No abstract

In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity. This type of inhibition can cause interactions with drugs such as omeprazole, paroxetine, macrolide antibiotics, or mirabegron. A good understanding of mechanism-based inhibition and proper clinical management is needed by clinicians when such drugs are prescribed. It is important to recognize mechanism-based inhibition since it cannot be prevented by separating the time of administration of the interacting drugs. Here, we provide a comprehensive overview of the different types of mechanism-based inhibition, along with illustrative examples of how mechanism-based inhibition might affect prescribing and clinical behaviors.

The risk‐benefit ratio associated with the use of repurposed drugs to treat severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)‐related infectious coronavirus disease 2019 (COVID‐19) is complicated because benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID‐19. A risk assessment of drug‐induced long QT syndrome (LQTS) associated with COVID‐19 repurposed drugs was performed and compared with 23 well‐known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (I Kr ) encoded by the human ether‐a‐go‐go gene ( hERG ), propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Seven different LQTS indices were calculated and compared. The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Estimators of LQTS risk levels indicated a very high or moderate risk for all COVID‐19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug‐induced LQTS for the 6 repurposed medications and 23 torsadogenic compounds. Based on our results, monitoring of the QT interval shall be performed when some COVID‐19 repurposed drugs are used, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients.

Background Patients taking medication with high anticholinergic and sedative properties are at increased risk of experiencing poor cognitive and physical outcomes. Therefore, precise quantification of the cumulative burden of their drug regimen is advisable. There is no agreement regarding which scale to use to simultaneously quantify the burden associated with medications.Objectives The objective of this review was to assess the strengths and limitations of available tools to quantify medicationrelated anticholinergic burden and sedative load in older adults. We discuss specific limitations and agreements between currently available scales and models and propose a comprehensive table combining drugs categorized as high, moderate, low, or no anticholinergic or sedative activity as excerpted from the selected studies. Methods A targeted search was carried out using the National Library of Medicine through PubMed using medical subject heading terms and text words around the following search terms: (anticholinergic OR sedative) AND (load OR burden OR scale) for studies published between 1 January 1945 and 5 June 2021. In addition, the following databases were searched using the same terms: MEDLINE-EBSCO, APA PsycInfo, CINAHL Plus, Cochrane Library, Scopus, OAIster, OVID-MEDLINE, Web of Science, and Google Scholar. Screening by titles was followed by an abstract and full-text review. After blind evaluation, agreement between reviewers was reached to establish drug characteristics and categories. Results After 3163 articles were identified, 13 were included: 11 assigned risk scores to anticholinergic drugs and two to sedative drugs. Considerable variability between anticholinergic scales was observed; scales included between 27 and 548 drugs. We generated a comprehensive table combining the anticholinergic and sedative activities of drugs evaluated and proposed a categorization of these drugs based on available scientific and clinical evidence. Our table combines information about 642 drugs and categorizes 44, 25, 99, and 474 drugs as high, moderate, low, or no anticholinergic and sedative activity, respectively. Conclusions Variability and inconsistency exists among scales used to categorize drugs with anticholinergic or sedative burden. In this review, we provide a comprehensive table that proposes a new categorization of these drugs. A longitudinal study will be required to validate the new proposed anticholinergic and sedative burden catalog in an evidence-based manner.

Determination of the risk–benefit ratio associated with the use of novel coronavirus disease 2019 (COVID-19) repurposed drugs in older adults with polypharmacy is mandatory. Our objective was to develop and validate a strategy to assess risk for adverse drug events (ADE) associated with COVID-19 repurposed drugs using hydroxychloroquine (HCQ) and chloroquine (CQ), alone or in combination with azithromycin (AZ), and the combination lopinavir/ritonavir (LPV/r). These medications were virtually added, one at a time, to drug regimens of 12,383 participants of the Program of All-Inclusive Care for the Elderly. The MedWise Risk Score (MRSTM) was determined from 198,323 drug claims. Results demonstrated that the addition of each repurposed drug caused a rightward shift in the frequency distribution of MRSTM values (p < 0.05); the increase was due to an increase in the drug-induced Long QT Syndrome (LQTS) or CYP450 drug interaction burden risk scores. Increases in LQTS risk observed with HCQ + AZ and CQ + AZ were of the same magnitude as those estimated when terfenadine or terfenadine + AZ, used as positive controls for drug-induced LQTS, were added to drug regimens. The simulation-based strategy performed offers a way to assess risk of ADE for drugs to be used in people with underlying medical comorbidities and polypharmacy at risk of COVID-19 infection without exposing them to these drugs.