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British Journal of Clinical Pharmacology Jul 2023The aim of this study is to estimate the association between anticholinergic burden, general cognitive ability and various measures of brain structural MRI in relatively...
AIMS
The aim of this study is to estimate the association between anticholinergic burden, general cognitive ability and various measures of brain structural MRI in relatively healthy middle-aged and older individuals.
METHODS
In the UK Biobank participants with linked health-care records (n = 163,043, aged 40-71 at baseline), of whom about 17 000 had MRI data available, we calculated the total anticholinergic drug burden according to 15 different anticholinergic scales and due to different classes of drugs. We then used linear regression to explore the associations between anticholinergic burden and various measures of cognition and structural MRI, including general cognitive ability, 9 separate cognitive domains, brain atrophy, volumes of 68 cortical and 14 subcortical areas and fractional anisotropy and median diffusivity of 25 white-matter tracts.
RESULTS
Anticholinergic burden was modestly associated with poorer cognition across most anticholinergic scales and cognitive tests (7/9 FDR-adjusted significant associations, standardised betas (β) range: -0.039, -0.003). When using the anticholinergic scale exhibiting the strongest association with cognitive functions, anticholinergic burden due to only some classes of drugs exhibited negative associations with cognitive function, with β-lactam antibiotics (β = -0.035, P < 0.001) and opioids (β = -0.026, P < 0.001) exhibiting the strongest effects. Anticholinergic burden was not associated with any measure of brain macrostructure or microstructure (P > 0.08).
CONCLUSIONS
Anticholinergic burden is weakly associated with poorer cognition, but there is little evidence for associations with brain structure. Future studies might focus more broadly on polypharmacy or more narrowly on distinct drug classes, instead of using purported anticholinergic action to study the effects of drugs on cognitive ability.
Topics: Middle Aged; Humans; Aged; Cholinergic Antagonists; Cognition; Brain; Central Nervous System Diseases; Neurodegenerative Diseases; Atrophy; Cognitive Dysfunction
PubMed: 36813260
DOI: 10.1111/bcp.15698 -
Clinical Interventions in Aging 2020Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of... (Review)
Review
Overactive bladder syndrome (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency incontinence, in the absence of urinary tract infection or other obvious pathology. The mainstay of treatment of OAB is anticholinergic/antimuscarinic medication. These drugs block muscarinic receptors throughout the body, not only the bladder, including in the brain, which may lead to cognitive side effects. Anticholinergic load or burden is the cumulative effect of taking drugs that are capable of producing anticholinergic adverse effects. The elderly are more susceptible to these effects, especially as there is increased permeability of the blood brain barrier. The anticholinergic drugs for OAB are able to enter the central nervous system and lead to central side effects. There is increasing evidence that a high anticholinergic load is linked to the development of cognitive impairment and even dementia. Some studies have found an increased risk of mortality. In view of this, care is needed when treating OAB in the elderly. Trospium chloride is a quaternary amine anticholinergic, which has a molecular structure, which theoretically means it is less likely to cross the blood brain barrier and exert central side effects. Alternatively, mirabegron can be used, which is a beta-3 adrenoceptor agonist, which does not add to the anticholinergic load or exert central nervous system side effects. Conservative therapy can be used as an alternative to pharmacological treatment in the form of behavioral modification, fluid management and bladder retraining. Neuromodulation or the use of botox can also be alternatives, but success may be less in the older adult and will require increased hospital attendances.
Topics: Acetanilides; Aged; Behavior Therapy; Benzilates; Blood-Brain Barrier; Cholinergic Antagonists; Cognitive Dysfunction; Female; Humans; Muscarinic Antagonists; Nortropanes; Thiazoles; Urinary Bladder, Overactive
PubMed: 32921995
DOI: 10.2147/CIA.S252852 -
GeroScience Jun 2022Many medications of different indications have a relevant anticholinergic activity. The anticholinergic burden of medication has been shown to have significant effects...
Many medications of different indications have a relevant anticholinergic activity. The anticholinergic burden of medication has been shown to have significant effects on the cognition and the risk for cognitive impairment and dementia particularly in older patients. So far, most of the studies used data from geriatric patients and the effect of the anticholinergic burden on brain structures is still unexplored. Our study aimed to analyze possible associations of hippocampus and cholinergic basal forebrain volumes as vulnerable brain structures for the development of dementia and the anticholinergic burden in a population-based cohort of non-demented participants spanning the adult age range from 21 to 80 years. We analyzed associations between medication-related anticholinergic burden and structural MRI volumes from participants (n = 3087, 52.2% female) of the population-based "Study of Health in Pomerania" (SHIP). Anticholinergic burden was obtained from the current medication plan using the Anticholinergic Burden Scale (ACB). All analyses were adjusted for age, sex, education, and total intracranial volume. We found statistically significant associations between the ACB and the left and right hippocampus volume but not for the basal forebrain cholinergic system. Complementary voxel-based analysis across all participants revealed FWE-corrected (p = < 0.05) clusters in the temporo-parietal regions reaching into frontal areas, showing reduced volumes with higher ACB scores. We identified an association between anticholinergic burden of medication on hippocampal volume suggesting a potential inverse effect of such medication. This association highlights the importance of a careful prescription of medication with anticholinergic activity at any adult age.
