Drug Interaction Management in Critically Ill Patient

Drug interaction in critically ill patient is very common and affecting patients Physically, Mentally and Financially. There are various measures which has been taken to minimize this burden on patient, such as books being prepared which include various drug interaction, maintain websites and database that provides information regarding drug interactions. With the use of these website and databases the drug interaction can be managed. It is common practice that side effects of drug interaction are being managed by additional drugs, the main reason behind it could be nonavailability of alternative drugs or costlier alternative. These factors remain the main cause of treatment failure in majority of patients leading to prolong. The current study was performed for the duration of 12 months, from this study it was identified that 113 types of major drug interactions commonly found in total 250 prescriptions which were evaluated and managed accordingly. Suggestions being prescribed by various sites were, avoid concomitant use of drug, use alternative therapy, and monitor closely for any adverse effect. During suggestion made by the Clinical Pharmacist, for the same drug interactions it was identified that more of drug therapy adjustment can be done then provided by the online database. The parameter on which the drug interactions management are being suggested were focused on just type of drug interaction and its effect, it does not include the actual pharmacodynamic and pharmacokinetic changes in therapy. The suggestion made by the clinical pharmacist were includes drug removal, drug dosage changes, alternative therapy, alternative route of administration, change in time interval etc. From this study it Original Research Article Rajput and Shah; JPRI, 33(43B): 396-416, 2021; Article no.JPRI.73643 397 was concluded that the drug interaction management can be done at various stages of treatment with proper therapy modification by the clinical pharmacist, and if done properly it will improve the overall outcome of patient health care.


INTRODUCTION
The treatment of critically ill patient is never been simple, these patients require special arrangements at hospital and expensive drug therapy. It becomes more difficult for a health care system to provide a good and satisfactory treatment to these patients as there are increase chance of Drug Interactions (DIs) with addition of every drug in the patient drug therapy. It is a known fact symptom either as disease condition or as side effect of drug interaction being treated with additional drugs rather than any other means. The impact of drug interactions has been very well studied and documented in various research articles. These research articles have shown that how it is being affecting patients physically, Mentally and financially. Any effect from a drug interaction also affects the decision making in the drug therapy, causing additional burden on the doctors who certainly relay on the gold standards and guidelines provided by various health care statutory bodies [1][2][3]. The DIs can be divided in majorly two categories Pharmacokinetic drug interactions and Pharmacodynamic drug interactions. Both of which may lead to increase the toxicity of the drug or decrease its effectiveness. There are various mechanisms through which either of increase or decrease of drug effects can be achieved. By understanding Pharmacokinetic and Pharmacodynamic properties of the drug it is possible to predict the effect of drug on the patient. The Pharmacokinetic drug interactions can be elaborated more as, the changes in the concentration of drug in the various body masses such as body fluids and body tissues. These changes generally occur during the process of drug absorption, drug distribution and elimination of the drug. For Pharmacokinetic interaction to occur metabolism of drug is necessary and for this to occur the drug should undergo through two phase of metabolism which are Phase I and Phase II metabolism. The Phase I includes the oxidative transformation of the drug and the Phase II increases the polarity of the drug by the means of conjugation reaction with the endogenous groups like glucuronides or sulfates. When it comes to Pharmacodynamic drug interactions, it is usually associated with alteration in safety and efficacy of the drug. Which may or may not include alteration in the drug Pharmacokinetic profile. Generally, when two drugs of same objective in a treatment given together can produce additive or synergistic effects on patient body, such effects can be considered under Pharmacodynamic drug interactions. DIs can be managed by understanding mechanism through which the interaction is occurring. The understanding of pharmacokinetic and pharmacodynamic properties and applying same on the individual patient can help in reduction of drug interaction and related effects drastically. With the understanding of pk and pd properties of drugs which are interacting a clinical pharmacist can provide a proper drug therapy of prescribed drugs. The prepared drug therapy may include changes in drug dosage, route of administration, different salt formation, addition or removal of drug if necessary [4]. The availability of various drug interaction related information providing database has gain popularity in the recent decade. The provided drug interaction database does contain information for severity, possible effect of interaction on patient, mechanism of drug interaction and source of information form where it has been collected. The very crucial part of provided information on drug interaction is first its management and second its source of information with appropriate justification. The database does lacks in quality of these two parameters. This lacuna can be fulfilled with the help of clinical Pharmacist actively managing drug interaction at the bedside with constant monitoring of the drug chart at the hospital [5]. The practice of Evidence based medicine is a part of the evolutionary medical care. It is necessary to keep in check the type of evidence available for the drug interactions also and keep them updating. The updated version for classification of evidence as per by Centre for Evidence Based Medicine: Levels of Evidence (March 2009) can be used to classify the level of evidence provided in various online drug interaction database to provide necessary strength to the claim of drug interaction. The current study is an attempt of provide best possible management of drug interactions to the critically ill patient with the help of the online drug interaction data bases and various research articles available online.

