The treatment journey of sildenafil
It’s the most prescribed treatment for pulmonary hypertension, but the origins of sildenafil may just surprise you. Consultant pharmacist Neil Hamilton explains…
As some of you may already know, sildenafil was not developed specifically for PH (like, for example ambrisentan or selexipag). In fact, sildenafil was not even originally intended for use in erectile dysfunction (ED).
During the 1980s, the manufacturer, Pfizer was very active in cardiac medicine research. They took ideas looking at potential treatments for heart failure and angina to try and find a new medicine. The result was the family of medicines which includes sildenafil (and tadalafil); the Phosphodiesterase-5 inhibitors. We often call them PDE5 inhibitors for short.
The way that PDE5is work is by opening up blood vessels. As such, sildenafil was originally in clinical trials as a treatment for angina. Angina causes tight, dull or heavy chest pain. This is because blood vessels close to the heart are narrowed or blocked, resulting in the heart not receiving enough oxygen. Some patients are referred to us, suspected of having PH, having previously been mis-diagnosed as having angina (as this is much more common and has these similar symptoms).
During the clinical trials into using sildenafil for angina, it was found that sildenafil had a limited benefit. In addition, the use of nitrate sprays or tablets (e.g GTN) during angina attacks caused problems with low blood pressure and dizziness.
Interestingly, men taking sildenafil in the trial were reporting ‘side effects’ of harder, stronger erections. The relatively quick onset and short duration of action would also suit use in erectile dysfunction (ED) much more than prevention of angina.
Consequently, Pfizer decided to turn their attention to this unexpected side effect and further trials into the use in ED proved far more successful. In the mid-1990s, sildenafil was approved and licensed across the world. It remains standard and important advice for our patients NOT to ever use GTN sprays or tablets once prescribed a PDE5i.
Soon after the approval for ED, scientists began researching sildenafil’s use for other conditions, including PH. Whilst sildenafil will open up blood vessels around the body, it has a greater effect in certain parts. The penis is one, but crucially for PH, so are the lungs.
The first studies took place in 1998-2000 and most UK PH centres enrolled patients into the main clinical trial of sildenafil in PH. Sildenafil was approved in the UK in 2005 and remains the most prescribed treatment for PH.
We can prescribe sildenafil on its own (called monotherapy) or in combination with other treatments, depending on the type of PH the patient has. There are different strengths and brands of sildenafil tablets used. These are all completely safe for women to use (packaging and leaflets in the boxes may say otherwise due to the intended use for ED).
As sildenafil is so widely used, it is understandable that there will be men prescribed sildenafil may also be struggling with ED. The dose prescribed for PH is usually 20mg or 25mg three times a day (occasionally higher doses are needed). These doses may not be sufficient for ED but you will be prescribed the lowest effective dose.
Sildenafil is available to buy from your local (or online) pharmacist after a consultation, but if you are already taking a PDE5i, it is possible that you will be advised to go to the GP or sexual health clinic.
At the specialist centres, we are often asked for advice for patients already prescribed a PDE5i. The best answer is about timing of the dose, as we would advise patients to substitute the regular PH sildenafil with a dose for ED, regardless of the time of day.
Taking a dose for ED in addition to regular dosing could result in side effects, such as low blood pressure or headache. Tadalafil (either 20mg or 40mg) is only taken once a day for PH because the effect of the dose lasts much longer in the body than sildenafil.
If an additional dose of sildenafil (or tadalafil) is prescribed for ED, I would advise to leave 12 hours after the ED before taking the next dose of tadalafil for PH, again to avoid side effects.
If patients are unable to take PDE5i for whatever reason but have ED, there are other options available. It is firstly worth considering lifestyle choices; lose weight if you’re overweight, stop smoking, eat a healthy diet, exercise daily, and try to reduce stress and anxiety. If you have explored these, your GP or local sexual health clinic can advise you.
Other options include a vacuum pump and alprostadil (available as a cream and injection). Alprostadil is a different type of medicine which works in a similar way by opening up the blood vessels in the penis.