Continuing Education Activity

Bethanechol is an FDA-approved medication used to manage postoperative and postpartum urinary retention, as well as overflow incontinence due to neurogenic bladder atony, and belongs to the parasympathomimetic drug class. This activity focuses on the clinical applications of bethanechol in managing nonobstructive urinary retention-related disorders. The indications, administration modalities, and contraindications will be covered. The program equips participants with essential knowledge to optimize patient outcomes by emphasizing the drug's mechanism of action, adverse event profile, monitoring strategies, and clinical toxicology considerations. Furthermore, this activity explores critical aspects such as drug interactions and pharmacokinetics, enhancing healthcare professionals' proficiency in tailoring therapeutic approaches for patients with conditions associated with nonobstructive urinary retention.

Objectives:

• Identify the mechanism of action of bethanechol.
• Assess the adverse drug reactions of bethanechol.
• Determine the appropriate monitoring of bethanechol.
• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from bethanechol therapy in nonobstructive urinary retention.

Indications

Bethanechol was first synthesized in 1935, and it is a direct-acting parasympathomimetic agent that acts on postganglionic parasympathetic receptors. Bethanechol's actions are similar to those of acetylcholine (ACh), but the agent is not broken down via cholinesterase, making its therapeutic effects more lengthened when compared to acetylcholine. Bethanechol's moieties as a quaternary amine do not allow it to cross the blood-brain barrier and cause depressive actions. Bethanechol is one of the most readily utilized agents to promote bladder emptying.[1] Bethanechol may be utilized in spinal shock subjects who have recovered to the point of voluntary control of the urethra and in patients with a sensory and motor paralytic bladder. The prescribed course of bethanechol varies following the character of the bladder dysfunction treated.[2] The pharmacological agent is FDA-approved for the treatment of the following conditions.[3][4][5]

FDA-Approved Indications

• Postoperative urinary retention
• Postpartum nonobstructive urinary retention
• Neurogenic atony of the bladder

Off-Label Uses

The guideline provided by the International Society of Oral Oncology, American Society of Clinical Oncology, and Multinational Association of Supportive Care in Cancer suggests that during radiation therapy for head and neck cancer, the systemic administration of the sialogogue bethanechol might be considered as a potential option to decrease the likelihood of experiencing salivary gland hypofunction and xerostomia. However, the panel recommends a careful discussion with the patient regarding potential benefits and likely adverse effects such as lightheadedness, dizziness, abdominal pain, nausea, increased urination, headache, and flushing. Factors such as the expected radiation dose to the salivary glands and patient compliance should be considered.[6]

Mechanism of Action

Bethanechol exerts its effects by directly stimulating the muscarinic receptors (M1, M2, M3, M4, and M5) of the parasympathetic nervous system, further increasing the tone of the detrusor muscle of the bladder, giving a contraction adequately effective to initiate micturition and void the bladder. The M3 receptors are where the agent acts in the bladder, smooth muscles, and exocrine glands.[7][4][8]

Bethanechol also acts on the M1 parasympathetic receptors of the gastric parietal cells found in the gastrointestinal tract, inciting gastric motility and increasing gastric tone, and may reestablish diminished rhythmic peristalsis. Bethanechol's effects are selective to muscarinic receptor stimulation, and its effects on nicotinic receptors are absent or minimal.

Pharmacokinetics

Absorption: Bethanechol chloride, when administered orally, initiates effects on the gastrointestinal (GI) and urinary tracts within approximately 30 minutes, reaching its maximum impact typically around 60 to 90 minutes post-administration. The usual action duration for oral therapeutic doses is about 1 hour. However, larger doses ranging between 300 and 400 mg can prolong effects for 6 hours. 

Distribution: Bethanechol's inability to traverse the blood-brain barrier is attributed to its charged quaternary amine moiety, which prevents it from exerting effects on the central nervous system.[9]

Metabolism: The metabolic breakdown pathways of bethanechol have not been extensively studied or fully understood in scientific research.

Elimination: The mechanisms of bethanechol elimination have not been thoroughly studied.

Administration

Adult Dosage, Dosage Forms, and Strengths

Bethanechol is available in oral and subcutaneous preparations. Tablets are available in 5 mg, 10 mg, 25 mg, and 50 mg dosages.[10] The suggested dosage is given below.

• Postoperative Urinary Retention: 10 to 50 mg 3 or 4 times daily.

• Postpartum Nonobstructive Urinary Retention: 10 to 50 mg 3 or 4 times daily.

