Update on Erection Dysfunction. Seacourses Eastern Caribbean December 30, 2017 January 6, 2018 Stacy Elliott MD

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1 Update on Erection Dysfunction Seacourses Eastern Caribbean December 30, 2017 January 6, 2018 Stacy Elliott MD

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 What is Sexual Medicine? Mind - body approach to persons with Female Genitalia Sexual desire/interest Ability to have vaginal lubrication and uterine tenting Ability to reach orgasm through hand, oral or intercourse methods Freedom from sexual pain or discomfort Fertility related sexual issues Male Genitalia Sexual desire/interest Ability to achieve an erection and maintain it (adequate for penetrative activities) Ability to have an antegrade ejaculation ( semen appears) Ability to experience orgasm Freedom pain with erection and ejaculation Fertility related sexual issues

4 Objectives To outline the medical options to manage erectile function (ED) in 2018 To provide a guideline as to how to manage difficult to treat ED Recognize common reasons for non-response to a PDE5 inhibitor Assess management strategies for PDE5 inhibitor nonresponders and incorporate these into clinical practice Evaluate alternative treatment options for ED

5 cgmp Tonic smooth muscle contraction Smooth muscle relaxation

6 Erection Parasympathetic Nerves Acetylcholine NANC Nitric Oxide guanylate cyclase Endothelial cells Smooth Muscle Cell Slide courtesy Dr.R.Stevenson

7 Parasympathetic Nerves Acetylcholine NANC Endothelial cells Erection Nitric Oxide enhanced with PDE-5i s guanylate cyclase Smooth Muscle Cell

8 Women also have erectile tissue The erectile tissue in women functions similarly to men Genital arousal = vaginal lubrication is a result of sweating from vasocongestion Treatments for ED have little effect on women since the erectile tissue is often already maximally engorged

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10 PDE5 Inhibitors Increase the Physiological Response to Sexual Stimulation

11 Etiologies of ED Think mechanics! Vascular Neurogenic ( chronic illness, post surgical) Endocrine ( thyroid, testosterone, DM) Venous leak ( congenital or acquired) Anatomical (i.e. Peyronie s) Lack of mental arousal

12 Options for ED treatment Talk therapy to reduce anxiety Martial/relationship therapy what s the real issue? Medical therapy - oral pills - topical solutions - mechanic devices - intracavernosal injections (ICI) - surgical Rule out testosterone deficiency Is there a role for combination therapy?

13 PDE5i: Which one? All PDE5 inhibitors demonstrate equivalent safety, tolerability and efficacy Treatment decisions should be based primarily on patient preference There is no typical patient prototype per PDE5i

14 PRN PDE5i Short acting Viagra and Levitra/Staxyn : act best 1 4 hours after taking : can be affected by high fat meal 25, 50, 100 mg 10 and 20 mg 10 mg dissolvable NOTE: AVANAFIL is available in via FDA ( 2012, Stendra) and EMA (2011, Spedra) and is marketed as a more specific PDE5i, shorter time to effect ( 30 min) and not affected by food Spinal Cord :

15 PRN PDE5i Longer acting Cialis : last hours after taking : prn and daily dosing available : not affected by food

16 Daily PDE5i therapy Advantages Able to improve REM sleep and sexual erections on a 24/7 basis Psychologically helpful Allows for better fullness and less turtling Helpful in young men with organic or situational ED Can safely use any PDE5i daily to max dose

17 Nitrates are contraindicated with PDE5i Angina medication Recreational drugs Poppers Amyl nitrate

18 Main side effects? Headache Facial flushing, nasal congestion Dyspepsia Blue vision ( Viagra only, 3% on high dose) Back pain, myalgia ( mainly associated with Cialis) nausea, dizziness Rash No causal relationship has been demonstrated for sudden blindness (NAION) or hearing loss ( usually unilateral) but share similar risk factors for ED

19 The oral ED treatments are available in several doses On-demand: Sildenafil (25, 50 and 100 mg) 100 mg is most common Tadalafil (10 and 20 mg) 20 mg is most common Vardenafil (5, 10 and 20 mg) 20 mg is most commonly used Vardenafil (orally dissolvable 10 mg) Start HIGH Daily use Tadalafil (2.5 and 5 mg) 5 mg is most common Dose adjustments are made based upon patient factors. References: Viagra Product Monograph. Pfizer Canada Inc. April 12, Cialis Product Monograph. Eli Lilly Canada Inc. June 28, Levitra Product Monograph. Bayer Inc. July 19, Staxyn Product Monograph. Bayer Inc. August 18, 2011.

