Sildenafil Teva
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Sildenafil is one of the most well studied medicines used to treat erectile dysfunction, but how it works is still often misunderstood. In simple terms, Viagra works because sildenafil inhibits an enzyme called phosphodiesterase type 5 (PDE5). This slows the breakdown of cyclic GMP (cGMP) in the smooth muscle of the penis, helping the blood flow response linked to sexual stimulation last longer. This can help an erection develop and be maintained when a man is sexually aroused.
Sildenafil is not a hormone, does not increase sexual desire and does not work by directly stimulating the brain. Instead, it acts mainly on a specific enzyme within a biochemical pathway involved in erections. This mechanism also helps explain how quickly sildenafil can start to work and why it must not be taken with nitrates.
This guide is for adults aged 18 and over in the UK who want to understand how sildenafil works. Whether you are considering treatment for erectile dysfunction, have been prescribed sildenafil or are looking for reliable patient information, the aim is to explain the science in clear and straightforward language.
We will look at how sildenafil works, how the body absorbs and processes it, how it compares with other PDE5 inhibitors such as tadalafil, and which interactions and safety considerations are important. We will also explain the difference between branded Viagra and generic sildenafil. The information is based on the approved product information for sildenafil and published medical literature.
Key things to know
- Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5). It blocks the enzyme that breaks down cyclic GMP (cGMP).
- Sildenafil works by supporting the natural process involved in an erection after sexual stimulation. It does not replace sexual arousal or create sexual desire.
- Peak plasma concentration is generally reached within 30 to 120 minutes when sildenafil is taken on an empty stomach, with a median of about 60 minutes.
- A high fat meal can delay the mean time to peak concentration by about 60 minutes and reduce peak concentration by about 29 per cent.
- The terminal half life of sildenafil is approximately 4 hours. The effect can vary between individuals, so the duration should not be treated as a guaranteed timeframe.
- Sildenafil is around 4,000 times more selective for PDE5 than for PDE3, an enzyme involved in regulating cardiac contractility. This selectivity contributes to its pharmacological effects, although sildenafil can still affect other parts of the body and cause side effects.
How Does Viagra Work? The Short Answer
Sexual arousal causes nerves and the lining of blood vessels in the penis to release nitric oxide. Nitric oxide activates an enzyme called guanylate cyclase, which converts GTP into cyclic guanosine monophosphate, usually called cGMP. Increased cGMP relaxes smooth muscle in the blood vessels and erectile tissue of the penis. This increases blood flow and helps an erection develop during sexual stimulation.
An enzyme called PDE5 naturally breaks down cGMP, helping the erection response return to its normal state. Sildenafil blocks PDE5, which slows the breakdown of cGMP. As a result, the blood flow response to sexual stimulation can be maintained for longer, which may help men with erectile dysfunction achieve and maintain an erection.
The important point is that sildenafil does not create an erection on its own. Sexual stimulation is still needed for the natural nitric oxide and cGMP pathway to become active.
That is the basic mechanism. The sections that follow explain how sildenafil moves through the body, how long it remains in the system, how it compares with other PDE5 inhibitors and which safety considerations are important when using it.
The Discovery of Sildenafil: From Angina to Erectile Dysfunction
It is sometimes said that sildenafil was originally developed for pulmonary hypertension. That is not correct. Understanding its actual history also helps explain some of the medicine's effects on blood vessels and blood pressure.
In the mid 1980s, cardiovascular researchers at Pfizer's European laboratories in Sandwich, Kent, were investigating selective PDE5 inhibitors as possible treatments for angina and hypertension. The idea was that increasing cGMP could help relax blood vessels. Researchers identified new pyrazolopyrimidine PDE5 inhibitors in 1986, and the compound later known as sildenafil was first synthesised in 1989.
Clinical studies in the 1990s did not show the level of benefit for angina that researchers had hoped for. However, participants reported an unexpected effect on erections. Pfizer subsequently redirected the development programme towards erectile dysfunction. Viagra was approved for the treatment of erectile dysfunction in 1998 and became the first widely available oral treatment of its type. Sildenafil was later approved for pulmonary arterial hypertension under the brand name Revatio in 2005.
So, the development history is essentially angina research, followed by erectile dysfunction, and later pulmonary arterial hypertension.
This history also helps explain why sildenafil can affect blood vessels and blood pressure. The medicine works on a pathway involved in vascular smooth muscle relaxation. In the penis, this pathway contributes to the blood flow changes needed for an erection.
The Nitric Oxide and cGMP Pathway in Regulating Blood Flow
An erection is a vascular process involving a series of chemical signals. Understanding these steps makes it easier to see where sildenafil works.
- Sexual stimulation causes nerves and cells lining the blood vessels in the penis to release nitric oxide.
- Nitric oxide enters smooth muscle cells and activates an enzyme called soluble guanylate cyclase.
