Overactive Bladder Agents
High-yield Verified · Oct 2026Parasympathetic acetylcholine on M3 contracts the detrusor; sympathetic norepinephrine on β3 relaxes it. OAB drugs either block the first — tolterodine, solifenacin, darifenacin, trospium, fesoterodine (oxybutynin is on the Anticholinergics page) — or stimulate the second — mirabegron, vibegron.
Nursing view → administration, monitoring and patient teaching
Compare: Autonomic receptors compared — muscarinic, nicotinic, adrenergic and dopamine →
Compare: Adrenergic agonists compared — receptors, hemodynamics and uses →
Drugs
Mechanism
Tolterodine, solifenacin, darifenacin, trospium and fesoterodine are competitive muscarinic receptor antagonists. Bladder contraction is mediated by cholinergic muscarinic receptors, so blockade lowers detrusor pressure and increases the volume at first detrusor contraction and bladder capacity. Tolterodine is metabolized by CYP2D6 to the active 5-hydroxymethyl metabolite, and fesoterodine is hydrolyzed by nonspecific esterases to the same metabolite. Mirabegron and vibegron are β3 adrenergic receptor agonists that relax detrusor smooth muscle during bladder filling, increasing bladder capacity.
M3 contracts the detrusor, β3 relaxes it
The detrusor is the smooth muscle of the bladder body. Parasympathetic stimulation encourages micturition: pre-ganglionic fibers leave the cord mainly at S2–S4, and post-ganglionic neurons release acetylcholine onto the detrusor, which contracts mainly through M3 receptors. M3 is Gq-coupled — intracellular calcium rises, binds calmodulin and activates myosin light-chain kinase. M2 is the predominant muscarinic subtype in the bladder, but M3 receptors mediate most bladder smooth-muscle contraction.
Sympathetic stimulation does the opposite and maintains continence: norepinephrine relaxes the detrusor principally through the Gs-coupled β3 receptor (adenylyl cyclase → cAMP) and contracts the bladder neck through Gq-coupled α1 receptors. Bladder-neck α1 is what the α1-blockers relax in outlet obstruction (Alpha-Adrenergic Antagonists page).
Why both classes treat urgency
In overactive bladder the detrusor may contract paroxysmally while the bladder should be storing urine, pushing urine against the taut outlet and causing a sudden urge. Because detrusor contraction runs through M3, antimuscarinics block these unwanted signals; trospium, for example, increases maximum cystometric bladder capacity and the volume at the first detrusor contraction. A β3 agonist directly opposes the M3 stimulus: mirabegron and vibegron relax the detrusor during filling, which increases bladder capacity.
The difference shows in the voiding contraction. In healthy volunteers tolterodine decreased detrusor pressure and increased residual urine — incomplete emptying, consistent with an antimuscarinic action on the lower urinary tract. Mirabegron did not adversely affect maximum flow or detrusor pressure at maximum flow in men with outlet obstruction, although it is still used with caution there.
Selectivity: for M3, and away from the brain
Darifenacin is the M3-selective agent: its affinity for M3 is 9- and 12-fold greater than for M1 and M5, and 59-fold greater than for M2 and M4. Solifenacin has modest M3 selectivity over M2 and marginal selectivity over M1. Tolterodine, fesoterodine and trospium are not subtype-selective (in experiments tolterodine shows functional selectivity for the bladder over the salivary glands). Still, no antimuscarinic has significant selectivity for the lower urinary tract, so adverse effects are common.
Brain entry depends on structure. Tertiary amines — darifenacin, fesoterodine, solifenacin, tolterodine, oxybutynin — have higher lipophilicity and less charge, which increases passage through the blood–brain barrier. Trospium is a hydrophilic quaternary ammonium compound with limited ability to cross it. Darifenacin, trospium and fesoterodine are also actively removed from the brain by a protein-mediated transporter, and solifenacin is highly distributed to non-CNS tissues. (Tertiary versus quaternary antimuscarinics in general: Anticholinergics page.)
