Urology Textbook
Clinical Essentials
By Dirk Manski, MD

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Phosphodiesterase-5-Inhibitors: Mechanism, Adverse Effects, Contraindications and Dosing

Mechanism of Action of Phosphodiesterase Type 5 Inhibitors

Phosphodiesterase type 5 (PDE5) plays a key role in the degradation of cyclic guanosine monophosphate (cGMP) in the corpora cavernosa and thereby terminates nitric oxide (NO)–mediated signal transduction of penile erection. Inhibition of PDE5 enhances cGMP-mediated erectile signaling and thereby improves erection. This mechanism of action requires sexual stimulation, at least partial intact innervation of the penis, and structurally intact corpora cavernosa to achieve a sufficient erection. All phosphodiesterase type 5 inhibitors mentioned below potently and (to varying degrees) selectively inhibit PDE5 (see Table Phosphodiesterase Type 5 Inhibitors).

PDE5 is not only expressed in cavernosal tissue of the penis but also in vascular and nonvascular smooth muscle cells in other organs, particularly in the pulmonary arteries as well as in the prostate and bladder trigone. Inhibition of PDE5 leads to vasodilation of the pulmonary vasculature and relaxation of smooth muscle in the prostatic urethra and bladder trigone. NO-mediated relaxation of smooth muscle contributes to the regulation of micturition.

Indications for Phosphodiesterase Inhibitors

Properties, pharmacokinetics, adverse effects, and dosage of the most common phosphodiesterase-5 inhibitors (Sildenafil, tadalafil, vardenafil, and avanafil). .
Sildenafil Tadalafil Vardenafil Avanafil
Year of approval 1998 (Viagra) 2003 (Cialis) 2003 (Levitra) 2013 (Spedra)
Dosage 25–100 mg 5–20 mg 5–20 mg 50–200 mg
Onset of action 30–60 min 60–120 min 25–60 min 15–30 min
Effect of food significant minimal significant moderate
Elimination half-life 3–5 h 17–18 h 4–5 h 6–17 h
Duration of action 4–5 h up to 36 h 4–5 h 6–12 h
Vascular adverse effects common less common common less common
Dyspepsia common common less common less common
Visual adverse effects common rare common very rare

Pharmacokinetics of PDE5 Inhibitors

After oral administration, PDE5 inhibitors are absorbed with variable oral bioavailability. High-fat meals delay and reduce absorption, particularly for sildenafil and vardenafil, whereas the effect of food is less relevant for tadalafil and avanafil. PDE5 inhibitors exhibit high plasma protein binding and undergo predominantly hepatic metabolism via CYP3A4, with a lesser contribution from CYP2C9. All agents are eliminated mainly as metabolites via the biliary–fecal route, with a smaller fraction excreted renally.

Adverse Effects of Phosphodiesterase Type 5 Inhibitors

The differing selectivity of PDE5 inhibitors for individual phosphodiesterase isoenzymes (e.g., PDE5, PDE6, PDE11) largely determines their adverse-effect profiles (see also Table Phosphodiesterase Type 5 Inhibitors). Overall, these agents are well tolerated; most adverse effects are dose dependent, mild to moderate in intensity, and self-limited. Sildenafil and vardenafil more frequently cause visual symptoms, whereas tadalafil more often leads to myalgia and back pain, and avanafil appears to have a somewhat more favorable profile with generally milder gastrointestinal and ocular adverse effects.

Nervous System:

Headache occurs very frequently. Dizziness, facial flushing, and a sensation of warmth are common. Fatigue or lightheadedness occurs occasionally. There are only minor differences between individual agents with respect to these nervous system adverse effects.

Eyes:

Visual adverse effects are common with sildenafil and vardenafil (including blurred vision, increased light sensitivity, and transient color vision disturbances) and are attributed to concurrent inhibition of retinal PDE6. Such visual symptoms occur less frequently with tadalafil and avanafil. Ocular pain or conjunctival hyperemia occurs occasionally. Very rarely, cases of non-arteritic anterior ischemic optic neuropathy (NAION) have been reported; a causal relationship has not been definitively established, but caution is warranted in patients with preexisting ophthalmologic risk factors.

