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Bethanechol

Bethanechol is a synthetic parasympathomimetic cholinergic agent that selectively stimulates muscarinic receptors to mimic the effects of acetylcholine, primarily used to treat urinary retention by promoting bladder emptying.^[1]
It is chemically known as 2-[(aminocarbonyl)oxy]-N,N,N-trimethyl-1-propanaminium chloride, a quaternary ammonium compound with the molecular formula C₇H₁₇ClN₂O₂, which renders it resistant to hydrolysis by cholinesterase enzymes and unable to cross the blood-brain barrier.^[2]^[3]
First synthesized in 1935, bethanechol acts mainly on M3 muscarinic receptors in the detrusor muscle of the bladder and smooth muscles of the gastrointestinal tract, increasing tone and contractility without significant nicotinic effects.^[1]^[2]
The U.S. Food and Drug Administration (FDA) approves bethanechol for acute postoperative and postpartum nonobstructive urinary retention, as well as neurogenic atony of the urinary bladder with retention.^[3]
Off-label applications include reducing xerostomia (dry mouth) associated with radiation therapy for head and neck cancers, as recommended by guidelines from the International Society of Oral Oncology (ISOO), Multinational Association of Supportive Care in Cancer (MASCC), and American Society of Clinical Oncology (ASCO).^[1]
Contraindications encompass hypersensitivity to the drug, hyperthyroidism, peptic ulcer disease, asthma, bradycardia, hypotension, coronary artery disease, epilepsy, parkinsonism, and any mechanical obstruction of the urinary or gastrointestinal tracts.^[3]^[1]
Administered orally as tablets (5–50 mg) or subcutaneously, bethanechol's effects onset within 30–90 minutes orally (peaking at 60–90 minutes and lasting about 1 hour) or 15–30 minutes subcutaneously (lasting up to 2 hours), with dosing typically starting at 10–25 mg three to four times daily on an empty stomach to minimize gastrointestinal upset.^[1]^[3]
Common adverse effects include abdominal cramps, nausea, diarrhea, hypotension, flushing, and bronchoconstriction, which are dose-dependent and more pronounced with subcutaneous administration; overdose is managed with atropine.^[1]^[2]

Pharmacology

Mechanism of action

Bethanechol is a direct-acting muscarinic receptor agonist that stimulates muscarinic acetylcholine receptors (M1-M5), with primary effects in smooth muscle mediated by the M3 subtype, while exhibiting no significant activity at nicotinic receptors.^[4]^[1] This allows bethanechol to mimic the effects of acetylcholine specifically on the parasympathetic nervous system without the broader nicotinic stimulation seen with other cholinergic agents.^[4] By binding to muscarinic receptors, bethanechol activates G-protein-coupled signaling pathways that increase intracellular calcium levels, leading to smooth muscle contraction in targeted organs.^[1] Unlike acetylcholine, bethanechol is resistant to hydrolysis by cholinesterases, which prevents rapid enzymatic degradation and results in a more prolonged duration of action.^[4]^[1] This structural modification—a carbamate ester in place of acetylcholine's acetate—ensures sustained receptor activation, making bethanechol suitable for therapeutic applications requiring consistent parasympathetic stimulation.^[4] Through parasympathetic stimulation, bethanechol promotes contraction of the detrusor muscle in the bladder, facilitating bladder emptying when there is no outlet obstruction.^[1]^[5] In the gastrointestinal tract, it enhances smooth muscle tone and peristalsis, increasing overall motility to support digestive function.^[4] These effects arise from muscarinic receptor-mediated excitation of smooth muscle cells, providing targeted cholinergic activity without systemic nicotinic interference.^[1]

