CENTRAL NERVOUS SYSTEM ADVERSE DRUG EVENTS OF ANTIMUSCARINIC MEDICATION

Česká verzia

Authors: E. Topinková
Authors place of work: Geriatrická klinika 1. LF UK a VFN v Praze
Published in the journal: Urol List 2012; 10(1): 69-74

Summary

Overactive bladder (OAB) is characterized by episodes of urgency, micturition frequency, nocturia and, in majority of patients, by urge incontinence. OAB is a chronic disease, which impairs quality of life. Its prevalence increases with advancing age and affects 11–16% of adult population and up to 20–30% of elderly persons above 70 years. The pharmacological treatments of choice are urinary spasmolytics (antimuscarinics) with antagonist effect on muscarinic (M) receptors in the bladder. As the tissue selectivity of antimuscarinics for bladder M receptors is only relative there is increasing awareness of potential adverse effects of antimuscarinics on the brain M receptors, which play significant role in cognitive and memory processes. The article reviews current knowledge on central nervous system anticholinergic adverse drug events (ADE) of antimuscarinics, providing information of pharmacochemical properties of individual drugs that determine brain penetration and their possible CNS ADE. The safe antimuscarinic seems to be trospium chloride which does not cross blood brain barrier and the central ADEs such as confusion, dizziness, memory impairment and impaired sleep architecture are clinically non significant. Metaanalyses of clinical trials confirm generally low frequency of CNS ADE. However, they stress that standard protocols of clinical trials do not consistently report occurrence of CNS ADE neither do they assess spectrum of cognitive performance. It is recommended to use standard neuropsychological battery in future clinical trials, which will enable to detect cognitive ADE of antimuscarinics during short- and long-term treatment. In clinical practice before starting treatment with antimuscarinics it is recommended to assess cognitive functions and identify patients with increased risk of CNS ADEs (patients with concomitant use of other anticholinergic drugs and patients with pre-existing structural brain pathology) for whom antimuscarinics with lowest potential of CNS ADEs are an option (trospium chloride, darifenacin, fesoterodin).

Key words:
overactive bladder, antimuscarinic drugs, adverse drug events, central anticholinergic effect, cognitive performance

Zdroje

1. Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50(6): 1306–1314.

2. Irwin DE, Abrams P, Milsom I et al. Understanding the elements of overactive bladder: questions raised by the EPIC study. BJU Int 2008; 101(11): 1381–1387.

3. Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Urology 2003; 61(1): 37–49.

4. Chapple C, Khullar V, Gabriel Z et al. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005; 48(1): 5–26.

5. Chapple CR, Khullar V, Gabriel Z. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008; 54(3): 543–562.

6. Kay GG, Abou-Donia MB, Messer WS Jr et al. Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients. J Am Geriatr Soc 2005; 53(12): 2195–2201.

7. Pagoria D, O'Connor RC, Guralnick ML. Antimuscarinic drugs: review of the cognitive impact when used to treat overactive bladder in elderly patients. Curr Urol Rep 2011; 12(5): 351–357.

8. Wagg A, Verdejo C, Molander U. Review of cognitive impairment with antimuscarinic agents in elderly patients with overactive bladder. Int J Clin Pract 2010; 64(9): 1279–1286.

9. Campbell NL, Boustani MA, Limbil T et al. The cognitive impact of anticholinergics: A clinical review. Clin Interv Aging 2009; 4: 225–233.

10. Hilmer SN, Mager DE, Simonsick EM et al. A Drug Burden Index to define the functional burden of medications in older people. Arch Intern Med 2007; 167(8): 781–787.

11. Tune LE. Anticholinergic effects of medications in elderly patients. J Clin Psych 2001; 62: 11–14.

12. Boustani MA, Campbell NL, Munger S et al. Impact of anticholinergics on the aging brain: a review and practical application. Aging Health 2008; 4: 311–320.

