PDE5 Inhibitors: Types, How They Work, Doses and Side Effects

PDE5 inhibitors are a group of popular and effective oral medicines widely used in erectile dysfunction treatment. The inability to achieve or maintain an erection for satisfactory sexual activity is a common form of male sexual dysfunction.

The four PDE5 inhibitors used to treat erectile dysfunction are: Sildenafil (both generic and branded as Viagra and Viagra Connect), Tadalafil (as generic and original Cialis), Vardenafil (brand name Levitra), and Avanafil (an active ingredient in Spedra).

Fundamentally, these medications work through the same pathway. However, they differ in how fast they take effect, how long their effects last, dosing schedule, etc. All four active ingredients are available in the UK, with sildenafil, tadalafil and avanafil marketed under brands such as Viagra, Cialis, Levitra and Spedra, alongside generic formulations; vardenafil is available as a generic medicine.

How do PDE5 inhibitors work?

Before we explain how PDE5 inhibitors work, it is best to share a bit about the physiology of a penile erection:

During sexual stimulation, nitric oxide (NO) is released in the erectile tissue. This activates guanylate cyclase and increases levels of cyclic guanosine monophosphate (cGMP), which relaxes smooth muscle and promotes blood flow into the penis [1].

cGMP relaxes the smooth muscle in the penis, allowing the blood vessels to widen and increasing blood flow into the corpora cavernosa, the erectile tissue that fills with blood during an erection.

PDE5 inhibitors temporarily block the PDE5 enzyme, which normally breaks down cGMP. This allows cGMP to remain active for longer, helping the smooth muscle in the penis relax and increasing blood flow during sexual stimulation.

What is the role of cGMP and nitric oxide in getting an erection?

We’ve already explained how cGMP and nitric oxide help the cavernosal smooth muscle to relax and how that helps the erection process. However, it is important to state that PDE5 inhibitors do not initiate this process independently.

Instead, these medications amplify a pathway that has already been activated by sexual arousal. By slowing cGMP breakdown, they facilitate and prolong the physiological response, thereby helping improve erectile function [2].

Because PDE5 is also present outside the penis, these medicines can cause some systemic blood-vessel relaxation and lower blood pressure.

What PDE5 inhibitors do and do not do?

PDE5 inhibitors do not automatically cause an erection! Sexual stimulation is still required. They also do not directly increase sexual desire or libido [3]. A man may have normal desire but still have erection problems due to various vascular, neurological, hormonal, psychological, or medication-related factors.

Simply put, PDE5 inhibitors improve the ability to achieve and maintain an erection, but they do not necessarily address the underlying causes of erectile dysfunction.

Additionally, PDE5 inhibitors may be a part of penile rehabilitation after prostate surgery.

What types of PDE5 inhibitors are available in the UK?

The main oral treatment options for erectile dysfunction include sildenafil, tadalafil, vardenafil and avanafil, which share the same basic mechanism of action but differ in onset, duration and dosing.

Sildenafil (Viagra, Viagra Connect and generic sildenafil)

Sildenafil is the first widely used PDE5 inhibitor for erectile dysfunction.

Sildenafil citrate, as it is chemically known, is generally taken approximately one hour before sexual activity. The effects usually start within 30-60 minutes (individual responses vary) and can improve erectile responsiveness for several hours, usually between 4-6 hours. Taking sildenafil with food, particularly a high-fat meal, can delay its onset of action.

The usual recommended dose of Viagra/sildenafil is 50 mg taken as needed, no more than once a day. But it can be reduced to 25 mg or increased to 100 mg, depending on efficacy and tolerability [4].

Tadalafil (Cialis, Cialis Together and daily tadalafil)

Tadalafil has a much longer duration of action than sildenafil, with effects lasting up to 36 hours. Hence the popular nickname the “weekend pill“ [5].

The usual dose is 10 mg, as needed. However, this can be increased to 20 mg when appropriate. The medicine can generally be taken with or without food and at least thirty minutes before anticipated sexual activity.