Cardiovascular System:

Flushing occurs very frequently. Palpitations, blood pressure reduction with orthostatic symptoms, and tachycardia are common. Occasional adverse effects include palpitations and mild cardiac arrhythmias. Serious events such as clinically significant arrhythmias, angina pectoris, myocardial infarction, or sudden cardiac death have been reported rarely; given the underlying cardiovascular risk profile of affected patients, a clear causal relationship with PDE5 inhibitor intake is often difficult to establish. There are no robust data indicating clinically relevant differences between available agents in the incidence of serious cardiovascular events.

Other Adverse Effects of Phosphodiesterase Type 5 Inhibitors:

Nasal congestion, facial flushing, heartburn or dyspepsia, and nausea are common with all PDE5 inhibitors. Myalgia and back pain occur frequently with tadalafil (likely related to PDE11 inhibition); such musculoskeletal complaints are reported less frequently with sildenafil, vardenafil, and avanafil. Cutaneous erythema or exanthema occurs occasionally. Prolonged and painful erections are rare; very rarely, priapism occurs and requires urgent urologic management. Severe allergic cutaneous reactions (e.g., Stevens–Johnson syndrome) or other serious hypersensitivity reactions are very rare.

Drug Interactions of Phosphodiesterase Inhibitors

Nitrates:

Phosphodiesterase type 5 inhibitors markedly potentiate the blood pressure–lowering effects of nitrates. Concomitant administration of nitrates and PDE5 inhibitors is contraindicated.

Riociguat:

Riociguat is used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Concomitant administration with PDE5 inhibitors is contraindicated.

Recreational Drugs (“Poppers” such as Amyl Nitrite):

Concomitant use of PDE5 inhibitors and inhaled nitrites (“poppers”) is contraindicated because of the risk of excessive vasodilation and severe hypotension up to syncope.

Inhibitors of Cytochrome P450 3A4:

Macrolide antibiotics (azithromycin), antifungal agents (ketoconazole and itraconazole), HIV protease inhibitors (ritonavir, saquinavir), and grapefruit juice increase plasma concentrations of PDE5 inhibitors, in some cases by several-fold. Concomitant use of strong CYP3A4 inhibitors is contraindicated for avanafil; for the other agents, substantial dose reduction and avoidance of daily dosing are recommended.

Alpha-Blockers:

Concomitant administration of alpha-blockers and PDE5 inhibitors increases the risk of orthostatic hypotension. The combination of tadalafil with alpha-blockers has been studied most extensively and is generally well tolerated when patients are hemodynamically stable and treatment is initiated at low doses.

Contraindications of Phosphodiesterase Inhibitors

Concomitant Medications:

Concomitant therapy with nitrates or other potent drugs that enhance the NO–cGMP pathway is contraindicated. Caution is required when using inhibitors of the cytochrome P450 isoenzymes CYP3A4 and CYP2C9 (see Drug Interactions).

Heart:

Severe heart failure (NYHA III–IV), unstable coronary artery disease, recent myocardial infarction (within the last 6 months), uncontrolled hypotension or uncontrolled hypertension represent contraindications. Caution is necessary in patients with aortic stenosis or hypertrophic obstructive cardiomyopathy.

Central Nervous System:

Recent stroke (within the last 6 months).

Liver:

Severe hepatic impairment (Child–Pugh class C).

Kidney:

In patients with severe renal impairment with an estimated glomerular filtration rate (eGFR) below 30 mL/min, dose reduction to approximately 25–50% of the maximum recommended dose and prolongation of the dosing interval are necessary.

Eye:

A history of non-arteritic anterior ischemic optic neuropathy and the presence of retinitis pigmentosa are considered contraindications to PDE5 inhibitors.

Other Contraindications of Phosphodiesterase Inhibitors:

For the treatment of erectile dysfunction, PDE5 inhibitors are not approved for use in women or children. Caution is warranted in patients with multiple system atrophy (due to the risk of marked hypotension). Caution is also necessary in patients with a predisposition to priapism such as sickle cell anemia, leukemia, or multiple myeloma.

Sildenafil

Pharmacokinetics of Sildenafil

Sildenafil is rapidly absorbed after oral administration, with an oral bioavailability of approximately 40%. Peak plasma concentrations are reached 30–120 minutes after ingestion on an empty stomach. Co-administration with a high-fat meal delays the time to maximum plasma concentration by about 1 hour and reduces peak plasma concentrations by approximately 30 %. The duration of action is about 4–5 hours. Sildenafil undergoes hepatic metabolism primarily via cytochrome P450 isoenzymes CYP3A4 and CYP2C9. The elimination half-life is 3–5 hours. Metabolites are excreted predominantly (about 80 %) in the feces, with the remainder excreted in the urine.

