Abstracts
Introduction:
Drug interactions (DIs) are common in clinical practice and are directly related to factors such as polypharmacy, aging, hepatic metabolism and decreased renal function. Individuals with chronic kidney disease (CKD) often require multiple classes of drugs being at important risk for the development of DIs.
Objective:
Identify potential interactions among drugs prescribed to patients with CKD on conservative treatment, and factors associated with their occurrence.
Methods:
Observational cross-sectional study, with analysis of 558 prescriptions. Potential DIs were identified by the database MICROMEDEX®, software that provides an internationally known pharmacopoeia.
Results:
There was a predominance of males (54.7%), seniors (69.4%), stage 3 CKD (47.5%), overweight and obese patients (66.7%). The most prevalent comorbidities were hypertension (68.5%) and diabetes mellitus (31.9%). Potential DIs were detected in 74.9% of prescriptions. Among the 1364 DIs diagnosed, 5 (0.4%) were contraindicated and 229 (16.8%) of greater severity, which need immediate intervention. Interactions of moderate and low severity were identified in 1049 (76.9%) and 81 (5.9%) prescriptions, respectively. The probability of one DI increased by 2.5 times for each additional drug (CI = 2.18 to 3.03). Obesity, hypertension, diabetes as well as advanced stage of CKD were risk factors strongly associated with DI occurrence.
Conclusion:
Drug associations in individuals with CKD were related to high prevalence of serious DIs, especially in the later stages of the disease
drug combinations; drug interactions; kidney failure, chronic
Introdução:
Interações medicamentosas (IMs) são frequentes na prática clínica e estão diretamente relacionadas a fatores como polifarmácia, idade avançada e deficiência na metabolização e excreção de fármacos. Indivíduos com doença renal crônica (DRC) comumente utilizam diversas classes de medicamentos, constituindo um importante grupo de risco para IMs.
Objetivo:
Identificar potenciais interações entre medicamentos prescritos a renais crônicos em tratamento conservador, e fatores associados a sua ocorrência.
Métodos:
Estudo observacional transversal, com análise de 558 prescrições. O potencial interativo dos medicamentos foi traçado tendo como suporte a base de dados MICROMEDEX®, software que disponibiliza farmacopeias conhecidas internacionalmente.
Resultados:
Houve predomínio de indivíduos do sexo masculino (54,7%), idosos (69,4%), no estágio 3 da DRC (47,5%), com sobrepeso e obesos (66,7%). As comorbidades mais prevalentes foram a hipertensão arterial sistêmica (68,5%) e o diabetes mellitus (31,9%). IMs potenciais foram detectadas em 74,9% das prescrições. De um total de 1.364 IMs detectadas, 229 (16,8%) foram de gravidade maior e 5 (0,4%) contraindicadas, com necessidade de intervenção imediata. Interações de gravidade moderada ou menor foram identificadas respectivamente em 1.049 (76,9%) e 81 (5,9%) das prescrições. Observou-se que a probabilidade de ocorrência de uma IM aumentou em 2,5 vezes para cada medicamento adicional (IC = 2,18-3,03). Obesidade, diabetes, hipertensão e estágio avançado da DRC foram fatores de risco fortemente associados para ocorrência de IM.
Conclusão:
A associação de medicamentos em indivíduos com DRC relacionou-se com alta prevalência de IMs potencialmente graves, especialmente nos estágios mais avançados da doença.
combinação de medicamentos; insuficiência renal crônica; interações de medicamentos
Introduction
In clinical practice, multiple drugs are often combined in the treatment of patients
with chronic diseases. These associations generally produce drug interactions (DI)
with expected beneficial effects, but in some cases undesired outcomes may also
occur, such as ineffective treatment and severe adverse events.11. Leone R, Magro L, Moretti U, Cutroneo P, Moschini M, Motola D, et al.
Identifying adverse drug reactions associated with drug-drug interactions: data
mining of a spontaneous reporting database in Italy. Drug Saf 2010;33:667-75. DOI:
http://dx.doi.org/10.2165/11534400-000000000-00000
http://dx.doi.org/10.2165/11534400-00000...
