:
4.2.2. Invasiveness:
4.2.3. Ease of administration:
4.2.4. Re-assessment:
4.2.5. Reversibility:
4.2.6. Availability:
4.2.7. Cost affects compliance:
4.3. Why are PDE5is most commonly used as a first-line?
4.4. What kind of PDE5is should be started with?
4.5. When to bypass this approach?
4.6. What are the other lines and combination therapy?
4.6.1. Herbal supplementation
5. Regimen considerations:
5.1. Considering the interval between pill intake and sexual act:
5.2. Dose adjustment with food:
5.3. Considerations regarding the duration of action:
5.3.1. The importance of duration:
5.3.2. What is the duration of action of each drug?
Sildenafil and vardenafil have a half-life of about 4 hours duration. Sildenafil and vardenafil have an effective window of 6 – 8 hours [102]. Tadalafil has an effective window of 36 hours, as its half-life is as long as 17 hours. Avanafil has a half-life of 5 – 10 hours [93, 94, 95], and has a similar window as sildenafil [102]. The consideration in this context is mainly to educate the patient about the timing profile of each drug so that he can adjust his social and relationship contexts accordingly.
5.4. Dose-response relationship:
5.5. Daily dose vs on-demand dose:
5.5.1. Rationale:
5.5.2. Advantage:
5.5.3. The biologic evidence of advantage: Tadalafil is the first PDE5i molecule approved for daily dosing. Tadalafil has a dose-dependent effect, in which the erectogenic effect increases with the increase in oral dose and plasma levels. The long-term effects of Tadalafil on the erectile tissue persist even after the cessation of the therapeutic regimen [94].
The long-term advantages of Tadalafil are related to its biologic effects on vascular and cavernosal functions. It has been shown that the chronic use of PDE5i reduces the vascular stress caused by endothelial injury associated with aging and diabetes as proved by Sildenafil [108] and Tadalafil [109]. Tadalafil also causes remodeling of the vascular bed. These changes have positive effects on the erectile function that persists after the stoppage of the daily dose [93, 94, 95].
5.5.4. The clinical evidence of advantage:
5.6. Generic vs brand products:
6. Considering comorbidities
6.1. Why should comorbidities be considered?
6.2. What is the importance of cardiovascular disease considerations? [2]
6.2.1. The intimate relationship:
6.2.2. The predictive value of ED:
6.2.3. Recommendations for screening and treatment:
6.2.4. Safety of PDE5i in heart diseases:
7. Follow-up Considerations
7.1. Monitoring (physician prospect)
7.1.1. Patient education:
7.1.2. Indices of success/failure:
7.1.3. Adverse effects:
7.1.3.1. Why should the adverse effects be considered?
7.1.3.2. What adverse effects should be followed?
7.2. Tolerability (patient prospect):
8. Social considerations:
8.1. Partner issues:
8.2. The pattern of sexual life:
8.3. Cultural issues:
9. Conclusion
Although several studies had investigated some considerations for preference and long-term adherence for oral treatment as PDE5i, however; thorough addressing of considerations for prescribing pharmacotherapy for ED treatment are still lacking in the literature. This prompted us to address the considerations for prescribing pharmacotherapy for the treatment of ED. Several issues had been addressed in the current review paper such as patient and partner expectations, etiologic considerations, performance status, safety, adverse effects, ease of administration, compliance, a bad experience with previous treatment, availability, cost, satisfaction, regimen considerations, and finally social factors.
10. Expert Opinion
Over the past 50 years, the treatment of ED has quickly promoted and endures to vary with new types of treatment. Intracavernosal therapy was emerged in the eighties of the last century and followed by intraurethral therapy. The actual advancement in the non-surgical ED treatment was with the institution of oral PDE5i in 1998 which rapidly became the primary monotherapy. Nowadays, four PDE5i are existing in the market, i.e., sildenafil, vardenafil, tadalafil, and avanafil. New PDE5Is, including udenafil, and mirodenafil are presently available in several countries, and other molecules are in process.
One effective model of thinking regarding ED problems is to consider patients with ED as having a complex medical and non-medical condition that should be targeted in assessment and modification of risk factors to properly manage ED. For example; a triad of ED, cardiovascular disease, and depression has shown in multiple investigative efforts, a significant correlation and association in both directions of occurrence and recovery. Currently, several forms for ED pharmacotherapy are accessible. With the determination of the factors that should be considered in the planning of pharmacotherapy, sexual function can be successful in most patients. Physicians should offer their patients a safe and effective drug for the disease of concern and also for the other conditions. In summary, the current mainstay treatments for ED comprise of oral PDE5Is, VEDs, penile ICI or intraurethral suppositories, and vascular surgery or penile prosthesis. In spite of the available progress and advancement in drug development, the sustainable ideal ED treatment is still far lagging behind.
In the near future, we will witness more progress in the field of ED treatment with the immerging of molecules with better safety profiles as well as long-term efficacy. With the appearance of new ED pharmacotherapies more concerns regarding their adverse events, efficacy, tolerability, and of course their cost will continue to be an important consideration in this context. In this review, we have emphasized the issues that should be considered in the planning of pharmacotherapy of ED such as, patients and partner expectations, etiologic considerations, performance status, safety, adverse effects, ease of administration, compliance, a bad experience with previous treatment, availability, cost, satisfaction, regimen considerations, and finally social factors.
