Potential Drug–drug Interactions of Frequently Prescribed Medications in Long COVID Detected by Two Electronic Databases

Abstract

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to a wide range of acute and chronic complications including long COVID, a well-known chronic sequela. Long COVID often necessitates long-term treatment, which may lead to an increased potential for drug–drug interactions (DDIs). The objective of this study was to assess potential DDIs among frequently prescribed medications in long COVID by using two electronic databases. Sixty frequently prescribed agents were selected from Thailand’s National List of Essential Medicine 2022 for potential DDI analysis by Micromedex and Drugs.com. From these databases, 488 potential DDIs were identified. There were 271 and 434 DDI pairs based on Micromedex and Drugs.com, respectively. Among these DDIs, 77 pairs were labeled as contraindicated or major by both databases. The most common mechanisms for these serious interactions are cytochrome P450 (CYP) inhibition (45%), CYP induction (19%), and QT interval prolongation (7.8%). Based on Fleiss’ kappa (0.073), there was only slight agreement of the DDI severity classifications between these two databases. In conclusion, a large number of potential DDIs were detected among frequently prescribed medications for long COVID.

Introduction

The coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. The disease is responsible for the ongoing COVID-19 pandemic that has affected over 769 million and claimed 6.9 million lives as of 7 August 2023 [2]. The symptoms of infection usually occur within the first 4 weeks, but some might persist long after [3]. The post-infection sequelae are sometimes informally referred to as post-COVID complications, one of which is termed ‘long COVID’. In October 2021, the World Health Organization clinically defined long COVID as a condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection (usually within 3 months from the onset of COVID-19). Patients generally have symptoms lasting at least 2 months that cannot be explained by any alternative diagnosis. Common symptoms of long COVID include–but are not limited to–fatigue, shortness of breath, chest pain and tightness, headaches, problems with memory and focus, coughing, diarrhea, changes to senses, and loss of appetite [4]. A recent meta-analysis of over 1.7 million cases of COVID-19 suggested that 43% of infected individuals experienced some form of sequelae [5]. Long COVID has been reported in 54% of hospitalized patients and 34% of non-hospitalized patients [5]. 

Materials and methods

Drug selection

The focus of this study was on frequently prescribed medications for patients with both long COVID and other common chronic conditions such as diabetes mellitus, hypertension, dyslipidemia, and chronic infections. Medications available to treat these diseases were subsequently chosen from Thailand’s National List of Essential Medicine 2022 and the Chakri Naruebodindra Medical Institute (CNMI) drug lists–accessed in July 2023. A total of 63 agents were chosen by an infectious specialist and immunology team, who has major responsibility in conducting clinical care to COVID patients. Three agents, namely manidipine, fenoterol and bromhexine, were not recognized by Drugs.com or Micromedex. Hence, a total of 60 frequently prescribed medications for long COVID were included in the analysis of potential DDIs using Micromedex and Drugs.com in July 2023 (Fig 1 and Table 1). Ethical approval and consent were not required, and no patient assessment or confidential information was collected in this study.

Results

Among the 60 agents of frequently prescribed medications in long COVID, 488 potential DDIs were detected. Micromedex reported 271 DDI pairs, while Drugs.com reported 434 DDI pairs. Of the 271 pairs reported by Micromedex, 35 (12.9%), 156 (57.6%), 75 (27.7%), and 5 (1.8%) were classified as contraindicated, major, moderate, and minor, respectively. Of the 434 pairs reported by Drugs.com, 93 (21.4%), 292 (67.3%), and 49 (11.3%) pairs were considered major, moderate, and minor, respectively. Fig 2 provides details on the severity classification. Of all potential DDI pairs detected, there were 77 severe interactions at the levels of contraindicated or major with high concurrence between the two databases (Table 2). Among serious DDIs reported by both databases, the major mechanistic categories of potential DDIs were cytochrome P450 (CYP) inhibition (45%), CYP induction (19%), and QT interval prolongation (7.8%). Some minor mechanistic categories were gastric pH change, hypo/hyperkalemia, decreased tubular secretion, chelation, and others (Fig 3). 

Discussion

During the height of the COVID-19 pandemic, leading tertiary-care hospitals were at the forefront of the battle against this deadly infection. CNMI, under the administration of the Faculty of Medicine Ramathibodi Hospital, Mahidol University, played the leading role in caring for severe cases of COVID-19 infections in Thailand. Situated in the Samut Prakan province, east of Bangkok where large industrial factories are located, CNMI has become the major institute providing medical care for patients with COVID-19, with extensive experience in dealing with the original Wuhan strain, and the Alpha, Delta, and, most recently, Omicron variants [11]. More than half of severely ill patients, who commonly had multiple chronic conditions, went on to develop long COVID, which required long-term pharmacological interventions. Therefore, this study was performed to determine potential DDIs among frequently prescribed medications in long COVID. 

Conclusion

There are a large number of potential DDIs among frequently prescribed medications for patients with long COVID according to Micromedex and Drugs.com. There was slight agreement of the severity classification between the two electronic databases as determined by Fleiss’ kappa. The main mechanistics of potential DDIs are CYP inhibition and induction. Clinicians should be familiar with these DDIs, especially the serious DDIs that can result in harm to the patients. Antiretrovirals, antifungals, anti-tuberculosis drugs, statins, and corticosteroids are among the top five culprits for DDIs. Careful evaluation of DDIs when managing patients with long COVID, especially those with multiple chronic conditions requiring polypharmacy, should be implemented to promote safe and effective treatment plans for the patients.

Acknowledgments

All authors are grateful to Asst. Prof. Pawin Numthavaj (Faculty of Medicine Ramathibodi Hospital, Mahidol University) for the supervision of statistical analysis.

Citation: Meakleartmongkol T, Tangpanithandee S, Vanavivit N, Jiso A, Pongchaikul P, Kirdlarp S, et al. (2023) Potential drug–drug interactions of frequently prescribed medications in long COVID detected by two electronic databases. PLoS ONE 18(11): e0293866. https://doi.org/10.1371/journal.pone.0293866

Editor: Dorina Onoya, University of the Witwatersrand, SOUTH AFRICA

Received: September 27, 2022; Accepted: October 23, 2023; Published: November 16, 2023

Copyright: © 2023 Meakleartmongkol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper files.

Funding: This work was supported by a Faculty of Medicine Ramathibodi Hospital, Mahidol University (to Phisit Khemawoot). There was no additional external funding received for this study.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: AIDS, Acquired Immunodeficiency Syndromes; AUC, Area Under Curve; BPH, Benign Prostatic Hyperplasia; CNMI, Chakri Naruebodindra Medical Institute; COVID-19, Coronavirus Disease 2019; CYPs, Cytochrome P450s; DDIs, Drug-Drug Interactions; HIV, Human Immunodeficiency Virus; NLEM, National List of Essential Medicines; NNRTIs, Non-Nucleoside Reverse Transcriptase Inhibitors; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0293866#abstract0