Erectile Dysfunction Primary Care Management

Louis Kuritzky, MD Family Physician 4510 NW 17th Place Gainesville, Florida 32605 [email protected] Question #1

• Which of the following is NOT a risk factor for ED? A) Elevated LDL B) Elevated BP C) Elevated Uric Acid D) Reduced HDL Question #2

• A patient took vardenafil (Levitra) 36 hours ago, and is now having chest pain. Which is true about administering nitroglycerin? A) It is contraindicated B) The dose should be reduced C) A higher dose will be required D) No dosing/administration change is needed Question #3

• A 28 year old single, heterosexual male patient has psychogenic ED. The most likely contributing disorder is? A) Excess sympathetic drive B) Excess parasympathetic drive C) An exaggerated Oedipal Syndrome D) Madonna Prostitute Syndrome Question #4

• The use of vacuum constriction devices… A) May be associated with decreased penile temperature B) May be associated with increased penile temperature C) Is associated with decreased penile girth D) Is only appropriate for men over age 60 ED: Agenda

• Why Bother • Scope of the Problem • Pathophysiology: Penodynamics • Definitions • Emotional Issues & ED • Obstacles to Rx • Rx

WHY BOTHER Why Bother

Erectile Endothelial Dysfunction Dysfunction ED

Compelling Epidemiology Massachusetts Male Aging Study: Key Prevalence Study of ED

Feldman HA et al. J Urol. 1994;151:54-61. Massachusetts Male Aging Study: Age-adjusted ED Progression

80 70 67% 60 57% 50 48% Prevalence 40 40% (%) 30 20 10 0 4040 5050 6060 7070 Age (y)

Minimal ED Moderate ED Complete ED Adapted with permission from Feldman HA, Goldstein I, Hatzichristou DG et al. Impotence and its medical and psychosocial correlates: results from the Massachusetts Male Aging Study. J Urol. 1994;151(1):54Feldman-61. HA et al. J Urol. 1994;151:54-61. Impotence and DM

• Frequency 35-75% • Age dependent AGE FREQUENCY 20-29 9% 30-34 15% 60-64 55%

Bennett, Alan Impotence WB Saunders 1994 Chapter 1 ED: Major Modifiable Risk Factors

• Hypertension • DM • Vaculopathy: (lipids, homocysteine) • Medications: HCTZ, Beta-blockers • Lifestyle: stress, fatigue • Toxins: smoking, alcohol

Feldman HA et al. J Urol. 1994;151:54-61. Major Risk Factors for ED: Chronic Diseases Chronic Disease ED Age-adjusted O.R. Diabetes1,2 ×4.1 LUTS1 ×2.9 PAD1 ×2.6 Cardiac problems1 ×1.8 Hyperlipidemia1 ×1.7 Hypertension1,2 ×1.6 1. Martin-Morales A et al. J Urol. 2001;166:569-575. 2. Braun M et al. Int J Impot Res. 2000;12:305-311.

Erectile Dysfunction (ED) Is a Vascular Disease1,2 Precursors

Diabetes Dyslipidemia

Hypertension Oxidative stress Tobacco

Endothelial Vasoconstriction cell injury Atherosclerosis

Erectile dysfunction Thrombosis

Outcomes

1Dzau VJ, et al. Am J Cardiol. 1997;80(9A):33I-39I. 2NIH Consensus Development Panel on Impotence. JAMA. 1993; 270:83-90. Penodynamics

The Physiology of the Erectile Process

Tumescence

1. Stimulation Psychic or sensory 2. Neurotransmitter release 3. Smooth muscle relaxation 4. Arterial flow increase 5. Veno-occlusive function Tumescence : Primary Messengers (In Cavernosal Smooth Muscle) cGMP cAMP Prostaglandin Mechanism of Erection