20 PDE5i selection: primary factors As the safety and efficacy of all available PDE5 inhibitors are comparable, patient/partner preference is characterized by: Drug characteristics (onset of action, duration, food interaction, side effects) Concomitant therapies : PDE5 inhibitor use is contraindicated in patients on organic nitrates. Frequency (spontaneity) of intercourse (ondemand vs. once-a-day PDE5 inhibitors) Corona G, Mondaini N, Ungar A, et al.. J Sex Med. 2011;8: Hatzimouratidis K, Amar E, Eardley I, et al.. Eur Urol. 2010;57(5):

21 Concomitant therapies with PDE5i Lower doses may be required for patients taking ketoconazole, itraconazole, erythromycin, clarithromycin, and HIV protease inhibitors (ritonavir, saquinavir). Note: use of vardenafil is contraindicated in patients using indinavir, ritonavir, ketoconazole or itraconazole. Higher doses of PDE5 inhibitors may be necessary in patients taking rifampicin, phenobarbital, phenytoin, or carbamazepine. Grapefruit juice will increase the PDE5i in the blood

22 When should an orally dissolvable PDE5 inhibitor be considered? Patients with no known contraindications to vardenafil should be made aware of an orally dissolvable formulation Not interchangeable with film-coated tablet Appropriate for patients who have difficulty swallowing pills Provides more discretion

23 When should a OaD be considered? When patient prefers spontaneous, rather than scheduled, sexual activity Salvage therapy for on-demand non-responders Salvage therapy for on-demand responders with side-effects Patient engaging in frequent sexual activity

24 COMMON REASONS FOR PDE5 INHIBITOR FAILURE Inadequate comprehension/communication of instructions ( patient listening? Doctor time?) Incorrect use ( timing, dose, food interaction, only 1 try) Lack of stimulation/sexual arousal ( Proper patient education has solved 40-55% of PDE5 inhibitor non-responder cases 1,2) Side effects Undiagnosed hypogonadism Presence of comorbidities and/or worsening vascular disease, diabetes, etc. ( little evidence for tachyphylaxis) Lack of efficacy due to severity of ED etiology 1. Basson et al. J Urol. 2002;168:204; 2. Billups. J Urol. 2002;168:204-5; 3. Guay. J Urol. 2002;168:205

25 HOW DO I MANAGE THE PATIENT WHO SAYS HIS PDE5i IS NOT WORKING? Medication-specific modifications: Assess if the patient has taken their medication correctly Educate the patient on common reasons for PDE5 inhibitor failure Pursue drug optimization Switch between PDE5 inhibitors Generalized modifications: Ensure proper diagnosis (i.e. not premature ejaculation, Peyronies disease, etc.) Modify associated risk factors Counsel psychosexual behaviour Assess for low testosterone levels 1. Hatzimouratidis et al. Eur Urol. 2010;57:804-14; 2. Katz et al. CMAJ. 2010;182:381-2; 3. McMahon et al. BMJ. 2006;332:

26 LIFESTYLE RECOMMENDATIONS: UNDER UTILIZED & UNDER APPRECIATED Good erectile function has been associated with: 1,2 Normal weight Increased physical activity Non-smoking Moderate alcohol consumption Minimal television watching Better glycemic control in diabetics Lifestyle modifications can make a difference 1. Esposito et al. Urol Clin North Am. 2011;38: ; 2. Bacon et al. Ann Intern Med. 2003;139:161-8.

27 OTHER MANAGEMENT STRATEGIES Switch PDE5 inhibitors Consider daily dosing with a PDE5 inhibitor Treat underlying low testosterone Psychosexual counselling 1. McMahon et al. BMJ. 2006;332:

28 Sex Supplements Sex supplements that are marketed in "pharmaspeak" with names such as Enzyte and Elexia, and Pro-EREX, Vahard, and VasoRect -- as well as Big Daddy, Libido- Max, Suregasm have deceptive advertising "It's basically just an expensive placebo. "Most of these companies make their millions in a few months, and then pull up stakes by the time they're found out. They don't care, they've made their money. Never buy off the internet

