chapt 58.docx

Drug use during pregnancy is common: about two-thirds of pregnant patients take at least one medication, and the majority take more. Some drugs are used to treat pregnancy-related conditions, such as nausea, constipation, and preeclampsia. Some are used to treat chronic disorders, such as hypertensi...

Drug use during pregnancy is common: about two-thirds of pregnant patients take at least one medication, and the majority take more. Some drugs are used to treat pregnancy-related conditions, such as nausea, constipation, and preeclampsia. Some are used to treat chronic disorders, such as hypertension, diabetes, and epilepsy. Still others are used for the management of invasive conditions, such as infectious diseases or cancer. In addition to taking these therapeutic agents, pregnant patients may use drugs of abuse, such as alcohol, cocaine, and heroin. Drug therapy in pregnancy presents a vexing dilemma. In pregnant patients, as in all other patients, the benefits of treatment must balance the risks. Of course, when drugs are used during pregnancy, risks apply to the fetus as well. Unfortunately, most drugs have not been tested during pregnancy. As a result, the risks for most drugs are unknown---hence the dilemma: the provider is obliged to balance risks versus benefits, without always knowing what the risks really are. Despite the imposing challenge of balancing risks versus benefits, drug therapy during pregnancy cannot and should not be avoided. Because the health of the fetus depends on the health of the mother, conditions that threaten the mother\'s health must be addressed. Chronic asthma is a good example. Uncontrolled maternal asthma is far more dangerous to the fetus than the drugs used to treat it. The incidence of stillbirth is doubled among pregnant patients who do not take medications for asthma control. One of the greatest challenges in identifying drug effects on a developing fetus has been the lack of clinical trials, which, by their nature, would put the developing fetus at risk. Current research often focuses on comparing histories of women who have had children with and without congenital anomalies. An early example was the National Birth Defects Prevention Study (http://www.nbdps.org), which examined births from 1997 to 2011. More recently, the Birth Defects Study to Evaluate Pregnancy Exposures (http://www.cdc.gov/ncbddd/birthdefects/bd-steps.html) began collecting data on children born in January 2014 and beyond. Additionally, there are several pregnancy registries in which a woman who needs to take a drug while pregnant can enroll. This allows researchers to monitor pregnancy outcomes associated with a drug. The US Food and Drug Administration (FDA) provides a list of pregnancy exposure registries at http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm. Although some studies are devoted to a single drug and its effect on pregnancy and the fetus, many study multiple drugs. Physiologic Changes During Pregnancy Pregnancy brings on physiologic changes that can alter drug disposition. Changes in the kidney, liver, and gastrointestinal (GI) tract are of particular interest. Because of these changes, a compensatory change in dosage may be needed. By the third trimester, renal blood flow is doubled, causing a large increase in the glomerular filtration rate. As a result, there is accelerated clearance of drugs that are eliminated by glomerular filtration. Elimination of lithium, for example, is increased by 100%. To compensate for accelerated excretion, dosage must be increased. For some drugs, hepatic metabolism increases during pregnancy. Three antiseizure drugs---phenytoin, carbamazepine, and valproic acid---provide examples. Tone and motility of the bowel decrease in pregnancy, causing intestinal transit time to increase. Because of prolonged transit, there is more time for drugs to be absorbed. In theory, this could increase levels of drugs whose absorption is normally poor. Similarly, there is more time for the reabsorption of drugs that undergo enterohepatic recirculation, possibly resulting in a prolongation of drug effects. In both cases, a reduction in dosage might be needed. Placental Drug Transfer The factors that determine drug passage across the membranes of the placenta are the same factors that determine drug passage across all other membranes. Accordingly, drugs that are lipid soluble cross the placenta easily, whereas drugs that are ionized, highly polar, or protein bound cross with difficulty. Nonetheless, for practical purposes, the provider should assume that any drug taken during pregnancy will reach the fetus. Adverse Reactions During Pregnancy Not only are pregnant patients subject to the same adverse effects as nonpregnant patients, but they may also suffer effects unique to pregnancy. For example, when heparin (an anticoagulant) is taken by pregnant patients, it can cause osteoporosis, which in turn can cause compression fractures of the spine. The use of prostaglandins (e.g., misoprostol), which stimulate uterine contraction, can cause abortion. Conversely, the use of aspirin near term can suppress contractions in labor. In addition, aspirin increases the risk for serious bleeding. Drugs taken during pregnancy can adversely affect the patient as well as the fetus. Regular use of dependence-producing drugs (e.g., heroin, barbiturates, alcohol) during pregnancy