For many years oxybutynin formed the cornerstone of the treatment for overactive bladder (OAB). Currently, trospium chloride, tolterodine, solifenacin, and darifenacin have made it to the market. Despite many studies the clinician might wonder where the differences among these products lie. One aspect, namely, the antimuscarinic side-effects on cognitive function, has been neglected by urologists.

A close relationship exists between central cholinergic activity and information processing in the brain. Studies on vigilance, memory, problem solving, stimulus processing, and response processing have shown the importance of the cholinergic system [1]. Acetylcholinesterase inhibitors are being prescribed in the treatment of dementia and cognitive impairment in an attempt to improve the cholinergic transmission.

2. Mechanisms

In the elderly, imbalances in neurotransmitters, caused by drugs, may lead to delirium, confusion, and cognitive deterioration. This can be caused by the drugs themselves, by interaction with other drugs, or by alterations in the pharmacokinetics and pharmacodynamics in the older patient [2]. Both oxybutynin and tolterodine have been associated with cognitive dysfunction and decreased sleep quality. Trospium chloride and darifenacin do not seem to have a significant impact on cognition and trospium chloride does not affect sleep. There are no clear data on solifenacin yet. Cytochrome P450 is an important player in the elimination of oxybutynin, darifenacin, solifenacin, and tolterodine. This cytochrome can decrease with age. Together with a decreased hepatic blood flow this can cause changes in the elimination or activation of these drugs. Only trospium chloride is not metabolised through this cytochrome [3].

Several other mechanisms are being proposed as well. One hypothesis focuses on the permeability of the blood–brain barrier for these drugs. This permeability might increase in older people and those with certain comorbidities. The penetration of the blood–brain barrier can be predicted by the lipophilicity, polarity, molecular size, and structure of the drug molecule. Oxybutynin has the highest permeability, trospium chloride the lowest with tolterodine in between. There are virtually no data on the other products [4].

Receptor selectivity might be another issue. For central procession the M1 receptor seems to be the most important muscarinic receptor, although others like the M2 receptor might be involved as well. The more an anticholinergic agent shows M3 selectivity, the less the impact on cognitive functions should be.

3. Clinical relevance

A recent study in elderly people showed that those taking anticholinergic drugs had significant deficits in cognitive function and were likely to be classified as mildly cognitively impaired, although not at increased risk for dementia. The authors concluded that before prescribing acetylcholinesterase inhibitors, all other drugs with anticholinergic properties should be stopped [5].

Another study in patients with Alzheimer disease showed that those taking incontinence medications with anticholinergic properties had a worse mental status and behavioural problems than those not taking these drugs [6].

Anticholinergic withdrawal may improve central side-effects after a few weeks. In a study on memory in schizophrenic patients, regional cerebral blood flow and extrapyramidal side-effects improved considerably after the anticholinergics were stopped [7]. The speed of recovery after stopping has had little attention. It may take at least a month before any significant improvement is noted [8], [9].

4. Conclusion

Where do we go from here? The study of Kay et al. shows that even normal elderly people suffer from mild cognitive deterioration when they take nonselective anticholinergics such as oxybutynin [10]. We know from the literature that people with a certain cognitive dysfunction may have a sudden or slower deterioration after starting on anticholinergics. Sudden changes such as hallucinations, delirium, or dementia will be noted quite soon. If these changes, however, occur more slowly, it is uncertain whether they would be attributed to the anticholinergic medication. This may lead to an incorrect diagnosis of dementia.

Many pathologies are known to carry the risk of cognitive dysfunction: Parkinson disease, cerebrovascular pathology, multiple sclerosis, and schizophrenia, among many others. In nearly all these diseases OAB symptoms are common and thus there is a need for anticholinergic medication.

The general adage is that we should adapt the anticholinergic medication to the individual needs of the patient. However, data on cognitive function are not available for all current anticholinergics and pharmaceutical companies should be urged to provide studies on this subject. The external validity of the placebo-controlled data, which were collected in highly selective groups of patients might be low, when translated to the real world of the elderly with mild cognitive impairment or with a neurologic disease.

The impact of the anticholinergic burden on rehabilitation in neurologic disease has not been studied yet. One could suppose that these drugs would interfere with the learning processes during rehabilitation.

On the other side, reimbursement strategies by the health insurances or authorities will not always consider the available data. In many countries the older and cheaper oxybutynin will still be the treatment of choice, according to their financial criteria. The urologic community has the task to inform the health authorities about the differential effects of antimuscarinic agents in these vulnerable patients.