Clinical Importance of Potential Genetic Determinants Affecting Propofol Pharmacokinetics and Pharmacodynamics.

Interindividual variability in response to drugs used in anesthesia has long been considered the rule, not the exception. It is important to mention that in anesthesiology, the variability in response to drugs is multifactorial, i.e., genetic and environmental factors interact with each other and thus affect the metabolism, efficacy, and side effects of drugs. Propofol (2,6-diisopropylphenol) is the most common intravenous anesthetic used in modern medicine. Individual differences in genetic factors [single nucleotide polymorphisms (SNPs)] in the genes encoding metabolic enzymes, molecular transporters, and molecular binding sites of propofol can be responsible for susceptibility to propofol effects. The objective of this review (through the analysis of published research) was to systematize the influence of gene polymorphisms on the pharmacokinetics and pharmacodynamics of propofol, to explain whether and to what extent the gene profile has an impact on variations observed in the clinical response to propofol, and to estimate the benefit of genotyping in anesthesiology. Despite the fact that there has been a considerable advance in this type of research in recent years, which has been largely limited to one or a group of genes, interindividual differences in propofol pharmacokinetics and pharmacodynamics may be best explained by the contribution of multiple pathways and need to be further investigated.

Contraindications Differ Widely Among Beta Blockers and Ought to be Cited for an Individual Drug, Not for the Entire Class.

Beta blockers (BBs) have important side effects that contribute to low adherence and persistence. Therefore, the optimal choice of BB is an important mode to prevent BB's side effects, leading to an increase in compliance, which can improve the outcomes in BBs' evidence-based indications, such as acute myocardial infarction, heart failure, etc. The aim of the paper is to suggest an improved method of reporting contraindications for BBs. We used a search of the following indexing databases: SCOPUS and PubMed, and web search engine Google Scholar to identify guidelines on arterial hypertension (HTN). HTN guidelines published during the last 2 decades were analyzed (from 2000 to 2020). Some of the contraindications (e.g., bradycardia, acute heart failure) are true for every BB. However, some contraindications do not belong to the whole BB class. For example, propranolol and carvedilol are contraindicated in chronic obstructive lung disease, but nebivolol and bisoprolol are not. We suggest that contraindications which are specific for some BBs (i.e., not for the whole class) ought to be listed with the exact name(s) of the individual BBs. In this way, we may decrease the number of wrong choices among BBs and consequently increase drug adherence (which is currently worse for the class of BBs than for most of the other antihypertensive drugs). To our knowledge, there is a lack of guidelines citing contraindications for individual BBs, because they vary a lot within-the-class of BBs. This is an approach to improve both basic medical education and guidelines.

The Effect of UGT1A9, CYP2B6 and CYP2C9 Genes Polymorphism on Propofol Pharmacokinetics in Children.

PURPOSE: This study was conducted to determine the effect of UGT1A9 98T>C, CYP2B6 516G>T and CYP2C9 430C>T genetic polymorphisms on the pharmacokinetics of propofol in children of different sexes and ages who undergone total intravenous anesthesia (ТIVA) and deep sedation during diagnostic and therapeutic procedures. PATIENTS AND METHODS: The prospective study included 94 children, ASA I-II status, 1 to 17 years of age, who undergone standard anesthetic protocol for TIVA, which implied the continuous use of propofol. Before the administration of propofol, venous blood was sampled to determine the presence of genetic variations in UGT1A9, CYP2B6 and CYP2C9 gene using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). From each patient included in the study blood samples were taken: 10 mins after the induction of anesthesia, immediately before the discontinuation of the propofol infusion, 10 mins after discontinuation of the propofol infusion and 20 mins after discontinuation of the propofol infusion to determine the pharmacokinetics of the drug in the plasma of the subjects The plasma propofol concentration was determined by HPLC analytical technique. RESULTS: UGT1A9 genotype is an independent predictor of the propofol concentration in children immediately after the end of the continuous infusion and 10 mins afterwards. In the carriers of the polymorphic UGT1A9 C allele, the propofol distribution constant was higher. The carriers of the polymorphic CYP2B6 T allele received a significantly lower overall and initial dose of propofol. Unlike polymorphism of the UGT1A9 gene, the tested CYP2C9 and CYP2B6 gene polymorphisms are not independent predictors of the pharmacokinetics of propofol. CONCLUSION: Further investigations of UGT1A9, CYP2B6 and CYP2C9 and other genes that participate in propofol metabolism as well as detailed analyses of the general conditions, administered therapies and associated diseases could explain the large interindividual variability of propofol metabolism in children.