Phosphodiesterase Type-5 Inhibitors

Mechanism of Action

An erection occurs when nitric oxide (NO) is released in the corpus cavernosum during sexual stimulation by nitrergic nerves. NO activates guanylate cyclase in smooth muscle cells, which increases cyclic guanosine monophosphate (cGMP), leading to smooth-muscle relaxation and increased blood flow to the penis, via protein kinase G mediated vasodilation.

Phosphodiesterase (PDE) type 5 is an enzyme found in the corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidneys, lungs and cerebellum. PDE type-5 inactivates cGMP, therefore PDE type-5 inhibitors increase cGMP levels and enhance the relaxant effect of NO.

NO is only released during sexual stimulation, therefore sexual activity must occur for PDE type-5 inhibitors to be effective. Generally they are taken 15-60 minutes prior to sexual activity.

• Sildenafil, tadalafil, avanafil and vardenafil are selective for type 5 PDE which is the phosphodiesterase involved in the erection process.
• PDE-6 (involved in retinal phototransduction) and PDE-3 (involved in cardiac contractility) may also be affected to a small extent, explaining certain side effects such as visual disturbances and cardiac effects.

PDE type 5 inhibitors can also be used in pulmonary arterial hypertension, a rare condition where blood pressure in the lung is abnormally high. PDE type 5 inhibitors cause the blood vessels to relax, thus increasing blood flow to the lungs and lowering blood pressure.

Furthermore, PDE type 5 inhibitors can play a role in the treatment of digital ulcers (open sores that can appear on the fingers or toes). Digital ulcers can be caused by conditions such as Raynaud’s syndrome or systemic sclerosis (scleroderma), usually due to poor blood flow to the fingertips or toes. PDE type-5 inhibitors have vasodilatory effects thereby increasing blood flow to fingertips and toes.

Pharmacokinetic Parameters

Although sildenafil and tadalafil belong to the same pharmacological class, their pharmacokinetic profiles differ in clinically meaningful ways that influence onset of action, duration of effect, dosing frequency, and suitability for specific patient groups. Differences in absorption, half-life, metabolic pathways, and elimination help explain why sildenafil is typically used on an “as-needed” basis, whereas tadalafil may be prescribed either as required or once daily.

Cautions

Caution is advised when prescribing PDE-5 inhibitors to patients with active peptic ulcer disease or bleeding disorders, as these agents may have mild effects on platelet aggregation. Individuals with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or those predisposed to priapism, including patients with sickle-cell disease, multiple myeloma, or leukaemia, should be treated carefully due to the risk of prolonged erections.

Patients with underlying cardiovascular disease require thorough assessment prior to initiation, particularly those with left ventricular outflow obstruction or autonomic dysfunction, where haemodynamic responses may be exaggerated. When used for pulmonary arterial hypertension, additional caution is required in patients with hypotension, intravascular volume depletion, or pulmonary veno-occlusive disease.

Vardenafil should be used cautiously in individuals with susceptibility to QT interval prolongation and in older patients, as age-related physiological changes may increase the risk of adverse cardiovascular effects. Careful patient selection and cardiovascular evaluation are therefore essential before initiating therapy with a PDE-5 inhibitor.

Contraindications

Phosphodiesterase type 5 (PDE-5) inhibitors are contraindicated in several cardiovascular, ophthalmological, and hepatic conditions where their vasodilatory effects may pose significant risk. They must not be used in patients with hereditary degenerative retinal disorders (such as retinitis pigmentosa) or in those with a history of non-arteritic anterior ischaemic optic neuropathy (NAION), due to concerns regarding potential visual complications.

Recent serious cardiovascular events represent important contraindications. Tadalafil, for example, is contraindicated in patients with a myocardial infarction within the previous 90 days, and all PDE-5 inhibitors should be avoided following a recent stroke. They are also contraindicated in patients with marked hypotension (systolic blood pressure <90 mmHg). Tadalafil and avanafil should not be used in patients with mild to severe heart failure or in those with uncontrolled hypertension or clinically significant arrhythmias. More broadly, PDE-5 inhibitors are contraindicated in individuals for whom sexual activity itself is inadvisable ,such as those with unstable angina, angina occurring during intercourse, or severe cardiac failure.

Severe hepatic impairment is a contraindication for sildenafil, avanafil, and vardenafil film-coated tablets, while moderate to severe hepatic impairment precludes use of vardenafil orodispersible tablets. In pulmonary arterial hypertension, additional contraindications may apply, including sickle-cell disease in certain contexts due to increased risk of complications.

Adverse Effects

Very common adverse effects for sildenafil include gastrointestinal disorders and vision disorders. Sildenafil rarely causes acute coronary syndrome, priapism, optic neuropathy (discontinue if sudden visual impairment occurs) and sudden cardiac death.

Tadalafil causes prolonged erections (uncommon) and priapism (rare). Decreased or sudden hearing loss has been reported with tadalafil (rare); patients should stop taking tadalafil immediately if either is experienced.

Vasodilation occurs likely due to increased cGMP levels in vascular smooth muscle. When being used for erectile dysfunction, the vasodilatory effect of PDE type-5 inhibitors should be considered, as alongside sexual activity (degree of cardiac risk), this may adversely affect patients with underlying cardiac conditions.

Interactions

Metabolism: All PDE-5 inhibitors are Primarily Metabolised by CYP3A4.

• CYP3A4 inducers (e.g. rifampicin) may decrease effectiveness of PDE-5 inhibitors
• CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, erythromycin, grapefruit juice) increase exposure and risk of toxicity of PDE-5 inhibitors. The combination of ritonavir and sildenafil leads to a increase in sildenafil exposure by x10-fold therefore use together is contraindicated.

Other Key Interactions:

• Alpha-1 blockers (e.g. doxazosin): increased risk of postural hypotension – recommended by manufacturer to stabilise patient before co-administration and start PDE-5 inhibitor at the lowest dose. The combination of tadalafil + doxazosin is not recommended.
• Nitric oxide donors (amyl nitrite), nitrates (nicorandil) and guanylate cyclase stimulators (riocigut) are contraindicated with PDE-5 inhibitors, due to the risk of potentiation of hypotensive effect via effects on cGMP pathway.

References

1. https://www.medicines.org.uk/emc/product/7141/smpc#gref
2. https://bnf.nice.org.uk/drugs/sildenafil/#medicinal-forms
3. https://www.medicines.org.uk/emc/product/13431/smpc
4. https://bnf.nice.org.uk/drugs/tadalafil/
5. https://www.phauk.org/about-ph-2/treatment-for-pulmonary-hypertension/oral-therapies/phosphodiesterase-5-inhibitors/#:~:text=PDE5%20helps%20control%20blood%20flow,lungs%20and%20lowers%20blood%20pressure.
6. https://cks.nice.org.uk/topics/erectile-dysfunction/prescribing-information/phosphodiesterase-5-pde-5-inhibitors/#contraindications-cautions
7. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.