Topics: Aged; Aged, 80 and over; Cholinergic Agents; Cholinergic Antagonists; Cognitive Dysfunction; Dementia; Female; Hippocampus; Humans; Male
PubMed: 34940948
DOI: 10.1007/s11357-021-00497-w -
Journal of the American Geriatrics... Oct 2014The objective of this paper is to review articles published in 2013 examining drug-related problems in the elderly and comment on their potential impact on clinical... (Review)
Review
The objective of this paper is to review articles published in 2013 examining drug-related problems in the elderly and comment on their potential impact on clinical practice. To identify articles, we did a systematic search of the English-language literature restricted to those aged 65 + from January 2013 to December 2013 using Medline and Google Scholar and a combination of the following search terms: drug-related problems, medication-related problems, medication errors, suboptimal prescribing, inappropriate prescribing, underutilization, polypharmacy, medication monitoring, medication dispensing, medication administration, medication adherence, adverse drug events, and adverse drug withdrawal events. A manual search of major general medicine and clinical pharmacology journals was also conducted to identify additional articles. A total of 51 articles were identified of which 20 were chosen to highlight. Three were annotated and critiqued and the additional 17 articles were summarized in an appendix. One article reported the results of a randomized controlled trial that showed that a pharmacist intervention successfully reduced suboptimal prescribing in older hospital patients. Another paper from this group previously reported data from the same study showing that the intervention also reduced medication related readmissions to the hospital. An observational study compared the use of two thiazide diuretics in older outpatients. They found that chlorthalidone was more likely to cause hypokalemia than hydrochlorothiazide. Finally, in a randomized controlled trial a pharmacist intervention resulted in the reduction of anticholinergic burden but did result in an improvement in cognition. These studies highlight that medication errors and adverse drug events continue to be important issues for health care professionals caring for older adults.
Topics: Aged; Anticholinergic Syndrome; Cholinergic Antagonists; Clinical Trials as Topic; Cognition Disorders; Humans; Inappropriate Prescribing; Medication Reconciliation; Pharmacists; Professional Role; Sodium Chloride Symporter Inhibitors
PubMed: 25333528
DOI: 10.1111/jgs.13026 -
PharmacoEconomics Oct 2022Overactive bladder (OAB) is associated with considerable clinical and economic burden. Treatment of patients with OAB using anticholinergics is limited by tolerability...
BACKGROUND
Overactive bladder (OAB) is associated with considerable clinical and economic burden. Treatment of patients with OAB using anticholinergics is limited by tolerability issues and increased anticholinergic burden, which is associated with increased risk of dementia and falls/fractures. This analysis assessed the budget impact of introducing the β-adrenergic agonist vibegron for the treatment of patients with OAB from US commercial payor and Medicare perspectives.
METHODS
A budget impact model (BIM) with a 5-year time horizon was developed using a top-down, prevalence-based approach and projected market shares for 1-million-member US commercial and Medicare plans. The BIM included vibegron, mirabegron, and anticholinergics, incorporating changes in clinical outcomes (efficacy, drug-drug interactions, anticholinergic burden (ACB), OAB-related comorbidities, and adverse events (AEs)). Costs per member per month (PMPM) and per treated member per month (PTMPM) were determined. One-way sensitivity analyses quantified the impact of changes in key variables.
RESULTS
The introduction of vibegron was associated with a modest increase in PMPM cost over 5 years of $0.12 (range for years 1‒5, $0.01‒$0.26) for commercial payors and $0.24 ($0.01‒$0.52) for Medicare (PTMPM cost: $2.70 ($0.17‒$4.85) and $3.15 ($0.19‒$5.82), respectively). Costs were partially offset by savings related to decreased third-line treatment use, yearly decreases in AE and comorbidity incidence, reduced drug-drug interactions, and reduced ACB associated with vibegron introduction. PMPM costs were most sensitive to vibegron market share assumptions, OAB prevalence, and vibegron persistence at 1 month for private payors and Medicare and additionally vibegron persistence at 12 months for Medicare.
