Treatment of Erectile Dysfunction with PDE5 Inhibitors and Apomorphine
First-Line Therapy: PDE5 Inhibitors Are Superior
Oral PDE5 inhibitors (sildenafil/Viagra, tadalafil/Cialis, vardenafil) are the recommended first-line treatment for erectile dysfunction, and sildenafil is more effective than apomorphine for improving erectile function, frequency of penile penetration, and successful intercourse attempts. 1, 2
Why PDE5 Inhibitors Over Apomorphine
Sildenafil demonstrates superior efficacy compared to sublingual apomorphine in head-to-head studies, showing better improvements in erectile function, frequency of penile penetration or erection maintenance, and percentage of successful intercourse attempts. 1
Apomorphine has a narrow therapeutic margin—approximately 90% of patients find the 2 mg dose insufficient, and the 3 mg dose is only marginally more effective, with nearly 90% preferring at least 4 mg. 3
Apomorphine's side effect profile includes dose-dependent nausea, dizziness, severe sweating, drowsiness, syncope, and hypotension, with serious consequences reported during clinical trials. 3
There is no evidence of significant differences in efficacy between PDE5 inhibitors and apomorphine, but the practical clinical experience and safety profile favor PDE5 inhibitors. 4
PDE5 Inhibitor Efficacy: All Three Work Equally Well
High-quality evidence shows that all three PDE5 inhibitors have similar efficacy in the general ED population, with success rates of approximately 69% for successful sexual intercourse versus 35% for placebo. 1, 2
Sildenafil: 69% successful intercourse attempts (range 52-85%) versus 35.5% placebo. 1
Tadalafil: 69% successful intercourse attempts (range 50-85%) versus 33% placebo. 1, 5
Vardenafil: 68% successful intercourse attempts (range 50-88%) versus 35% placebo. 1
All three agents improve erections in 73-88% of patients compared to 26-32% with placebo. 1
Choosing Between PDE5 Inhibitors: Pharmacokinetics Matter
The choice between PDE5 inhibitors should be based on pharmacokinetic differences and patient lifestyle preferences rather than efficacy, since all three work equally well. 2, 6, 7
Tadalafil (Cialis) Advantages:
Significantly longer half-life of 17.5 hours providing a 36-hour window of opportunity, ideal for men who prefer spontaneity over scheduled sexual activity. 2, 8, 7
Lower rates of flushing compared to other PDE5 inhibitors. 2, 8, 9
Not affected by food intake, including fatty meals, unlike sildenafil and vardenafil. 7
Can be dosed daily (2.5-5 mg once daily) to eliminate the need to time medication with sexual activity. 8, 9
Sildenafil (Viagra) and Vardenafil Characteristics:
Both have similar molecular structures and half-lives of approximately 4 hours. 7
Faster onset: 35% of sildenafil patients achieve successful intercourse within 14 minutes, and 21% of vardenafil patients within 10 minutes, compared to 16% for tadalafil within 16 minutes. 7
Food, especially fatty food, affects absorption and should be avoided. 7
Dosing Strategy: Optimize Before Declaring Failure
Start with standard dosing and titrate to maximum tolerated dose before declaring treatment failure. 2
Tadalafil: Begin at 10 mg as needed, can increase to 20 mg. 2, 5
An adequate trial requires at least 5 separate occasions at the maximum dose before considering the medication ineffective. 2, 8
Important: Tadalafil does NOT show dose-dependent improvement between 5 mg, 10 mg, and 20 mg, unlike sildenafil and vardenafil where higher doses provide greater efficacy. 1, 9
Many perceived failures are due to modifiable factors: lack of adequate sexual stimulation, incorrect timing, undiagnosed hormonal abnormalities, or inadequate trials. 2, 8
Critical Safety: Absolute Contraindications
Never prescribe PDE5 inhibitors to patients taking nitrates—this combination causes potentially fatal hypotension. 2, 8, 5
Wait at least 24 hours after sildenafil or vardenafil before administering nitrates. 8
