How Drugs Modify The Micturition Reflex: A Review
Micturition is the process of expelling urine from the body via the bladder and urethra. Disorders of micturition such as Overactive Bladder and Urge Incontinence affect many people and the first-line treatment is drug therapy. In this review the current standard drugs, anti-muscarinics, are critically assessed against newer drugs and drug targets, some of which are still in experimental stages.
Micturition – the classical term for urination - is a complex action which relies on both the lower urinary tract and the micturition areas of the central nervous system (CNS) working together. It is comprised of two phases: storage, where urine from the kidneys is stored in the bladder until it is appropriate, and voiding where the urine is expelled from the bladder via the urethra. The detrusor is the smooth muscle of the bladder which is distended upon filling and is contracted during voiding. The outlet comprises the bladder neck along with the smooth and striated urethral sphincter muscles. The outlet is contracted during filling and relaxed during voiding .
The bladder is controlled by the CNS, both voluntarily through the somatic nervous system and also unconsciously through the two anatomical divisions of the autonomic nervous system. The sympathetic branch, when active, triggers the "fight or flight" response to danger and the parasympathetic branch allows us to relax and digest our food.
Nerves from the bladder to the CNS convey bladder filling via stretch receptors in the bladder wall along with pain and temperature via receptors for noxious stimuli. Central control of micturition comes from the Pontine Micturition Centre and the Periaqueductal Gray in the Pons with higher voluntary functions located in the forebrain .
Disorders of micturition can be categorised into storage and voiding (incontinence) symptoms. Of most interest is the storage symptom Overactive Bladder (OAB), and the diagnosis of Detrusor Overactivity (DO). The 4th International Consultation on Incontinence defines Overactive Bladder as having the storage symptoms of urgency with or without urge incontinence and is usually demonstrated by a high frequency of urination episodes per day . Detrusor Overactivity is defined as involuntary detrusor contractions during the storage phase of micturition. A patient with DO will feel the need to urinate regardless of how much urine is in the bladder. DO is diagnosed through invasive testing of bladder pressure . DO is not synonymous with OAB, as only 69% of male and 44% of female OAB sufferers have DO . Pharmacological treatment is the first course of action for these symptoms, which can be abated theoretically by increasing bladder capacity, reducing detrusor activity and strengthening outlet sphincter resistance . Therefore, a patient's micturition may be modified with drugs, hopefully to improve their quality of life.
In this paper I will outline the pharmacology, efficacy and safety of the current standard drugs (antimuscarinics) for OAB and DO as well as several novel drugs where research is still ongoing, targeting both the periphery and the central nervous system, using as current data as possible.
The parasympathetic branch of the autonomic nervous system is the main drive of bladder contraction. Nerve terminals release the transmitter chemical acetylcholine for which there are specific receptors on the detrusor muscle. Activation of these receptors causes contraction . Antimuscarinic drugs block these receptors and so reduce the frequency of contractions. They are the current front-line treatment of bladder disorder , and have been shown to be safe, effective and well tolerated for DO and OAB. A Cochrane review analysing the results of several different clinical trials by Nabi  compared antimuscarinics with placebo and showed statistically significant improvements of OAB symptoms. However, they have a side effects due to lack of receptor specificity (there are similar receptors all throughout the body and these will be blocked too), the most common being dry mouth. This is shown in 31% of patients which can lead to poor compliance. The most recent antimuscarinic on the market, fesoterodine (currently being heavily marketed on the underground by Pfizer) has been shown to be superior at reducing the frequency of urges to its predecessor tolterodine with fewer instances of dry mouth . However Chapple goes on to suggest that "the ceiling may have been reached for therapeutic efficacy".
A toxin, botulinum inhibits acetylcholine release for up to 6 months after injection, decreasing detrusor contractility . The most common subtype of botulinum toxin used in urology is botulinumtoxinA. It has shown to reduce the frequency of urge incontinence compared to placebo when injected into the detrusor muscle . The above study mentions urinary retention and urinary tract infection (UTI) as adverse effects in a minority of cases. However the most recent study of over 400 women with DO against placebo showed positive results in reducing DO with a 31% incidence of UTI and a 16% incidence of urinary retention resulting in self-catheterisation . Lucioni has shown it also inhibits sensory neurotransmitter release, which may explain its effect on decreasing urgency . BotulinumtoxinA is still not licensed for intravesical injection in the UK but is used off-label.
β3 adrenoceptor agonists
Sympathetic nerves on the bladder release the transmitter chemical noradrenaline, which causes relaxation via specific receptors on the detrusor, the most common subtype being the β3 . YM178 (Mirabegron), activates these receptors to increase bladder capacity during storage without affecting the voiding bladder contraction which can occur in antimuscarinics. It compared favourably in a random controlled trial against placebo and tolterodine and has passed phase III clinical trials . The common side effects are headache and gastrointestinal effects .
