Erectile Dysfunction

Changes with Aging

• of all risk factors, AGE is the strongest association

• arousal

  • delayed

  • less rigidity

• orgasm

  • weaker, shorter

• Plateau

  • prolonged

  • urge to ejaculate is diminished

• Detumescence

  • more rapid

  • prolonged refractory period

Pathophysiology

• flaccid

  • sympathetic system

  • arterial and smooth muscle contracted

• erect

  • parasympathetic system

  • vasodilation, decrease in peripheral vascular resistance (PVR)

  • NO primary mediator

Risk factors

Disease

• endocrine - DM, hypogonadism, obesity

• CVD - HTN, hypercholesterolemia, stroke

• renal and hepatic failure (changes in testosterone)

• cancer - irradiation

• trauma (surgery etc)

• BPH - compression of vasculature

• LUTS

• pulmonary - COPD, OSA

• periodontitis (chronic - inflamm can also cause vascular damage)

• HIV infection

• neuro - depression, MS, alzheimer’s, parkinson’s, spinal cord injury

Lifestyle

• sedentary lifestyle

• cigarette smoking

• alcohol use

• bicycle riding (as little as 3hrs/week)

• shift work - circadian rhythm is messed up; testosterone won’t completely normalize like someone who has a normal day and night cycle

• diet - reduced risk w/ Mediterranean diet

• psychological - stress, performance anxiety, partner conflict, misinformation (partly through porn - what’s realistic and what’s not can stress ppl out)

Environment

• bisphenol A

• polychlorinated biphenyl

• phytoestrogens

• heavy metals

Drug factors

• antidepressants - psychotropic meds:

  • SSRI, SNRI, TCA, MAOI - need 5HT, DA, NE and epi for stimulation

    • bupropion, mirtazapine PREFERRED

  • neuroleptics (1st gen, risperidone)

    • 2nd gen PREFERRED (quetiapine, olanzapine, aripiprazole)

• CV drugs - antihypertensives:

  • centrally acting, BBs, TZDs, aldosterone antagonists (interfere w/ testosterone production)

    • ACEi, ARB, CCB generally PREFERRED in ED pts w/ HTN

• antibacterials

• anticholinergic drugs

• antiandrogens

  • spironolactone, cimetidine

• hormone therapy (suppression of testosterone production)

  • CS, estrogens, progestins, GnRH agonists, 5alpha reductase inhibitors

• drugs assoc w/ substance use disorder

  • tobacco, heroin, cocaine, EtOH

• analgesia

  • NSAIDs (chronic use, high dose)

  • opioids (strongly assoc w/ hypogonadism)

COVID

• mechanisms:

  • endothelial dysfxn

  • psychological distress

  • impaired pulmonary hemodynamics

  • exacerbation of CVD

  • impact on T levels

  • sensory loss (anosmia, ageusia)

Assessment and Diagnosis

• Hx

  • sexual fxn (onset, duration, new partner? assoc w/ distress? how long has it lasted?)

  • medical hx

  • drug use

  • psychosocial

• physical exam

• lab tests

• additional tests (Doppler U/S, relationship evaluation)

Assessment tools

• SQoL assessment

• self-esteem and relationship questionnaire (SEAR)

• erectile dysfxn inventory of tx satisfaction (EDITS)

• # of events (penetration, attempts)

• international index of erectile fxn (IIEF)

  • 5 domains:

    • erectile fxn

    • orgasmis fxn

    • sexual desire

    • intercourse satisfaction

    • overall satisfaction

Goals

• how broad are goals of tx?

• what can these drug therapies address?

• consider FEASIBLE goals:

  • increased # of erections

  • improved quality of erections

  • restore self-esteem of both partners

  • restore sexual relationship w/ partner

  • improve QofL

Non-pharm intervention

• counseling of both partners (can be $$$ tho and sometimes ppl don’t want to talk about it)

• lifestyle

  • smoking cessation

  • avoid EtOH, substance misuse

  • healthy diet

  • exercise

  • adequate sleep

PDE5 inhibitors

• response rate:

  • 60-80% (dose dependent)

  • 50-55% in pts w/ diabetes (less NO response in these pts***)

  • sometimes start them on high dose depending on pt’s distress about the situation to get faster response

  • Sildenafil (Viagra)

    • decreased absorption w/ high fat meals

    • metabolism: CYP3A4 (major)

    • worst SE profile bc less selective

  • Tadalafil (Cialis) - indicated for chronic use

    • no interaction w/ food

    • metabolism: CYP3A4

    • less AEs @ higher doses bc more selective

  • Vardenafil (Levitra)

    • absorption decreased w/ high fat meals

    • metabolism: CYP3A4 (major)

    • less AEs @ higher doses bc more selective

• SEs:

  • flushing

  • headache

  • dyspepsia

  • nasal congestion

  • visual disturbances (more w/ sildenafil)

  • signal PDE5i may increase risk of malignant melanoma or basal cell carcinoma

• Ophthalmic Safety:

  • non-arteritic anterior ischemic optic neuropathy (NAION) - so much vasodilation that there’s not enough pressure to perfuse to other organs

    • acute ischemia of optic nerve

    • infarction may result

    • visual field defect or vision loss may occur

    • pt counselling: inform MD if experiencing vision loss

  • glaucoma - worsening or new onset

  • change in color perception

    • PDE6 interaction w/ sildenafil in retina

    • blue tinged vision

ACC/AHA Risk

• absolute CI: use of PDE5i and concurrent use of nitrates***

• CV effects of sildenafil may be potentially hazardous in pts w/:

