Oxybutynin

Mechanism of Action

Oxybutynin is classified as an anticholinergic drug that acts as an antispasmodic against smooth muscle, particularly in the bladder. The active metabolite of oxybutynin is N-desethyloxybutynin.[9] This medication competitively inhibits the postganglionic muscarinic 1, 2, and 3 receptors, thereby blocking the muscarinic effect of acetylcholine and leading to the relaxation of the bladder smooth muscles of the bladder. As a result, oxybutynin increases bladder capacity and reduces urinary urgency and frequency. Oxybutynin also has been shown to delay the initial desire to void.[10][11] 

Oxybutynin acts by competitive acetylcholine antagonism at postganglionic muscarinic receptors, which results in the relaxation of the smooth muscles of the bladder. The FDA has approved several dosage forms of oxybutynin, including oral immediate-release and extended-release tablets, topical gel, and transdermal patches. Oxybutynin is available for intravesical instillation and as a rectal suppository. Moreover, there is ongoing development of vaginal preparation. Each formulation has different efficacy and adverse-event profiles.[12]

Pharmacokinetics

Absorption: Oxybutynin is rapidly absorbed by the body after the oral administration of oxybutynin chloride immediate-release tablets, with an absolute bioavailability of approximately 6% (ranging between 1.6% and 10.9%). The drug reaches its maximum plasma concentration (Cmax) within 1 hour and exhibits a plasma half-life of approximately 2 to 3 hours. Clinical data in the literature indicates that oxybutynin solution exhibits a slightly delayed absorption when co-administered with food, resulting in increased bioavailability of approximately 25%. 

Distribution: Oxybutynin demonstrates a substantial volume of distribution, measuring 193 L, following the intravenous administration of 5 mg oxybutynin chloride. Furthermore, both enantiomers of oxybutynin (R and S) exhibit a high protein binding rate of 99%. This drug can cross the blood-brain barrier, possibly impairing cognitive function.[13][14]

Metabolism: Oxybutynin is primarily metabolized by the cytochrome P450 enzyme systems, mainly processed by CYP3A4 in the liver. The metabolism of oxybutynin produces 2 metabolites, including phenyl cyclohexyl glycolic acid and desethyloxybutynin. The first substance, phenyl cyclohexyl glycolic acid, is inactive, whereas the second substance, desethyloxybutynin, has pharmacological activity.[15]

Excretion: Oxybutynin is primarily metabolized in the liver, with less than 0.1% of the administered dose excreted unchanged in the urine and less than 0.1% excreted as the desethyloxybutynin metabolite.

Administration

Various formulations and routes of administration are available for oxybutynin, offering different options to help patients manage their overactive bladder or related issues. The most common choices include oral administration of the drug in the form of pills or tablets, which can be either immediate-release or extended-release formulations. The initial dosage for both formulations of oxybutynin starts at 5 mg. In addition, the medication can also be administered to patients in the form of a syrup, transdermal patch, or gel. Oxybutynin syrup is available in 16-ounce containers and is formulated as 1 mg/mL. Notably, both the immediate-release and the extended-release tablets have the same starting and maximum doses.

The long-acting or extended-release oxybutynin tablets are available in strengths of 5 mg, 10 mg, or 15 mg of oxybutynin chloride. This formulation is designed as a once-daily oral medication and employs an osmotic pressure delivery system to release the drug over a period of 24 hours gradually. The oral forms of oxybutynin are absorbed similarly, regardless of whether the patient is in the fed or fasted state.

The oxybutynin transdermal system or patch provides continuous medication delivery for 3 to 4 days following its application. The patch contains 36 mg of oxybutynin, resulting in an average daily absorbed dose of 3.9 mg. The steady-state concentrations of the drug are achieved during the second application of the patch. The oxybutynin patch should be applied to a patient's abdomen, buttock, or hip. To ensure safety, patients should refrain from reapplying the transdermal patch to the same site within 7 days of applying it. Notably, the safety of this medication has not been established in pediatric patients.

The oxybutynin gel (10%) is supplied in sachets, and to use the medication, the contents of 1 sachet should be opened and applied onto clean, dry, and unbroken skin on the abdomen, upper arms, or thighs. The steady-state concentrations of the drug are achieved within 7 days of continuous medication dosing. Application sites of the drug should be rotated to avoid irritation or skin problems. The safety of oxybutynin has not been established in pediatric patients.

Various treatment options are available for patients experiencing overactive bladder or related issues, including medications such as oxybutynin, behavioral therapies, and lifestyle changes. These treatments can help patients to manage their symptoms and enhance their comfort and overall well-being. Below is the recommended dosage chart for oxybutynin across all age groups.

