Phosphodiesterase Inhibitors

Phosphodiesterase (PDE) inhibitors block enzymes that degrade the cyclic nucleotides cAMP and cGMP, prolonging their signalling. The PDE superfamily has 11 families, with differing tissue distribution and substrate specificity. Clinical use concentrates on PDE5 (cGMP specific), PDE3 (cAMP, inhibited by cilostazol and milrinone), PDE4 (roflumilast, apremilast, crisaborole) and non-selective methylxanthines.

PDE5 inhibitors (the focus of this article)

• Mechanism: nitric oxide released from nerve endings and endothelium activates soluble guanylate cyclase, raising cGMP, which reduces intracellular calcium and relaxes smooth muscle. PDE5 degrades cGMP. Inhibition amplifies the nitric oxide signal, but does not initiate erection, so sexual stimulation is required.
• Tissues: corpus cavernosum, pulmonary vasculature, prostate, bladder and urethra, platelets, and skeletal and cardiac muscle (PDE5 expression is modest).

Agents and pharmacology:

All are metabolised by CYP3A4 (and CYP2C9 for sildenafil and vardenafil), with sildenafil, vardenafil and avanafil mainly cleared hepatically and tadalafil with high exposure.

Indications

• Erectile dysfunction: efficacy about 70 to 80% in general populations, lower in diabetes (50 to 60%), post-prostatectomy (30 to 50%), and spinal cord injury (70 to 80%).
• Pulmonary arterial hypertension: sildenafil 20 mg three times daily and tadalafil 40 mg daily (Revatio, Adcirca).
• Benign prostatic hyperplasia with lower urinary tract symptoms: tadalafil 5 mg daily.
• Others: altitude sickness, Raynaud phenomenon with digital ulcers (off-label), fetal growth restriction (not recommended), heart failure with preserved ejection fraction (investigational), premature ejaculation (off-label), secondary prevention of recurrent miscarriage (not recommended), and female sexual arousal disorder (off-label).

Other PDE inhibitors (brief)

• PDE3: cilostazol (claudication, contraindicated in heart failure), milrinone (acute decompensated heart failure).
• PDE4: roflumilast (COPD exacerbation prevention), apremilast (psoriatic arthritis, plaque psoriasis), crisaborole (atopic dermatitis).
• Non-selective: theophylline, aminophylline, caffeine, dipyridamole, pentoxifylline.

Therapeutic and adverse effects

• Common (10 to 40%): headache, facial flushing, nasal congestion, dyspepsia, dizziness. Myalgia and back pain (tadalafil, 5 to 10%) usually appear 12 to 24 hours after dose and resolve within 48 hours. Visual changes (blue-tinged vision, photophobia, blurring) with sildenafil and vardenafil through PDE6 inhibition.
• Serious but rare:
• Hypotension and syncope, particularly with nitrates, alpha blockers and alcohol.
• Non-arteritic anterior ischaemic optic neuropathy (NAION): sudden painless unilateral vision loss, extremely rare (about 1 in 100,000), more likely with crowded optic disc, diabetes, hypertension, hyperlipidaemia, smoking and age over 50. Avoid PDE5 inhibitors if NAION has occurred in the other eye.
• Sudden sensorineural hearing loss.
• Priapism (erection above 4 hours): rare, more common with sickle cell disease, leukaemia, myeloma, or combined with intracavernosal injections.
• Myocardial ischaemia: sexual activity itself carries cardiac risk. Interaction with nitrates is the principal hazard.
• Cutaneous reactions, including Stevens-Johnson syndrome (rare).
• Expected clinical benefit: improvement in erection firmness, successful intercourse in about 65 to 80%. They do not increase libido.

Contraindications

• Absolute: concomitant organic nitrates (glyceryl trinitrate, isosorbide mononitrate and dinitrate, nicorandil, amyl nitrite "poppers") and riociguat (soluble guanylate cyclase stimulators), because of profound, potentially fatal hypotension. A history of hypersensitivity.
• Relative or caution: recent myocardial infarction or stroke (within 90 days to 6 months), unstable angina, severe heart failure (NYHA IV), resting hypotension (below 90/50 mmHg) or uncontrolled hypertension (above 170/110), hypertrophic obstructive cardiomyopathy, severe aortic stenosis, hepatic impairment (Child-Pugh C), severe renal impairment (dose reduction), anatomical penile deformity (Peyronie disease, angulation), predisposition to priapism, retinitis pigmentosa (PDE6 variants), prior NAION, bleeding disorders and active peptic ulcer (sildenafil), and alpha blocker therapy.
• Nitrate timing: if nitrates are needed after sildenafil or vardenafil, wait at least 24 hours (48 hours after tadalafil, and 12 hours after avanafil in some labelling). In patients who take PDE5 inhibitors and present with chest pain, avoid nitrates and use alternatives.

Drug interactions:

• CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir and other protease inhibitors, erythromycin, grapefruit juice, diltiazem, verapamil) increase levels, so reduce doses.
• CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John's wort) reduce levels.
• Alpha blockers (tamsulosin, doxazosin): additive hypotension, so start the PDE5 inhibitor at the lowest dose after alpha blocker stabilisation, separated by hours where possible.
• Antihypertensives, alcohol, and amyl nitrate recreational use.