,22. Pirmohamed M. Drug-drug interactions and adverse drug reactions:
separating the wheat from the chaff. Wien Klin Wochenschr 2010;122:62-4. PMID:
20213370 DOI: http://dx.doi.org/10.1007/s00508-010-1309-1
http://dx.doi.org/10.1007/s00508-010-130...
DI can be
defined as the set of alterations introduced upon the therapeutic effect of a given
drug stemming from the coadministration of one or more medications.22. Pirmohamed M. Drug-drug interactions and adverse drug reactions:
separating the wheat from the chaff. Wien Klin Wochenschr 2010;122:62-4. PMID:
20213370 DOI: http://dx.doi.org/10.1007/s00508-010-1309-1
http://dx.doi.org/10.1007/s00508-010-130...
,33. Robertson S, Penzak S. Drug interactions. In: Atkinson AJ, Abernethy
DR, Daniels CE, Dedrick RL, Markey SP. Principles of clinical pharmacology. 2nd ed.
Burlington: Elsevier Academic Press; 2007. p.229-47. In this context, DI appear as the cause of a drug-related problem (DRP)
which, when present, produces negative impacts on morbidity, mortality, length of
hospitalization, quality of life, and cost of care.44. Cardone KE, Bacchus S, Assimon MM, Pai AB, Manley HJ.
Medication-related problems in CKD. Adv Chronic Kidney Dis 2010;17:404-12. DOI:
http://dx.doi.org/10.1053/j.ackd.2010.06.004
http://dx.doi.org/10.1053/j.ackd.2010.06...
5. Mason NA. Polypharmacy and medication-related complications in the
chronic kidney disease patient. Curr Opin Nephrol Hypertens 2011;20:492-7. DOI:
http://dx.doi.org/10.1097/MNH.0b013e328349c261
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6. Fernández-Llimós F, Tuneu L, Baena MI, Garcia-Delgado A, Faus MJ.
Morbidity and mortality associated with pharmacotherapy. Evolution and current
concept of drug-related problems. Curr Pharm Des 2004;10:3947-67. DOI:
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medication-related problems at a university hospital. Am J Health Syst Pharm
1995;52:2415-8.
Despite the scarce reports of clinically evident cases of DI, knowledge of the
pharmacodynamic and pharmacokinetic properties of different medications suggests the
potential risks connected to drug interactions.22. Pirmohamed M. Drug-drug interactions and adverse drug reactions:
separating the wheat from the chaff. Wien Klin Wochenschr 2010;122:62-4. PMID:
20213370 DOI: http://dx.doi.org/10.1007/s00508-010-1309-1
http://dx.doi.org/10.1007/s00508-010-130...
,88. Jia J, Zhu F, Ma X, Cao Z, Li Y, Chen YZ. Mechanisms of drug
combinations: interaction and network perspectives. Nat Rev Drug Discov
2009;8:111-28. DOI: http://dx.doi.org/10.1038/nrd2683
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,99. Hisaka A, Ohno Y, Yamamoto T, Suzuki H. Prediction of pharmacokinetic
drug-drug interaction caused by changes in cytochrome P450 activity using in vivo
information. Pharmacol Ther 2010;125:230-48. PMID: 19951720 DOI:
http://dx.doi.org/10.1016/j.pharmthera.2009.10.011
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The occurrence of DI may be mitigated with
preventive measures and intervention.1010. Monteiro C, Marques FB, Ribeiro CF. Interacções medicamentosas como
causa de iatrogenia evitável. Rev Port Clin Geral 2007; 23:63-73.
11. Grattagliano I, Portincasa P, D'Ambrosio G, Palmieri VO, Palasciano
G. Avoiding drug interactions: here's help. J Fam Pract 2010;59:322-9. PMID:
20544064-1212. Grassby PF. Adverse drug interactions. Pract Nurse
2010;40:32-5. In this sense, the
identification and classification of drug interactions by a pharmacist may optimize
the clinical management of this type of event.1313. Murphy JE, Malone DC, Olson BM, Grizzle AJ, Armstrong EP, Skrepnek
GH. Development of computerized alerts with management strategies for 25 serious
drug-drug interactions. Am J Health Syst Pharm 2009;66:38-44. DOI:
http://dx.doi.org/10.2146/ajhp070046
http://dx.doi.org/10.2146/ajhp070046...
,1414. Al-Hajje AH, Atoui F, Awada S, Rachidi S, Zein S, Salameh P.
