Via Research Recognition Day 2024 VCOM-Carolinas

Biomedical Studies

Current Knowledge of Genetic Variants Influencing the Activity of the Sedatives Propofol, Midazolam, and Remimazolam Brittany Cook, OMS-III, Steven Enkemann, Ph.D. Edward Via College of Osteopathic Medicine, Dept. of Cell Biology & Physiology, Spartanburg, SC. Co-authorship should be given to collaborators such as a Statistician, who have made intellectual contribution in terms of writing, research design, study implementation, and data analysis and interpretation.

Abstract

Results

Conclusions

Figure 1 . Metabolism Flowchart of Selected Sedatives

This review has sought to consolidate current research on the pharmacogenetics of the sedatives midazolam, remimazolam, and propofol. Given the risk of serious adverse effects associated with sedative use, exploration of genetic factors is valuable. This analysis summarized that variants in ABCB1, CYP3A4, CYP3A5, GABRA1, and VDR affected the pharmacokinetics of midazolam, while VDR is the only gene found to affect the metabolism of remimazolam at this time. Propofol has been more extensively studied and its use appears to be affected by polymorphisms in CYP2B6, GABRA1, GABRA2, GABRB2, UGT1A9, 5HT2A, SCN9A, and CHRM2. Moving forward, it could be worthwhile to investigate the effects of GABAA receptor and CES1 variants on remimazolam use. Table 2 . Genes with Evidence for Polymorphic Variation Impacting Drug Effect Gene Midazolam Remimazolam Propofol ABCB1 (MDR1)

Context : Research in recent years has turned to investigating genetic variants to try to explain the variation in adverse effects experienced by patients. Propofol has long been the dominant sedative in the perioperative space, leaving a lesser role for benzodiazepine drugs like midazolam due to their effects of prolonged sedation. The emergence of remimazolam, a new, rapid-acting benzodiazepine, prompts renewed investigation into the adverse effects of benzodiazepines used as sedatives. Objective : To summarize current literature regarding the pharmacogenetic effects of sedatives remimazolam, midazolam, and propofol. Results : Midazolam pharmacokinetics are affected by human alleles containing notable SNPs. The SNPs include ABCB1 rs1045642, CGT haplotype, CYP3A4 rs2740574, CYP3A5 rs776746, GABRA1 rs4263535, and VDR rs1544410. Propofol was also found to be impacted by multiple SNPs: GABRA1 rs4263535 and rs1157122, GABRA2 rs11503014 and rs76774144, UGT1A9 rs72551330, CYP2B6 rs3745274, CHRM2 rs2283265, 5HT2A rs6313, and SCN9A rs6746030. So far, only the CT allele carriers of the rs1544410 variant of VDR demonstrated allele-specific drug concentrations for remimazolam. Conclusion : Current literature on pharmacogenetics of remimazolam, midazolam, and propofol is limited in volume and generalizability. Remimazolam is a new benzodiazepine with pharmacokinetics that could address problems of midazolam and propofol. Remimazolam would benefit from further pharmacogenetic investigation, possibly into genes CES1 and GABRA1 / GABRA2 . INTRODUCTION Newer agents for anesthesia induction are being developed to address the problems with traditional sedatives 1 . Remimazolam is a rapid-acting benzodiazepine that has a structural resemblance to midazolam and is being explored as an alternative to midazolam and widely used propofol for procedural sedation 1,2 . The use of sedatives brings about risks of cardiopulmonary adverse effects, such as hypotension and respiratory depression, in addition to less lethal effects such as oversedation, injection site pain, and delayed emergence 1 . These risks are magnified when treating elderly patients who comprise a large proportion of surgical patients 3 . Understanding and evaluating the pharmacogenomics of drugs such as remimazolam, midazolam, and propofol may prove crucial in predicting adverse effects and lead to eventually tailoring a person's drug regimen to their genotype, reducing the risk of adverse effects. This investigation compiles current evidence of the genetic influence on the use of these drugs. METHODS The electronic search for this narrative review was conducted using the PubMed and Google Scholar databases. Search terms included “remimazolam,” “midazolam,” and “propofol,” in combination with “pharmacogenetic,” “pharmacogenomic,” “polymorphism,” “gene,” “pharmacokinetics,” and “adverse events.” Inclusion criteria included articles for which the full text was available and research performed in human subjects or human tissue. Exclusion criteria included articles that were not available in English. Additional articles were discovered using cross-referencing. Original research articles (observational studies, randomized controlled trials, etc.), metanalyses, systematic reviews, and a scoping review were included in this review. Introduction and Methods

CHRM2 CYP3A4 CYP3A5 CYPB26 GABRA1 GABRA2 GABRB2 SCN9A UGT1A9 VDR 5HT2A Table 2: Y-axis displays genes discussed in this review and X-axis displays the three drugs discussed. Shaded cells indicate evidence of gene-drug interaction.

Figure 2 . Effects Associated with Slow-Metabolizing or Non-Functional Genetic Variant

Greater sedation grade

Longer sedation length

Patient has non-functional copy of protein involved in the metabolism of the sedative or its signaling

Alteration in drug plasma concentration, volume of distribution, or clearance Altered heart rate or mean arterial pressure variability

Altered dose required to induce/maintain sedation

References

1. Sneyd JR, Gambus PL, Rigby-Jones AE. Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review. Br J Anaesth. 2021;127(1):41-55. doi:10.1016/J.BJA.2021.03.028 2. Kilpatrick GJ, McIntyre MS, Cox RF, et al. CNS 7056A Novel Ultra–short-acting Benzodiazepine. Anesthesiology. 2007;107(1):60-66. doi:10.1097/01.ANES.0000267503.85085.C0 Please scan QR code for the complete list of references

Table 1 . Most Commonly Reported and Rare, Important Adverse Effects .

Midazolam

Remimazolam

Propofol

Respiratory

respiratory depression, airway obstruction, hypoxia, apnea

hypoxia, respiratory depression apnea, hypoxia, upper airway obstruction

Cardiovascular bradycardia, hypotension

hypotension, hypertension, bradycardia, tachycardia

bradycardia, arrythmia, tachycardia, hypotension, hypertension, decreased cardiac output involuntary movements

Neurologic

drowsiness, prolonged sedation, agitation, involuntary movements

Gastrointestinal postoperative nausea and vomiting Metabolic

Acknowledgements

respiratory acidosis at weaning, hypertriglyceridemia, propofol related infusion syndrome

We are thankful for the assistance of the library staff of Edward Via College of Osteopathic Medicine, Carolinas Campus in locating several research articles.

Immunologic hypersensitivity/anaphylaxis hypersensitivity/anaphylaxis hypersensitivity/anaphylaxis injection site pain, rash, pruritis Table 1: X-axis displays drugs covered in this review. Y-axis displays organ systems associated with the listed adverse effects. Italicized print denotes rare adverse effects. Dermatologic tenderness at injection site

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2024 Research Recognition Day