Erectile Dysfunction (ED) Notes

Erectile Dysfunction (ED)

Learning Objectives

  • Identify medications that can cause/contribute to erectile dysfunction.
  • List the pharmacologic and nonpharmacologic treatment options for erectile dysfunction and discuss their mechanisms.
  • Describe the benefits and risks for phosphodiesterase inhibitors (PDEi).
  • Apply the treatment guidelines to manage a given patient with erectile dysfunction.

Erectile Dysfunction

  • Failure to achieve a penile erection suitable for satisfactory sexual intercourse.
Epidemiology
  • Prevalence increases with age.
    • 20-40% of men aged 60-69 years.
    • Over 50% of men > 70 years.
  • Sometimes thought to be part of the “aging process”.
  • More likely related to concurrent disease processes and/or medications.
  • Erectile dysfunction and cardiovascular disease share many of the same risk factors (hypertension, diabetes, dyslipidemia, smoking, etc.).
  • In many cases, erectile dysfunction is the first indication of cardiovascular disease.

Physiology of Penile Erection

Overview of Erection Cycle of the Penis
  • Erection:
    • Physical or mental stimulation.
    • Activation of the parasympathetic nervous system.
    • Release of acetylcholine and nitric oxide.
    • Smooth muscle of the penile arteries and carvernosum space relax.
    • Increased blood flow into corpora cavernosa.
    • Increase blood in the corpus cavernosa leads occlusion of veins and increased to rigidity of the penis.
  • Loss of Erection (Detumescence):
    • Parasympathetic activity subsides.
    • Smooth muscles of blood vessels contract.
    • Blood drains from the penis.

Molecular Basis of Penile Erection

  • Acetylcholine enhances production of nitric oxide which in turn activates guanylyl cyclase.
  • Guanylyl cyclase increases concentrations of cGMP.
  • cGMP causes sequestration of Ca2+Ca^{2+}.
  • Decreased intracellular Ca2+Ca^{2+} leads to dephosphorylation of myosin and inability of attach to actin.
  • Results in smooth muscle relaxation in penile arteries.
  • Penis becomes rigid and elongated.

Erectile Dysfunction - Etiology

  • Vascular
  • Neurologic
  • Hormonal
  • Psychogenic

Vascular - Pathophysiology

  • Diseases that compromise vascular flow to corpora cavernosa are associated with ED:
    • Peripheral vascular disease
    • Arteriosclerosis
    • Essential hypertension
    • Smoking

Neurologic - Pathophysiology

  • Diseases that impair nerve conduction to the brain can cause ED:
    • Stroke
    • Spinal cord injury
  • Diseases that impair peripheral nerve conduction to penile vasculature can cause ED:
    • Peripheral neuropathy (e.g. due to Diabetes mellitus)

Hormonal Etiology

  • Libido is stimulated by testosterone.
  • Normal serum concentration:
    • Total testosterone: ~300 – 1,100 ng/dL
    • Free testosterone: ~3.5 – 13.5 ng/dL (60-70 years of age)
  • Over 30% of men over 50 years of age experience hypogonadism (decreased testosterone).
  • Symptoms:
    • Depression
    • Loss of energy
    • Loss of muscle strength
    • Loss of libido
Primary Hypogonadism
  • Normal aging process or through surgical removal to testes.
Secondary Hypogonadism
  • Due to hypothalamic or pituitary disorders, chronic renal failure (through elevated prolactin levels).
  • Results in decreased libido and secondary ED.

Psychogenic Etiology

  • Malaise
  • Depression
  • Performance Anxiety
  • Relationship difficulties
  • Patients who have organic ED may develop a psychogenic component as they struggle to cope with their sexual dysfunction

Drug Induced ED

  • Drug Classes Examples Mechanism
    • Anti-cholinergic activity Antihistamines, Tricyclic Antidepressants Anticholinergics
    • Increase prolactin levels Metoclopramide, Phenothiazines Dopamine antagonists
    • Suppress testosterone Ketoconazole, Spironolactone, 5 α Hydroxy Reductase inhibitors Estrogens, antiandrogenic agents
    • Suppress perception of psychogenic stimuli Narcotics Alcohol CNS depressants
    • Reduced blood flow to corpora Alpha adrenergic blockers Agents that decrease blood flow

Diagnosis of Erectile Dysfunction

  • When patient reports difficulty attaining or retaining an erection, an assessment of possible causes is performed
  • Medical history with emphasis on cardiovascular and psychiatric disorders
  • Also important is a history of diabetes, BPH, physical trauma including surgery
  • Medication history both prescription and over the counter (including herbals)