Drug-related problems identified by clinical pharmacist's students and pharmacist's
interventions. Ann Pharm Fr 2012;70:169-76. PMID: 22655585 DOI:
http://dx.doi.org/10.1016/j.pharma.2012.02.004
http://dx.doi.org/10.1016/j.pharma.2012....
The most frequently used classification for DI considers as contraindicated or
significant the drug interactions that require immediate medical intervention due to
imminent risk of death. In turn, minor and moderate drug interactions may produce
limited clinical effect without the need to significantly change the therapy, in
addition to calling for increased awareness from the medical staff in order not to
compromise the treatment.1515. MICROMEDEX® 2.0 Healthcare Series [on line]. Thomson Reuters:
1974-2011. Available from: http://www.periodicos.capes.gov.br.
http://www.periodicos.capes.gov.br...
When looking for possible occurrences of DI, one must pay attention to determining
factors such as the chemical nature of the drugs, the number of drugs used, patient
age, and the presence of liver and kidney involvement.33. Robertson S, Penzak S. Drug interactions. In: Atkinson AJ, Abernethy
DR, Daniels CE, Dedrick RL, Markey SP. Principles of clinical pharmacology. 2nd ed.
Burlington: Elsevier Academic Press; 2007. p.229-47.,1616. Gagne JJ, Maio V, Rabinowitz C. Prevalence and predictors of
potential drug-drug interactions in Regione Emilia-Romagna, Italy. J Clin Pharm Ther
2008;33:141-51. DOI:
http://dx.doi.org/10.1111/j.1365-2710.2007.00891.x
http://dx.doi.org/10.1111/j.1365-2710.20...
The kidneys play a key role in the maintenance of homeostasis and in regulatory, excretory and endocrine functions. Therefore, the gradual decreases in the glomerular filtration rate (GFR) and/or loss of kidney function seen in chronic kidney disease (CKD) patients compromise the homeostasis of the entire body.1717. Bastos MG, Carmo WB, Abrita RR, Almeida EC, Mafra D, Costa DMN, et al. Doença renal crônica: problemas e soluções. J Bras Nefrol 2004;26:202-15.,1818. Romão Júnior JE. Doença renal crônica: definição, epidemiologia e classificação. J Bras Nefrol 2004;26:1-3.
In Brazil, the estimated number of patients on renal replacement therapy (RRT) grew
from 42,000 in 2000 to more than 90,000 in late 2010.1919. Sesso RC, Lopes AA, Thomé FS, Lugon JR, Santos DR. Relatório do
Censo Brasileiro de Diálise de 2010. J Bras Nefrol 2011;33:442-7. DOI:
http://dx.doi.org/10.1590/S0101-28002011000400009
http://dx.doi.org/10.1590/S0101-28002011...
The prevalence of dialysis in 2010 was 483 patients per million
population (pmp), ranging from 265 pmp in Northern Brazil to 591 pmp in the
Southeast. Hemodialysis was offered to 89.7% of the patients and peritoneal dialysis
to 5.1%. Previous censuses revealed systemic hypertension (SH) was the most common
etiologic diagnosis of CKD, followed by diabetes mellitus (DM).1919. Sesso RC, Lopes AA, Thomé FS, Lugon JR, Santos DR. Relatório do
Censo Brasileiro de Diálise de 2010. J Bras Nefrol 2011;33:442-7. DOI:
http://dx.doi.org/10.1590/S0101-28002011000400009
http://dx.doi.org/10.1590/S0101-28002011...
Based on the above, individuals with CKD constitute a population at high risk for potentially severe DI, as members of this group are predominantly elderly, hypertensive, diabetic, and experience impaired drug renal excretion.
This study looked into the profile of the most common types of DI in CKD patients undergoing conservative treatment.
Methods
This cross-sectional observational study was carried out at the clinic for CKD of the Centro Hiperdia Minas in Juiz de Fora and at the Interdisciplinary Center for Studies and Research in Nephrology (NIEPEN) of the Federal University of Juiz de Fora (UFJF). The database of prescriptions for individuals with CKD admitted between January and December 2011 for conservative treatment was analyzed. Patients aged 18 and above with complete medical records were enrolled.
