Emerging Drugs for Treatment of Overactive Bladder and Detrusor Overactivity

Overactive bladder is a key battleground for the pharmaceutical industry and an area of considerable significance to health delivery systems. Given the substantial effects on quality of life, patients are understandably keen for therapeutic strategies which are effective without the significant side effects of anticholinergic drugs. Finally, clinicians have to deal with refractory urinary urgency, which constitutes a significant burden. Published evidence appears to set a confident and positive outlook; a range of effective anticholinergic drugs is available, whilst botulinum toxin is perceived to mop up those who remain bothered despite conservative and medical management. The reality is, however, that many patients do not do well with standard management. Furthermore, a degree of suspicion has to be maintained that those patients who apparently responded to anticholinergic drugs and were discharged from follow-up may not actually have done so well in the longer term. Their failure to return to the Outpatient Clinic may reflect a loss of confidence in the ability of doctors to manage the problem, or an adjustment of their expectations. Ongoing research to identify new areas that could yield management options in the future is therefore valuable.

As set out in the article, there are some targets which could provide opportunities for future intervention, but not as extensive as might have been hoped. The front-runner for the next generation of drugs is the beta-agonists. Clinical trials are now getting fairly well advanced. Nonetheless, the key trials have yet to be completed and clinicians must wait with bated breath to find out whether they will provide a new option for the future. Beyond that the field is less certain. Manipulation of second messenger systems is interesting but there is still no uroselectivity using this approach; cellular second messenger systems are generic, and bladder selectivity remains a somewhat disingenuous concept (beyond direct instillation into the bladder lumen).

Targeting the periphery in managing overactive bladder has proved effective; the success of anticholinergic drugs and the now withdrawn calcium antagonist, Terodiline, is testament to this. However, the crucial contribution of neurogenic changes within the central nervous system in a significant proportion of overactive bladder cases has to be considered. Centrally-acting drugs (CNS modulators) could be hoped for, but realistically, central reflexes are complex and alterations in OAB are likely to be extremely varied. The potential for a drug to achieve demonstrable success in a viable proportion of cases in such a multifactorial situation appears to be rather unrealistic. Accordingly, the group for which expectations were highest, the neurokinin modulators, continue to struggle and have yet to make any substantive mark.

Afferent modulation is an important theoretical concept and the future may bring us oral agents to target transient receptor potential sites. Intravesical instillation of the vanilloid agents Capsaicin and Resiniferatoxin was shown to be beneficial in a proportion of neuopathic patients. However, such an approach is some way off and may never come to fruition.

The interested reader will clearly see that future developments are not extensive and that intensive research will be essential.

Written by Marcus Drake, MD, as part of Beyond the Abstract on UroToday.com.

Source: UroToday