Pediatric Drug Therapy PDF

Young patients respond differently to drugs than do the rest of the population. Most differences are quantitative. Specifically, younger patients are more sensitive to drugs than adult patients, and they show greater individual variation. Drug sensitivity in the very young results largely from organ...

Young patients respond differently to drugs than do the rest of the population. Most differences are quantitative. Specifically, younger patients are more sensitive to drugs than adult patients, and they show greater individual variation. Drug sensitivity in the very young results largely from organ system immaturity. Because of heightened drug sensitivity, they are at increased risk for adverse drug reactions. In this chapter we discuss the physiologic factors that underlie heightened drug sensitivity in pediatric patients and ways to promote safe and effective drug use. Pediatrics covers all patients up to age 16 years. Because of ongoing growth and development, pediatric patients in different age groups present different therapeutic challenges. Traditionally, the pediatric population is subdivided into six groups: Premature infants (less than 36 weeks gestational age) Full-term infants (36 to 40 weeks gestational age) Neonates (first 4 postnatal weeks) Infants (postnatal weeks 5 to 52) Children (1 to 12 years) Adolescents (12 to 16 years) Not surprisingly, as young patients grow older, they become more like adults physiologically, and hence more like adults with regard to drug therapy. Conversely, the very young---those younger than 1 year, and especially those younger than 1 month---are very different from adults. If drug therapy in these patients is to be safe and effective, we must account for these differences. Managing pediatric drug therapy is made even more difficult by insufficient drug information. To address this deficit, the US Food and Drug Administration (FDA) Safety and Innovation Act of 2012 permanently reauthorized two laws previously enacted by Congress to promote drug research in children: the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). Additionally, in 2012, the National Academies of Medicine (formerly the Institutes of Medicine \[IOM\]), published a synopsis of findings from previous research conducted under the BPCA and PREA. This report is available at http://nationalacademies.org/hmd/reports/2012/safe-and-effective-medicines-for-children.aspx. As more studies are done, the gaps in our knowledge will shrink. In the meantime, we must still treat children with drugs---even though we lack the information needed to prescribe rationally. Similar to drug therapy during pregnancy, providers must try to balance benefits and risks, without precisely knowing what the benefits and risks really are. Pharmacokinetics: Neonates and Infants Pharmacokinetic factors determine the concentration of a drug at its sites of action and hence determine the intensity and duration of responses. If drug levels are elevated, responses will be more intense. If drug elimination is delayed, responses will be prolonged. Because the organ systems that regulate drug levels are not fully developed in very young patients, they are at risk for both drug effects that are unusually intense and prolonged. By accounting for pharmacokinetic differences in the very young, we can increase the chances that drug therapy will be both effective and safe. Fig. 9.1 illustrates how drug levels differ between infants and adults after administration of doses adjusted for body weight. When a drug is administered intravenously, levels decline more slowly in the infant than in the adult. As a result, drug levels in the infant remain above the minimum effective concentration (MEC) longer than in the adult, thereby causing effects to be prolonged. When a drug is administered subcutaneously, not only do levels in the infant remain above the MEC longer than in the adult, but these levels also rise higher, causing effects to be more intense as well as prolonged. From these illustrations, it is clear that adjustment of dosage for infants on the basis of body size alone is not sufficient to achieve safe results. FIG. 9.1 Comparison of Plasma Drug Levels in Adults and Infants. (A) Plasma drug levels after intravenous injection. Dosage was adjusted for body weight. Note that plasma levels remain above the minimum effective concentration (MEC) much longer in the infant. (B) Plasma drug levels after subcutaneous injection. Dosage was adjusted for body weight. Note that both the maximal drug level and the duration of action are greater in the infant. If small body size is not the major reason for heightened drug sensitivity in infants, what is? The increased sensitivity of infants is due largely to the immature state of five pharmacokinetic processes: (1) drug absorption, (2) protein binding of drugs, (3) exclusion of drugs from the central nervous system (CNS) by the blood-brain barrier, (4) hepatic drug metabolism, and (5) renal drug excretion. Absorption Oral Administration Gastrointestinal physiology in the infant is very different from that in the adult. As a result, drug absorption may be enhanced or impeded, depending on the physicochemical properties of the drug involved. Gastric emptying time is both prolonged and irregular in early infancy, and then gradually reaches adult values by 6 to 8 months. For drugs that are absorbed primarily from the stomach, delayed gastric emptying enhances absorption. On the other hand, for drugs that are absorbed primarily from the intestine, absorption is delayed. Because gastric emptying time is irregular, the precise effect on absorption is not predictable. Gastric acidity is very low 24 hours after birth and does not reach adult values for 2 years. Because of low acidity, absorption of acid-labile drugs is increased. Intramuscular Administration Drug absorption after intramuscular injection