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Antimuscarinic Drugs and Memory Loss in Patients With Overactive Bladder: An Expert Interview With Dr. Gary Kay


Editor's note:
Overactive bladder (OAB) is a debilitating and chronic syndrome that can negatively affect health-related quality of life. Approximately 33 million adults in the United States are affected, representing an overall prevalence of about 16%.[1] In addition, at least 20% of the population 70 years or older report symptoms of OAB, and the prevalence may be as high as 30% among those 75 years or older.[2]

Anticholinergic agents prevent involuntary contractions of the bladder detrusor muscle by blocking acetylcholine from binding to the M2 and M3 muscarinic receptor subtype and are highly effective in treating OAB. While anticholinergic agents have served as first-line treatment of OAB for decades, a concern exists with regard to the memory function effects of some of these agents. In this interview, Dr. Gary Kay of Georgetown University School of Medicine discusses the findings of his clinical trial presented at the American Urological Association annual meeting. The goal of the study was to compare the memory loss effects of darifenacin and oxybutynin in older, healthy patients. The findings suggest that oxybutynin ER significantly impairs memory.

Medscape: Please describe the rationale and design of your study comparing darifenacin and oxybutynin ER.

Dr. Kay: Our intention was to evaluate 2 overactive bladder medications and compare them with respect to their ability to affect brain function. We know these drugs are effective for overcoming OAB, but because of their anticholinergic properties, and depending on whether they cross the blood brain barrier, they could have an adverse effect on brain function -- especially memory function. Other types of cognitive function, such as attention and reasoning ability, do not appear to be affected -- they really only affect the ability to retain short-term information.

We designed a trial to evaluate important parameters of everyday memory function in older adults comparing oxybutynin ER and darifenacin.[3,4] Patients were aged 60 to 83 years of age, with a mean age of 67 years. We enrolled 150 healthy individuals, who were randomized to 1 of 2 treatment groups or placebo and underwent treatment for 3 weeks. We followed standard dosing and prescribing information. People in the oxybutynin ER group were started on 10 mg per day for the first week, 15 mg per day for the second week, and 20 mg per day for the third week. Those receiving darifenacin started at 7.5 mg, remained on 7.5 mg for the second week, and then took 15 mg for the third week. Patients were evaluated after each dose increase. We evaluated several aspects of recent memory such as ability to learn names and associate them with faces.

Medscape: Please describe the results of your study.

Dr. Kay: The primary endpoint was to evaluate change in short-term memory relative to baseline. We showed that darifenacin was no different from placebo in terms of patients' performance on memory testing. The affect on memory with oxybutynin ER was comparable to about 10 years of cognitive aging -- in other words, we transformed these people from functioning like 67 year olds to 77 year olds; however, patients were typically unaware of this change in their memory function.

Darifenacin is not highly lipophilic, and it is a fairly large molecule. It is also a substrate for P-glycoprotein. These are all characteristics that indicate that darifenacin will be unable to cross the blood-brain barrier.

By contrast, oxybutynin ER is lipophilic, and it is a small molecule that is likely to pass through the blood-brain barrier. It is neutral in charge. At the 15-mg and 20-mg doses, the memory performance among patients was significantly different from that observed with placebo and darifenacin. On one of the secondary memory measures, the First Name-Last Name Association test, oxybutynin ER had a negative effect even at the 10-mg dose.

It should be noted that the patients in our study were not characteristic of many patients that doctors might see in clinical practice. They were healthy and were not taking any other antimuscarinic drugs or drugs that would affect the central nervous system, so in clinical practice, the additive effects of other drugs need to be taken into account.

Medscape: Were other side effects similar between these 2 drugs?

Dr. Kay: The side effects of these drugs were comparable to those listed in their respective package inserts.

Medscape: What other drugs in this class would be expected to affect memory?

Dr. Kay: There have not been any published memory studies with the other drugs in this class. With tolteradine -- certainly in terms of physiological and sleep studies -- it appears that tolterodine is not likely to affect brain function,[5,6] but there are no published memory studies.

Trospium chloride, which is a quaternary amine, is a large polar molecule that is unlikely to get into the brain. There have been studies on attention, but nothing has been published on the effects of trospium on memory. For solifenacin, there are no studies reporting on the effect of this medication on the brain. However, solifenacin has a similar structure to oxybutynin ER. Therefore, I would expect that solifenacin may have some of the same effects as oxybutynin ER on memory, but this has yet to be studied.

Medscape: How will these findings affect clinical practice?

Dr. Kay: I think the drugs look very comparable in terms of efficacy -- they all work. But I think we now need to differentiate these drugs in terms of their safety. On the basis of these results, we can now say very confidently that darifenacin will not impair memory function.

Tolterodine is the most widely used overactive bladder drug, followed by oxybutynin, but I think oxybutynin, which is available as a generic, would be my last choice for treating overactive bladder. I think it is unfortunate that many of the managed-care plans force older patients to initially try generic oxybutynin because it is inexpensive, especially now that our data clearly show that oxybutynin ER has a significant deleterious effect on memory. This effect would become even more pronounced in the common clinical scenario of multiple antimuscarinic drugs. People who work in geriatric medicine now talk about anticholinergic "load" or "burden." We really have to try to minimize the extent to which our patients experience central nervous system effects and preferentially prescribe those drugs that we know are unlikely to cross the blood-brain barrier.

Medscape: Would the memory-loss effect be as much of a concern in younger compared with older patients?

Dr. Kay: Older people are particularly vulnerable to the effects of antimuscarinic agents; the blood-brain barrier becomes more permeable with age, disease, and with the use of certain drugs. These factors are less relevant in younger patients, and studies have shown that older individuals have a more pronounced memory loss in response to antimuscarinic drugs than do younger people.

Medscape: When did the patients in your study recover from the memory-loss effect?

Dr. Kay: We did not study that. We do not know exactly how many days or weeks it took for the participants to resume their baseline function, but this is definitely an issue that needs further evaluation.

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