Adverse drug reactions and medication errors

CHAPTER 7


Adverse drug reactions and medication errors


In this chapter we discuss two related issues of drug safety: (1) adverse drug reactions (ADRs), also known as adverse drug events (ADEs), and (2) medication errors, a major cause of ADRs. We begin with ADRs and then discuss medication errors.




Adverse drug reactions


An ADR, as defined by the World Health Organization, is any noxious, unintended, and undesired effect that occurs at normal drug doses. Note that this definition excludes undesired effects that occur when dosage is excessive (eg, because of accidental poisoning or medication error). Adverse reactions can range in intensity from mildly annoying to life threatening. Fortunately, when drugs are used properly, many ADRs can be avoided, or at least minimized.



Scope of the problem


Drugs can adversely affect all body systems in varying degrees of intensity. Among the more mild reactions are drowsiness, nausea, itching, and rash. Severe reactions include neutropenia, hepatocellular injury, cardiac dysrhythmias, anaphylaxis, and hemorrhage—all of which can be fatal.


Although ADRs can occur in all patients, some patients are more vulnerable than others. Adverse events are most common in the elderly and the very young. (Patients over 60 account for nearly 50% of all ADR cases.) Severe illness also increases the risk of an ADR. Likewise, adverse events are more common in patients receiving multiple drugs than in patients taking just one drug.


Some data on ADRs will underscore their significance. Each year in the United States, about 700,000 people visit emergency departments because of ADRs. Among patients already in a hospital, estimates suggest that over 770,000 experience a serious ADR, and about 110,000 die. If these numbers are correct, ADRs would be the fourth leading cause of death, exceeded only by heart disease, cancer, and stroke.



Definitions





Allergic reaction

An allergic reaction is an immune response. For an allergic reaction to occur, there must be prior sensitization of the immune system. Once the immune system has been sensitized to a drug, re-exposure to that drug can trigger an allergic response. The intensity of allergic reactions can range from mild itching to severe rash to anaphylaxis. (Anaphylaxis is a life-threatening response characterized by bronchospasm, laryngeal edema, and a precipitous drop in blood pressure.) Estimates suggest that less than 10% of ADRs are of the allergic type.


The intensity of an allergic reaction is determined primarily by the degree of sensitization of the immune system, not by drug dosage. Put another way, the intensity of allergic reactions is largely independent of dosage. As a result, a dose that elicits a very strong reaction in one allergic patient may elicit a very mild reaction in another. Furthermore, since a patient’s sensitivity to a drug can change over time, a dose that elicits a mild reaction early in treatment may produce an intense reaction later on.


Very few medications cause severe allergic reactions. In fact, most serious reactions are caused by just one drug family—the penicillins. Other drugs noted for causing allergic reactions include the nonsteroidal anti-inflammatory drugs (eg, aspirin) and the sulfonamide group of compounds, which includes certain diuretics, antibiotics, and oral hypoglycemic agents.



Idiosyncratic effect

An idiosyncratic effect is defined as an uncommon drug response resulting from a genetic predisposition. To illustrate this concept, let’s consider responses to succinylcholine, a drug used to produce flaccid paralysis of skeletal muscle. In most patients, succinylcholine-induced paralysis is brief, lasting only a few minutes. In contrast, genetically predisposed patients may become paralyzed for hours. Why the difference? Because in all patients the effects of succinylcholine are terminated through enzymatic inactivation of the drug. Since most people have very high levels of the inactivating enzyme, paralysis is short lived. However, in a small percentage of patients, the genes that code for succinylcholine-metabolizing enzymes are abnormal, producing enzymes that inactivate the drug very slowly. As a result, paralysis is greatly prolonged.




Physical dependence

Physical dependence develops during long-term use of certain drugs, such as opioids, alcohol, barbiturates, and amphetamines. We can define physical dependence as a state in which the body has adapted to drug exposure in such a way that an abstinence syndrome will result if drug use is discontinued. The precise nature of the abstinence syndrome is determined by the drug involved.


