Sildenafil: how it works, and why it doesn't work for some men

Sildenafil is the most prescribed erectile dysfunction treatment in the UK and it works for most men who take it. But a lot of men try it, get nothing, and conclude it isn't for them. It is the generic version of the more well-known Viagra or "blue pill".

Sildenafil is the name of the active ingredient and it is a PDE5 inhibitor. It was sold as Viagra until the patent expired, and it is now available as a generic at a fraction of the price. It is also used to treat pulmonary arterial hypertension.

An erection depends on nitric oxide, which your body releases during sexual arousal. Nitric oxide raises levels of a molecule called cyclic guanosine monophosphate or cGMP, and cGMP relaxes the smooth muscle in the penis so blood can flow in. An enzyme called PDE5 breaks cGMP back down again. Sildenafil blocks PDE5, so cGMP hangs around longer and the erection is easier to get and easier to keep.

You may therefore notice no effect at all while sitting and waiting for the tablet to “kick in”. Its effect only becomes apparent when you are sexually stimulated and it will not cause an erection on its own. Sildenafil also does not directly increase libido. Someone with a low sex drive may still have limited arousal even though the medicine is present in their body.

The usual starting dose for erectile dysfunction is 50mg taken approximately one hour before sexual activity. Depending on how well it works and whether it causes side effects, a prescriber may reduce the dose to 25mg or increase it to 100mg.

The maximum recommended dose is 100mg and it should not be taken more than once per day.

For the best chance of a response:

1. Take the prescribed dose with water approximately one hour before sex.
2. Avoid taking it immediately after a large or high-fat meal.
3. Allow time for sexual stimulation rather than waiting for an automatic erection.
4. Avoid excessive alcohol before taking it.
5. Do not take another tablet later that evening because the first tablet appears slow.
6. Do not combine it with tadalafil, vardenafil, avanafil or another sildenafil product.

Sildenafil can be taken with or without food, so it does not have to be taken on a completely empty stomach. However, food can affect how quickly it is absorbed.

In pharmacokinetic studies, taking sildenafil with food delayed the time taken to reach its peak blood concentration by an average of approximately 60 minutes and reduced the peak concentration by 29%. This does not mean that every meal delays sildenafil by exactly one hour, but it explains why a tablet taken after a heavy meal may feel slower or less predictable.

Excessive alcohol can also make getting an erection more difficult, regardless of whether sildenafil has been taken. It may therefore appear that the medicine has failed when alcohol is contributing to the erection problem.

The 74% figure that gets quoted everywhere is real, but it is specific. It comes from fixed dose trials, and it is the 50mg number. Across those trials, the proportion of men reporting improved erections was 62% on 25mg, 74% on 50mg and 82% on 100mg. On placebo it was 25%.^[1]

That placebo figure is worth sitting with. A quarter of men reported improvement on a dummy tablet, which tells you how much expectation and confidence feed into this.

Response also varies a lot depending on why you have ED in the first place. In the pooled trial data, improvement was reported by 84% of men with psychogenic ED, 77% with mixed, and 68% with organic causes. It was 59% in men with diabetes and 43% after radical prostatectomy.

None of that means it won't work for you. It means "74%" is an average across a very mixed group, and your own odds depend on your circumstances more than on the drug.

From the study we can see that sildenafil 100mg produced a higher average response than the 50mg but the increase is not as large as the increase in dose, with improvement only increasing by around 8%. This higher dose increases the risk of side effects including headaches, dizziness, indigestion, congestion and visual disturbances. This is the reason for 50mg being the starting dose; it gives a high effective rate (74%) with a lower chance of side effects.

People are usually advised to take sildenafil approximately 30-60 minutes before sex. A controlled study of fasted men who achieved an erection firm enough for intercourse, the median onset was 25 minutes, with a range of 12 to 37 minutes. That does not mean everyone should expect sildenafil to work within 25 minutes. The study was conducted under controlled conditions, and food, alcohol, anxiety and the time taken to become sexually aroused can all alter the real-world experience. Taking the tablet ten or fifteen minutes before sex may therefore not give it enough time to start working, particularly if it was taken after eating.

Sildenafil may continue to help with erections for approximately four to five hours after a dose. Sildenafil's half-life is 3 to 5 hours, meaning that is how long it takes for half of it to be cleared. Then half of what's left, and so on. Practically, it takes around a day to leave your system completely. This does not mean it will give you an erection that will last a day; it will make it easier to get an erection for 3 to 5 hours. If you do get an erection lasting more than four hours, that is priapism and it needs urgent medical attention rather than reassurance

Even if the useful effect appears to have worn off, you should not take a second dose within the same day. 

In a study of 100 men who described themselves as sildenafil non-responders, 56% had never been given adequate instructions on how to take it, and only 34% had been given a follow-up appointment. When those men were simply re-educated on how to use the drug, 31% of them became responders. Nothing was changed except they were actually given advice on how to take it and advice about how to get the best out of it.

A larger study looked at 253 men referred to a urology clinic as sildenafil failures. After structured re-education, 41.5% were converted to responders. The same pattern turns up with tadalafil and vardenafil, where a stepwise approach of correcting usage, adjusting timing and titrating the dose salvaged around half of self-described non-responders.^[2][3]

The recurring reasons for apparent failure were consistent across these studies:

Taking it after a heavy meal. Covered above. An hour's delay and a lower peak.

