What is Avanafil (phosphodiesterase type 5 inhibitor)?

Avanafil: A Phosphodiesterase Type 5 Inhibitor for Erectile Dysfunction

Avanafil is an FDA-approved phosphodiesterase type 5 (PDE5) inhibitor specifically designed for the treatment of erectile dysfunction in adult males, with a rapid onset of action and favorable selectivity profile compared to other medications in its class. 1

Mechanism of Action

• Avanafil enhances the natural erectile response by inhibiting PDE5, an enzyme that degrades cyclic guanosine monophosphate (cGMP) in the corpus cavernosum 1
• When sexual stimulation occurs, nitric oxide (NO) is released in the corpus cavernosum, activating guanylate cyclase and increasing cGMP levels, which produces smooth muscle relaxation and allows blood flow into the penis 1
• Avanafil does not directly cause erections but enhances the body's natural response to sexual stimulation by preventing the breakdown of cGMP 1

Pharmacological Properties

• Avanafil is chemically designated as (S)-4-[(3-Chloro-4-methoxybenzyl)amino]-2-[2-(hydroxymethyl)-1-pyrrolidinyl]-N-(2-pyrimidinylmethyl)-5-pyrimidinecarboxamide 1
• It is highly selective for PDE5 compared to other phosphodiesterase enzymes:

  • 100-fold more selective for PDE5 than PDE6 (found in the retina)

  • 1,000-fold more selective for PDE5 than PDE4, PDE8, and PDE10

  • 5,000-fold more selective for PDE5 than PDE2 and PDE7

  • 10,000-fold more selective for PDE5 than PDE1, PDE3, PDE9, and PDE11 1

• This high selectivity contributes to its lower incidence of side effects compared to other PDE5 inhibitors 2

Clinical Efficacy

• Avanafil has demonstrated efficacy similar to other PDE5 inhibitors in the general erectile dysfunction population 3
• It is effective in various special populations including men with diabetes and those who have undergone radical prostatectomy, although these groups typically have more severe ED at baseline and may respond less robustly 3
• Avanafil has a rapid onset of action, becoming effective within approximately 15 minutes of dosing, making it suitable for as-needed use shortly before sexual activity 2
• Approximately two-thirds of sexual attempts made within 15 minutes or more than 6 hours after administration were successful, compared to only one-quarter of attempts with placebo 4

Dosage and Administration

• Avanafil is available in 50 mg, 100 mg, and 200 mg oral tablets 1
• Dose should be titrated to provide optimal efficacy while minimizing adverse effects 3
• The 100 mg and 200 mg doses have shown greater efficacy than the 50 mg dose in clinical trials 4, 5
• No dosage adjustments are required based on age, gender, or mild to moderate renal or hepatic impairment 1

Safety Profile

• Most common adverse events include:
  • Headache
  • Flushing
  • Nasal congestion
  • Nasopharyngitis
  • Sinusitis
  • Dyspepsia 6
• Avanafil has the lowest reported rates of dyspepsia among PDE5 inhibitors 3
• Like other PDE5 inhibitors, avanafil should not be used with nitrates due to the risk of significant hypotension 1
• Avanafil is generally well-tolerated, with discontinuation rates due to adverse events similar to placebo in clinical trials (≤2%) 4

Special Considerations

• Avanafil is contraindicated in patients taking nitrates due to the risk of dangerous hypotension 1
• Caution is advised in patients with mild to moderate hepatic or renal impairment, and it should not be used in patients with severe renal disease or hepatic impairment 1
• For optimal efficacy, patients should be instructed that:
  • Sexual stimulation is necessary for the medication to work
  • More than one trial may be required to establish efficacy
  • Taking the medication with a large meal may delay effectiveness 3
• In men with testosterone deficiency who also have ED, combination therapy with testosterone and avanafil may be more effective than avanafil alone 3

Pharmacokinetics

• Rapidly absorbed after oral administration with a median time to maximum plasma concentration of 30-45 minutes 4, 7
• Terminal elimination half-life of approximately 5 hours 7
• Predominantly metabolized by cytochrome P450 3A4, so strong CYP3A4 inhibitors should be avoided 6
• Absorption and effectiveness may be delayed when taken with a large meal 3

Avanafil represents an advancement in PDE5 inhibitor therapy with its rapid onset of action and high selectivity for the PDE5 enzyme, potentially offering advantages for patients seeking an on-demand treatment option with fewer side effects.