can result in the birth of a drug-dependent infant. If the newborn\'s dependence is not supported with drugs, a withdrawal syndrome will ensue. Symptoms include shrill crying, vomiting, and extreme irritability. The neonate should be weaned from dependence by giving progressively smaller doses of the drug on which he or she is dependent. Additionally, certain pain relievers used during delivery can depress respiration in the neonate. The infant must be closely monitored until respiration is normal. The drug effect of greatest concern is teratogenesis. This is the production of congenital anomalies (also known as birth defects) in the fetus. Drug Therapy During Pregnancy: Teratogenesis and Other Risks The term teratogenesis is derived from teras, the Greek word for monster. Translated literally, teratogenesis means to produce a monster. Consistent with this derivation, we usually think of congenital anomalies in terms of gross malformations, such as cleft palate, clubfoot, and hydrocephalus. Incidence and Causes of Congenital Anomalies The incidence of major structural abnormalities (e.g., abnormalities that are life threatening or require surgical correction) is between 1% and 3%. Half of these are obvious and are reported at birth. The other half involve internal organs (e.g., heart, liver, GI tract) and are not discovered until later in life or at autopsy. The incidence of minor structural abnormalities is unknown, as is the incidence of functional abnormalities (e.g., growth delay, intellectual disabilities). Congenital anomalies have multiple causes, including genetic predisposition, environmental chemicals, and drugs. Genetic factors account for about 25% of all congenital anomalies. Of the genetically based anomalies, Down syndrome is the most common. Less than 1% of all congenital anomalies are caused by drugs. For most congenital anomalies, the cause is unknown. Teratogenesis and Stage of Development Fetal sensitivity to teratogens changes during development; thus the effect of a teratogen is highly dependent on when the drug is given. As shown in Fig. 8.1, development occurs in three major stages: the preimplantation/presomite period (conception through week 2), the embryonic period (weeks 3 through 8), and the fetal period (week 9 through term). During the preimplantation/presomite period, teratogens act in an all-or-nothing fashion. That is, if the dose is sufficiently high, the result is death of the conceptus. Conversely, if the dose is sublethal, the conceptus is likely to recover fully. FIG. 8.1 Effects of teratogens at various stages of development of the fetus. CNS, Central nervous system. (From Moore K, Persaud TVN, Torchia M. The Developing Human: Clinically Oriented Embryology. 9th ed. Philadelphia: Elsevier; 2012, with permission.) Gross malformations are produced by exposure to teratogens during the embryonic period (roughly the first trimester). This is the time when the basic shape of internal organs and other structures is being established. Because the fetus is especially vulnerable during the embryonic period, pregnant patients must take special care to avoid teratogen exposure during this time. Teratogen exposure during the fetal period (i.e., the second and third trimesters) usually disrupts function rather than gross anatomy. Of the developmental processes that occur in the fetal period, growth and development of the brain are especially important. Disruption of brain development can result in learning deficits and behavioral abnormalities. Identification of Teratogens For the following reasons, human teratogens are extremely difficult to identify: The incidence of congenital anomalies is generally low. Animal tests may not be applicable to humans. Prolonged drug exposure may be required. Teratogenic effects may be delayed. Behavioral effects are difficult to document. Controlled experiments cannot be done in humans. As a result, only a few drugs are considered proven teratogens. Drugs whose teratogenicity has been documented (or at least is highly suspected) are listed in Table 8.1. However, it is important to note that lack of proof of teratogenicity does not mean that a drug is safe---it only means that the available data are insufficient to make a definitive judgment. Conversely, proof of teratogenicity does not mean that every exposure will result in a congenital anomaly. In fact, with most teratogens, the risk for malformation after exposure is only about 10%. TABLE 8.1 Drugs That Should Be Avoided During Pregnancy Because of Proven or Strongly Suspected Teratogenicity Drug Teratogenic Effect Anticancer/Immunosuppressant Drugs Cyclophosphamide CNS malformation, secondary cancer Methotrexate CNS and limb malformations Thalidomide Shortened limbs, internal organ defects Antiseizure Drugs Carbamazepine Neural tube defects, craniofacial defects, malformations of the heart, hypospadias Phenytoin Growth delay, CNS defects Topiramate Growth delay, cleft lip with cleft palate Valproic acid Neural tube defects, craniofacial defects, malformations of the heart and extremities, and hypospadias Sex Hormones Androgens (e.g., danazol) Masculinization of the female fetus Diethylstilbestrol Vaginal carcinoma in female offspring Estrogens Congenital defects of female reproductive organs Antimicrobial Drugs Tetracycline Tooth and bone anomalies Trimethoprim-sulfamethoxazole Neural tube defects, cardiovascular