Erectile Dysfunction

Joseph A. Aloi, MD Associate Professor of Clinical Internal Medicine

Oral Phosphodiesterase Type 5 (PDE5) Inhibitors1,2
 Sildenafil  Currently available  Tadalafil and vardenafil  NDA submitted  Potent and selective for PDE5 isoenzyme

1. Lue TF. N Engl J Med. 2000;342:1802-1813. 2. Padma-Nathan H, Giuliano F. Urol Clin North Am. 2001;28:321-334. Med.

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Mechanism of Action of PDE5 Inhibitors

Adapted with permission from Lue TF. N Engl J Med. 2000;342:1802-1813. Med.

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Mechanism of Action of PDE5 Inhibitors

Adapted with permission from Lue TF. N Engl J Med. 2000;342:1802-1813. Med.

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Distribution of PDE Isoenzymes
PDE1 PDE2 PDE3 PDE4 PDE5 Testes, heart, olfactory cilia, CNS CNS, adrenal cortex Adipose tissue, cardiac muscle, vascular smooth muscle, liver, platelets Neural and endocrine tissues1 Vascular smooth muscle, corpus cavernosum, lung, kidney, platelets1,2

1. Francis SH, et al. In: Progress in Nucleic Acid Research and Molecular Biology. Academic Press; 2001;65:1-52. Biology. 2. Ballard SA, et al. J Urol. 1998;159:2164-2171. Urol.

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Distribution of PDE Isoenzymes (cont)
PDE6 PDE7 PDE8 PDE9 Retina (rods and cones)1,2 Skeletal and cardiac muscle, lymphoid tissue1 Testes, ovary, colon, small intestine Spleen, intestine, kidney, heart, brain

PDE10 Not reported1 PDE11 Penile smooth muscle, corpus cavernosum,2 testes, pituitary
1. Francis SH, et al. In: Progress in Nucleic Acid Research and Molecular Biology. Academic Press; 2001;65:1-52. Biology. 2. Baxendale RW, et al. J Urol. 2001;165(suppl):223-224. Abstract 922. Urol.
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Assumed Role of PDEs
Isoform Assumed Role

PDE1 PDE2 PDE3 PDE4 PDE5 PDE6

CNS modulation, vasodilation Uncertain Positive inotropism, vascular and airway dilation, platelet inhibition Airway dilation, CNS modulation, sperm and egg maturation Penile detumescence, vasoconstriction, platelet inhibition Phototransduction

PDE5: Localization1,2
 PDE5 is localized in vascular and penile smooth muscle cells  Concentration in corpus cavernosum is higher than systemic vasculature  PDE5 is not localized in the following:     Cardiac myocytes Endothelial cells Lymphatic cells Cardiac conduction tissue

1. Wallis RM, et al. Am J Cardiol. 1999;83(suppl 5A):3C-12C. 2. Parums DV, et al. Abstract presented at: XXII Annual Cardiol. Congress of the European Society of Cardiology; August 26-30, 2000.

PDE5 Inhibitors: Selectivity for PDE5 vs Other PDEs
PDE Isoenzyme Sildenafil1,2 PDE1 PDE2 PDE3 PDE4 PDE6 PDE7-10
nr = not reported. 1. Ballard SA, et al. J Urol. 1998;159:2164-2171. 2. Viagra prescribing information, January 2000. 3. Data on file, Lilly ICOS LLC. Urol. 4. Sorbera LA, et al. Drugs Future. 2001;26:141-144. Future.
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Tadalafil3 >10,000 >10,000 >10,000 >10,000 780 >10,000

Vardenafil4 >200 >14,000 >3000 >5000 >200 nr

>80 >1000 4000 >1000 9 nr

PDE5 Inhibitors: Pharmacokinetics
Parameter Bioavailability
∆ Cmax with food Tmax (h) t1/2 (h)