Pharmacokinetics

Bethanechol demonstrates poor oral bioavailability owing to limited absorption from the gastrointestinal tract; while oral administration is commonly used, subcutaneous administration may provide more reliable effects due to bypassing absorption issues.^[7]^[8] Following oral dosing, the onset of action typically occurs within 30 to 90 minutes, while subcutaneous injection produces effects in 5 to 15 minutes; peak therapeutic responses are observed at 60 to 90 minutes for oral administration and 15 to 30 minutes for subcutaneous.^[1]^[4] The duration of action is generally about 1 hour after oral doses, though larger doses (300 to 400 mg) may extend effects up to 6 hours, and approximately 2 hours following subcutaneous administration.^[9] Urinary recovery of unchanged drug after oral dosing is dose-dependent, with approximately 10-20% of the administered dose typically recovered in the urine.^[10] Due to its polar quaternary ammonium structure, bethanechol exhibits minimal systemic distribution and does not cross the blood-brain barrier, allowing it to primarily exert local effects on the gastrointestinal and urinary tracts without significant central nervous system involvement.^[1]^[9] This limited distribution contributes to its targeted parasympathomimetic activity while reducing the risk of widespread systemic cholinergic effects. Bethanechol is resistant to hydrolysis by acetylcholinesterase or pseudocholinesterase, distinguishing it from acetylcholine and permitting a longer duration of action; it is instead slowly degraded by other esterases.^[4]^[9] The drug undergoes minimal metabolism overall. Elimination occurs primarily via renal excretion as unchanged drug, with a plasma half-life of approximately 1 to 2 hours.^[11] The exact mechanisms of elimination have not been extensively characterized in human studies.^[1]

Clinical uses

Indications

Bethanechol is primarily indicated for the treatment of acute postoperative and postpartum nonobstructive (functional) urinary retention, where it promotes bladder contraction to facilitate urination in the absence of mechanical obstruction.^[12] It is also approved for neurogenic atony of the urinary bladder with associated retention, particularly in cases leading to overflow incontinence, by stimulating detrusor muscle activity through muscarinic receptor agonism.^[1] These indications are supported by longstanding clinical evidence from FDA approvals dating to the 1980s, with efficacy demonstrated in restoring bladder tone and emptying in functional disorders.^[9] In specific patient populations, bethanechol has shown effectiveness for urinary retention related to diabetic neuropathy, where autonomic dysfunction impairs bladder contractility, though it is contraindicated in obstructive uropathy due to the risk of exacerbating urine backup.^[13] Clinical trials and guidelines affirm its utility in postoperative settings, but outcomes vary based on underlying etiology.^[1] Off-label uses include the management of xerostomia associated with radiation therapy for head and neck cancers, where bethanechol stimulates salivary gland secretion to alleviate dry mouth symptoms, as recommended by guidelines from the International Society of Oral Oncology (ISOO), Multinational Association of Supportive Care in Cancer (MASCC), and American Society of Clinical Oncology (ASCO).^[1] It is also employed off-label for gastroesophageal reflux disease (GERD) and gastric atony, enhancing lower esophageal sphincter tone and gastric motility to reduce reflux episodes and restore peristalsis, as evidenced by a double-blind study in pediatric patients demonstrating significant decreases in reflux frequency and duration.^[14] These applications are guided by its parasympathomimetic effects but lack robust, large-scale randomized controlled trials for broad endorsement.^[15]

Administration and dosage

Bethanechol is available in oral tablet form in strengths of 5 mg, 10 mg, 25 mg, and 50 mg, as well as subcutaneous injection at a concentration of 5 mg/mL.^[16]^[1] The oral route is most commonly used due to its convenience, while subcutaneous administration is reserved for situations requiring more rapid onset.^[17] For oral administration, the standard adult dosing begins with an initial dose of 5 to 10 mg to determine the minimum effective amount, repeated at hourly intervals until a satisfactory response is achieved, not exceeding 50 mg per dose.^[16]^[18] Maintenance dosing typically ranges from 10 to 50 mg administered two to four times daily, with a maximum daily oral dose of 120 mg.^[16] Subcutaneous dosing involves 2.5 to 5 mg as needed, with a maximum of four doses per day.^[19]^[1] Due to bethanechol's poor oral absorption, higher oral doses are often necessary compared to parenteral routes.^[1] Dose adjustments are recommended for elderly patients, starting at the lower end of the dosing range due to increased sensitivity to cholinergic effects and potential for adverse reactions.^[1] In patients with renal impairment, dosing should be reduced cautiously, although specific guidelines are limited; close monitoring is advised to avoid accumulation.^[1] To minimize gastrointestinal upset, oral doses should be taken 30 to 60 minutes before meals or on an empty stomach.^[16]^[19] Monitoring involves assessing bladder emptying after administration, typically within 30 to 60 minutes for oral doses or 5 to 15 minutes for subcutaneous injections.^[1] If no response occurs within one hour of a subcutaneous dose, the treatment should be discontinued and alternative options considered.^[1] Dosing should be individualized based on clinical response, with gradual titration to optimize efficacy while minimizing side effects.^[16]

