Erectile Dysfunction: Causes, Physiology, PDE5 Inhibitors & Treatment

Erectile dysfunction (ED): definition

Inability to achieve or maintain an erection sufficient for sexual intercourse

Massachusetts Male Aging Study (MMAS): ED prevalence

52% of 1,290 men aged 40-70 had some degree of ED

MMAS: % with total absence of erectile function

Almost 10%

ED risk with age

Rises sharply; 3.6-fold greater prevalence at age 50-59 vs. 18-29

ED comorbidities

Cardiovascular disease and HTN; diabetes; lower urinary tract symptoms; prostate cancer; depression

% of ED caused by medication side effects

25%

Drug classes that cause ED

Alpha-adrenergic blockers; CNS depressants; diuretics; antihypertensives; antihistamines; antidepressants

Alpha-adrenergic blocker that causes ED (example)

Tamsulosin

CNS depressants that cause ED

Benzodiazepines; narcotics; antipsychotics

Diuretics that cause ED

Loop and potassium-sparing diuretics

Antihypertensives that cause ED

Beta-blockers; clonidine

Antidepressants that cause ED

SSRIs (selective serotonin reuptake inhibitors)

Erection physiology: main nervous system response

Primarily parasympathetic; also an important noncholinergic (nonadrenergic noncholinergic) neuronal response

Two requirements for a successful erection

Intact parasympathetic nervous system + release of adequate nitric oxide

Erection cascade: first 3 steps

CNS stimulation → spinal nerves → parasympathetic and nonadrenergic noncholinergic responses

Erection cascade: enzyme that makes nitric oxide

Nitric oxide synthase

Erection cascade: what nitric oxide activates

Guanylyl cyclase → produces cGMP

Erection cascade: what cGMP does

Dilates smooth muscle via dephosphorylation of myosin light chains

Erection cascade: final steps

Corpus cavernosum smooth muscle relaxes + penile arteries dilate → erection

Erection cascade: what inactivates cGMP

PDE (phosphodiesterase) converts cGMP → inactive GMP

6 etiologies of ED

Vasculogenic; psychogenic; hormonal; neurogenic; drug use; other

Vasculogenic ED: examples

Arterial or cavernosal causes: atherosclerosis, hypertension

Psychogenic ED: examples

Depression; relationship problems

Hormonal ED: examples

Hypothyroidism; hyperthyroidism; hyperprolactinemia

Neurogenic ED: examples

Diabetes; spinal cord injury

'Other' causes of ED

Anatomic anomaly; mechanical abnormalities; surgical complications; chronic disease; old age

Pharmacologic ED treatments

PDE5 inhibitors (sildenafil, tadalafil, vardenafil); injectable prostaglandins

Non-pharmacologic ED treatments

Vacuum erection devices; penile prostheses (implants); penile revascularization

PDE5 inhibitors: cost/insurance issue

Expensive; many insurers limit or refuse coverage

PDE5 inhibitors: typical tablets prescribed per month

4 to 10 tablets

Priapism: more common with PDE5 inhibitors or alprostadil?

Alprostadil (rare with PDE5 inhibitors)

Priapism treatment

Corpora aspiration, then intracavernosal alpha-adrenergic agonist such as phenylephrine (Neo-Synephrine)

ED drug for spinal cord injury patients who fail PDE5 inhibitors

Alprostadil, because it does not depend on nitric oxide

ED patient education: nitrates

Patients on nitrates should NOT take PDE5 inhibitors

ED patient education: STDs and pregnancy

No ED treatment protects against STDs/HIV; use other methods to prevent STDs and pregnancy

ED patient education: prolonged erection

Seek medical care for priapism lasting >4 hours

ED patient education: transurethral alprostadil and pregnancy

Do not have intercourse with a pregnant woman

PDE5 inhibitors: 3 drugs (generic/trade)

Sildenafil (Viagra); vardenafil (Levitra); tadalafil (Cialis)

Sildenafil (Viagra): route and dose

PO; 25-100 mg

Vardenafil (Levitra): route and dose

PO; 10-20 mg

Tadalafil (Cialis): route and dose

PO; 2.5-5 mg daily or as needed

Phosphodiesterases: general role

Found throughout the body; convert compounds from one form to another

PDE5 role in the corpus cavernosum

Main catalyst converting cGMP → GMP (guanosine monophosphate)