Sildenafil1,2 40%
⇓29% 1* 3-5

Tadalafil3,4 nd
no change 2* 17.5

Vardenafil5-7 nr
nr <1 ~4

∆ Cmax=change in maximum plasma concentration Tmax=time to maximum plasma concentration t1/2 =plasma half-life nd=not determined nr = not reported *Median 1. Viagra prescribing information, January 2000. 2. Padma-Nathan H, Giuliano F. Urol Clin North Am. 2001;28:321-334. 3. Patterson B, et al. Poster presented at: 4th Congress (Biennial Meeting) of the European Society for Sexual and Impotence Research; September 30, 2001; Rome. 4. Data on file, Lilly ICOS LLC. 5. Klotz T, et al. World J Urol. 2001;19:32-39. 6. Stark S, et al. Eur Urol. 2001;40:181-190. 7. Sorbera LA, et al. Drugs Future. 2001;26:141-144. Urol. Future.

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PDE5 Inhibitors: Onset and Duration of Activity*

PDE5 Inhibitor Sildenafil1,2 Tadalafil3 Vardenafil4

Onset (min) 30-60* 30-45*;16† nr

Duration (h) 4* ≥ 24*‡ nr

*RigiScan® with visual sexual stimulation; oral dosing, empty stomach. † Home setting; stopwatch recording. ‡ Home setting; journal recording based on time frames. nr = not reported. 1. Viagra prescribing information, January 2000. 2. Boolell M, et al. Int J Impot Res. 1996;8:47-52. 3. Padma-Nathan H. Res. J Urol. 2001;165(suppl):224, Abstract 923. 4. Sorbera LA, et al. Drugs Future. 2001;26:141-144. Urol. Future.

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Novel PDE5 Inhibitors: Pharmacokinetic Implications
 Broader therapeutic window (>24 h)  Greater spontaneity  Bioavailability unaffected by food  More acceptable “real-life” setting  Greater selectivity

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PDE5 Inhibitors Meet Important Patient Needs
 Most patients prefer oral therapy1  Mechanism of action is physiologically-based  Newer agent(s) may offer an opportunity to increase spontaneity/flexibility  Consideration of partner needs and satisfaction1  Long-term improvement in quality of life1,2

1. Jarow JP, et al. J Urol. 1996;155:1609-1612. 2. Marwick C. JAMA. 1999;281:2173-2174. Urol. JAMA.

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Optimizing PDE5 Inhibitor Therapy
Incorrect use ⇒ treatment failure  Patients should be advised that:  Sexual stimulation is needed1  A number of drug trials may be required  Sildenafil may be taken with food but onset of action may be delayed

1. Sadovsky R, et al. Int J Clin Pract. 2001;55:115-128. Pract.

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Optimizing PDE5 Inhibitor Therapy (cont)
Incorrect use ⇒ treatment failure  Testosterone augmentation should be prescribed in documented hypogonadism1  Risk factor modification may improve treatment outcomes2  Follow-up visits are essential3

1. AACE Clinical Practice Guidelines. Endocrine Pract. 1998;4:220-235. 2. Guay AT, et al. J Androl. 2001;22:793-797. Pract. 3. Sadovsky R, et al. Int J Clin Pract. 2001;55:115-128.

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Tadalafil Treatment Effect on *† Successful Intercourse: SEP Q3

*

Did your erection last long enough to have successful intercourse? All randomized patients. Studies LVBN, LVCE, LVCO, and LVDJ.
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Brock GB, et al. J Urol. 2002;168:1332-1336. Urol.

Tadalafil Treatment Effect on *† Improved Erections: GAQ

*Has the treatment you have been taking improved your erections? † All randomized patients. Studies LVBN, LVCE, LVCO, and LVDJ. Brock GB, et al. J Urol. 2002;168:1332-1336. Urol.
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Tadalafil: Most Common Treatment-Related Adverse Events*
Adverse Event % of Patients Reporting Event Placebo (n=758) Headache Dyspepsia Back pain Myalgia Nasal congestion Flushing
*Phase II/Ill – Adverse Events ≥ 2%. McMahon CG. Paper presented at: 4th Congress (Biennial Meeting) of the European Society for Sexual and Impotence Research; September 30-October 3, 2001; Rome.

