JAMA ; 18 — Health care providers have misconceptions about reporting ADRs. However, the temporal relationship of a reaction with regard to the administration of a new medication can be helpful. The bottom line is, even when in doubt about whether a drug caused the reaction, report it. A health care provider does not have to be absolutely certain that a drug caused a reaction. All reports contribute to the heightening of the awareness of FDA safety scientists as they monitor all of the evidence to evaluate the potential for drug-related toxicity.
Many drug withdrawals began with one clinical report that initiated further investigation. In the example case in this module, a single report ultimately led to the removal of terfenadine from the market. This report potentially saved many lives and led to a better understanding of the mechanism involved in causing torsades de pointes. Almost all drugs are now evaluated prior to being released on the market for their potential to induce cardiac arrhythmias, also as a result of this single case report.
Med Care ;37 8 Attitudinal survey of voluntary reporting of adverse drug reactions. Br J Clin Pharmacol ;48 4 — Reporting of adverse drug reactions by poison control centres in the US. Drug Saf ;23 1 — The inability of the FDA to effectively warn health care providers and patients about drug interactions and our inability to translate existing knowledge into changes in prescribing have resulted in huge economic consequences for the pharmaceutical industry and the loss from the marketplace of effective drugs, including terfenadine, mibefradil, astemizole, and cisapride.
These 4 drugs were removed from the market or restricted in their use because it became clear that they continued to be prescribed in an unsafe manner, even after multiple warning letters were disseminated by the manufacturer and the FDA to health care professionals concerning their proper use.
Each of these drugs has value in the pharmaceutical marketplace, and each has value to patients. However, because the manufacturer and the FDA could not prevent co-prescription of these drugs with interacting drugs resulting in fatal interactions, the risk associated with continued widespread availability could not be justified.
This figure shows data from a national survey conducted in by the American Society of Health Systems Pharmacists ASHP 1 that evaluated patient concerns about health systems. This was a random telephone survey of 1, adults. Although the respondents were very concerned about suffering from pain and the cost of filling prescriptions, they were most concerned about being given the wrong drug or that a drug interaction would occur.
The public in general has a much greater level of concern about ADRs than most health care providers would suspect. These data demonstrate that drug interactions and reactions are not only a concern to health care providers but to patients as well. Bethesda, MD. Types of Drug Interactions.
The previous slides have reviewed information about the magnitude of adverse drug reactions and the burden they place on the health care system. How much do drug interactions contribute to the total number of preventable ADRs? Again, estimates of the numbers of patients injured due to drug interactions vary widely.
However, some reasonable estimates come from the work of Dr. Lucien Leape and colleagues. Drug interactions are also an important cause of patient visits to emergency departments. Systems analysis of adverse drug events. JAMA ; 1 — Suspected adverse drug events requiring emergency department visits or hospital admissions.
Eur J Clin Pharmacol ;54 12 — Recent publications have shown that many adverse drug reactions can be prevented and detected through the use of systems interventions.
For example, many health systems have instituted new technologies to minimize patient injury due to medication errors and drug-drug interactions. These technological solutions do have limitations, however. The fragmentation of healthcare delivery may result in incomplete records. More significant is the fact that, although this information is avail-able, it is not uniformly or optimally incorporated into decision making. This is exemplified in the observation by Cavuto et al.
These findings should reinforce the need for the health care practitioner to develop their own systems approach to prescribing without creating undesirable drug interactions. A fundamental understanding of the clinical pharmacology of drug interactions and a framework for avoiding preventable drug interactions remains critically important.
Thus we need to overlay technologic solutions on a base that is strong in basic principles of clinical pharmacology and drug interactions. Incorporation of up-to-date computerized databases is valuable, and frequent consultation with other members of the healthcare team, such as nurses and pharmacists, is essential.
Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA ; 15 — Preventing adverse drug events in hospitalized patients. Ann Pharmacother ;28 4 — VA facility slashes drug errors via bar-coding.
Drug Topics ; Pharmacies and prevention of potentially fatal drug interactions. JAMA ; — Contraindicated use of cisapride: impact of food and drug administration regulatory action.
JAMA ; 23 — We will discuss an approach to prescribing drugs in ways that avoid adverse drug interactions as a cause for preventable medication errors.
We will be looking at this topic in depth. Both slow the heart rate by different mechanisms, and the combination is relatively contraindicated because heart block can result. Because of this interaction many textbooks and computer pro-grams warn against concomitant use of any beta-blocker and any calcium channel blocker.