NANC NO Endothelial cells

NANC Guanylate cyclase NO GTP Penile cGMP Relax erection GMP

PDE5 cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; NANC = nonadrenergic-noncholinergic neurons; NO = nitric oxide; PDE5 = phosphodiesterase type 5. Adapted from Sadovsky R, et al. Int J Clin Pract. 2001;55:115-128. Erection Pathways: Endothelium & cGMP

Parasympathetic stimulation (Acetylcholine) endothelium

NO ↑ cGMP→ relaxation/dilation

Corpora Cavernosa Vascular Smooth Muscle Cell Erection Pathways: Nitrergic NS & cGMP

NANC (Non-adrenergic, Non-cholinergic NS)

endothelium

NO ↑ cGMP → relaxation/dilation

Corpora Cavernosa Vascular Smooth Muscle Cell Erection Pathways: Nitrergic NS & cGMP

Prostaglandins (ICI, urethral suppository)

endothelium

↑ cAMP → relaxation/dilation

Corpora Cavernosa Vascular Smooth Muscle Cell ED : Emotional Consequences & Comorbidities ED : Emotional Consequences & Comorbidities

• Anxiety • Depression • Bruised Self-Esteem • Relationship Conflict • QOL decrement Male Sexual Function Master-Control Center AnatomyAnatomy ofof thethe MaleMale BrainBrain Female Sexual Function Master Control Center AnatomyAnatomyThe ofFemaleof thethe MaleMaleBrain BrainBrain

Shoes Acquisition Complex Parallel parking center Need More Black Shoes Synapse Too Cold Maintenance Site High Heels Adaptation Glands

Color Coordination Center Brad Pitt Appreciation Lobe Fart Appreciation Romance Lobes Molecule Candles (yellow) Flowers (blue) Increased Incidence of Depressive Symptoms in ED

60 ** ** 50

40

30

20

10

0 Incidence of depression (%) of depressionIncidence ED only BPH only ED + BPH N = 48 N = 34 N = 18 ** p < 0.005 Shabsigh et al. Urology. 1998;52:848-52.

OBSTACLES Undertreatment of ED

With permission McKinlayfrom McKinlay JB. Int J JB.Impot Res Int. 2000;12(suppl J Impot 4):S6-S11. Res Based on. data2000;12 from the Massachusetts (suppl Male Aging 4):S6 Study (MMAS).-S11. Source: AARP. Modern Maturity, Washington DC, 1999. Data from AARP Survey. Modern Maturity Magazine, Wash DC, 1999. Etiologies of Impotence in Seniors Etiology Frequency Neurologic and vascular 30.3% Vascular 21.1% DM neuropathy 17.1% Non-DM neuropathy 10.5% Psychological 9.2% Meds 3.9% ↓ TST 2.6% Peyronie’s disease 1.3% Unknown 4.1%

Mulligan T. Arch Int Med. 1989;149:1365-1366

OBSTACLES The Top 10 Medical Conditions too Embarrassing for Patients to Discuss With Their Family Physician MA Preboth Am Fam Phys 1999;59(1):18 1. Impotence 2. STDs 3. Physical and sexual abuse 4. Prostate problems 5. Incontinence of bladder or bowels 6. Emotional problems like depression 7. Eating disorders 8. Alcohol or drug abuse 9. Birth control and sex (especially teens) 10. Menopause Preboth MA Am Fam Phys. 1999;59(1):18 Patient Misconceptions Sexual Health Issues

• Poll of 500 US adults aged ≥25 years . 71% – thought clinician would dismiss sexual concerns . 68% – feared clinician embarrassement

Marwick C. JAMA. 1999;281:2173-2174

Getting the Information: (Men or Women) [Whilst Perfecting ‘Swan Posture’]

If you ask the “standard question”: “How is your sex life?” Getting the Information: (Men or Women) [Whilst Perfecting ‘Swan Posture’]

You’ll get the “standard answer”: “fine” Getting the Information: (Men or Women) [Whilst Perfecting ‘Swan Posture’]

With a twist on the standard: “How would you rate your sex life on a scale of 1–10?” Getting the Information: (Men or Women) [Whilst Perfecting ‘Swan Posture’]

You’ll still likely get the politically correct: “Oh, about a 7…” Getting the Information

So encourage them further by: “So what would have to be different to change it from a ‘7’ to a ‘10’?”

