Dear Dr G,

I am a 55-year-old man who is not in the best of health.

I was diagnosed with high cholesterol and high blood pressure during the pandemic.

Due to a sedentary lifestyle and family history, my most recent blood tests also revealed that I have diabetes.

Naturally, I was started on a range of medications to control these conditions.

Unfortunately, after starting these medications, I began to experience problems with my erections.

I explained to my doctors how the erectile issues were affecting my relationship with my wife and asked whether my medications could be reduced to improve rigidity.

The doctors assured me that the erectile weakness was caused by the underlying diseases and not necessarily by the medications they prescribed.

They explained that the way forward was to control my diet and exercise, and in the meantime to take medication to enhance erections.

I was somewhat surprised to discover that the blue pills have actually been around for nearly three decades.

I was even more surprised to learn that there are several options to choose from.

The doctors tried to explain how differences in drug mechanisms can result in varying effects and side effects.

I must admit that I do not fully understand all of them.

Can you explain the different types of medications for erectile dysfunction?

How are they taken? How quickly do they work?

And how long do they last?

Lastly, do they all have the same side effects?

Regards,

Choosing Choo

The phosphodiesterase-5 (PDE5) inhibitors sildenafil, vardenafil, udenafil, tadalafil and avanafil are closely related drugs used primarily to treat erectile dysfunction.

Although they share the same mechanism of action by enhancing nitric oxide–mediated increases in cyclic GMP to promote smooth muscle relaxation and penile blood flow, their pharmacokinetic differences strongly influence clinical efficacy, onset and duration of action, and side-effect profiles.

Because their mechanism is identical, variations in absorption rate, half-life, selectivity and metabolism largely determine how each drug performs in real-world treatment.

Sildenafil, the first drug in this class, has a relatively rapid onset of action.

Peak plasma concentration is typically reached in about one hour.

Its half-life of up to five hours produces a therapeutic window of roughly four to six hours.

Clinical trials consistently show that sildenafil improves erectile function in a majority of patients, with response rates commonly around 60–80% in the general population.

Response rates are lower in individuals with diabetes or post-prostatectomy erectile dysfunction.

Because sildenafil also inhibits PDE6 in the retina, visual disturbances such as blue-tinted vision and increased light sensitivity are common side effects.

Systemic vasodilation can also cause headache, flushing, nasal congestion, dizziness and heartburn.

Due to its short half-life, these side effects are usually transient and resolve within several hours.

Vardenafil has pharmacokinetic properties similar to sildenafil but is slightly more potent and more selective for PDE5. Peak levels occur within about one hour, and the half-life is approximately four to five hours, providing a slightly longer duration of action than sildenafil. Efficacy studies show that vardenafil performs particularly well in more challenging patient populations, including men with diabetes and those who did not respond adequately to sildenafil.

Because of its improved selectivity, visual disturbances occur less frequently.

Adverse effects are similar to others in the class and include headache, flushing, rhinitis and dyspepsia.

Tadalafil differs significantly due to its long half-life of approximately 17.5 hours. This allows efficacy for up to 36 hours after a single dose. The extended duration supports both on-demand dosing and daily low-dose therapy. Clinical trials show high efficacy comparable to other PDE5 inhibitors. The prolonged effect improves spontaneity and satisfaction, as sexual activity does not need to be precisely timed.

However, tadalafil’s pharmacokinetics also explain its distinctive side effects. Because it inhibits PDE11 in skeletal muscle, muscle aches and lower back pain occur more frequently than with other drugs.

Headache, flushing and nasal congestion may also occur and can last longer due to the extended half-life.

Udenafil occupies an intermediate position between shorter-acting agents and tadalafil. It has a half-life of about 11 to 13 hours, with peak levels reached in one to two hours. Clinical studies indicate that udenafil has efficacy comparable to sildenafil and tadalafil. It is often preferred by patients who want longer action without effects lasting more than a day.

The side-effect profile is similar to the class overall, with headache and flushing being most common.

Visual disturbances are relatively uncommon due to improved selectivity. The intermediate half-life means that side effects usually resolve within half a day.

Avanafil represents the newest generation of PDE5 inhibitors. It is characterised by rapid absorption and high selectivity for PDE5. Peak plasma levels occur within 30 to 45 minutes. Some patients experience effects as early as 15 minutes.

Its half-life of about five hours produces a duration similar to sildenafil and vardenafil.

High selectivity reduces off-target effects.

Clinical trials show efficacy comparable to earlier drugs, with faster onset and improved tolerability.

Visual disturbances and muscle pain are less common. Headache and flushing remain the most frequently reported side effects.

Because of its rapid onset and favourable side-effect profile, avanafil is often considered a convenient option for on-demand use.

The pharmacokinetic differences among PDE5 inhibitors strongly influence their clinical performance.

Shorter half-life drugs such as sildenafil and vardenafil provide reliable short-term efficacy with transient side effects.

Tadalafil offers prolonged efficacy along with longer-lasting adverse effects. Udenafil provides an intermediate duration of action. Avanafil prioritises rapid onset and improved selectivity.