Adverse effects and contraindications

Adverse effects

Bethanechol, a cholinergic agonist, can produce a range of adverse effects due to its stimulation of muscarinic receptors, primarily affecting the gastrointestinal, cardiovascular, and secretory systems. These effects are generally dose-dependent and more pronounced with subcutaneous administration compared to oral use, where they are considered rare.^[9] Adverse effects include gastrointestinal disturbances such as abdominal cramps, nausea, diarrhea, increased salivation, as well as sweating, flushing, and urgent urination. These symptoms arise from enhanced parasympathetic activity on smooth muscle and glandular tissues. Cardiovascular effects like bradycardia may also occur in susceptible individuals.^[1]^[20] Other adverse effects encompass hypotension, headache, dizziness, and lacrimation. These are typically mild and transient, often resolving with continued use or dose adjustment, but they reflect the drug's broader cholinergic influence on the autonomic nervous system.^[1]^[9] Rare but serious adverse effects include bronchospasm particularly in patients with asthma, cardiac arrhythmias, and exacerbation of symptoms resembling severe gastrointestinal obstruction. Such events necessitate immediate medical attention, as they can lead to significant morbidity in at-risk populations. Frequencies of these effects vary by route and patient factors.^[20]^[1] Management of adverse effects involves dose reduction for mild symptoms, administration on an empty stomach to minimize gastrointestinal upset, and supportive care. In cases of overdose or severe effects, anticholinergics such as atropine (0.6 mg intravenously for adults, repeatable every 2 hours as needed) serve as the specific antidote to counteract cholinergic excess.^[9]^[20] With long-term use, potential development of tolerance has been reported in isolated cases (approximately 0.16% in one survey), though data remain limited. No evidence of carcinogenicity has been established, as long-term studies in humans are lacking and animal carcinogenicity tests have not been conducted.^[21]^[20]

Contraindications

Bethanechol is contraindicated in patients with hypersensitivity to the drug. Absolute contraindications include hyperthyroidism, peptic ulcer disease, latent or active bronchial asthma, pronounced bradycardia or hypotension, vasomotor instability, coronary artery disease, epilepsy, and parkinsonism.^[1]^[22] It is also contraindicated in the presence of mechanical obstructions of the gastrointestinal or genitourinary tracts, acute inflammatory lesions of the gastrointestinal tract, peritonitis, recent surgery of the bladder or gastrointestinal tract, urinary bladder neck obstruction, or spastic gastrointestinal disturbances, as these conditions increase the risk of complications from enhanced cholinergic activity.^[1]^[22] Use of bethanechol requires caution in patients with conditions that may be exacerbated by muscarinic stimulation, such as potential for urinary reflux leading to kidney infection in the presence of bacteriuria if bladder contraction occurs without adequate sphincter relaxation.^[1]^[22] Drug interactions with bethanechol include additive cholinergic effects when co-administered with other cholinomimetics or acetylcholinesterase inhibitors such as donepezil or rivastigmine, potentially increasing adverse reactions.^[1] Its effects may be antagonized by anticholinergic agents like atropine.^[1] Caution is advised with ganglion-blocking agents such as mecamylamine, as they may precipitate severe hypotension.^[1]^[22] Bethanechol is classified as FDA Pregnancy Category C, with no adequate studies in pregnant women and unknown potential for fetal harm; it should be used only if the potential benefit justifies the risk to the fetus.^[1]^[22] It is unknown whether bethanechol is excreted in human breast milk, but due to the possibility of serious adverse reactions in nursing infants from cholinergic exposure, a decision should be made to discontinue nursing or the drug, considering the importance of the drug to the mother.^[1]^[22]^[2] In cases of overdose, symptoms may include abdominal discomfort, salivation, flushing, sweating, nausea, and vomiting; the antidote is atropine sulfate, administered subcutaneously at 0.6 mg every 2 hours as needed in adults or 0.01 mg/kg (up to 0.4 mg) in children, with intravenous use in emergencies.^[1]^[22]