Assume Swan Position NOW Swan Posture

• More than once a year • 5 Times a Day • More than 1 minute • Less than 1 hour • After an Argument • After Drinking • Standing up in a Hammock The Universal-to-Specific Shepherding Technique

Mr. Jones, many of my patients with

_ (fill in the blank)_

notice changes in their sexual function; has this been an issue for you? Universal-to-Specific Technique Some Things that Go in the Blank

• HTN • Depression • Hyperlipidemia • Sedentary • Smoking • Relationship conflict • Obesity • Meds • DM • Anxiety • Homocysteine↑ • Midlife and beyond Universal-to-Specific Shepherding Technique: Benefits

• Informs: perhaps Jones didn’t know of the linkup between ‘X’ and sexual function • Informs: makes the relationship ‘common’ • Announces: clinician willing to address sex • Legitimizes: not just a QOL thing; disorder associated with recognized comorbidity Aging and Potency ∆

Prolongation of arousal phase ↑ Stimulation to arouse ↑ Refractory period ↓ Duration of orgasm ↓ or absent testicular elevation

Galindo D. Patient Care. April 1995 Typical Patient Scenarios

Complaint Scenario Timing Frequency Presenting ED main reason for 12-14 min Least Complaint visit Doorknob “Oh, by the way. . .” 1-2 min Occasional Consultation During routine visit Ask for other medical Competing patient to problems, inquiry Most Complaint prioritize about sexual health uncovers ED 1-15 min Basic ED assessment is achievable during a standard office visit. How to Avoid “Oh by the way…” A Patient-Centered Introduction

Clinician: “Hello, Mr. Jones. I see from your chart that you’re back for a recheck on your diabetes. Before we get started today, are there any other issues you’d like to bring up, so we can decide how we’re going to use our time today?” ED: Basic Evaluation

.Targetted History

.Targetted Physical Exam

.Targetted Lab Targeted Medical Hx • Is it ED, or something else? • If it is ED, is it a problem? • Is it clearly psychogenic (eg. depression)? • Is there a clear secondary cause? . Meds (eg, SSRIs, thiazides) . Hypogonadism (Primary, chronic opioids) . Endothelial dysfunction (any vasculopathy) • Taking nitrates? ED Evaluation: Optional Basic Labs

.Serum testosterone (A.M. best) .Serum lipids .Liver function tests .Serum creatinine

.Glucose or HbA1c .Thyroid function tests .Prolactin Presenting Complaint: Successful Management • Targeted medical, sexual, psychosocial Hx . (Typically 4-6 min) • (Optional) PE of genitalia (2-4 mins) . Testes >2.5 cm . Peyronie’s . Sensation • Optional Lab (eg, TST,lipids, A1C) •Rx Total Time = 12 min Competing Complaint : Management • Solicit patient’s priority stratification • High priority: streamline plan as per presenting complaint = 7 to 15 min • Low priority: reschedule, provide education, and/or invitation for partner participation Doorknob Complaint: Management • Reward for inquiry . Inform: multiple Rx available . ED:CVD risk factor association • Epidemiologic reassurance: a common problem • No nitrates • Sample PDE5 inhibitor and/or Rx* • Return 3-4 weeks for . Targeted history and physical . Selected labs Partner Issues • Be sure partner ‘prepared’ to re- initiate sexually intimate behaviors • Encourage inclusion of partner for Rx decision/choice • Address partner limitations/obstacles And Don’t Forget STD Counseling Issues

Rx ED Treatment options

• Counseling • Oral PDE5 Inhibitors • Vacuum Constriction Device • MUSE • Intracavernosal Injection • Surgery Oral PDE5 Inhibitors

• Sildenafil(Viagra) • Tadalafil (Cialis) • Vardenafil (Levitra) • Avanafil (Stendra) PDE5 Inhibitors: Mechanism of Action

Penile/sexual stimulation NO e cells NANC and endothelial cells Guanylate cyclase GTP Penile PDE5 inh cGMP RELAX GMP erection

PDE5

NO=nitric oxide; cGMP=cyclic guanosine monophosphate; PDE5=phosphodiesterase type 5; GTP=guanosine triphosphate; NANC=nonadrenergic-noncholinergic neurons.