An already well-known and widely used opioid analgesic (painkiller), tramadol has been shown to cause an increase in bladder storage capacity in conscious rats through a complex mechanism . In humans bladder capacity and compliance were increased with no ill-effect upon voiding when administered epidurally, in contrast to other opioids such as morphine which cause urinary retention, an adverse side effect . Singh also suggests tramadol would be useful in treating post-operative pain as the lack of urine retention would negate the need for catheterisation and so improve patient comfort. Research is still ongoing and tramadol has a large range of side-effects, the most common being nausea, as well as the method of administration favoured by Singh being impractical for most patients.
Although originally developed as an analogue of the neurotransmitter gamma-aminobutyric acid (GABA), it doesn't have any effects on GABA receptors. Instead it is believed to be active on specific calcium channels . Carbone et al showed that gabapentin reduced detrusor activity in patients with brain-derived bladder disorders . Ansari et al showed gabapentin orally administered to children with OAB who were unresponsive to antimuscarinic drugs increased bladder capacity and reduced frequency of contractions . Both studies showed few adverse side effects but they both had very small sample sizes.
Found to be a more potent analgesic than aspirin, Cizolirtine's mechanism of action is still controversial but it is believed to module the release of two signalling molecules in the spinal cord, substance-P and cacitonin gene-related peptide (CGRP) . A dose-finding study of patients with clinical OAB and/or urodynamic DO showed a "clear improvement" in urination frequency with orally-administered cizolirtine . A phase II clinical trial showed cizolirtine to perform very similarly to the antimuscarinic oxybutynin in increasing bladder capacity and decreasing frequency of urination compared to placebo, albeit with its own side effect profile, mainly gastrointestinal effects .
I hope this essay has shown the breadth and diversity of current pharmacological research in treating OAB and DO. Although all of the research on the "alternative" drugs heavily disparages antimuscarinics for their side-effects, there still seems to be no better treatment as yet due to adverse effects and the difficulty of selectivity through oral administration.
 Bissada, N K, Finkbeiner, A E and Welch, L T 1997 Lower urinary tract pharmacology I. Anatomic considerations. Urology 9(1): 107-113. DOI: http://dx.doi.org/10.1016/0090-4295(77)90298-9.
 Abrams, P, Andersson, K, Birder, L, Brubaker, L, Cardozo, L, Chapple, C, Cottenden, A, Davila, W, de Ridder, D, Dmochowski, R, Drake, M, DuBeau, C, Fry, C, Hanno, P, Smith, J H, Herschorn, S, Hosker, G, Kelleher, C, Koelbl, H, Khoury, S, Madoff, R, Milsom, I, Moore, K, Newman, D, Nitti, V, Norton, C, Nygaard, I, Payne, C, Smith, A, Staskin, D, Tekgul, S, Thuroff, J, Tubaro, A, Vodusek, D, Wein, A and Wyndaele, J 2010 Fourth international consultation on incontinence recommendations of the international scientific committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourology and Urodynamics 29: 213–240. DOI: http://dx.doi.org/10.1002/nau.20870.
 Drake, M J 2008 Emerging drugs for treatment of overactive bladder and detrusor overactivity. Expert Opin. Emerging Drugs 13(3): 431-446. DOI: http://dx.doi.org/10.1517/14728126.96.36.1991.
 Hashim, H and Abrams, P 2006 Is the Bladder a Reliable Witness for Predicting Detrusor Overactivity? The Journal of Urology 175(1): 191-194. DOI: http://dx.doi.org/10.1016/S0022-5347(05)00067-4.
 de Groat, W C and Yoshimura, N 1997 Pharmacology of the lower urinary tract. Annual Review of Pharmacology and Toxicology 41: 691-721. DOI: http://dx.doi.org/10.1146/annurev.pharmtox.41.1.691.
 Nabi, G, Cody, J D, Ellis, G, Hay-Smith, J and Herbison, G P 2006 Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database of Systematic Reviews 4. DOI: http://dx.doi.org/10.1002/14651858.CD003781.pub2.
 Chapple, C R, Van Kerrebroeck, P E, Jünemann, K-P, Wang, J T and Brodsky, M 2008 Comparison of fesoterodine and tolterodine in patients with overactive bladder. BJU International 102: 1128–1132. DOI: http://dx.doi.org/10.1111/j.1464-410X.2008.07907.x.
 Hanna-Mitchell, A T and Birder, L A 2008 New insights into the pharmacology of the bladder. Curr Opin Urol. 18(4): 347–352. DOI: http://dx.doi.org/10.1097/MOU.0b013e3283023bfc.