malformations, cleft palate, clubfoot, and urinary tract abnormalities Other Drugs Alcohol Fetal alcohol syndrome, stillbirth, spontaneous abortion, low birth weight, intellectual disabilities 5-α-reductase inhibitors (e.g., dutasteride, finasteride) Malformations of external genitalia in males Angiotensin-converting enzyme inhibitors Renal failure, renal tubular dysgenesis, skull hypoplasia (from exposure during the second and third trimesters) Antithyroid drugs (propylthiouracil, methimazole) Goiter and hypothyroidism HMG CoA reductase inhibitors (atorvastatin, simvastatin) Facial malformations and CNS anomalies, including holoprosencephaly (single-lobed brain) and neural tube defects Isotretinoin and other vitamin A derivatives (etretinate, megadoses of vitamin A) Multiple defects (CNS, craniofacial, cardiovascular, others) Lithium Epstein anomaly (cardiac defects) Nicotine replacement products Orofacial clefts, intrauterine growth restriction, CNS defects NSAIDs Premature closure of the ductus arteriosus Oral hypoglycemic drugs (e.g., tolbutamide) Neonatal hypoglycemia Warfarin Skeletal and CNS defects The absence of a drug from this table does not mean that the drug is not a teratogen. CNS, Central nervous system; HMG CoA, 3-hydroxy-3methylglutaryl coenzyme A; NSAIDs, nonsteroidal antiinflammatory drugs. To prove that a drug is a teratogen, three criteria must be met: The drug must cause a characteristic set of malformations. The drug must act only during a specific window of vulnerability (e.g., weeks 4 through 7 of gestation). The incidence of malformations should increase with increasing dosage and duration of exposure. Obviously, we cannot do experiments on humans to determine whether a drug meets these criteria. The best we can do is systematically collect and analyze data on drugs taken during pregnancy in the hope that useful information on teratogenicity will be revealed. Studies in animals may be of limited value, in part because teratogenicity may be species specific. That is, drugs that are teratogens in laboratory animals may be safe in humans. Conversely, and more important, drugs that fail to cause anomalies in animals may later prove teratogenic in humans. The most notorious example is thalidomide. In studies with pregnant animals, thalidomide was harmless; however, when pregnant patients took thalidomide, about 30% had babies with severe malformations. The take-home message is this: lack of teratogenicity in animals is not proof of safety in humans. Accordingly, we cannot assume that a new drug is safe for use in human pregnancy just because it has met FDA requirements based on tests done in pregnant animals. Some teratogens act quickly, whereas others require prolonged exposure. Thalidomide represents a fast-acting teratogen: a single dose can cause malformation. In contrast, alcohol (ethanol) must be taken repeatedly in high doses if gross malformation is to result. (Lower doses of alcohol may produce subtle anomalies.) Because a single exposure to a rapid-acting teratogen can produce obvious malformation, they are easier to identify than slow-acting teratogens. Teratogens that produce delayed effects are among the hardest to identify. The best example is diethylstilbestrol, an estrogenic substance that causes vaginal cancer in female offspring 18 years or so after they were born. Teratogens that affect behavior may be nearly impossible to identify. Behavioral changes are often delayed and therefore may not become apparent until the child goes to school. By this time, it may be difficult to establish a correlation between drug use during pregnancy and the behavioral deficit. Furthermore, if the deficit is subtle, it may not even be recognized. Although we have been discussing the effect of teratogens, it is important to note that drug-related effects are not limited to the distortions of gross anatomy caused by teratogens. Drugs may also include neurobehavioral and metabolic anomalies. For example, benzodiazepines taken late in pregnancy may cause hypoglycemia and respiratory complications along with a hypotonic state that is commonly called floppy infant syndrome. The aminoglycoside streptomycin provides another example. Although the teratogen risk of aminoglycosides is low, children born to women taking streptomycin have been born with congenital deafness. Some drugs taken by pregnant women may be dangerous (e.g., the anticoagulant warfarin has been associated with fetal hemorrhage) or life threatening (e.g., misoprostol, a drug taken to protect the stomach of people taking nonsteroidal antiinflammatory drugs) can cause a spontaneous abortion. US Food and Drug Administration Pregnancy Risk Categories In 1979, the FDA established a system for classifying drugs according to their probable risks to the fetus. According to this system, drugs can be put into one of five risk categories: A, B, C, D, and X (Table 8.2). Although this rating system is helpful, it is far from ideal. For example, some drugs that were placed in Category B---to indicate animal reproduction studies---do not indicate risk, and may not have undergone an adequate type or number of studies to adequately determine risk. Because of problems and confusion with the rating system, the FDA decided to phase it out over a period that will end in 2020. Nevertheless, because these categories are frequently referenced in recent pre-2020 