Although physical dependence is usually associated with “narcotics” (heroin, morphine, and other opioids), these are not the only dependence-inducing drugs. In addition to the opioids, a variety of other centrally acting drugs (eg, ethanol, barbiturates, amphetamines) can promote dependence. Furthermore, some drugs that work outside the central nervous system can cause physical dependence of a sort. Because a variety of drugs can cause physical dependence of one type or another, and because withdrawal reactions have the potential for harm, patients should be warned against abrupt discontinuation of any medication without first consulting a health professional.



Carcinogenic effect

The term carcinogenic effect refers to the ability of certain medications and environmental chemicals to cause cancers. Fortunately, only a few therapeutic agents are carcinogenic. Ironically, several of the drugs used to treat cancer are among those with the greatest carcinogenic potential.


Evaluating drugs for the ability to cause cancer is extremely difficult. Evidence of neoplastic disease may not appear until 20 or more years after initial exposure to a cancer-causing compound. Consequently, it is nearly impossible to detect carcinogenic potential during preclinical and clinical trials. Accordingly, when a new drug is released for general marketing, we cannot know with certainty that it will not eventually prove carcinogenic.


Diethylstilbestrol (DES) illustrates the problem posed by the delayed appearance of cancer following exposure to a carcinogenic drug. DES is a synthetic hormone with actions similar to those of estrogen. At one time, DES was used to prevent spontaneous abortion during high-risk pregnancies. It was not until years later, when vaginal and uterine cancers developed in females who had been exposed to this drug in utero, that the carcinogenic actions of DES became known.




Organ-specific toxicity


Many drugs are toxic to specific organs. Common examples include injury to the kidneys caused by amphotericin B (an antifungal drug), injury to the heart caused by doxorubicin (an anticancer drug), injury to the lungs caused by amiodarone (an antidysrhythmic drug), and injury to the inner ear caused by aminoglycoside antibiotics (eg, gentamicin). Patients using such drugs should be monitored for signs of developing injury. In addition, patients should be educated about these signs and advised to seek medical attention if they appear.


Two types of organ-specific toxicity deserve special comment. These are (1) injury to the liver and (2) altered cardiac function, as evidenced by a prolonged QT interval on the electrocardiogram. Both are discussed below.



Hepatotoxic drugs

In the United States, drugs are the leading cause of acute liver failure, a rare condition that can rapidly prove fatal. Most cases end with a liver transplant or in death. The ability to cause severe liver damage is the most common reason for withdrawing an approved drug from the market.


Fortunately, liver failure from using known hepatotoxic drugs is rare, with an incidence of less than 1 in 50,000. (Drugs that cause liver failure more often than this are removed from the market—unless they are indicated for a life-threatening illness.) More than 50 drugs are known to be hepatotoxic. Some of these are listed in Table 7–1.



How do drugs damage the liver? Recall that the liver is the primary site of drug metabolism. As some drugs undergo metabolism, they are converted to toxic products that can injure liver cells.


Combining a hepatotoxic drug with certain other drugs may increase the risk of liver damage. A good example is the combination of acetaminophen [Tylenol] with alcohol. When taken in therapeutic doses in the absence of alcohol, acetaminophen cannot harm the liver. However, if the drug is taken with just two or three drinks, severe liver injury can result. Of course, excessive doses of acetaminophen, without any alcohol, can also damage the liver.


Patients taking hepatotoxic drugs should undergo liver function tests (LFTs) at baseline and periodically thereafter. How do we assess liver function? By testing a blood sample for the presence of two liver enzymes: aspartate aminotransferase (AST, formerly known as SGOT) and alanine aminotransferase (ALT, formerly known as SGPT). Under normal conditions blood levels of AST and ALT are low. However, when liver cells are injured, blood levels of these enzymes rise. LFTs are performed on a regular schedule (eg, every 3 months) in hopes of detecting injury early. Unfortunately, since drug-induced liver injury can develop very quickly, it may progress from undetectable to advanced between scheduled tests. Nonetheless, since death from liver failure can often be avoided with early detection, routine testing of liver function is still indicated.


All patients receiving hepatotoxic drugs should be informed about signs of liver injury—jaundice (yellow skin and eyes), dark urine, light-colored stools, nausea, vomiting, malaise, abdominal discomfort, loss of appetite—and advised to seek medical attention if these develop.



QT interval drugs

The term QT interval drugs—or simply QT drugs—refers to the ability of some medications to prolong the QT interval on the electrocardiogram, thereby creating a risk of serious dysrhythmias. As discussed in Chapter 49 (Antidysrhythmic Drugs), the QT interval is a measure of the time required for the ventricles to repolarize after each contraction. When the QT interval is prolonged, patients can develop a dysrhythmia known as torsades de pointes, which can progress to potentially fatal ventricular fibrillation. How long must the QT interval be to be considered long? More than 470 msec for postpubertal males, or more than 480 msec for postpubertal females.


More than 100 drugs are known to cause QT prolongation, torsades de pointes, or both. As shown in Table 7–2, QT drugs are found in many drug families. Seven QT drugs—including astemizole [Hismanal], terfenadine [Seldane], and fenfluramine [Pondimin]—have been withdrawn because of deaths linked to their use, and use of another QT drug—cisapride [Propulsid]—is now restricted. To reduce the risks from QT drugs, the Food and Drug Administration (FDA) now requires that all new drugs be tested for the ability to cause QT prolongation.



TABLE 7–2 


Drugs That Prolong the QT Interval, Induce Torsades de Pointes, or Both


Cardiovascular: Antidysrhythmics


Amiodarone [Cordarone]
Disopyramide [Norpace]
Dofetilide [Tikosyn]
Flecainide [Tambocor]
Ibutilide [Corvert]
Mexiletine [Mexitil]
Procainamide [Procan, Pronestyl]
Quinidine
Sotalol [Betapace]


Cardiovascular: ACE Inhibitors/CCBs


Bepridil [Vascor]
Isradipine [DynaCirc]
Moexipril
Nicardipine [Cardene]


Cardiovascular: Others


Dobutamine [Dobutrex]
Dopamine
Norepinephrine [Levophed]
Ranolazine [Ranexa]


Antibiotics


Azithromycin [Zithromax]
Clarithromycin [Biaxin]
Erythromycin
Gatifloxacin [Tequin]
Gemifloxacin [Factive]
Levofloxacin [Levaquin]
Moxifloxacin [Avelox]
Ofloxacin [Floxin]
Sparfloxacin [Zagam]
Telithromycin [Ketek]


Antifungal Drugs



Fluconazole [Diflucan]
Itraconazole [Sporanox]
Ketoconazole [Nizoral]
Voriconazole [Vfend]


Antidepressants


Amitriptyline [Elavil]
Citalopram [Celexa]
Desipramine [Norpramin]
Doxepin [Sinequan]
Fluoxetine [Prozac]
Imipramine [Tofranil]
Protriptyline [Pamelor, Aventyl]
Sertraline [Zoloft]
Trimipramine [Surmontil]
Venlafaxine [Effexor]


Antipsychotics


Chlorpromazine [Thorazine]
Clozapine [Clozaril]
Haloperidol [Haldol]
Mesoridazine [Serentil]
Pimozide [Orap]
Quetiapine [Seroquel]
Risperidone [Risperdal]
Thioridazine [Mellaril]
Ziprasidone [Geodon]


Antiemetics/Antinausea Drugs


Dolasetron [Anzemet]
Domperidone [Motilium]
Droperidol [Inapsine]
Granisetron [Kytril]
Ondansetron [Zofran]


Bronchodilators


Albuterol [Proventil, Ventolin]
Ephedrine
Epinephrine [Bronkaid, Primatene]
Isoproterenol [Isuprel]
Levalbuterol [Xopenex]
Metaproterenol [Alupent]
Salmeterol [Serevent]
Terbutaline


