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PDE5 Inhibitors: Onset and Duration of Activity

PDE5 inhibitor Onset (min) Duration (h)

Sildenafil1,2 30-60* 4*

Tadalafil3-5 120 36‡

Vardenafil6-8 25* 4

Avanafil 7 35-45 5

1. Viagra® (sildenafil) prescribing information, September 2002. 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. Porst H. J Urol. 2002;167(suppl):176. Abstract 709. 5. Brock GB, et al. J Urol. 2002;168:1332-1336. 6. Vivanza (vardenafil) EU prescribing information, March 2003. 7. Klotz T, et al. World J Urol. 2001;19:32-39. 8. Stark S, et al. Eur Urol. 2001;40:181-188.7. Kedia G et al Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties. TherAdv Urol. 2013 Feb;5(1):35-41

Tadalafil: Efficacy Evaluation inMen With Diabetes*

*Patients with diabetes. Studies LVBN, LVCE, LVCO, and LVDJ. †Did your erection last long enough to have successful intercourse?

‡P<.001 vs placebo.With permission from Saenz de Tejada I, et al. Poster presented at: 16th Congress of European Association of Urology; April 7-10, 2001; Geneva, Switzerland.

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When to refer a patient to a Urologist?

• PDE5i treatment failure

• Daily Cialis 5mg + Viagra 100mg PRN

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Your Patient Has Failed Phosphodiesterase Type 5 (PDE5) Inhibitor Therapy . . . What Now?

• Reeducate and rechallenge with same agent

• Switch to another PDE5 inhibitor

• Try different therapeutic approach– Vacuum erection devices

– Prostaglandin E1 (PGE1) injections

– Implants

Diagnosis and Evaluation of ED post

• Penis – stretched length, plaque location, dimensions

• Discuss patient’s goals

• Determine nature/degree of erectile insufficiency– Duplex ultrasonography (US)

Gholami SS, et al. J Urol. 2003;169:1234-1241. Levine LA. Int J Impot Res. 2003;15:(suppl 5):S113-S120.

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Evaluation of Penile Blood Flow

• Duplex Ultrasonography

– Penile blood flow study (CIS & blood flow measurement by US) is most reliable & least invasive evidence based assessment of ED

• Red = towards probe

• Blue = away from probe

– Can visualize dorsal & cavernous arteries in real time

2nd line - Ultrasound

• Technique

– Measure flow velocities 5-10 min after injection

– Rate erectile quality

– Look at both cavernous arteries

2nd line - Ultrasound

• Peak Systolic Velocity (PSV)

– PSV < 25 correlates with abnormal pudendal arteriography

– Severe unilateral arterial insufficiency >10 cm/s asymmetry

– Severe vascular ED, diameter increase is <75%, diameter rarely exceeds 0.7 mm

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2nd line - Ultrasound

• Veno-occlusive Dysfuntion

– Need to trap blood & limit venous outflow

– Venogenic impotence• High systolic flow (>25 cm/s)

• Persistent end-diastolic flow (EDV) (>5 cm/s)

– Resistive Index (RI)

• RI = PSV – EDV/PSV– Measure 20 min after injection & stimulation

• RI > 0.9 normal

• RI < 0.75 venous leakage

Recommendations on US

• Intracavernosal injection with color duplex Doppler ultrasound

– Most informative diagnostic test

– Least invasive for vascular ED, high vs. low flow priapism, Peyronie’s plaque

– Useful measurements

• PSV, cavernous artery diameter, EDV, RI

• PSV <25 = severe cavernous artery insufficiency

• PSV >35 = normal inflow

• Negative relationship between age & PSV

Vacuum Erection Devices

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Second-Line Therapy: Vacuum Erection Devices (VEDs)

• Lack of interest in drug therapy

• Specific contraindications to drug therapy

• Patient preference

Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:357-404.

VED: Basic Principles

• Externally applied device mechanically effects penile blood engorgement

• Cylinder/pump placed over penis creates closed chamber; pump creates vacuum, drawing blood into corpora cavernosa

• Constrictive elastic ring then placed at base of penis to restrict flow of suctioned blood

Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341.Montague DK, et al, for the AUA Clinical Guidelines Panel on Erectile Dysfunction. J Urol. 1996;156:2007-2011.