literature, it is wise for the provider to have some familiarity with these categories. TABLE 8.2 US Food and Drug Administration Pregnancy Risk Categories Category Category Description A Remote risk for fetal harm: Controlled studies in women have been done and have failed to demonstrate a risk for fetal harm during the first trimester, and there is no evidence of risk in later trimesters B Slightly more risk than A: Animal studies show no fetal risk, but controlled studies have not been done in women. or Animal studies do show a risk for fetal harm, but controlled studies in women have failed to demonstrate a risk during the first trimester, and there is no evidence of risk in later trimesters C Greater risk than B: Animal studies show a risk for fetal harm, but no controlled studies have been done in women. or No studies have been done in women or animals D Proven risk for fetal harm: Studies in women show proof of fetal damage, but the potential benefits of use during pregnancy may be acceptable despite the risks (e.g., treatment of life-threatening disease for which safer drugs are ineffective). A statement on risk will appear in the WARNINGS section of drug labeling X Proven risk for fetal harm: Studies in women or animals show definite risk for fetal abnormality. or Adverse reaction reports indicate evidence of fetal risk. The risks clearly outweigh any possible benefit. A statement on risk will appear in the CONTRAINDICATIONS section of drug labeling Pregnancy Risk Categories became obsolete in 2020. US Food and Drug Administration Pregnancy and Lactation Labeling Rule In December 2014, the FDA issued the Pregnancy and Lactation Labeling Rule (PLLR) providing new guidance for labeling. The PLLR requires three sections for labeling: (1) pregnancy, (2) lactation, and (3) females and males of reproductive potential. These are further divided into subsections containing specified content (Table 8.3). The full report is available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm450636.pdf. TABLE 8.3 FDA Pregnancy and Lactation Labeling Rule Requirements Sections Subsections Headings and/or Content Pregnancy Pregnancy Exposure Registry (This subsection is omitted if there are no known pregnancy exposure registries for the drug.) If a pregnancy exposure registry exists, the following sentence will be included. "There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to (name of drug) during pregnancy." The statement is followed by registry enrollment information Risk Summary (This subsection is required.) Risk summaries are statements that summarize outcomes for the following content relative to drug dosage, length of time drug was taken, and weeks of gestation when the drug was taken as well as known pharmacologic mechanisms of action. Human data Animal data  Pharmacology Clinical Considerations (This subsection is omitted if none of the headings is applicable.) Information is provided for the following five headings. Disease-associated maternal and/or embryo/fetal risk Dose adjustments during pregnancy and the postpartum period Maternal adverse reactions Fetal/neonatal adverse reactions Labor or delivery (Any heading that is not applicable is omitted.) Data (This subsection is omitted if none of the headings is applicable.) This section describes research that served as a source of data for Risk Summaries. The following categories are included. a\. Human data b\. Animal data (Any heading that is not applicable is omitted.) Lactation Risk Summary (This subsection is required.) Risk summaries are statements that summarize outcomes for the following content. Presence of drug in human milk Effects of drug on the breastfed child Effects of drug on milk production/excretion  Risk and benefit statement Clinical Considerations (This subsection is omitted if none of the headings is applicable.) Information is provided for the following headings. Minimizing exposure Monitoring for adverse reactions (Any heading that is not applicable is omitted.) Data (This subsection is omitted if none of the headings is applicable.) This section expands on the Risk Summary and Clinical Considerations subsections. There are no defined headings. Females and males of reproductive potential (There is no defined subsection for this section.) The following headings are included to address the need for pregnancy testing or contraception and adverse effects associated with preimplantation loss or adverse effects on fertility. a\. Pregnancy testing b\. Contraception c\. Infertility (Any heading that is not applicable is omitted.) Adapted from U.S. Department of Health and Human Services, Food and Drug Administration. (2015, June). Appendix A: Organization and Format for Pregnancy, Lactation, and Females and Males of Reproductive Potential Subsections. Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products---Content and Format. