Erectile Dysfunction

www.ViagraDiscount.co.uk

This is not a pharmacy Store!

 Oral Phosphodiesterase Type 5
(PDE5) Inhibitors1,2

 Sildenafil
 Currently available
 Tadalafil and vardenafil
 NDA submitted
 Potent and selective for PDE5 isoenzyme

www.ViagraDiscount.co.uk
 Mechanism of Action of
PDE5 Inhibitors

www.ViagraDiscount.co.uk
 Mechanism of Action of
PDE5 Inhibitors

www.ViagraDiscount.co.uk
 Distribution of PDE Isoenzymes

PDE1 Testes, heart, olfactory cilia, CNS

PDE2 CNS, adrenal cortex

PDE3 Adipose tissue, cardiac muscle, vascular smooth muscle, liver,

platelets

PDE4 Neural and endocrine tissues1

PDE5 Vascular smooth muscle, corpus cavernosum, lung, kidney,

platelets1,2

www.ViagraDiscount.co.uk
 Distribution of PDE Isoenzymes (cont)

PDE6 Retina (rods and cones)1,2

PDE7 Skeletal and cardiac muscle, lymphoid
tissue1
PDE8 Testes, ovary, colon, small intestine
PDE9 Spleen, intestine, kidney, heart, brain

PDE10 Not reported1

PDE11 Penile smooth muscle, corpus
cavernosum,2 testes, pituitary
www.ViagraDiscount.co.uk
 Assumed Role of PDEs
Isoform Assumed Role

PDE1 CNS modulation, vasodilation

PDE2 Uncertain
PDE3 Positive inotropism, vascular and
airway dilation, platelet inhibition
PDE4 Airway dilation, CNS modulation,
sperm and egg maturation
PDE5 Penile detumescence,
vasoconstriction, platelet inhibition
PDE6 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

www.ViagraDiscount.co.uk
 PDE5 Inhibitors: Selectivity for
PDE5 vs Other PDEs

PDE
Sildenafil1,2 Tadalafil3 Vardenafil4
Isoenzyme
PDE1 >80 >10,000 >200

PDE2 >1000 >10,000 >14,000

PDE3 4000 >10,000 >3000

PDE4 >1000 >10,000 >5000

PDE6 9 780 >200

PDE7-10 nr >10,000 nr

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. 4. Sorbera LA, et al. Drugs Future. 2001;26:141-144.
 PDE5 Inhibitors:
Pharmacokinetics

Parameter Sildenafil1,2 Tadalafil3,4 Vardenafil5-7

Bioavailability 40% nd nr

Cmax with food 29% no change nr

Tmax (h) 1* 2* <1

t1/2 (h) 3-5 17.5 ~4

Cmax=change in maximum plasma concentration

Tmax=time to maximum plasma concentration

t =plasma half-life
1/2
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.
 PDE5 Inhibitors:
Onset and Duration of Activity*

PDE5 Inhibitor Onset (min) Duration (h)

Sildenafil1,2 30-60* 4*

Tadalafil3 30-45*;16† 24*‡

Vardenafil4 nr 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.

J Urol. 2001;165(suppl):224, Abstract 923. 4. Sorbera LA, et al. Drugs Future. 2001;26:141-144.
 Novel PDE5 Inhibitors:
Pharmacokinetic Implications

 Broader therapeutic window (>24 h)

 Greater spontaneity
 Bioavailability unaffected by food
 More acceptable “real-life” setting
 Greater selectivity

www.ViagraDiscount.co.uk
 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

www.ViagraDiscount.co.uk
 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

www.ViagraDiscount.co.uk
 Optimizing PDE5 Inhibitor Therapy (cont)

Incorrect use  treatment failure

 Testosterone augmentation should be
prescribed in documented hypogonadism 1
 Risk factor modification may improve
treatment outcomes2
 Follow-up visits are essential3

www.ViagraDiscount.co.uk
 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.

Brock GB, et al. J Urol. 2002;168:1332-1336.

 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.

 Tadalafil: Most Common
Treatment-Related Adverse Events*

% of Patients Reporting Event

Adverse Event
Placebo Tadalafil
(n=758) (n=1561)
Headache 4 11
Dyspepsia 1 7
Back pain 3 4
Myalgia 1 4
Nasal congestion 2 4
Flushing 1 4

*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.
 *
Vardenafil: Tolerability

% of Patients Reporting Event

Adverse Event
Placebo Vardenafil
(n=152) (n=438)
Headache 4 10
Flushing 1 11
Dyspepsia 0 3
Rhinitis 3 5

*Phase IIb – Adverse Events 5%.

Porst H, et al. Int J Impot Res. 2001;13:192-199.

 Cardiovascular Tolerance
for Sexual Activity

Arousal Exertion
(Risk) (Metabolism)

www.ViagraDiscount.co.uk
 Metabolic Equivalents (METs)
of Selected Physical Activities

Resting1 1

Walking 2 mph, level1 2

Walking 3 mph, level1 3

"Sexual activity" pre-orgasm2 2-3

"Sexual activity" during orgasm2 3-4

Cycling 10 mph, level1 6-7

Walking 4.2 mph, 16%1 13

(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.
 Blood Pressure and
Heart Rate During Sex

170

SBP = Systolic Blood Pressure

150
Man on Top
SBP
Man on Bottom
130
BP (mm Hg)
HR (bpm)

HR = Heart Rate
110
Man on Top

Man on Bottom
HR
90

70 DBP = Diastolic Blood Pressure

Man on Top
DBP
Man on Bottom
50

R I O 30 60 120
R = Rest; I = Intromission; O = Orgasm.
Sec Sec Sec

Phase of Intercourse

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

 Sexual Activity and
Cardiac Risk Assessment

Princeton Guidelines
High
Sexual activity deferred until
Risk
stabilization of cardiac condition

Cardiovascular
Sexual Clinical
Indeterminate Risk Assessment and
Inquiry Evaluation
Restratification

Low Initiate or resume sexual activity or

Risk treatment for sexual dysfunction

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

 Management Recommendations Based on
Graded Cardiovascular Risk Assessment

Grade of Risk Management Recommendations

Low risk Primary care management

Consider all first-line therapies

Reassess at regular intervals (6-12 mo)

Indeterminate risk 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

www.ViagraDiscount.co.uk
 ED Is Vascular
Diabetes
Diabetes Precursors
Precursors Dyslipidemia
Dyslipidemia

Oxidative stress
Hypertension
Hypertension Tobacco
Tobacco

Endothelial cell

injury
Vasoconstriction
Vasoconstriction Atherosclerosis
Atherosclerosis

Erectile
Erectile dysfunction
dysfunction Thrombosis
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

www.ViagraDiscount.co.uk
 SHIM Score Characterizes
ED Severity*

 22-25 Normal erectile function

 17-21 Mild ED

 12-16 Mild to moderate ED

 8-11 Moderate ED

 7 Severe ED

www.ViagraDiscount.co.uk