Tolterodine and fesoterodine: two roads to 5-HMT
Tolterodine is oxidized in the liver by CYP2D6 to 5-hydroxymethyl tolterodine (5-HMT), which has antimuscarinic activity similar to the parent and contributes significantly to the therapeutic effect. About 7% of people lack CYP2D6; in these poor metabolizers tolterodine is dealkylated by CYP3A4 instead, giving significantly higher tolterodine concentrations and negligible 5-HMT.
Fesoterodine is a prodrug: nonspecific esterases rapidly and extensively hydrolyze it to the same 5-HMT, so fesoterodine itself cannot be detected in plasma. 5-HMT is then cleared by hepatic metabolism through CYP2D6 and CYP3A4 and by renal excretion. Because both drugs deliver 5-HMT, hypersensitivity to either one contraindicates the other.
Comparing the drugs
Receptor action, brain entry and elimination
| Drug | Receptor action | Structure and CNS entry | Main elimination |
|---|---|---|---|
| Tolterodine | Muscarinic antagonist, not subtype-selective; active metabolite 5-HMT | Tertiary amine | Liver: CYP2D6 → 5-HMT (CYP3A4 in poor metabolizers) |
| Solifenacin | Modest M3 selectivity over M2, marginal over M1 | Tertiary amine; highly distributed to non-CNS tissues | Liver, mainly CYP3A4; under 15% unchanged in urine |
| Darifenacin | M3-selective (59-fold over M2 and M4) | Tertiary amine; actively removed from the brain | Liver, CYP2D6 and CYP3A4; 3% unchanged |
| Trospium | Muscarinic antagonist, not subtype-selective; negligible nicotinic affinity | Quaternary ammonium; limited passage into the CNS | Absorbed drug mainly unchanged in urine by active tubular secretion; CYP not significant |
| Fesoterodine | Prodrug of 5-HMT; not subtype-selective | Tertiary amine; actively removed from the brain | 5-HMT: CYP2D6 and CYP3A4 plus renal excretion |
| Mirabegron | β3 agonist; β1 stimulation only at four times the maximum recommended dose | — | Several pathways (dealkylation, oxidation, glucuronidation, amide hydrolysis); renal clearance about 25% of total |
| Vibegron | Selective β3 agonist | — | Metabolism minor (CYP3A4); largely excreted unchanged (feces 54%, urine 19%) |
Oxybutynin (Anticholinergics page), the oldest OAB antimuscarinic, is a tertiary amine that also has musculotropic relaxant and local anesthetic activity; at starting oral doses it had the highest adverse-event rates of the antimuscarinics in a network meta-analysis.
— = not applicable (not an antimuscarinic).
Pharmacokinetics at a glance
| Drug | Oral bioavailability | Food | Half-life |
|---|---|---|---|
| Tolterodine | At least 77% absorbed | Raises tolterodine bioavailability 53% (5-HMT unchanged in extensive metabolizers) | 2.4 h (5-HMT about 3 h) |
| Solifenacin | About 90% | No meaningful effect | 45–68 h |
| Darifenacin | 15–19% (extended release) | AUC not affected | 13–19 h |
| Trospium | 9.6% (under 10% absorbed) | High-fat meal cuts AUC 70–80%; take at least 1 h before meals | About 20 h |
| Fesoterodine | 52% as 5-HMT (fesoterodine undetectable) | No clinically relevant effect | About 7 h (5-HMT, oral) |
| Mirabegron | 29–35% | With or without food (adults) | About 50 h |
| Vibegron | — | No clinically significant effect of a high-fat meal | 30.8 h (effective) |
Label values. Protein binding sorts them too: tolterodine, solifenacin and darifenacin are highly bound (mainly to α1-acid glycoprotein; about 96–98%), whereas 5-HMT and vibegron are about 50% bound and trospium 50–85%.
— = not stated in the listed label.
Pharmacokinetics
- Strong CYP3A4 inhibitors — solifenacin, darifenacin, fesoterodine, tolterodine
- Ketoconazole raised solifenacin AUC 2.7-fold and 5-HMT AUC about 2.3-fold (from fesoterodine, in extensive metabolizers); in CYP2D6 poor metabolizers it raised tolterodine AUC 2.5-fold, because CYP3A4 is their remaining route. Each of these labels therefore caps the dose with strong CYP3A4 inhibitors. Mirabegron AUC rose 80% with ketoconazole, whereas vibegron showed no clinically significant change.
