Background: Frailty and polymedication are closely interrelated. Addressing these concurrent conditions in primary care settings relies on the utilization of potentially inappropriate medication (PIM) lists and medication reviews (MRs), particularly in rural areas, where healthcare professionals serve as the sole point of access to the medical system. The aim of this study was to examine the relationship between medication appropriateness and variables related to frailty in a rural municipality in order to propose potential strategies for therapy optimization. Methods: This cross-sectional study included all adult community dwellers aged 50 and above officially registered in the municipality of Tiriez (Albacete, Spain) in 2023 (n = 241). The primary outcome variable was frailty (assessed using the fatigue, resistance, ambulation, illness, and loss of weight (FRAIL) scale). The independent variables were age, gender, medication regimen, history of falls, comorbidities, PIMs (evaluated using the screening tool of older persons' prescriptions (STOPP) 2023 criteria), fall-risk-increasing drugs (FRID), and anticholinergic burden (ACB). Results: The prevalence of frailty was approximately 20%. FRID and ACB scores were statistically associated (p-value < 0.001) with frailty, 1.1 ± 1.3 vs. 2.5 ± 1.7, and 1.0 ± 1.3 vs. 2.8 ± 2.5, respectively. Regardless of age, frailty was observed to be more prevalent among females (odds ratio (OR) [95% confidence interval (CI)]: 3.5 [1.5, 9.0]). On average, 2.1 ± 1.6 STOPP criteria were fulfilled, with the prolonged use of anxiolytics and anti-peptic-ulcer agents being the most frequent. Priority interventions (PIs) included opioid dose reduction, benzodiazepine withdrawal, and the assessment of antidepressant and antiplatelet treatment plans. Conclusions: The optimization of medication in primary care is of paramount importance for frail patients. Interventional measures should focus on ensuring the correct dosage and combination of drugs for each therapeutic regimen.
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