13. Caeiro L, Ferro JM, Claro MI et al. Delirium in acute stroke: a preliminary study of the role of anticholinergic medications. Eur J Neurol 2004; 11(10): 699–704.

14. Ancelin ML, Artero S, Porter F et al. Non-degenerative mild cognitive impairment in older people and use of anticholinergic drugs: Longitudinal cohort study. Br Med J 2006; 332(7539): 455–459.

15. Bottigi KA, Salazar JC, Yu L et al. Long-term cognitive impact of anticholinergic medications in older adults. Am J Geriatr Psychiatry 2006; 14(11): 980–984.

16. Han L, McCusker J, Col M et al. Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med 2006; 161(8): 1099–1105.

17. Chew ML, Musant BH, Pollock BG. Serum anticholinergic activity and cognition in patients with moderate-to-severe dementia. Am J Geriatr Psychiatry 2005; 13(6): 5354–5358.

18. Oefelein MG. Safety and tolerability profiles of anticholinergic agents used for the treatment of overactive bladder. Drug Saf 2011; 34(9): 733–754.

19. Callegari E, Malhotra B, Bungay PJ et al. A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder. Br J Clin Pharmacol 2011; 72(2): 235–246.

20. Chancellor M, Boone T. Anticholinergics for overactive bladder therapy: central nervous system effects. CNS Neurosci Ther 2012; 18(2): 167–174.

21. Chancellor MB, Staskin DR, Kay GG et al. Blood-Brain Barrier Permeation and Efflux Exclusion of Anticholinergics Used in the Treatment of Overactive Bladder. Drugs Aging 2012 [Epub ahead of print].

22. Glavind K, Chancellor M. Antimuscarinics for the treatment of overactive bladder: understanding the role of muscarinic subtype selectivity. Int Urogynecol J 2011; 22(8): 907–917.

23. Kay GG, Ebinger U. Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin. Int J Clin Pract 2008; 62(11): 1792–1800.

24. Wesnes KA, Edgar C, Tretter RN et al. Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single dose of solifenacin 10 mg. Expert Opinion Drug Saf 2009; 8(6): 615–626.

25. Krhut J, Slíva J. Trospium chlorid. Farmakoterapie 2006, 2(5): 509–513.

26. Staskin DR, Harner MD. Effect of trospium chloride on somnolence and sleapiness in patients with overactive baldder. Curr Urol Rep 2004; 5(6): 423–426.

27. Staskin D, Kay G, Tannenbaum C et al. Trospium chloride has no effect on memory testing and is assay undetectable in the central nervous system of older patients with overactive bladder. Int J Clin Pract 2010; 64(9): 1294–1300.

28. Katz IR, Sands LP, Bilker W et al. Identification of medications that cause cognitive impairment in older people. The case of oxybutynin chloride. J Am Geriatr Soc 1998; 46(1): 8–13.

29. Kay G, Crook T, Rekeda L et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 2006; 50(2): 317–326.

30. Todorova A, Vonderheid-Guth B, Dimpfel W. Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous systém. J Clin Pharmacol 2001; 41(6): 636–644.

31. Paquette A, Gou P, Tannenbaum C. Systematic review and meta-analysis: Do clinical trials testing antimuscarinic agents for overactive bladder adequately measure central nervous systém adverse events? J Am Geriatr Soc 2011; 59(7): 1332–1339.

32. Minassian VA, Ross S, Sumabat O et al. Randomized trial of oxybutynin extended versus immediate release for women aged 65 and older with overactive bladder: Lessons learned from conduction a trial. J Obstet Gynaecol Can 2007; 29(9): 726–732.

33. Biastre K, Burnakis T. Trospium chloride treatment of overactive bladder. Ann Pharmacother 2009; 43(2): 283–295.

34. Diefenbach K, Donath F, Maurer A et al. Randomised, double-blind study of the effects of oxybutynin, tolterodine, trospium chloride and placebo on sleep in healthy young volunteers. Clin Drug Investig 2003; 23(6): 395–404.