- Trospium: the kidney, not the liver — trospium
- Less than 10% of a dose is absorbed, and a high-fat meal lowers AUC by 70–80%, so it is taken at least an hour before meals or on an empty stomach. CYP is not expected to contribute significantly to its elimination, and it does not inhibit CYP enzymes at clinical concentrations. Its renal clearance is 4-fold higher than the glomerular filtration rate — active tubular secretion is a major route — so it may compete with other tubularly secreted drugs (e.g. procainamide, pancuronium, morphine, vancomycin, tenofovir). Severe renal impairment raised AUC 4.2-fold, and metformin lowered trospium exposure by about 29%.
- Inhibiting CYP2D6 — mirabegron, darifenacin
- Mirabegron is a moderate, time-dependent CYP2D6 inhibitor (and a weak CYP3A inhibitor): it raised metoprolol AUC by 229% and desipramine AUC by 241%, so narrow-therapeutic-index CYP2D6 substrates such as thioridazine, flecainide and propafenone need monitoring. Darifenacin raised imipramine AUC 70% and desipramine exposure 260%. Vibegron does not inhibit CYP2D6, and tolterodine causes no clinically relevant CYP2D6 inhibition in vivo.
- Kidney and liver impairment — tolterodine, solifenacin, darifenacin, fesoterodine, vibegron
- Tolterodine and 5-HMT levels were 2–3-fold higher with creatinine clearance 10–30 mL/min, and tolterodine’s half-life was 7.8 h in cirrhosis versus 2–4 h in healthy volunteers. Severe renal impairment raised solifenacin AUC 2.1-fold and 5-HMT AUC 2.3-fold. Unbound darifenacin exposure was 4.7-fold higher in moderate hepatic impairment. Vibegron’s pharmacokinetics did not change significantly in mild, moderate or severe renal impairment.
- Digoxin — mirabegron, vibegron, trospium
- Mirabegron raised digoxin Cmax 29% and AUC 27%, and vibegron raised digoxin Cmax 21% and AUC 11%, so serum digoxin is monitored when either is added. Trospium did not affect digoxin pharmacokinetics.
- Older patients — solifenacin, trospium, fesoterodine
- Solifenacin Cmax, AUC and half-life were 20–25% higher in volunteers aged 65–80. With trospium, age did not significantly affect pharmacokinetics, yet anticholinergic adverse reactions were more common at 75 years and older — possibly an enhanced sensitivity to anticholinergic agents. Fesoterodine’s pharmacokinetics are not significantly influenced by age, but antimuscarinic adverse reactions were likewise more frequent at 75 and older.
Pharmacogenomics
Uses & drug choice
- Tolterodine, solifenacin, darifenacin, trospium, fesoterodine, mirabegron and vibegron for overactive bladder with urge urinary incontinence, urgency and frequency in adults
- Mirabegron in combination with solifenacin for overactive bladder in adults
- Vibegron for overactive bladder in adult men taking drug therapy for benign prostatic hyperplasia
- Fesoterodine (age 6 and older, over 25 kg) and mirabegron (age 3 and older) for neurogenic detrusor overactivity in children
Adverse effects
- Dry mouth, constipation, blurred vision, dry eyes
- Muscarinic receptors are present throughout the body and no antimuscarinic has significant selectivity for the lower urinary tract, so blocking them also blocks salivation, gut motility and accommodation — the expected antimuscarinic effects. Higher doses of any antimuscarinic bring higher rates. Rates of dry mouth and constipation are lower with mirabegron, most strikingly in patients 75 and older.
- Urinary retention, especially with outlet obstruction
- Inhibiting detrusor contraction can worsen bladder emptying: against clinically significant bladder outlet obstruction, an antimuscarinic may cause further retention and kidney injury. The doses used for OAB are thought to be lower than those needed to significantly reduce the voiding contraction; even so, monitoring the post-void residual is recommended in BPH or incomplete emptying. Retention has also been reported with mirabegron and vibegron, particularly with outlet obstruction or a concurrent antimuscarinic.