• Neurogenic Bladder: 10 to 50 mg 3 or 4 times daily.

The dosage for bethanechol is decided on a case-by-case basis, depending on the type and severity of the urinary retention. Patients are initiated on a 5 to 10 mg dosage to ascertain the minimum effective dosage and are repeated at hourly intervals until an adequate response transpires. Patients should not consume more than 50 mg per single dose as adverse effects may occur. Bethanechol should be taken on an empty stomach to avoid nausea and vomiting.

Specific Patient Populations

Hepatic impairment: The manufacturer's labeling does not specify any dosage adjustments for bethanechol in cases of hepatic impairment.

Renal impairment: The manufacturer's labeling does not specify any dosage adjustments for bethanechol in renal impairment cases.

Breastfeeding considerations: There is inadequate clinical data regarding using bethanechol during breastfeeding. If this medication is administered while breastfeeding, it is crucial to observe the infant for potential signs of cholinergic excess closely. These signs may include diarrhea, increased tearing, excessive salivation, or urination, particularly in younger infants who are exclusively breastfed.[11]

Pregnancy considerations: Bethanechol is classified as FDA Pregnancy Category C. There is uncertainty about its potential to harm a developing fetus if administered to a pregnant woman or impact her reproductive capacity. Therefore, bethanechol chloride should only be used during pregnancy in essential cases and after thoroughly evaluating potential risks and benefits.

Pediatric patients: The safety and effectiveness of bethanechol in pediatric patients have not been established. Bethanechol is used off-label in tracheobronchomalacia.[12]

Older patients: Bethanechol could raise static intravesical pressure, potentially triggering sensory responses in the bladder at lower volumes than typical. In older patients, bethanechol should be used cautiously due to its limited effectiveness and adverse effects, including flushing, vomiting, diarrhea, gastrointestinal cramps, bronchospasm, headache, salivation, and sweating.[13]

Adverse Effects

The adverse drug reactions of bethanechol are described below.[14][15]

• Gastrointestinal: abdominal cramps, abdominal discomfort, colicky pain, nausea, vomiting, diarrhea, borborygmi and salivation [16]
• Central nervous system: headache, lacrimation and miosis
• Cardiovascular: hypotension, reflex tachycardia, and vasomotor response
• Respiratory: Bronchoconstriction and asthmatic attacks
• Renal: Urinary urgency
• Dermatology: Flushing and diaphoresis [6]

If taken immediately after eating, the agent may cause nausea and vomiting and is advised to be administered 2 hours post-meal or 1 hour before eating. Bethanechol parasympathetic effects of the M2 receptors in the heart stimulate the SA node and AV node, resulting in bradycardia and decreased electrical conduction rate. This may lead to more severe conditions such as heart block, cardiac arrest, and arrhythmias.[4]

The parasympathetic actions on the M3 receptors present in vasculature cause vasodilation, further decreasing blood pressure. This vasodilation can precipitate postural hypotension, causing dizziness and lightheadedness when standing from a supine or prone position.[4][17] Adverse effects are observed more frequently with an increased dose and subcutaneous injections rather than oral administration.

Drug-Drug Interactions

Ganglion-blocking agents, such as mecamylamine and hexamethonium, can reduce blood pressure.[18] Administering bethanechol with ganglion-blocking agents requires caution due to the potential for hypotension. Acetylcholinesterase inhibitors such as donepezil and rivastigmine have the potential to increase the adverse effects of other cholinergic agonists like bethanechol.[19]

Contraindications

Boxed Warnings

The following are the contraindications that are listed in the FDA-approved labeling.

• Hypersensitivity
• Hyperthyroidism
• Bradycardia
• Orthostatic hypotension
• Vasomotor instability
• Coronary artery disease
• Parkinsonism
• Arrhythmias 
• Intestinal resection or anastomosis
• Urinary obstruction
• Severe miosis  
• Acute inflammatory lesions of the gastrointestinal tract
• Peritonitis
• Recent urinary bladder surgery
• Peptic ulcer [20]
• Epilepsy/seizures [21]
• Latent bronchial asthma
• Active bronchial asthma [22]

Bethanechol should not be administered to subjects with compromised durability of the urinary bladder wall and GI tract. The agent is also contraindicated if a mechanical obstruction is present or suspected, as the therapeutic effects on the muscular tone of the GI tract and bladder may cause harm as retained urine may reflux back into the kidneys.[4]

Warning and Precautions

Potential for reflux infection: When bethanechol contracts the bladder, but the sphincter fails to relax, the urine may be forced up the ureter into the pelvis. In bacteriuria, this could lead to reflux infection.