With Tadalafil, users also get a unique option of continuous treatment. A 5 mg once per day regimen can be considered for men who anticipate frequent sexual activity. Also, a lower 2.5 mg daily dose may be used when tolerability is an issue.

Vardenafil: how does it differ from sildenafil?

Vardenafil (both generic and branded Levitra) is another PDE5 inhibitor. The recommended dose is generally 10 mg (as needed), taken approximately twenty-five to sixty minutes before sexual activity [6]. This may be reduced to 5 mg or increased to 20 mg, depending on individual response to treatment.

Vardenafil can be taken with or without food, although a high-fat meal may delay absorption. It is a solid alternative for men who do not achieve adequate results with, or do not tolerate, another PDE5 inhibitor.

Avanafil (Spedra): why does it work faster?

Avanafil has a relatively rapid onset of action. The recommended starting dose is 100 mg, fifteen to thirty minutes before sexual activity [7]. This may be reduced to 50 mg or increased to 200 mg, depending on tolerability and efficacy.

Clinical studies show a rapid erectile response (in around 15 minutes) in some men. However, sexual stimulation is still required.

PDE5 inhibitors overview

	Sildenafil	Tadalafil	Vardenafil	Avanafil
UK brand names	Viagra, Viagra Connect, generic sildenafil	Cialis, Cialis Together, daily tadalafil	Levitra, generic vardenafil	Spedra
Usual starting dose	50 mg	10 mg as needed; 5 mg daily option	10 mg	100 mg
Dose range	25–100 mg	2.5–20 mg	5–20 mg	50–200 mg
Take before sex	~60 min	~30 min	25–60 min	15–30 min
Onset of action	~30–60 min	~30–45 min	~25–60 min	~15–30 min (fastest)
Duration of effect	4–6 hours	Up to 36 hours ("weekend pill")	~4–6 hours	~6 hours
Effect of food	High-fat meals delay onset	Not significantly affected	High-fat meals may delay onset	Minimal effect
Daily dosing option	No	Yes (2.5 mg or 5 mg daily)	No	No

When are PDE5 inhibitors used?

The main clinical application of PDE5 inhibitors is treating erectile dysfunction, but other uses exist:

Treating erectile dysfunction as the primary use

For most men with erectile dysfunction, PDE5 inhibitors are the first line treatment. Here’s why:

Multiple clinical trials demonstrate that phosphodiesterase inhibitors can significantly improve erectile function compared with placebo. Clinical evidence from placebo controlled clinical trials and randomized clinical trials consistently show that these ED meds improve erectile function and the likelihood of successful intercourse in erectile dysfunction patients, although individual response varies.

However, erectile dysfunction can be an early marker of endothelial dysfunction [8]. Therefore, it often coexists with obesity, diabetes, dyslipidaemia, smoking and high blood pressure. These risk factors require addressing too, as a part of comprehensive sexual medicine care.

PDE5 inhibitors primarily treat erectile dysfunction; they are not designed to directly address low libido or premature ejaculation, although different sexual problems can sometimes occur together.

What other conditions can PDE5 inhibitors treat?

Some PDE5 inhibitors have licensed indications beyond erectile dysfunction treatment:

Sildenafil and tadalafil are also licensed in specific formulations and under different brand names for pulmonary arterial hypertension (PAH). The doses used for pulmonary hypertension differ from those used for erectile dysfunction [9].

Tadalafil (Cialis daily 5 mg) is licensed for the treatment of the signs and symptoms of benign prostatic hyperplasia [10]. Clinical studies show improvements in urinary symptoms and quality of life. However, the effects on urinary flow rate are less consistent. Daily tadalafil may therefore be considered in men who have both ED and lower urinary tract symptoms associated with BPH, where clinically appropriate.

When should you not take PDE5 inhibitors?

Individuals undergoing treatment with organic nitrates or nitric oxide donors, including the medications for angina and recreational alkyl nitrites such as “poppers”, should not use PDE5 inhibitors [11]. Combining PDE5 inhibitors with nitrates can cause a severe fall in blood pressure that may be life threatening, which is why these medicines must not be used together.