Dosing of Sildenafil

Tadalafil

Pharmacokinetics of Tadalafil

Tadalafil is well absorbed after oral administration with a high bioavailability (approximately 80%). Peak plasma concentrations are reached after about 2 hours, and food has only little effect on the rate or extent of absorption. The duration of action extends up to 36 hours. Tadalafil undergoes hepatic metabolism primarily via CYP3A4. The elimination half-life is approximately 17–18 hours. Metabolites are excreted mainly (about 60 %) in the feces and to a lesser extent in the urine.

Dosing of Tadalafil

Vardenafil

Pharmacokinetics of Vardenafil

Vardenafil is absorbed after oral administration with an oral bioavailability of approximately 15%. Co-administration with a meal delays the time to maximum plasma concentration by about 1 hour and reduces peak plasma concentrations by approximately 20 %. Peak plasma levels are reached 30–120 minutes after ingestion. The duration of action is about 4–5 hours. Vardenafil undergoes hepatic metabolism primarily via CYP3A4. The elimination half-life is 4–5 hours. Metabolites are excreted predominantly (about 90 %) in the feces.

Dosing of Vardenafil

The recommended starting dose of vardenafil is 10 mg, with adjustment to 5 mg or 20 mg based on efficacy and tolerability. Dosing should not exceed once daily. In men with hepatic impairment, severe chronic kidney disease, significant cardiovascular risk factors, older age, or concomitant treatment with antihypertensive agents or cytochrome P450 inhibitors, the starting dose should be reduced to 5 mg vardenafil.

Avanafil

Pharmacokinetics of Avanafil

Avanafil is absorbed very rapidly after oral administration. The absolute oral bioavailability is not precisely known, but clinical data indicate good oral absorption with substantial first-pass metabolism. Peak plasma concentrations are reached 30–45 minutes after dosing, and the onset of effect may occur as early as 15 minutes. Co-administration with a high-fat meal delays the time to maximum plasma concentration by approximately 1.25 hours and reduces peak plasma concentrations by about 30–40%. Avanafil is metabolized predominantly by CYP3A4. The half-life varies greatly between 6 and 17 hours. The typical duration of action is 6–12 hours. Metabolites are excreted in the feces (around 60%) and urine (around 20%).

Dosing of Avanafil

The recommended starting dose of avanafil is 100 mg, with adjustment to 50 mg or 200 mg based on efficacy and tolerability. The tablet is taken as needed approximately 15–30 minutes before anticipated sexual activity; the maximum recommended dosing frequency is once daily. In older patients or in those receiving moderate CYP3A4 inhibitors, a starting dose of 50 mg should be considered. Concomitant use with strong CYP3A4 inhibitors is contraindicated.






Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

References

Hatzimouratidis und Hatzichristou 2007 HATZIMOURATIDIS, Konstantinos ; HATZICHRISTOU, Dimitrios: Phosphodiesterase type 5 inhibitors: the day after.
In: Eur Urol
51 (2007), Jan, Nr. 1, S. 75–88; discussion 89

R. A. Kloner et al., “Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men,” J Urol, vol. 172, no. 5 Pt 1, pp. 1935–40, 2004.

Laydner, H. K.; Oliveira, P.; Oliveira, C. R. A.; Makarawo, T. P.; Andrade, W. S.; Tannus, M. & Araújo, J. L. R. Phosphodiesterase 5 inhibitors for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a systematic review.
BJU Int, 2011, 107, 1104-1109.

F. Montorsi et al., “Effect of nightly versus on-demand vardenafil on recovery of erectile function in men following bilateral nerve-sparing radical prostatectomy.,” Eur Urol, vol. 54, no. 4, pp. 924–931, 2008.

Oelke, M.; Giuliano, F.; Mirone, V.; Xu, L.; Cox, D. & Viktrup, L. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial.
Eur Urol, 2012, 61, 917-925.



  Deutsche Version: MNebenwirkungen und Kontraindikationen der Phosphodiesterase-5-Hemmer

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