Barriers and enablers to deprescribing in long-term care facilities: a 'best-fit' framework synthesis of the qualitative evidence.

INTRODUCTION: older adults are at risk of adverse outcomes due to a high prevalence of polypharmacy and potentially inappropriate medications (PIMs). Deprescribing interventions have been demonstrated to reduce polypharmacy and PIMs. However, deprescribing is not performed routinely in long-term care facilities (LTCFs). This qualitative evidence synthesis aims to identify the factors which limit and enable health care workers' (HCWs) engagement with deprescribing in LTCFs. METHODS: the 'best-fit' framework approach was used to synthesise evidence by using the Theoretical Domains Framework (TDF) as the a priori framework. Included studies were analysed qualitatively to identify LTCF barriers and enablers of deprescribing and were mapped to the TDF. Constructs within domains were refined to best represent the LTCF context. A conceptual model was created, hypothesising relationships between barriers and enablers. RESULTS: of 655 records identified, 14 met the inclusion criteria. The 'best-fit' framework included 17 barriers and 16 enablers, which mapped to 11 of the 14 TDF domains. Deprescribing barriers included perceptions of an 'established hierarchy' within LTCFs, negatively affecting communication and insufficient resources which limited HCWs' engagement with deprescribing. Enablers included tailored deprescribing guidelines, interprofessional support and working with a patient focus, allowing the patients' condition to influence decisions. DISCUSSION: this study identified that education, interprofessional support and collaboration can facilitate deprescribing. To overcome deprescribing barriers, change is required to a patient-centred model and HCWs need to be equipped with necessary resources and adequate reimbursement. The LTCF organisational structure must support deprescribing, with communication between health care systems.

Application of a physiologically-based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate.

Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically-based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration-time curve, maximum concentration in plasma and time to maximum plasma concentration, within two-fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.

Treating disorders of the neonatal central nervous system: pharmacokinetic and pharmacodynamic considerations with a focus on antiepileptics.

A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment - the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only ~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally-acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs.

Identification of Potentially Inappropriate Medications in Frail Older Adults Residing in Long-Term Care: A Retrospective Chart Review Study.

INTRODUCTION: Deprescribing is associated with positive health outcomes for older adults in long-term care (LTC), however deprescribing is not universally implemented. OBJECTIVE: The primary aim of this study was to estimate the prevalence of potentially inappropriate medications (PIMs) prescribed to frail older adults in Irish long-term care facilities (LTCFs), as identified by the Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy, version 2 (STOPPFrail v2). METHODS: A retrospective chart review was conducted in two publicly funded LTCFs in Ireland. Eligible participants were those (1) ≥ 65 years of age; (2) resident in a LTCF; (3) eligible as per the STOPPFrail v2 criteria by the site's Medical Officer; and (4) receiving regular medication. Data collected included age, sex, drug, dose, frequency, regular/pro re nata prescribing and indication/relevant diagnoses. Rates of polypharmacy (taking five or more medications) and excessive polypharmacy (taking 10 or more medications) were calculated. STOPPFrail v2 was used to identify PIMs; however, clinical measurements were not taken. Descriptive and association statistics were calculated. RESULTS: Of the 103 residents, 89 were ≥ 65 years of age and categorised as frail and were therefore eligible for inclusion in the study. Of those eligible, 85 (95.5%) had polypharmacy and 57 (64%) experienced excessive polypharmacy. The mean number of regular medications was 10.8 (± 3.8), total medications 17.7 (± 5) and diagnoses 5.5 (± 2.5). The mean number of PIMs per resident was 4.8 (± 2.6). Of the eligible participants, 59.6% had at least one medicine without a documented indication, while 61.8%, 42.7% and 30.3% had at least one PIM from the vitamin D, antihypertensives and proton pump inhibitors drug classes, respectively. CONCLUSION: Medication and PIM use was high among LTC residents, with inappropriate polypharmacy of concern. Lack of clear indication for prescribing medications appears to be an issue in LTC, potentially affecting healthcare professionals' engagement with deprescribing. The prevalence of PIMs may be overestimated in the antihypertensives/antidiabetic classes due to the lack of clinical measurements.

Multidisciplinary DEprescribing review for Frail oldER adults in long-term care (DEFERAL): Implementation strategy design using behaviour science tools and stakeholder engagement.