Adult Dosage

Here is the list of the recommended oxybutynin dosages for adults:

• The starting dosage for immediate-release oxybutynin is a 5 mg tablet to be administered 2 to 3 times daily. Physicians advise that the daily intake of oxybutynin 5 mg tablets should not exceed 4 tablets per day for adults.
• The initial dosage for extended-release oxybutynin is a 5 mg tablet administered once daily, and the drug should be taken at the same time every day. The daily dose of the medication can be raised by 5 mg, with a maximum limit of up to 30 mg.
• For the topical gel formulation, the content of 1 pump actuation or 1 sachet of oxybutynin should be applied daily to the affected area as directed by the physician.
• For the transdermal patch, a 3.9 mg patch of oxybutynin should be applied twice weekly. Before using a new patch on the same area for 2 days each week, the old patch should be removed to ensure proper dosing and efficacy of the medication. Patients can use a 3.9 mg oxybutynin patch every fourth day as an over-the-counter product.

Specific Patient Populations

Geriatric patients: As per the American Geriatric Society (Beers Criteria), oxybutynin is considered a potentially inappropriate medication for older patients due to its anticholinergic adverse effects. Therefore, oxybutynin should only be administered to older patients if the potential benefit outweighs the risks. Physicians recommended starting oxybutynin treatment with a lower dosage of 2.5 mg administered 2 to 3 times daily for immediate release. This cautious approach is due to the prolonged elimination half-life of oxybutynin, which ranges from 2 to 3 hours and can extend up to 5 hours in older populations.[16]

Pediatric patients: The starting or maximum dosage recommended for pediatric patients aged 5 and older is a 5 mg tablet administered 2 to 3 times daily for immediate release. The recommended starting dosage for pediatric patients aged 6 and older is 5 mg of extended-release oxybutynin administered once daily. The maximum daily dosage for this group of pediatric population should not exceed 20 mg. The extended-release form of oxybutynin should not be administered to pediatric patients younger than 6 or those unable to swallow the tablet whole. The extended-release tablets should not be chewed, crushed, or divided, as they are designed to release the medication gradually. In certain cases, oxybutynin is used as an off-label drug to control overactive bladder in children aged 1 to 5, with a dosing regimen of 0.2 mg/kg orally administered 2 to 4 times daily. The recommended maximum daily dosage for this group should not exceed 15 mg.

Pregnancy considerations: In an observational study, the use of oxybutynin in pregnant patients with spinal cord injuries did not show any adverse effects on pregnancy outcomes. However, further research is necessary to fully assess the safety of oxybutynin use during pregnancy.[17] Oxybutynin is classified as a category B medication for pregnant patients. Although animal studies have not provided definitive evidence of harm to the fetus during pregnancy, conclusive safety data for this period have not been established yet. Oxybutynin should be prescribed in pregnancy only if the clinical benefits to the mother outweigh the potential risks to the fetus.[18]

Breastfeeding considerations: Currently, no evidence is available regarding the use of oxybutynin in nursing mothers. In certain cases where breastfeeding women take oxybutynin for an extended period, it is recommended to monitor their baby for any indications of reduced milk supply, such as slow weight gain or signs of in-satiety.[19]

Primary focal hyperhidrosis: For individuals who have primary focal hyperhidrosis, a dosage of oxybutynin immediate-release formulation starting at 2.5 mg is administered once daily and adjusted gradually based on tolerance. The dosage of the medication can range from 5 to 10 mg daily, divided into 2  doses.[20] The dosage for extended-release oxybutynin for this group of patients typically ranges from 5 to 10 mg, administered once daily.

Refractory nocturnal enuresis: A combination of desmopressin and oxybutynin therapy is suggested as a treatment option for pediatric patients with refractory nocturnal enuresis. Combination therapy with desmopressin and oxybutynin is more effective than using desmopressin-only therapy. The initial dose of oxybutynin for this condition is 5 mg, with the maximum recommended dose being 10 mg.[4][21][22]

Hepatic and renal impairment: Caution should be exercised while prescribing oxybutynin to patients with hepatic or renal impairment, as the dosages allocated for these cases are not defined yet.

Adverse Effects

The immediate-release form of oxybutynin can cause various adverse effects in patients, including dry mouth (71.4%), dizziness (16.6%), constipation (15.1%), somnolence (14.0%), and nausea (11.6%). Some of the less common adverse effects of immediate-release oxybutynin include blurred vision (9.6%), urinary hesitation (8.5%), urinary retention (6.0%), and dyspepsia (6.0%). Notably, a dry mouth is considered a dose-related adverse effect of oxybutynin.[23][24] Oxybutynin hydrochloride has a more favorable profile than other antimuscarinic drugs regarding adverse effects on heart rate increase.[25]

Although the adverse effects caused by the extended-release form of oxybutynin are similar to the immediate-release form, the rates of the extended-release form have been reported as lower compared to the immediate-release form. These include dry mouth (29% to 61%), constipation (7% to 13%), somnolence (2% to 12%), headache (6% to 10%), diarrhea (7% to 9%), nausea (2% to 9%), blurred vision (1% to 8%) and dry eyes (3% to 6%). A dry mouth is considered a dose-related adverse effect of oxybutynin. The various adverse events led to the discontinuation of the medicine in 6.8% of patients.

