Wooten, James M. PharmD
* Utilization of pharmaceuticals has increased substantially over the past several years, and made the incidence of drug-related problems a common occurrence.
* Pharmacovigilance is a science incorporating the detection, assessment, understanding, and prevention of adverse effects, particularly long-term and short-term side effects of medicines.
* Medication errors do frequently occur, but not all adverse drug reactions are attributable to medication errors. Some result from drug-drug or drug-disease state interactions, and others are due to toxic reactions caused by overdosage.
* Adverse drug reactions may be caused by drug allergy, which can induce severe responses that may be deadly to susceptible individuals.
* Health care workers must consider the potential for an adverse drug reaction at the time the drug is ordered, rather than waiting until a problem occurs.
In an attempt to define obscenity in a 1964 case, Justice Potter Stewart famously stated, “I know it when I see it.”1 In contrast to this statement, adverse drug reactions (ADRs) are not easily identified or recognized. This is surprising, since utilization of pharmaceuticals has increased substantially over the past several years and made the incidence of drug-related problems a common occurrence. Even though ADRs have gained notoriety, health care professionals still have trouble recognizing and preventing these calamities.2,3
The World Health Organization (WHO) defines an ADR as “any response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function.”4 Adverse drug reactions, then, are essentially any type of untoward event related to a drug's administration, regardless of etiology. Over the past several years, ADRs have gained national attention. The media has published numerous articles discussing the disturbing trend in the proliferation of adverse reactions from drugs prescribed by doctors. Law firms advertise on television and the internet, asking patients to contact them if they are even taking certain notorious agents. These details have caught the attention of government bureaucrats, who have made tackling ADRs a governmental priority. What does all this mean? It means that ADRs are mainstream news. Consumers are interested in avoiding ADRs, and health care workers must get serious about preventing them. As the number of pharmaceuticals proliferates, so does the number of untoward effects caused by new drugs, which means that the potential for ADRs is always increasing.
The science of adverse drug reactions is called pharmacovigilance (PV).5,6 Pharmacovigilance is a science incorporating the detection, assessment, understanding, and prevention of adverse effects, particularly long-term and short-term side effects of medicines.6 Because ADRs have become commonplace, the United States Food and Drug Administration (FDA) has made a mandate to enact a system of PV to be followed by regulatory agencies, pharmaceutical companies, and individual health care providers.7 The rules and regulations generated by the FDA are important, and PV is a science that must be practiced by all health care workers. In fact, pharmacovigilance is most effective when all those responsible for providing health care take an active role in monitoring for adverse drug reactions.
ADRs pose a considerable threat to the population at large. Various studies provide a wide range of epidemiological data regarding adverse drug reactions. ADRs are listed as one of the top ten causes of death in the United States, with more than 100,000 deaths annually attributed to various ADRs.7–9 The cost of ADRs is estimated to be $1.5–$4 billion per year.10 Approximately 2–5% of all hospital admissions can be attributed to adverse drug reactions.5 Adverse drug reactions have become a big liability for health care providers, and account for a significant number of lawsuits. These numbers are already staggering, and they will only get worse.
Unfortunately, many practitioners still consider adverse drug reactions to be an exception, rather than a primary diagnosis. Health care providers do not ignore the occurrence of ADRs or the potential serious effects of medications, but in many instances, ADRs are relegated to the thought process of, “Well, everything else is negative; maybe it is one of the patient's medications causing this.” This pattern of thinking is understandable. ADRs are still thought to be mistakes or medication errors, and health care providers are taught to not admit culpability in any way.8,11,12 Medication errors do frequently occur, but not all ADRs are attributable to medication errors. Many ADRs occur unexpectedly or by happenstance, while others are expected. Some result from drug-drug or drug-disease state interactions, and others are due to toxic reactions caused by overdosage.13 Properly identifying and classifying ADRs is a vital step in addressing this problem.4,7,8
Adverse drug reactions have become an epidemic, and health care providers must begin to consider ADRs prospectively and thoughtfully. Health care workers must consider the potential for an adverse drug reaction at the time the drug is ordered, rather than waiting until a problem occurs. Problems that do occur are often not attributed to an adverse effect from a drug until other causes are ruled out. This retrospective approach to ADRs may provide adequate patient care, but one wonders if consideration of potential adverse effects from a particular drug at the time the prescription is written, rather than later in the process, might result in rapid recognition of the adverse event and thus reduce patient morbidity. Prospective consideration and rapid recognition are the keys to avoiding drug-related problems. Even if a patient experiences no problems, the practitioner should take the time to consider the most probable ADRs that could be attributed to the patient's pharmacotherapy regimen. Physicians should always include “potential adverse drug reactions” in their patient assessments, and have a plan for monitoring and treating reactions should they occur. Prospective recognition of ADRs cannot prevent adverse drug reactions from occurring, but it can reduce the time it takes to identify an ADR, potentially improving patient outcomes.12–15
Classifying Adverse Drug Reactions