Laboratory Tests

  • These tests do not help with diagnosis but can shed a light on potential cause of the patients ED
    • Serum testosterone
    • Glucose/ myoglobin A1c
    • Lipid panel
    • Thyroid panel
    • Prostate specific antigen (PSA)

Treatment of Erectile Dysfunction

  • AUA Guidelines for Erectile Dysfunction
  • Burnett, A. L., Nehra, A., Breau, R. H., Culkin, D. J., Faraday, M. M., Hakim, L. S., Heidelbaugh, J., Khera, M., McVary, K. T., Miner, M. M., Nelson, C. J., Sadeghi-Nejad, H., Seftel, A. D., & Shindel, A. W. (2018). Erectile Dysfunction: AUA Guideline. Journal of Urology, 200(3), 633–641

Erectile Dysfunction – Treatment Goal

  • Improve the quantity and quality of penile erections suitable for satisfactory intercourse and improvement of quality of life.
  • Ideally convenient to administer, rapid onset of action with minimal side effects or drug interactions.

Erectile Dysfunction - Treatment

  • Reversible causes of ED should be identified and addressed first.
  • Discontinue contributing medications if applicable.
  • Lifestyle changes
    • Quit smoking, reduce ethanol consumption
    • Improve diet & physical activity
    • Control other disease states

Erectile Dysfunction - Treatment

  • Pharmacologic
  • Non-pharmacological
    • Vacuum erection devices
    • Surgery
  • Treatment Algorithm for ED

Pharmacological Treatment

  • American Urological Association: Guideline on the Management of Erectile Dysfunction
  • Identifies phosphodiesterase inhibitors (PDEi’s) as first line therapy unless contraindicated
  • Other options should be instituted in stepwise fashion with increasing levels of invasiveness

Pharmacological Treatments

  • Phosphodiesterase inhibitors (PDEi’s)
    • Sildenafil (Viagra)
    • Vardenail (Levitra)
    • Tadalafil (Cialis)
    • Avanafil (Stendra)
  • Alprostadil (Caverject, Edex)
  • Testosterone

Mechanism of Action of PDE-5i

  • Sexual stimulation causes the release of nitric oxide (NO) in penile tissue
  • NO enhances guanylyl cyclase, which converts GTP to cGMP
  • cGMP is a secondary messenger which causes smooth muscle relaxation, increasing blood flow and causing an erection
  • Catabolism of cGMP is mediated by phosphodiesterse-5 (PDE5)
  • PDEi’s decrease the catabolism of cGMP by inhibiting PDE-5 in the genital tissue

Phosphodiesterase 5 - Inhibitors

  • Key Side Effects:
    • Facial Flushing
    • Dizziness
    • Hypotension
    • Nonarteritic anterior ischemic optic neuropathy (NAION)
    • Sudden Sensorineural Hearing Loss (SNHL)
    • Priapism
  • Sildenafil (Viagra)
    • < 1 hour to onset
    • Up to 4 hrs. duration
    • No dose adjustment for renal impairment
  • Vardenail (Levitra)
    • < 1 hour to onset
    • Up to 6 hrs duration
    • Reduce dose if CrCl < 30 ml/min
  • Tadalafil (Cialis)
    • < 1 hour to onset
    • Up to 36 hrs duration
    • No dose adjustment for renal impairment
  • Avanafil (Stendra)
    • 15 minutes to onset
    • Up to 6 hrs duration
    • No dose adjustment for renal impairment
Some unique Adverse Effects of PDE-5 Inhibitors
  • Sildenafil and Vardenafil cause photophobia, blurry vision, loss of blue-green discrimination
    • Related to inhibition of PDE-6 in retina
  • Tadalafil causes back/muscle pain
    • Related to inhibition of PDE-11
  • Sudden Sensorineural Hearing Loss (SNHL)
    • Loss of hearing that me be permanent
  • Vardenafil may prolong the QT interval

Phosphodiesterase Inhibitors Adverse Effects

  • The Princeton Consensus Guideline Conference II promulgated recommendations
  • PDEi’s are contraindicated in patients with high cardiac risk (sexual intercourse in general is not recommended) in patients presenting with any of the following:
    • Unstable angina
    • Uncontrolled hypertension
    • Severe congestive heart failure
    • Recent myocardial infarction or stroke
  • Nonarteritic anterior ischemic optic neuropathy (NAION)
    • Blood flow is optic nerve is impaired
    • Sudden, unilateral blindness that may be irreversible
  • Sudden Sensorineural Hearing Loss (SNHL)
    • Loss of hearing that me be permanent
  • Vardenafil may prolong the QT interval
  • Priapism

