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PDE-5 Inhibitors
Mechanism of Action
Vardenafil
Tadalafil Udenafil Avanafil SLX-2101
Bayer AG
Eli Lilly Dong Pharmaceutical Co Ltd Tanabe Seiyaku, licence by Vivus Surface logics
PDE 5 inhibitors
Its relatively safe and efficient
Agents are selective (Sildenafil and vardenafil cross react slightly with PDE-6 and tadalafil with PDE-11)
FDA approved it for the treatment of Erectile dysfunction and Pulmonary Hypertension The other possible targets are still experimental
Possible targets
Non-urological
Cardiovascular diseases Central nervous system
Urological
Lower urinary tract symptoms Priapism Premature ejaculation Overactive bladder Female sexual arousal dysfunction Peyronies disease
Cardiovascular diseases
Endothelial dysfunction
Erectile dysfunction is a vascular disorder in most cases Endothelial dysfunction initial step in artherosclerosis of the penile vasculature and systemic vasculature
Endothelial dysfunction
Reduction in the bioavailability of vasodilators Shift towards vasoconstriction Leads to impairment of endothelial dependant vasodilatation
Markers of endothelial dysfunction Early intervention Decrease the risk of a cardiovascular event
Studies
PDE 5 inhibitor treatment have shown a decreased infarct size after ischemia-reperfusion injury in animal models
Chronic PDE 5 inhibitors increases endothelium dependant flow and improve endothelium function in patients at risk for myocardial injury (Foresta et al,2006)
Endothelial dysfunction is an early marker for atherosclerosis (Bocchio et al,2004) Endothelial dysfunction patient had a two field increase in the risk of acute myocardial infarction compared to non-endothelial dysfunction patients (Blumentals et al,2005)
Animal models : PDE 5 (Sildenafil) reduces pulmonary arterial pressure and right heart hypertrophy Clinical study SUPER 1 (Sildenafil use in pulmonary hypertension), multinational randomized controlled trial Results - well tolerated , improved exercise capacity and haemodynamic parameters Improving the cardiac output by decreasing the pulmonary arterial pressure Approved by FDA in 2005 for treatment of PAH
STUDIES
Anti proliferative factors Landmark experiment by (Takimoto et al,2005) in mice showed that chronic PDE 5 inhibitors prevent and reverse cardiac hypertrophy
Studies
Patients c an ejection fraction of 35% a single dose of 50mg sildenafil improved cardiac performance by decreasing peripheral resistance (Hirata et al) Sildenafil-increased endothelium dependant, flow mediated vasodilation in patients in chronic heart failure (Katz et al, 2000) The effect of left ventricular function is unknown
Hypertension
PDE 5 inhibitors due to its vasodilatory effect are a possible treatment option for hypertension Studies PDE 5 Inhibitors decrease the BP average 9/8 mm Hg (systolic/diastole) (Jackson et al, 2005)
CVA
Multiple studies in rats confirmed the neurogenic effect of PDE 5 inhibitors Treatment with Sildenafil for 7 days after an ischaemic event in the brain of rats
Results increase endothelial proliferation and synaptogenesis, increase functional recovery in the rodents (Zhang et al) However in humans PDE 5 inhibitors due to its vasodilatory effect are contraindicated in the first 6 months post stroke
Raynauds disease
Raynauds disease
Increasing evidence that NO/cGMP plays an important role
Open label pilot study investigated the effects of vardenafil on clinical symptoms in 40 patients c Raynaud phenomenon Doppler flow studies revealed increase in blood flow in 75% of the patients (Caglayan et al, 2006) Double blind placebo controlled trial ( Fries et al, 2005) showed decrease in frequency of the attacks and duration with capillary blood flow increasing in all the patients
Urological diseases
Lower urinary tract symptoms Overactive bladder Premature ejaculation Female sexual dysfunction Priapism Peyronies disease
Priapism
Stuttering priapism Hypothesis is that long term treatment c PDE 5 inhibitors may prevent the down regulation of PDE5 protein Therefore prevent the chronic cGMP accumulation and excessive blood flow in patients with priapism
Stuttering Priapism
Peyronies Disease
Cyclic GMP has been found to be anti fibrotic in Peyronies disease Long term treatment with PDE 5 inhibitors prevent plaque formation in rat models PDE 5 is expressed in tunical and Peyronies disease fibroblasts (Valente et al,2005) Treatment option further human studies required
Overactive Bladders
Mechanism of action Decrease the tone of the bladder (Sandner P et al) showed a decrease in the tone of the muscle strips of the male beagle dog between 70-20 %. Decreasing the frequency of urination and increases the volume of the bladder of conscious dogs
Premature Ejaculation
Hypothesis Prolongs intravaginal ejaculation latency time Two theories: central and peripheral
Central
NO/cGMP in the medial pre optic area of the brain causes erection and decrease central sympathetic output in the animal models Animal models Administration of PDE 5 inhibitors increase cGMP in the medial pre optic area (Sato et al,2007)
Peripheral
NO/cGMP causes relaxation of corporal smooth muscle Relaxation of the smooth muscle of the vas deferens, seminal vesicles, prostate and urethra
Studies
However no convincing evidence that on demand or daily PDE 5 inhibitors play a role in the treatment of premature ejaculation ( Atan et al,2006)) randomized control trial compared Placebo alone Sildenafil alone EMLA cream alone Sildenafil and EMLA cream Results Sildenafil was not more effective than the placebo EMLA cream alone was as effective as EMLA cream and Sildenafil
Conclusion
Daily low dose PDE-5 inhibitors may play a role in certain disease processes Drawback is the costs involved Further multinational randomized control trials or prospective studies are required to define the exact role of PDE-5 Inhibitors
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References
Anthony J, Ling X et al. Daily administration of Phosphodiesterase type 5 inhibitors for urological and nonurological conditions, European urology (2007) 52, 9901005 P sander, J Hutter, H Tinel et al. PDE 5 inhibitors beyond erectile dysfunction, International journal of impotence research (2007) 19, 533-543 P Montsori, P Ravagnani, S Galli et al. The triad of Endothelial Dysfunction, Cardiovascular Disease and Erectile Dysfunction Clinical implications, European urology (2009) 8, 58-66 M Guazzi et al. Clinical use of phosphodiesterase inhibitors in CHF, Circulation heart failure (2008) 1, 272-280