PDE5 inhibitors are the first drug treatment for erectile dysfunction and they work for around two-thirds of men. A large share of apparent failures are men who were never told how to take them: wrong dose, too few attempts, taken with a heavy meal, or taken expecting the tablet to work without arousal. This article covers correct use, the differences between the four molecules, the absolute contraindications, and what genuine non-response means.
The short version
- PDE5 inhibitors do not initiate an erection. They block the enzyme that ends one, so sexual arousal is still required for the drug to do anything.
- A tablet has not failed until it has been taken at the maximum dose, with stimulation, on six to eight separate occasions — and until a second molecule has been tried.
- Sildenafil is blunted by a heavy or fatty meal. Tadalafil is not, and can be taken as a low daily dose for men who dislike planning sex around a drug.
- Nitrates are an absolute contraindication. Taken together with a PDE5 inhibitor they can cause a catastrophic drop in blood pressure.
- Loss of efficacy over years is almost always the underlying disease progressing, not the body becoming tolerant to the drug.
- Tablets bought from unregulated websites are the single most dangerous thing men do about erectile dysfunction. Counterfeits are common and their contents are unknown.
What the tablet actually does
Sexual stimulation makes nerve endings in the erectile bodies release nitric oxide. Nitric oxide raises cyclic GMP, cyclic GMP relaxes the smooth muscle in the cavernosal arteries, blood floods in, and an erection follows. An enzyme called phosphodiesterase type 5 — PDE5 — then breaks the cyclic GMP down, which is how the erection ends.
A PDE5 inhibitor blocks that enzyme. It does not add nitric oxide, does not relax anything by itself, and does not produce desire. What it does is stop the signal from being dismantled, so whatever signal your nerves generate goes further and lasts longer. Everything about how to use these drugs follows from that single fact.
It explains why arousal is non-negotiable: with no signal, there is nothing to amplify. It explains why the drugs work less well in diabetes and after prostate surgery, where the nerves and arteries generating the signal are damaged. And it explains why they eventually stop working in progressive disease — not because the tablet has weakened, but because the signal it depends on has.
The four molecules compared
All four are similarly effective in trials. Choosing between them is about timing, food, side effect profile and how you would prefer sex to be organised — which is a lifestyle question, not a pharmacological one.
| Drug | Onset | Useful window | Food | Typical dosing |
|---|---|---|---|---|
| Sildenafil | 30–60 minutes | 4–6 hours, sometimes longer | Significantly delayed and blunted by a heavy or fatty meal — take on an empty stomach | 50 mg to start, adjusted to 25 mg or 100 mg |
| Tadalafil | 30 minutes to 2 hours | Up to 36 hours | Unaffected | 10 mg or 20 mg as needed, or 2.5–5 mg once daily |
| Vardenafil | 30–60 minutes | 8–10 hours | Delayed by a fatty meal; the orodispersible form is taken without water | 10 mg to start, adjusted to 5 mg or 20 mg |
| Avanafil | 15–30 minutes | Around 6 hours | Minimally affected | 100 mg to start, adjusted to 50 mg or 200 mg |
Doses and licensing vary by country, and dose reduction is required with some other drugs and in liver or kidney impairment. This table is for orientation; the prescription must come from a clinician who has seen your medication list.
How to take a PDE5 inhibitor properly
Studies that re-educated so-called non-responders and then retested them found that a substantial proportion responded the second time round. Nothing about the drug had changed. These are the points that make the difference.
- Use the maximum tolerated dose before judging it. Being started on the lowest dose and never titrated upward is the commonest reason a tablet is written off.
- Allow enough time. Sildenafil and vardenafil need roughly an hour; tadalafil is more forgiving; avanafil is the fastest. Taking a tablet fifteen minutes before sex and concluding it does not work is a timing error.
- Watch the meal. Sildenafil taken after a large or fatty dinner may barely reach an effective blood level. Take it on an empty stomach, or choose tadalafil.
- Limit alcohol. A drink or two is fine. More than that suppresses erection through the central nervous system, and no tablet compensates for that.
- Ensure there is genuine stimulation. The drug amplifies arousal; it does not replace it. Attempting without foreplay is the second most common reason for apparent failure.
- Try at least six to eight times. Response often improves across attempts as anxiety about failure falls. One or two disappointing evenings is not a therapeutic trial.
- Then try a different molecule. Individual response varies more between drugs than the trial data suggest. A man who gets nothing from sildenafil may do well on tadalafil.
- Consider the daily option. Low-dose daily tadalafil separates the drug from the sexual act entirely, which suits men who find planning the worst part. It also treats lower urinary tract symptoms, which many men in this age group have anyway.
Why they stop working
Men frequently describe a tablet that worked well for a few years and then gradually did less. The intuitive explanation is tolerance — that the body has got used to the drug. That is not what the evidence shows. True pharmacological tachyphylaxis to PDE5 inhibitors has not been demonstrated; the receptor does not become desensitised in the way it does with some other drug classes.
What is almost always happening instead is progression of the disease underneath. The arteries have narrowed further, the nerves are more impaired, the smooth muscle has been replaced by more collagen. The drug is doing exactly what it always did to a signal that has become weaker. This is why a loss of efficacy should trigger a review of blood pressure, glucose, lipids and testosterone rather than simply a higher dose.
