Portal de Periódicos da CAPES

Advances in Medical Management of Overactive Bladder

2003; Elsevier BV; Volume: 78; Issue: 6 Linguagem: Inglês

10.4065/78.6.681

1942-5546

Elliott Richelson, Daniel S. Elliott,

Circadian rhythm and melatonin

Clinicians are increasingly forced to deal with 2 great, and frequently opposing, forces in modern medicine. First, cure the sick. Second, do it as inexpensively as possible. In the United States alone, an estimated 17 million individuals suffer from the effects of overactive bladder.1Abrams P Kelleher CJ Kerr LA Rogers RG Overactive bladder significantly affects quality of life.Am J Manag Care. 2000; 6: S580-S590PubMed Google Scholar Additionally, the cost of caring for the effects of urinary incontinence is no insignificant amount; in 1995, it was estimated at $25 billion per year.2Wagner TH Hu TW Economic costs of urinary incontinence in 1995.Urology. 1998; 51: 355-361Abstract Full Text PDF PubMed Scopus (309) Google Scholar Also, as the US population ages, the number of patients suffering from overactive bladder and the sum of medical dollars consumed will, without question, increase. Therefore, it is imperative for all practicing clinicians not only to be aware of the latest treatment options available but also to be cognizant of the most cost-effective options. This editorial comments on 2 articles in the current issue of the Mayo Clinic Proceedings covering different approaches to the pharmacological treatment of overactive bladder. The article by Diokno et al3Diokno A Appell RA Sand P OPERA Study Group et al.Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial.Mayo Clin Proc. 2003; 78: 687-695Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar is a prospective, randomized, double-blind study of the oral extended-release forms of 2 different muscarinic receptor antagonists, oxybutynin and tolterodine. It assessed clinical outcomes in patients with overactive bladder. The article by Appell et al4Appell RA Chancellor MB Zobrist RH Thomas H Sanders SW Phamacokinetics, metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects.Mayo Clin Proc. 2003; 78: 696-702Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar is a pharmacokinetic comparison in normal volunteers of 2 different methods of oxybutynin delivery, oral extended-release form vs transdermal patch preparation. Muscarinic receptors are 1 of the 2 classes of receptors for the neurotransmitter acetylcholine.5Richelson E Cholinergic transduction.in: Bloom FE Kupfer DJ Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, NY1995: 125-134Google Scholar The second class is the nicotinic acetylcholine receptor. Muscarinic receptors were defined more than 100 years ago by the agonist muscarine, the toxic ingredient in the poisonous mushroom Amanita muscaria. Nicotinic receptors were defined by nicotine derived from the tobacco plant. Muscarinic receptors are present throughout the body and exist in 5 different subtypes (m1-m5), based on molecular cloning studies. These subtypes vary in their distribution throughout various organs in the body. In the bladder, m2 and m3 subtypes exist, with most receptors being of the m2 subtype.6Chapple CR Yamanishi T Chess-Williams R Muscarinic receptor subtypes and management of the overactive bladder.Urology. 2002; 60: 82-88Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar However, it is the less abundant m3 subtype that is thought to play an important role in overactive bladder because this subtype appears to mediate direct contraction of the detrusor muscles.7Chess-Williams R Chapple CR Yamanishi T Yasuda K Sellers DJ The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro.J Auton Pharmacol. 2001; 21: 243-248Crossref PubMed Scopus (150) Google Scholar The m2 and m3 muscarinic receptors are also present in the brain and in smooth muscle, whereas the heart and exocrine glands (eg, salivary glands) contain m2 and m3 receptors, respectively.5Richelson E Cholinergic transduction.in: Bloom FE Kupfer DJ Psychopharmacology: The Fourth Generation of Progress. Raven Press, New York, NY1995: 125-134Google Scholar Ideally, with any drug it is desirable to have it work selectively on the target of interest (eg, the m3 muscarinic receptor) because this could, in theory, minimize adverse effects. However, because of the extremely high sequence homology of the 5 identified muscarinic receptors, it has been difficult for medicinal chemists to develop selective compounds at these receptors. Neither oxybutynin nor tolterodine has much selectivity for the various subtypes of the muscarinic receptor, and each has about the same affinity for the m3 subtype.8Watson N Daniels DV Ford AP Eglen RM Hegde SS Comparative pharmacology of recombinant human M3 and M5 muscarinic receptors expressed in CHO-K1 cells.Br J Pharmacol. 1999; 127: 590-596Crossref PubMed Scopus (52) Google Scholar However, with the 2 muscarinic receptor subtypes in the bladder, because of their widespread distribution throughout the body, even if a highly selective m3 antagonist were available, the drug would affect other organ systems, such as the salivary glands. Blockade of muscarinic receptors in these glands would decrease the flow of saliva. This would be reported by the patient as dry mouth. Diokno et al reported dry mouth and other adverse events in their study. Although most likely clinically irrelevant, the frequency of dry mouth with tolterodine (22.3%) compared with oxybutynin (29.7%) was statistically significantly different. Oral extended-release forms of drugs are particularly useful for compounds with short elimination half-lives. These forms provide slower rates of absorption of the drug in the gastrointestinal tract. As a result, concentrations of drug in the blood are detectable for longer durations because the drug is absorbed over a longer period than is the immediate-release formulation. Therefore, with a drug that has a short elimination half-life, the extended-release form allows less frequent dosing than its immediate-release form. Additionally, with the slow-release form, peak concentrations in the blood are less than those with an equivalent dose of an immediate-release formulation. This may lead to reduced adverse effects. Of note, once the extended-release form of a drug is absorbed, it is chemically no different from the immediate-release form; thus, the elimination half-life is unaffected on discontinuation of the medication. The