PDE 5 Inhibitors beyond erectile dysfunction

University of Witwatersrand Dr Nathan October

PDE-5 Inhibitors

Mechanism of Action

Approved and emerging PDE 5 inhibitors

Compound Company

Sildenafil Pfizer

Vardenafil Bayer AG

Tadalafil Eli Lilly

Udenafil Dong Pharmaceutical Co Ltd

Avanafil Tanabe Seiyaku, licence by Vivus

SLX-2101 Surface logics

• Is there any other application for the PDE 5 inhibitors?

Concentration sites of PDE- 5 • Corpora Cavernosum• Bladder• Prostate• Smooth muscle of systemic vasculature• Cardiac tissue• Brain• Platelets

PDE 5 inhibitors

• It’s relatively safe and efficient• Agents are selective (Sildenafil and vardenafil cross

react slightly with PDE-6 and tadalafil with PDE-11)

ALTERNATIVE DOSE REGIMEN

• On demand versus daily PDE 5 inhibitors

Daily PDE 5 inhibitors in Erectile dysfunction

• Multiple studies – improved outcome > Patients with poor response to on demand PDE 5 inhibitors > Diabetic patients > Post radical prostatectomy patients Triggered multiple attempts to find alternative applications for your PDE 5 inhibitors

• 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 Peyronie’s 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

• Causes of endothelial dysfunction

• Hypertension• Smoking• Diabetes Mellitus• Dyslipidemia• Smoking

Endothelial dysfunction

• Reduction in the bioavailability of vasodilators• Shift towards vasoconstriction• Leads to impairment of endothelial dependant

vasodilatation

Endothelial dysfuntion cont…

• Conclusions • Onset of sexual dysfunction is a marker of subclinical

vascular disease• Predictor of future cardiovascular event• Early recognition and treatment of endothelial

dysfunction may prevent future ischaemic heart disease

• PDE 5 inhibitors as a therapeutic tool in endothelial dysfunction ?

• Markers of endothelial dysfunction • Early intervention • Decrease the risk of a cardiovascular event

Clinical Indicators of Endothelial dysfunction

• Integrity of the endothelium• Circulating markers and Brachial artery mediated

dilatation

Endothelial dysfunction cont…

• Circulating markers• Indicates the integrity of the endothelium• Activated endothelial cells – indicates early development of

artherosclerosis• Namely : ADAM (Assymmetric dimethyl arginine)

hsCRP (High sensitivity c reactive protein)• Evidence that ADAM decrease the production of NO (Thum T

et al, 2005)• Exact pathological role of hsCRP unknown• hsCRP prognostic value for future cardiovascular events

(Bassuk et al,2004)

Brachial artery mediated dilatation

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)

• Cardio protective role is unclear ?

Cardiovascular & Endothelial

• Pulmonary Hypertension

• 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

• Congestive heart failure

• Vasoconstriction is a pathophysiological hallmark of congestive heart failure

• Hypothesis – PDE 5 inhibitors causes vasodilation most prominently in the pulmonary vasculature

• Increase the compliance of the larger vessels • Therefore decreasing the afterload, increases the

cardiac output

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 it’s 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 it’s vasodilatory effect are contraindicated in the first 6 months post stroke

Raynaud’s disease

Raynaud’s 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

Memory and Cognition

• PDE 5 inhibitors showed increase in the memory performance of rodents

• However the results in humans have only been studied sporadically

• Further trials required

Urological diseases

• Lower urinary tract symptoms• Overactive bladder• Premature ejaculation• Female sexual dysfunction• Priapism • Peyronie’s disease

LOWER URINARY TRACT SYMPTOMS

• PDE 5 inhibitors have shown to relax human prostate tissue in vitro

• Clinical trials - patient treated with 100mg Sildenafil or tadalafil 20 mg daily or placebo for 12 weeks

• IPSS was reduced with an average of 6.3 in the treatment group compared to 1.9 in the placebo group

• No change in the urodynamics of these patients (Mcvary.et al)

• Additional treatment option?

Priapism

• Stuttering priapism• Hypothesis is that long term treatment c PDE 5

inhibitors may prevent the down regulation of PDE- 5 protein

• Therefore prevent the chronic cGMP accumulation and excessive blood flow in patients with priapism

Stuttering Priapism

Peyronie’s Disease

• Cyclic GMP has been found to be anti fibrotic in Peyronie’s disease

• Long term treatment with PDE 5 inhibitors prevent plaque formation in rat models

• PDE 5 is expressed in tunical and Peyronie’s disease fibroblasts (Valente et al,2005)

• Treatment option further human studies required

Female sexual dysfunction

• Increase blood flow in the clitoral cavernosum and vagina

• Hypothesis it may benefit women with female sexual dysfunction

• The results were not very encouraging• Moderate effect in pre and post menopausal females

(Caruso et al, 2006)

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

THANK YOU

References

• Anthony J, Ling X et al. Daily administration of Phosphodiesterase type 5 inhibitors for urological and nonurological conditions, European urology (2007) 52, 990-1005

• 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