VED: Practical Aspects

• Requires manual dexterity1

• Instructional video and/or in-office teaching1

• 30-minute maximum duration of constriction is advised to prevent penile ischemia1

• Precautions necessary in patients on anticoagulant therapy or those easily bruised1,2

• Success rates highest in stable relationships2

1. Montague DK, et al, for the AUA Clinical Guidelines Panel on Erectile Dysfunction. J Urol. 1996;156:2007-2011.2. Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341.

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1. Levine LA, Dimitriou RJ. Urol Clin North Am. 2001;28:335-341. 2. Jarow JP. J Urol. 1996;155:1609-1612. 3. The Process of Care Consensus Panel. Int J Impot Res. 1999;11:59-70.

VED: Profile

• Efficacy1

– Uniformly produces erection

– Reported satisfaction rate ~55% (at 2 years)2

• Advantages2,3

– On-demand use

– No systemic side effects

– Cost

• Disadvantages2,3

– Cumbersome

– Unnatural erection

– Possible side effects may include

• Petechiae/ecchymosis

• Penile pain

• Ejaculatory blockage

• Numbness

• Penile hinging

Medicated Urethral System for Erection (MUSE)

Second-Line Therapy: Transurethral System

• Lack of response to oral therapy1

• Contraindications to specific oral drugs1

• Adverse reactions/intolerance to oral drugs1

• Rapid, predictable erection

• Failed penile prostheses2

• Failed intracavernosal therapy3

• Patient preference

1. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711-726. 2. Benevides MD, Carson CC. J Urol. 2000;163:785-787. 3. Engel JD, McVary KT. Urology. 1998;51:687-692.

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Transurethral Alprostadil (MUSE)

Smooth muscle–relaxing urethra suppository mimics physiology of erection (PGE1)

Intraurethral Alprostadil (MUSE): Advantages

• Alleviates need for needles/injections

• High safety, local therapy, no systemic side effects

• No effect on sensation, ejaculation, fertility

• Erection within 5 to 10 minutes

• 75% to 80% of prescriptions covered by medical plans

• No fibrosis, prolonged erections, or curvature

Intraurethral Alprostadil (MUSE): Disadvantages

• Transient penile burning in 32%– Reduced pain with ≥4 administrations reported

– Few discontinue use because of it

• Less effective than injection therapy

• Patients with poor manual dexterity/vision or severe obesity may find administration difficult

• Technique must be taught

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Transurethral Medications

• Method of application: 2-mm pellet into urethra

• Mechanism of action: urethral absorption and distribution into cavernosal tissue → smooth muscle relaxation

• Study results– 66% of 1511 patients had erections in office

– Of these, 65% had successful intercourse at home vs 18.6% with placebo

– Treatment efficacy was similar regardless of age or cause of ED (vascular, diabetes, surgery, or trauma)

• Overall success reported was 30% to 60%

Alprostadil: MUSE

Padma-Nathan H, et al. N Engl J Med. 1997;336:1-7.

Intracavernosal Injection

Smooth muscle–relaxing medication injected directly into the penis(papaverine, phentolamine, PGE1)

Penile Injection Therapy

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Second-Line Therapy: Intracavernosal Injection

• Lack of response to oral therapy1,2

• Contraindications to specific oral drugs1

• Adverse reactions/intolerance to oral drugs1

• More reliable, instant, predictable erection

• Patient preference

1. Recommendations of the 1st International Consultation on Erectile Dysfunction. In: Jardin A, et al, eds. Erectile Dysfunction. Plymouth, United Kingdom: Health Publication, Ltd; 2000:711-726. 2. Shabsigh R, et al. Urology. 2000;55:477-480.

Penile Injection Therapy: Advantages

• Highly effective

• Mimics natural physiology of erection

• No effect on sensation, ejaculation, fertility

• Higher level of discretion, thus spontaneity

Penile Injection Therapy: Disadvantages

• Poor long-term tolerability (dropout rate >60%)• Bruising, prolonged erection, cavernosal fibrosis,

pain at injection site, penile deformity (rare)• Cumbersome, especially for patients with poor

manual dexterity/vision or severe obesity• Requires training, follow-up, and dosing

adjustments• May be risky with heart disease, previous strokes,

or liver or blood disorders• May not be covered by insurance

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Low Intensity Shockwave Therapy

• Not incorporated into AUA guidelines yet

• Shockwaves at 1/10th the dose of traditional ESWL for stones

Vardi Y, et al.. Can low-intensity extracorporeal shockwave therapy improve erectile function? European Urology. 2010;58: 243-48

Low Intensity Shockwave Therapy

• Meta-analysis: combined improvement in IIEF-EF score is 4.28

• Greater than the minimal clinically important difference (MCID) of 4 IIEF points as described by Rosen et al.

