What is the best first‑line medication to prescribe for erectile dysfunction in a man without contraindications such as nitrate use or severe uncontrolled cardiovascular disease?

Best First-Line Medication for Erectile Dysfunction

Prescribe a PDE5 inhibitor—specifically tadalafil, sildenafil, or vardenafil—as first-line therapy for erectile dysfunction, with tadalafil offering the advantage of a 36-hour window for spontaneous sexual activity. 1

Why PDE5 Inhibitors Are First-Line

• All three FDA-approved PDE5 inhibitors (sildenafil, tadalafil, vardenafil) demonstrate equivalent efficacy with approximately 69% of men reporting successful intercourse attempts compared to 35% with placebo. 1

• These medications are well-tolerated with mild to moderate adverse events including headache, flushing, nasal congestion, dyspepsia, back pain, and myalgia, with serious adverse events occurring in less than 2% of patients. 1, 2

Choosing Between PDE5 Inhibitors

Select based on pharmacokinetic differences and patient lifestyle preferences rather than efficacy, since all three work equally well. 1

Tadalafil Advantages:

• Significantly longer half-life (17.5 hours) providing a 36-hour window of opportunity, making it ideal for men who prefer spontaneity over scheduled sexual activity. 1, 2

• Lower rates of flushing compared to other PDE5 inhibitors, which is one of the most bothersome side effects. 1, 3

• Can be dosed daily (2.5-5 mg once daily) to eliminate the need to time medication with sexual activity entirely. 3

• FDA-approved to treat both erectile dysfunction and benign prostatic hyperplasia simultaneously when dosed at 5 mg daily. 3

Sildenafil Advantages:

• Preferred when the patient wants scheduled sexual activity with a more predictable 4-hour window of action. 3

• Shorter waiting time (24 hours vs 48 hours for tadalafil) if emergency nitrate administration becomes necessary. 3, 2

• Demonstrates dose-response relationship with 50 mg being more effective than 25 mg. 3

Critical Pre-Prescription Safety Screening

Never prescribe PDE5 inhibitors to patients taking nitrates in any form—this combination causes potentially fatal hypotension. 1, 3, 2

Cardiovascular Risk Stratification Required:

• Ask if the patient can walk 1 mile in 20 minutes or climb 2 flights of stairs without symptoms—if unable, refer to cardiology before prescribing. 3, 2

• High-risk patients who should defer treatment include those with 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, and moderate-to-severe valvular disease. 1

• Low-risk patients safe to treat include those with asymptomatic coronary artery disease with <3 risk factors, controlled hypertension, mild stable angina, successful coronary revascularization, uncomplicated past MI, mild valvular disease, and CHF (NYHA class I). 3

Practical Dosing Strategy

For Tadalafil:

• Start with 10 mg as needed, can increase to 20 mg. 1, 2

• Note that tadalafil does NOT show dose-dependent improvement between 5 mg, 10 mg, and 20 mg—choice between doses should be based primarily on tolerability rather than expecting dramatically better efficacy at higher doses. 3

• For daily dosing, start with 2.5-5 mg once daily. 3

For Sildenafil:

• Start with 50 mg as needed, can adjust to 25 mg or 100 mg based on response and tolerability. 3

Critical Dosing Principle:

An adequate trial requires at least 5 separate attempts at the maximum tolerated dose before declaring treatment failure. 1, 3, 2

Common Pitfalls Leading to Apparent Treatment Failure

Many perceived failures are actually due to modifiable factors rather than true medication inefficacy. 1, 2

Before declaring failure, systematically evaluate:

• Lack of adequate sexual stimulation—PDE5 inhibitors require sexual arousal to work. 1, 3

• Improper timing—taking medication with large or fatty meals can reduce efficacy. 3

• Heavy alcohol use—impairs erectile function independent of medication. 1, 3

• Hormonal abnormalities—measure testosterone levels when patients present with decreased libido, premature ejaculation, fatigue, testicular atrophy, or muscle atrophy. 1

• Relationship issues with partner—psychological factors significantly impact response. 1, 3

• Drug interactions—identify medications that worsen ED such as antihypertensives, antidepressants, opioids. 3

Special Population Considerations

• Men with diabetes and post-prostatectomy patients have more severe ED at baseline and respond less robustly to PDE5 inhibitors, though they remain effective. 1, 3

• For men with testosterone deficiency (morning total testosterone <300 ng/dL), combining a PDE5 inhibitor with testosterone therapy may be more effective than PDE5 inhibitor alone. 3, 2

• Testosterone therapy alone is not effective monotherapy for ED. 3

Lifestyle Modifications to Prescribe Alongside Medication

Counsel all ED patients on risk factor modification regardless of pharmacologic treatment. 1

• Recommend smoking cessation, weight loss if overweight, increasing physical activity, avoiding excess alcohol consumption, and optimal management of diabetes, hypertension, and dyslipidemia. 1, 2

When to Escalate to Second-Line Therapies

Proceed to second-line therapies only after failure of at least two different PDE5 inhibitors at maximum dose with proper technique, and after addressing all modifiable factors. 3

• Second-line options include vacuum erection devices, intraurethral alprostadil suppositories, intracavernosal injection therapy, and penile prosthesis implantation. 1, 3

Emergency Nitrate Protocol

If a patient on PDE5 inhibitors requires emergency nitrate administration:

• Wait 24 hours after sildenafil or vardenafil before giving nitrates. 3, 2

• Wait 48 hours after tadalafil before giving nitrates. 3, 2

• Administer under close medical supervision with continuous patient monitoring. 3

Absolute Contraindication

• Co-administration of riociguat (a soluble guanylate cyclase stimulator) with tadalafil is contraindicated because it can cause severe hypotension. 3