What it is:Erectile dysfunction (ED) is the persistent or recurrent inability to get or keep an erection firm enough for intercourse, present for at least 3 months. Patients often call it "impotence." It's extremely common: about 52% of men aged 40 to 70report some degree of it.
The core problem:An erection needs four systems working together: intact blood vessels, intact nerves, adequate hormones(testosterone), and an intact psychologicaldrive/arousal pathway. Break any one and you get ED. Most ED in an aging population is vasculogenic, meaning it shares the same risk factors as cardiovascular disease.
What you do about it:Fix what's fixable first (stop the offending drug, treat the diabetes or hypertension, replace testosterone if he's hypogonadal), then move through the least invasive option first: vacuum device or a PDE5 inhibitor, then alprostadil, then surgeryas the last resort.
Sexual stimulation triggers nitric oxide release → guanylate cyclase → cGMP → smooth muscle relaxationin the corpora cavernosa → blood rushes in and venous outflow is compressed → erection. Every drug class in this chapter either boosts that cGMP signal(PDE5 inhibitors, which block the enzyme that tears cGMP down) or works around it entirely(alprostadil raises cAMP through a completely separate pathway, which is exactly why it still works when PDE5 inhibitors fail). Once you see the pathway, the whole drug list makes sense.
The penis has two corpora cavernosa and a corpus spongiosum full of interconnected vascular sinuses. In the flaccid state those sinuses are constricted and venous channels are open, letting blood drain out as fast as it comes in. Sexual stimulation flips that: acetylcholine and nitric oxide relax the smooth muscle of the arterioles and sinuses, blood floods in, and the engorged tissue compresses the veins against the tunica albuginea so outflow is trapped. That trapping, not just inflow, is what makes an erection sustainedrather than a brief flush.
Clinically it's useful to sort ED into organic(vascular, neurologic, or hormonal) versus psychogenic(no identifiable organic lesion, drops out with anxiety, depression, or relationship stress). Psychogenic ED responds better to treatment than organic ED, which matters for counseling expectations. Most real patients are a mix.
| Category | Common drivers | What actually breaks |
|---|---|---|
| Vasculogenic(most common overall) | Hypertension, atherosclerosis, hyperlipidemia, diabetes, obesity, smoking, trauma, Peyronie's disease | Impaired arterial inflow and/or failure of venous occlusion, endothelial dysfunction blunting nitric oxide release |
| Neurogenic | Stroke, Parkinson's/Alzheimer disease, spinal cord injury, pelvic surgery, diabetic neuropathy, epilepsy | Interrupted neural signal to the corpora, failure to trigger nitric oxide release in the first place |
| Hormonal | Hypogonadism, hyperprolactinemia, chronic opioid use | Loss of libido plus inadequate nitric oxide tone; long-standing cases can cause tissue atrophy |
| Drug-induced | See the causes table below | Varies by drug: anticholinergic block, dopamine antagonism, reduced penile blood flow, CNS suppression |
| Psychogenic | Depression, performance anxiety, relationship conflict, sedation | Sympathetic activation and loss of libido override the nitric oxide signal even when the plumbing is fine |
| Systemic disease | Aging, diabetes, chronic renal failure, generalized atherosclerosis | Usually several of the above mechanisms stacked together |
Because vasculogenic ED shares its risk factors (hypertension, atherosclerosis, hyperlipidemia, diabetes, smoking, obesity) almost one-for-one with cardiovascular disease, new-onset ED is now treated as an early warning sign of CV disease, sometimes appearing years before a cardiac event. Every man with new ED deserves a look at his CV risk, not just a prescription.
Testosterone isn't required to generate an erection mechanically, but it drives libidoand helps maintain nitric oxide synthase activity in the corpora. Levels decline gradually starting around age 40. When testosterone is truly low (confirmed, not assumed), you get a secondaryED layered on top of decreased sexual interest, and replacing testosterone can help, though the erectile benefit takes far longer to show up than the libido benefit does (see the Testosterone section).