- Guanylate cyclase converts guanosine triphosphate (GTP) into cyclic GMP (cGMP).
- Increased cGMP lowers the concentration of calcium inside the smooth muscle cells, helping the smooth muscle in the penile arteries and corpus cavernosum relax.
- This relaxation increases blood flow into the erectile tissue. As the erectile tissue expands, it can compress the veins that normally allow blood to leave the penis. This helps retain blood in the erectile tissue and contributes to penile rigidity.
- PDE5 then breaks down cGMP into 5' GMP, helping end the erectile response.
Why sexual stimulation is still required
This is one of the most important things to understand about sildenafil. The medicine does not create the initial sexual signal. It slows the breakdown of cGMP after the natural erectile pathway has already been activated.
When sexual stimulation occurs, nitric oxide is released and cGMP levels increase. Sildenafil inhibits PDE5, allowing cGMP to remain active for longer. This can help support an erection when sexual stimulation is present. The approved product information confirms that sexual stimulation is required for sildenafil to work.
This also means that sildenafil is not a treatment for low sexual desire. It does not increase libido or directly increase testosterone levels. If erectile difficulties are linked to factors such as low sexual desire, anxiety, relationship difficulties or another underlying condition, a higher dose of sildenafil may not address the underlying cause. Speaking with a healthcare professional can help identify the most appropriate approach.
PDE5 Inhibition: The Mechanism of Action in Detail
Phosphodiesterases are a group of enzymes that help break down cyclic nucleotides, including cAMP and cGMP. There are 11 recognised phosphodiesterase families, and they are found in different tissues throughout the body. Some, such as PDE3 and PDE4, mainly act on cAMP, while PDE1 and PDE2 can act on both cAMP and cGMP. PDE5 specifically breaks down cGMP and is found in the smooth muscle of the corpus cavernosum, making it an important target for medicines used to treat erectile dysfunction.
Sildenafil is a potent and selective inhibitor of PDE5. It binds to the enzyme and prevents PDE5 from breaking down cGMP as quickly. This allows cGMP to remain active for longer, supporting the smooth muscle relaxation and increased blood flow involved in an erection when sexual stimulation is present.
Selectivity across the phosphodiesterase family
Selectivity is an important part of how sildenafil works. The medicine is designed to have a stronger effect on PDE5 than on several other phosphodiesterase enzymes. According to the approved sildenafil product information, its relative potency against different phosphodiesterases varies considerably.
The figures below show how sildenafil interacts with different PDE enzymes and help explain why its main clinical effect is linked to the PDE5 pathway.
| Enzyme | Selectivity for PDE5 | Why it matters |
|---|---|---|
| PDE6 | About 10-fold | Found in the retina and involved in phototransduction. The narrow margin here is thought to underlie the transient blue tinge and light sensitivity some people notice, particularly at higher doses |
| PDE1 | More than 80-fold | Present in brain, heart and vascular smooth muscle |
| PDE3 | Approximately 4,000-fold | PDE3 controls cardiac contractility. This wide margin is the most clinically important number in the whole profile |
| PDE2, PDE4, PDE7 to PDE11 | More than 700-fold | Broad separation from the remaining families, which limits off-target effects |
The 4,000-fold gap against PDE3 is the figure that deserves emphasis and is usually the one left out. This high degree of selectivity helps minimise effects on cardiac contractility and contributes to sildenafil's suitability as an oral treatment for erectile dysfunction .
Where else PDE5 is found
It is sometimes said that sildenafil acts only on penile tissue, but that is not quite accurate. PDE5 is also found, at lower concentrations, in platelets, vascular and visceral smooth muscle, and skeletal muscle.
Blocking PDE5 in these tissues can contribute to some of sildenafil's effects outside the penis, including mild widening of blood vessels. This is also one reason some of the medicine's common side effects, such as headache, facial flushing, nasal congestion and indigestion, can occur. These effects are linked to changes in blood vessel tone and smooth muscle activity in tissues outside the erectile tissue.
Understanding this can help explain why sildenafil can have effects elsewhere in the body as well as its intended effect on erectile function.
Viagra Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion
Pharmacokinetics describes what the body does to a medicine, while pharmacodynamics describes what the medicine does to the body. For a medicine such as sildenafil, which is usually taken when needed, pharmacokinetics helps explain how quickly it is absorbed, how long it remains in the body and how it is eventually removed.
Absorption and the effect of food
Sildenafil is rapidly absorbed after it is taken by mouth, with an absolute bioavailability of approximately 41 per cent. When taken on an empty stomach, peak plasma concentrations are generally reached within 30 to 120 minutes, with a median of around 60 minutes.
Food can affect how quickly sildenafil reaches its peak concentration. When taken with a high fat meal, the mean time to peak concentration is delayed by about 60 minutes and the mean peak concentration falls by about 29 per cent. Overall exposure, measured by the area under the curve, is not significantly affected.
