Antimuscarinics for Urinary Incontinence

Mechanism of Action

The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine contracts the detrusor smooth muscle through activation of muscarinic receptors (mainly M3 receptors which control urinary bladder muscle contraction). 

Urinary antimuscarinics antagonise muscarinic receptors and block acetylcholine from binding, leading to relaxation of smooth muscle, helping to alleviate symptoms of urgency, frequency, and incontinence.

Selective M3 antagonists:

• Darifenacin, solifenacin, tolterodine and fesoterodine are all selective muscarinic M3 receptor antagonists. Fesoterodine is also a prodrug which is rapidly and extensively hydrolysed to its primary active metabolite.

Non-selective M3 antagonists:

• Oxybutynin: competitive antagonist at M3 and M2 receptors. Direct antispasmodic effect on the detrusor muscle of the bladder leads to a reduced incidence of spontaneous contraction of the detrusor muscle in the bladder. 
• Propiverine: non-selective muscarinic receptor antagonist. Also inhibits calcium influx and modulates intracellular calcium in urinary bladder smooth muscle cells causing musculotropic spasmolysis. 
• Trospium chloride: high affinity to M1, M2 and M3 muscarinic receptors, competes concentration dependently with acetylcholine to do so. 

Created in BioRender. Boucher, M. (2025) https://BioRender.com/fy8guyx

Fig 1: Mechanism of action: antimuscarinics for overactive bladder. Muscarinic antagonists such as solifenacin bind the M3 receptor and prevent acetylcholine from binding. This leads to inhibition of voluntary contraction of the bladder.

Pharmacokinetics

The following table describes the key pharmacokinetic properties of urinary antimuscarinic drugs:

Cautions

More broadly, antimuscarinics should be prescribed cautiously in patients with autonomic neuropathy, Parkinson’s disease, or pre-existing cognitive impairment. This is due to central anticholinergic effects such as confusion, agitation, hallucinations, and somnolence may occur.

Care is also required in individuals with gastrointestinal disorders including ulcerative colitis, diarrhoea, gastro-oesophageal reflux disease, or hiatus hernia with reflux oesophagitis, given their effects on gastric emptying and lower oesophageal sphincter tone.

Patients with renal or hepatic impairment may require dose adjustment or closer monitoring, particularly when treated with propiverine, tolterodine, trospium chloride, or solifenacin.

Cardiovascular considerations are also important: antimuscarinics may cause tachycardia and should be used cautiously in patients in whom increased heart rate is undesirable, such as those with significant cardiac disease or hyperthyroidism. Furthermore, fesoterodine, solifenacin and tolterodine have been associated with QT interval prolongation and should be used with caution in patients with known QT prolongation or those taking other QT-prolonging medications.

Contraindications

Antimuscarinic agents are contraindicated in patients with Myasthenia gravis, as their anticholinergic effects may exacerbate muscle weakness. They must also not be used in individuals with significant bladder outflow obstruction or established urinary retention, where further reduction in detrusor contractility could precipitate acute retention.

As these agents reduce gastrointestinal motility, they are contraindicated in conditions such as gastrointestinal obstruction, intestinal atony, paralytic ileus, pyloric stenosis, toxic megacolon, and severe ulcerative colitis

Use in patients with narrow-angle glaucoma, particularly with oxybutynin, darifenacin and fesoterodine, is contraindicated due to the risk of precipitating acute angle closure. Severe hepatic impairment represents a contraindication for darifenacin, fesoterodine, propiverine and trospium chloride, while solifenacin is not recommended in patients undergoing haemodialysis.

Additionally, some preparations of solifenacin and trospium chloride are unsuitable in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Concomitant use with potent CYP3A4 inhibitors may also be contraindicated for specific agents (such as darifenacin and tolterodine), particularly in the presence of hepatic or renal impairment (fesoterodine, solifenacin).

Adverse Effects

General, dose-dependent antimuscarinic effects include:

Interactions

Class-wide interactions:

• Potentiation of anticholinergic effects with other anticholinergic agents e.g. amantadine, levodopa, antihistamines, antipsychotics, quinidine, TCAs, atropine, dipyridamole, baclofen, clozapine (constipation)
• Antagonism of the effects of prokinetic therapies e.g. metoclopramide 

Drug-specific interactions:

Oxybutynin is metabolised by CYP3A4

• Medicinal products that can cause or exacerbate oesophagitis such as bisphosphonates 
• Caution with concomitant administration with CYP3A4 inhibitors, which can lead inhibit oxybutynin metabolism and therefore increase exposure to oxybutynin.

Darifenacin is metabolised by CYP2D6 and CYP3A4, and a substrate for P-Gp efflux pumps

• Potent CYP2D6 inhibitors (paroxetine, cimetidine, quinidine) or moderate CYP3A4 inhibitors (fluconazole, clarithromycin, grapefruit juice) increase exposure to darifenacin. Recommendation by manufacturer is to start at 7.5mg daily and increase to 15mg daily if required and tolerated 
• Contraindicated with potent CYP3A4 inhibitors (e.g. rontinavir, ketoconazole, itraconazole)
• Contraindicated with PGP inhibitors (e.g. ciclosporin, verapamil)
• Caution with CYP2D6 substrates with a narrow therapeutic window (e.g. flecainide and imipramine) 

Fesoterodine is metabolised by CYP2D6 and CYP3A4

• Max dose 4mg recommended by manufacturer with potent CYP3A4 inhibitors e.g. ketoconazole, clarithromycin, itraconazole, ritonavir (unless also has moderate-severe renal/hepatic impairment then contraindicated) 
• Not recommended with potent CYP3A4 inducers e.g. rifampicin, phenobarbital, carbamazepine, phenytoin, St Johns Wort
• Max dose 4mg with potent CYP2D6 inhibitor 

Propiverine is a weak CYP3A4 inhibitor/substrate

• Potent inhibitors of CYP3A4 combined with methimazole should start with a dose of 15 mg per day.
• Risk of reduced blood pressure with isoniazid

Trospium chloride

• Inhibition of absorption with cholestyramine and colestipol 

References

1. Antimuscarinics | Prescribing information | Incontinence – urinary, in women | CKS | NICE
2. Oxybutynin Hydrochloride 2.5mg Tablets – Summary of Product Characteristics (SmPC) – (emc)
3. Darifenacin 15 mg prolonged-release tablets – Summary of Product Characteristics (SmPC) – (emc)
4. Fesoterodine fumarate 4 mg prolonged-release tablets – Summary of Product Characteristics (SmPC) – (emc)
5. Propiverine 15mg film coated tablets. Summary of product characteristics. Date of last revision: 14/05/2024. Available from: Microsoft Word – 6325816112074089666_spc-doc.doc 
6. Solifenacin 5 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc)
7. Detrusitol 1mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc)
8. Trospium chloride 20mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc)