Problem-Oriented Diagnosis

Drug-Induced Disorders

EILEEN G. HOLLAND, PHARM.D., and FRANK V. DEGRUY, M.D.

University of South Alabama College of Medicine, Mobile, Alabama

Recent estimates suggest that each year more than 1 million patients are injured while in the hospital and approximately 180,000 die because of these injuries. Furthermore, drug-related morbidity and mortality are common and are estimated to cost more than $136 billion a year. The most common type of drug-induced disorder is dose-dependent and predictable. Many adverse drug events occur as a result of drug-drug, drug-disease or drug-food interactions and, therefore, are preventable. Clinicians' awareness of the agents that commonly cause drug-induced disorders and recognition of compromised organ function can significantly decrease the likelihood that an adverse event will occur. Patient assessment should include a thorough medication history, including an analysis of all prescribed and over-the-counter medications, vitamins, herbs and "health-food" products to identify drug-induced problems and potentially reversible conditions. An increased awareness among clinicians of drug-induced disorders should maximize their recognition and minimize their incidence.

Drug-induced disorders, in the form of adverse drug events or drug interactions, occur daily in all health care environments. Unfortunately, significant morbidity and mortality are often the consequence of these reactions. Several studies have reported that an average of 10 percent of all hospital admissions may be attributable to drug-induced disorders; this percentage may be a significant underestimate.¹ Furthermore, an evaluation of a large sample of 30,195 randomly selected hospital records revealed that 1,133 patients (3.7 percent) experienced a disabling injury caused by medical treatment while hospitalized.² Other studies report that hospitalized patients have a 1.5 to 43.5 percent chance of having a drug-induced disorder.¹ Using the conservative figure, that 4 percent of hospitalized patients have an adverse event due to medical treatment, and extrapolating to the United States, each year over 1 million patients are injured while in the hospital, and approximately 180,000 die as a result of these injuries.³

In the ambulatory care environment, the incidence of drug-induced disorders not causing hospitalization or death is less well known because different, less effective methods are used to collect data. Reported rates have ranged from 2.6 to 50.6 percent, depending on the source of the data.⁴ The lower rates generally reflect data collected from physicians, and the higher rates come from patient surveys.

Drug-related morbidity and mortality are estimated to cost more than $136 billion a year in the United States.⁵ A recent study⁶ of hospitalized patients demonstrated that adverse drug events extended the hospital stay by nearly two days and increased the cost of hospitalization by about $2,000. Furthermore, patients experiencing an adverse drug event had an increased risk of death that was nearly two-fold greater.

Many drug-induced disorders are predictable. Compared with those that cannot be foreseen, anticipated drug reactions are more likely to be serious and costly.^2,7 Certain characteristics of the patient and the drug affect the likelihood that a drug-induced disorder will occur. Many adverse drug events are preventable if the clinician maintains a high degree of suspicion and pays close attention to details.

Definitions

The definition of a drug-induced disorder varies considerably, depending on the source used. Many clinicians rely on a combination of the definitions of the World Health Organization (WHO) and the American Society of Health-System Pharmacists (ASHP).^8,9 This commonly used definition states that an adverse drug reaction (ADR) is an adverse drug event (ADE) or drug interaction that results in an undesirable or unexpected event that requires some change in the clinician's care of the patient; such as discontinuing a drug, modifying a dosage, prolonging hospitalization or administering supportive treatment. ADRs do not include drug withdrawal, drug-abuse syndromes, accidental poisonings or complications of drug overdose.

Types of Adverse Drug Reactions

Although not all adverse drug reactions conform neatly to a simple classification system, drug-induced disorders have historically been classified as type A and type B reactions.^10,11

Type A reactions are the normal pharmacologic effects of a drug that are exaggerated to the point of being undesirable. These reactions are usually dose-dependent and are fairly predictable. They may also be caused by drug-drug, drug-disease or drug-food interactions. Although their incidence and morbidity are high, these reactions are rarely life-threatening. Type A reactions are the most common type of drug-induced disorders. Clinicians should be aware that these reactions may occur at any time during drug therapy.

Type B reactions are effects of a drug that are unrelated to its known pharmacologic actions. These reactions may or may not be dose-related. They are unpredictable and include idiosyncratic, immunologic and allergic reactions, and carcinogenic and teratogenic events. The incidence of type B reactions is relatively low, but the mortality is high.

EXAMPLES OF ADVERSE DRUG EVENTS

Adverse drug events that involve extension of the agent's pharmacologic activity are common. For example, a patient who develops pancytopenia following the administration of an antineoplastic agent and then develops bleeding, hypoxia and an opportunistic infection has experienced several adverse drug events while, hopefully, halting the growth of the cancer. Even though many chemotherapeutic agents predictably produce these events, the events are certainly undesirable and force the clinician to alter the care of the patient by discontinuing the chemotherapy, hospitalizing the patient, and administering blood products, antibiotics and oxygen, or administering alternative therapy.

Many other examples of adverse drug events that are extensions of the agent's pharmacologic action may be found. For example, pseudoparkinsonism and other extrapyramidal symptoms related to a relative dopamine deficiency are common adverse drug events occurring in patients taking antipsychotics such as haloperidol (Haldol), prochlorperazine (Compazine), fluphenazine (Prolixin, Permitil), and thiothixene (Navane). Other examples of adverse drug events are the proarrhythmic effects of all antiarrhythmic agents, including quinidine (Quinidex), procainamide (Pronestyl), lidocaine (Xylocaine) and amiodarone (Cordarone).

With nonsteroidal anti-inflammatory drugs (NSAIDs), the anti-inflammatory action occurs as a result of inhibition of production of prostaglandins. Because the formation of the prostaglandin responsible for protecting the gastric mucosa is also inhibited, an increased incidence of peptic ulcer disease is a common adverse drug event in patients taking NSAIDs.

Many adverse drug reactions are caused by drug interactions. An interaction between some nonsedating antihistamines (i.e., astemizole [Hismanal], terfenadine [Seldane]) and certain antimicrobials (i.e., erythromycin, clarithromycin [Biaxin], ketoconazole [Nizoral]) resulting in a potentially fatal cardiac arrhythmia is an example of a preventable adverse drug reaction. The ability of amiodarone to inhibit the metabolism of warfarin (Coumadin, Panwarfin), resulting in a significantly increased INR (international normalized ratio) and a higher risk of bleeding, is another preventable adverse drug reaction caused by a predictable drug interaction.

Some adverse drug reactions occur as a result of a drug-disease interaction. A common example is a patient with renal dysfunction who is prescribed a normal dosage of a renally eliminated drug. Because the patient cannot eliminate the drug, its pharmacologic activity may become exaggerated and cause a drug-induced disorder. For example, more than 90 percent of amantadine (Symmetrel) is eliminated renally as unchanged drug. If a normal dosage is administered to a patient with decreased renal function, amantadine is likely to accumulate, and seizures can occur. Approximately 80 percent of digoxin (Lanoxin) is eliminated renally. If the dosage is not adjusted for renal dysfunction, the drug will accumulate and may cause anorexia, and bradycardia or other arrhythmias.

Some adverse drug reactions are idiosyncratic and unpredictable. Stevens-Johnson syndrome and toxic epidermal necrolysis are potentially fatal dermatologic reactions that may occur following the administration of a variety of drugs, including allopurinol (Zyloprim), sulfa-containing antibiotics, NSAIDs and phenytoin (Dilantin).

Drugs Associated with Drug-Induced Problems

Certain drugs and drug classes are commonly associated with drug-induced disorders and warrant special attention by the clinician. Table 1 lists classes of drugs that are most commonly responsible for drug-induced disorders, including antibiotics, chemotherapeutic agents, anticoagulants and cardiovascular agents.² Antibiotics and chemotherapeutic agents were responsible for approximately 30 percent of all adverse reactions in this sample of 30,195 patients. Anticoagulants and cardiovascular agents accounted for another 20 percent of adverse events. These figures are consistent with other reports.

Clinical Manifestations of Drug-Induced Disorders

Table 2 lists the most common clinical manifestations of drug-induced disorders. Approximately 60 percent of drug-induced disorders present as bone marrow suppression, bleeding, central nervous system effects and dermatologic reactions.² Careful attention to and evaluation of these toxicities, along with a high degree of suspicion, may enable the clinician to detect drug-induced problems early, before significant morbidity and mortality occur.

