adverse drug reactions 1
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Product Code: SMJ10-10C
CME Topic
Adverse Drug Reactions: Part I James M. Wooten, PharmD
Abstract: Pharmacovigilance is the process of identifying, monitoring,
and effectively reducing adverse drug reactions. Adverse drug reactions
(ADRs) are an important consideration when assessing a patient’s
health. The proliferation of new pharmaceuticals means that the inci-
dence of ADRs is increasing. The goal for all health care providers must
be to minimize the risk of ADRs as much as possible. Steps to achieve
this include understanding the pharmacology for all drugs prescribed
and proactively assessing and monitoring those patients at greatest risk
for developing an ADR. Groups at greatest risk for developing ADRs
include the elderly, children, and pregnant patients, as well as others.
Pharmacovigilance must effectively be practiced by all health providers
in order to avoid ADRs.
Key Words: adverse drug reactions, adverse reactions, drugs, phar-
macology
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 substan-
tially 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 pro-
phylaxis, diagnosis, or therapy of disease, or for the modifi-
cation 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 me-
dia 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? Itmeans that ADRs are mainstream news. Consumers are in-
terested in avoiding ADRs, and health care workers must get
serious about preventing them. As the number of pharmaceu-
ticals proliferates, so does the number of untoward effects
caused by new drugs, which means that the potential for
ADRs is always increasing.
Pharmacovigilance
The science of adverse drug reactions is called pharma-
covigilance (PV).5,6 Pharmacovigilance is a science incorpo-
rating the detection, assessment, understanding, and preven-
tion of adverse effects, particularly long-term and short-term
From the Department of Medicine, University of Missouri-Kansas City,Kansas City, MO.
Reprint requests to James M. Wooten, PharmD, Department of Medicine,School of Medicine, University of Missouri-Kansas City, 2411 HolmesStreet, Kansas City, MO 64108. Email: [email protected]
Dr. Wooten has no financial disclosures to declare and no conflicts of interestto report.
Accepted March 10, 2010.
Copyright © 2010 by The Southern Medical Association
0038-4348/02000/10300-1025
Key Points• Utilization of pharmaceuticals has increased substan-
tially over the past several years, and made the inci-
dence of drug-related problems a common occurrence.
• Pharmacovigilance is a science incorporating the de-
tection, 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 ad-verse drug reactions are attributable to medication er-
rors. 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 al-
lergy, 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.
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side effects of medicines.6 Because ADRs have become com-
monplace, 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 regula-
tions generated by the FDA are important, and PV is a sci-
ence that must be practiced by all health care workers. In fact, pharmacovigilance is most effective when all those respon-
sible for providing health care take an active role in moni-
toring for adverse drug reactions.
ADRs pose a considerable threat to the population at
large. Various studies provide a wide range of epidemiolog-
ical 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 bil-
lion per year.10 Approximately 2–5% of all hospital admis-
sions 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 di-
agnosis. 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 notadmit culpability in any way.8,11,12 Medication errors do fre-
quently 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 prospec-
tively 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. Prob-lems that do occur are often not attributed to an adverse effect
from a drug until other causes are ruled out. This retrospec-
tive 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 recog-
nition 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 experi-
ences 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 al-
ways include “potential adverse drug reactions” in their pa-
tient 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, inappropri-
ate 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 Anexample of a Type A reaction is insulin-induced hypoglyce-
mia, is a known and predictable side effect caused by the
exogenous administration of insulin. The effect of this exam-
ple 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 individ-
uals 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.5,8,9The 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 ex-
plained 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 reac-
tions are difficult to anticipate and predict. Often, ADRs classi-
fied 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 ini-