PDE types in the corpus cavernosum

PDE2, 5, 9, 11

PDE types: brain

PDE1, 2

PDE type: retina

PDE6

PDE types: heart

PDE4, 11

PDE types: skeletal muscle

PDE1, 2, 4, 5

PDE type: lungs

PDE4

PDE types: visceral smooth muscle

PDE1-5

PDE type: adrenal cortex

PDE2

PDE types: liver and kidneys

PDE1-3

PDE type: platelets

PDE3

PDE type: mast cells

PDE4

PDE type: vascular smooth muscle

PDE4

PDE types with unknown distribution

PDE7-10

PDE5 inhibitors: mechanism of action

Inhibit PDE5 → cGMP not rapidly converted to inactive GMP → cGMP persists to create and maintain erection

PDE5 selectivity: sildenafil

10-fold

PDE5 selectivity: tadalafil

10,000-fold

PDE5 selectivity: vardenafil

15-fold

Do PDE5 inhibitors work without sexual stimulation?

No; they don't cause erections, only allow the penis to respond to stimulation

PDE5 inhibitors: absorption

All 3 well absorbed orally

Which PDE5 inhibitor's absorption is inhibited by food?

Sildenafil (Viagra)

Sildenafil and vardenafil: onset and duration

Onset 30-120 min; duration ~4 hours

Tadalafil: onset and duration

Onset 15 min; duration 36 hours

PDE5 inhibitors: distribution

Extensive tissue binding

PDE5 inhibitors: metabolism

Hepatic (CYP450)

Which PDE5 inhibitor has an active metabolite?

Sildenafil

Sildenafil and vardenafil: excretion

80% in feces

Tadalafil: excretion

~2/3 in feces; remainder in urine

PDE5 inhibitors: clinical use of all 3

Erectile dysfunction

PDE5 inhibitors used for pulmonary hypertension

Sildenafil and tadalafil

PDE5 inhibitor used for BPH

Tadalafil

PDE5 inhibitors: CV adverse reaction

Flushing

PDE5 inhibitors: EENT adverse reactions

Rhinitis; sinusitis; visual disturbance; epistaxis

PDE5 inhibitors: GI adverse reactions

Dyspepsia; nausea

PDE5 inhibitors: GU adverse reaction

Priapism (rare)

PDE5 inhibitors: neuro adverse reaction

Headache

PDE5 inhibitors + nitrates (any form) or sodium nitroprusside

Exaggerated BP drop → can cause cardiac arrest and death

PDE5 inhibitors + antihypertensives

Small additive BP drops (beta-blockers, CCBs, ACEIs, ARBs, diuretics)

PDE5 inhibitors: contraindication - nitrates

Concurrent organic nitrates: nitroglycerin, isosorbide mononitrate, isosorbide dinitrate

PDE5 inhibitors: contraindication - priapism risk

Conditions associated with priapism: sickle cell disease, myeloma, leukemia

PDE5 inhibitors: use cautiously in

Elderly patients; any renal impairment

Before giving nitroglycerin, what must you ask?

Whether the patient has taken a PDE5 inhibitor

How long to hold nitroglycerin after sildenafil or vardenafil?

At least 24 hours after last dose

How long to hold nitroglycerin after tadalafil?

48 hours after last dose

PDE5 inhibitors: use caution with which drug classes?

Antihypertensives; alpha blockers for BPH (e.g., doxazosin/Cardura, tamsulosin/Flomax)

PDE5 inhibitors: timing and frequency

Take 30-60 min before intercourse; no more than once a day

Alprostadil: trade names and routes

Caverject = intracavernosal; Muse = intraurethral

Caverject (alprostadil) dose

2.5-60 mcg; no more than 1 dose/day or 3 times/week as needed

Muse (alprostadil) dose

125-1,000 mcg; no more than 2 times/24 hr as needed

Alprostadil: what it is

Synthetic prostaglandin E1

Alprostadil: mechanism of action

Relaxes arterial smooth muscle → more arterial blood flow into corpus cavernosum → erection

Why do prostaglandins work when PDE5 inhibitors fail?

They bypass many steps of the erectile cascade

Do prostaglandins need intact nerves/nitric oxide?

No; they don't require an intact cord or innervation to produce nitric oxide

Alprostadil: absorption and duration

Absorbed within 10 min when injected locally; effect lasts ~1 hour

Alprostadil: distribution

Insignificant

Alprostadil: metabolism

75% metabolized by one-pass mechanism in the lungs

Alprostadil: excretion

90% of metabolites excreted in urine within 24 hours

Alprostadil: clinical use

ED of vascular, psychogenic, or neurogenic etiology