Premarketing and Postmarketing Studies

In the United States, the Food and Drug Administration (FDA) requires careful evaluation of all medications before their release to the public. These premarketing studies, known as phase I, phase II and phase III clinical trials, are intended to prove efficacy and detect adverse drug reactions. However, while this system is one of the most rigorous in the world, there are obvious limitations. The "Rule of Too's," listed in Table 3, describes five limitations of this drug approval system.¹²

Because of the limited size and the nature of the premarketing clinical trials, only those adverse drug reactions that occur more frequently than one in 1,000 patient exposures are noted and listed in the package insert for the agent. Generally, during the first week a drug is released on the market, it is administered to several thousand patients with multiple medical problems who are taking concomitant medications. Since many drug-induced disorders are a result of interactions with other diseases and drugs, they are often not detected before marketing. The likelihood that a previously unknown significant adverse reaction or drug-drug interaction will occur during the first year after FDA approval is fairly high. The events following the approval of the anticonvulsant felbamate (Felbatol),¹³ illustrate the reality of this limitation of the drug-approval process. Felbamate was first marketed in September 1993, and by July 1994, when 100,000 patients had been taking the drug for less than one year, nine cases of aplastic anemia were reported. Patients exposed to felbamate were 50 times more likely to develop aplastic anemia compared with the general population.

There is a critical need to pay special attention to problems associated with newly released medications. In addition, to assist in identifying important trends in the detection of unwanted effects from drugs, any significant or previously unknown drug-induced problem caused by any medication must be reported to a central agency. In 1993, the FDA established MedWatch, a medical products reporting program, to provide a means for health professionals to report serious adverse events and product problems that occur with any and all medical products. To simplify the reporting process, a toll-free phone number (1-800-FDA-1088) has been established for use by health professionals. The FDA also maintains a Web page (http://www.fda.gov/) to increase access to this safety-related drug information. Known as "postmarketing drug surveillance," this process of gathering and disseminating data may be more important than the premarketing trials in ensuring the safety of marketed drugs.

Factors that Contribute to the Development of Adverse Drug Reactions

Numerous factors that contribute to the development of adverse drug reactions have been identified. These factors may be patient-dependent, such as the patient's degree of organ function and/or dysfunction, and underlying disease states. Or the factors may depend on the specific drug and its pharmacokinetic parameters. Some of these characteristics are modifiable, and some are not.

Variability in patient-specific pharmacokinetics, such as drug absorption, distribution, metabolism and elimination, influences the effects of a specific drug in a patient and contributes to the incidence of drug-induced disorders. Most frequently, type A reactions result from altered patient-specific pharmacokinetics. A thorough understanding of the normal pharmacokinetics of a drug and the patient characteristics that make the parameters abnormal enables the clinician to make dosage adjustments and/or changes in drug therapy to produce minimal toxicity with maximal therapeutic benefit.

Table 4 lists some patient characteristics that may alter a drug's normal pharmacokinetic profile. The pharmacologic effects of nearly all medications diminish when the drugs are either metabolized to inactive substrates or eliminated renally as intact drug. Not surprisingly then, alterations in the metabolism and/or elimination of drugs are the most significant and common causes of drug-induced disorders. These alterations may occur as a result of concomitant disease states, drug-drug interactions or patient-specific characteristics (e.g., renal dysfunction caused by age).

Many of the most significant drug-drug interactions involve the cytochrome P₄₅₀ isoenzyme system.¹⁴ The cytochrome P₄₅₀ enzymes are involved in human drug metabolism. Certain drugs can inhibit the actions of these enzymes, resulting in significant drug interactions, with accumulation of unmetabolized drug, or substrate. Table 5 lists some of the most commonly administered medications that can interfere with this enzymatic system to produce potentially significant consequences related to accumulation of the substrate.

The relationship between advancing age and the risk for drug-induced disorders is complex. Older patients experience more adverse drug reactions than do younger patients; however, age is probably not an independent risk factor for the development of drug-induced disorders.¹⁵ Rather than a patient's age, patient-specific pharmacokinetic characteristics are the most accurate predictors of beneficial and toxic effects of drug therapies. Furthermore, the common practice of prescribing multiple medications for an older patient's multiple medical problems appears to contribute significantly to their risk of drug-induced disease.¹⁵

Clinicians should have a thorough understanding and working knowledge of the way a drug becomes inactivated and is eliminated from the body. Dosage adjustments and/or changing the drug that is prescribed for a patient based on the pharmacokinetics of a drug and the patient-specific characteristics are the most significant methods of minimizing drug-induced disorders while maximizing therapeutic benefit.