tiated. APPROVe was a multicenter, randomized, pla-
cebo-controlled, double-blind study which aimed to
determine the effect of Vioxx on the recurrence of
Wooten • Adverse Drug Reactions
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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 manufac-
turer are still trying to sort out the exact cause of the
drug’s adverse effect.18
• Terfenadine (Seldane, Hoechst Marion Roussel, Kan-
sas 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 docu-
menting the risk of cardiac arrhythmia due to QT in-
terval prolongation caused by the drug. Patients with a
cardiac history and patients on specific medicationswhich were known to interact with terfenadine (result-
ing 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 immunoglob-
ulin E (IgE)-mediated. An example of this type of
allergy is anaphylaxis induced by beta-lactam antibi-
otics (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 (immunoglob-
ulin G [IgG] or immunoglobulin M [IgM]) accumulate in
the body in equal amounts, causing extensive cross link-
ing. An example of this reaction is hydralazine-induced
systemic lupus erythematosus (SLE).20
• Type IV reactions are described as delayed or hyper-
sensitivity 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 prod-
uct is an excellent example of this type of reaction.20
Other types of allergic drug responses have been de-
scribed, but the above categories illustrate the most common
forms. The practitioner must understand the difference be-
tween 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 discom-
fort. 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 es-tablished, the FDA usually also rates the severity of the re-
action. 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 fre-
quency of the occurrence of a particular drug-induced reac-
tion. Based on pre-approval studies and postmarketing re-
ports, the frequency of a particular ADR can also behypothesized. 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
References1. Oyez Project, U.S. Supreme Court Media on Potter Stewart. Available
at: http://www.oyez.org/justices/potter_stewart/.Accessed February 1, 2010.
CME Topic
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2. Hohl CM, Robitaille C, Lord V, et al. Emergency physician recognition
of adverse drug-related events in elder patients presenting to an emer-
gency department. Acad Emerg Med 2005;12:197–205.
3. Farcas A, Bojita M. Adverse drug reactions in clinical practice: a cau-
sality assessment of a case of drug-induced pancreatitis. J Gastrointestin
Liver Dis 2009;18:353–358.
4. Safety of Medicines: A Guide to Detecting and Reporting Adverse Drug
Reactions. Geneva, Switzerland, World Health Organization, 2002.Available at: http://whqlibdoc.who.int/hq/2002/WHO_EDM_QSM_
2002.2.pdf. Accessed January 26, 2010.
5. Kavitha D. Adverse drug reaction (ADR) monitoring and pharmacovigi-
lance. J Pharm Res Health Care 2010;2:127–134.
6. Pharmacovigilance: ensuring the safe use of medicines. WHO Policy
Perspectives on Medicines. World health Organization 2004. pg 1–5.
Available at: http://whqlibdoc.who.int/hq/2004/WHO_EDM_2004.8.
pdf. Accessed January 26, 2010.
7. Ann. Guidance for Industry—Good Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment. 2005. US Food and Drug Admin-
istration. Available at: http://www.fda.gov/downloads/Regulatory
Information/Guidances/UCM126834.pdf. Accessed March 1, 2010.
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.
15. Kelly WN. How can I recognize an adverse drug event? Medscape CME
Pharmacists 2008. Available at: http://cme.medscape.com/viewarticle/
569794?srcmp. Accessed March 2, 2010.
16. Pillans PI. Clinical perspectives in drug safety and adverse drug reac-
tions. Expert Rev Clin Pharm 2008;1:695–705.
17. Corrigan OP. A risky business: the detection of adverse drug reactionsin 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.
19. Meadows M. Why drugs get pulled from the market. FDA Consumer
Magazine 2002. Available at: http://permanent.access.gpo.gov/lps1609/
www.fda.gov/fdac/features/2002/102_drug.html. Accessed March 2,
2010.
20. Greenberger PA. 8. Drug allergy. J Allergy Clin Immunol 2006;117:
S464–S470.
21. Ann. Guidance for industry: questions and answers regarding adverse event
reporting and recordkeeping for dietary supplements as required by the
dietary supplement and nonprescription drug consumer protection act.
United States Food and Drug Administration 2007. Available at: http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/Guidance
Documents/DietarySupplements/ucm171383.htm. Accessed March 2,
2010.
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.
Please see “Adverse Drug Reactions: Part II” in
the November 2010 issue of the Southern Medical
Journal.
Wooten • Adverse Drug Reactions
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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 reactionD. Type I allergic reaction
E. none of the above
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