Data collection was performed in two stages. In the first stage, the electronic charts of every patient enrolled in the study were analyzed for demographic, clinical, and prescription variables, including the drug names based on the Brazilian Common Denomination (DCB) and the Anatomical Therapeutical Chemical (ATC) classification systems, in order to establish the profile of the individuals seen in the clinic.
The second stage involved the identification of possible drug interactions. To that end, database MICROMEDEX® 2.0 (2011) was accessed through the journal portal of the Brazilian Federal Agency for the Support and Evaluation of Graduate Education (CAPES).
The MICROMEDEX® Health Series database contains information on
medications, etiology, epidemiology, diagnosis and treatment. It provides access to
internationally known pharmacopoeias such as Martindale and USP DI, in addition to
some original systems made available only through the database, such as
DRUGDEX® and DRUG-REAX® .1515. MICROMEDEX® 2.0 Healthcare Series [on line]. Thomson Reuters:
1974-2011. Available from: http://www.periodicos.capes.gov.br.
http://www.periodicos.capes.gov.br...
Searches were carried out considering that the database provides descriptions of drug interactions for pairs of drugs, their likely mechanisms of interaction, scientific publications, severity, and indicated clinical management.
Statistical analysis
Descriptive analysis was performed using frequencies for categorical variables, and mean, median, standard deviation, and variance for quantitative variables.
Logistic regression analysis was applied to find the factors associated with potential drug interactions. Exposure to DI (yes/no) was the dependent variable in the model. Multivariate analysis was carried out for variables showing significant correlations.
Results were expressed as odds ratios (OR) and statistical significance was set at 5%.
Data sets were entered and treated on software packages Excel 1.0, STATA 11.0, and SPSS version 17.0.
The study was approved by the Ethics Committee of the Federal University of Juiz de Fora (CEP/UFJF) and given permit Nº. 328/2011.
Results
Pharmacotherapeutic profile
The first stage of the protocol consisted of a review of the pharmacotherapeutic profile of the 1,651 prescriptions issued to 850 CKD patients seen in 2011. A total of 10,023 medications with 289 different active ingredients were listed in the prescriptions.
Cardiovascular drugs were the most commonly prescribed class of medications (5,772/57.6%), followed by alimentary tract and metabolism medications (1,647/16.4%), and drugs affecting the blood and blood-forming organs (1,088/10.9%).
The ten most frequently prescribed medications were furosemide (8.4%), simvastatin (7.1%), losartan (7.1%), acetylsalicylic acid (5.2%), captopril (4.7%), hydrochlorothiazide (4.7%), omeprazole (4.5%), enalapril (4.1%), amlodipine besylate (3.3%), and nifedipine (3.1%).
Potential drug interactions
In the second stage of the study, 558 patients met the enrollment criteria and were analyzed for drug interactions. Subjects were predominantly male (54.7%), elderly (69.4%), overweight or obese (66.7%), and had stage 3 CKD (47.5%). The WHO criteria dictates that overweight individuals have a BMI between 25 and 29.99, while obese subjects have a BMI greater than or equal to 30.00. The most prevalent comorbidities were hypertension (68.5%) and DM (31.9%).
The prescriptions in effect used by the patients in their last visit at the clinic were assessed, as their records contained data from multiple visits to the clinic occurred throughout the year. Enrolled patients took a mean of 5.6 ± 3.2 drugs, and 418 (74.9%) of them had a potentially interacting pair of drugs in their prescriptions. A mean of 3.4 ± 2.3 drug interactions were observed in patients with some form of DI.
The assessment of the prescriptions on software program MICROMEDEX® revealed a total of 1,364 drug interactions. Figure 1 and Table 1 show the frequencies according to the severity of the drug interactions. Cases of absolute contraindication were seen in 0.4% of the patients; severe contraindications in 16.8%; moderate in 76.9%; and minor in 5.9% of the enrolled individuals.
Therefore, approximately a fifth of the identified drug interactions were absolute contraindications or severe cases of DI.
The five cases of absolute contraindication included prescriptions of a calcium channel blocker (nifedipine) and an anticonvulsant (carbamazepine, phenytoin, phenobarbital). Noteworthy severe drug interactions included the dual blockade of the renin-angiotensin system, accounting for 22% of the cases of severe DI, and prescriptions of an inhibitor of the renin-angiotensin system combined with a xanthine oxidase inhibitor (allopurinol).