History and availability

Development

Bethanechol was first synthesized in 1935 as a synthetic analog of acetylcholine, specifically designed to withstand hydrolysis by cholinesterase enzymes through its carbamate ester structure, which provided greater stability compared to earlier choline esters. It was synthesized by R.H. Major at the suggestion of A. Simonart.^[1]^[2]^[23]^[4] Bethanechol, first synthesized in 1935, was later developed and marketed by Merck under the trade name Urecholine, targeting urinary disorders by leveraging its selective stimulation of muscarinic receptors in the bladder. Early research focused on its potential to address atonic bladder conditions without the broader systemic effects of natural acetylcholine.^[24]^[4] Early clinical studies confirmed its efficacy in treating postoperative urinary retention, demonstrating improved bladder emptying in patients following surgery. These investigations built on the drug's resistance to enzymatic breakdown, allowing sustained parasympathomimetic activity.^[25] Key milestones in preclinical research included animal models that illustrated bethanechol's ability to stimulate bladder contraction via muscarinic pathways while exhibiting minimal nicotinic effects, thus avoiding cardiovascular or skeletal muscle side effects observed with non-selective cholinergics. This selectivity was pivotal in distinguishing it from prior carbamate derivatives.^[26]^[4] Subsequent human trials further established the safety profile of bethanechol for both gastrointestinal and urinary applications, with studies showing reliable detrusor muscle stimulation and peristalsis enhancement in controlled settings. These efforts marked the evolution of carbamate-based parasympathomimetics toward clinical viability.^[1]

Brand names and regulatory status

Bethanechol is commercially available under several brand names, including Duvoid, Myotonachol, and Urecholine Chloride, although the primary brand Urecholine has been discontinued in the United States and some other markets since the early 2000s.^[9]^[27]^[28] The drug received FDA approval under New Drug Application (NDA) 6-536 for the treatment of urinary retention, with initial marketing occurring prior to 1948 as part of the early post-1938 regulatory framework for new drugs.^[29]^[24] Generic versions of bethanechol chloride are widely available and not subject to controlled substance scheduling.^[7] Bethanechol is available in oral tablet and subcutaneous injectable forms in the United States, Canada, and various European countries through nationally authorized medicinal products, though its use is limited in some regions due to the preference for non-pharmacological alternatives like urinary catheterization.^[30]^[31]^[32] It is classified as a prescription-only medication worldwide, with no major regulatory updates as of November 2025, but supplies are periodically monitored for shortages, particularly in postoperative care settings.^[33]^[34] In addition to human medicine, bethanechol is employed in veterinary practice for treating urinary retention and bladder atony in dogs, cats, and horses, often under the same generic name.^[35]

References

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Bethanechol is an FDA-approved medication used to manage postoperative and postpartum urinary retention, as well as overflow incontinence due to neurogenic ...
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As a cholinergic agent, bethanechol is similar in structure and pharmacological function to acetylcholine and is used in specific cases when stimulation of the ...
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Bethanechol chloride, USP, a cholinergic agent, is a synthetic ester which is structurally and pharmacologically related to acetylcholine.
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Jul 24, 2025 · Initial dose: 5 to 10 mg orally once to obtain minimum effective dose; repeat the same amount at hourly intervals until satisfactory response occurs.
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Feb 1, 2025 · Bethanechol is taken to treat certain disorders of the urinary tract or bladder. It helps to cause urination and emptying of the bladder.
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Bethanechol chloride is used to stimulate muscular contractions in the bladder. It is used in animals that have difficulty urinating due to weak bladder ...