29 NON-RESPONDER TREATMENT ALGORITHM Failure with PDE5 inhibitor on-demand Failure with PDE5 inhibitor OaD Assessment of cause of failure Reversible cause Irreversible or nonidentifiable cause Incorrect usage or noncompliance Patient reeducation and retrial of oral therapy with follow-up Incorrect dosage Retrial of PDE5 inhibitor with dose optimization and follow-up Comorbid disease Appropriate investigations Patient education Modification and treatment of comorbidities with continued PDE5 inhibitor use Possible psychological component Commence counselling, when possible referral to sex therapist and follow-up Hypogonadism Combination therapy with PDE5 inhibitor and testosterone Trial the following: ICI VCD Daily PDE5 inhibitor Combination treatment PDE5 inhibitor + ICI PDE5 inhibitor + VCD Failure of medical therapy Penile prosthesis ICI: intracorporal injection; OaD: once-a-day; VCD: vacuum constriction device. 1. McMahon et al. Medicine Today. 2008;9:18-31.

30 Topical Gels ( Vitaros) Topical PGE1 on the glans and urethra ( not on the shaft) Efficacy observed 5-30 min after application Side effects include penile burning or erythema at application site, meatal or glans pain at the application site, and prolonged or painful erection

31 Intraurethral pellet of PGE1 ( MUSE) Medicated urethral system for erection (MUSE); intraurethral delivery of alprostadil Lower success rates compared with intracavernosal injections Side effects include local pain, dizziness and urethral bleeding

32 Vacuum erection devices Produces an erection through negative pressure to the penis; maintained by an elastic band for up to 30 min Less invasive therapy; can be used daily Side effects can include painful ejaculation, inability to ejaculate, generalized pain, petechiae, bruising and numbness

33 Mechanical Methods Vacuum devices

34 Intracavernosal Injections Self injection of a vasodilator drug alprostadil (PGE1), efficacy observed in 5-10 min Can result in penile pain, prolonged erections, priapism and fibrosis Can be combined with papaverine and phentolamine (Bimix) Trimix ( Bimix + prostaglandin) Quad Mix ( Trimix + atropine)

35 Penile Prosthesis ( surgery) Most invasive; ideal for patients who fail pharmacotherapy Complications: mechanical failure, infection, pain, penile shortening and autoinflation

36 Low energy shock wave therapy Thermal and non-thermal effects of therapeutic ultrasound Healing associated with LEWST is still under investigation but seems to relate to upregulation of cell proliferation and differentiation of mesenchyme stem /progenitor cell lines Animal models with appropriate acoustic dosages- activate in situ progenitor cell production, enhance angiogenesis (seems to be the effect for vasculogenic/dm clinically in men) and improves EF 58 men with vasculogenic ED and failed PDE5i responders in R,DB,sham-controlled study...about 50% changed from PDE5i non-responders to responders * Not for post radical as of yet ( but may help chronic prostatitis/chronic pelvic pain syndrome) *Vardi et al Eur Ass Urology 2014

37 Pelvic floor and sexual function Pelvic floor physical therapy is a necessary tool in a more comprehensive bio-neuromusculoskeletalpsychosocial approach to the treatment of male sexual dysfunction and pelvic pain. Male pelvic floor

38 Psychological therapies Sexual function is a mind-body phenomenon

39 What are your options? Treatment pyramid Implant Lack of success ED a concern Discuss Injection Vacuum Intraurethral Lack of success ED a concern Initiate oral medications if not contraindicated Lack of success Lifestyle modifications Support Disease control Fazio L, Brock G. CMAJ 2004;70:

40 Combination therapy Utilizing OaD with another short acting PDE5i Utilizing indirect ( PDE5i) with direct methods ( ICI) Utilizing oral or topical medications with penile implant Warnings of adding 2 erectogenic agents true?

41 Low energy shock wave therapy ( LESWT)

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43 Low energy shockwave therapy LESWT Mouse model Low energy shock wave therapy ( LESWT) has been shown to recruit endogenous mesenchymal stem cells (MSC) within the corpora cavernosa as compared with sham controls ( AUA,T. Lue 2016)

44 Drugs in preclinical to phase II clinical development for the treatment of erectile dysfunction. Smith-Harrison L 1, Starke NR 1, Smith RP 1, Kovac JR 2. Expert Opin Investig Drugs Jun;26(6): Stem cells problem is retaining them Stem cells injected into the corpora cavernosa tend to washout immediately Low intensity pulsed ultrasound (LIPUS) suppresses adipogenesis and promotes osteogenesis of mesenchymal stem cells Innovative treatments such as alternative vasoactive agents, trophic factors and biocompounds as well as gene therapy are considered.

45 Thank you for listening! Questions?