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Induces smooth-muscle relaxation in cavernosal arteries & in peripheral circulation
MOA of PDE5 5 inhibitors
Comparison of sildenafil, vardenafil, tadalafil
They all are all PDE5 inhibitors with the same mechanism of action and similar adverse effects.
They all require sexual stimulation as a prerequisite and are effective regardless of the cause of erectile dysfunction.
Sidenafil has been around the longest and thus has the benefit of having long-term safety data.
However, it is also administered in higher doses than the others.
Comparison of sildenafil, vardenafil, tadalafil PDE5 inhibitor Duration Sildenafil 12 hours Vardenafil 4-5 hours Tadalafil 36 hours Vardenafil, however, is the most potent (lowest maximal concentration) and binds to PDE5 more rapidly than the others, thus it has a potential time of onset of 10 minutes.
10mg and 20mg doses
To take tadalafil 2 hours before sexual intercourse
Neither the consumption of a high-fat meal nor the timing of the dosing (morning or evening) had an effect on changes in plasma concentration or time to maximal response.
Maximum dosing frequency is once every other day
Efficacy is maintained for at least 36 hours
Improved erections have been reported by 82.8% of treated men.
36 hours after administration of Tadalafil, 59.2% of intercourse attempts were successful.
Headache, flushing, rhinitis and back pain/myalagia.
Precautions - Use with alpha-blockers: contraindicated except with tamsulosin 0.4 mg once daily
Use in renal insufficiency: dose decreased to 5 mg once daily in moderate or severe renal insufficiency (creatinine clearance < 30 mL/minute); no data available in patients on dialysis
It also serves as an inhibitor of PDE11, an enzyme in the testes, so there is concern on the effect that it has on sperm and spermatogenesis
High incidence of myopathy could be there if simvastatin is used concomitantly with CYP3A4 inhibitors such as PDE5 inhibitors as muscle toxicity is a potential adverse effect not only for statins, but also with PDE5 inhibitors .
Studies on Tadalafil on ED in Diabetic men
191 (88%) of 216 patients completed the study.
Treatment with tadalafil significantly improved all primary efficacy variables, regardless of baseline HbA1c level but tadalafil did not alter mean HbA1c levels.
Tadalafil was well tolerated,
Headache and dyspepsia were the most frequent adverse events.
A randomized, double-blind, placebo-controlled, multicenter, 12-week study of 298 diabetic men with erectile dysfunction was done by 9 investigators in Greece to study whether once-daily use of smaller doses, 2.5 or 5 mg, would also work.
Parameters measured included:
completion of intercourse, and
the International Index of Erectile Function Domain scores to assess success.
Adverse effects included back pain, headache, and dyspepsia.
Low dose taken daily produced statistically significant improvement.
Medscape J Med. 2008; 10(5): 127 by George D. Lundberg.
CLASS EFFECT OR MOLECULE EFFECT? Bonus effects of Tadalafil
Tadalafil and metabolic syndrome
PDE5 inhibition may not only help in improving ED in diabetic male patients but also in improving β-cell function in metabolic syndrome.
Diabetes Care May 2009 vol. 32 no. 5 857-859 by Kevin D. Hill et al.
Tadalafil, alone or in combination with ramipril, improved basal and glucose-stimulated β-cell function.
The metabolic improvement effect was independent of insulin sensitivity, as indicated by improvement in the disposition index
Tadalafil and cardiovascular medicine
Pulmonary arterial hypertension (PAH) secondary to chronic obstructive pulmonary disease (COPD) is incurable and it has an unpredictable survival rate .
The Korean Journal of Internal Medicine : 22:37-39, 2007, Use of Tadalafil for treating PAH Secondary to COPD by Hyun-Sook Kim et al .
Patients suffering from COPD with progressive dyspnea and edema, viz. PAH, were prescribed tadalafil 10 mg orally every other day in addition to the baseline therapy for their depressed ventilatory function for 2 weeks
Then the dosage was doubled. The medication was well tolerated without any notable side effects.
After 4 weeks of tadalafil treatment, the patients' pulmonary arterial pressure was decreased and the MPI of the RV [myocardial performance index] improved.
The exercise capacity, as measured by the respiratory oxygen uptake, also improved.
Tadalafil and PAH and beyond
Thus, PDE5 inhibition by Tadalfil has been shown to be effective for the treatment of idiopathic PAH.
This therapeutic potential also extends to
essential hypertension and
Therapy of heart failure is the indication where PDE-5 inhibitors seem to find clinical application but preclinical data also support a role in cardiac preconditioning.
Curr Pharm Des. 2009;15(30):3521-39. PDE5 inhibitors in non-urological conditions by Vlachopoulos C, et al. Curr Pharm Des. 2009;15(30):3540-51. Phosphodiesterase-5 inhibitors: future perspectives by Konstantinos G et al
Problems with PDE5 inhibitors
Despite the fact that more than 50 million ED patients have been treated successfully worldwide with PDE5 inhibitors, several issues remain to be addressed.
Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors.
Inappropriate instructions, lack of follow-up and lack of patient-care models have been identified as main reasons for "nonresponse", with drop-out rates of even > 50%.
Curr Pharm Des. 2009;15(30):3476-85. Phosphodiesterase type 5 inhibitors: unmet needs by Hatzimouratidis K, Hatzichristou DG..
Problems of ED in patients with heart disease
The ACC/AHA consensus statement about the groups of patients at risk of potentially hazardous cardiovascular effects of PDE-5 inhibitors.
Patients with active coronary ischemia , even who are not taking nitrate ( positive ETT )
Patients with HF and borderline low BP and /or low volume status .
Patients on a complicated multidrug antihypertensive drugs regimen .
Patients taking drugs that prolong the half life of PDE5 inhibitors by blocking CYP 3A4