Clinical pharmacology of functional disorders of the urogenital system

Authors


Professor Martin C. Michel M.A.E., Department of Pharmacology & Pharmacotherapy, Academic Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, the Netherlands.
Tel.: +31 20 566 6762
Fax: +31 20 696 5976
E-mail: m.c.michel@amc.nl

This issue of the Journal comprises a number of review and original articles related to the clinical pharmacology of functional disorders of the urogenital tract. These disorders comprise, for example, voiding dysfunction related to benign prostatic hyperplasia (LUTS/BPH), the overactive bladder symptom complex (OAB), urinary incontinence in general, nocturia, erectile dysfunction and premature ejaculation, although manuscripts in this issue largely relate to OAB and LUTS/BPH. While this is a heterogeneous group of conditions, they share a number of aspects which have implications for their treatment and hence the clinical pharmacology of drugs used in such treatment.

The functional disorders of the urogenital system typically are non-life-threatening conditions. However, they can have major adverse effects on quality of life of the patient and his/her partner. They also have a major economic impact. For example, the costs of OAB in the USA alone have been estimated at about $66 billion per year [1]. Such personal and societal impact creates a medical need for effective treatment. On the other hand, the treatment of a non-life-threatening condition implies particularly high safety standards, and many articles in this issue of the Journal directly or indirectly relate to such safety standards.

Unfortunately, there is no universal agreement what these safety standards need to be. For example, the selective serotonin/noradrenaline uptake inhibitor duloxetine [2] and the selective serotonin uptake inhibitor dapoxetine [3] have been licensed in Europe for the treatment of stress urinary incontinence and premature ejaculation, respectively, whereas the US regulatory authorities have refused such authorization based upon the benefit/risk profiles of these drugs (of note, duloxetine is registered in the US for two non-urological indications). Apparently, the scientific and regulatory communities in various parts of the world have not yet agreed what establishes acceptable benefit/risk profiles for such drugs, indicating that the scientific basis for such statements remains too weak. Clinical pharmacology should play an important role in forging a science-based consensus for acceptable benefit/risk ratios in the treatment of non-life-threatening diseases.

Safety concerns related to drug use in functional urology often relate to systemic effects of such medication, as the molecular targets of such drugs tend to be widely expressed. Examples are the use of α1-adrenoceptor antagonists for the treatment of LUTS/BPH and of muscarinic receptor antagonists for the treatment of OAB, as both receptor systems are involved in the regulation of many homeostatic functions in the body, particularly in the cardiovascular system. For example, the use of muscarinic receptor antagonists for the treatment of bradycardia predates its use in OAB patients. However, elevations of a normal heart rate may be harmful, and one review in this issue is devoted to cardiac effects of anti-muscarinic OAB medication [4]. On the other hand, drug effects in multiple organ systems may also be beneficial. For example, phosphodiesterase type 5 inhibitors were originally introduced for the treatment of erectile dysfunction, but the breakdown of cyclic GMP is also important for the regulation of smooth muscle tone in other tissues. Hence, these phosphodiesterase inhibitors are not only used for the treatment of erectile dysfunction but also for pulmonary hypertension and, as reviewed here, may additionally be useful options for LUTS/BPH and perhaps OAB patients [5].

If drug effects in multiple tissues can have both beneficial and adverse effects, it becomes necessary to identify when and where a drug is present. Accordingly, one paper in this issue reviews ex vivo and in vivo techniques to assay tissue distribution of urogenital drugs over time in experimental animals [6]. They enable performing three-dimensional pharmacokinetic studies, i.e. simultaneous measurements of drug concentration and location over time. While these techniques are not yet routinely available for human pharmacokinetic studies, one paper in this issue highlights that pharmacokinetics derived from plasma samples may sometimes be insufficiently predictive of those in tissues [7], emphasizing the need for such three-dimensional pharmacokinetics. That paper also solves a long-lasting riddle related to the use of α1-adrenoceptor antagonists in LUTS/BPH patients, i.e. the phenomenon of ‘uroselectivity’. This term describes the relative lack of cardiovascular as compared with urogenital effects of some members of this drug class. Originally, it had been assumed that such uroselectivity was primarily due to selectivity for α1A-adrenoceptors, i.e. the subtype dominating in the human prostate [8]. However, some degree of uroselectivity was also found with drugs not discriminating between α1-adrenoceptor subtypes, such as alfuzosin. Moreover, plasma concentrations of these drugs correlated only poorly with pharmacodynamic effects in the urogenital tract, if anything with some time lag [9]. While the molecular determinants creating selective access to target tissue remain to be elucidated, tissue-dependent pharmacokinetics create an exciting option to generate drugs with improved tolerability profiles.

Another aspect related to preferential drug action in target tissue vs. other organ systems relates to brain penetration of drugs used in functional urology. While this may be desirable or even required with some drugs such as duloxetine [2] or dapoxetine [3], it is considered unnecessary or even undesirable for others such as α1-adrenoceptor or muscarinic receptor antagonists. One study in this volume compares factors related to brain penetration of various anti-muscarinic OAB drugs [10]. Central nervous adverse events may be of particular relevance in the elderly, as this age group can exhibit alterations of the blood–brain barrier function [11] and an associated greater risk for central nervous system-related adverse events. Specifically, the elderly may be more prone to adverse events on cognitive functions or sleep disturbance. Genetic factors, such as CYP 2D6 polymorphisms, may further complicate this issue. Thus, the muscarinic antagonist tolterodine can cause sleep disturbance in poor metabolizers which apparently are absent in extensive metabolizers [12]. This finding may directly loop back to the issue of central nervous system penetration, as the CYP 2D6-dependent tolterodine metabolite 5-hydroxymethyl tolterodine is less likely to penetrate into the brain than its parent compound [10]. Another paper in this issue highlights the role of CYP 2D6 genotype with regard to the pharmacokinetics of tolterodine as compared with those of fesoterodine, the latter generating 5-hydroxymethyl tolterodine by a CYP 2D6-independent mechanism [13].

As most functional urogenital disorders typically occur more frequently in the elderly, additional considerations also apply to these urogenital drugs based upon the frequent comorbidities and associated comedications of the elderly. Preferential use in such populations emphasizes the need for limited drug–drug-interactions, and several papers in this issue relate to this [14–16]. In light of phenomena such as uroselectivity drug–drug-interaction studies should preferably include not only pharmacokinetic but also pharmacodynamic assessment of interaction, as exemplified in some of these papers.

Taken together the specific aspects of functional disorders of the urogenital system create a number of scientific challenges and opportunities for clinical pharmacology. Moreover, it should be considered that in the past, treatment of these conditions was limited to physical and behavioural therapy and surgery. While the former was often insufficiently effective, the latter was not accepted by many patients because of its degree of invasiveness. The progress in drug development for the treatment of functional urological conditions has generated a third option, medical therapy, and this is becoming increasingly popular. For example, surgery was the preferred treatment option for LUTS/BPH until 20 years ago, but today the vast majority of patients primarily receive medical treatment, mostly α1-adrenoceptor antagonists [17]. One of them, tamsulosin, has recently become available as an over-the-counter medication in the UK. The down-side of this development is that many physicians practicing today, particularly specialists such as urologists and gynaecologists, have been trained at a time when most of these medications were not yet available and their disciplines viewed themselves as primarily surgical. Therefore, continuing medical education about the safe use of urogenital drugs remains a task for clinical pharmacology.

Competing Interests

Within the last 5 years the author has received research funds, consultancy and/or lecturer honoraria related to urogenital pharmacology from the following pharmaceutical companies: Allergan, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly, GSK, Pfizer, Schwarz and Theravance.

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