Comparison of Urinary Anticholinergics

Anticholinergic medications are well known for their often dose-limiting adverse effects, so do any of the medications typically used in the treatment of lower urinary tract symptoms (LUTS) associated with BPH stand above the others with a more favorable adverse effect profile? In this article, we provide a comparison of urinary anticholinergics.

The anticholinergic medications typically used in the treatment of BPH are oxybutynin, tolterodine, darifenacin, solifenacin, fesoterodine, and trospium. They are recommended for patients whose LUTS symptoms are primarily irritative and who do not have an elevated PVR volume (caution should be taken in patients with PVR >250-300 mL), and they have been shown to reduce the frequency of incontinence episodes, the number of voids per day, and the number and severity of urgency episodes. Choosing an anticholinergic medication for a patient should be based on achieving the highest therapeutic benefit with the least adverse effects. Unfortunately, cost may have to be a part of the equation as well. The most common adverse effects are dry mouth and constipation. Other less common effects include blurred vision, somnolence, and cognitive effects.

One method that is employed to increase tolerability is using extended-release formulations. Both oxybutynin and tolterodine have extended-release formulations available, and these have been shown to have better tolerability compared to their immediate-release formulations due to a lower maximum concentration.

Two relatively newer agents that may be slightly more effective and tolerable are solifenacin and darifenacin. This is due to their selective antagonism of the M3 muscarinic receptor on the bladder, which can lead to increased concentrations in the bladder and reduced off-target anticholinergic effects, compared to the older agents oxybutynin and tolterodine as well as other newer agents that are nonselective. Solifenacin in particular has been shown to be more effective and cause less dry mouth than tolterodine IR, and is equally as effective as darifenacin but more tolerable than darifenacin.

In our comparison of urinary anticholinergics, we have to discuss CNS penetration as this can affect tolerability. Trospium is a water-soluble anticholinergic with a positive charge, and thus less likely to have significant CNS penetration, leading to decreased CNS effects such as drowsiness, dizziness, and confusion. Fesoterodine has low-moderate lipophilicity after rapid hydrolysis to 5-HMT and thus may have less cognitive effects. Oxybutynin has the greatest cognitive impact of these medications due to its small molecular weight and high lipophilicity. Darifenacin is also a highly lipophilic molecule, however, it is also a substrate for P-gp and thus is quickly removed from the CNS.

Drug interactions are another factor to help guide clinical decision-making in selecting an anticholinergic. Most of these medications are metabolized through the CYP450 enzyme pathway: oxybutynin is metabolized by CYP3A4, tolterodine, fesoterodine and darifenacin are metabolized by CYP2D6 and CYP3A4, and solifenacin through CYP3A4 plus about 15% is eliminated unchanged in the urine. Trospium is only renally eliminated, so may be a good option for a patient who may be on several interacting drugs or with severe hepatic impairment. Also notable is the impact tolterodine has on the QT interval. Doses above 8 mg/day can significantly increase the QT interval, recommended max dose is 4 mg/day because of this. Patients who have a history of QT interval prolongation or who are concomitantly taking class IA or III antiarrhythmics should avoid tolterodine or at a minimum have further EKG monitoring.

The adverse effects caused by the anticholinergics used in treating LUTS often lead to the discontinuation of therapy, so keeping patient-specific factors in mind can have a big impact. Choosing one of the anticholinergics with little risk of cognitive effects and minimal incidence of other side effects such as dry mouth and constipation, while also keeping drug-drug interactions in mind, can increase the chances of the patient tolerating the medication enough to experience the benefits of treatment.

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The article was written by Lincoln Haiby in collaboration with Eric Christianson, PharmD, BCPS, BCGP

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Lepor H. A comparison of anticholinergic therapies in the treatment of overactive bladder. Rev Urol. 2001;3(4):209. Accessed July 28, 2021.

Kessler TM, Bachmann LM, et al. Adverse event assessment of antimuscarinics for treating overactive bladder: a network meta-analytic approach. PLoS One. 2011 Feb 23;6(2):e16718. Accessed July 28, 2021.

Jayarajan J, Radomski S. Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life. Res Rep Urol. 2014;6:1-16. Accessed July 29, 2021.Srikrishna, S., et al. Important drug–drug interactions for treatments that target overactive bladder syndrome. Int Urogynecol J 25, 715–720 (2014). Accessed July 29, 2021.

Written By Eric Christianson

August 22, 2021

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