Tadalafil (n=1561) 11 7 4 4 4 4

4 1 3 1 2 1

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Vardenafil: Tolerability
Adverse Event

*

% of Patients Reporting Event Placebo (n=152) Vardenafil (n=438) 10 11 3 5

Headache Flushing Dyspepsia Rhinitis

4 1 0 3

*Phase IIb – Adverse Events ≥ 5%. Porst H, et al. Int J Impot Res. 2001;13:192-199. Res.
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Cardiovascular Tolerance for Sexual Activity

Arousal
(Risk)

Exertion
(Metabolism)

Metabolic Equivalents (METs) of Selected Physical Activities
Resting1 Walking 2 mph, level1 Walking 3 mph, level1 "Sexual activity" pre-orgasm2 "Sexual activity" during orgasm2 Cycling 10 mph, level1 Walking 4.2 mph, 16%1 (Bruce treadmill stage 4)
1. Fox SM 3rd , et al. Ann Clin Res. 1971;3:404-432. 2. Bohlen JG, et al. Arch Intern Med. 1984;144:1745-1748. Res.

1 2 3 2-3 3-4 6-7 13

Blood Pressure and Heart Rate During Sex
170 SBP = Systolic Blood Pressure 150 SBP Man on Top Man on Bottom HR = Heart Rate Man on Top Man on Bottom

HR (bpm) BP (mm Hg)

130 110 90 70 50 R I DBP HR

DBP = Diastolic Blood Pressure Man on Top Man on Bottom 30 Sec 60 120 Sec Sec

O

R = Rest; I = Intromission; O = Orgasm.

Phase of Intercourse
Pollock ML, et al. Heart Disease and Rehabilitation. Human Kinetics: Champaign, Ill. 1995:372. Rehabilitation.

Risk of Acute MI Triggered by Sexual Activity
 1663 MI survivors  858 sexually active prior to MI  27 sexually active in 2 hours prior to index MI  Relative risk of acute MI = 2x  Actual MI triggered by sexual activity: 0.9% of cases

Muller JE, et al. JAMA. 1996;275:1405-1409. JAMA.

Sexual Activity and Cardiac Risk Assessment
Princeton Guidelines
Sexual activity deferred until stabilization of cardiac condition

High Risk

Sexual Inquiry

Clinical Evaluatio n

Indeterminate Risk

Cardiovascular Assessment and Restratificatio n

Low Risk

Initiate or resume sexual activity or treatment for sexual dysfunction

Adapted from DeBusk R, et al. Am J Cardiol. 2000;86:175-181. Cardiol.

Management Recommendations Based on Graded Cardiovascular Risk Assessment
Grade of Risk Low risk Management Recommendations Primary care management Consider all first-line therapies Reassess at regular intervals (6-12 mo) Specialized cardiovascular testing (eg, ETT, echo) Restratification into high risk or low risk based on the results of cardiovascular assessment High risk Priority referral for specialized cardiovascular management Treatment for sexual dysfunction to be deferred until cardiac condition stabilized and dependent on specialist recommendations

Indeterminate risk

DeBusk R, et al. Am J Cardiol. 2000;86:175-181. Cardiol.

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ED Is Vascular
Diabetes

Precursors Oxidative stress

Dyslipidemia

Hypertension

Tobacco

Vasoconstriction

Endothelial cell injury

Atherosclerosis

Erectile dysfunction

Thrombosis

Outcomes Outcomes

Why Use Patient Questionnaires?
 Facilitate dialogue and diagnosis  Evaluate treatment changes  Examples of self-administered, standardized questionnaires  Sexual Health Inventory for Men (SHIM)1  International Index of Erectile Function (IIEF)2

1. Rosen RC, et al. Int J Impot Res. 1999;11:319-326. 2. Rosen RC, et al. Urology. 1997;49:822-830.

SHIM Score Characterizes ED Severity*
 22-25  17-21  12-16  8-11  ≤7 Normal erectile function Mild ED Mild to moderate ED Moderate ED Severe ED

*

Total score ranges from 5 to 25 and is based on 5 questions. Each rated on a Likert scale of 1 = least functional to 5 = most functional. Rosen RC, et al. Int J Impot Res. 1999;11:319-326.

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