Analysis of variables correlated with DI
Once the presence of a drug interaction was confirmed, the possibly correlated clinical variables and conditions were assessed.
In this study, the probability of occurrence of a drug interaction increased 2.5 fold for each drug added to the prescription (CI = 2.18 to 3.03) (Figure 2).
Probability of drug interactions as a function of the number of prescribed medications; generated from logistic regression model. OR = 2.57 (2.18; 3.03) (for each additional medication, the chance of drug interaction increases 2.5 times).
The analysis of risk factors for the occurrence of DI revealed that the variables more strongly correlated with the presence of drug interactions were age, stage of CKD, body mass index (BMI), hypertensive nephropathy, diabetic nephropathy, DM, and hypertension (Table 2).
These variables were then submitted to a multivariate logistic regression. The results of this analysis showed that advanced stage CKD, obesity, and diagnosis of DM and hypertension were the main risk factors for the occurrence of drug interactions (Table 3). Interestingly, the probability of occurrence of DI increased 4.7 fold in patients with stage 5 CKD when compared to individuals with CKD stages 1 and 2 (p = 0.003).
Multivariate logistic regression: analysis of risk factors correlated to potential drug interactions of patients with CKD
Discussion
This study included the prescriptions of 558 CKD patients treated conservatively at a nephrology service within one year. Potential drug interactions were detected in 418 patients and 74.9 % of the prescriptions. A grand total of 1,364 drug interactions were identified, with severe DI accounting for 16.8% of the cases and absolute contraindications for 0.4%. Risk factors for the occurrence of DI in the population were obesity, DM, hypertension, and advanced stage CKD.
DI is defined as a clinical event in which the coadministration of drugs alters the effect of one or both drugs. DI is a cause of DRP frequently seen in individuals exposed to polypharmacy, patients with liver disease, and subjects with impaired renal excretion, conditions that may worsen the processes of drug absorption, distribution, metabolism and excretion.
Software tool MICROMEDEX® Health Series is one of the most effective means
to evaluate drug interactions. It is an established method in specialized literature
used to promptly and reliably identify cases of DI.11. Leone R, Magro L, Moretti U, Cutroneo P, Moschini M, Motola D, et al.
Identifying adverse drug reactions associated with drug-drug interactions: data
mining of a spontaneous reporting database in Italy. Drug Saf 2010;33:667-75. DOI:
http://dx.doi.org/10.2165/11534400-000000000-00000
http://dx.doi.org/10.2165/11534400-00000...
,1313. Murphy JE, Malone DC, Olson BM, Grizzle AJ, Armstrong EP, Skrepnek
GH. Development of computerized alerts with management strategies for 25 serious
drug-drug interactions. Am J Health Syst Pharm 2009;66:38-44. DOI:
http://dx.doi.org/10.2146/ajhp070046
http://dx.doi.org/10.2146/ajhp070046...
,1616. Gagne JJ, Maio V, Rabinowitz C. Prevalence and predictors of
potential drug-drug interactions in Regione Emilia-Romagna, Italy. J Clin Pharm Ther
2008;33:141-51. DOI:
http://dx.doi.org/10.1111/j.1365-2710.2007.00891.x
http://dx.doi.org/10.1111/j.1365-2710.20...
,2020. Clauson KA, Marsh WA, Polen HH, Seamon MJ, Ortiz BI. Clinical
decision support tools: analysis of online drug information databases. BMC Med Inform
Decis Mak 2007;7:7. DOI: http://dx.doi.org/10.1186/1472-6947-7-7
http://dx.doi.org/10.1186/1472-6947-7-7...
21. Macedo EI, Lopes LC, Barberato-Filho S. A technical analysis of
medicines request-related decision making in Brazilian courts. Rev Saude Publica
2011;45:706-13. PMID: 21739077 DOI:
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-2222. Guastaldi RBF. Interações medicamentosas potenciais: um estudo dos
antimicrobianas utilizados em pacientes submetidos ao transplante de medula óssea
[Dissertação]. São Paulo: Universidade de São Paulo, Escola de enfermagem;
2006.
