Editing Evaluation and Management of Erectile Dysfunction (section)

=== Oral medication ===

* '''Phosphodiesterase type 5 inhibitors (PDE5i)'''
** Facilitate a penile erection by promoting vascular and cavernosal smooth muscle relaxation in response to sexual stimulation
** '''FDA-approved oral PDE5i available for management of ED (4):'''
**# '''Sildenafil'''
**# '''Tadalafil'''
**# '''Vardenafil'''
**# '''Avanafil'''
*** '''All have similar efficacy and tolerability, though limited data available on avanafil'''
**** Mean change in IIEF-EF scores is similar across drugs (≈7 points, slightly higher with tadalafil§)
*** '''Only tadalafil is currently FDA-approved for daily dosing'''
**** On-demand dosing versus daily dosing for tadalafil appears to produce the same level of efficacy
**** Potential advantages of daily dosing§
***** Increases sexual spontaneity
***** Improves sexual self-confidence
***** Less concern regarding timing of medication
***** Female partners preferred daily dosing compared to on-demand regimens.
***** In patients experiencing co-morbid lower urinary tract symptoms, daily tadalafil (5 mg) is an approved treatment option and has been shown to decrease symptom scores significantly more than on-demand dosing
***** May be more cost-effective than on-demand dosing, depending on the dosing and frequency of use
**** '''2021 CUA Guidelines conditionally recommend against preferentially prescribing daily tadalafil for patients presenting with erectile dysfunction.'''
***** No meaningful difference in side effects or discontinuation rates between either dosing regimen
*** In general, '''these agents effectively result in successful sexual intercourse rates of ≈70%.''' There is no sustained erectile function improvement after discontinuing PDE5i
** '''Mechanism of action'''
*** '''Inhibits the phosphodiesterase type 5 enzyme from breaking down cyclic guanasine monophosphate (cGMP) to 5’GMP'''
**** '''This results in increased concentration of penile cavernosal cGMP that then causes smooth muscle relaxation in the corpus cavernosum vasculature.'''
***** '''Smooth muscle relaxation results in increased erection hardness and duration in men with ED who have sufficient intact vasculature'''
*** '''Augments but does not induce the erectile response'''
**** '''Initiation of erection requires the release of nitric oxide from penile nerve endings and vascular endothelium under the influence of sexual stimulation'''
** '''Contraindications:'''
*** '''Absolute (2):'''
***# '''Concomitant use of nitrate-containing medications''' (e.g., sublingual nitroglycerin, isosorbide dinitrate, other nitrate preparations used to treat angina, amyl nitrite, and amyl nitrate “poppers”); '''combination with a PDE5i can cause a precipitous drop in blood pressure'''
***#* If angina occurs during sex when using a PDE5i, patients should stop having sex and seek emergency care immediately. They should inform medical personnel that a PDE5i was taken and should '''avoid nitroglycerin use for a period of 24 hours for sildenafil and vardenafil and 48 hours for tadalafil'''
***#* '''No pharmacologic antidote to the PDE5i/nitrate interaction exists'''
***# '''Known hypersensitivity to any component of the tablet'''
*** '''Relative (5):'''
***# '''Severe renal or liver disease; in men with mild to moderate hepatic or renal impairment or men with spinal cord injury, dose adjustment should be considered given the potential for delayed metabolism'''
***#* '''CUA guidelines do not include severe renal or liver disease as contraindication, but do suggest dose adjustment'''
***# '''Severe cardiac disease'''
***#* Controlled and post-marketing studies have shown that PDE5i do not cause an increase in myocardial infarction or death rates when compared with expected rates in study control populations.
***#* '''Caution is advised for the use of PDE5i in patients with certain conditions: aortic stenosis, left ventricular outflow obstruction, hypotension, and hypovolemia.'''
***#* '''FDA recommends against use in patients with MI in last 6 months'''
***# '''Concomitant use of non-selective alpha blockers'''
***#* '''Caution is advised when PDE5i are co-administered with α-adrenergic blockers, because both agents are vasodilators with blood pressure lowering effects.'''
***#* '''There is a potential risk of significant hypotension when using non-selective alpha blockers (terazosin, alfuzosin, doxazosin)'''
***#* '''Concomitant use of selective alpha blockers (silodosin, tamsulosin) does not present a risk for significant hypotension.'''
***# '''Concomitant use of anti-arrhythmics'''
***#* '''Vardenafil is not recommended in (2):'''
***#** '''Patients who take''' type 1A '''(e.g., quinidine or procainamide)''' or type 3 '''(e.g., sotalol or amiodarone) anti-arrhythmics'''
***#** '''Congenital prolonged QT syndrome'''
***# '''Known hereditary degenerative retinal disorders'''
***** '''FDA recommends against use in patients with known hereditary degenerative retinal disorders, such as retinitis pigmentosa'''
** '''Metabolism'''
*** '''Metabolized by the cytochrome P450 3A4 enzyme'''
**** '''Dose increase required with concomitant use of''' '''(inducers of this enzyme):'''
***** '''Rifampin'''
**** '''Dose reduction required with concomitant use of''' '''(inhibitors of this enzyme):'''
****# '''Ketoconazole, itraconazole, fluconazole'''
****# '''Ritonavir, indinavir'''
****# '''Cimetidine'''
****# '''Macrolide antibiotics (e.g. erythromycin)'''
*** '''Dose adjustment''' (2021 CUA Guidelines)
**** '''May be needed if (3):'''
****# '''Age >65'''
****# '''Hepatic impairment'''
****# '''Renal impairment (creatinine clearance <30 mL/min)'''
** '''Adverse events'''
*** Most AEs associated with the administration of PDE5i are mild to moderate and improve over time
**** Out of 1000 patients taking the drug on average 8 will experience a serious adverse event with sildenafil, 7 with tadalafil and 8 with vardenafil§
*** Side effects prompt discontinuation only in a few patients
**** '''The most common reason for discontinuation of PDE5i is lack of treatment efficacy (e.g., hardness of erection)'''
*** Most AEs follow a dose-response pattern
**** '''Generally, daily dosing associated with lower rates of AEs'''
*** '''The most frequently reported AEs (occurring in ≥2% of patients): HARD DICK F***S MY NIGHT DAMN VISION'''
***# '''Headache''' (7-16%)
***# '''Dyspepsia''' (4-10%)
***# '''Flushing''' (4-10%)
***# '''Myalgia/back pain''' (0-3%)
***# '''Dizziness'''
***# '''Nasal congestion''' (3-4%)
***# '''Visual disturbances (e.g., photophobia, blue vision)''' (0-3%)
**** '''Sildenafil and vardenafil associated with higher rates of visual disturbance'''
***** '''Sildenafil and vardenafil cross-react to a greater extent with PDE type 6''', '''which is expressed in the retina''', than tadalafil and avanafil.
**** '''Tadalafil associated with higher rates of back pain and myalgia'''
**** '''Vardenafil associated with higher rates of nasal congestion'''
*** '''Non-arteritic Anterior Ischemic Optic Neuropathy (NAION)'''
**** '''A rare visual condition characterized by the sudden onset of loss of vision in one eye'''
***** Several studies have suggested that PDE5i use is associated with an increased risk of NAION, although the absolute risk is small (3 additional cases per 100,000 men age ≥ 50).
**** '''Men in higher-risk groups (e.g., older males, males of Caucasian ethnicity, males with vascular risk factors) should be counseled about this small increased risk, including the fact that the absolute risk of NAION is extremely low with or without the use of PDE5i,''' and that the association does not imply causation.
**** Patients should be advised to stop use of PDE5i and to seek immediate medical attention as a safety measure in the event of a sudden loss of vision
*** No increased risk of skin cancers or prostate cancer recurrence after prostate cancer treatment
** '''Instructions regarding onset and duration of action and effect of food intake should be provided to maximize benefit/efficacy.'''
*** Studies of men who report non-response to PDE5i indicate that incorrect use (e.g., lack of sexual stimulation, medication taken with a large meal) accounts for 56-81% of treatment failures
*** '''Patients with an unsatisfactory response to PDE5is should first be counselled regarding proper use of the medication and may require a potential dose adjustment'''
** '''Characteristics of PDE5is'''