Pre-prescription evaluation:

• Sexual history, symptoms (ED vs other dysfunction), onset and severity (IIEF-5 score), medications (nitrates, alpha blockers, riociguat, antihypertensives, CYP3A4 modifiers), drugs of abuse (poppers), and alcohol.
• Cardiovascular risk: exercise tolerance (ability to climb two flights of stairs or walk 1 mile briskly is a rough guide), ECG when indicated, and risk stratification by the Princeton consensus (low risk: may start therapy, intermediate: further evaluation, high: defer until stabilised).
• Examination: blood pressure and heart rate, genital examination (Peyronie plaques, phimosis), cardiac exam (murmurs), and secondary sexual characteristics.
• Laboratory tests: fasting glucose or HbA1c, lipids, creatinine, liver enzymes, morning testosterone (with LH, prolactin if low), and TSH where clinically indicated, PSA as per age-based screening.
• Eye history: prior vision loss, retinitis pigmentosa, and optic disc risk.

Assessing response:

• A trial of at least 4 to 8 attempts at maximum tolerated dose, with sexual stimulation, empty stomach for sildenafil and vardenafil, and appropriate timing, before declaring failure. Common reasons for failure: inadequate dose or trials, heavy meal, alcohol, no stimulation, hypogonadism, performance anxiety, and relationship issues.

Prescribing for erectile dysfunction (on demand)

• Sildenafil: start 50 mg 30 to 60 minutes before sexual activity (25 mg if age over 65, hepatic or severe renal impairment (creatinine clearance below 30), or with CYP3A4 inhibitors). Titrate to 25 to 100 mg. Maximum once daily.
• Tadalafil: 10 mg at least 30 minutes before activity, adjustable to 5 or 20 mg. Daily dosing 2.5 to 5 mg, for men with frequent activity (more than twice weekly) or with BPH symptoms. Reduce in severe renal impairment (maximum 10 mg every 48 hours or 5 mg daily).
• Vardenafil: 10 mg 25 to 60 minutes before sex (5 mg in the elderly, 5 to 20 mg range). Orodispersible 10 mg. Avoid with QT-prolonging drugs and congenital long QT syndrome.
• Avanafil: 100 mg (range 50 to 200 mg) 15 to 30 minutes before activity.
• Choose by desired onset, duration, food interactions, and side-effect profile. Patients often prefer tadalafil for spontaneity and sildenafil for rapid onset.
• Counselling: needs sexual stimulation, expected efficacy, take on an empty stomach (sildenafil, vardenafil), avoid excess alcohol and heavy meals, expected side effects, never combine with nitrates or "poppers", seek urgent care for erection beyond 4 hours, sudden visual loss or hearing loss, or chest pain.

Optimising response

• Treat hypogonadism (testosterone replacement) in men with low testosterone and non-response. Optimise cardiovascular risk, diabetes control, lipids, weight loss, exercise, smoking cessation and alcohol reduction. Review contributing drugs.
• Combine with psychosexual therapy, vacuum devices, or intracavernosal injection (alprostadil 5 to 20 micrograms) for non-responders.
• Penile rehabilitation after radical prostatectomy: daily tadalafil 5 mg (benefit uncertain), early vacuum devices, and intracavernosal alprostadil.

Other indications

• Pulmonary arterial hypertension: sildenafil 20 mg three times daily (about 4 to 6 hours apart), tadalafil 40 mg once daily. Adverse effects include headache, flushing, epistaxis.
• BPH: tadalafil 5 mg daily alone or with tamsulosin or finasteride (take alpha blocker with caution for hypotension).
• Raynaud phenomenon and digital ulcers: sildenafil 20 mg three times daily or tadalafil 20 mg every other day.

Management of adverse events

• Headache, flushing: simple analgesia (paracetamol 1 g), dose reduction.
• Dyspepsia: antacids, avoid taking with large meals.
• Prolonged erection above 4 hours (priapism): urgent evaluation. Treat ischaemic priapism with penile aspiration and irrigation, intracavernosal phenylephrine 100 to 500 micrograms every 3 to 5 minutes (maximum 1 mg/h) with blood pressure and ECG monitoring, and shunt surgery for refractory cases. In sickle cell disease, add hydration, oxygen and exchange transfusion according to protocols.
• Hypotension: lie flat, fluids, vasopressors for profound hypotension. Nitrate co-ingestion needs critical care, with fluids and norepinephrine.
• Sudden vision loss: urgent ophthalmology, stop drug permanently.
• Sudden hearing loss: urgent ENT/audiology with oral prednisolone 1 mg/kg (maximum 60 mg) for 7 to 14 days.
• Rash: stop drug.

Pregnancy and special populations

• Sildenafil may be used in selected pregnancies with pulmonary hypertension under specialist care. Not for use in women for other reasons, nor in fetal growth restriction.
• Older adults: lower starting doses. Renal and hepatic impairment: dose adjustments.
• Avoid counterfeit and online-purchased products that carry contaminants.

Follow-up

• Review after 4 to 8 doses for efficacy and tolerability, adjust dose or switch agent. Annual cardiovascular and testosterone reassessment. Address underlying cause of ED as a marker of cardiovascular risk.