Tolterodine

Mechanism of Action

Tolterodine is an antimuscarinic medication that selectively and competitively binds to muscarinic M3 receptors in the bladder, thereby decreasing bladder contraction by decreasing detrusor muscle tone and increasing internal urethral sphincter tone. Upon administration, it undergoes first-pass metabolism, where CYP2D6 metabolizes the drug to its active form, 5-hydroxymethyl.[6]

Administration

Tolterodine administration occurs in two different ways – orally or transdermally as a topical gel formulation (proniosomes).

Oral

Orally, it is available in two forms: immediate-release (IR) and extended-release (ER) (i.e., administering tolterodine ER 4mg once daily is pharmacokinetically equivalent to tolterodine ER 2mg twice daily). 

Adults

The initial dosage for IM begins at 2mg, twice daily, and has been shown to decrease the number of micturition every 24 hours, whereas EM is given as 4mg once a day.[7] The IM and ER dose can be decreased to 1mg twice a day and 2mg once a day, respectively, depending on the individual reaction to the drug and tolerability.  

A clinical study regarding male overactive bladder symptoms shows an increased effect of tolterodine ER compared to tolterodine IM.[3] Tolterodine EM also manifests fewer adverse effects.[2]

Pediatric

Doses from 0.03 to 0.12mg/kg are considered safe for children from the ages of 1 month to 15 years. A clinical study showed that the drug was well-tolerated, and there was no relationship between the dose levels and adverse events; however, complete safety and efficacy have not been established.[8]

Transdermal Topical Gel Formation (proniosomes)

A study on transdermal patches demonstrated similar therapeutic effects as the oral dose form, but it showed a decrease in the adverse effects of the drug, such as dry mouth and constipation. Both transdermal and oral administration of tolterodine had a similar level of inhibitory effects in the bladder.[9] Additionally, this method of administration was effective for over 72 hours after the application because of the constant entry into the systemic circulation through the patch.

Adverse Effects

Adverse effects of tolterodine are significantly lower than that of other antimuscarinic drugs indicated for the same use.  

However, the following effects are still present:

• Dry mouth
• Dry eyes
• Constipation
• Headache
• Blurred vision
• Drowsiness

Elderly patients who use multiple medications are more at risk for adverse effects because of drug-to-drug interactions.

Considering more clinically relevant adverse effects, tolterodine has the potential to cause disturbances in the cardiac and central nervous systems. Because of muscarinic receptors in the heart, low doses of tolterodine can cause an increase in heart rate by acting on M1 and leading to tachycardia, palpitations, and cardiac rhythm disorders. Due to this potential adverse effect, the suggestion is that those with any heart-related problems use caution when taking this drug. In the central nervous system, all five subtypes of the muscarinic receptors are present, and because of the lipophilicity of tolterodine, it can cross the blood-brain barrier. This situation can give rise to CNS problems such as depression, cognitive impairment, confusion, or the most common effect, dizziness. Therefore, any patients with pre-existing neurological conditions should be cautious, and further advisement from their physician is strongly recommended. 

Contraindications

Along with other OAB drugs, tolterodine is contraindicated in patients at risk for or currently have gastric retention or uncontrolled angle-closure glaucoma. It is also not for use in patients with myasthenia gravis, severe constipation, intestinal atony, ulcerative colitis, or bladder outflow obstructions.[10]

Because of its tertiary property, tolterodine should be monitored and used with caution if the patient has a neurological disorder or neurodegenerative disease. Additionally, if a patient is about to perform a potentially dangerous task, this medication should not be administered, as it can cause drowsiness and blurred vision.

Monitoring

Healthcare professionals should monitor patients for antimuscarinic effects on the cardiac and central nervous systems. These effects include tachycardia, palpitations, prolonged QT intervals (more common in females), hallucinations, confusion, dizziness, and more. This vigilance is vital for elderly patients taking multiple medications and who are at risk for drug-to-drug interactions.

Patients should be explained the most common adverse side effects, such as dizziness, after administration of tolterodine, as it can put them at risk if they are about to perform a potentially dangerous task.

Toxicity

To prevent toxicity, patients with hepatic impairment should be given a lower dose since the drug's elimination is lower than that of healthy patients. Additionally, tolterodine demonstrated higher concentrations in patients with renal impairment. Therefore, recommendations include a decrease in drug dosage in both patients with hepatic or renal impairment. 

Enhancing Healthcare Team Outcomes

All clinicians prescribing tolterodine should be familiar with the potential adverse effects. Managing tolterodine therapy should involve the efforts of an interprofessional healthcare team, including clinicians, specialists, mid-level practitioners, nurses, and pharmacists, all coordinating their activities and exercising open communication so that optimal patient outcomes are achieved with minimal adverse effects. [Level 5] Nurses can counsel patients on proper dosing and administration and what to watch for regarding possible adverse events. Pharmacists can reinforce those points and also check the patient's medication profile for potential interactions and contraindications.

Patients require monitoring for any possible cardiac or central nervous system disturbances, especially those older, as there is a higher probability of drug interactions in this population of patients. Patients should also understand potential common side effects, such as drowsiness or blurred vision, to ensure their safety and to decrease the risk of an accident were they to perform a potentially dangerous task.