Drug-related problems are common to all stages of CKD.44. Cardone KE, Bacchus S, Assimon MM, Pai AB, Manley HJ.
Medication-related problems in CKD. Adv Chronic Kidney Dis 2010;17:404-12. DOI:
http://dx.doi.org/10.1053/j.ackd.2010.06.004
http://dx.doi.org/10.1053/j.ackd.2010.06...
However, most studies enroll patients with advanced stage CKD on
hemodialysis.44. Cardone KE, Bacchus S, Assimon MM, Pai AB, Manley HJ.
Medication-related problems in CKD. Adv Chronic Kidney Dis 2010;17:404-12. DOI:
http://dx.doi.org/10.1053/j.ackd.2010.06.004
http://dx.doi.org/10.1053/j.ackd.2010.06...
,2323. Manley HJ, Cannella CA, Bailie GR, St Peter WL. Medication-related
problems in ambulatory hemodialysis patients: a pooled analysis. Am J Kidney Dis
2005;46:669-80. PMID: 16183422 DOI:
http://dx.doi.org/10.1053/j.ajkd.2005.07.001
http://dx.doi.org/10.1053/j.ajkd.2005.07...
24. Bailie GR, Eisele G, Liu L, Roys E, Kiser M, Finkelstein F, et al.
Patterns of medication use in the RRI-CKD study: focus on medications with
cardiovascular effects. Nephrol Dial Transplant 2005;20:1110-5. DOI:
http://dx.doi.org/10.1093/ndt/gfh771
http://dx.doi.org/10.1093/ndt/gfh771...
-2525. Belaiche S, Romanet T, Allenet B, Calop J, Zaoui P. Identification
of drug-related problems in ambulatory chronic kidney disease patients: a 6-month
prospective study. J Nephrol 2012;25:782-8. DOI:
http://dx.doi.org/10.5301/jn.5000063
http://dx.doi.org/10.5301/jn.5000063...
A study with 395 patients on dialysis reported 1,593 cases of DRP.
Inadequate workup monitoring (23.5%) topped the list of prevalent drug-related
problems, followed by subtherapeutic dosage (11.2%) and overdosage (9.2%). The
authors reported that only 4.5% of the patients suffered from drug interactions.2323. Manley HJ, Cannella CA, Bailie GR, St Peter WL. Medication-related
problems in ambulatory hemodialysis patients: a pooled analysis. Am J Kidney Dis
2005;46:669-80. PMID: 16183422 DOI:
http://dx.doi.org/10.1053/j.ajkd.2005.07.001
http://dx.doi.org/10.1053/j.ajkd.2005.07...
Another study included 619 patients on conservative therapies and reported
'indication without corresponding drug prescription' as the most frequent DRP. Only
24% of the individuals with coronary disease were on HMG-CoA reductase inhibitors;
only 58% of the subjects with DM and 23% if the individuals with proteinuria were on
renin-angiotensin system blockers.2424. Bailie GR, Eisele G, Liu L, Roys E, Kiser M, Finkelstein F, et al.
Patterns of medication use in the RRI-CKD study: focus on medications with
cardiovascular effects. Nephrol Dial Transplant 2005;20:1110-5. DOI:
http://dx.doi.org/10.1093/ndt/gfh771
http://dx.doi.org/10.1093/ndt/gfh771...
The
authors did not report data on drug interactions.
Similarly, a prospective study on DRP in individuals with CKD treated conservatively
reported 'indication without corresponding drug prescription' as the most frequent
DRP. Again, the authors did not look into drug interactions.2525. Belaiche S, Romanet T, Allenet B, Calop J, Zaoui P. Identification
of drug-related problems in ambulatory chronic kidney disease patients: a 6-month
prospective study. J Nephrol 2012;25:782-8. DOI:
http://dx.doi.org/10.5301/jn.5000063
http://dx.doi.org/10.5301/jn.5000063...
The prevalence of drug interactions among outpatients is known to be high in
populations such as the elderly2626. Venturini CD, Engroff P, Ely LS, Zago LF, Schroeter G, Gomes I, et
al. Gender differences, polypharmacy, and potential pharmacological interactions in
the elderly. Clinics (São Paulo) 2011;66:1867-72., individuals
with chronic diseases1616. Gagne JJ, Maio V, Rabinowitz C. Prevalence and predictors of
potential drug-drug interactions in Regione Emilia-Romagna, Italy. J Clin Pharm Ther
2008;33:141-51. DOI:
http://dx.doi.org/10.1111/j.1365-2710.2007.00891.x
http://dx.doi.org/10.1111/j.1365-2710.20...