CONCLUSIONS
Vibegron may address unmet needs in treating OAB and is a useful addition to health plans while minimizing risks of anticholinergic AEs, ACB, and drug-drug interactions, which may partially offset increased pharmacy costs.
Topics: Adrenergic Agonists; Aged; Cholinergic Antagonists; Humans; Medicare; Pyrimidinones; Pyrrolidines; United States; Urinary Bladder, Overactive
PubMed: 35881325
DOI: 10.1007/s40273-022-01163-5 -
British Journal of Clinical Pharmacology Mar 2022The use of prescription drugs with anticholinergic properties has been associated with multiple negative health outcomes in older people. Moreover, recent evidence...
BACKGROUND
The use of prescription drugs with anticholinergic properties has been associated with multiple negative health outcomes in older people. Moreover, recent evidence suggests that associated adverse effects may occur even decades after stopping anticholinergic use. Despite the implicated importance of examining longitudinal patterns of anticholinergic prescribing for different age groups, few such data are available.
METHODS
We performed an age-period-cohort (APC) analysis to study trends in an aggregate measure of anticholinergic burden between the years 1990 and 2015, utilising data from >220 000 UK Biobank participants with linked prescription data from primary care.
RESULTS
Anticholinergic burden in the sample increased up to 9-fold over 25 years and was observed for both period and age effects across most classes of drugs. The greatest increase was seen in the prescribing of antidepressants. Female sex, lower education and greater deprivation were associated with greater anticholinergic burden.
CONCLUSIONS
The increase in anticholinergic prescribing is mostly due to an increase in polypharmacy and is attributable to both ageing of participants and period-related changes in prescribing practices. Research is needed to clarify the implications of rising anticholinergic use for public health and to contextualise this rise in light of other relevant prescribing practices.
Topics: Aged; Biological Specimen Banks; Cholinergic Antagonists; Cohort Studies; Female; Humans; Polypharmacy; United Kingdom
PubMed: 34409635
DOI: 10.1111/bcp.15045 -
Expert Review of Clinical Pharmacology Feb 2017Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics... (Review)
Review
Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders. Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the glucocorticoid system, and the inflammation pathway, as well as several additional targets of interest. Clinical evidence is emphasized, and non-pharmacological somatic treatments are not reviewed. In general, this paper only explores agents available in the United States. Expert commentary: Of these novel targets, the most promising - and the ones for whom the most evidence exists - appear to be the ionotropic glutamate receptors. However, moving forward will require us to fully embrace the goal of personalized medicine and will require health professionals to pre-emptively identify potential responders.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Antioxidants; Cholinergic Antagonists; Depression; Excitatory Amino Acid Agents; Humans
PubMed: 27781556
DOI: 10.1080/17512433.2017.1253472 -
Journal of Medical Economics 2022To evaluate the cost-effectiveness of vibegron compared with other oral pharmacologic therapies as treatment for overactive bladder (OAB).
AIMS
To evaluate the cost-effectiveness of vibegron compared with other oral pharmacologic therapies as treatment for overactive bladder (OAB).
METHODS
A semi-Markov model with monthly cycles was developed to support a lifetime horizon of vibegron 75 mg from a US commercial payor or Medicare perspective. The model incorporated efficacy (reductions in daily micturitions and urinary incontinence episodes), adverse events, OAB-related comorbidities, drug-drug interactions, anticholinergic burden, and treatment persistence. Direct costs and quality-adjusted life years (QALY) were accumulated over time. The primary outcome was the cost per QALY incremental cost-effectiveness ratio (ICER). One-way (OWSA) and probabilistic sensitivity analyses (PSA) were performed.
RESULTS
For commercial payors, vibegron was cost-effective at a willingness-to-pay (WTP) threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $9,311) and at a WTP threshold of $150,000/QALY versus mirabegron 25 mg (ICER, $141,957) and versus an anticholinergic basket based on market share (ICER, $118,121). For Medicare, vibegron was cost-effective at a WTP threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $12,154) and at a WTP threshold of $100,000/QALY versus mirabegron 25 mg (ICER, $99,150) and versus an anticholinergic market basket (ICER, $60,756). For commercial payors and Medicare, OWSAs for vibegron versus mirabegron indicated cost-effectiveness was most sensitive to vibegron persistence at 1 and 12 months. PSAs indicated that vibegron was cost-effective versus mirabegron 50 mg 98.6% and 100% of the time at $50,000/QALY for commercial payors and Medicare payors, respectively.