A large share of ED referrals trace back to the med list. Always screen for this before assuming a purely organic or psychogenic cause, and remember that nonadherence to a drug the patient suspects is causing ED can itself be a cluethat something on the list is the culprit.
| Drug class | Examples | Why it happens |
|---|---|---|
| Diuretics | Thiazides, spironolactone | Reduced intravascular volume drops penile arteriolar flow; spironolactone also has antiandrogenic/estrogenic activity at higher doses |
| Antihypertensives | Beta-blockers (especially propranolol, atenolol, metoprolol), central sympatholytics (methyldopa, clonidine, guanethidine) | Reduced penile blood flow. Newer vasodilating beta-blockers like nebivolol are gentler. ACEi, ARBs, CCBs, and alpha1-blockers (terazosin, doxazosin) are the safer swaps |
| Antidepressants | TCAs, MAOIs, and SSRIs (paroxetine, sertraline, fluvoxamine, fluoxetine worse than venlafaxine, bupropion, mirtazapine, escitalopram, vilazodone) | Anticholinergic effects (TCAs) or serotonergic effects blunting arousal and delaying orgasm; SNRIs like duloxetine and NRIs like atomoxetine also carry meaningful ED rates (roughly 8–21%) |
| Anticholinergics | First-generation antihistamines, antiparkinsonian agents, phenothiazines, disopyramide | Direct anticholinergic blockade of the acetylcholine arm of the erectile pathway. Second-generation antihistamines (loratadine, fexofenadine, cetirizine) are much safer |
| Antiandrogens / hormonal agents | 5-alpha reductase inhibitors (finasteride, dutasteride), LHRH agonists, estrogens, ketoconazole, cimetidine, digoxin | Suppress testosterone-driven libido; 5-ARI sexual dysfunction can rarely persist after stopping the drug |
| CNS depressants | Opioids, benzodiazepines, barbiturates, large acute doses of alcohol | Blunt the psychogenic/CNS arm of arousal |
| Other | Lithium, gemfibrozil, clofibrate, interferon, metoclopramide/phenothiazines (dopamine antagonism → hyperprolactinemia) | Mechanisms are less clean; several are simply reported associations |
A patient on an SSRI/SNRI, a beta-blocker, and an anticonvulsant walks in with new ED. Don't just blame the SSRI. Anticonvulsants like lamotrigine and older beta-blockers both carry their own ED signal, and NRIs like atomoxetine (used off-label for adult ADHD) are an easy one to miss because it doesn't "look like" a psych drug. Go through the whole list before picking a culprit.
ED is under-reported. Signs are subtle and the partner is often the one who actually brings it up. There's no lab test that "shows" ED on its own, so the history does the heavy lifting.
Diagnosis is clinical. The job is to characterize severity, find reversible contributors, and screen for the conditions ED is an early marker of.
Baseline IIEF → treat/remove reversible causes → start therapy → reassess with the same questionnaire at 1 to 3 weeks. Reassessing too early (before an adequate trial of the drug) is a common reason patients get labeled "PDE5 failures" when they weren't actually failures of the drug, just failures of technique or timing.
The Third Princeton Consensus Conference (2012) is the framework everyone cites. Step one, before any prescription, is to fix what's fixable.
From there, treatment escalates from least to most invasive:
First-line for most patients. Can be combined together.
Intracavernosal injection or intraurethral insert. For PDE5i failures, contraindications, or intolerance.
VED + alprostadil, or alprostadil + papaverine/phentolamine, when monotherapy underperforms.
Most invasive option, reserved for true non-responders or those who can't use less invasive therapy.
Confirm the patient actually had 7–8 attemptsat an adequately titrated dose, took it correctly (timing, without a heavy fatty meal for sildenafil/vardenafil/avanafil), and had genuine sexual stimulation, since the drug does nothing without arousal. Incorrect use accounts for a large share of "treatment failures."
