Drug therapy for lower-urinary-tract symptoms targets the relevant receptors: antimuscarinics and β3-agonists increase storage; α-blockers, 5α-reductase inhibitors, and PDE5 inhibitors decrease outlet resistance; and a few agents target the sphincter, contractility, or urine production.
Muscarinic Physiology
Detrusor contraction occurs when acetylcholine stimulates muscarinic receptors. There are 5 subtypes (M1 cognition; M2 cardiac; M3 salivation/bowel/accommodation; M4/M5). All are present in the bladder; M2 predominates ≥3:1 over M3, but M3 is most important for contraction (Ca²⁺ influx + IP3-mediated release). In obstructed/neurogenic bladders the subtype shifts from M3 toward M2.
Antimuscarinics (Increase Storage)
- Mechanism: primarily decrease afferent (C and Aδ) activity during storage (when there is no parasympathetic input), with a lesser direct detrusor effect. They are safe in men with BOO (no change in flow, voiding pressure, or retention) — caution with large PVRs. In patients with involuntary contractions they raise volume to first DO, total capacity, and mean voided volume, and reduce urgency and contraction amplitude, without affecting leak-point pressures.
- Pharmacology: tertiary amines (oxybutynin, tolterodine, fesoterodine, solifenacin, darifenacin) cross the BBB (high lipophilicity, small size, low charge increase penetration); quaternary amines (trospium, propantheline) penetrate the CNS minimally. Many are CYP2D6/3A4 metabolized (drug-interaction risk).
- Contraindications: untreated narrow-angle glaucoma, GI obstruction, myasthenia gravis, history of urinary retention, cognitive impairment, hypersensitivity.
- Adverse effects: dry mouth (~30% vs 8% placebo), constipation, blurred vision, CNS effects, and rarely cardiac (QT prolongation via hERG, not muscarinic). Longest persistence reported with solifenacin.
| Agent | Notable features |
|---|---|
| Oxybutynin | Antimuscarinic + direct relaxant + local anesthetic; metabolite N-desethyloxybutynin causes dry mouth (transdermal reduces it); may impair cognition (elderly, children) |
| Tolterodine | Bladder-selective; active metabolite 5-HMT; low cognitive effect; no QT effect |
| Fesoterodine | Prodrug → 5-HMT; 4/8 mg (8 mg more effective, more dry mouth) |
| Darifenacin | Relatively M3-selective; no effect on cognition, QT, or heart rate; no nocturia benefit |
| Solifenacin | Modest M3 selectivity; reduces nocturia; no cognitive/HR effect (30 mg may prolong QT) |
| Trospium | Quaternary amine, renally excreted, not CYP-metabolized; reduces nocturia; no cognitive effect |
| Propiverine | Antimuscarinic + calcium-antagonist; available in Canada (not US at time of writing) |
β3-Adrenoreceptor Agonists
Mirabegron stimulates β3 receptors (the most expressed β-AR subtype in the bladder) → adenylyl cyclase → cAMP → detrusor relaxation, and inhibits afferent activity. It improves capacity/frequency/urgency/incontinence without affecting flow or PVR. Contraindicated with severe uncontrolled hypertension (SBP ≥180 or DBP ≥110), pregnancy, or hypersensitivity; CYP-mediated drug interactions; small reversible rises in BP/HR (monitor); no QT effect.
Toxins
- Botulinum toxin (onabotulinumtoxinA/Botox; abobotulinumtoxinA/Dysport): from Clostridium botulinum (subtype A has the longest action). Mechanisms: cleaves SNAP-25 → blocks acetylcholine release → paralysis (recovers in 2–4 months), terminal axonal degeneration, blocks other transmitters (ATP, substance P), and reduces afferent activity. Effective in neurogenic and idiopathic DO and OAB. Dose: 200 U for neurogenic OAB; 100 U (off-label) for idiopathic OAB. Contraindicated with active UTI, retention, inability/unwillingness to catheterize, or hypersensitivity. Adverse effects: bladder pain, hematuria, UTI; most serious is urinary retention requiring CIC (~5–6%); avoid aminoglycosides during treatment.
- Vanilloids (capsaicin, resiniferatoxin): RTX is ~1000× more potent than capsaicin for desensitization; not commonly used.
Increasing Outlet Resistance (for SUI)
- Imipramine (TCA) — anticholinergic + serotonin/noradrenaline reuptake blockade; the only agent widely used for storage symptoms despite limited RCT support; effective for childhood nocturnal enuresis. Contraindicated with MAOIs; serious cardiovascular toxicity and QTc prolongation (children especially sensitive); taper to stop.