INTRODUCTION: Deprescribing is a strategy for reducing the use of potentially inappropriate medications for older adults. Limited evidence exists on the development of strategies to support healthcare professionals (HCPs) deprescribing for frail older adults in long-term care (LTC). OBJECTIVE: To design an implementation strategy, informed by theory, behavioural science and consensus from HCPs, which facilitates deprescribing in LTC. METHODS: This study was consisted of 3 phases. First, factors influencing deprescribing in LTC were mapped to behaviour change techniques (BCTs) using the Behaviour Change Wheel and two published BCT taxonomies. Second, a Delphi survey of purposively sampled HCPs (general practitioners, pharmacists, nurses, geriatricians and psychiatrists) was conducted to select feasible BCTs to support deprescribing. The Delphi consisted of two rounds. Using Delphi results and literature on BCTs used in effective deprescribing interventions, BCTs which could form an implementation strategy were shortlisted by the research team based on acceptability, practicability and effectiveness. Finally, a roundtable discussion was held with a purposeful, convenience sample of LTC general practitioners, pharmacists and nurses to prioritise factors influencing deprescribing and tailor the proposed strategies for LTC. RESULTS: Factors influencing deprescribing in LTC were mapped to 34 BCTs. The Delphi survey was completed by 16 participants. Participants reached consensus that 26 BCTs were feasible. Following the research team assessment, 21 BCTs were included in the roundtable. The roundtable discussion identified lack of resources as the primary barrier to address. The agreed implementation strategy incorporated 11 BCTs and consisted of an education-enhanced 3-monthly multidisciplinary team deprescribing review, led by a nurse, conducted at the LTC site. CONCLUSION: The deprescribing strategy incorporates HCPs' experiential understanding of the nuances of LTC and thus addresses systemic barriers to deprescribing in this context. The strategy designed addresses five determinants of behaviour to best support HCPs engaging with deprescribing.

Assessing community pharmacists' attitudes towards identifying opportunities for deprescribing in clinical practice in Ireland.

OBJECTIVES: The main objective of this study was to assess community pharmacists' thoughts regarding the role they can play in effectively integrating deprescribing into clinical practice in Ireland. The aim was to assess pharmacists' (1) knowledge of deprescribing, (2) confidence in deprescribing, (3) attitudes towards deprescribing and (4) barriers and facilitators to deprescribing in a community pharmacy setting. METHODS: An online questionnaire was disseminated to pharmacists currently registered with the Pharmaceutical Society of Ireland, with instruction only to complete if working in community pharmacy. Statistical analysis was conducted on the quantitative data, whereas thematic analysis was carried out on the open-ended responses. KEY FINDINGS: Results indicate good knowledge scores and positive attitudes surrounding deprescribing, with demographic factors having no significant effect on results. Although deprescribing knowledge is high, willingness to engage is hindered by obstacles such as time. Remuneration was identified as an enabler for deprescribing. Interdisciplinary educational opportunities and bidirectional communication channels with prescribers are viewed as the major facilitators of deprescribing. CONCLUSIONS: Community pharmacists demonstrate that they possess sufficient knowledge, confidence and willingness to play a greater role in facilitating deprescribing. To enable this role expansion, enablers such as education and funding need to be implemented, to overcome barriers such as insufficient time. Further studies are required to assess community pharmacists' deprescribing competence, to demonstrate their ability to fulfil this role in clinical practice in Ireland.

Barriers and enablers to deprescribing in long-term care: A qualitative investigation into the opinions of healthcare professionals in Ireland.

INTRODUCTION: The prevalence of polypharmacy increases with age, increasing the exposure of older adults to potentially inappropriate medications (PIMs). Deprescribing has been shown to reduce PIMs for older residents in long-term care; however, deprescribing is not universally implemented. This study aims to identify the barriers and enablers to deprescribing in Irish long-term care facilities from the healthcare professionals' (HCPs) perspective. METHODS: A qualitative descriptive approach was conducted using semi-structured interviews with HCPs working in long-term care (general practitioners, pharmacists and nurses). Purposive sampling with maximum variation was applied to select long-term care sites to identify HCPs, supplemented with convenience sampling of post-graduate HCPs from University College Cork. Data was thematically analysed and mapped to a framework of deprescribing barriers and enablers informed by the Theoretical Domains Framework. RESULTS: Twenty-six HCPs participated from 13 long-term care facilities. The main barriers and enablers identified mapped to five domains. Barriers included insufficient resources, lack of co-ordination between healthcare settings and negative social influences. Additional barriers exist in private settings including deprescribing awareness, commitment and the need for incentives. Deprescribing enablers included interprofessional support and patient social influence. To encourage deprescribing, potential enablers include HCP education, pharmacist role expansion and tailored deprescribing guidelines within a structured process. CONCLUSION: Interventions to support deprescribing should build on existing systems, involve stakeholders and utilise guidelines within a structured process. Any intervention must account for the nuanced barriers and enablers which exist in both public and private settings.

The Prevalence of and Documented Indications for Antipsychotic Prescribing in Irish Nursing Homes.

