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Treating Lower Urinary Tract Symptoms in Older Adults: Intravesical Options

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Abstract

This article provides an overview of the diagnosis and the treatment of lower urinary tract symptoms in older adults complicated by the neurodegenerative changes in the micturition reflex and further confounded by age-related decline in hepatic and renal clearance raising the propensity of adverse drug reactions. The first-line drug treatment for lower urinary tract symptoms, orally administered antimuscarinics, fails to reach the equilibrium dissociation constant of muscarinic receptors even at their maximum plasma concentration and tends to evoke a half-maximal response at a muscarinic receptor occupancy of just 0.206% in the bladder with a minimal difference from exocrine glands, which raises the adverse drug reaction risk. On the contrary, intravesical antimuscarinics are instilled at concentrations 1000-fold higher than the oral maximum plasma concentration and the equilibrium dissociation constant erects a downhill concentration gradient that drives passive diffusion and achieves a mucosal concentration around ten-fold lower than the instilled concentration for a long-lasting occupation of muscarinic receptors in mucosa and sensory nerves. A high local concentration of antimuscarinics in the bladder triggers alternative mechanisms of action and is supposed to engage retrograde transport to nerve cell bodies for neuroplastic changes that underlie a long-lasting therapeutic effect, while an intrinsically lower systemic uptake of the intravesical route lowers the muscarinic receptor occupancy of exocrine glands to lower the adverse drug reaction relative to the oral route. Thus, the traditional pharmacokinetics and pharmacodynamics of oral treatment are upended by intravesical antimuscarinics to generate a dramatic improvement (~ 76%) noted in a meta-analysis of studies enrolling children with neurogenic lower urinary tract symptoms on the primary endpoint of maximum cystometric bladder capacity as well as the secondary endpoints of filling compliance and uninhibited detrusor contractions. The therapeutic success of intravesical multidose oxybutynin solution or oxybutynin entrapped in the polymer for sustained release in the pediatric population bodes well for patients with lower urinary tract symptoms at the other extreme of the age spectrum. Though generally used to predict oral drug absorption, Lipinski’s rule of five can also explain the ten-fold lower systemic uptake from the bladder of positively charged trospium over oxybutynin, a tertiary amine. Chemodenervation by an intradetrusor injection of onabotulinumtoxinA is merited for patients with idiopathic overactive bladder discontinuing oral treatment because of a lack of efficacy. However, age-related peripheral neurodegeneration potentiates the adverse drug reaction risk of urinary retention that motivates the quest of liquid instillation, delivering larger fraction of onabotulinumtoxinA to the mucosa as opposed to muscle by an intradetrusor injection can also probe the neurogenic and myogenic predominance of idiopathic overactive bladder. Overall, the treatment paradigm of lower urinary tract symptoms in older adults should be tailored to individual’s overall health status and the risk tolerance for adverse drug reactions.

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Acknowledgments

We acknowledge Prof. Scott Glickman for his critical review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Urology, E313 Montefiore Hospital, University of Pittsburgh, 3459 Fifth Ave, Pittsburgh, PA, 15213, USA

    Anirban Ganguly, Christopher Chermansky, Mamoru Hashimoto, Kang Jun Cho, Naoki Yoshimura & Pradeep Tyagi

  2. Department of Medicine, University of Pittsburgh, 3459 Fifth Ave, Pittsburgh, PA, 15213, USA

    Shachi Tyagi & Anthony Kanai

  3. Department of Pharmacology, University of Pittsburgh, 3459 Fifth Ave, Pittsburgh, PA, 15213, USA

    Jonathan Beckel

  4. William Beaumont School of Medicine, Rochester, USA

    Michael Chancellor

  5. Lipella Pharmaceuticals Inc, Pittsburgh, USA

    Jonathan Kaufman

Authors
  1. Anirban Ganguly
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  2. Shachi Tyagi
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  3. Christopher Chermansky
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  4. Anthony Kanai
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  5. Jonathan Beckel
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  6. Mamoru Hashimoto
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  7. Kang Jun Cho
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  8. Michael Chancellor
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  9. Jonathan Kaufman
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  10. Naoki Yoshimura
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  11. Pradeep Tyagi
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Corresponding author

Correspondence to Pradeep Tyagi.

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Funding

This work was partly supported by National Institutes of Health Grants: R44DK108397, CA251341, and CA263243.

Conflicts of Interest/Competing Interests

Michael Chancellor and Jonathan Kaufman are board members of Lipella Pharmaceuticals. Pradeep Tyagi is a consultant for Vensica Therapeutics and Uropharma.

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Authors’ Contributions

AG and ST wrote the initial draft and performed the literature search; CC, AK, and JB offered valuable suggestions to modify the draft; MC, JK, and NY edited and help secure funding; PT was responsible for the overall theme, direction, and formatting of the submitted work.

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Ganguly, A., Tyagi, S., Chermansky, C. et al. Treating Lower Urinary Tract Symptoms in Older Adults: Intravesical Options. Drugs Aging 40, 241–261 (2023). https://doi.org/10.1007/s40266-023-01009-5

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