- Duloxetine (SNRI) — improves SUI storage symptoms; licensed in the EU for moderate–severe female SUI but withdrawn from the US SUI process.
- α-agonists (ephedrine) — largely abandoned (phenylpropanolamine raised stroke risk in women). There is currently no effective drug for male SUI.
- Estrogens — oral estrogen ± progestogen worsens UI; vaginal estrogen treats urogenital atrophy/OAB symptoms but is not effective for SUI.
Facilitating Bladder Emptying
- α1-blockers reduce smooth-muscle tone at the bladder outlet and prostate. The α1A subtype mediates prostatic/urethral contraction; α1D blockade improves storage symptoms. Non-selective (TAD): terazosin, alfuzosin, doxazosin; selective: silodosin (most selective), tamsulosin, naftopidil. Effective for storage and voiding symptoms in BOO; ineffective (and may cause SUI) for female OAB. Adverse effects: dizziness (most common; highest with terazosin/doxazosin), orthostatic hypotension, headache, nasal congestion, and retrograde/ejaculatory dysfunction (silodosin 14% > tamsulosin 2%). Cautions: planned cataract surgery (intraoperative floppy iris syndrome — tamsulosin highest risk, 40× alfuzosin; hold 4–7 days preop but risk persists), multiple antihypertensives/orthostasis (prefer silodosin), and concomitant PDE5 (sildenafil/vardenafil potentiate terazosin/doxazosin hypotension; tamsulosin 0.4 mg does not).
- 5α-reductase inhibitors convert testosterone to DHT — finasteride inhibits type 2; dutasteride inhibits types 1 and 2. The Finasteride Study Group (Gormley 1992): 5 mg reduced symptoms, prostate size (~19%), and PSA (~50%). Adverse effects: reduced ejaculate volume (~4%), ED (4%), reduced libido (3%), gynecomastia (2%). Other benefits: improved PSA/DRE sensitivity for cancer detection, reduced prostatitis, and reduced risk of retention and BPH surgery.
- Striated sphincter: no drug selectively relaxes it; botulinum toxin is used (e.g. neurologic sphincter dyssynergia).
- Contractility: no effective drug for underactive bladder; bethanechol has little proven efficacy.
- PDE5 inhibitors: monotherapy improves IPSS and IIEF but not Qmax; combined with an α-blocker, improves IPSS, IIEF, and Qmax. Only tadalafil is approved for LUTS/BPH.
- Phytotherapy: saw palmetto showed no benefit over placebo (Bent 2006).
Other Agents
- Desmopressin — a vasopressin analogue (V2-receptor water reabsorption); fast onset, used for nocturia/nocturnal polyuria and childhood enuresis (suppresses but does not cure; combine with an alarm). Main risk: hyponatremia (risk factors: increasing age, female sex, cardiac disease, high 24-h urine volume). Females are more sensitive — 25 μg MELT for females, 50–100 μg for males; check serum sodium at baseline, ~day 7, ~day 30, then every 6 months. Contraindicated with type IIB/platelet-type vWD, impaired water excretion (hyponatremia, severe liver/renal/cardiac disease, polydipsia), or sodium-losing states.
- Phenazopyridine (Pyridium): urinary analgesic; ≤2 days when used with a UTI antibiotic; causes orange urine/skin discoloration; rare methemoglobinemia.
- Others: DMSO (intravesical, for interstitial cystitis), baclofen (GABA-B; poor DO efficacy), and calcium antagonists/potassium-channel openers (no bladder selectivity).
Combinations
- α-blocker + 5-ARI — MTOPS (n=3047): combination reduced clinical progression (1.5/100 person-years) more than doxazosin (2.7) or finasteride (2.9) alone (placebo 4.5). CombAT (n=4844, prostate ≥30 g): combination beat tamsulosin (but not dutasteride) for AUR/BPH surgery, and beat both monotherapies for clinical progression and symptoms at 4 years.
- α-blocker + antimuscarinic — better than an α-blocker alone in men with OAB + BOO.
- β3-agonist + antimuscarinic — mirabegron + solifenacin beats solifenacin alone without the added anticholinergic burden.
Self-Test
1. List the benefits of 5-ARIs. Reduced prostatitis risk, improved PSA/DRE sensitivity for prostate-cancer detection, reduced risk of acute urinary retention, and reduced risk of BPH-related surgery.
2. List the side effects of 5-ARIs. Reduced ejaculate volume, erectile dysfunction, loss of libido, and gynecomastia.
3. Which muscarinic receptor is most important for detrusor contraction, and which predominates in number? M3 is most important for contraction; M2 predominates ≥3:1 in number.