In practical terms, a high fat meal may make sildenafil take longer to reach its peak effect. It does not mean that the medicine will necessarily stop working. Individual responses can vary, but sildenafil is generally taken before anticipated sexual activity and may take longer to work when taken after a high fat meal.
Distribution and protein binding
After absorption, sildenafil is distributed throughout the body. Both sildenafil and its major circulating metabolite are approximately 96 per cent bound to plasma proteins. This binding is independent of the total drug concentration within the range studied.
Less than 0.001 per cent of an administered dose is reported to appear in semen. This is a small amount, but it is a detail that some patients may want to know when discussing how sildenafil is distributed in the body.
Metabolism and the active metabolite
Sildenafil is mainly broken down in the liver. CYP3A4 is the main enzyme involved, while CYP2C9 makes a smaller contribution. This is clinically important because medicines and other substances that affect these enzymes can change the amount of sildenafil in the bloodstream.
For example, some medicines, including ketoconazole, erythromycin and ritonavir, can slow the breakdown of sildenafil and increase exposure to the medicine. Grapefruit and grapefruit juice may also affect CYP3A4 activity. If you regularly consume grapefruit products or take other medicines, speak with your prescriber or pharmacist about whether this could affect your treatment.
The main circulating metabolite is called N desmethyl sildenafil. It is produced when sildenafil is metabolised and remains pharmacologically active. It has a similar PDE selectivity profile to sildenafil and approximately 50 per cent of the parent drug's potency at PDE5.
However, the metabolite reaches plasma concentrations of only about 40 per cent of those seen with sildenafil. Based on these figures, it contributes approximately 20 per cent of the overall pharmacological effect. Looking at potency alone can therefore give an incomplete picture of how much the metabolite contributes to the medicine's overall action.
Sildenafil is eventually eliminated mainly as metabolites in the faeces, with a smaller proportion excreted in the urine.
Half life and duration of action
Sildenafil and its N desmethyl metabolite both have terminal half lives of approximately 4 hours. The medicine may be cleared more slowly in older adults and in people with liver or kidney impairment. This can increase sildenafil levels in the blood and is one reason why the appropriate dose and suitability need to be assessed for each person.
Sildenafil is generally described as having an effect for around 4 hours, although individual responses can vary. The effect may gradually decrease as the medicine is cleared from the body.
It is important to understand what this timeframe means. It does not mean that an erection will last for 4 hours. Instead, during this period, sildenafil may make it easier to achieve and maintain an erection when sexual stimulation is present.
Viagra Composition: What Is Actually in the Tablet
The active ingredient in Viagra is sildenafil citrate. A 50mg tablet contains sildenafil citrate equivalent to 50mg of sildenafil. The same applies to the 25mg and 100mg strengths.
The other ingredients are called excipients. They can include substances used to help the tablet hold its shape, break down properly and provide its film coating. These ingredients do not provide the main pharmacological effect of sildenafil, but they are important to how the tablet is manufactured and used.
Some sildenafil tablets contain lactose monohydrate, which may be relevant for people with certain diagnosed sugar intolerances. However, excipients can differ between manufacturers and products. For the exact ingredients in your medicine, check section 6.1 of the Summary of Product Characteristics or the patient information leaflet supplied with your pack.
Dose and Response
Sildenafil is available in licensed strengths of 25mg, 50mg and 100mg. Higher doses generally produce higher sildenafil concentrations and greater PDE5 inhibition, but the clinical response can vary between individuals. Higher doses can also increase the likelihood of side effects, so a higher dose is not necessarily better or more effective for everyone.
The appropriate dose and whether an adjustment is needed should be decided by the prescriber based on factors such as your response to treatment, tolerability, medical history and other medicines you take.
It is also important to remember that a lack of response does not always mean that a higher dose is needed. Sexual stimulation is required for sildenafil to work, and factors such as taking the medicine after a high fat meal or expecting it to work immediately can affect the experience.
If sildenafil does not seem to be working as expected, speak with your prescriber rather than taking more than the prescribed dose.
Cardiovascular Pharmacology and the Nitrate Interaction
Because PDE5 is also found in vascular smooth muscle, sildenafil can cause some widening of blood vessels throughout the body. In studies involving healthy volunteers, the product information reports an average maximum reduction in blood pressure of around 8 to 10 mmHg in systolic blood pressure and 5 to 6 mmHg in diastolic blood pressure. This effect was temporary in these studies.
However, sildenafil can cause a serious drop in blood pressure when combined with nitrates. Nitrates, including medicines such as glyceryl trinitrate and isosorbide mononitrate or dinitrate, increase nitric oxide activity and raise cGMP levels. Sildenafil slows the breakdown of cGMP. When the two effects occur together, blood pressure can fall significantly.