Sexual activity raises heart rate and myocardial oxygen demand roughly the way climbing two flights of stairs does. The Princeton III framework sorts patients into three tiers before you write for a PDE5 inhibitor or clear them for sex at all.
| Risk | Who's in this category | What to do |
|---|---|---|
| Low risk | Asymptomatic with <3 CV risk factors, well-controlled hypertension, mild CHF (NYHA I–II), mild valvular disease, MI >8 weeks ago | Start a PDE5 inhibitor |
| Intermediate risk | ≥3 CV risk factors, mild-moderate stable angina, MI or stroke 2–8 weeks ago, moderate CHF (NYHA III), history of stroke/TIA/PAD | Cardiovascular workup and exercise stress test to reclassify into low or high risk before treating |
| High risk | Unstable/refractory angina, uncontrolled hypertension, severe CHF (NYHA IV), MI or stroke within 2 weeks, moderate-severe valvular disease, high-risk arrhythmia, obstructive hypertrophic cardiomyopathy | PDE5 inhibitor contraindicated; defer sexual activity until restratified |
Regardless of cardiac risk tier, any patient on a nitrate cannot take a PDE5 inhibitor, period, because the combined vasodilation can cause profound, sometimes fatal hypotension. This is an absolute contraindication, not a dose-adjustment situation.
| Drug | Starting dose | Usual range | Notes |
|---|---|---|---|
| PDE5 Inhibitors (max 1 dose/day) | |||
| Sildenafil (Viagra) | 50 mg, 1 h before sex | 25–100 mg | Start 25 mg if age ≥65, CrCl <30, severe hepatic impairment, or on a protease inhibitor |
| Vardenafil (Levitra) | 5–10 mg, 1 h before | 5–20 mg | Start 5 mg if ≥65 or moderate hepatic impairment; avoid if severe hepatic impairment or congenital long QT |
| Vardenafil ODT (Staxyn) | 10 mg, dissolve on tongue | Fixed 10 mg | No titration; do not initiate with alpha-blockers; avoid with moderate-severe hepatic impairment |
| Tadalafil (Cialis) - on demand | 5–10 mg, ≥30 min before | 10–20 mg | The "weekend pill" - lasts up to 36 h |
| Tadalafil - daily dosing | 2.5–5 mg once daily | 2.5–5 mg daily | Removes the need to time sex around the dose |
| Avanafil (Stendra) | 100 mg, 15 min before | 50–200 mg | Fastest onset of the class (as little as 15–25 min) |
| Alprostadil (Prostaglandin E1) | |||
| Intracavernosal injection (Caverject, Edex) | 2.5 mcg, 5–10 min before | 10–40 mcg, max 60 mcg | Max 1 injection/day, max 3/week, ≥24 h apart |
| Intraurethral pellet (Muse) | 125–250 mcg, 5–10 min before | 250–1,000 mcg | Max 2 doses/day; void bladder before insertion |
| Testosterone (for confirmed hypogonadism, not routine ED) | |||
| Testosterone cypionate/enanthate IM | 100–200 mg every 2–4 wk | 200–400 mg every 2–4 wk | Preferred: cheap, effective, no first-pass hepatotoxicity; causes supraphysiologic peaks mid-cycle |
| Testosterone undecanoate IM (Aveed) | 750 mg once | 750 mg at wk 0, wk 4, then q10wk | REMS-restricted facility administration; risk of pulmonary oil microembolism |
| Transdermal patch (Androderm) | 4 mg at bedtime | 2–6 mg at bedtime | Rotate sites; may need multiple patches |
| Transdermal gel (AndroGel, Testim) | 5–10 g in the morning | Titrate q14d | REMS required; risk of transference to others |
| Subcutaneous pellet (Testopel) | 150–450 mg (2–6 pellets) | Every 3–6 months | Minor procedure; onset delayed 3–4 months |
MOA:Phosphodiesterase type 5 normally breaks down cGMP in the corpora. Blocking it lets cGMP accumulate after sexual stimulation, prolonging and amplifying the smooth muscle relaxation that fills the corpora with blood. Critically, PDE5 inhibitors do nothing without arousal first, because they only amplify a signal that has to already be triggered by nitric oxide release. That's why "the pill doesn't work" is so often actually "the pill was taken without enough stimulation."