This creates a great deal of confusion and distrust of drug interaction warnings, because most health care providers know that drugs in these two classes are often employed successfully and safely in patients with hypertension.
The next few slides will review some of the mechanisms for drug interactions in more detail. Several examples of drug interactions that occur prior to drug administration are listed here. When phenytoin is added to solutions of dextrose, a precipitate forms and the phenytoin falls to the bottom of the IV bag as an insoluble salt.
When this happens, it is no longer available to control seizures. Amphotericin is still used widely as a urinary bladder perfusion to treat aggressive fungal infections. If it is administered in saline, the drug precipitates and can erode through the bladder wall if not removed. The clinical presentation of such cases is an acute abdomen due to perforation of the bladder.
This can markedly reduce antibiotic efficacy. A number of interactions occur in the GI tract and reduce the entry of drugs into the systemic circulation. Particularly notable among these is the ability of aluminum-containing medicines such as sucralfate Carafate and antacids to reduce the absorption of expensive and potentially life-saving antibiotics like ciprofloxacin Cipro and azithromycin Zithromax.
Women taking iron supplements often do not consider them as a medicines, and should be specifically questioned about whether they are taking iron if they are to be prescribed a quinolone or azithromycin. Drugs such as ketoconazole Nizoral and delavirdine Rescriptor require an acidic environment to be in the non-charged form that is preferentially absorbed. Some drugs can "bump" other drugs off proteins in the plasma and result in an increased amount of free drug, but this is only transient because the usual elimination mechanisms respond by increasing the rate of elimination.
There is no clinically relevant protein-bumping interaction that has been reported. The previously cited examples have subsequently been shown to be due to inhibition of elimination, not plasma protein displacement. The next few slides will focus on drug metabolism.
Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either inhibition reduced activity of the enzyme or induction increased activity of the enzyme.
There are many potential consequences of changes in drug metabolism for a given drug. It is made more complex by the fact that there are multiple pathways of metabolism for many drugs. The majority of drugs that are metabolized are converted to inactive metabolites. This is the most common fate for most drugs. Of the remaining drugs, some are converted to metabolites that retain the same activity as the parent.
An example of this is fexofenadine Allegra , the active metabolite of terfenadine that has equal potency at the histamine receptor and now is on the market and used clinically for allergic rhinitis. However, fexofenadine is more than 50 times less active in blocking potassium channels in the heart and therefore, unlike terfenadine, does not cause torsades de pointes.
In some cases the metabolites are actually more potent than the parent. For example, a pro-drug such as enalapril must be hydrolyzed to enalaprilat to become active. In some cases, the metabolites have entirely new pharmacologic actions not seen with the parent drug. Metabolites can also be toxic, such as the metabolites of acetaminophen, which can cause liver failure, or the metabolite of meperidine, which can cause seizures. Inhibition of metabolism could result in potentially toxic concentrations of the parent compound.
On the other hand, if the parent drug needs to be metabolized to the active compound and metabolism is inhibited, then a therapeutic failure could result. This happens, for example, if codeine, a prodrug, is not metabolized to morphine. Induction of drug metabolizing enzymes could similarly result in a subtherapeutic effect by reducing drug levels below that required for efficacy. Mechanism of the cardiotoxic actions of terfenadine. JAMA ; 12 — The major group of enzymes in the liver that metabolize drugs can be isolated in a subcellular fraction termed the microsomes.
The largest and most important of these enzymes are the cytochrome P family of enzymes. The origin of the term "cytochrome P" will be explained later. In addition to cytochrome P, there are other enzymes in microsomes such as flavin monooxygenase termed FMO3. These are also responsible for metabolism of some drugs, but have not been as well characterized as the cytochrome P system, and will not be discussed further in this presentation. Phase I reactions include oxidation or reduction reactions, usually through the actions of cytochrome P oxidative enzymes or reductases.
These enzymes prepare very lipophilic molecules for Phase II reactions by creating a conjugation site, often a reactive group such as an hydroxyl group. There are some characteristics of drug metabolism that can help predict important interactions due to inhibition of metabolism.
Since Phase II reactions generally result in conjugation of a drug to a water-soluble group like a sugar, peptide glutathione or sulfur group, and, because there is a large excess of these groups in well nourished cells, these reactions are rarely rate-limiting. Thus, they are rarely involved in drug interactions. In contrast, the Phase I reactions carried out by cytochrome P enzymes, flavin monooxygenases, and reductases are more frequently rate-limiting. These are the target of clinically significant drug interactions, such as the inhibition of cyclosporine metabolism by erythromycin.
