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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.

Southern Medical Journal • Volume 103, Number 10, October 2010 1025



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

1026 © 2010 Southern Medical Association



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

Southern Medical Journal • Volume 103, Number 10, October 2010 1027



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

1028 © 2010 Southern Medical Association



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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