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm450636.pdf. Minimizing Drug Risk During Pregnancy A first step in decreasing drug risk during pregnancy is to develop a comprehensive list of current drugs used. It is crucial to include not only prescription drugs but also over-the-counter and nutritional supplements, as well as recreational drug use, at every visit. A drug as common as vitamin A is dangerous when taken in excess. Vitamin A can cause craniofacial anomalies and central nervous system, cardiac, and thymus abnormalities. If pregnancy status is unknown and a high-risk drug is recommended for management of a condition, a pregnancy test should be performed before prescribing. As noted, some disease states (e.g., epilepsy, asthma, diabetes) pose a greater risk to fetal health than the drugs used for treatment. However, even with these disorders, in which drug therapy reduces the risk for disease-induced fetal harm, we must still take steps to minimize harm from drugs. Accordingly, drugs that pose a high risk for danger to the developing embryo or fetus should be discontinued, and safer alternatives substituted. Sometimes the use of a high-risk drug is unavoidable. Some anticancer drugs, for example, are highly toxic to the developing fetus, yet cannot be ethically withheld from the pregnant patient. If a patient elects to use such drugs, termination of pregnancy should be considered. Reducing the risk for dangerous drug effects also applies to female patients who are not pregnant because approximately 50% of pregnancies are unintended. Accordingly, if a patient of reproductive age is taking a teratogenic medication, she should be educated about the teratogenic risk as well as the necessity of using at least one reliable form of birth control. Responding to Teratogen Exposure When a pregnant patient has been exposed to a known teratogen, the first step is to determine exactly when the drug was taken and exactly when the pregnancy began. If drug exposure was not during the period of organogenesis (i.e., weeks 3 through 8), the patient should be reassured that the risk of drug-induced malformation is minimal. What should be done if the exposure did occur during organogenesis? First, a reference (such as FDA-approved prescribing information for the drug) should be consulted to determine the type of malformation expected. Next, at least two ultrasound scans should be done to assess the extent of injury. If the malformation is severe, termination of pregnancy should be considered. If the malformation is minor (e.g., cleft palate), it may be correctable by surgery, either shortly after birth or later in childhood. Drug Therapy During Breastfeeding Drugs taken by lactating patients can be excreted in breast milk. Although nearly all drugs can enter breast milk, the extent of entry varies greatly. The factors that determine entry into breast milk are the same factors that determine passage of drugs across membranes. Accordingly, drugs that are lipid soluble enter breast milk readily, whereas drugs that are ionized, highly polar, or protein bound tend to be excluded. If drug concentrations in milk are high enough, a pharmacologic effect can occur in the infant, raising the possibility of harm. To address concerns about drug risks for breastfed infants and children, the US National Library of Medicine created the LactMed database. (See https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm) LactMed is a comprehensive searchable site that provides the most current information on prescription and nonprescription drugs and their effects on breastfed infants and children. Unfortunately, relatively little systematic research has been done on many drugs. As a result, although a few drugs are known to be hazardous (Table 8.4), the possible danger posed by many others remains undetermined. TABLE 8.4 Drugs That Are Contraindicated During Breastfeeding Controlled Substances Amphetamine Cocaine Heroin Marijuana Phencyclidine Anticancer Agents/Immunosuppressants Cyclophosphamide Cyclosporine Doxorubicin Methotrexate Others Atenolol Bromocriptine Ergotamine Lithium Nicotine Radioactive compounds (temporary cessation) Fortunately, most drugs detected in milk are in concentrations that are too low to cause harm. Still, prudence is in order: if the nursing patient can avoid drugs that may pose a risk, she should. Moreover, when these drugs must be used, steps should be taken to minimize risk. These include the following: Dosing immediately after breastfeeding (to minimize drug concentrations in milk at the next feeding) Avoiding drugs that have a long half-life Avoiding sustained-release formulations Choosing drugs that tend to be excluded from milk Choosing drugs that are least likely to affect the infant (Table 8.5) TABLE 8.5 Drugs of Choice for Breastfeeding Patients Drug Category Drugs and Drug Groups of Choice Comments Analgesic drugs Acetaminophen, ibuprofen, flurbiprofen, ketorolac, mefenamic acid, sumatriptan, morphine Sumatriptan may be given for migraine. Morphine may be given for severe pain Anticoagulant drugs Warfarin, acenocoumarol , heparin (unfractionated) Among breastfed infants whose mothers were taking warfarin, the drug was undetectable in plasma, and bleeding time was not affected. The large molecular size of unfractionated heparin decreases the amount excreted in breast milk. Furthermore, it is not bioavailable from the GI tract, so heparin in breast milk is not systemically absorbed Antidepressant drugs Sertraline, paroxetine, TCAs Fluoxetine (Prozac) may be given if other SSRIs are ineffective; however, caution is needed because levels are higher in breast milk than levels of other SSRIs. Infant risk with TCAs cannot be ruled out; however, no significant adverse effects have been reported Antiepileptic drugs Carbamazepine, phenytoin, valproic acid The estimated level of exposure to these drugs in infants is less than 10% of the