 Dmochowski, R, Chapple, C, Nitti, V W, Chancellor, M, Everaert, K, Thompson, C, Daniell, G, Zhou, J and Haag-Molkenteller, C 2010 Efficacy and Safety of OnabotulinumtoxinA for Idiopathic Overactive Bladder: A Double-Blind, Placebo Controlled, Randomized, Dose Ranging Trial. The Journal of Urology 184(6): 2416-2422. DOI: http://dx.doi.org/10.1016/j.juro.2010.08.021.
 Tincello, D G, Kenyon, S, Abrams, K R, Mayne, C, Toozs-Hobson, P, Taylor, D and Slack, M 2011 Botulinum Toxin A Versus Placebo for Refractory Detrusor Overactivity in Women: A Randomised Blinded Placebo-Controlled Trial of 240 Women (the RELAX Study). EURURO 4307: 1–8. DOI: http://dx.doi.org/10.1016/j.eururo.2011.12.05.
 Lucioni, A, Bales, G T, Lotan, T L, McGehee, D S, Cook, S P and Rapp, D E 2008 Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU International 101: 366–370. DOI: http://dx.doi.org/10.1111/j.1464-410X.2007.07312.x.
 Andersson, K E 1999 The pharmacological perspective: role for the sympathetic nervous system in micturition and sexual function. Prostate Cancer Prostatic Dis. Dec 2(S4):S5-S8. PubMed PMID: 12496767. .
 Chapple, C R, Yamaguchi, O, Ridder, A, Liehne, J, Carl, S, Mattiasson, A, Aramburu, MAL, Lucas, M and Everaert, K 2007 Clinical proof of concept study (Blossom) shows novel b3 andrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 7: 239. Abstract 674.
 Tyagi, P, Tyagi, V and Chancellor, M 2011 Mirabegron: a safety review. Expert Opinion on Drug Safety 10(2): 287-294. DOI: http://dx.doi.org/10.1517/14740338.2011.542146.
 Pandita, R K, Pehrson, R, Christoph, T, Friderichs, E and Andersson, K E 2003 Actions of tramadol on micturition in awake, freely moving rats. British Journal of Pharmacology 139: 741–748. DOI: http://dx.doi.org/10.1038/sj.bjp.0705297.
 Singh, S, Agarwal, M, Batra, Y, Kishore, A and Mandal, A 2008 Effect of lumbar-epidural administration of tramadol on lower urinary tract function. Neurourology and Urodynamics 27: 65–70. DOI: http://dx.doi.org/10.1002/nau.20465.
 Striano, P and Striano, S 2008 Gabapentin: A Ca2+ channel alpha2-delta ligand far beyond epilepsy therapy Drugs Today 44(5): 353. DOI: http://dx.doi.org/10.1358/dot.2008.44.5.1186403.
 Carbone, A, Palleschi, G, Conte, A, Bova, G, Iacovelli, E, Bettolo, R M, Pastore, A and Inghilleri, M 2006 Gabapentin Treatment of Neurogenic Overactive Bladder. Clinical Neuropharmacology 29(4): 206-214. DOI: http://dx.doi.org/10.1097/01.WNF.0000228174.08885.AB.
 Ansari, M S, Bharti, A, Kumar, R, Ranjan, P, Srivastava, A and Kapoor, R 2011 Gabapentin: A novel drug as add-on therapy in cases of refractory overactive bladder in children. Journal of Pediatric Urology. DOI: .
 Ballet, S, Aubel, B, Mauborgne, A, Poliénor, H, Farré, A, Cesselin, F, Hamon, M and Bourgoin, A S 2001 The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats, Neuropharmacology 40(4): 578-589. DOI: .
 Martínez-García R, Abadías M, Arañó P, Perales L, Luis Ruíz J, Sust M and Conejero J, for the ESCLIN 006/00 study group 2009 Cizolirtine Citrate, an Effective Treatment for Symptomatic Patients with Urinary Incontinence Secondary to Overactive Bladder: A Pilot Dose-Finding Study, European Urology 56(1): 184-192. DOI: http://dx.doi.org/10.1016/j.eururo.2008.04.027.
 Zát'ura, F, Všetiča, J, Abadías, M, Pavlík, I, Schraml, P, Brod'ák, M, Villoria, J and Sust, M, for the E-4018/CL50 Study Group 2010 Cizolirtine Citrate Is Safe and Effective for Treating Urinary Incontinence Secondary to Overactive Bladder: A Phase 2 Proof-of-Concept Study. European Urology 57(1): 145-153. DOI: http://dx.doi.org/10.1016/j.eururo.2009.04.045.
How to cite: Humphrey, J 2012. How Drugs Modify The Micturition Reflex: A Review. Opticon1826 7(12):9-11, DOI: http://dx.doi.org/10.5334/opt.121204
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
This article has been peer reviewed (journal peer review policy).
Published on 30 April 2012.