{| class="wikitable"
|'''PDE5i'''
|'''Onset of action'''
|'''Duration of action (T1/2)'''
|'''Available doses (maximum)'''
|'''Effect of food intake'''
|-
|'''Sildenafil'''
|'''30-60 min'''
|'''Up to 12 hours'''

'''(4 hours)'''
|25 mg, 50 mg, 100 mg PRN

(100mg daily)
|'''High-fat meal decreases efficacy'''
|-
|'''Vardenafil'''
|'''30-60 min'''
|'''Up to 10 hours'''

'''(4 hours)'''
|10 mg oral dissolvable tablet

2.5 mg, 5 mg, 10 mg, 20 mg PRN (20mg daily)
|'''High-fat meal decreases efficacy'''
|-
|'''Tadalafil'''
|'''60-120 min'''
|'''Up to 36 hours'''

'''(17.5 hours)'''
|2.5 mg, 5 mg daily

5 mg, 10 mg, 20 mg PRN

(20mg daily)
|'''Not affected'''
|-
|'''Avanafil'''
|'''15-30 min'''
|'''Up to 6 hours'''

'''(5 hours)'''
| 
|'''Not affected'''
|}
Advantage of sildenafil and vardenafil over tadalafil: faster onset

Advantages of tadalafil over sildenafil and vardenafil: longer duration of action and not affected by meals

* '''The dose should be titrated to provide optimal efficacy'''
** '''Given that men with diabetes or post-prostatectomy often present with more severe levels of ED, consider initiating therapy at a higher dose.'''
** '''Dose-response effects across PDE5i medications are small and non-linear''' (i.e., doubling the dose does not double the effect)
** As part of the process of identifying the optimal dose, males may be offered dosing frequency changes or different PDE5i.
* Few studies focused on '''special populations (diabetes, metabolic syndrome, post-prostatectomy, etc.),''' but in general, '''findings are similar to those reported in the general ED population'''. For example, '''for males with diabetes, sildenafil, tadalafil, and vardenafil appear equally effective''' with limited data reported for avanafil.