What are the treatment options for a patient with erectile dysfunction (ED), considering their medical history and potential interactions with other medications, such as nitrates and alpha-blockers?

Erectile Dysfunction Treatment Options

First-Line Therapy: PDE5 Inhibitors

Oral phosphodiesterase type 5 (PDE5) inhibitors should be offered as first-line therapy for erectile dysfunction unless contraindicated 1.

Available PDE5 Inhibitors

Four PDE5 inhibitors are available with similar efficacy profiles 1, 2:

• Sildenafil (25 mg, 50 mg, 100 mg)
• Tadalafil (5 mg, 10 mg, 20 mg for on-demand use; 2.5 mg, 5 mg for daily use)
• Vardenafil (5 mg, 10 mg, 20 mg)
• Avanafil (50 mg, 100 mg, 200 mg)

Choosing Between PDE5 Inhibitors

For patients prioritizing maximum efficacy, sildenafil 50 mg is the treatment of choice 3. For those prioritizing tolerability, tadalafil 10 mg offers the lowest overall adverse event rate with intermediate efficacy 3.

Key pharmacokinetic differences that guide selection:

• Onset of action: Avanafil works fastest (64-71% successful intercourse within 15 minutes), followed by vardenafil (21% within 10 minutes), sildenafil (35% within 14 minutes), and tadalafil (16% within 16 minutes) 2, 4
• Duration of action: Tadalafil has a 17.5-hour half-life enabling a 36-hour window of opportunity, while sildenafil and vardenafil have ~4-hour half-lives 4
• Food interactions: Fatty meals reduce absorption of sildenafil and vardenafil but not tadalafil or avanafil 5, 4

Dosing Strategies

Starting doses:

• Sildenafil: 50 mg taken 1 hour before sexual activity 6
• Tadalafil: 10 mg on-demand OR 5 mg daily 5
• Vardenafil: 10 mg taken 1 hour before sexual activity 1
• Avanafil: 100 mg taken 15-30 minutes before sexual activity 2

Before declaring treatment failure, patients must complete at least 5 separate attempts at maximum dose 6. Dose titration balances efficacy against adverse effects, with higher doses increasing both response rates and side effects 6.

Common Adverse Effects

• Headache, flushing, nasal congestion, and nasopharyngitis occur with all PDE5 inhibitors 2
• Avanafil has the lowest dyspepsia rates among all PDE5 inhibitors 2
• Tadalafil and avanafil have lower myalgia rates compared to sildenafil and vardenafil 2
• Serious adverse events occur in <2% of patients, similar to placebo 6

Critical Contraindications and Drug Interactions

Absolute Contraindications

PDE5 inhibitors are absolutely contraindicated with any nitrate use due to life-threatening hypotension risk 5.

Required waiting periods after PDE5 inhibitor use before nitrate administration in emergencies:

• Sildenafil: 24 hours 1
• Tadalafil: 48 hours 5
• Vardenafil: 24 hours 1

PDE5 inhibitors are also contraindicated with guanylate cyclase stimulators (e.g., riociguat) 5.

Alpha-Blocker Interactions

For erectile dysfunction patients on alpha-blockers: stabilize alpha-blocker therapy first, then initiate PDE5 inhibitors at the lowest dose 5. However, PDE5 inhibitors should not be combined with alpha-blockers for benign prostatic hyperplasia treatment 5.

CYP3A4 Inhibitor Interactions

When co-administering with potent CYP3A4 inhibitors (ketoconazole, ritonavir, erythromycin):

• Sildenafil: reduce to 25 mg 6
• Tadalafil on-demand: maximum 10 mg every 72 hours 5
• Tadalafil daily: maximum 2.5 mg 5

Cardiovascular Risk Stratification

Before prescribing any PDE5 inhibitor, assess cardiovascular fitness for sexual activity 6, 5. Sexual activity equals walking 1 mile in 20 minutes or climbing 2 flights of stairs in 20 seconds 2.