Six cytochrome P isoforms have been well characterized in terms of drug metabolism in humans. These will be reviewed in the next few slides.
Phase I oxidative enzymes are mostly found in the endoplasmic reticulum, a subcellular organelle in the liver. The predominant enzymes responsible for Phase I reactions are those involving the microsomal mixed function oxidation system. These enzymes are companions and part of a cascade that shuttles electrons from molecular oxygen to oxidize drugs.
There are many different isoforms of cytochrome P, but 6 have been especially well characterized in terms of clinically relevant drug metabolism and will be discussed here.
As shown in the slide, the enzymes function in a cascade of oxidation-reduction reactions that ultimately result in one atom of oxygen being incorporated into an oxidized metabolite, such as the hydroxylated form of drug shown in the slide. This slide lists the major cytochrome P isozymes that are responsible for metabolism of drugs in humans.
These enzymes will be reviewed in detail. Because many drugs are metabolized principally by these enzymes, important interactions between drugs can be predicted by using a list of drugs that are inhibitors or inducers of that enzyme. This simplifies the search for interacting drugs and provides a framework for prediction of interactions. Next we will review how these enzymes are named. Cytochrome Ps were named by molecular biologists and protein chemists.
The enzymes are named according to families that are defined by the similarity of their amino acid sequence. A very important principle in pharmacology applies in this case: A small change in the structure of a drug or a protein that interacts with it can result in major changes in the actions of the drug.
Because of this great sensitivity, small changes in amino acid sequence can result in huge changes in substrate specificity for the cytochrome P enzymes. For example, 2C19 is the principal metabolic enzyme for omeprazole Prilosec metabolism, but a closely related enzyme, 2C9, has no catabolic effect on omeprazole. Thus, little functional similarity is imparted by the similarity in amino acid sequence on which this nomenclature is based.
However, as will be seen later, there is some concordance between classes of drugs and the P family that metabolizes them. The focus of the subsequent slides will be to outline the role of the cytochrome P isozymes in metabolism of commonly used drugs and to identify tools that can be used in clinical practice to avoid cytochrome Pmediated drug interactions.
The graph on the left lists the major isoforms of CYP and their relative roles in drug metabolism not relative amounts found in the liver based upon the number of drugs that are known to be metabolized by that particular isozyme.
The graph on the right summarizes the relative quantity of specific P families found in the liver. A large amount of cytochrome P has not yet been characterized.
There is tremendous variability between individuals in terms of expression of cytochrome P isozymes. For example, CYP2D6 is not present at all in some livers. Interindividual variations in human liver cytochrome P enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther ; 1 — The cytochrome P enzymes have 3 interesting properties that often make it possible to predict drug interactions.
First, some people have mutations in one or more of the nucleic acids in the DNA sequence expressing a given cytochrome P isozyme. As a result, the enzyme may be absent or have low, or no, metabolizing activity for drugs that are usually metabolized by that enzyme. People expressing a polymorphism will therefore metabolize drugs at a different rate than the rest of the population. This graph demonstrates a population drug metabolism distribution for CYP2D6.
On the graph, PM means poor metabolizer, EM means extensive metabolizer, which is the normal or usual phenotype, and URM means ultra-rapid metabolizer. As there is no fixed way to divide CADEC into two parts, one for system development and the other one for system evaluation, we adopt fold cross-validation.
The results of different methods are shown in Table 2 , where the highest values are highlighted in bold. In addition, we also analyze the performances of different methods on continuous and discontinuous ADR mentions, respectively, as shown in Table 3 , where the highest indices are highlighted in bold.
The strict -score difference between the methods using the two different representations ranges from 0. In this study, we propose a deep neural network i. It may be the reason for the improvement from subject-based embeddings and why simultaneously adding both the subject-based embeddings and knowledge-based embeddings does not bring further improvements.
As the distributions of continuous and discontinuous ADR mentions are imbalanced, it is easy to understand that the strict -score difference of the same methods for continuous and discontinuous ADR mentions is not small. How to tackle data imbalance is a possible direction for further improvement, which will be considered in the future.
The main challenge is exactly determining all words or tokens of mentions, not some of them. The errors of LSTM may fall into the following three categories. Some modifiers are missing. It is another case of our future work. The proposed representations actually provide two ways to connect different parts of discontinues entities; therefore, the proposed methods may have potential use for relation extraction, such as drug-drug interaction extraction.