Men suffering from significant cardiovascular disease, unstable angina, recent myocardial infarction (heart attack), uncontrolled hypertension, severe hypotension or certain forms of heart failure require extra caution or additional specialist assessment [12].

Drug interactions: how do other medications interact with PDE5 inhibitors?

As with all other drugs, potential drug interactions should always be reviewed before prescribing PDE5 inhibitors:

Particular care is required with alpha blockers. PDE5 inhibitors can enhance the blood-pressure-lowering effect of alpha-blockers and may cause symptomatic hypotension in some patients. Dose and timing may therefore need adjustment [13].

Other antihypertensive medicines can add to the blood-pressure-lowering effect of PDE5 inhibitors, although the additional reduction is usually modest.

As described above, nitrates and nitric oxide donors are particularly problematic. Their combination with PDE5 inhibitors can have a profound effect on blood pressure.

Other drugs can alter PDE5 inhibitor concentrations by affecting hepatic (liver) metabolism. Examples include certain macrolide antibiotics, azole antifungals and HIV medicines [14].

What side effects can PDE5 inhibitors cause?

Most PDE5 inhibitors are well tolerated. The most frequently reported side effects are mild and temporary [15], and include:

• Headache
• Facial flushing
• Indigestion (dyspepsia) 
• Nasal congestion
• Dizziness

Additionally, sildenafil may also cause visual disturbances, while tadalafil is more commonly associated with muscle or back pain. Avanafil and vardenafil have broadly similar PDE5-class adverse-effect profiles.

Rare but serious side effects to consult a healthcare provider about

A prolonged erection (priapism) is not common but requires urgent medical attention [16]. Seek immediate medical attention for an erection that lasts around 4 hours or longer, as it can cause permanent penile damage if untreated. Sudden loss or significant reduction of vision or hearing loss is also rare, but requires an immediate medical assessment. Severe allergic reactions are also possible.

Serious cardiovascular events have been reported rarely. However, current evidence does not indicate that PDE5 inhibitors increase the rates of myocardial infarction in appropriately selected men [17]. However, any chest pain occurring during or after sexual activity requires urgent assessment.

What doses of PDE5 inhibitors are prescribed?

Typical adult doses for treating ED are [3]:

• Sildenafil: 50 mg as needed, approximately one hour before sexual activity (25-100 mg depending on response and tolerability).
• Tadalafil: 10 mg as needed, increasing to 20 mg if necessary (2.5–5 mg once a day in selected patients).
• Vardenafil: 10 mg as needed, approximately 25 to 60 minutes before sexual activity (5-20 mg depending on response).
• Avanafil: 100 mg as needed, approximately 15 to 30 minutes before sexual activity (50-200 mg depending on response).

These are not personalised recommendations. They are general prescribing ranges to achieve adequate erectile function. Dose selection depends on factors such as age, renal and hepatic function, concurrent medications, cardiovascular status, and previous response to ED treatment.

Are food or supplements a natural alternative to PDE5 inhibitors?

There are many supplements with purported ED benefits. However, these claims are largely lacking in strong evidence and require more research to substantiate them. Here are some examples:

• L-arginine is an amino acid involved in nitric oxide synthesis. One clinical trial found that adding L-arginine to sildenafil improved some erectile-function outcomes compared with sildenafil alone. However, evidence remains limited and supplements should not be considered equivalent alternatives to licensed ED treatments [18]. 
• Horny Goat Weed (Epimedium) contains icariin, a compound with PDE5-inhibitory activity demonstrated in laboratory and animal research [19]. However, evidence for meaningful clinical benefits in humans remains limited.

Can you buy PDE5 inhibitors without a prescription in the UK?

Although it is technically possible to buy Viagra online, access to PDE5 inhibitors in the UK depends on the specific medicine and formulation.

Sildenafil and Tadalafil can be supplied by pharmacies following a pharmacist consultation:

• Viagra Connect 50 mg was reclassified by the MHRA as a pharmacy medicine for adult men with erectile dysfunction. 
• You can also buy Tadalafil, in a pharmacy-medicine formulation (Cialis Together 10 mg) reclassified for supply through pharmacies following appropriate assessment.