therapeutic dose standardized by weight Antihistamines (histamine-1 blockers) Loratadine, fexofenadine First-generation antihistamines are associated with irritability or sedation and may decrease milk supply Antimicrobial drugs Penicillins, cephalosporins, aminoglycosides, macrolides Avoid chloramphenicol and tetracycline β-adrenergic antagonists Labetalol, metoprolol, propranolol Angiotensin-converting enzyme inhibitors and calcium channel--blocking agents are also considered safe Endocrine drugs Propylthiouracil, insulin, levothyroxine The estimated level of exposure to propylthiouracil in breastfeeding infants is less than 1% of the therapeutic dose standardized by weight; thyroid function of the infant is not affected Glucocorticoids Prednisolone and prednisone The amount of prednisolone the infant would ingest in breast milk is less than 0.1% of the therapeutic dose standardized by weight This list is not exhaustive. Cases of overdoses of these drugs must be assessed on an individual basis. GI, Gastrointestinal; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Avoiding drugs that are known to be hazardous (see Table 8.4) Using the lowest effective dosage for the shortest possible time Abandoning plans to breastfeed if a necessary drug is known to be harmful to the child Side Effect A side effect is formally defined as a nearly unavoidable secondary drug effect produced at therapeutic doses. Common examples include drowsiness caused by traditional antihistamines and gastric irritation caused by aspirin. Side effects are generally predictable, and their intensity is dose dependent. Some side effects develop soon after drug use starts, whereas others may not appear until a drug has been taken for weeks or months. Toxicity The formal definition of toxicity is the degree of detrimental physiologic effects caused by excessive drug dosing. Examples include profound respiratory depression from an overdose of morphine and severe hypoglycemia from an overdose of insulin. Although the formal definition of toxicity includes only those severe reactions that occur when dosage is excessive, in everyday language the term toxicity has come to mean any severe ADR, regardless of the dose that caused it. For example, when administered in therapeutic doses, many anticancer drugs cause neutropenia, thereby putting the patient at high risk for infection. This neutropenia may be called "toxicity" even though it was produced when dosage was therapeutic. Allergic Reaction An allergic reaction is an immune response. For an allergic reaction to occur, there must be prior sensitization of the immune system. After the immune system has been sensitized to a drug, reexposure to that drug can trigger an allergic response. The intensity of allergic reactions can range from mild itching to severe rash to anaphylaxis. 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, because 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 antiinflammatory drugs (e.g., 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. An example of an idiosyncratic effect occurs in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an X-linked inherited condition that occurs primarily in people with African and Mediterranean ancestry. When people with G6PD deficiency take drugs such as sulfonamides or aspirin, they develop varying degrees of red blood cell hemolysis, which may become life threatening. Paradoxical Effect A paradoxical effect is the opposite of the intended drug response. A common example is the excitement that may occur when some children take first-generation antihistamines (available over-the-counter as a sleep aid). Similarly, older adults may experience paradoxical excitement when they are given benzodiazepines for sedation. Iatrogenic Disease An iatrogenic disease is a disease that occurs as the result of medical care or treatment. The term iatrogenic disease is also used to denote a disease produced by drugs. Iatrogenic diseases are nearly identical to naturally occurring diseases. For example, patients taking certain antipsychotic drugs may develop a syndrome with symptoms that closely resemble those of Parkinson disease. Physical Dependence Physical dependence is 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. Physical dependence develops during long-term use of certain drugs, such as opioids, alcohol, barbiturates, and amphetamines. The precise nature of the abstinence syndrome is determined by the drug involved. Although physical dependence is usually associated with opioids, these are not the only dependence-inducing drugs. A variety of other centrally acting drugs (e.g., 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. Teratogenic Effect A teratogenic effect is a drug-induced birth defect. Medicines and other chemicals capable of causing birth defects are called teratogens. Teratogenesis is discussed in Chapter 8. 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 (e.g., gentamicin). Patients using these 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 next. Hepatotoxic Drugs As some drugs undergo metabolism by the liver, they are converted to toxic products that can injure liver cells. These drugs are called hepatotoxic drugs. In the United States, drugs are the leading cause of acute liver failure, a rare condition that can rapidly prove fatal. 