Phosphodiesterase type 5 (PDE5) inhibitors are the most widely prescribed oral treatment for erectile dysfunction in the UK. Three molecules dominate everyday practice — sildenafil (the active ingredient in Viagra), tadalafil (Cialis) and vardenafil (Levitra) — and although they share a mechanism, they behave differently once you look at onset, duration and how food affects them. This article explains what these medicines actually do, how they differ, and what a clinician weighs up before recommending one.
The physiology of an erection — a quick recap
An erection is a vascular event. When a man is sexually aroused, nerves in the penis release nitric oxide, which triggers the production of a messenger molecule called cyclic guanosine monophosphate (cGMP). cGMP relaxes the smooth muscle lining the arteries of the corpus cavernosum — the two columns of spongy tissue that run the length of the penis. As those arteries relax and widen, blood flows in, the tissue expands, and the resulting pressure compresses the veins that would normally drain it. The blood is effectively held in place, and an erection is maintained.
The whole process depends on arousal. Without the initial nerve signal and nitric oxide release, none of the downstream steps happen — a point that matters when we look at what these medicines can and cannot do. If you want a fuller picture of the vascular, hormonal and psychological factors involved, our guide to understanding erectile dysfunction covers the causes in more depth.
What PDE5 inhibitors do at a cellular level
cGMP is broken down by an enzyme called phosphodiesterase type 5. In men who struggle to achieve or maintain an erection, that breakdown can happen too quickly, so the smooth muscle never stays relaxed long enough. PDE5 inhibitors block this enzyme. By slowing the breakdown of cGMP, they let the natural signal build up and persist, which enhances the nitric-oxide pathway rather than replacing it.
This is the single most important thing to understand about how they work: they amplify a normal response, they do not create one. A PDE5 inhibitor is not an aphrodisiac and does nothing on its own — sexual stimulation is still required for an erection to occur. Many men are surprised by this, and it is a common reason treatment is wrongly judged as "not working" when in fact the medicine was taken without arousal.
Sildenafil, tadalafil and vardenafil — how they differ
Because they share a target, the three medicines are similar in effectiveness for many men. The practical differences lie in timing and interactions.
Sildenafil typically starts to work within about 30 to 60 minutes and lasts around four to six hours. Its absorption is slowed by a heavy or fatty meal, so it is usually taken on a relatively empty stomach for the most reliable effect.
Tadalafil is the outlier for duration. A single dose can last up to around 36 hours, which is why it is sometimes described as the "weekend" option, and its absorption is largely unaffected by food. It is also available as a lower-strength daily tablet for men who prefer not to plan around a single dose.
Vardenafil sits closer to sildenafil, with a similar onset and a duration of roughly four to eight hours, though some men find its effect a little more consistent when food is involved. A newer molecule, avanafil (Spedra), is designed for a quicker onset in some men. There is no single option that suits everyone, and the right choice depends on lifestyle, other medicines and individual response. Our comparison of sildenafil vs tadalafil vs vardenafil goes through these trade-offs in detail.
Effectiveness is broadly comparable across the group, but individual response varies, and it is common to need a dose adjustment or to try a second molecule before finding the right fit. As a rule, a medicine should be trialled several times — taken correctly, with arousal, and at an adequate dose — before it is judged unhelpful. Giving up after a single disappointing attempt is one of the commonest reasons men wrongly conclude that tablets do not work for them.
Common side effects and interactions
Because PDE5 inhibitors act on blood vessels throughout the body, not only in the penis, their side effects tend to be predictable extensions of that action. The most common are headache, facial flushing, nasal congestion, indigestion and, less often, temporary visual changes such as a blue tinge or light sensitivity (more associated with sildenafil). These are usually mild and settle as the dose wears off.
A few side effects are more serious and need prompt attention. A painful erection lasting more than four hours (priapism) is a medical emergency and should be treated urgently, because prolonged episodes can damage the tissue. Very rarely, men have reported sudden loss of vision or hearing while taking a PDE5 inhibitor; although a direct cause has not been proven, these symptoms warrant stopping the medicine and seeking urgent advice straight away.
The most important safety issue is the interaction with nitrates. Medicines such as glyceryl trinitrate (GTN), used for angina, and related nitrate drugs also work through the nitric-oxide pathway. Taken together with a PDE5 inhibitor, they can cause a dangerous drop in blood pressure. For this reason the BNF lists concurrent nitrate use as a contraindication, and it is one of the first things a prescriber will ask about. Recreational "poppers" (amyl nitrite) fall into the same category and must not be combined with these medicines. Alpha-blockers and some other blood-pressure treatments also need to be reviewed, as can certain protease inhibitors and antifungals that change how the drug is cleared.
Who should be cautious or avoid them
Beyond nitrates, there are situations where a PDE5 inhibitor is used with caution or avoided altogether. Men who have had a recent heart attack or stroke, who have unstable angina, very low blood pressure or significant heart failure may need their cardiovascular condition stabilised and assessed before treatment is considered. Severe liver or kidney impairment can change how the drug is handled and may call for a lower starting dose.
A few less common conditions matter too. Hereditary degenerative retinal conditions such as retinitis pigmentosa are a reason for caution, and men with a tendency to prolonged erections — for example those with sickle cell disease, leukaemia or myeloma — need particular care because of the risk of priapism. This is why an honest, complete medical history is the foundation of safe prescribing, and why these medicines are prescription-only rather than something to source unchecked.
What a UK clinician checks before prescribing
Erectile difficulties can be an early sign of cardiovascular disease, so a consultation is about more than writing a prescription. A UK-registered clinician will usually ask about your cardiovascular health — blood pressure, chest pain on exertion, previous heart attack or stroke — and about every other medicine you take, prescribed or otherwise. They will consider diabetes, cholesterol, smoking and alcohol, all of which affect both erectile function and overall risk.
From there, the choice between the molecules is individualised. Someone who wants spontaneity across a weekend may be better suited to tadalafil; someone with an occasional need may prefer a shorter-acting option. Suitability depends on your cardiovascular status and the other medicines you take, and your clinician will advise based on your individual circumstances rather than a one-size-fits-all rule. If a first choice does not help, dose adjustment or a switch is often worth trying before concluding that oral treatment is unsuitable. You can explore related topics in the Farmeci Men's Health library, and a consultation is the safest way to work out what fits your health.