Wait at least 48 hours after tadalafil before administering nitrates due to its longer half-life. 8, 9
Also contraindicated with guanylate cyclase stimulators (riociguat). 5
Recreational drugs ("poppers") containing amyl nitrite or butyl nitrite are also contraindicated. 5
Both apomorphine and PDE5 inhibitors interact with nitrates, increasing hypotension risk. 3
Cardiovascular Risk Stratification Required
Assess cardiovascular risk before initiating ED treatment using the Princeton Consensus Panel criteria. 2
High-risk patients (defer treatment until stabilized) include those with: 2
- Unstable or refractory angina
- Uncontrolled hypertension
- Left ventricular dysfunction/CHF (NYHA class II or greater)
- MI or stroke within previous 2 weeks
- High-risk arrhythmias
- Hypertrophic obstructive cardiomyopathies
- Moderate-to-severe valvular disease
Patients who cannot walk 1 mile in 20 minutes or climb 2 flights of stairs in 20 seconds without symptoms require cardiology referral before treatment. 8
Common Side Effects: Generally Well-Tolerated
Common side effects include headache, flushing, nasal congestion, dyspepsia, back pain, myalgia, and visual disturbances. 1, 8, 9
Serious adverse events occur in less than 2% of patients, with no significant difference between medications and placebo. 8
Stop sexual activity immediately and seek medical help if chest pain, dizziness, or nausea occurs during sex. 5
Special Populations: Reduced Response Expected
Men with diabetes have more severe ED at baseline and respond less robustly to PDE5 inhibitors, though they still benefit. 2, 9
Post-prostatectomy patients show reduced response compared to the general population. 2, 9
Men with spinal cord injury require lower initial doses due to potential delayed metabolism. 2
Hormonal Testing: Not Routine, But Targeted
Do not routinely measure testosterone in all ED patients—individualize based on clinical presentation. 2
Measure testosterone when patients present with decreased libido, premature ejaculation, fatigue, testicular atrophy, or muscle atrophy. 2
For men with testosterone deficiency (morning total testosterone <300 ng/dL) and ED, combining PDE5 inhibitors with testosterone therapy may be more effective than PDE5 inhibitors alone. 8, 9
Testosterone therapy alone is not effective monotherapy for ED. 9
Renal and Hepatic Impairment Adjustments
For creatinine clearance <30 mL/min: Tadalafil for once daily use is not recommended. 5
For creatinine clearance 30-50 mL/min: Start tadalafil at 2.5 mg once daily, increase to 5 mg based on response. 5
For mild or moderate hepatic impairment: Tadalafil should not exceed 10 mg for as-needed dosing. 5
Severe hepatic impairment: Use of PDE5 inhibitors is generally not recommended. 9, 5
Drug Interactions: CYP3A4 Inhibitors
Tadalafil is metabolized predominantly by CYP3A4. 5
With potent CYP3A4 inhibitors (ritonavir, ketoconazole, itraconazole): Limit tadalafil to 10 mg no more than once every 72 hours for as-needed dosing, or maximum 2.5 mg for daily dosing. 5, 10
Precaution with azole antifungals, antiretroviral protease inhibitors, and macrolide antibiotics. 10
Lifestyle Modifications: Always Counsel
Counsel all ED patients on risk factor modification regardless of pharmacologic treatment. 2
Recommend smoking cessation, weight loss if overweight, increasing physical activity, avoiding excess alcohol consumption (>5 units with tadalafil increases orthostatic symptoms), and optimal management of diabetes, hypertension, and dyslipidemia. 2, 5
Second-Line Therapies if PDE5 Inhibitors Fail
If PDE5 inhibitors fail after adequate trial, proceed to intraurethral alprostadil suppositories, intracavernosal vasoactive drug injection, or vacuum constriction devices. 2
Intracavernosal alprostadil is more effective than intraurethral alprostadil. 4
Bottom Line on Apomorphine
Sildenafil remains the first-line treatment for men with erectile dysfunction over apomorphine due to superior efficacy and a more favorable risk-benefit profile. 3