LIMITATIONS
Due to lack of real-world data available on persistence, vibegron was assumed to have the same persistence as mirabegron 50 mg. Long-term efficacy was assumed to be sustained beyond 52 weeks in the absence of clinical trials longer than 52 weeks.
CONCLUSIONS
Vibegron is cost-effective from a commercial payor (WTP threshold $150,000/QALY) and Medicare (WTP threshold $100,000/QALY) perspective when compared with other oral pharmacologic treatments for OAB.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aged; Cholinergic Antagonists; Cost-Benefit Analysis; Humans; Medicare; Muscarinic Antagonists; Pyrimidinones; Pyrrolidines; Treatment Outcome; United States; Urinary Bladder, Overactive
PubMed: 35993729
DOI: 10.1080/13696998.2022.2115754 -
Quality of anticholinergic burden scales and their impact on clinical outcomes: a systematic review.European Journal of Clinical... Feb 2021Older people are at risk of anticholinergic side effects due to changes affecting drug elimination and higher sensitivity to drug's side effects. Anticholinergic burden... (Comparative Study)
Comparative Study
PURPOSE
Older people are at risk of anticholinergic side effects due to changes affecting drug elimination and higher sensitivity to drug's side effects. Anticholinergic burden scales (ABS) were developed to quantify the anticholinergic drug burden (ADB). We aim to identify all published ABS, to compare them systematically and to evaluate their associations with clinical outcomes.
METHODS
We conducted a literature search in MEDLINE and EMBASE to identify all published ABS and a Web of Science citation (WoS) analysis to track validation studies implying clinical outcomes. Quality of the ABS was assessed using an adapted AGREE II tool. For the validation studies, we used the Newcastle-Ottawa Scale and the Cochrane tool Rob2.0. The validation studies were categorized into six evidence levels based on the propositions of the Oxford Center for Evidence-Based Medicine with respect to their quality. At least two researchers independently performed screening and quality assessments.
RESULTS
Out of 1297 records, we identified 19 ABS and 104 validations studies. Despite differences in quality, all ABS were recommended for use. The anticholinergic cognitive burden (ACB) scale and the German anticholinergic burden scale (GABS) achieved the highest percentage in quality. Most ABS are validated, yet validation studies for newer scales are lacking. Only two studies compared eight ABS simultaneously. The four most investigated clinical outcomes delirium, cognition, mortality and falls showed contradicting results.
CONCLUSION
There is need for good quality validation studies comparing multiple scales to define the best scale and to conduct a meta-analysis for the assessment of their clinical impact.
Topics: Age Factors; Aged; Aging; Cholinergic Antagonists; Cognition Disorders; Cost of Illness; Drug-Related Side Effects and Adverse Reactions; Humans; Metabolic Clearance Rate; Outcome Assessment, Health Care; Validation Studies as Topic
PubMed: 33011824
DOI: 10.1007/s00228-020-02994-x -
Clinical Pharmacokinetics May 2021Glycopyrronium tosylate (GT; Qbrexza [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged...
BACKGROUND
Glycopyrronium tosylate (GT; Qbrexza [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged ≥ 9 years.
OBJECTIVE
The objective of this study was to compare the pharmacokinetics and safety of GT to oral glycopyrrolate (phase I study) and assess the relationship between glycopyrronium pharmacokinetics and anticholinergic-related adverse events or efficacy with population pharmacokinetics using data from two phase II studies.
METHODS
In the phase I study, study staff applied GT to axillae of patients with primary axillary hyperhidrosis (aged 9-65 years) once daily (5 days); oral glycopyrrolate was administered to healthy adults (aged 18-65 years) every 8 hours (15 days). In the phase II studies (NCT02016885 [20 December, 2013], NCT02129660 [2 May, 2014]), adults with primary axillary hyperhidrosis applied topical glycopyrronium (0.8-3.2%) or vehicle to axillae once daily (4 weeks). Pharmacokinetic and adverse event data were collected in all studies.
RESULTS
Glycopyrronium pharmacokinetic parameters were similar between adult and pediatric patients treated with GT; there was no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events occurred with GT in the phase I study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic adverse events occurred in the phase II studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related adverse events increased with higher glycopyrronium concentration; no relationship was observed between efficacy and pharmacokinetic measures.
CONCLUSIONS
These studies indicate limited absorption of GT compared to oral glycopyrrolate and a low risk of anticholinergic adverse events with proper GT administration when following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact).
Topics: Adolescent; Adult; Aged; Axilla; Child; Cholinergic Antagonists; Glycopyrrolate; Humans; Hyperhidrosis; Middle Aged; Muscarinic Antagonists; Young Adult
PubMed: 33433785
DOI: 10.1007/s40262-020-00975-y