- Confusion, hallucinations, somnolence, impaired cognition
- Muscarinic receptors are abundant in the CNS and take part in memory, problem solving and vigilance, so antimuscarinics that reach the brain can cause neurological effects, especially in elderly patients and those with neurological conditions. Tertiary amines cross the blood–brain barrier more readily than quaternary trospium — yet the trospium label still reports CNS effects, including confusion and hallucinations.
- Heat prostration
- Antimuscarinics reduce sweating, so heat prostration can occur in a hot environment.
- QT prolongation (tolterodine, solifenacin)
- Tolterodine’s QT effect correlates with its plasma concentration, so it is greater at higher doses and in CYP2D6 poor metabolizers; solifenacin prolonged QTcF by about 8 msec at three times its maximum dose. Darifenacin, trospium and fesoterodine did not prolong QT in their thorough QT studies.
- Raised heart rate and blood pressure (mirabegron)
- Mirabegron has very low intrinsic activity at β1 and β2 receptors, but β1 stimulation occurred in humans at four times the maximum recommended dose; heart rate and blood pressure rise with dose. At the maximum dose supine systolic/diastolic pressure rose about 4.0/1.6 mm Hg more than placebo in healthy volunteers; in OAB trials the mean increases were about 0.5–1 mm Hg and reversed on stopping. In a 4-week ambulatory study, vibegron caused no clinically significant change in blood pressure.
Toxicity & antidote
Antimuscarinic OAB drugs in overdose cause severe antimuscarinic effects — with tolterodine, severe central anticholinergic effects. Solifenacin overdose has been associated with mental status changes and decreased consciousness; a 7-month-old given trospium by a sibling developed mydriasis and tachycardia. Treatment is symptomatic and supportive, and ECG monitoring is recommended. (The anticholinergic toxidrome is covered on the Anticholinergics page.)
Mirabegron overdose looks adrenergic instead: palpitations and a pulse above 100 bpm after very high single doses, and rising pulse and systolic pressure with repeated high doses. Management is supportive, with pulse, blood pressure and ECG monitoring. There is no experience with vibegron overdose.
Interactions
Contraindications
- Urinary retention (tolterodine, solifenacin, darifenacin, trospium, fesoterodine) — Labeled contraindication — blocking detrusor contraction worsens retention; darifenacin and trospium also list patients at risk for it.
- Gastric retention (tolterodine, solifenacin, darifenacin, trospium, fesoterodine) — Labeled contraindication — antimuscarinics further slow gastrointestinal motility.
- Uncontrolled narrow-angle glaucoma (tolterodine, solifenacin, darifenacin, trospium, fesoterodine) — Labeled contraindication — antimuscarinics can worsen narrow-angle glaucoma.
- Known hypersensitivity to tolterodine, solifenacin, trospium, fesoterodine, mirabegron or vibegron — Labeled contraindication — reactions have included angioedema and anaphylaxis.
- Tolterodine in someone hypersensitive to fesoterodine, or fesoterodine in someone hypersensitive to tolterodine — Labeled contraindication — both are metabolized to the same active compound, 5-hydroxymethyl tolterodine.
- Clinically significant bladder outlet obstruction use caution — Not contraindicated, but retention risk rises — solifenacin and fesoterodine are not recommended; tolterodine, darifenacin, trospium and mirabegron are used with caution; vibegron needs monitoring.
- Decreased gastrointestinal motility or GI obstruction (severe constipation, ulcerative colitis, intestinal atony), or myasthenia gravis use caution — Caution with the antimuscarinics (solifenacin and fesoterodine: not recommended in decreased GI motility) — they slow the gut further and can worsen myasthenia gravis.
- Controlled narrow-angle glaucoma under treatment use caution — Antimuscarinics are used with caution, and trospium only with careful monitoring.
- Severe uncontrolled hypertension (mirabegron) use caution — Not recommended — mirabegron can raise blood pressure.