BACKGROUND: Antipsychotic medications are often used 'off-licence' to treat neuropsychiatric symptoms and disorders of aging and to manage behavioural and psychological symptoms of dementia despite the warnings of adverse effects. OBJECTIVE: To establish the prevalence of and documented indication for antipsychotic medication use in the Irish nursing home setting. SETTING: This study was conducted in six nursing homes located in Co. Cork, Ireland. METHOD: A retrospective, cross-sectional study was employed. All patients who met the inclusion criteria (≥65 years, residing in a nursing home on a long-term basis) were eligible for inclusion. There were 120 nursing home residents recruited to the study. MAIN OUTCOME MEASURE: The prevalence of antipsychotic medication use in nursing home residents (with and without dementia). RESULTS: The overall prevalence of antipsychotic prescribing was found to be 48% and patients with dementia were significantly more likely to be prescribed an antipsychotic compared to those without dementia (67% vs. 25%) (χ2 (1, N = 120) = 21.541, p < 0.001). In the cohort of patients with dementia, there was a trend approaching significance (p = 0.052) of decreasing antipsychotic use with increasing age (age 65-74 = 90%; age 75-84 = 71%; age 85 and over = 58%). An indication was documented for 84% of the antipsychotic prescriptions in this cohort. CONCLUSIONS: The findings of this study highlight that high rates of antipsychotic medication use remains an issue in Irish nursing homes. Further work should explore factors in influencing prescribing of these medications in such settings.

Perspectives of pharmacists on facilitating experiential learning placements for pharmacy students in non-patient facing settings.

INTRODUCTION: Recently, the model of pharmacy education in Ireland changed to a five-year pharmacy degree, with three distinct blocks of experimental placements dispersed throughout the degree. The United Kingdom is also considering the introduction of a similar five-year pharmacy degree, while the United States is looking to further expand non-clinical experiential learning opportunities. This study was carried out to ascertain the perspectives of pharmacists working in non-patient facing roles on the barriers to and facilitators of placements to aid in identifying placement recruitment strategies for non-patient facing placements. METHODS: A questionnaire was distributed to pharmacists employed in non-patient facing settings, including in pharmaceutical industry, education, and regulation. Quantitative responses were analyzed using descriptive statistics, while qualitative questions were analyzed thematically. RESULTS: Regardless of experience in the practice setting or supervision, the majority expressed a preference for offering paid placements of six months' duration. There was divided opinion regarding whether students should be given study leave, whether the student's supervisor should be a pharmacist, and whether students should undertake specialized postgraduate training. The main barriers to placements were time, the placement structure, availability of suitable projects or supervisors, and awareness of placement opportunities. Prior experience in the practice area, developing the talent pipeline, and personal interests were all placement facilitators. CONCLUSIONS: Given the increasing roles for pharmacists in non-patient facing practice settings, this study highlights the importance of stakeholder involvement during the implementation of a new model of education to ensure that placements in all settings are feasible.

Pharmacotherapy for Neonatal Seizures: Current Knowledge and Future Perspectives.

Seizures are the most common neurological emergencies in the neonatal period and are associated with poor neurodevelopmental outcomes. Seizures affect up to five per 1000 term births and population-based studies suggest that they occur even more frequently in premature infants. Seizures are a sign of an underlying cerebral pathology, the most common of which is hypoxic-ischaemic encephalopathy in term infants. Due to a growing body of evidence that seizures exacerbate cerebral injury, effective diagnosis and treatment of neonatal seizures is of paramount importance to reduce long-term adverse outcomes. Electroencephalography is essential for the diagnosis of seizures in neonates due to their subtle clinical expression, non-specific neurological presentation and a high frequency of electro-clinical uncoupling in the neonatal period. Hypoxic-ischaemic encephalopathy may require neuroprotective therapeutic hypothermia, accompanying sedation with opioids, anticonvulsant drugs or a combination of all of these. The efficacy, safety, tolerability and pharmacokinetics of seven anticonvulsant drugs (phenobarbital, phenytoin, levetiracetam, lidocaine, midazolam, topiramate and bumetanide) are reviewed. This review is focused only on studies reporting electrographically confirmed seizures and highlights the knowledge gaps that exist in optimal treatment regimens for neonatal seizures. Randomised controlled trials are needed to establish a safe and effective treatment protocol for neonatal seizures.

In vitro bidirectional permeability studies identify pharmacokinetic limitations of NKCC1 inhibitor bumetanide.

