Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly

Scheife, Richard T.; Takeda, Masayuki

doi:10.1016/j.clinthera.2005.02.014

Cited by 142 publications

(100 citation statements)

References 49 publications

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“…The observed difference among antimuscarinic agents in the potency of brain muscarinic receptor occupancy may be defined by BBB permeability, which is responsible for CNS effects in patients. The passive penetration of antimuscarinic agents through this physiologic barrier generally depends on physicochemical factors such as high lipophilicity, low degree of ionization (neutral charge), and small molecular size (Scheife and Takeda, 2005). The characteristics of chemical properties of oxybutynin relative to tolterodine, lipophilicity (Log K o/w , 4.68 versus 1.83) (Abrams, 2001;Watanabe, 2007) and neutral polarity (pK a , 6.44 versus 9.87) (Yokoyama et al, 1996;Abrams, 2001), make it the most likely to cross the BBB (Kay and Granville, 2005).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

J Pharmacol Exp Ther

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We evaluated the effects of five clinically used antimuscarinic agents for overactive bladder (OAB) treatment on in vivo muscarinic receptor binding in rat brain by quantitative autoradiography. There was a dose-related decrease in in vivo specific (ϩ)N-[11 C]methyl-3-piperidyl benzilate ([ 11 C](ϩ)3-MPB) binding in each brain region of rats 10 min after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine. Rank order of the i.v. dose for 50% receptor occupancy (RO 50 ) of antimuscarinic agents in rat brain regions was propiverine Ͼ solifenacin Ͼ tolterodine, oxybutynin. There was a good linear relationship between in vivo (pRO 50 values in the rat hippocampus) and in vitro (pK i values in human M 1 receptors) receptor binding activities of propiverine, solifenacin, and tolterodine. The observed RO 50 value of oxybutynin was approximately five times smaller than the predicted in vitro K i value. The dose ratios of antimuscarinic agents for the brain receptor occupancy (RO 50 ) to the inhibition of carbachol-and volume-induced increases in intravesical pressure (ID 50 ), which reflects in vivo selectivity for the urinary bladder over the brain, were greater for solifenacin, tolterodine, and propiverine than oxybutynin. Darifenacin displayed only a slight decrease in specific [11 C](ϩ)3-MPB binding in the rat brain regions, and it was not dose-related. In conclusion, in vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy may provide fundamental basis for managing central nervous system (CNS) side effects in antimuscarinic therapy for OAB. It is suggested that in the treatment of OAB, CNS side effects can be avoided by antimuscarinic agents with high selectivity for the urinary bladder over the brain.

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Section: Discussionmentioning

confidence: 99%

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

J Pharmacol Exp Ther

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“…Antihistaminics, antipsychotics, tricyclic antidepressants, digoxin, frusemide, isosorbide dinitrate, warfarin, dipyridamole, codeine, and captopril are among the mostly used d u r s t h a t h a v e p r i m a r y o r s e c o n d a r y anticholinergic effects contributing to risk of delirium (Burns, 2004,). Many commonly used drugs in the elderly, that are the principal treatments of clinical conditions, such as urinary incontinence and cardiovascular disease, have anticholinergic properties (Scheife & Takeda, 2005;Uusvaara et al, 2011). Older patients and those with mental illness are particularly vulnerable to the adverse neuropsychiatric effects of anticholinergics as they may already have cognitive impairment (Gerretsen & Pollock, 2011).…”

Section: Anticholinergic Drugsmentioning

confidence: 99%

A Review of the Etiology Delirium

Kocabaşoğlu¹,

Karaçetin²,

Bayar³

et al. 2012

Epidemiology Insights

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“…The observed difference among antimuscarinic agents in the potency of brain muscarinic receptor occupancy may be defined by BBB permeability, which is responsible for CNS effects in patients. The passive penetration of drugs through this physiologic barrier generally depends on physicochemical factors such as high lipophilicity, low degree of ionization (neutral charge), and small molecular size (64). The characteristics of chemical properties of oxybutynin relative to tolterodine -lipophilicity (Log K o/w : 4.68 vs. 1.83) (67,68) and neutral polarity (pKa: 6.44 vs. 9.87) (68, 69)-make it the most likely to cross the BBB (70).…”

Section: Muscarinic Receptor Selectivity In the Bladder Over The Brainmentioning

confidence: 99%

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Bladder Selectivity Based on In Vivo Drug–Receptor Binding Characteristics of Antimuscarinic Agents for Treatment of Overactive Bladder

et al. 2010

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Abstract.We have reviewed the binding of antimuscarinic agents, used to treat urinary dysfunction in patients with overactive bladder, to muscarinic receptors in target and non-target tissues in vivo. Transdermal administration of oxybutynin in rats led to significant binding in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin showed significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M 3 subtype. Oral tolterodine bound more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding activity of oral darifenacin in mice was shown to be pronounced and long-lasting in the bladder, submaxillary gland, and lung. In vivo quantitative autoradiography using (+) N -[11 C] methyl-3-piperidyl benzilate in rats showed significant occupancy of brain muscarinic receptors on intravenous injection of oxybutynin, propiverine, solifenacin, and tolterodine. The estimated in vivo bladder selectivity compared to brain was significantly greater for solifenacin and tolterodine than oxybutynin. Darifenacin occupied few brain muscarinic receptors. Similar findings were also observed with positron emission tomography in conscious rhesus monkeys. The newer generation of antimuscarinic agents may be advantageous in the bladder selectivity after systemic administration.

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Central nervous system safety of anticholinergic drugs for the treatment of overactive bladder in the elderly

Cited by 142 publications

References 49 publications

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

A Review of the Etiology Delirium

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Bladder Selectivity Based on In Vivo Drug–Receptor Binding Characteristics of Antimuscarinic Agents for Treatment of Overactive Bladder

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