In this paper, we investigate deep neural network-based ADR mention recognition. A deep neural network called LSTM-CRF combining long short-term memory LSTM neural networks a type of recurrent neural networks and conditional random fields CRFs is proposed to recognize continuous and discontinuous ADR mentions from social media in medicine and analyze effects of ADR mention representations, subject-based embeddings, and knowledge-based embeddings.
Moreover, some possible directions for further improvement are also presented. The authors declare that there are no conflicts of interest regarding the publication of this paper. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Academic Editor: Tianyong Hao. Received 26 Dec Accepted 13 Mar Published 19 Apr Abstract Social media in medicine, where patients can express their personal treatment experiences by personal computers and mobile devices, usually contains plenty of useful medical information, such as adverse drug reactions ADRs ; mining this useful medical information from social media has attracted more and more attention from researchers.
Introduction With rapid growth of online health social networks, such as DailyStrength. Related Work In recent years, social media has been increasingly used for medical research, especially for pharmacovigilance via mining ADRs from health-related posts.
Methods Before recognizing continuous and discontinuous ADR mentions, we should know how to represent them. Sentence 1 I experienced severe pain in my left shoulder. Table 1. Figure 1. Table 2. Table 3. Performances of different methods on continuous and discontinuous ADR mentions, respectively using strict criterion.
View at: Google Scholar I. Segura-Bedmar, P. View at: Google Scholar Z. Huang, W. Xu, and K. View at: Google Scholar Y. Zeng, X. Liu, Y. Wang et al. View at: Google Scholar R. Leaman, L. Wojtulewicz, R. Sullivan et al. View at: Google Scholar A. Benton, L. Ungar, S. Hill et al. Hadzi-Puric and J. Adverse drug reaction ADR is the fifth leading cause of death among Americans, surpassed only by heart disease, stroke, cancer, and lung diseases [ 3 , 4 ].
The economic consequences are still not well elucidated, but there are two points to consider: the cost related to treatment and the cost related to prevention. Estimates in France suggest that up to , patients per year require medical treatment due to ADRs and these patients often require hospitalization [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ].
Although there are systems to report ADRs, there is consistent under reporting. Therefore, the true rates of ADRs are difficult to determine, and cases leading to hospitalization or death may not be captured. Additionally, ADRs are important to detect and to report because the majority of them are considered preventable [ 13 , 14 , 15 ]. The Institute for Healthcare Improvement IHI trigger tool is a low-cost, low-tech method for detecting adverse events and adverse reactions through clues triggers such as: the use of antidotes, antiemetics, or antidiarrhea agents, variations in relevant laboratory tests such as the prothrombin time, INR international normalized ratio , plasma levels of low therapeutic index drugs phenytoin, carbamazepine, etc.
This technique seems to increase the detection rate of adverse events by a factor of approximately 50 compared to traditional methodologies [ 4 , 14 , 15 , 16 , 17 ]. The Hospital Israelita Albert Einstein , accredited by the JCI Joint Commission International is heavily involved in patient safety issues and has a pharmacovigilance program that monitors adverse events and ADRs; however, it suffers from a lack of accurate information about the actual number of adverse reactions and from a lack of specific monitoring indicators.
The objective of the present study is to estimate the prevalence of suspected adverse reaction to drugs in patients seeking treatment in the emergency room — ER , describing the causes and the related factors, using the trigger tool method. Its emergency department treats patients daily. The study gathered data from randomly selected patients treated in the emergency department Fig. This study was approved by Institutional Research Ethics Committee. Inclusion criteria included the administration of specified trigger medications, drugs that might be given in response to suspected adverse reactions to other drugs.
Each trigger medication administration was identified via review of the electronic medical record. The following medications were used as triggers: antihistamines and anti-allergy medications that can be used in cases of anaphylactoid or allergic reactions: diphenhydramine, fexofenadine, methylprednisolone, hydrocortisone, and hydroxyzine. Medications used to reverse the action of other drugs were also used as triggers: phytomenadione, used to reverse the action of oral anticoagulants such as warfarin; acetylcysteine, which, among other things, is used in cases of paracetamol and acetaminophen overdose; naloxone, a medication used to reverse the action of opioids morphine, methadone, fentanyl, codeine ; and flumazenil, a medication used to reverse the action of benzodiazepines alprazolam, bromazepam, clobazam, clonazepam, diazepam, flunitrazepam, midazolam, and lorazepam.