All four agents are considered roughly equally effective(response rate 60–80%) despite having no head-to-head trials, and patients can be switched between them if one isn't tolerated. Nonresponse (30–40%) is more likely in patients with diabetes or after prostatectomy.
| Sildenafil | Vardenafil | Tadalafil | Avanafil | |
|---|---|---|---|---|
| Onset | ~60 min | 30–60 min | ~60 min | 15–40 min |
| Duration | 2–4 h (up to 12h) | 4–5 h | 24–36 h | 6+ h |
| Half-life | 3.7 h | 4.4–4.8 h | 18 h | 5 h |
| Food effect | Fatty meal slows absorption | Fatty meal slows absorption | No food effect | Fatty meal slows rate only |
| Nitrate washout window | 24 h | 24 h | 48 h | 12 h |
Its 18-hour half-life gives it the longest duration of action (up to 36 hours) and lets it be dosed once daily at a low dose instead of on-demand, which is why it's the only PDE5 inhibitor with an FDA-approved daily regimen. It's also why its nitrate washout is the longest at 48 hours: if EMS is called for chest pain, they need to know exactly which PDE5 inhibitor was taken and when, because giving nitroglycerin to a patient who took tadalafil 12 hours ago can cause severe, refractory hypotension.
Metabolism:all four are metabolized primarily by CYP3A4. Strong 3A4 inhibitors (azole antifungals, protease inhibitors, macrolides) require a lower starting dose across the board; strong inhibitors plus a moderate-potent CYP3A4 inhibitor with avanafil caps the dose at 50 mg/24h, and vardenafil with ritonavir is capped to 2.5 mg every 72 hours. Grapefruit juice should be avoided with all of them.
Absolute:concurrent nitrates by any route (short- or long-acting), and use in patients at high cardiac risk per the Princeton III table. Use cautiously:concurrent alpha-blockers (additive orthostatic hypotension - Staxyn specifically should not be initiated in a patient already on an alpha-blocker), multiple antihypertensives, baseline hypotension, and history of retinitis pigmentosa or nonarteritic anterior ischemic optic neuropathy (NAION), a rare, sudden, painless, potentially permanent vision loss reported (though not proven causal) with PDE5 inhibitor use.
Common dose-related side effects:headache, facial flushing, dyspepsia, nasal congestion, dizziness; tadalafil also causes back pain/myalgia more than the others. Sildenafil, vardenafil, and avanafil can cause transient blue-green color discrimination changes or light sensitivity in 2–3% of patients (tadalafil inhibits a different PDE isoenzyme profile and largely spares this). Sildenafil and vardenafil also drop systolic/diastolic BP by roughly 8–10/5–8 mm Hg for a few hours after dosing.
MOA:Alprostadil is synthetic prostaglandin E1. It stimulates adenylyl cyclase to raise cAMPdirectly in the corporal smooth muscle, a completely separate pathway from the cGMP route PDE5 inhibitors work through. That's the whole reason it still works in men who fail PDE5 inhibitors: it doesn't depend on nitric oxide release or cGMP at all, so it bypasses whatever is broken upstream.
It's approved as monotherapy and is generally reserved for patients who fail or can't use PDE5 inhibitors or a vacuum device. The intracavernosal route outperforms the intraurethral route.
| Intracavernosal injection | Intraurethral pellet (MUSE) | |
|---|---|---|
| Efficacy | 70–90% | 40–66% |
| Onset | 5–15 min | 5–10 min |
| Discontinuation | 30–50% within 6–12 months | Lower efficacy limits use to non-injection candidates |
| Local pain | 10–44% of patients | 24–32% of patients, plus partner may feel vaginal burning/itching from drug transfer |
Why patients stop:perceived lack of effectiveness, the hassle of administration, the erection feeling "unnatural" or nonspontaneous, needle phobia, and cost. This is worth naming out loud during counseling so it isn't a surprise.
Local adverse effects include hematoma/bruising (mostly in year 1), cavernosal fibrosis or plaques (2–12%), penile pain (10–44%, usually mild and self-limited), and priapism in 1–15% of patients. Any painful erection beyond the expected duration needs prompt evaluation. Avoid intracavernosal alprostadil in patients at baseline priapism risk (sickle cell disease, leukemia, multiple myeloma) or with a bleeding disorder.
Injection technique has to be taught (aseptic intracavernosal technique with a fine 27–30 gauge needle), and combining alprostadil with a vacuum device or with papaverine/phentolamine (different mechanisms) is a legitimate strategy when monotherapy underperforms.
Testosterone replacement is for confirmed, symptomatic hypogonadism, meaning low libido or ED plus two separate low early-morning testosterone levels, not for ED with a normal testosterone level. It restores serum testosterone to the normal range of 300–1100 ng/dL (10.4–38.2 nmol/L).