*Other formulations and medications remain prescription-only (POM), so patients should check the specific product.

When looking to buy Spedra online (or other PDE5 inhibitors), the NHS advises extra caution and the use of regulated pharmacies. Counterfeit or unregulated medications may contain incorrect doses or undisclosed ingredients.

How much do PDE5 inhibitors cost in the UK?

Cost depends heavily on the route you take, and on whether you choose a branded or generic version.

• Generic sildenafil: typically around £0.30–£0.55 per tablet, depending on strength and pack size.
• Branded Viagra: typically around £5.50–£7.50 per tablet.
• Generic tadalafil (as-needed): typically around £0.65–£1.00 per tablet; the once-daily generic version is often cheaper, from around £0.30 per tablet.
• Branded Cialis Daily: typically around £2.35–£2.60 per tablet.
• Generic vardenafil: from around £1.90 per tablet; branded Levitra is considerably more, typically around £6–£10 per tablet.
• Spedra (avanafil): typically around £4–£7 per tablet — there is currently no generic avanafil available in the UK, so this tends to be the most expensive option per dose.

Prices are approximate, fluctuate with pack size and supplier, and should be checked at the time of purchase.

Going through the NHS: if a GP prescribes a PDE5 inhibitor (eligibility is limited — for example, some men with diabetes, or those in penile rehabilitation after prostate surgery, may qualify), the cost is simply the standard NHS prescription charge, currently £9.90 per item in England (free in Scotland, Wales and Northern Ireland), regardless of quantity or brand.

Going through a private/online route: most online healthcare providers charge a separate prescription or consultation fee — commonly in the £15–£20 range per order — on top of the per-tablet medication cost shown above.

FAQs

Below are answers to the questions men considering PDE5 inhibitors ask most often, covering effectiveness, safety and how the medications compare.

Do PDE5 inhibitors work for everyone with erectile dysfunction?

No. PDE5 inhibitors are effective for many men, but they do not work for everyone. Response can depend on many factors. Some men may need a different PDE5 inhibitor, a different dose, or treatment of underlying conditions. Psychological factors, testosterone deficiency, vascular disease and neurological disorders may also need investigation. In men with symptoms suggesting a hormonal problem, testosterone levels may need to be assessed, as testosterone deficiency can contribute to erectile dysfunction.

Can I take a PDE5 inhibitor if I have a heart condition?

Men with unstable angina, recent myocardial infarction, uncontrolled arrhythmias, severe heart failure or other high-risk cardiovascular conditions should have their cardiovascular status assessed before PDE5 inhibitor treatment is considered.

Most importantly, PDE5 inhibitors must not be combined with nitrates or nitric oxide donors.

Can I drink alcohol while taking PDE5 inhibitors?

PDE5 inhibitors will usually work with moderate alcohol consumption. However, excessive alcohol can undermine sexual function, increase dizziness or lower blood pressure.

What is the difference between brand-name and generic versions?

Brand-name and generic medications contain the same active pharmaceutical ingredient and must meet regulatory standards for quality, safety and efficacy.

For example, both generic sildenafil and Viagra contain the same active ingredient, sildenafil. The inactive ingredients, tablet appearance and packaging may differ.

The key distinction is not in the name but in the legitimate and regulated supply chain.

How long does it take for a PDE5 inhibitor to start working?

Timing varies between medicines.

For example, sildenafil usually begins working within around thirty to sixty minutes, while vardenafil should be taken twenty-five to sixty minutes before planned sexual activity.

Tadalafil can be taken at least thirty minutes beforehand and has a much longer duration of action.

Avanafil has the fastest onset of action. It is generally taken fifteen to thirty minutes before sexual activity and has demonstrated effects in some men within approximately fifteen minutes.

*Food can influence the onset of some medications, especially sildenafil and vardenafil.

The bottom line

The most appropriate PDE5 inhibitor depends on a man’s medical history, treatment goals, sexual activity pattern, concurrent medicines and tolerance. With ppropriate prescribing and use, PDE5 inhibitors are an effective and well-established treatment option for erectile dysfunction.