Kloner RA, Zusman RM. Am J Cardiol. 1999;84:11N-17N. Sildenafil: 12 weeks (PRN)

* Padma-Nathan H, et al. Int J Clin Pract. 1998;52:375-379.

Tadalafil: 12 weeks (PRN)

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: 12 weeks (PRN)

*Sexual Encounter Profile 3: Did your erection last long enough to have successful intercourse? †P<.001 vs placebo. Adapted from Porst H, et al. Int J Impot Res. 2001;13:192-199. Slide property of Consortium for Improvement in Erectile Function Cialis (tadalafil): Efficacy in DM

80 70 60 Positive ‡ 48 ‡ Responses 50 42 to 40 † SEP 3 30 20 (%) 20 10 0 Placebo 10 mg 20 mg Cialis (tadalafil) Treatment Group

Cialis Prescribing Information 2003 Comparing the PDE5i

Avanafil Sildenafil Tadalafil Vardenafil (Stendra) (Viagra) (Cialis) (Levitra) Onset 15-30 min 30-60 mins 1-2 hrs 30-60 mins T1/2 3 hrs 4hrs 18 hrs 4 hrs Duration ≤6 hrs ≤12 hrs ≤36 hrs ≤10 hrs Food effect none ↓absorption none ↓absorption Unique* AE PDE6 myalgias

Hellstrom W Medscape Aug 14, 2012 Add Testosterone to PDE5?

• Study: RDBPCT hypogonadal men with ED • Inclusion (n=140): . Total TST < 330 ng/ml OR . Free TST < 50 pg/mL • Rx: 7weeks ‘optimized’ sildenafil followed by 14 weeks ‘optimized TD-TST 5-15 g/d

Spitzer M et al Ann Intern Med 2012;157:681-691 Add Testosterone to PDE5? NOT

“Sildenafil + TST was not superior to sildenafil + placebo in improving erectile function in men with ED and low testosterone levels.”

Spitzer M et al Ann Intern Med 2012;157:681-691 TST Added to Sildenafil

Spitzer M et al Ann Intern Med 2012;157:681-691 Cialis (tadalafil): Administration of Nitrates

“In a patient who has taken Cialis (tadalafil) where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Cialis (tadalafil) before nitrate administration is considered.”

Cialis Prescribing Information 2015 Does PDE5 Rx Do the Patient a ‘Nitrate Disservice’?

“… two large RCTs compared nitrates given acutely versus placebo in 58,050 and 17,817 people with AMI …. Neither trial found a significant improvement in survival, either in the total sample or in subgroups….”

Clinical Evidence 2001 Stuart Barton (editor) BMJ Publishing London page 15 25

20

15

10

5

0 <6 6.1-7 7.1-8 8.1-9 >9 So Which is the Best PDE5 Inhibitor? So Which is The Best PDE5 Inhibitor?

Whichever one your patient likes the best….Try them all.

Vacuum Devices • Advantages − Cost − Low complexity − Minimal side effects − Reversible • Disadvantages − May be difficult to integrate into sexual relations − Non-cosmetic erection − Discomfort − Poor compliance Intracavernosal Injection Therapy

• Technique • Direct injection of vasodilator substances into the corpus • Advantages • Rapid onset • Highly efficacious • Consistent response • Cost ± • Disadvantages • Involves corporal injection • Complications • Drop-out rates

Penile Prosthesis Surgery

• Advantages − Rigidity profile − Spontaneity − “One-time fix”

• Disadvantages − Operative procedure − Irreversible − Complications − Cost