- Known QT prolongation or QT-prolonging drugs (tolterodine, solifenacin) use caution — Solifenacin is not recommended at high QT risk; tolterodine’s QT effect is weighed in these patients.
- Severe hepatic impairment (solifenacin, darifenacin, fesoterodine, mirabegron, vibegron) or end-stage kidney disease (mirabegron, vibegron) use caution — Not recommended (not studied); several labels set a lower maximum dose in moderate hepatic or severe renal impairment.
High-yield
- Tolterodine → CYP2D6 → 5-HMT (poor metabolizers: CYP3A4, high tolterodine, negligible 5-HMT)
- Fesoterodine → nonspecific esterases → 5-HMT (fesoterodine itself is undetectable in plasma)
Same active metabolite — hypersensitivity to one contraindicates the other.
- Quaternary ammonium → limited passage into the CNS
- Renal clearance 4 × GFR → active tubular secretion
- 4.2-fold AUC in severe renal impairment
- Under 10% absorbed — a high-fat meal cuts it 70–80%, so it is taken an hour before meals
Practice questions
Q1A 79-year-old woman with mild cognitive impairment has urgency and urge incontinence despite bladder training. Her physician wants a drug that will not add to her anticholinergic burden.
The drug chosen most likely relaxes the detrusor by which mechanism?
- A.Blockade of M3 receptors on the detrusor
- B.Blockade of α1 receptors at the bladder neck
- C.Activation of Gs-coupled β3 receptors, raising cAMP
- D.Inhibition of acetylcholinesterase
- E.Blockade of nicotinic receptors at the external sphincter
Show answer
C. Activation of Gs-coupled β3 receptors, raising cAMP — A β3 agonist (mirabegron or vibegron) relaxes the detrusor during filling through Gs-coupled β3 receptors and cAMP, opposing the M3 signal without antimuscarinic action; mirabegron showed no cognitive deterioration in patients 65 and older. M3 blockade is the antimuscarinic route she should avoid, and α1 blockade relaxes the bladder neck in outlet obstruction.
Q2A 66-year-old man with heart failure takes metoprolol. Two weeks after a new drug for overactive bladder is started, his resting heart rate falls to 46/min and he feels light-headed. His blood pressure is mildly higher than before.
Which property of the new drug best explains the bradycardia?
- A.Direct β1 blockade
- B.Antimuscarinic action at the sinoatrial node
- C.Induction of CYP3A4
- D.Competition for renal tubular secretion
- E.Inhibition of CYP2D6, raising metoprolol levels
Show answer
E. Inhibition of CYP2D6, raising metoprolol levels — Mirabegron is a moderate, time-dependent CYP2D6 inhibitor and raised metoprolol AUC by 229%, so metoprolol’s effect is amplified; it can also raise blood pressure. Antimuscarinics such as fesoterodine raise heart rate slightly rather than lowering it, and competition for tubular secretion is trospium’s interaction mechanism. Vibegron does not inhibit CYP2D6.
Q3A 72-year-old man on many hepatically metabolized drugs is started on trospium for urge incontinence. He is told to take it on an empty stomach, and because his creatinine clearance is 25 mL/min the dose frequency is reduced.
Which property of trospium explains both its limited CNS penetration and its reliance on the kidney?
- A.It is a prodrug activated by esterases
- B.It is a charged, hydrophilic quaternary ammonium compound cleared largely by active tubular secretion
- C.It is metabolized by CYP2D6 to an active metabolite
- D.It is highly selective for M3 receptors
- E.It is a β3 agonist
Show answer
B. It is a charged, hydrophilic quaternary ammonium compound cleared largely by active tubular secretion — Trospium is a hydrophilic quaternary amine with limited ability to cross the blood–brain barrier. CYP does not contribute significantly to its elimination; its renal clearance is about 4-fold the GFR, reflecting active tubular secretion, and severe renal impairment raised its AUC 4.2-fold. Less than 10% is absorbed, and a high-fat meal lowers that by 70–80%.