METHODOLOGY
The Intensive Care Unit of Dhiraj General Hospital was the site of data collection for this study. The study was a retrospective observation study conducted for the duration of 12 months (November 2019 to October 2020). The objective of the study was to identify common drug interaction in critically ill patient, To identify the level of evidence references used by various drug interaction database, and to identify type of drug interaction categories in major and moderate type. Total 251 cases were analysed for the drug interactions. The drug interaction was identified with the help of various drug interaction data providing websites Micromedex and Medscape. The selection of Critically Ill patient was made on the basis of inclusion and exclusion criteria.
Inclusion criteria: Patient admitted at Intensive care unit, only patient who were 18 year and above included in the study. The Patient admitted in ICU will be considered Critically Ill. Exclusion criteria: Those patient drug charts which does not containing drug interaction was not included. The identified drug interaction was assessed for its severity and interaction with Major and Severe type of drug interaction were selected for further analysis. Drug interaction found to be Major or Severe then provided with Management from either source of online drug interaction database and Clinical Pharmacist approach of information retrieval from research article and available medical books. The gathered information was then provided to treating doctor who will manage patient treatment accordingly. Descriptive statistics was applied for the analysis of data.

RESULTS
In this study total 345 drug interaction were identified from 251 prescription out of which 113 were Major and 232 were Moderate type of interaction (Fig 1). Total 24 type of Major drug interaction were found to be most frequent (Table 1).
Total number of drug interaction found was 345 out of which 113(32.75%) was Major or Severe, 232(67.24%) was Moderate. Table 2 shows all major drug interactions, common types of disease conditions possible effect of drug interaction on the patient, management give as per the online database, frequency of drug interactions and level of evidence of the interactions.
This table shows Highest Level of Evidence provided for drug interaction in online data base. The level of Evidence has been provided on the basis of chart provided by Centre for Evidence Based Medicine: Levels of Evidence (March 2009). Majority of drug interaction provide in online database were having a poor level of evidence i.e., 71 drug interaction was having level 5 evidence followed by 15 drug interactions were having level 3b and only 10 drug interactions were having level 1b evidence.

DISCUSSION
In this study 251 prescriptions were included from which total 345 drug interactions was found. Out of those 345-drug interaction 113 were major drug interactions and 232 were moderate drug interactions. 1/3rd of total interaction was major drug interaction. In a similar study conducted at Cardiothoracic ICU has shown that 1/4th of the total interaction found were major drug interaction [6]. Another study conducted in ICU have shown that 15 percent of total drug interaction were highly significant [7]. Another similar study has shown that 54 percent of potential drug-drug interaction occurred in ICU patient and from those interaction 90 percent of interactions can be set in 20 set of potential drug interactions types [8]. The study also shows that the most common type of effect form drug interaction was QT interval prolongation, Increased risk of bleeding and cardiac arrythmias. Majority of patients were suffering from Cardiovascular, Neurological and Nephrological disease conditions. The most frequent major drug interaction found were Aspirin with Furosemide, Aspirin with Clopidogrel, Aspirin with Heparin, Aspirin with Ramipril, Aspirin with Spironolactone and Aspirin with Heparin. Similar study has shown most common drug interaction were between antihypertensive, anticoagulants and antiplatelet agents [9]. In a study conducted at United Kingdom on combination therapy of clopidogrel and aspirin shows significant increase in bleeding time through synergistic antiplatelet action [10]. Similar study conducted titled antagonism of spironolactone induced natriuresis by aspirin has been observed. The study has shown that 1/3rd reduction in sodium excretion can affect the treatment of patient adversely for the patient treated with spironolactone for ascites or edema [11]. Another study shows that Dexamethasone, Ciprofloxacin, Tramadol, Moxifloxacin, Diclofenac, Pantoprazole and Theophylline [12]. The level of evidence provided by the online database for the given major drug interaction were majorly of poor level of evidence i.e., 71 drug interaction with level 5 evidence followed by 15 drug interactions of 3b, 10 drug interaction of 1b, 6 drug interaction of 4 and 5 drug interaction of 2b. Article reviewed for the identification of level of evidence of the drug interaction in Table 1 [13-51].

CONCLUSION
From this study it was concluded that 1/3 rd of the total drug interaction was major drug interaction in critically ill patient. The most common drug interaction found were between anticoagulants, antiplatelet and antihypertensive drugs. The level of evidence provided for majority of drug interaction were of level 5, 3b, 1b and 2b. The evidence provided for majority of drug interaction in various database were poor and least reliable.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors. Synergistic interactions between the dual serotonergic, noradrenergic reuptake inhibitor duloxetine and the non-steroidal anti-inflammatory drug ibuprofen in inflammatory pain in rodents. European