Not enough sexual stimulation. Sildenafil is not a switch. Taking it and then waiting for something to happen will not produce a result.

Too short a gap between the dose and sex. Related to the food point, and worse if the two are combined.

Too few attempts. This is the big one. A single attempt at using sildenafil does not give you enough information that the drug has not worked. You should try a strength at least 8 times with correct instructions before calling it a failure.

There is a fifth, which is dose. In the salvage study, of the men who converted to responders, 69% needed 100mg and 31% responded at 50mg. If you have had a partial response at a lower dose, that is a conversation with the prescriber rather than a reason to stop.

These studies are around twenty years old, from urology referral clinics, and done before generic sildenafil made it cheap and widely available. Roughly half to two thirds of these men remained non-responders after doing everything right.

Some medicines are "take with caution" and others are absolute in that they should never be taken together.

Never with nitrates. Isosorbide mononitrate, GTN spray, anything in that family. Sildenafil potentiates their blood pressure lowering effect and the combination is contraindicated. This includes nicorandil, which is used for angina in the UK and contains a nitrate component, so it carries the same risk. It also includes poppers, sold as room odourisers or leather cleaner. Amyl nitrite is a nitrate and the SmPC names it specifically. Most pharmacy pages leave this out. It is probably the most likely way someone reading this page gets seriously hurt.

Never with riociguat. A pulmonary hypertension drug that works on the same pathway. Contraindicated.

Not with ritonavir. The HIV protease inhibitor increases sildenafil exposure elevenfold. Co-administration is not advised.

Alpha-blockers. Doxazosin and tamsulosin can cause symptomatic low blood pressure when combined with sildenafil, most likely within four hours of the dose. You should be stable on the alpha-blocker first and start sildenafil at a lower dose (such as 25mg), not that the two can never be combined. In the interaction studies, men stabilised on doxazosin saw additional blood pressure drops in the region of 4 to 11 mmHg, with reports of dizziness and light-headedness but not fainting.

Some antifungals and antibiotics raise your levels. Ketoconazole, itraconazole, erythromycin and clarithromycin slow sildenafil's breakdown. Erythromycin nearly triples exposure. Your prescriber may start you on a lower dose. Grapefruit juice has a mild version of the same effect.

Statins are fine. Atorvastatin, simvastatin, rosuvastatin. No interaction.

Most blood pressure medication is fine. Across pooled trial data covering diuretics, beta-blockers, ACE inhibitors, angiotensin II antagonists and calcium channel blockers, there was no difference in side effects compared with placebo. Sildenafil combined with amlodipine produced an extra 8 mmHg drop in systolic blood pressure, which is about the same as sildenafil produces on its own. Sacubitril/valsartan (Entresto) is the exception and needs caution.

Alcohol. Sildenafil at 50mg did not add to alcohol's blood pressure lowering effect in healthy volunteers at a blood alcohol level of around 80mg/dl. The practical problem with drinking is not an interaction, it is that alcohol makes erections harder to get in the first place.

Headache is very common, meaning it affects at least 1 in 10 men. Flushing, nasal congestion, dizziness, nausea, indigestion and mild visual changes such as a blue tinge to your vision are all common, meaning up to 1 in 10.

The ones people worry about most are rare. Priapism, an erection lasting more than four hours, falls in the rare category of between 1 in 10,000 and 1 in 1,000. It still needs urgent medical attention if it happens, because untreated it can cause permanent damage. Sudden loss of vision or hearing is also rare and also needs immediate attention.

Sildenafil is not suitable if you take nitrates or riociguat, if you have had a recent stroke or heart attack, if your blood pressure is below 90/50, if you have severe liver problems, if you have an inherited retinal condition such as retinitis pigmentosa, or if you have previously lost vision in one eye due to NAION. It is also not appropriate where sexual activity itself is inadvisable, such as unstable angina or severe heart failure.

Do not take this as a complete list, it is a guide of who may not be able to take it and what to expect, after filling in your consultation form one of our prescribers will judge if it is suitable for you.

Stop taking sildenafil and seek urgent help if you experience:

1. Chest pain, severe breathlessness or symptoms of a heart attack
2. A serious allergic reaction
3. Fainting, a seizure or a serious irregular heartbeat
4. Sudden loss or major deterioration of vision
5. Sudden loss or major deterioration of hearing
6. A severe skin reaction
7. An erection lasting longer than four hours

An erection does not have to remain painful for four hours before you act. Any erection persisting for more than four hours requires immediate treatment because delaying care can damage penile tissue and lead to permanent erectile problems.

Sildenafil may improve an erection without identifying why the problem developed.

Persistent erectile dysfunction can be associated with:

1. High blood pressure
2. Raised cholesterol
3. Diabetes
4. Cardiovascular disease
5. Smoking and excess weight
6. Low testosterone or another hormonal problem
7. Side effects from medication
8. Depression, stress or anxiety
9. Neurological conditions
10. Previous prostate or pelvic surgery
11. Relationship or psychosexual factors

We highly recommend booking in with your GP to discuss what may be causing your erectile dysfunction and using an ED treatment in the meantime.