Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor widely prescribed in the UK for erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. A common question is whether tadalafil increases nitric oxide in the body. Understanding the relationship between tadalafil and nitric oxide is essential for safe prescribing and patient counselling. Tadalafil does not directly increase nitric oxide production; rather, it enhances the effects of nitric oxide already present by preventing the breakdown of cyclic guanosine monophosphate (cGMP). This mechanism underpins both its therapeutic benefits and critical drug interactions, particularly the absolute contraindication with nitrate medications.

How Tadalafil Works in the Body

Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor licensed in the UK for the treatment of erectile dysfunction and benign prostatic hyperplasia. It is also prescribed for pulmonary arterial hypertension (PAH) under a separate licence (e.g., Adcirca) with different dosing and specialist-only use.

The drug's mechanism of action centres on its ability to inhibit the PDE5 enzyme, which is found predominantly in the smooth muscle cells of blood vessels in the corpus cavernosum of the penis, as well as in pulmonary vasculature and other tissues.

When sexual stimulation occurs, nerve endings release nitric oxide, which activates an enzyme called guanylate cyclase. This enzyme increases levels of cyclic guanosine monophosphate (cGMP), a chemical messenger that causes smooth muscle relaxation and vasodilation. Under normal circumstances, PDE5 breaks down cGMP, limiting the duration of this vasodilatory effect. By inhibiting PDE5, tadalafil prevents the breakdown of cGMP, thereby prolonging smooth muscle relaxation and enhancing blood flow to the penis, which facilitates an erection in response to sexual stimulation.

Tadalafil has a relatively long half-life of approximately 17.5 hours, which distinguishes it from other PDE5 inhibitors such as sildenafil. This extended duration of action allows for greater spontaneity in sexual activity. The drug is absorbed after oral administration, with onset of action in approximately 30 minutes and peak plasma concentrations typically reached within two hours. Food has no clinically relevant effect on its absorption, although high-fat meals may slightly delay the time to peak concentration.

Key pharmacological features include:

• Selective inhibition of PDE5 enzyme

• Enhancement of cGMP-mediated vasodilation

• Long duration of action (up to 36 hours)

• Hepatic metabolism via CYP3A4 pathway (making it susceptible to interactions with CYP3A4 inhibitors/inducers)

• Predominantly faecal elimination

The Relationship Between Tadalafil and Nitric Oxide

A common misconception is that tadalafil directly increases nitric oxide production in the body. In reality, tadalafil does not increase nitric oxide levels. Instead, it potentiates the effects of nitric oxide that is already present. This is a crucial distinction for understanding both the drug's therapeutic action and its potential interactions.

Nitric oxide acts as the initial trigger in the erectile response pathway. It is released from nerve endings and endothelial cells in response to sexual stimulation. Once released, nitric oxide activates guanylate cyclase, leading to increased cGMP production. Tadalafil works downstream of this process by preventing the enzymatic degradation of cGMP. Therefore, the drug requires endogenous nitric oxide to be present and released naturally for it to exert its therapeutic effect. Without sexual stimulation and the subsequent release of nitric oxide, tadalafil alone will not produce an erection.

This dependency on the nitric oxide pathway explains why tadalafil may be less effective in conditions where nitric oxide production or release is impaired, such as in advanced diabetes with significant nerve damage or severe vascular disease. The drug essentially amplifies the body's natural erectile response rather than creating an artificial one.

Clinical studies have demonstrated that tadalafil's efficacy is directly related to the integrity of the nitric oxide-cGMP pathway. Patients with preserved nitric oxide signalling typically respond better to treatment. This understanding has important implications for patient selection and counselling, as it helps set realistic expectations about the medication's effects and the continued importance of sexual stimulation for achieving an erection.

Why Nitrates and Tadalafil Should Never Be Combined

The combination of tadalafil with nitrate medications represents an absolute contraindication and poses a serious risk of life-threatening hypotension. This interaction is one of the most clinically significant drug interactions in cardiovascular medicine and is emphasised in MHRA guidance and product literature.

Nitrate medications, such as glyceryl trinitrate (GTN), isosorbide mononitrate, and isosorbide dinitrate, are commonly prescribed for angina and other cardiovascular conditions. These drugs work by releasing nitric oxide, which activates the same guanylate cyclase pathway that is involved in tadalafil's mechanism of action. When nitrates are administered, they cause widespread vasodilation and a reduction in blood pressure. If tadalafil is present in the system, it prevents the breakdown of the cGMP produced in response to the nitrate-derived nitric oxide, leading to excessive and prolonged vasodilation.