Recognizing an Adverse Drug Reaction

The key to recognizing adverse drug reactions is to be aware of their existence and have a high degree of suspicion. Every differential diagnosis should include drugs as the disease- and/or symptom-producing agent. Furthermore, an accurate and thorough medication history should regularly be obtained from every patient. A comprehensive medication history includes all prescription and nonprescription medications, vitamins, herbs and "health-food" products. In addition, significant past adverse drug experiences and allergic reactions should be noted.

It is often impossible to be absolutely certain of the diagnosis of an adverse drug reaction. The pathophysiology of the typical symptoms produced by diseases and of the symptoms caused by drugs are often quite similar. Evaluating the time course between the administration of a drug and the onset of the symptomatology is critical in distinguishing between an adverse drug reaction and another event. Discontinuing the drug should result in some, if not complete, resolution of the symptoms, if they are drug-induced.

To be more certain of the cause-and-effect relationship, and if not considered too dangerous for the patient, restarting the drug and monitoring for the recurrence of any adverse reactions may be useful. It is important to realize that the initial exposure to the drug may have desensitized the patient to the reaction, so that no adverse reaction occurs with a rechallenge.

Furthermore, clinicians should be aware of and always suspect a drug-drug, drug-disease or drug-food interaction as the cause of a patient's symptoms. This is especially true in patients taking numerous medications, such as elderly patients and patients in hospitals or nursing homes. Clinicians who observe drug-induced disorders have an obligation to report the occurrence of these events to the FDA through the MedWatch program. Specifically, because type B reactions are unpredictable, it is important for clinicians to report these events promptly to inform other health care providers of their existence.

Final Comment

Most drugs have a dosage that produces desired pharmacologic activity with minimal toxicity and a higher dosage that is associated with toxicity. The difference between these two dosages can decrease in certain situations. Factors that contribute to converting a typically safe and effective dosage to one that produces adverse effects include age-related morbidity, the drug's pharmacokinetic and pharmacodynamic activities, co-morbid conditions and concomitant medications. Many adverse drug reactions are extensions of the known and desired pharmacologic properties of an agent.

Conscientious and cautious prescribing, and evaluation of drug regimens by clinicians may decrease the frequency of adverse drug reactions. Clinicians' appreciation of the drugs that are commonly associated with adverse drug reactions, the most common clinical manifestations of adverse drug reactions and the patient-specific factors that contribute to an increased incidence of adverse drug reactions should increase the recognition and reporting of drug-induced disorders. An increased awareness of drug-induced disorders by clinicians should maximize their recognition and minimize their incidence. Clinicians should strive to maximize the benefit of drug therapy while minimizing the toxicities by adjusting medication regimens as dictated by the patient-specific circumstances.

BACK TO ALTERNATIVES PAGE

See editorial on page 1718.

The Authors

EILEEN G. HOLLAND, PHARM.D.
is an associate professor in the Department of Clinical Pharmacy Practice at Auburn University School of Pharmacy, Mobile, Ala., and adjunct associate professor in the Department of Family Practice and Community Medicine and the Department of Pharmacology at the University of South Alabama College of Medicine, Mobile. She graduated from Purdue University School of Pharmacy and completed a pharmacy residency/fellowship in family medicine at the Medical College of Georgia, Augusta.

FRANK V. DEGRUY, M.D.
is professor and chairman of the Department of Family Practice and Community Medicine at the University of South Alabama College of Medicine. He graduated from the University of South Alabama College of Medicine. He completed a family practice residency at the Medical Center, Columbus, Ga., and a Robert Wood Johnson fellowship at Case Western Reserve University, Cleveland.

Address correspondence to Eileen G. Holland, Pharm. D., Department of Family Practice, 1504 Springhill Ave., Mobile, AL 36604.

Each year members of a different family practice department develop articles for "Problem-Oriented Diagnosis." This series is coordinated by the Department of Family and Community Medicine at the University of Alabama at Birmingham. Guest editors of the series are T. Michael Harrington, M.D., and Myra A. Crawford, Ph.D.

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Copyright 1997 by the American Academy of Family Physicians.
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