Drug Interactions with PDE 5 inhibitors

  • Nitrates – increase cGMP, risk for hypotension
    • Contraindicated with PDEi’s
    • Nitrates must be withheld for 12 hours after avanafil, 24 hours after sildenafil or vardenafil administration, 48 hours after tadalafil
  • Beta blockers or calcium channel blockers should be used to treat angina in patients taking a PDEi

Alprostadil

  • Prostaglandin E1 analogue
  • Stimulates adenylyl cyclase resulting in increased cAMP
  • Results in smooth muscle relaxation, increased blood flow, increased penile rigidity
  • Indicated for those who do not respond to or cannot use less invasive interventions
  • Administration
    • Intercavernosal (more effective): Caverject or Edex
    • Intraurethral: MUSE
Intracavernosal Alprostadil
  • Dose: 2.5-20 mcg, max 60 mcg
  • Onset: 5-10 minutes
  • Duration: 12-44 minutes
  • Efficacy: 70-90%
  • Adverse effects
    • Cavernosal plaques
    • Burning pain around injection site
    • Priapism
Intra-cavernosal Alprostadil Patient Instructions
  • Hold glans penis against thigh with one hand to expose lateral shaft
  • Inject at 90-degree angle
  • Massage the area to help distribute drug to the other cavernosum.
  • Apply pressure to injection site for 5 min to reduce hematoma formation
  • Rotate injection sites.
Intra-urethral Alprostadil
  • Dose: 125-1000 mcg
  • Onset: 5-10 minutes
  • Duration: 12-44 minutes
  • Efficacy: 43-60%
  • Third-line therapy due to lower efficacy and inconvenient administration
  • Contraindicated with pregnant partner unless condom is used
  • Adverse effects:
    • Urethral injuries
    • Urethral pain/burning
    • Priapism
Intra-urethral Alprostadil Patient Instructions Continued
  • Gently rock the applicator from side to side to separate the medicated pellet from the applicator tip.
  • Remove the applicator while keeping the penis upright.
  • Extending the penis to its full length, massage the penis firmly between your hands for at least 10 seconds. This will help the medication be absorbed. If there is a burning sensation, continue massaging the penis for another 30-60 seconds or until the discomfort stops.

Testosterone

  • For treatment of primary or secondary hypogonadism
  • Diagnosed by morning serum testosterone levels and luteinizing hormone levels
  • Improves libido and secondary erectile dysfunction
  • Formulations
    • Intramuscular (Depo-Testosterone)
    • Subcutaneous implantable pellets (Testospel)
    • Dermal Gel (AndroGel), Transdermal patch (Androderm )
    • Buccal (Testopel)
Testosterone – Adverse Effects
  • Can reactivate prostate cancer (contraindicated in these patients)
  • Benign prostatic hypertrophy – precaution
  • Sodium retention
  • Weight gain, CHF, HTN
  • Gynecomastia
  • Dyslipidemia
  • Increased hematocrit
  • Contact dermatitis (patches)

Off-label Options

Off-labelled Pharmacological Options
  • Trazodone:
    • Peripheral α blockade results in arteriolar vasodilation
  • Papaverine:
    • Nonspecific PDEi
  • Phentolamine:
    • α antagonist causing vasodilation
  • Yohimbine:
    • Central α-2 antagonist, increasing catecholamine release and improving mood. Possible peripheral reduction in α tone resulting in vasodilation

Non-Pharmacological Treatment

  • Some Common Approaches
    • Surgical implants
    • Vacuum devices

Surgical implants

  • Penile implant
    • Most invasive treatment, reserved for those who do not respond to or are not candidates for other therapies
    • Two options – malleable or inflatable
    • >90% reported success rate
    • Complications include infection, mechanical failure, erosion of rods through the penis

Vacuum Erection Devices

  • Pump, chamber, and constriction bands
  • Manual or electronic
  • Up to 90% efficacy rate
  • Similarly high satisfaction rate
  • Adverse effects
    • Slow onset of action (30 minutes)
    • Indiscreet (best for use in stable relationship)
    • Complaints about color and temperature
    • Hinge effect: discomfort caused by compression of the glans

Vacuum Erection Devices - Contraindications

  • Contraindicated in patients with conditions like sickle cell disease
  • Use with caution in patients:
    • on anticoagulant therapy
    • lacking sensation
    • Peyronie’s disease
    • venoocclusive conditions