transdermal preparation of a drug has some interesting pharmacokinetic properties different from those of an oral drug form, whether the oral form is an immediate-or slow-release formulation. At present, 11 different preparations of 10 different drugs are marketed in the United States as a transdermal preparation. Examples of drugs available for transdermal delivery are estrogen, nicotine, nitroglycerin, and scopolamine. The major pharmacokinetic difference between a transdermal preparation and an oral preparation of a drug is that with the former, the drug bypasses metabolism by the liver while the drug is absorbed in the gastrointestinal tract. This metabolism is often referred to as first-pass metabolism. Consequently, blood levels of the parent compound relative to its metabolites can be very different for transdermal compared with those for oral preparations of a drug. This important pharmacokinetic difference between transdermal and oral preparations is illustrated in the study by Appell et al, in which transdermal oxybutynin (3.9 mg/d) was compared to its extended-release formulation (10 mg/d). Thus, for subjects receiving the oral form of oxybutynin, the concentration in the blood of the active metabolite (N-desethyloxybutynin) was about 4-fold higher than that of the parent compound (oxybutynin), while in the subjects who received the transdermal preparation, the blood concentrations of the active metabolite averaged only about 20% more than those of the parent compound. Additionally, blood levels of oxybutynin were higher with the transdermal patch than with the oral preparation. However, overall, the blood levels of the oxybutynin plus its active metabolite, which has about equal affinity for muscarinic receptors as does its parent compound, were lower in the transdermal patch group than in the oral preparation group. As measured by the total area under the curve, this was about 600 ng · h−1 · mL−1 for the group receiving the transdermal patch and about 1100 ng · h−1 · mL−1 for the group receiving the oral extended-release form. Rather than elicit a subjective report about dry mouth from the study participants, Appell et al measured weight of saliva. By this measure, salivary flow was about 30% greater in subjects receiving the transdermal preparation compared with those receiving the oral extended-release formulation (about 8 g/min and about 6 g/min for transdermal vs oral preparations, respectively). The authors attribute this difference to lower levels of the metabolite in those receiving the transdermal medication. However, since the affinities of both oxybutynin and its metabolite for m3 receptors are about the same,9Smith ER Wright SE Aberg G Fang Y McCullough JR Comparison of the antimuscarinic and antispasmodic actions of racemic oxybutynin and desethyloxybutynin and their enantiomers with those of racemic terodiline.Arzneimittelforschung. 1998; 48: 1012-1018PubMed Google Scholar it may be possible that this difference in salivary flow is the result of an approximately 40% reduction in total antimuscarinic activity in the blood of the transdermal group compared with that in the oral extended-release group, as determined by the area under the curve data of the parent compound plus its metabolite. The conclusions derived from the OPERA (Overactive bladder: Performance of Extended Release Agents) study by Diokno et al and the study by Appell et al have an obvious and important effect not only for patients but also for treating clinicians. Clearly, anticholinergic therapy has been, and remains, the cornerstone for the treatment of overactive bladder. Most recently, 2 new oral agents were introduced in the US market: long-acting tolterodine and a long-acting form of oxybutynin. Before the current study by Diokno et al, no study performed a direct head-to-head comparison of the 2 most commonly prescribed oral medications for this disorder. Diokno et al showed that both medications exhibited comparable frequency and severity of adverse effects. The 1 notable exception to this was that oxybutynin exhibited a 7.4% increased incidence of dry mouth compared with tolterodine. However, the severity of the dry mouth was relatively mild. The most salient conclusion to be drawn from the OPERA study is that oxybutynin was more effective at reducing all the symptoms of overactive bladder compared with tolterodine. Although statistical significance was not shown with all symptoms, a trend toward superior symptom relief was demonstrated. The most recent and exciting advance in overactive bladder therapy is the introduction of the transdermal oxybutynin patch. Because of the ease of application and the duration of use of a single patch, the patch will require less frequent dosing than oral medication and subsequently should increase patient compliance. If one considers this increased compliance and the fact that the transdermal patch theoretically provides patients with improved results by providing more stable serum levels of active agents, the result should be an increased degree of reduction of symptoms compared with oral anticholinergics. As more clinical investigation into its effectiveness, long-term compliance, and adverse effects is completed, it would appear that the transdermal patch will benefit millions of patients. Full endorsement of the transdermal patch should be reserved until studies are completed. However, this latest step in the treatment of overactive bladder may show that transdermal oxybutynin is a medically effective, cost-effective, and safe treatment alternative to oral oxybutynin. As the US population ages, the problem of managing over-active bladder is clearly increasing. More physicians are seeing that a larger portion of their patient population is having this condition. Even though an overactive bladder is not life-threatening, it decreases the quality of life for many patients. Therefore, our responsibility is to prescribe the most effective medication, with the least adverse-effects profile, and the medication that can achieve this goal in the most cost-effective manner. On the basis of the results of the work by Appell et al, it is possible that in the future the introduction of an effective transdermal patch may greatly change the way overactive bladder is treated. However, before the completion of future trials comparing the clinical benefit of oral vs transdermal oxybutynin, oral medications will remain the gold standard.