Low-Risk Patients (Safe for PDE5 Inhibitors)

• Asymptomatic coronary artery disease with <3 risk factors 6
• Controlled hypertension 6
• Mild stable angina 6
• Successful coronary revascularization 6
• Uncomplicated past MI (>6 weeks) 6
• NYHA Class I heart failure 6

Intermediate-Risk Patients (Require Cardiology Evaluation First)

• ≥3 cardiac risk factors 6
• Moderate stable angina 6
• Recent MI (2-6 weeks) 6, 5
• NYHA Class II heart failure 6, 5

High-Risk Patients (Defer Treatment Until Stabilized)

• Unstable or refractory angina 6, 5
• NYHA Class III-IV heart failure 6, 5
• Very recent MI or stroke (<2 weeks) 6, 5
• High-risk arrhythmias 6
• Hypertrophic obstructive cardiomyopathy 6

Dose Adjustments for Organ Dysfunction

Renal Impairment

For on-demand dosing:

• CrCl 30-50 mL/min: Start sildenafil 5 mg, maximum 10 mg every 48 hours 5
• CrCl <30 mL/min or hemodialysis: Maximum sildenafil 5 mg every 72 hours 5

For daily tadalafil:

• CrCl 30-50 mL/min: Start 2.5 mg, may increase to 5 mg 5
• CrCl <30 mL/min or hemodialysis: Not recommended 5

Hepatic Impairment

Mild-moderate hepatic impairment (Child-Pugh A or B):

• Use caution with lower initial doses 2
• Tadalafil maximum 10 mg on-demand 5

Severe hepatic impairment (Child-Pugh C): PDE5 inhibitors are not recommended 6, 5.

Optimizing Treatment Success

Common reasons for apparent PDE5 inhibitor failure that are correctable 1:

• Inadequate sexual stimulation (medication requires arousal to work) 2
• Insufficient dosing or inadequate trial duration 1, 6
• Incorrect timing relative to sexual activity 1
• Food interference (with sildenafil/vardenafil) 4
• Undiagnosed hypogonadism 6
• Heavy alcohol consumption 1
• Unrealistic patient/partner expectations 1

After re-education on proper use and dose optimization, many initial non-responders achieve success 1.

Special Population Considerations

Men with testosterone deficiency respond less robustly to PDE5 inhibitors alone 6. Combining testosterone replacement with PDE5 inhibitors improves efficacy in confirmed hypogonadism 2, 6.

Patients with diabetes and post-prostatectomy have more severe baseline ED and may show less robust responses, but PDE5 inhibitors remain effective 2, 6.

Second-Line Therapies

For patients who fail adequate PDE5 inhibitor trials, second-line options include 1:

• Intracavernosal alprostadil injection (FDA-approved, most effective alternative) 1, 7
• Intraurethral alprostadil suppositories 1
• Vacuum constriction devices 1
• Combination intracavernosal injections (alprostadil, papaverine, phentolamine) 1, 7

Monitoring and Follow-Up

Periodic follow-up should assess 1, 6:

• Treatment efficacy and satisfaction 1
• Adverse effects 1
• Changes in cardiovascular health 1, 6
• New medications that may interact 1
• Overall health status changes 6

Typical follow-up occurs at prescription renewal, ideally between 4 weeks and 6 months 6.

Critical Safety Warnings

Patients must seek emergency care for erections lasting >4 hours to prevent permanent erectile tissue damage 5. PDE5 inhibitors should be used cautiously in patients predisposed to priapism (sickle cell anemia, multiple myeloma, leukemia, penile anatomical deformities) 5.

Patients should stop PDE5 inhibitors immediately and seek medical attention for sudden vision loss, which may indicate non-arteritic anterior ischemic optic neuropathy (NAION) 2, 5. The risk of NAION approximately doubles with PDE5 inhibitor use, and patients with prior NAION are at increased recurrence risk 5.

Patients should stop PDE5 inhibitors and seek prompt medical attention for sudden hearing loss or tinnitus 5.