Similarly, tadalafil must never be combined with riociguat (a soluble guanylate cyclase stimulator used for PAH), as this also presents a serious risk of severe hypotension.

The result of these interactions can be severe, potentially fatal hypotension characterised by:

• Profound drops in blood pressure

• Dizziness, syncope, or loss of consciousness

• Myocardial ischaemia due to reduced coronary perfusion

• Cardiovascular collapse in severe cases

This contraindication extends to all forms of nitrate administration, including sublingual tablets, sprays, patches, and intravenous preparations. Recreational nitrates, such as amyl nitrite ('poppers'), also pose the same risk and must be avoided. Due to tadalafil's long half-life, nitrates must be avoided for at least 48 hours after taking tadalafil; if life-saving nitrates are absolutely necessary, this requires specialist monitoring.

Patients prescribed tadalafil must be explicitly counselled never to use nitrates. In emergency situations where a patient taking tadalafil develops chest pain, healthcare professionals must be informed immediately, as alternative treatments for acute coronary syndrome will be required. The UK Resuscitation Council guidelines specifically address this scenario, recommending alternative antianginal strategies in patients who have recently taken PDE5 inhibitors.

Safe Use of Tadalafil: What UK Patients Need to Know

Safe use of tadalafil requires careful patient selection, appropriate prescribing, and ongoing monitoring. In the UK, tadalafil is available both on NHS prescription and through private services, including registered online pharmacies. NICE guidance emphasises that erectile dysfunction should be assessed within the context of overall cardiovascular health, as it may be an early indicator of cardiovascular disease.

Before starting tadalafil, patients should:

• Undergo a thorough medical assessment including cardiovascular risk evaluation

• Disclose all current medications, particularly nitrates, riociguat, alpha-blockers, and antihypertensives

• Discuss any history of heart disease, stroke, or significant hypotension

• Be screened for contraindications including recent cardiovascular events (MI within 90 days, stroke within 6 months), unstable angina, severe hypotension (<90/50 mmHg), uncontrolled arrhythmias, and heart failure where sexual activity is inadvisable

The standard starting dose for erectile dysfunction is 10 mg taken prior to anticipated sexual activity, which may be adjusted to 20 mg or reduced to 5 mg based on efficacy and tolerability. For daily use, a lower dose of 2.5–5 mg is typically prescribed. For benign prostatic hyperplasia, the dose is 5 mg once daily. Tadalafil should not be taken more than once daily, and daily doses should be taken at approximately the same time each day.

Dose adjustments are required in renal and hepatic impairment. Daily dosing is not recommended in severe renal impairment, and tadalafil should be used with caution in severe hepatic impairment. Caution is also needed when using tadalafil with alpha-blockers due to the risk of symptomatic hypotension.

Important interactions include strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) which increase tadalafil exposure, CYP3A4 inducers (e.g., rifampicin) which reduce effectiveness, and grapefruit juice which may increase blood levels. Alcohol may increase the risk of orthostatic hypotension.

Common adverse effects include:

• Headache (most frequent)

• Dyspepsia and gastro-oesophageal reflux

• Back pain and myalgia

• Flushing and nasal congestion

Patients should seek immediate medical attention if they experience sudden vision or hearing loss, or an erection lasting more than four hours (priapism), which requires emergency treatment to prevent permanent damage. Those with anatomical penile abnormalities or conditions predisposing to priapism (such as sickle cell disease) require specialist assessment before treatment.

Tadalafil is not indicated for use in women or individuals under 18 years of age. There is no evidence of clinically significant effects on fertility, though small changes in sperm parameters with daily dosing have uncertain clinical relevance.

Regular medication reviews are important, particularly for patients with evolving cardiovascular conditions. The MHRA advises that patients purchasing tadalafil online should ensure they use registered UK pharmacies that require appropriate medical questionnaires. Any new chest pain, particularly during sexual activity, warrants immediate cessation of tadalafil and urgent GP review to exclude underlying cardiac pathology.

Patients should report suspected side effects via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or via the Yellow Card app).

Frequently Asked Questions