Libido, mood, and quality of life improve in 3–4 weeks. Erectile function itself doesn't catch up until around 6 months.Other hypogonadal symptoms like bone density take even longer. If you don't warn the patient about this lag, he'll assume it "isn't working" and stop.
Route matters:injectable testosterone (cypionate or enanthate IM) is generally preferred first: effective, inexpensive, and free of the first-pass hepatotoxicity that plagues oral testosterone. Oral testosterone (methyltestosterone) is essentially avoidedin practice because of hepatotoxicity risk ranging from mild transaminase elevation to peliosis hepatis and hepatocellular tumors. Transdermal patches, gels, and sprays are reserved for patients who refuse injections since they cost more, though they avoid the supraphysiologic mid-cycle peaks injections can cause (which have been linked to mood swings).
Continue treatment 3–6 monthsbefore considering a dose increase, since the clinical effect lags well behind the lab value.
Sodium and fluid retention (can worsen hypertension, HF, or edema), gynecomastia, erythrocytosis (check hematocrit), and adverse lipid changes. Topical patches can cause contact dermatitis. Gels, sprays, and solutions all carry REMS requirementsaround accidental transference to women and children through skin contact, so counsel on covering the site and hand washing.
Vacuum erection devices (VEDs)are genuinely first-line, especially for older patients in stable relationships: 60–80% effective, fast onset (3–20 minutes), and the erection is held in place with a constriction/tension ring at the base. They're also useful afterdrug failure, and response improves when combined with alprostadil or a PDE5 inhibitor. Contraindicated in sickle cell disease or a history of unexplained priapism; use cautiously on warfarin because of increased bruising risk. Downsides include petechiae and a coolness to the erection some men dislike, plus possible impaired ejaculation.
Penile prosthesis (surgery)is the most invasive option and is reserved for patients who fail or can't use anything less invasive.
Papaverine and phentolamineare unapproved but still used intracavernosally, usually in combination with each other or with alprostadil, since they work by different mechanisms (papaverine is a nonspecific PDE inhibitor; phentolamine is an alpha-antagonist that enhances the cholinergic vasodilatory response).
Botulinum toxininjection is an emerging option, roughly 40–50% effective specifically in patients who don't respond to PDE5 inhibitors.
Trazodoneshows up off-label as an alpha-antagonist with weak evidence for ED, which is clinically ironic since trazodone's own well-known adverse effect is drug-induced priapism. Worth knowing for counseling, not for recommending.
| OTC/supplement | Evidence | What to counsel |
|---|---|---|
| L-arginine | Possibly effective | Dizziness, headache, flushing; avoid combining with a PDE5 inhibitor(additive vasodilation/hypotension risk) |
| Panax ginseng | Possibly effective | Increased bleeding risk |
| Yohimbine | Insufficient evidence | GI upset, anxiety, tachycardia, arrhythmias |
| Eroxon (topical gel, FDA approved 2023) | FDA-cleared device | Applied to the glans, claims onset within 10 minutes; ingredients are essentially inactive (ethanol, propylene glycol, glycerin, carbomer, potassium hydroxide) and it began life as the placebo arm of a trial |
| Parameter | When | Watching for |
|---|---|---|
| IIEF score | Baseline, then 1–3 weeks after starting therapy | Objective response, since "better" is subjective otherwise |
| Blood pressure | Before starting a PDE5 inhibitor and with any add-on antihypertensive | Symptomatic hypotension, especially with alpha-blockers |
| Cardiac symptoms / functional capacity | Baseline and any new chest pain, dyspnea, or exertional symptoms | Need to reclassify cardiac risk tier |
| Erection duration | Every use, especially with alprostadil | Priapism >4 h is an emergency |
| Serum testosterone | Two early-morning draws before starting replacement; periodically on therapy | Confirms hypogonadism; ensures replacement lands in 300–1100 ng/dL without overshoot |
| Hematocrit / hemoglobin | Baseline and periodically on testosterone | Erythrocytosis |
| Liver enzymes | If using (avoiding, ideally) oral testosterone | Hepatotoxicity |
| Injection sites (alprostadil) | Ongoing | Fibrosis, plaques, hematoma |