Q4A 58-year-old woman with overactive bladder is known from earlier genotyping to be a CYP2D6 poor metabolizer. Her physician prescribes fesoterodine.
Why does fesoterodine still produce the active metabolite in her?
- A.Nonspecific esterases, not CYP2D6, convert fesoterodine to 5-HMT
- B.CYP3A4 converts fesoterodine to 5-HMT when CYP2D6 is absent
- C.Fesoterodine is itself the active drug and has no metabolite
- D.The kidney converts fesoterodine to 5-HMT
- E.Fesoterodine induces CYP2D6
Show answer
A. Nonspecific esterases, not CYP2D6, convert fesoterodine to 5-HMT — Fesoterodine is rapidly hydrolyzed by nonspecific esterases to 5-hydroxymethyl tolterodine, the same active metabolite that tolterodine forms through CYP2D6; fesoterodine cannot be detected in plasma. Poor metabolizers clear 5-HMT more slowly (about 2-fold higher AUC). Tolterodine in poor metabolizers is dealkylated by CYP3A4 and forms negligible 5-HMT.
Q5A 74-year-old man with benign prostatic hyperplasia and a weak stream is started on solifenacin for urgency. A week later he cannot void and has a distended bladder.
Which mechanism best explains his retention?
- A.Stimulation of α1 receptors at the bladder neck
- B.Activation of β3 receptors in the urethra
- C.Contraction of the external sphincter through nicotinic receptors
- D.Muscarinic blockade weakening detrusor contraction against an obstructed outlet
- E.CYP3A4 inhibition raising tamsulosin levels
Show answer
D. Muscarinic blockade weakening detrusor contraction against an obstructed outlet — Blocking detrusor M3 receptors can worsen emptying; with clinically significant bladder outlet obstruction an antimuscarinic may cause further retention and kidney injury, so it is not recommended there and is contraindicated in retention. Post-void residual is monitored in men with BPH. α1 stimulation tightens the bladder neck but is not an action of solifenacin.
Sources
- Detrol (tolterodine) — FDA label: mechanism, 5-hydroxymethyl metabolite, contraindications, QT, CYP3A4 inhibitors — FDA / DailyMed
- Solifenacin succinate tablets — FDA label: contraindications, urinary retention, CNS effects, QT, CYP3A4 inhibitors — FDA / DailyMed
- Darifenacin extended-release tablets — FDA label: contraindications, GI motility, CYP3A4 and CYP2D6 interactions — FDA / DailyMed
- Trospium chloride tablets — FDA label: quaternary ammonium, renal tubular secretion, food effect, interactions — FDA / DailyMed
- Toviaz (fesoterodine) — FDA label: esterase conversion to 5-HMT, contraindications, pediatric NDO, interactions — FDA / DailyMed
- Myrbetriq (mirabegron) — FDA label: β3 mechanism, blood pressure, urinary retention, CYP2D6 and digoxin — FDA / DailyMed
- Gemtesa (vibegron) — FDA label: β3 mechanism, urinary retention, angioedema, digoxin, crushing — FDA / DailyMed
- Oxytrol (oxybutynin transdermal) — FDA label: muscarinic antagonist for overactive bladder — FDA / DailyMed
- Urge Incontinence — antimuscarinic adverse events, selective agents, older adults with dementia — StatPearls / NCBI Bookshelf
- The use of stems in the selection of INN (stems -fenacin, -begron, -ium) — World Health Organization
- Physiology, Bladder — detrusor M3 (Gq) and β3 (Gs), bladder-neck α1, overactive bladder — StatPearls (NCBI)
- Current pharmacotherapy of overactive bladder (Int Braz J Urol 2021) — selectivity, tertiary vs quaternary, cognition, β3 agonists — PubMed Central (CC BY 4.0)
- Bethanechol Chloride Tablets (Upsher-Smith) — nonobstructive retention, obstruction contraindication (FDA label) — FDA / DailyMed
- Table of Pharmacogenomic Biomarkers in Drug Labeling (CYP2D6: tolterodine, fesoterodine, darifenacin, mirabegron) — U.S. Food and Drug Administration
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.