1. Evolving Strategy in Erectile Dysfunction Management TY Chu Urology Division Department of Surgery PYNEH

3. Don’t Be Shy !!!

4. No erectile dysfunction (48%) Erectile dysfunction (52%) Complete (10%) Moderate (25%) Mild (17%) Men aged 40 to 70 years Prevalence of Erectile Dysfunction Massachusetts Male Aging Study (N=1,290) Feldman et al, 1994

5. 0 20 40 60 80 Age and Prevalence 40506070 Age (yr) 39% 48% 57% 67% Prevalence (%) Complete ED Moderate ED Mild ED Massachusetts Male Aging Study (N=1,290) Feldman et al, 1994

6. Pump it Up ! Inject it Up ! Put in Rods ! In the past ……

7. Erectile dysfunction (ED) is defined as the consistent inability to attain and maintain a penile erection adequate for satisfactory sexual activity. Definition NIH Consensus Development Panel on Impotence, 1993 In the past: … … penile erection adequate for vaginal penetration

8. Etiology of Erectile Dysfunction For simplicity, erectile dysfunction can be classified as: Organic - due to vasculogenic, neurologic, hormonal, or cavernosal abnormalities or lesions Psychogenic - due to central inhibition of the erectile mechanism without a physical insult *However, in most patients with erectile dysfunction, a combination of organic and psychogenic components is involved. NIH Consensus Development Panel on Impotence, 1993 Benet and Melman, 1995

9. Physiology of penile erection

10. Central Control of Penile Erection Cortex Proerectile stimuli: imagination, audiovisual, tactile Inhibitory stimuli: depression, anxiety, fear + PVN – Dopamine Dopamine receptors Neural erectile signalling Penile erection NO

11. Penile Erection Cavernosal smooth muscle cells

12. PDE-5 Inhibitors Because these drugs do not stimulate the cascade of events, but rather prevent a catabolic step, they have no inherent ability to produce an erection. Therefore, sexual stimulation is required for the medications to be effective, leading some to characterize PDE5 inhibitors as facilitators rather than instigators of tumescence. Krenzelok EP. Sildenafil: clinical toxicology profile. Clin Toxicol. 2000;38:645-51.

13. PDE5 – inhibitors Sildenafil (Viagra) – initially under trial for cardiac conditions such as angina found to increased blood flow to the penis & increased erections in 1994 1998 – sildenafil the first oral anti-impotence drug approved by the FDA Various newer oral anti-impotence drugs emerged within the last few years (introduction of Tadalafil and Vardenafil to HK in the years 2003 and 2004 respectively) The treatment of ED was revolutionized because of their effectiveness and convenience

14. Sildenafil is effective in all types of ED † p=0.0001 sildenafil vs placebo Results of a combined, retrospective analysis of the intent-to-treat population from 11 randomized, placebo- controlled, flexible-dose, clinical trial at week 12 n=755n=766 n=145n=166n=295n=312 † † †

15. Percentage patients with improvement in erections by age n=1567n=1968n=143n=222n=470n=586n=603n=753n=351n=407 +p=0.0001 sildenafil vs placebo Results of a combined, retrospective analysis of the intent-to-treat population from 11 randomized, double-blind, placebo-controlled, flexible-dose, clinical trials at week 12 on the Global Efficacy Assessment measure of improvement in erections Age ≥65

17. Current PDE-5 Inhibitors N H N N O O C H 3 O O H H Tadalafil OH O O P O Cyclic GMP NH N N N O O H2NH2N O CH 3 S N N CH 3 O O Vardenafil N H N O CH 3 N 3 CH N O CH S N N CH 3 O O Sildenafil NH N N N O 3 CH 3 CH

18. PDE5 – Inhibitors Efficacy Sidenafil (Viagra)Vardenafil (Levitra)Tadalafil (Cialis) Potency IC50 (nM) 3.50.16.7 Dosage50 / 100 mg10 / 20 mg Response Rate82 % (100mg)80 % (20mg)70 % (20mg) *IC50: inhibitory concentration – concentration of chemical agent to inhibit 50% of receptors

19. PDE5 – Inhibitors Therapeutic window Sidenafil (Viagra)Vardenafil (Levitra)Tadalafil (Cialis) Peak plasma concentration (hours) 0.5 – 2 Median: 1 0.5 – 2 Median: 1 0.5 – 6 Median: 2 To Be taken~1 hour before sexual activity Prior to anticipated sexual activity Duration (hours)4536 Half-life (hours) 44 - 517.5

20. SildenafilVardenafilTadalafil Headache20%17%12% Flush16%10%7% Rhinitis7%6%4% Dyspepsia6% 5% Myalgia / back pain <1% 3% Visual disturbance 3%<2%<0.1% Side Effects of the 3 PDE-5 Inhibitors

21. In the Past … …

22. What’s New … … The current availability of these high efficacy oral drugs, have changed our strategy in ED management Any men who wishes to have erectile function can do so regardless of the etiology of the problem, and the task of the physician is to help the patient seek the best solution - Goal Directed Approach – the single most important concept in managing ED Men with ED could be treated with PDE5 inhibitors (no cause-specific treatment option) with little or no evaluation, in view of its efficacy, safety, invasivess and cost, as well as patient preference Lue TF. Erectile dysfunction. N Engl J Med 2000

23. Take Home Messages Erectile dysfunction is a common condition. Advances in understanding the physiology of penile erection make a great deal of progress in the pharmacological treatment of ED. Modern treatment of ED has been revolutionized by the worldwide availability of the oral PDE5 inhibitors, which are associated with high efficacy and safety rates, regardless of the causes.