Anticancer Drugs


Arsenic trioxide [Trisenox]
Sunitinib [Sutent]
Tamoxifen [Nolvadex]


Drugs for ADHD


Amphetamine/dextroamphetamine [Adderall]
Atomoxetine [Strattera]
Dexmethylphenidate [Focalin]
Dextroamphetamine [Dexedrine]
Methylphenidate [Ritalin, Concerta]


Nasal Decongestants


Phenylephrine [Neo-Synephrine, Sudafed PE]
Pseudoephedrine [Sudafed]


Other Drugs


Alfuzosin [Uroxatral]
Amantadine [Symmetrel]
Chloroquine [Aralen]
Cisapride [Propulsid]*
Cocaine
Felbamate [Felbatol]
Foscarnet [Foscavir]
Fosphenytoin [Cerebyx]
Galantamine [Razadyne]
Halofantrine [Halfan]
Indapamide [Lozol]
Lithium [Lithobid, Eskalith]
Methadone [Dolophine]
Midodrine [ProAmatine]
Octreotide [Sandostatin]
Pentamidine [Pentam, Nebupent]
Phentermine [Fastin]
Ritodrine [Yutopar]
Salmeterol [Serevent]
Solifenacin [Vesicare]
Tacrolimus [Prograf]
Tizanidine [Zanaflex]
Tolterodine [Detrol]
Vardenafil [Levitra]


ACE = angiotensin-converting enzyme; ADHD = attention-deficit/hyperactivity disorder; CCB = calcium channel blocker.


*Restricted availability.


When QT drugs are used, care is needed to minimize the risk of dysrhythmias. These agents should be used with caution in patients predisposed to dysrhythmias. Among these are the elderly and patients with bradycardia, heart failure, congenital QT prolongation, and low levels of potassium or magnesium. Women are also at risk. Why? Because their normal QT interval is longer than the QT interval in men. Concurrent use of two or more QT drugs should be avoided, as should the concurrent use of a QT drug with another drug that can raise its blood level (eg, by inhibiting its metabolism). Obviously, excessive dosing should be avoided. Additional information on QT drugs, including a current list of these agents, is available online at www.QTdrugs.org.



Identifying adverse drug reactions


It can be very difficult to determine whether a specific drug is responsible for an observed adverse event. Why? Because other factors—especially the underlying illness and other drugs being taken—could be the actual cause. To help determine if a particular drug is responsible, the following questions should be asked:



If the answers reveal a temporal relationship between the presence of the drug and the adverse event, and if the event cannot be explained by the illness itself or by other drugs in the regimen, then there is a high probability that the drug under suspicion is indeed the culprit. Unfortunately, this process is limited: It can only identify adverse effects that occur while the drug is being used; it cannot identify adverse events that develop years after drug withdrawal. Nor can it identify effects that develop slowly, that is, over the course of prolonged drug use.



Adverse reactions to new drugs


As we discussed in Chapter 3, preclinical and clinical trials of new drugs cannot detect all of the ADRs that a drug may be able to cause. In fact, about 50% of all new drugs have serious ADRs that are not revealed during Phase II and Phase III trials.


Because newly released drugs may have as-yet unreported adverse effects, you should be alert for unusual responses when giving new drugs. If the patient develops new symptoms, it is wise to suspect that the drug may be responsible—even if the symptoms are not described in the literature. If the drug is especially new, you may be the first clinician to have observed the effect.


If you suspect a drug of causing a previously unknown adverse effect, you should report the effect to MEDWATCH, the FDA Medical Products Reporting Program. You can file your report online at www.fda.gov/medwatch. The form used for reporting is shown in Figure 7–1. Because voluntary reporting by healthcare professionals is an important mechanism for bringing ADRs to light, you should report all suspected ADRs, even if absolute proof of the drug’s complicity has not been established.


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Figure 7–1  Form for reporting adverse drug events to the FDA.
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Jul 24, 2016 | Posted by in NURSING | Comments Off on Adverse drug reactions and medication errors

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