Potential Drug-drug Interactions Analysis in Children Out-patients with Bronchopneumonia Medication Prescriptions

Drug-drug interactions (DDIs) is defined as the alteration of efficacy and toxicity of some drugs in the presence of other drugs. In the treatments of bronchopneumonia in outpatient settings, there is a lack of documentation of DDIs. This study was aimed to observe the potential DDIs on the prescriptions of children with bronchopneumonia. An observational and cross-sectional study was conducted on outpatient children with bronchopneumonia prescriptions during 2017. Potential for DDI was identified by online drug interaction checkers. The potential DDI then classified based on its severity (minor, moderate, and major) and mechanism (pharmacokinetic and pharmacodynamic). Among 86 prescriptions analyzed, potential DDIs observed at 48.84% of it. Of that, there were 67 potential DDIs where 72.34% of it were categorized as moderate. The majority of potential DDIs was pharmacodynamic interaction (76.12%) with the most frequently involved drug pair was EphedrineSalbutamol (29.85%). Children outpatients with bronchopneumonia are at risk of potential DDIs, especially to minor and moderate potential DDIs. Prescriptions screening for potential DDIs followed by monitoring of therapeutical effects and associated adverse drug events will optimize patient safety.


INTRODUCTION
Drug-drug interactions (DDIs) is defined as the change of efficacy and toxicity of some drugs in the presence of other drugs (Shetty et al., 2018). The alterations occure both in pharmacokinetics (absorbtion, distribution, metabolism, and excretion) and pharmacodynamics (sinergism, antagonism, and competition in receptors) phase (Kulkarni et al., 2013;Palleria et al., 2013). In the clinical settings, DDIs is the main source of adverse drug event (Somogyi-Vegh et al., 2019). A recent meta-analysis of several studies reports that DDIs has contributed to 1.1-5% of hospitalization and 0.25-25% of the adverse drug reaction related to hospitalization (Dechanont et al., 2014;Ismail et al., 2018). In outpatient settings, there is a lack documentation of DDIs and its prevalence is reported lower than in hospitalized patients because they are usually prescribed less drug combination (Vaidhun & Sathish, 2011). However, if they are prescribed with polypharmacy the potential of DDIs occurence will also rise.
Bronchopneumonia is one of life-threatning pneumonia manifestation commonly occur in children under 5 y.o.
As the treatment of pneumonia, causative management using antibiotics and symptomatic drugs like antitusive, expecorant, antihistamine, analgesic-antipyretic used in bronchopneumonia management (Harris et al., 2011;Chang et al., 2014). Hence, high combination drugs potentially prescribed to the children with

Abstract
Drug-drug interactions (DDIs) is defined as the alteration of efficacy and toxicity of some drugs in the presence of other drugs. In the treatments of bronchopneumonia in outpatient settings, there is a lack of documentation of DDIs. This study was aimed to observe the potential DDIs on the prescriptions of children with bronchopneumonia. An observational and cross-sectional study was conducted on outpatient children with bronchopneumonia prescriptions during 2017. Potential for DDI was identified by online drug interaction checkers. The potential DDI then classified based on its severity (minor, moderate, and major) and mechanism (pharmacokinetic and pharmacodynamic). Among 86 prescriptions analyzed, potential DDIs observed at 48.84% of it. Of that, there were 67 potential DDIs where 72.34% of it were categorized as moderate.
The majority of potential DDIs was pharmacodynamic interaction (76.12%) with the most frequently involved drug pair was Ephedrine-Salbutamol (29.85%). Children outpatients with bronchopneumonia are at risk of potential DDIs, especially to minor and moderate potential DDIs. Prescriptions screening for potential DDIs followed by monitoring of therapeutical effects and associated adverse drug events will optimize patient safety.
bronchopnaumonia and its leading to the occurence of DDIs. The DDIs identification in bronchopneumonia prescriptions will optimize the outcome therapy and prevent the incidence of adverse drug reactions (Noor et al., 2019). This study was aimed to observe the potential DDIs on the prescriptions of children with bronchopneumonia. The prescriptions contained drugs that not listed in that two online applications were also excluded. The potential

MATERIALS AND METHODS
DDIs then classified based on its severity (minor, moderate, and major) and mechanism (pharmacokinetic and pharmacodinamic). The management suggestion from the online applications also included. Generally, the prevalence of potential DDIs is linear to the number of drug prescribed as Loya et al. (2009) reported that 46.2% dan 72.3% of polypharmacy had at least one potential DDIs. However, in this study the majority potential DDIs observed in the prescriptions contained less than five drugs. This discrepancy might be due to the prescribing culture and formulary used in the hospital.

RESULTS AND DISCUSSION
Out of the 42 potential DDIs found, most of them had moderate (80.95%) and minor (73.80%) severity that is sufficiently to warn us to have a monitoring for the potential dangerous, as shown in Figure 1. The prevalence of potential DDIs, its manifestations, and suggested management predominantly occur in the pharmacodynamic phase, as presented in Table II Elevated catecholamine concentrations will lead to adverse effects such as metabolic acidosis, hyperglycemia, cardiac arrhythmias, and hypokalemia (Kardalas et al., 2018). Additionally, corticosteroids conduce sodium retention through the increase of sodium tubular absorption and potassium excretion.
Sodium retention and potassium loss may result in hypokalemic alkalosis in patients receiving glucocorticoids (Nasralla et al., 2010). Consequently, if the benefits outweight the drawbacks, the use of dexamethasone and theophylline in children with bronchopneumonia should be followed by monitoring in potassium levels and the cardiovascular events (Zec et al., 2016).
In the pharmacokinetics phase, the most common DDIs observed was ephedrine+vitamin C. Acidic urine increases the urinal elimination of ephedrine. However, the severity is minor and the clinical significance is unknown. Apart from the result above, this study has several limitations. As this study showed the potential for DDIs in the prescriptions, the actual occurr of DDIs in the patients could not be determined because the study was a single point cross-sectional and out-patient based.
Moreover, herbal medicine and probiotics-contained prescriptions could not be determined for the DDIs.
Therefore, future studies on potential and actual occurrence DDIs in outpatient children with bronchopneumonia in future still need to be conducted.

CONCLUSION
A considerable prevalence of potential DDIs has been observed in children outpatients with bronchopneumonia (48.84%) where moderate potential DDIs were the most common. Moreover, the use of probiotics and herbal medicine in bronchopneumonia treatments still need to be considered related unknown potential DDIs. Prescriptions screening for potential DDIs followed by monitoring of therapeutical effects and associated adverse drug events will optimize patient safety.