Adverse drug reactions can be classified in various ways. Remember, ADRs are a subset of a larger group known as medication errors or medication misadventures. Medication errors occur for a wide variety of reasons not limited simply to the adverse reactions of the drug, but encompassing the entire realm of drug-induced problems, such as willful or unintentional negligence, intentional overdosage, inappropriate medication use, etc. ADRs can be divided into Type A and B drug reactions. Type A reactions are probable and predictable based on the drug's pharmacologic profile.8 An example of a Type A reaction is insulin-induced hypoglycemia, is a known and predictable side effect caused by the exogenous administration of insulin. The effect of this example is also dose-related, but Type A ADRs are not necessarily caused by overdosage. These reactions are predictable, and expected to possibly occur in a certain percentage of individuals based on current scientific evidence. Generally, Type A reactions are identified in premarketing trials mandated by the FDA. After a drug is approved by the FDA, collected postmarketing information may identify further information about its known reactions, and may also identify susceptible groups who are predisposed to certain ADRs.5,8,9
The more troublesome category is Type B adverse drug reactions. Type B ADRs are unpredictable and unanticipated. These drug effects are also referred to as idiosyncratic drug reactions. Unlike Type A reactions, idiosyncratic drug reactions are generally defined as untoward effects that cannot be explained by the known pharmacologic actions of the offending agent, are not dose-related in most patients, and may develop quite unpredictably in susceptible individuals.8,16 These reactions are difficult to anticipate and predict. Often, ADRs classified as Type B reactions are not identified in premarketing trials, and are only exhibited when the drug has been on the market for some time and used in a wide variety of patient populations. Examples of this type of ADR include the following16,17:
* The selective cyclo-oxygenase inhibitor rofecoxib (Vioxx®, Merck & Co., Inc., Whitehouse Station, NJ) was approved by the FDA in 1999. Vioxx® quickly became a money-making product for treating arthritis. In 2000, a study on rofecoxib known as APPROVe (Adenomatous Polyp Prevention on Vioxx®) was initiated. APPROVe was a multicenter, randomized, placebo-controlled, double-blind study which aimed to determine the effect of Vioxx® on the recurrence of neoplastic polyps. Over 2,600 patients were involved in this study. The patients receiving Vioxx appeared to have an increased risk of cardiovascular complications. It was later determined that the drug's manufacturer may have had information prior to the study which was corroborated by the new information obtained from the APPROVe study. Vioxx® was withdrawn from the market in 2004. The FDA and the manufacturer are still trying to sort out the exact cause of the drug's adverse effect.18
* Terfenadine (Seldane®, Hoechst Marion Roussel, Kansas City, MO) was one of the first second-generation, non-sedating antihistamines approved for use by the FDA. In 1997, the FDA recommended that the drug be taken off the market because of several reports documenting the risk of cardiac arrhythmia due to QT interval prolongation caused by the drug. Patients with a cardiac history and patients on specific medications which were known to interact with terfenadine (resulting in increased terfenadine serum concentrations) were at greatest risk. This effect was not common, but potentially deadly if it did occur.19
The examples above illustrate side effects that were not expected or anticipated based on the pharmacology of the drug. These side effects came to light after further studies were conducted or various case reports were supplied via postmarketing surveillance documenting the adverse events.
ADRs may also be caused by drug allergy. The term allergy implies that specific side effects to the drug develop when the drug acts as an antigen or allergen, and an immune-mediated drug response is exhibited. Drug allergies can be further subdivided in several ways, and can induce severe responses that are deadly to susceptible individuals.5,8,9
* Type I allergic reactions are classified as immunoglobulin E (IgE)-mediated. An example of this type of allergy is anaphylaxis induced by beta-lactam antibiotics (penicillin allergy).20
* A Type II reaction is cytotoxic. An example of this is a specific type of thrombocytopenia induced by heparin, which can be quite severe.20
* A Type III reaction is categorized as immune complex, and occurs when antigens and antibodies (immunoglobulin G [IgG] or immunoglobulin M [IgM]) accumulate in the body in equal amounts, causing extensive cross linking. An example of this reaction is hydralazine-induced systemic lupus erythematosus (SLE).20
* Type IV reactions are described as delayed or hypersensitivity reactions. These generally take 2–3 days to develop and are not described as antibody-mediated, but instead are induced by a cell-mediated response. Contact dermatitis caused by an offending skin product is an excellent example of this type of reaction.20
Other types of allergic drug responses have been described, but the above categories illustrate the most common forms. The practitioner must understand the difference between a drug allergy and a drug side effect. All allergic drug responses (drug allergies) can be considered as drug side effects, but not all side effects induced by drugs are caused by an allergic response. This is not a trivial difference; many patients are labeled allergic to a particular drug, when in reality they simply experienced a dose-related side effect. For example, a patient may state that he or she is allergic to narcotics because these drugs caused gastrointestinal discomfort. This response is not an allergy, but a Type A adverse effect. In patients with true drug allergies, the specific drug and drugs in the same class should be avoided if possible. A patient with a known drug side effect may respond to simply lowering the drug dose. Patients may not understand this difference, so a thorough patient history must be conducted to differentiate between drug allergies and drug side effects.5,8,9
Once the occurrence of an adverse drug reaction is established, the FDA usually also rates the severity of the reaction. ADRs can be assigned as mild, moderate, severe, or lethal based on the severity of patient response. The term “serious” has been defined by the FDA as an adverse drug reaction that “results in death, a birth defect, disability, or hospitalization; is life-threatening; or requires intervention to prevent harm.”21 These descriptors are largely subjective, and are generally established by the health care provider.