Application site reactions were reported in 5.4% of patients using oxybutynin gel and 16.8% using the oxybutynin transdermal system compared to 6.1% of patients in the placebo group. The signs of a dry mouth were less common in patients receiving transdermal oxybutynin than in the oral forms, with rates reported as 7.5% for the gel and 9.6% for the patch. Adverse effects of oxybutynin are often related to the dose of the medication. The oxybutynin-induced brief psychotic disorder has been reported in the medical literature.[26] Moreover, a recent case report documents oxybutynin overuse resulting in repeated delirious states and subsequent hospitalization of a patient.[27]

Drug-Drug Interactions

• CYP3A4 primarily metabolizes oxybutynin. Caution should be exercised when using potent CYP3A4 inhibitors, such as ketoconazole, as they may increase the plasma concentration of oxybutynin.[28] Likewise, other inhibitors of the CYP3A4 enzyme, such as itraconazole, miconazole, clarithromycin, erythromycin, and grapefruit juice, have the potential to affect the plasma concentration of oxybutynin; therefore, concurrent use of these substances requires caution.[29][30][31]

• Oxybutynin can decrease gut motility, which may reduce the effectiveness of prokinetic drugs, such as metoclopramide.

• Caution should be exercised while using oxybutynin concurrently with other anticholinergic drugs, as they can lead to an increased risk of adverse effects, such as xerostomia (dry mouth), constipation, and urinary retention.[32]

Contraindications

Oxybutynin is contraindicated in patients with urinary retention, bladder obstruction, poorly controlled narrow-angle glaucoma, obstructive gastric disorders, or gastric dysmotility. In addition, oxybutynin should not be used in patients with hypersensitivity to the drug or its excipients. Angioedema of the face, tongue, lips, and larynx has been reported with oxybutynin use, necessitating the discontinuation of the medication and ensuring a patent airway to manage the condition promptly and effectively.[33]

As recommended by physicians, caution should be exercised while using oxybutynin for patients who are old, diagnosed with myasthenia gravis, who have dementia and are being treated with cholinesterase inhibitors, with Parkinson disease, and with renal or hepatic impairments.

The dose of the extended-release formulation needs to be reduced or discontinued if a patient experiences anticholinergic central nervous system adverse reactions to oxybutynin. In addition, in patients with autonomic neuropathy, the use of the extended-release formulation of oxybutynin should be approached with caution, as it may exacerbate symptoms of decreased gastric motility.[34]

Monitoring

Patients should be closely monitored for anticholinergic adverse effects related to the central nervous system, including hallucinations, agitation, confusion, and somnolence. This monitoring is critical for older patients and for patients during their initial few months of oxybutynin treatment or after increasing the dosage of the medication.

Healthcare professionals should counsel patients that concomitant use of alcohol with oxybutynin may increase drowsiness, and taking oxybutynin in a high-temperature environment can lead to heat prostration, which may manifest as fever and heat stroke due to reduced sweating.[35] Furthermore, administering oxybutynin with other anticholinergic medications can increase the frequency and severity of the above-mentioned adverse effects.

Toxicity

If an overdose of oxybutynin is suspected, a medical professional should be sought for immediate care. Symptoms of oxybutynin overdose may include central nervous system overactivity, fever, cardiac arrhythmias, vomiting, respiratory failure, paralysis, and coma. The treatment for oxybutynin overdose typically involves supportive care from healthcare providers. In some cases, medical professionals may consider administering activated charcoal to patients to help absorb the excess medication in their digestive system. Alternatively, a cathartic agent might be used to promote bowel movements in patients to facilitate the elimination of the drug from the body.

There have been 2 reported cases of drug overdose due to the consumption of 100 mg of oxybutynin: 1 case involved a 13-year-old boy, and the other case involved a 34-year-old woman. In addition, there was another report of simultaneous alcohol ingestion with the medication. In another case, a 4-year-old boy experienced a drug overdose and central anticholinergic syndrome after taking 17 mg of oxybutynin over 12 hours.[36] Patients in all the above cases completely recovered after receiving supportive care from healthcare professionals. The controlled-release formulation of oxybutynin contains insoluble contents, which may result in the formation of bezoars.[37]

Enhancing Healthcare Team Outcomes

Healthcare professionals, including primary care physicians and advanced practice practitioners, who prescribe oxybutynin to patients, should be well-informed about its adverse effect profile. The adverse reactions of oxybutynin are often dosage-related. Patients should be monitored for anticholinergic adverse effects related to the central nervous system, which include hallucinations, agitation, confusion, and somnolence. These adverse reactions are critical in older patients and for patients during their initial few months of oxybutynin treatment or after increasing the dosage of the medication.

Pharmacists are critical in medication reconciliation and should counsel patients about the increased risk of drowsiness when using oxybutynin concurrently with alcohol. Moreover, patients should be informed that taking oxybutynin in a high-temperature environment may lead to heat prostration, manifesting as fever and heat stroke due to reduced sweating. Nursing staff should ensure the patient's comprehension of the medication and verify the correct dosage before administering oxybutynin. They should promptly report their observations and findings to the prescriber to ensure appropriate management of the condition. In cases of drug overdose or suspected toxicity, medical toxicologists should be consulted to provide expert guidance and assist in the patient's optimal care.

Open communication and shared decision-making among interprofessional team members are essential in enhancing the efficacy and safety outcomes for patients undergoing oxybutynin treatment.