, patients undergoing
treatment for cancer2727. van Leeuwen RW, Swart EL, Boom FA, Schuitenmaker MS, Hugtenburg JG.
Potential drug interactions and duplicate prescriptions among ambulatory cancer
patients: a prevalence study using an advanced screening method. BMC Cancer
2010;10:679. DOI: http://dx.doi.org/10.1186/1471-2407-10-679
http://dx.doi.org/10.1186/1471-2407-10-6...
, and subjects with
liver disease.2828. Franz CC, Egger S, Born C, Rätz Bravo AE, Krähenbühl S. Potential
drug-drug interactions and adverse drug reactions in patients with liver cirrhosis.
Eur J Clin Pharmacol 2012;68:179-88. PMID: 21842337 DOI:
http://dx.doi.org/10.1007/s00228-011-1105-5
http://dx.doi.org/10.1007/s00228-011-110...
However, searches with
keywords 'drug interactions,' 'chronic kidney failure,' 'drug interaction and renal
failure,' and 'drug related problems and kidney failure' failed to yield results on
DI in individuals with CKD treated conservatively.
A recently published study looked into the prevalence of drug interactions in CKD
inpatients by analyzing 205 prescriptions. A total of 474 (76.09%) cases of drug
interactions were detected, with a mean of 2.7 interactions per prescription. Severe
drug interactions involving cardiovascular medications were seen in 19.6% of the
cases.2929. Rama M, Viswanathan G, Acharya LD, Attur RP, Reddy PN, Raghavan SV.
Assessment of Drug-Drug Interactions among Renal Failure Patients of Nephrology Ward
in a South Indian Tertiary Care Hospital. Indian J Pharm Sci 2012;74:63-8. DOI:
http://dx.doi.org/10.4103/0250-474X.102545
http://dx.doi.org/10.4103/0250-474X.1025...
Although the study included
hospitalized patients, its findings were similar to what was observed in our study,
in which the mean number of drug interactions was 3.4 ± 2.3 and approximately 16% of
the patients had severe drug interactions involving cardiovascular medications.
Severe drug interactions, along with absolute contraindications (0.4%), may pose
significant risk to the health of patients, and hence require medical and/or
pharmaceutical intervention to prevent against the occurrence of severe adverse
effects.1515. MICROMEDEX® 2.0 Healthcare Series [on line]. Thomson Reuters:
1974-2011. Available from: http://www.periodicos.capes.gov.br.
http://www.periodicos.capes.gov.br...
Furthermore, a significant
portion of the studied population (76.9%) had moderate drug interactions, which also
require attention so as not to deteriorate the patients' condition.
Polypharmacy is one of the factors involved in the occurrence of drug
interactions.2626. Venturini CD, Engroff P, Ely LS, Zago LF, Schroeter G, Gomes I, et
al. Gender differences, polypharmacy, and potential pharmacological interactions in
the elderly. Clinics (São Paulo) 2011;66:1867-72.,3030. Vyas A, Pan X, Sambamoorthi U. Chronic Condition Clusters and
Polypharmacy among Adults. Int J Family Med 2012;2012:193168. PMID: 22900173 DOI:
http://dx.doi.org/10.1155/2012/193168
http://dx.doi.org/10.1155/2012/193168...
According to the literature, patients taking
five drugs are 50% more likely to suffer from drug interactions, while subjects on
seven or more medications are 100% more likely to experience the effects of drug
interactions.3131. Delafuente JC. Understanding and preventing drug interactions in
elderly patients. Crit Rev Oncol Hematol 2003;48:133-43. DOI:
http://dx.doi.org/10.1016/j.critrevonc.2003.04.004
http://dx.doi.org/10.1016/j.critrevonc.2...
Patients with CKD are at a high risk for cardiovascular and metabolic events, and
consequently require the prescription of multiple drugs.2424. Bailie GR, Eisele G, Liu L, Roys E, Kiser M, Finkelstein F, et al.