Another ADR classification scheme is based on frequency of the occurrence of a particular drug-induced reaction. Based on pre-approval studies and postmarketing reports, the frequency of a particular ADR can also be hypothesized. ADR frequency definitions for adverse events are generally defined as very common (≥1/10), common (≥1/100 but <1/10), uncommon (≥1/1,000 but <1/100), rare (≥1/10,000 but <1/1,000), and very rare (<1/10,000).13,14 These basic definitions are utilized to describe and classify adverse drug events. These data attempt to quantify adverse drug reactions to some degree, and may simply refer to the general population, rather than specific groups in which a particular ADR may be common. For instance, a potential side effect may be much more likely if it is administered to a patient with known hepatic or renal insufficiency because of the potential for reduced metabolism. ADRs are usually more prevalent in the elderly, who experience a reduction in drug metabolism due to age. Geriatric patients might also be more prone to a particular drug's side effects because of potential interactions with other agents, as medication use is much more prevalent in the elderly than in the general population.
Statistics are only true if it happens to the other guy. If it happens to me—it's 100 percent.22
2.Hohl CM, Robitaille C, Lord V, et al. Emergency physician recognition of adverse drug-related events in elder patients presenting to an emergency department. Acad Emerg Med 2005;12:197–205.
3.Farcas A, Bojita M. Adverse drug reactions in clinical practice: a causality assessment of a case of drug-induced pancreatitis. J Gastrointestin Liver Dis 2009;18:353–358.
5.Kavitha D. Adverse drug reaction (ADR) monitoring and pharmacovigilance. J Pharm Res Health Care 2010;2:127–134.
8.Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options [Review]. Am Fam Physician 2003;68:1781–1790.
9.Oberg KC. Adverse drug reactions. Am J Pharm Educ. 1999;63:199–204.
10.Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200–1205.
11.Bond CA, Raehl CL. Adverse drug reactions in United States hospitals. Pharmacotherapy 2006;26:601–608.
12.Davies EC, Green CF, Taylor S, et al. Adverse drug reactions in hospital in-patients: a prospective analysis of 3695 patient-episodes. PLoS One 2009;4:e4439.
13.Wooten J. Reporting adverse drug reactions. South Med J 2009;102:345–346.
14.Wooten J. Adverse drug reactions. South Med J 2006;99:915.
16.Pillans PI. Clinical perspectives in drug safety and adverse drug reactions. Expert Rev Clin Pharm 2008;1:695–705.
17.Corrigan OP. A risky business: the detection of adverse drug reactions in clinical trials and post-marketing exercises. Soc Sci Med 2002;55:497–507.
18.Woloshin S, Schwartz LM. Bringing the FDA's information to market. Arch Intern Med 2009;169:1985–1987.
20.Greenberger PA. 8. Drug allergy. J Allergy Clin Immunol 2006;117:S464–S470.
22.Tseng DS, Kwong J, Rezvani F, et al. Angiotensin-converting enzyme-related cough among Chinese-Americans. Am J Med 2010;123:183.e11–183.e15.
Product Code: SMJ10-10C
Adverse Drug Reactions: Part I
October 2010 CME Questions
1. True statements regarding adverse drug reactions (ADRs) in the United States include which of the following?
A. Currently, ADRs cost an estimated $1.5–$4.3 billion/year.
B. Approximately 2–5% of all hospital admissions can be attributed to an ADR.
C. ADRs have become a major liability for healthcare providers.
D. All of the above are correct.
2. ADRs classified as Type A reactions:
A. are not usually identified in premarketing trials mandated by the Food and Drug Administration.
B. are also referred to as idiosyncratic drug reactions.
C. are generally predictable and probable because they are based on the drug's pharmacologic profile.
D. are usually difficult to anticipate and predict.
3. A patient breaks out in a rash soon after receiving amoxicillin. This is considered a
A. Type IV allergic reaction
B. Type II allergic reaction
C. Type III allergic reaction
D. Type I allergic reaction
E. none of the above
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October 2010 CME Questions — Answer Key
1. D, 2. C, 3. D