Occupational exposure: An observational study scrutinized pharmacist exposure to drug powders, including drugs such as bethanechol, during their preparation in dispensing pharmacies. This study identified detectable levels of various drugs in the air, suggesting potential contamination within the workspace. The study demonstrated that wearing a medical mask reduced the accumulation of drug powders on filters, indicating its potential efficacy in mitigating drug dust allergies among pharmacists.[23]

Monitoring

Therapeutic effects of bethanechol develop within 30 minutes following oral administration. The maximum effectiveness often ensues between 60 to 90 minutes. Therapeutic effects usually last for 1 hour. Subcutaneous injection administration delivers a more powerful effect on the detrusor muscle when compared to the oral administration of the agent. Its effects on muscarinic receptors customarily occur within 5 to 15 minutes after subcutaneous administration and arrive at a maximum therapeutic efficacy in 15 to 30 minutes, persisting for approximately 2 hours.[4] The American Urological Association recommends the evaluation of post-void residual volume. Additionally, a successful voiding trial without catheterization can be used to identify outcome measures for non-neurogenic chronic urinary retention.[24]

Toxicity

Atropine sulfate competes with bethanechol at the muscarinic receptor junction, competitively blocking its binding at the postganglionic arch receptors and preventing parasympathetic cholinergic activation.[4][25] A 0.6 mg dosage of atropine is recommended for adults and is repeatable every 2 hours as needed, depending on therapeutic responses. Dosages that range from 0.01 to 0.4 mg/kg can be administered in the pediatric population (infant/children) and should be repeated every 2 hours as needed, depending on therapeutic responses. The subcutaneous route via injection is also an option. An emergency indicates the use of the intravenous administration route.

This diagnosis of overdose and toxicity is based on clinical manifestations, as there are no definite lab examinations or radiographic imaging that will affirm the determination. The excessive parasympathetic action at M2 and M3 muscarinic receptors in the heart, GI tract, vasculature, and bronchial muscles generate an increased response resulting in bronchorrhea, salivation, lacrimation, diaphoresis, bronchoconstriction, chest tightness, decreased heart rate, decreased blood pressure, vomiting, increased gastrointestinal motility, abdominal tightness, diarrhea, and cramps. The disproportionate effects of muscarinic receptors in the eyes cause miosis and blurring vision.[15][17][26]

Enhancing Healthcare Team Outcomes

Bethanechol is a direct-acting parasympathomimetic agent that is FDA-approved for the treatment of postoperative urinary retention, postpartum urinary retention, and overflow incontinence caused by neurogenic atony of the bladder. Patients with urologic conditions require critical care from an interprofessional team of healthcare professionals. Pharmacologic management can lead to a better quality of life for patients. These healthcare professionals include family or primary care clinicians, urologists, gynecologists, nurses, and pharmacists.

Primary care clinicians and specialists must be well-informed regarding the latest information for the appropriate dosage and indications of bethanechol. Prescribing clinicians should determine the minimum effective dosage via 5 to 10 mg repeated at hourly intervals until the desired therapeutic result is achieved. The primary care physician should routinely monitor patients taking this medication for therapeutic efficacy, as dosing modifications may be necessary. The prescriber should also be aware of any underlying contraindications, such as epilepsy, peptic ulcer disease, and COPD, before administration, as these conditions can exacerbate upon using the parasympathomimetic agent like bethanechol.[21]

Patients should fully understand the multisystemic adverse events that may occur with bethanechol use. In the event of toxicity and overdose-causing systemic effects, atropine should be administered at a dose of 0.6 mg and repeated every 2 hours as needed until the effects subside. Counseling and careful monitoring are necessary during pregnancy, as clinical studies during its use in pregnancy are limited, and bethanechol is FDA pregnancy category C. This is where the nursing staff and pharmacists can contribute to therapy, with patient counseling on dosing and possible adverse events and helping to monitor therapeutic progress.

Interprofessional teamwork and communication are crucial to building patient rapport and developing a therapeutic alliance so the patients comply with therapy competently. Continued teamwork between healthcare professionals will improve patient outcomes and quality of life while mitigating potential adverse drug reactions.

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Disclosure: Inderbir Padda declares no relevant financial relationships with ineligible companies.

Disclosure: Armen Derian declares no relevant financial relationships with ineligible companies.