How Does Avanafil Compare for Erectile Dysfunction?

Introduction

Erectile dysfunction (ED) affects an estimated 30 million American men, and that number is expected to grow as the elderly population increases.^[1] As more men struggle with the negative impact of ED on their quality of life, the need for effective and safe therapies has increased.

For the past decade or so, oral phosphodiesterase type 5 (PDE5) inhibitors have been used as first-line therapy for ED: sildenafil, tadalafil, and vardenafil.^[2] Despite these treatment options, many men have remained dissatisfied for a variety of reasons, including lack of potency, prolonged onset of action, and tolerability issues.

Enter avanafil (Stendra™; Vivus, Inc.; Mountain View, California). Approved by the US Food and Drug Administration in April, avanafil is a novel second-generation PDE5 inhibitor. How will it compare with the other agents previously on the market in terms of efficacy, time to onset, and side effects?

The PDE5 Inhibitor Class

An erection is achieved by increasing blood flow to the penis and concurrently diminishing outflow. Nitric oxide and cyclic guanosine monophosphate (cGMP) are the mediators involved in cavernosal smooth muscle relaxation that leads to penile erection.^[3,4,5] The release of nitric oxide from endothelial cells in the arteriole walls of the corpora cavernosa produces reflex vasodilation, which results in increased penile blood flow.^[6,7,8] PDE5 is the enzyme responsible for breaking down cGMP, leading to detumescence. By blocking PDE5, cGMP is available to augment vasodilation of the penile arterioles and corpora smooth muscle and to potentiate erection (Figure).

Figure. Nitric oxide-cGMP signaling pathway in a cavernosal smooth muscle cell. Ca = calcium; cG = cyclic guanosine; cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; PDE5 = phosphodiesterase 5; PKG = protein kinase G. From Montague DK, et al. ^[9]

All PDE5 inhibitors employ this mechanism, with reported clinical efficacy rates of up to 70%. However, no single drug in this family has been shown to be more efficacious or safer than the others.^[9] Major clinical differences include the onset, duration of action, and the side-effect profile (Table 1). Sildenafil and vardenafil have similar onsets and duration of action, and both demonstrate a decreased efficacy with the intake of high-fat foods^[10-12]; tadalafil is unaffected by fat intake and has a longer duration of action.^[13,14] In addition to the currently available options, a number of newer PDE5 inhibitors are being studied. These include udenafil, which has a similar affinity for PDE5 as sildenafil and is already approved in Russia and Korea, and SLx-2101, which works similarly to tadalafil in that its long half-life makes it a candidate for once-daily dosing.^[15]

Table 1. Comparison of All Currently Available PDE5 Inhibitors in the United States

	Avanafil	Sildenafil	Vardenafil	Tadalafil
Onset of action	15-30 minutes	30-60 minutes	30-60 minutes	60-120 minutes
Plasma half-life	3 hours	4 hours	4 hours	17.5 hours
Duration of action	Up to 6 hours	Up to 12 hours	Up to 10 hours	Up to 36 hours
Effect of food intake	Not affected	High-fat meals decrease efficacy	High-fat meals decrease efficacy	Not affected
Unique side effects		Vision abnormalities (PDE6)	Vision abnormalities (PDE6)	Back pain, myalgias

PDE6 = phosphodiesterase 6. From Gingell C, et al^[10]; Hatzimouratidis K, et al^[11]; Gupta M, et al^[12]; Coward RM, et al^[13]; and Forgue ST, et al.^[14]

All PDE5 inhibitors share generally similar side effects, which tend to be mild and somewhat transient. Common adverse effects include: headache (10%-16%), flushing (5%-12%), dyspepsia (4%-12%), nasal congestion (1%-10%), and dizziness (2%-3%).^[16] These side effects are due to the cross-reactivity with other PDE isoenzymes throughout the body, specifically in the vascular, visceral, and pulmonary smooth muscle. Because of the particularly high concentration of PDE5 in the smooth muscle of the corpora cavernosa of the penis, treatment that is more selective for PDE5 relative to other PDE isoenzymes results in more specific effects in the penis and fewer systemic side effects.^[17]

In particular (Table 1), PDE6 receptors are present in the retina and can exhibit cross-reactivity with the use of sildenafil and, to a lesser extent, vardenafil. Up to 6% of patients experience transient vision abnormalities including a bluish hue to vision, blurred vision, and photosensitivity while taking sildenafil.^[18] Tadalafil also cross-reacts with PDE11, found in the testicles and prostate, but no related adverse reproductive side effects have been reported. Up to 6% of patients report myalgias and back pain with tadalafil^[19]; the exact cause is yet to be determined.

Of particular note, all PDE5 inhibitors are contraindicated for concomitant use with nitrates.^[20] PDE5 inhibitors have mild vasodilatory properties and potentiate nitroglycerin-induced hypotension, which can be life threatening in certain instances. Alpha-blockers, which are commonly used for treatment of benign prostatic hyperplasia and lower urinary tract symptoms, were previously contraindicated for use with PDE5 inhibitors because of the increased risk for symptomatic orthostatic hypotension.^[21] Currently, all PDE5 inhibitors are labeled for use with alpha-blockers with caution.^[22] It is recommended that patients achieve a stable alpha-blocker dose before adding on a PDE5 inhibitor at the lowest available dose.

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