  • active coronary ischemia (not on nitrates)

  • CHF and borderline low BP

  • borderline low volume status

  • on complicated, multi-drug, antihypertensive regimen

  • taking meds that can prolong t1/2 (CYP3A4 and 2C9 inhibitors)

• warnings/precautions

  • non-selective alpha antagonists (e.g. terazosin, doxazosin)

    • black box warning in USA (leads to too much vasodilation)

  • selective alpha-antagonists (e.g. tamsulosin) - considered fairly safe

• washout periods:

  • viagra - can start taking nitrates next day

  • cialis - need more longer washout period

  • vardenafil - can start taking nitrates next day

PED5i - Treatment Failure

• rx renewal

  • 4mo = 60%

  • 12mo = 30%

• reasons for failure

  • people

    • HCP issues (maybe didn’t give pt realistic expectations, not taking a thorough med hx etc)

    • patient - compliance, not having feasible expectations

    • partner - can also create expectations for their partner

  • condition

    • ED, comorbidities

  • treatment

    • drug (choice, dose)

Prostaglandin E1

• MOA: increases cAMP, leading to smooth muscle relaxation, veno-occlusion and erection (endogenous NO not required) - better for diabetics

• response rate - 70-90%

• role: local therapy used when systemic therapy CI

• injection into side of penis - corpus cavernosum; start low and go slow w/ dose; given <1hr prior to sexual activity (erection can occur w/i 5mins)

• max = 1 dose/24 hrs

• max = 3 doses/week

• SEs:

  • penile pain

  • priapism

• CIs:

  • any condition that increases risk of priapism

    • sickle cell anemia, multiple myeloma, leukemia, anatomical deformity of penis

MUSE - Medical urethral suppository

• MOA: as per PGE1

• 30-50% response rate

• role: local therapy for pts who refuse injection

• dose: 15-30 min prior to intercourse

  • starting dose: 125mcg

  • max = 2 doses/24 hrs

• caution if partner is pregnant - product can be ejaculated into partner leading to loss of pregnancy

• AEs: penile pain, urethral burning, vaginal irritation for partner

Triple therapy

Papaverine

• nonspecific PDEi

• increases cAMP and cGMP in penile erectile tissue

• intracavernosal injection

• SE: penile fibrosis and potential hepatotoxicity

Phentolamine

• alpha-1, alpha-2 selective antagonist

• blocks sympathetic receptors to control tone

• intracavernosal injection

Triple therapy: papaverine + phentolamine + PGE1 (fallen out of favor)

Drawbacks of injection therapy

• non-spontaneous

• manual dexterity

• eyesight

• priapism

• fibrosis

• drop out/adherence

• if they aren’t rotating sites → scar tissue isn’t flexible so can cause deformities then they can’t get injections anymore

NHPs

• Yohimbine

  • MOA: alpha2 antagonist, acts at brain centre to control libido, penile erection (more of a psychological benefit)

  • TID or daily dosing, often used in combination

  • mixed results but superior to placebo

  • SE: Mild BP elevation, palpitations, nervousness, irritability

  • role: psychogenic ED

• Panax ginseng

  • MOA: increases cGMP, relaxation of corpus cavernosum

  • TID dosing

  • role: subgroup of psychogenic ED greatest benefit

• Butea superba (aka Kwoa Krua Deng)

  • MOA: corpus cavernosum relaxation

  • dried plant product

  • role: not recommended at this time***

• L-Arginine

  • L-citrulline converted to L-arginine

  • MOA: NO production

  • daily-TID dosing

  • role: combined w/ PDE5i if resistant (considered if diabetic pt; may be some benefit used as combo)

Trazodone

• MOA: facilitates 5HT and DA pathways

• SEs: priapism - viewed as a SE but can be used to help facilitate an erection; if lasts for >4hrs it can cause vasculature damage and need to go to ER***, sedation

Penile prostheses

• 95% response rate

• pharmacology: analgesics and abx for one day post op

• complications:

  • require surgery

  • infection

  • bleeding

  • thrombotic risk

  • erosions

  • mechanical failure

Devices e.g. vacuum

• 98% response rate

• very low acceptance rate

• complications: penile edema, ecchymosis

• less control and more risk for injury depending on sexual activity

Monitoring of ED Treatment

Efficacy

• dose required (titration necessary?)

• # and quality of erections after taking meds

General question:

• “has the tx you have been taking improved your erections?”

International Index of Erectile Function (IIEF or IIEF-5)

Sexual Encounter Profile

• 5 Q patient diary (yes/no)

  • able to achieve at least some erection?

  • able to insert penis into partner’s vagina?

  • did erection last long enough for you to have successful sex?

  • satisfied w/ hardness of erection?

  • satisfied w/ overall sex?

• completed by pt after each sexual encounter

Priapism

• unwanted erection lastin >4hrs (medical emergency**)

  • not assoc w/ sexual desire

• permanent ED at 36 hrs

• most common type:

  • low flow

  • high flow is rare; may occur after trauma or surgery

• Tx (done w/i mins-hrs of pt coming into ER):

  • early stage - ice packs, cold shower

  • analgesia

  • decompression

    • aspiration of blood (at least 5mL) - resolves approx 30% of cases

  • intracavernosal sympathomimetics - resolves approx 80% of cases

    • phenylephrine

      • titrate to detumescence or until total 10mg given

  • oral sympathomimetics (note CV risk)

    • terbutaline

    • pseudophedrine po

  • shunt surgery