Recently, it has been suggested that bumetanide, an inhibitor of the Na-K-2Cl co-transporter (NKCC1), may be useful in the treatment of central nervous system (CNS) disorders. However, from a physicochemical perspective, bumetanide may not cross the blood-brain barrier to the extent that is necessary for it to be an effective brain NKCC1 inhibitor in vivo. High plasma-protein binding, potentially high brain-tissue binding and putative efflux transporters including organic anion transporter 3 (OAT3) contribute to the poor pharmacokinetic profile of bumetanide. Bidirectional permeability assays are an in vitro method to determine the impact of plasma-protein/brain tissue binding, as well as efflux transport, on the permeability of a compound. We established and validated a cell line stably overexpressing human OAT3 using lentiviral cloning techniques for use in in vitro bidirectional permeability assays. Using efflux transport studies, we show that bumetanide is a transported substrate of human OAT3, exhibiting a transport ratio of ≥1.5, which is attenuated by OAT3 inhibitors. Bidirectional permeability assays were carried out in the presence and absence of either albumin or brain homogenate to elucidate the effect of plasma-protein/brain tissue binding. These tests confirmed the pharmacokinetic limitations for brain delivery of bumetanide. In this experiment, bumetanide is 53% bound to albumin, 77% bound to brain tissue and accumulates in brain cells. Moreover, we conclusively established that bumetanide is a transported substrate of OAT3. Taken together, these bidirectional permeability studies highlight the potential of efflux transporter inhibition as an augmentation strategy for enhanced delivery of bumetanide to the CNS.

Pharmacokinetic, pharmacodynamic and biodistribution following oral administration of nanocarriers containing peptide and protein drugs.

The influence of nanoparticle (NP) formulations on the pharmacokinetic, pharmacodynamic and biodistribution profiles of peptide- and protein-like drugs following oral administration is critically reviewed. The possible mechanisms of absorption enhancement and the effects of the physicochemical properties of the NP are examined. The potential advantages and challenges of physiologically-based pharmacokinetic (PBPK) modelling to help predict efficacy in man are discussed. The importance of developing and expanding the regulatory framework to help translate the technology into the clinic and accelerate the availability of oral nanoparticulate formulations is emphasized. In conclusion, opportunities for future work to improve the state of the art of oral nanomedicines are identified.

The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat.

OBJECTIVES: Recent data highlight the potential of bumetanide as a treatment for neonatal seizures and autism, as it facilitates the excitatory to inhibitory switch in gamma-aminobutyric acid signalling. This study examines the extent of blood-brain barrier (BBB) permeation of bumetanide, a key determinant of the efficacy of centrally acting drugs. Furthermore, the impact of efflux transporter organic anion transporter 3 (oat3) inhibition on bumetanide pharmacokinetics was investigated. METHODS: Bumetanide levels in extracellular fluid (ECF) and plasma in the presence and absence of oat3 inhibitor probenecid were monitored using integrated microdialysis. KEY FINDINGS: Following a bumetanide bolus/continuous infusion of 10 mg/kg and 6 mg/kg/h, bumetanide was detected in hippocampal ECF at the estimated concentration of 131 ± 55 ng/ml. Plasma bumetanide levels were ∼20 mg/l at steady state. Coadministration of probenecid resulted in an increase in bumetanide levels in both ECF and plasma, indicating that oat3 inhibition influences the pharmacokinetics of bumetanide primarily in the periphery. CONCLUSION: Although bumetanide reached detectable levels in hippocampal ECF, bumetanide concentration in ECF was low relative to systemic concentration. Oat3 inhibition by probenecid resulted in increased bumetanide concentrations in brain and plasma. As an acute treatment in neonatal seizures, the bumetanide/probenecid combination may hold therapeutic potential.

The P-glycoprotein inhibitor cyclosporin A differentially influences behavioural and neurochemical responses to the antidepressant escitalopram.

Recent studies have raised the possibility that P-glycoprotein (P-gp) inhibition may represent a putative augmentation strategy for treatment with certain antidepressants. Indeed, we have previously shown that administration of the P-gp inhibitor verapamil increased the brain distribution and behavioural effects of the antidepressant escitalopram. The aim of the current study was to investigate if similar effects occur with another P-gp inhibitor, cyclosporin A (CsA). CsA pre-treatment exacerbated the severity of behaviours in an escitalopram-induced mouse model of serotonin syndrome, a potentially life-threatening adverse drug reaction associated with serotonergic drugs. P-gp inhibition by CsA enhanced the brain distribution of escitalopram by 70-80%. Serotonin (5-HT) turnover in the prefrontal cortex was reduced by escitalopram, and this effect was augmented by CsA. However, CsA pre-treatment did not augment the effect of escitalopram in the tail suspension test (TST) of antidepressant-like activity. Microdialysis experiments revealed that pre-treatment with CsA failed to augment, but blunted, the increase in extracellular 5-HT in response to escitalopram administration. This blunting effect may contribute to the lack of augmentation in the TST. Taken together, the present studies demonstrate that co-administration of CsA and escitalopram produces differential effects depending on the behavioural and neurochemical assays employed. Thus, the results highlight the need for further studies involving more selective pharmacological tools to specifically evaluate the impact of P-gp inhibition on behavioural responses to antidepressants which are subject to efflux by P-gp.