Erectile Dysfunction This is not a pharmacy Store! www.ViagraDiscount.co.uk
Nov 16, 2014
Erectile Dysfunction
This is not a pharmacy Store!
www.ViagraDiscount.co.uk
Oral Phosphodiesterase Type 5 (PDE5) Inhibitors1,2
Sildenafil
Currently available
Tadalafil and vardenafil
NDA submitted
Potent and selective for PDE5 isoenzyme
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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
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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
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Assumed Role of PDEs
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
Isoform Assumed Role
PDE5: Localization1,2
PDE5 is localized in vascular and penilesmooth 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
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PDE5 Inhibitors: Selectivity for PDE5 vs Other PDEs
PDE Isoenzyme Sildenafil1,2 Tadalafil3 Vardenafil4
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
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.
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
PDE5 Inhibitors: Onset and Duration of Activity*
*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.
PDE5 Inhibitor Onset (min) Duration (h)
Sildenafil1,2 30-60* 4*
Tadalafil3 30-45*;16† 24*‡
Vardenafil4 nr nr
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
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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
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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
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Tadalafil Treatment Effect onSuccessful 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*
*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.
Adverse Event% of Patients Reporting Event
Placebo(n=758)
Tadalafil(n=1561)
Headache 4 11
Dyspepsia 1 7
Back pain 3 4
Myalgia 1 4
Nasal congestion 2 4
Flushing 1 4
Vardenafil: Tolerability*
*Phase IIb – Adverse Events 5%.
Porst H, et al. Int J Impot Res. 2001;13:192-199.
Adverse Event% of Patients Reporting Event
Placebo(n=152)
Vardenafil(n=438)
Headache 4 10
Flushing 1 11
Dyspepsia 0 3
Rhinitis 3 5
Cardiovascular Tolerancefor Sexual Activity
Exertion
(Metabolism)
Arousal
(Risk)
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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)
Metabolic Equivalents (METs) of Selected Physical Activities
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.
Pollock ML, et al. Heart Disease and Rehabilitation. Human Kinetics: Champaign, Ill. 1995:372.
Blood Pressure and Heart Rate During Sex
HR
(b
pm
)
BP
(m
m H
g)
SBP
HR
DBP
R I O 30
Sec
60
Sec
120
Sec
Phase of Intercourse
170
150
130
110
90
70
50
SBP = Systolic Blood Pressure
Man on Top
Man on Bottom
R = Rest; I = Intromission; O = Orgasm.
HR = Heart Rate
Man on Top
Man on Bottom
DBP = Diastolic Blood Pressure
Man on Top
Man on Bottom
Muller JE, et al. JAMA. 1996;275:1405-1409.
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
Sexual Activity and Cardiac Risk Assessment
Adapted from DeBusk R, et al. Am J Cardiol. 2000;86:175-181.
Sexual activity deferred until
stabilization of cardiac
condition
Cardiovascular
Assessment and
Restratification
Indeterminate Risk
High
Risk
Low
Risk
Sexual
Inquiry
Initiate or resume sexual
activity or treatment for
sexual dysfunction
Clinical
Evaluation
Princeton Guidelines
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
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ED Is VascularDiabetesDiabetes
HypertensionHypertensionOxidative stress
Endothelial cell
injury
VasoconstrictionVasoconstriction
Erectile dysfunctionErectile dysfunction
OutcomesOutcomes
DyslipidemiaDyslipidemia
TobaccoTobacco
ThrombosisThrombosis
AtherosclerosisAtherosclerosis
PrecursorsPrecursors
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
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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
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