Emergency department patients that did not receive a trigger medication were excluded. Among the triggers used to detect adverse events, we chose drugs that are normally used to reverse adverse reactions in the hospital. We did not use other trigger medications related to diagnostic exams, use of specific treatments like dialysis or blood transfusion, or surgical procedures, transfer to critical care units, or activation of a rapid response team.
The Naranjo Scale was used to assess causality, and the cases were classified as: doubtful, possible, probable, or definite [ 18 ]. The patients were stratified into three age groups: under the age of 18 years, between 18 and 60 years, and those over 60 years. The International Code of Diseases — ICD 10 [ 19 ] was used to classify the diagnoses for the emergency department visit.
The cost was calculated for the visits of patients involved in the suspected events. It included all procedures, medications and daily hospitalization costs. Inter-rater reliability regarding the identification of suspected ADRs was determined using the Kappa coefficient [ 20 , 21 ]. The study was exempted from the requirement for informed consent after an evaluation by the Committee for Ethics in Research.
Categorical variables were described by absolute frequencies and percentages, and the numerical variables, by median and interquartile range IQR , in addition to the minimum and maximum values. The sample size was calculated based on the proportion of suspected adverse reaction to drugs in patients seeking treatment in the emergency room.
Assuming that the rate of occurrence of ADR is 2. To estimate the prevalence of visits to the emergency room due to suspected adverse drug reactions, a model of generalized estimating equations GEE was set, considering the correlation between measurements on the same patient on different visits. Stratifying by age, There were 44 evaluations conducted by two raters to assess inter rater reliability. As for the presence of adverse reactions, the raters agreed in As for the Naranjo Scale, the raters agreed in The most frequent diagnoses for which the offending drug was prescribed the underlying diseases identified by the physician who attended the patients were related to otorhinolaryngology The majority of patient did not require hospitalization The rate of occurrence of ADR was 2.
Thus, it was necessary to adjust the ratio to monitor this duplication. Considering the repetition of events in one patient, the estimated rate is 2. By adjusting the model to estimate the prevalence of visits to the emergency department due to suspected adverse reactions, we found the estimated prevalence to be 2.
The prevalence was 2. With regards to age, the prevalence of ADR was 1. Among the most frequent diagnoses at the time of presentation for the ADR in this group were upper airway infections There were no reaction cases classified as doubtful or definite, and there were no fatal cases Table 2. Of the 21 ADRs observed in the sample, Although there are various reporting systems for adverse reactions and adverse events, there is consistent under-reporting of ADR, and it has been shown that many ADRs represent known interactions and are likely to be preventable [ 13 , 14 , 15 ].
In this study, drugs considered as triggers were used to identify suspected adverse reactions of patients presenting to the emergency room, and a 2. Several studies conducted to identify adverse events among patients in the emergency room using various other methodologies found incidence rates between 0. In spite of studies indicating that the number of visits to emergency departments due to an ADR is higher in elderly patients [ 29 ], the present study did not find an association between cases of suspected ADRs and age.
A recent — study of surveillance data in the United States [ 28 ] identified that the most common cause of these events were related to anti-infectives, similar to what we found in the present study.
Anticoagulants, diabetes agents and opioid analgesics were implicated as other commons reasons for emergency department visits related to ADRs in the national survey [ 28 ], while the present study found cardiovascular drugs and musculoskeletal drugs as common medications causing ADRs, with these categories also appearing in other studies [ 26 , 27 , 28 , 29 , 30 , 31 ].
Another American study found their most frequent diagnoses associated with the adverse reaction to be: skin conditions, gastrointestinal illnesses, and neurological conditions [ 27 ].
In the present study, the most frequent diagnoses were: upper airway infections, unspecified acute bronchitis, unspecified dermatitis, urticaria, and unspecified allergies. The present study had no reaction cases classified as definite or doubtful. In another study in elderly patients, In the United States, In the present study, we found that One of the limitations of the present study was the use of trigger drugs alone to identify suspected ADRs [ 28 ].
No searches for abnormal results from laboratory tests were included. It needs to be stated that not all ADRs require medications that would be identified as trigger drugs, so in this study such ADRs would not have been detected. Another limitation is that, since it was a retrospective study, there was no access to other information from the patients, such as the use of herbal medicines and other alternative therapies before the event; the information was limited to what was described in the medical charts of these patients.
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