What are the indications for Phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra)?

PDE5 Inhibitor Indications

PDE5 inhibitors are FDA-approved for two primary indications: erectile dysfunction (ED) as first-line therapy, and pulmonary arterial hypertension (PAH), with sildenafil specifically approved for PAH treatment. 1, 2

FDA-Approved Indications

Erectile Dysfunction (Primary Indication)

• Oral PDE5 inhibitors (sildenafil, tadalafil, vardenafil) are recommended as first-line therapy for erectile dysfunction unless contraindicated. 3
• All three agents demonstrate approximately 69% successful sexual intercourse attempts compared to 33-36% with placebo in the general ED population. 1
• These medications work by inhibiting PDE5 enzyme, increasing cyclic GMP levels, and enhancing nitric oxide-mediated smooth muscle relaxation in penile tissue—but only in the presence of sexual stimulation. 4, 5

Pulmonary Arterial Hypertension

• Sildenafil is FDA-approved and marketed under a different proprietary name (Revatio) specifically for PAH treatment. 6
• This represents a distinct indication from ED, utilizing the same mechanism of PDE5 inhibition to promote pulmonary vasodilation. 2

Dual Indication: BPH and ED

• Tadalafil 5 mg daily is FDA-approved to treat both benign prostatic hyperplasia (BPH) and ED simultaneously. 3
• This represents the only PDE5 inhibitor with formal approval for BPH, eliminating the need for separate medications when both conditions coexist. 3

Special Population Efficacy

Effective in Multiple Medical Conditions

• PDE5 inhibitors remain effective (though with variable response rates) in men with diabetes, depression, cardiovascular disease, post-prostatectomy status, multiple sclerosis, colorectal cancer, schizophrenia, and mild-to-moderate hepatic or renal impairment. 1, 7
• Men with diabetes and post-prostatectomy patients have more severe baseline ED and respond less robustly, but still achieve meaningful benefit—these populations typically require higher doses. 1, 3

Combination Therapy Indication

• For men with both ED and confirmed testosterone deficiency, combining a PDE5 inhibitor with testosterone therapy is more effective than PDE5 inhibitor monotherapy. 3, 8
• Testosterone therapy alone is not effective as monotherapy for ED. 3

Critical Contraindications

Absolute Contraindication

• Concurrent use of nitrates in any form is an absolute contraindication due to risk of dangerous, potentially fatal hypotension. 1, 3, 2
• If emergency nitrate administration is required, wait 24 hours after sildenafil/vardenafil and 48 hours after tadalafil before giving nitrates under close medical supervision. 3

Relative Contraindications and Cautions

• Severe hepatic impairment: PDE5 inhibitors are generally not recommended. 3, 8
• Anatomical penile deformities (angulation, cavernosal fibrosis, Peyronie's disease) or conditions predisposing to priapism (sickle cell anemia, multiple myeloma, leukemia): use with caution. 2
• Patients with bleeding disorders or active peptic ulceration: safety is unknown, particularly for sildenafil in PAH. 2

Cardiovascular Risk Stratification Required

Low-Risk Patients (Safe for PDE5 Inhibitors)

• The majority of ED patients fall into low-risk category and can safely receive PDE5 inhibitors, including those with: 3
  • Asymptomatic coronary artery disease with <3 risk factors
  • Controlled hypertension
  • Mild, stable angina
  • Successful coronary revascularization
  • Uncomplicated past MI
  • Mild valvular disease
  • CHF (NYHA class I)

Mandatory Cardiology Referral

• Patients whose cardiovascular risk is indeterminate or who cannot perform moderate physical activity must be referred to cardiology before prescribing PDE5 inhibitors. 3

Practical Prescribing Considerations

Dosing Principles

• Start with standard recommended doses for general ED population: sildenafil 50 mg, vardenafil 10 mg, or tadalafil 10 mg as-needed. 1
• For diabetes or post-prostatectomy patients, consider starting at the higher end of dosing range due to more severe baseline ED. 1
• Tadalafil uniquely shows no dose-dependent improvement between 5-20 mg, unlike sildenafil and vardenafil where higher doses demonstrate greater efficacy. 3
• For patients preferring spontaneous sexual activity, tadalafil 2.5-5 mg once daily eliminates the need to time medication with sexual activity. 3

Adequate Trial Definition

• An adequate trial consists of at least 5 separate attempts at maximum dose before declaring treatment failure. 3, 8
• Many apparent failures result from inadequate trials, improper timing, lack of sexual stimulation, or modifiable factors. 3

Before Declaring Treatment Failure

• Systematically evaluate: hormonal abnormalities (check testosterone), food or drug interactions, timing and frequency of dosing, adequacy of sexual stimulation, heavy alcohol use, and relationship issues. 3, 8

Common Adverse Effects

• Most frequently reported: dyspepsia, headache, flushing, back pain, nasal congestion, myalgia, visual disturbance, and dizziness. 1, 3
• Serious adverse events occur in <2% of patients with no significant difference from placebo. 8
• Tadalafil has lower rates of flushing compared to other PDE5 inhibitors. 3

Rare but Serious Warnings

Visual Loss (NAION)

• Non-arteritic anterior ischemic optic neuropathy causing permanent vision loss has been reported postmarketing, though causality is uncertain. 2
• Advise patients to seek immediate medical attention for sudden vision loss in one or both eyes. 2
• Risk factors include: low cup-to-disc ratio, age >50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. 2

Hearing Loss

• Sudden decrease or loss of hearing (potentially with tinnitus and dizziness) has been reported in temporal association with PDE5 inhibitor use. 2
• Advise patients to seek prompt medical attention for sudden hearing changes. 2

Priapism

• If erection persists >4 hours, patient should seek immediate medical assistance; priapism >6 hours can cause permanent penile tissue damage and loss of potency. 2