In patients with renal and hepatic insufficiency special dose adjustments have to be considered in dependence of the severity of organ failure and the appliedPDE-5 inhibitor (see Table Pharmacodynamic issues with the three PDE-5 inhibitors)

Table Pharmacodynamic issues with the three PDE-5 inhibitors

Parameter/Condition Sildenafil Tadalafil Vardenafil
CYP3A4 inhibitors1 Start dose 25 mg Max.dose 10mg/72h Max. 2.5mg/day
CYP3A4 inhibitors2 Start dose 25 mg

Max.dose 25 mg/day

Max.dose 10mg/72h Max.dose 2.5 mg/72h
Age >65 years Start dose 25 mg No dose adjustment Start dose 5mg
Severe renal failure (Creatinine clearance <30ml/min.) Start dose 25 mg Max.dose 5mg No dose adjustment
Mild/mod.hepatic failure (Child PughA/B) Start dose 25 mg Max.dose 10mg Start dose 5mg Max.dose 10mg
Blood pressure drop systolic/diastolic 8.4/5.5 mmHg 1.6/0.8mmHg 7/8mmHg
Alpha-blockers Interval of 4h recommended Stable alpha-blocker therapy recommend. Start dose 5mg Stable alpha-blocker therapy recommend. Start dose 10mg
Anti hypertens ives (all drug classes) No interactions of clinical relevance No interactions of clinical relevance No interactions of clinical relevance
Alcohol intake (0.5-0.6g/Kg) No additional hypotensive effect No additional hypotensive effect No additional hypotensive effect
Contraindications Nitrates and NO donors3 Nitrates and NO donors Nitrates and NO donors
Safe interval for nitrate medication in emergencies Not defined (presumably 24h) 48 hours 24 hours

1 CYP3A4 inhibitors: erythromycin, ketoconacole, itraconacole: up to 3-10 fold increases in the plasma concentrations of the respective PDE-5 inhibitors. Cimetidine: 56% increase insildenafil plasma concentrations; not valid for vardenafil; tadalafil not reported.

2 CYP 3A4 inhibitors: protease inhibitors ritonavir, indinavir, saquinavir: increase in plasma concentrations of the respective PDE-5 inhibitors between 1.5-fold (tadalafil) and 16-fold (vardenafil). CYP3A4inducers: Rifampin: decrease of PDE-5 inhibitor plasma levels up to 88% (reported for tadalafil)

3 Nitratesand NO donors: all short and long-acting nitrate-containing drugs, including recreational drugs such as “poppers” as well asmolsidomineand nitroprussid-natrium containing medications

Bleeding time

Both with aspirin 150 mg and warfarin, no increase in bleeding time was observed with the PDE-5 inhibitors. After heparin, sildenafil showed an additive effect on bleeding time in rabbits, but this interaction trial was not conducted in humans.

Cardiovascular risk patients

Those with left ventricular outflow obstruction (aortic and subaortic stenosis), recent (<6 months) my-ocardial infarction, and stroke or life threatening arrhythmias, as well as hypotensive (RR < 90/50) and hypertensive (RR > 170/110) patients, can be particularly sensitive to the systemic actions of PDE-5 inhibitors.

In conditions/drugs with a known risk of priapism, such as sickle cell disease, leukemia and multiple myeloma, PDE-5 inhibitors must be used with special precautions.

Alpha blockers

Sildenafil 25 mg simultaneously applied with doxazosin 4mg resulted in symptomatic postural hypotension, which was also the case with tadalafil 20mg. After tamsulosin 0.4mg, both tadalafil 20 mg and vardenafil 5mg did not exert any clinically relevant influence on blood pressure, whereas vardenafil 5 mg, if simultaneously applied with terazosin 10 mg, resulted in symptomatic hypotension, which could not be observed if both drugs were taken six hours apart. Tadalafil 20mg applied with alfuzosin 10 mg did not result in clinically significant hemodynamic interaction.

Nitrate-/NO donor interactions

All three phosphodiesterase – 5 inhibitors showed clinically relevant interactions with nitrates in the sense of symptomatic blood pressure decays if given simultaneously. Therefore all three PDE-5 inhibitors are contraindicated for patients with nitrate medications. The time interval considered to be safe between the administration of a PDE-5 inhibitor and a nitrate medication is 24 hours for the short-acting sildenafil and vardenafil, and 48 hours for tadalafil.

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