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. Combining a hepatotoxic drug with certain other drugs may increase the risk of liver damage. Acetaminophen (Tylenol) is a hepatotoxic drug that can damage the liver when taken in excessive doses. When taken in therapeutic doses, acetaminophen does not usually create a risk for liver injury; however, if the drug is taken with just two or three alcoholic beverages, severe liver injury can result. 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 for serious dysrhythmias. The QT interval is a measure of the time required for the ventricles to repolarize after each contraction. When the QT interval is prolonged (more than 470 ms for postpubertal males or more than 480 ms for postpubertal females), patients can develop a dysrhythmia known as torsades de pointes, which can progress to potentially fatal ventricular fibrillation. More than 100 drugs are known to cause QT prolongation, torsades de pointes, or both. As shown in Table 5.2, QT drugs are found in many drug families. Several QT drugs have been withdrawn from the market because of deaths linked to their use, and the use of another QT drug---cisapride (Propulsid)---is now restricted. To reduce the risks from QT drugs, the US Food and Drug Administration (FDA) now requires that all new drugs be tested for the ability to cause QT prolongation. Identifying Adverse Drug Reactions It can be very difficult to determine whether a specific drug is responsible for an observed adverse event because other factors---especially the underlying illness and other drugs being taken---could be the actual cause. To help determine whether a particular drug is responsible, the following questions should be considered: Did symptoms appear shortly after the drug was first used? Did symptoms abate when the drug was discontinued? Did symptoms reappear when the drug was reinstituted? Is the illness itself sufficient to explain the event? Are other drugs in the regimen sufficient to explain the event? 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 over the course of prolonged drug use. Adverse Reactions to New Drugs 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 1 and phase 3 trials. Because newly released drugs may have as yet unreported adverse effects, you should be alert for unusual responses when prescribing 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. It is a good practice to initially check postmarket drug evaluations at www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm204091.htm to determine whether serious problems have been reported. If the drug is especially new, however, you may be the first provider 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. Because voluntary reporting by health care 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. Ways to Minimize Adverse Drug Reactions The responsibility for reducing ADRs lies with everyone associated with drug production and use. The pharmaceutical industry must strive to produce the safest medicines possible; the provider must select the least harmful medicine for a particular patient and provide clear instructions for its use; the nurse must evaluate patients for ADRs and educate patients in ways to avoid or minimize harm; and patients and their families must take medication only as directed, watch for signs that an ADR may be developing, and seek medical attention if one appears. When patients are using drugs that are toxic to specific organs, function of the target organ should be monitored. The liver, kidneys, and bone marrow are important sites of drug toxicity. For drugs that are toxic to the liver, the patient should be monitored for signs and symptoms of liver damage (jaundice, dark urine, light-colored stools, nausea, vomiting, malaise, abdominal discomfort, loss of appetite), and periodic tests of liver function (e.g., aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) should be performed. For drugs that are toxic to the kidneys, the patient should undergo routine urinalysis and measurement of serum creatinine or creatinine clearance. For drugs that are toxic to bone marrow, periodic complete blood cell counts are required. Individualizing therapy can reduce adverse effects. When choosing a drug for a patient, the provider must balance the drug\'s risks and benefits. Drugs that are likely to harm a specific patient should be avoided unless the benefit of the drug exceeds the risk for injury. Special Alerts and Management Guidelines To decrease harm associated with drugs that cause serious adverse effects, the FDA requires special alerts and management guidelines. These may take the form of a Medication Guide for patients, a boxed warning to alert providers, or a Risk Evaluation and Mitigation Strategy (REMS), which can involve patients, providers, and pharmacists. Medication Guides Medication Guides, commonly called MedGuides, are FDA-approved documents created to educate patients about how to minimize harm from potentially dangerous drugs. In addition, a MedGuide is required when the FDA has determined that (1) patient adherence to directions for drug use is essential for efficacy or (2) patients need to know about potentially serious effects when deciding to use a drug. All MedGuides use a standard format that provides information under the following main headings: What is the most important information I should know about (name of drug)? What is (name of drug)? Include a description of the drug and