There are also reversible reasons worth excluding before accepting failure: a new beta blocker, thiazide or SSRI; untreated testosterone deficiency; worsening sleep apnoea; increased alcohol; depression; and weight gain. Fixing one of those occasionally restores a response that had been written off.
Genuine non-response versus apparent non-response
This distinction decides whether the next step is better instruction or a different treatment altogether — and it is the reason we ask detailed questions about how tablets were taken.
Signs the tablet was never given a fair trial
- Only ever prescribed the starting dose
- Fewer than six attempts, or all of them in a stressful period
- Taken after a large meal, or with significant alcohol
- Taken without foreplay, or in the expectation of an automatic erection
- Only one molecule tried
- Confirmed low testosterone, or a culprit medication, never addressed
- Erections still occur on waking or during masturbation
Signs the tablet has genuinely reached its limit
- Maximum dose of at least two different molecules, taken correctly, over many attempts
- No morning or nocturnal erections at all
- Erection begins and then collapses within a minute — the pattern of venous leak
- Erectile dysfunction after radical prostatectomy or pelvic radiotherapy with no recovery at 18–24 months
- Long-standing diabetes with established neuropathy and poor Doppler inflow
- Extensive corporal fibrosis after priapism, infection or a removed implant
Who must not take these drugs, and what to watch for
PDE5 inhibitors have a well-characterised safety record over more than two decades, but there are hard rules.
- Never with nitrates. Glyceryl trinitrate spray, isosorbide mononitrate or dinitrate, and recreational “poppers” (amyl nitrite) all combine with PDE5 inhibitors to cause a potentially fatal fall in blood pressure. This is absolute, not relative.
- Never with riociguat or other soluble guanylate cyclase stimulators, for the same reason.
- Caution with alpha blockers used for prostate symptoms — start at a low dose, separate the timing, and expect possible dizziness.
- Defer after a recent cardiac event. Recent myocardial infarction, unstable angina, uncontrolled arrhythmia, severe aortic stenosis or uncontrolled hypotension all need cardiology clearance first. Sex itself is an exertion; if you cannot manage a flight of stairs without chest pain, that needs assessing before anything is prescribed.
- Common side effects are headache, flushing, nasal congestion, indigestion and — with sildenafil and vardenafil — a transient blue tinge to vision. Tadalafil more often causes back and muscle ache. These are dose-related and usually tolerable.
- Stop and seek help urgently for sudden loss of vision in one eye, sudden hearing loss, or an erection lasting more than four hours. All three are rare; all three are emergencies.
What comes after tablets
When tablets have genuinely reached their limit, there are still options below surgery. A vacuum erection device is inexpensive and works mechanically. Intracavernosal injection of alprostadil, or a bi-mix or tri-mix, delivers the drug directly into the erectile body and bypasses the nerve signal entirely — which is why it works after prostate surgery when tablets do not. Response rates are high, and a proper test dose in clinic settles quickly whether it suits you.
A penile implant is the last rung, and it is the one to consider when injections work poorly, hurt, or have simply become the price of sex. It restores rigidity mechanically and carries the highest satisfaction of any erectile dysfunction treatment. It is also irreversible, which is why we insist the rungs below it are climbed first.
If you are not sure where on that ladder you are, that is the normal position and it is what an assessment is for. Send your medication history and what you have tried through our case review form — including doses and how many attempts — and a urologist will tell you whether the next step is a better prescription or a different treatment.
Questions we are asked
Which is better, sildenafil or tadalafil?
Neither is superior in trials; they suit different lives. Sildenafil is short-acting, cheap and works best on an empty stomach, which suits planned sex. Tadalafil lasts up to 36 hours, is unaffected by food, and can be taken as a low daily dose so that sex needs no planning at all. Men who respond poorly to one sometimes respond well to the other, so trying both is reasonable.
Is it safe to take an ED tablet every day?
Low-dose tadalafil is licensed for daily use and has a good long-term safety record; it also helps prostate-related urinary symptoms. The other molecules are intended for on-demand use. Daily dosing should be a clinical decision, not a self-started one, particularly if you take drugs for blood pressure or prostate symptoms.
Do these tablets damage the penis or cause dependence?
No. There is no physical dependence and no evidence of harm to the erectile tissue from long-term use. Some men become psychologically reliant on having a tablet before sex, which is worth addressing with a psychosexual therapist rather than by stopping abruptly. Priapism — an erection lasting over four hours — is rare with tablets but requires emergency treatment if it happens.
Can I take a tablet after I have had a penile implant?
Often, yes, and for a specific reason: the implant makes the shaft rigid but the glans is not part of the erectile bodies and stays softer. A low dose of a PDE5 inhibitor after healing improves glans engorgement in many men. It is a small refinement that frequently goes unmentioned.
How do I know whether my tablets have really failed?
When you have taken the maximum dose of at least two different molecules, with genuine stimulation, on eight or more occasions, and had testosterone and your medication list reviewed — and the erection is still not firm enough for intercourse. Anything short of that is a trial that has not finished, and it is worth completing before considering surgery you cannot undo.
Written and clinically reviewed by the Santa Urology surgical team, last reviewed . This article describes typical findings reported in the surgical literature and in our own practice; individual cases vary and nothing here is a substitute for a personal consultation. See our medical disclaimer.