Patterns of medication use in the RRI-CKD study: focus on medications with
cardiovascular effects. Nephrol Dial Transplant 2005;20:1110-5. DOI:
http://dx.doi.org/10.1093/ndt/gfh771
http://dx.doi.org/10.1093/ndt/gfh771...
,3232. Menon V, Gul A, Sarnak MJ. Cardiovascular risk factors in chronic
kidney disease. Kidney Int 2005;68:1413-8. PMID: 16164615 DOI:
http://dx.doi.org/10.1111/j.1523-1755.2005.00551.x
http://dx.doi.org/10.1111/j.1523-1755.20...
,3333. McCullough PA, Verrill TA. Cardiorenal interaction: appropriate
treatment of cardiovascular risk factors to improve outcomes in chronic kidney
disease. Postgrad Med 2010;122:25-34. PMID: 20203453 DOI:
http://dx.doi.org/10.3810/pgm.2010.03.2119
http://dx.doi.org/10.3810/pgm.2010.03.21...
In our study, each
patient took a mean of 5.6 ± 3.2 active ingredients as part of their drug regimen, in
a situation which certainly implied greater risk of DI. Moreover, most of the
individuals had CKD stages 3 and 4 and were on cardiovascular medication (57.6%),
drugs acting on the alimentary tract and metabolism (16.4%), and drugs affecting the
blood and blood-forming organs (10.9%). A recently published prospective study found
similar percentages of use of medications in CKD patients undergoing conservative
treatment.2525. Belaiche S, Romanet T, Allenet B, Calop J, Zaoui P. Identification
of drug-related problems in ambulatory chronic kidney disease patients: a 6-month
prospective study. J Nephrol 2012;25:782-8. DOI:
http://dx.doi.org/10.5301/jn.5000063
http://dx.doi.org/10.5301/jn.5000063...
Therefore, polypharmacy in
this population has been associated with increased potential for drug
interactions.
The use of cardiovascular drugs and medications acting on the metabolism as seen in our group of patients was consistent with the observed strong correlation between drug interactions and DM, hypertension and advanced CKD.
Another significant finding was the correlation between obesity and DI, which could
stem from changes in the pharmacokinetics of lipophilic drugs secondary to the
accumulation of adipose tissue,3434. Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den
Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults
and children. Clin Pharmacokinet 2012;51:277-304. DOI:
http://dx.doi.org/10.2165/11599410-000000000-00000
http://dx.doi.org/10.2165/11599410-00000...
,3535. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the
pharmacokinetics of drugs in humans. Clin Pharmacokinet 2010;49:71-87. DOI:
http://dx.doi.org/10.2165/11318100-000000000-00000
http://dx.doi.org/10.2165/11318100-00000...
as well as the
increased propensity toward polypharmacy seen in this population. However, these
mechanisms were not the object of this study.
Notwithstanding the limitations inherent to a single-center study, the results reported herein were promising and revealed the significant potential of clinically relevant drug interactions. Our findings call for the optimization of the drug regimens offered to CKD patients in order to prevent the incidence of DRP. Studies with larger numbers of patients may confirm this hypothesis.
Conclusion
A significant percentage of individuals with chronic kidney disease managed conservatively had potentially severe drug interactions in their prescriptions. In this population, the risk factors for the occurrence of drug interactions were diabetes mellitus, hypertension, obesity, and advanced chronic kidney disease.
Acknowledgement
The authors with to thank the Centro Hiperdia Minas, the Interdisciplinary Center for Studies and Research in Nephrology of the Federal University of Juiz de Fora (NIEPEN); the IMEPEN Foundation in Juiz de Fora, and CAPES. And Dr. Hélady Sanders Pinheiro, Luanda Santos, Moisés Carminatti, and Gean César Vieira for reviewing the manuscript.
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34Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet 2012;51:277-304. DOI: http://dx.doi.org/10.2165/11599410-000000000-00000
» http://dx.doi.org/10.2165/11599410-000000000-00000 -
35Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 2010;49:71-87. DOI: http://dx.doi.org/10.2165/11318100-000000000-00000
» http://dx.doi.org/10.2165/11318100-000000000-00000
Publication Dates
-
Publication in this collection
Jan-Mar 2014
History
-
Received
18 May 2013 -
Accepted
11 Oct 2013