For this reason, sildenafil must not be taken with nitrate medicines. Recreational nitrates known as poppers can also interact with sildenafil and should not be used with it.
Alpha blockers, which may be prescribed for conditions such as prostate symptoms or high blood pressure, can also lower blood pressure. Using them with sildenafil may require additional assessment and caution.
Sildenafil may not be suitable for some people with certain cardiovascular conditions, a recent stroke or heart attack, very low blood pressure or severe liver impairment. Your prescriber can assess your medical history and current medicines before recommending treatment.
Seek urgent medical attention if you experience chest pain during sexual activity, sudden loss or significant changes in vision or hearing, or an erection that lasts longer than four hours. These symptoms can require immediate medical assessment.
Cialis vs Viagra: How the Mechanisms Compare
The four PDE5 inhibitors licensed in the UK work in broadly the same way. They inhibit the PDE5 enzyme, support the natural erectile response when sexual stimulation is present, and must not be used with nitrate medicines.
The main differences are in how each medicine is absorbed, processed and cleared by the body, as well as how selective it is for PDE5 compared with other phosphodiesterase enzymes. These differences can affect factors such as how quickly a medicine takes effect, how long its effects may last and which side effects are more likely.
This is why Viagra (sildenafil) and Cialis (tadalafil), although they work through the same basic pathway, can feel different in practice. The most suitable option depends on the individual's health, other medicines, treatment needs and response to the medicine. A prescriber can help determine which treatment is appropriate.
| Medicine | Active ingredient | Approximate half-life | Distinguishing pharmacology |
|---|---|---|---|
| Viagra | Sildenafil | About 4 hours | Absorption delayed by a high-fat meal; about 10-fold selectivity over retinal PDE6 |
| Cialis | Tadalafil | About 17.5 hours | Much longer window, up to around 36 hours; absorption not meaningfully affected by food; greater PDE6 selectivity but inhibits PDE11 |
| Levitra | Vardenafil | About 4 to 5 hours | High in vitro potency at PDE5; absorption reduced by high-fat meals |
| Spedra | Avanafil | About 5 hours | Rapid onset and high PDE6 selectivity |
No PDE5 inhibitor is universally better than another . They suit different people and different circumstances, and which one is appropriate depends on your medical history, your other medicines and your own preferences, as determined by your prescriber during a clinical assessment.
Branded Viagra and Generic Sildenafil: Uses in Erectile Dysfunction and Pulmonary Arterial Hypertension
From a pharmacological perspective, branded Viagra and generic sildenafil contain the same active ingredient. Generic sildenafil contains sildenafil at the same stated strength and must meet regulatory requirements for quality and bioequivalence to the reference medicine.
A generic medicine contains the same active ingredient as the branded medicine and is required to meet applicable standards for quality, strength, safety and effectiveness. This means that generic sildenafil works through the same PDE5 mechanism as branded Viagra.
What can differ is the manufacturer, tablet appearance, excipients and price. Generic sildenafil became widely available in the UK after the relevant patent protections for Viagra expired. Price differences generally reflect factors such as manufacturing and market competition rather than a difference in the active ingredient.
Viagra Connect is available from UK pharmacies without a prescription, but a pharmacist must assess whether it is suitable before it is supplied.
Getting a Clinical Assessment
Sildenafil 50mg is a prescription only medicine in the UK and should only be supplied following an appropriate clinical assessment.
Sildenafil is used to treat erectile dysfunction. Sildenafil is also used to treat pulmonary arterial hypertension under the brand name Revatio, although the dosing and product information for this condition differ from those for erectile dysfunction.
For erectile dysfunction, an online consultation may be available through a legitimate UK service. The consultation can be completed from home and reviewed by a UK registered prescriber. If treatment is considered appropriate, the medicine can be dispensed by a GPhC registered pharmacy.
Viagra Connect is available without a prescription in the UK, but a pharmacist assessment is required before it can be supplied.
Medical Disclaimer
This article provides general educational information about the pharmacology of sildenafil and does not constitute medical advice. It does not replace advice from a qualified healthcare professional or the patient information leaflet supplied with your medicine.
Sildenafil is a prescription only medicine and should be used following an appropriate clinical assessment. Whether it is suitable for you, and which strength is appropriate, depends on factors such as your medical history, other medicines and individual circumstances.
Sildenafil must not be taken with nitrate medicines or recreational nitrites known as poppers because the combination can cause a dangerous drop in blood pressure.
Seek urgent medical attention if you experience chest pain, sudden changes or loss of vision or hearing, or an erection lasting longer than four hours. Sudden vision or hearing loss is rare but requires prompt medical attention.
Erectile dysfunction can sometimes be associated with underlying health conditions, including cardiovascular disease and diabetes. If erectile difficulties persist, discussing them with a healthcare professional can help identify whether further assessment is appropriate.
