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Prescribed Doses of CYP2D6-Metabolized Drugs and Hemodynamic Responses in Relation to CYP2D6 Genotype Among Older Patients Exposed to Polypharmacy.

ABSTRACT: BACKGROUND:Many drugs with dose-dependent effects on hemodynamic variables are metabolized by cytochrome P450 2D6 (CYP2D6). The aim of this study was to compare prescribed dosages and hemodynamic responses of such drugs in relation to pharmacogenetic variability in CYP2D6 metabolism among patients aged???70 years exposed to polypharmacy. MATERIALS AND METHODS:We included 173 patients with detailed information about drug use. The patients were retrospectively subjected to CYP2D6 genotyping, which comprised the most common variant alleles encoding reduced, absent, or increased CYP2D6 metabolism. In order to compare dosages across different CYP2D6-metabolized drugs, all prescribed daily doses were harmonized to the 'percent of a daily defined dose' (DDD). The mean harmonized DDD was compared between genotype-predicted normal metabolizers (NMs) and patients with reduced or absent CYP2D6 enzyme activity, defined as intermediate or poor metabolizers (IMs/PMs). Blood pressure, pulse, and patient proportions with orthostatism and bradycardia were also compared between genotype subgroups. RESULTS:The genotype-predicted phenotype subgroups comprised 79 NMs (45.7%), 75 IMs (43.4%), and 16 PMs (9.2%). There were no differences in dosing of CYP2D6 substrates between NMs and IMs/PMs (p?=?0.76). A higher proportion of CYP2D6 IMs/PMs experienced orthostatism (p?=?0.03), while there were no significant subgroup differences for the other hemodynamic variables. CONCLUSION:In this real-life clinical setting of patients aged???70 years, dosing of CYP2D6 substrates were not adjusted according to genotype-predicted CYP2D6 metabolism. The increased occurrence of orthostatism in patients with reduced/absent CYP2D6 metabolism may indicate that individualized dosing based on genotype has the potential to prevent adverse effects in these vulnerable patients.

SUBMITTER: Romskaug R

PROVIDER: S-EPMC7272489 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Prescribed Doses of CYP2D6-Metabolized Drugs and Hemodynamic Responses in Relation to CYP2D6 Genotype Among Older Patients Exposed to Polypharmacy.

Romskaug Rita R Wyller Torgeir Bruun TB Straand Jørund J Kersten Hege H Molden Espen E

Drugs & aging 20200601 6

<h4>Background</h4>Many drugs with dose-dependent effects on hemodynamic variables are metabolized by cytochrome P450 2D6 (CYP2D6). The aim of this study was to compare prescribed dosages and hemodynamic responses of such drugs in relation to pharmacogenetic variability in CYP2D6 metabolism among patients aged ≥ 70 years exposed to polypharmacy.<h4>Materials and methods</h4>We included 173 patients with detailed information about drug use. The patients were retrospectively subjected to CYP2D6 ge ...[more]

PMID: 32346827

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Project description:ObjectivesThe aim of this study was to demonstrate the existence of systematic associations in drug prescription that lead to the establishment of patterns of polypharmacy, and the clinical interpretation of the associations found in each pattern.MethodsA cross-sectional study was conducted based on information obtained from electronic medical records and the primary care pharmacy database in 2008. An exploratory factor analysis of drug dispensing information regarding 79,089 adult patients was performed to identify the patterns of polypharmacy. The analysis was stratified by age and sex.ResultsSeven patterns of polypharmacy were identified, which may be classified depending on the type of disease they are intended to treat: cardiovascular, depression-anxiety, acute respiratory infection (ARI), chronic obstructive pulmonary disease (COPD), rhinitis-asthma, pain, and menopause. Some of these patterns revealed a clear clinical consistency and included drugs that are prescribed together for the same clinical indication (i.e., ARI and COPD patterns). Other patterns were more complex but also clinically consistent: in the cardiovascular pattern, drugs for the treatment of known risk factors-such as hypertension or dyslipidemia-were combined with other medications for the treatment of diabetes or established cardiovascular pathology (e.g., antiplatelet agents). Almost all of the patterns included drugs for preventing or treating potential side effects of other drugs in the same pattern.ConclusionsThe present study demonstrated the existence of non-random associations in drug prescription, resulting in patterns of polypharmacy that are sound from the pharmacological and clinical viewpoints and that exist in a significant proportion of the population. This finding necessitates future longitudinal studies to confirm some of the proposed causal associations. The information discovered would further the development and/or adaptation of clinical patient guidelines to patients with multimorbidity who are taking multiple drugs.

Project description:BackgroundThe objective of this study was to investigate the relation of severe COVID-19 to prior drug prescribing.MethodsSevere cases were defined by entry to critical care or fatal outcome. For this matched case-control study (REACT-SCOT), all 4251 cases of severe COVID-19 in Scotland since the start of the epidemic were matched for age, sex and primary care practice to 36,738 controls from the population register. Records were linked to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days.ResultsSevere COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in a care home, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.8, 13.3), and in those without any of the conditions designated as conferring increased risk of COVID-19. Of 17 drug classes postulated at the start of the epidemic to be "medications compromising COVID", all were associated with increased risk of severe COVID-19 and these associations were present in those without any of the designated risk conditions. The fraction of cases in the population attributable to exposure to these drug classes was 38%. The largest effect was for antipsychotic agents: rate ratio 4.18 (3.42, 5.11). Other drug classes with large effects included proton pump inhibitors (rate ratio 2.20 (1.72, 2.83) for = 2 defined daily doses/day), opioids (3.66 (2.68, 5.01) for = 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates and were stronger with recent than with non-recent exposure.ConclusionsSevere COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression, or dyskinesia; have anticholinergic effects; or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Measures to reduce the burden of mortality and morbidity from COVID-19 should include reinforcing existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy.RegistrationENCEPP number EUPAS35558.

Dataset Information

Prescribed Doses of CYP2D6-Metabolized Drugs and Hemodynamic Responses in Relation to CYP2D6 Genotype Among Older Patients Exposed to Polypharmacy.

Publications

Prescribed Doses of CYP2D6-Metabolized Drugs and Hemodynamic Responses in Relation to CYP2D6 Genotype Among Older Patients Exposed to Polypharmacy.

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