its indications. Who should not take (name of drug)? How should I take (name of drug)? Include importance of adherence to dosing instructions, special instructions about administration, what to do in case of overdose, and what to do if a dose is missed. What should I avoid while taking (name of drug)? Include activities (e.g., driving, sunbathing), other drugs, foods, pregnancy, and breastfeeding. What are the possible or reasonably likely side effects of (name of drug)? General information about the safe and effective use of prescription drugs. Additional headings may be added by the manufacturer as appropriate, with the approval of the FDA. MedGuides for all drug products that require one are available online at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=medguide.page.The MedGuide should be provided whenever a prescription is filled, and even when drug samples are handed out. Boxed Warnings The boxed warning, also known as a black box warning, is the strongest safety warning a drug can carry and still remain on the market. Text for the warning is presented inside a box with a heavy black border. The FDA requires a boxed warning on drugs with serious or life-threatening risks. The purpose of the warning is to alert providers to (1) potentially severe side effects (e.g., life-threatening dysrhythmias, suicidality, major fetal harm) as well as (2) ways to prevent or reduce harm (e.g., avoiding a teratogenic drug during pregnancy). The boxed warning provides a concise summary of the adverse effects of concern. A boxed warning must appear prominently on the package insert, on the product label, and even in magazine advertising. Drugs that have a boxed warning must also have a MedGuide. An example of a drug with a boxed warning is promethazine (Phenergan). Promethazine is contraindicated in patients less than 2-years-old because it can cause respiratory depression. Additionally, when administered by injection, there is a risk for severe tissue injury and necrosis. Risk Evaluation and Mitigation Strategies A REMS is simply a plan to minimize drug-induced harm. For most drugs that have a REMS, a MedGuide is all that is needed. For a few drugs, however, the REMS may have additional components. For example, the REMS for the antiacne drug isotretinoin has provisions that pertain to the patient, provider, and pharmacist. This program, known as iPledge, is needed because isotretinoin can cause serious birth defects. The iPledge program was designed to ensure that patients who are pregnant, or may become pregnant, will not have access to the drug. Details of the iPledge program are presented in Chapter 87. All REMS that have received FDA approval can be found online at https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm. Medication Errors Medication errors are a major cause of morbidity and mortality. According to the National Academy of Medicine (formerly the Institute of Medicine \[IOM\]), every year medication errors injure at least 1.5 million Americans and kill an estimated 7000. The financial costs are staggering: among hospitalized patients alone, treatment of drug-related injuries costs at least \$3.5 billion per year. What Is a Medication Error? The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) defines a medication error as "any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the healthcare professional, patient, or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use." Note that, by this definition, medication errors can be made by many people---beginning with workers in the pharmaceutical industry, followed by people in the health care delivery system, and ending with patients and their family members. In this chapter, we focus on medication errors attributed to health care providers. These typically fall into one of the following categories: Prescribing Practices Inappropriate drug selection Error in drug dosage Lack of clear instructions Illegible writing Oversight Failure to keep an up-to-date medication list Failure to continue or discontinue medications Absence of medication reconciliation Communication Inadequate or unclear instructions Failure to verify drugs that sound alike Inadequate patient education Ways to Reduce Medication Errors Organizations throughout many countries are working to design and implement measures to reduce medication errors. Changes having the most dramatic effect have been those that focused on the National Academy of Medicine recommendations to (1) help and encourage patients and their families to be active, informed members of the health care team, and (2) give health care providers the tools and information needed to prescribe, dispense, and administer drugs as safely as possible. Foremost among these recommendations are requiring electronic prescribing, making drug reference material available electronically, and regulating abbreviations. Implementation of technology to reduce errors has had remarkable success, as well. For example, replacing handwritten medication orders with a computerized order entry system has reduced medication errors by 50%. Using barcode systems that match the patient\'s armband bar code to a drug barcode has decreased medication errors in some institutions by as much as 85%. Targeted interventions to address provider-related errors can be employed to decrease medication errors by health care providers. These are provided in Table 5.3.