• Zero adverse effects

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Should We Doing Implants Earlier?

Clavijo RI, et al Time course and predictors of use of erectile dysfunction treatment in a Veterans Affairsmedical center. Int J Impot Res. 2016 May 19.

Penile Prosthesis Implantation

Types of Prostheses

• Malleable/semirigid (AMS, Mentor)

• Mechanical rod (Duraphase)

• Inflatable– 2-piece (Ambicor)

– 3-piece – AMS (CX, CXM)

– Coloplast ( Titan )

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www.amselabeling.com

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Penile Implant Indications

• Oral drug (PDE5 inhibitor) failure– Radical prostatectomy– Diabetes mellitus

• Scarred penis– Priapism– Previous implant– Trauma

• Peyronie’s disease• Severe venous leak

Issues Regarding Informed Consent

• Size of penis—stretched penile length• Possible need for revision surgery

– Infection– Malfunction– Tissue damage

• Sensation• Ejaculation• Discuss alternative treatments, eg, vacuum constriction

device (VCD), Medicated Urethral System for Erections(MUSE), etc

• Variety of prostheses• Reduced erectile function if device removed

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Reliability—Device Survival

Montague Ultrex 78% 5 yearsLevine Ambicor 93% 3-5 yearsChoi CXM 90% 5 yearsCarson CX 86% 5 yearsMontorsi AMS700 96% 5 yearsWilson Mentor Alpha-1 93% 5 yearsGovier AMS 91% 3 yearsDhabuwala Mentor 96% 5 years

AMS 84% 5 years

Penile Implant -Satisfaction

• In contemporary series, satisfaction is >80%

Bernal, R et al. Adv in Uro. 2012

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Reasons for Dissatisfaction With Penile Implant

• Loss of penile length

• Reduced sexual spontaneity

• Unrealistic expectations

• Malfunction

• Infection- 1-4%

Penile Prosthesis

Pros• High patient satisfaction rate

• 7 to 10 years average functional prosthesis life

• Higher spontaneity

• Discreet, normal appearance

• Erection longevity controllable

• Significant clinical data on procedure and results

Penile Prosthesis (cont’d)

Cons• Potential for infection, device malfunction

• Surgical procedure, postoperative pain, irreversible

• Additional surgery at product end-of-life

• Potential decreased sensation, glans sensitivity, ability to ejaculate/reach orgasm

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Implant Surgical Technique

• Infrapubic approach– Familiar surgical approach for urologists– Easy placement of reservoir– Potential injury to dorsal penile nerve

• Penoscrotal approach– Easy dissection and corporal dilation– Penile nerves not in surgical field– Blind placement of reservoir sometimes

difficult

Synchronous Prosthetic Implantation Through Transscrotal Incision

• Multi-institutional evaluation from 2000 to 2003 revealed 22 patients undergoing synchronous IPP and AUS

• 14% revision rate: 2 urethral erosions and 1 reservoir migration, no infections; postoperation <1 pad/day urinary leakage

• Risk factors: diabetes, hypertension, radiation therapy

• Advantage of single anesthetic and single transcrotal incision in high-risk, complex genitourinary patients should encourage widespread acceptance of this technique

Shaw MB, et al. J Urol. 2004:171:898A.

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Post-Op Care:

• Foley catheter for 24 hours

• Bed rest from 48 hours

• Cylinder straight, up and deflated

• Warm baths bid starting on post-op day #3

• Prosthesis cycling at 6 to 8 weeks

Keys to Successful IPP Surgery:

• Dedicated set of instruments• Penile pack

• Full inventory of devices• Strategy to decrease skin bacteria flora

• Strategy to prevent contact with the skin during the procedure

Conclusions

• ED can be identified and managed in the primary care setting—detection is key!

• Effective treatments are available

• Treatment efficacy can be optimized by establishing its proper usage and pursuing risk-factor modification and vascular disease treatment

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Thank

@ranjithramamd

ramasamy@miami.edu