in the neonate is slow and erratic. Delayed absorption is due in part to low blood flow through muscle during the first days of postnatal life. By early infancy, absorption of intramuscular drugs becomes more rapid than in neonates and adults. Transdermal Absorption Drug absorption through the skin is more rapid and complete in infants than in older children and adults. The stratum corneum of the infant\'s skin is very thin, and blood flow to the skin is greater in infants than in older patients. Because of this enhanced absorption, infants are at increased risk for toxicity from topical drugs. Distribution Protein Binding Binding of drugs to albumin and other plasma proteins is limited in the infant because (1) the amount of serum albumin is relatively low, and (2) endogenous compounds (e.g., fatty acids, bilirubin) compete with drugs for available binding sites. Consequently, drugs that ordinarily undergo extensive protein binding in adults undergo much less binding in infants. As a result, the concentration of free levels of such drugs is relatively high in the infant, thereby intensifying the effects. To ensure that the effects are not too intense, dosages in infants should be reduced. Protein-binding capacity reaches adult values within 10 to 12 months. Blood--Brain Barrier The blood--brain barrier is not fully developed at birth. As a result, drugs and other chemicals have relatively easy access to the CNS, making the infant especially sensitive to drugs that affect CNS function. Accordingly, all medicines employed for their CNS effects (e.g., morphine, phenobarbital) should be given in reduced dosage. Dosage also should be reduced for drugs used for actions outside the CNS if those drugs are capable of producing CNS toxicity as a side effect. Hepatic Metabolism The drug-metabolizing capacity of newborns is low. As a result, neonates are especially sensitive to drugs that are eliminated primarily by hepatic metabolism. When these drugs are used, dosages must be reduced. The capacity of the liver to metabolize many drugs increases rapidly about 1 month after birth and approaches adult levels a few months later. Complete maturation of the liver develops by 1 year. Renal Excretion Renal drug excretion is significantly reduced at birth. Renal blood flow, glomerular filtration, and active tubular secretion are all low during infancy. Because the drug-excreting capacity of infants is limited, drugs that are eliminated primarily by renal excretion must be given in reduced dosage or at longer dosing intervals, or both. Adult levels of renal function are achieved by 1 year. Pharmacokinetics: Children 1 Year and Older By age 1 year, most pharmacokinetic parameters in children are similar to those in adults. Therefore drug sensitivity in children older than 1 year is more like that of adults than that of the very young. Although pharmacokinetically similar to adults, children do differ in one important way: they metabolize drugs faster than adults. Drug-metabolizing capacity is markedly elevated until age 2 years and then gradually declines. A further sharp decline takes place at puberty, when adult values are reached. Because of enhanced drug metabolism in children, an increase in dosage or a reduction in dosing interval may be needed for drugs that are eliminated by hepatic metabolism. Adverse Drug Reactions Like adults, pediatric patients are subject to adverse reactions when drug levels rise too high. In addition, pediatric patients are vulnerable to unique adverse effects related to organ system immaturity and to ongoing growth and development. Among these age-related effects are growth suppression (caused by glucocorticoids), discoloration of developing teeth (caused by tetracyclines), and kernicterus (caused by sulfonamides). Table 9.1 presents a list of drugs that can cause unique adverse effects in pediatric patients of various ages. These drugs should be avoided in patients whose age puts them at risk. TABLE 9.1 Adverse Drug Reactions Unique to Pediatric Patients Drug Adverse Effect Androgens Premature puberty in males; reduced adult height from premature epiphyseal closure Aspirin and other salicylates Severe intoxication from acute overdose (acidosis, hyperthermia, respiratory depression); Reye syndrome in children with chickenpox or influenza Chloramphenicol Gray syndrome (neonates and infants) Fluoroquinolones Tendon rupture Glucocorticoids Growth suppression with prolonged use Hexachlorophene Central nervous system toxicity (infants) Nalidixic acid Cartilage erosion Phenothiazines Sudden infant death syndrome Promethazine Pronounced respiratory depression in children younger than 2 years Sulfonamides Kernicterus (neonates) Tetracyclines Staining of developing teeth Dosage Determination Because of the pharmacokinetic factors discussed previously, dosage selection for pediatric patients can be challenging. Selecting a dosage is especially difficult in the very young because pharmacokinetic factors are undergoing rapid change. Pediatric doses have been established for a few drugs, but not for most. For drugs that do not have an established pediatric dose, dosage can be extrapolated from adult doses. The method of conversion employed most commonly is based on body surface area (BSA): Please note that initial pediatric doses---whether based on established pediatric doses or extrapolated from adult doses---are at best an approximation. Subsequent doses must be adjusted on the basis of clinical outcome and plasma drug concentrations. These adjustments are especially important in neonates and younger infants. If dosage adjustments are to be optimal, it is essential that we monitor the patient for therapeutic and adverse responses as a component of optimizing dosage. Promoting Adherence Achieving accurate and timely dosing requires informed participation of the child\'s caregiver and, to the extent possible, active involvement of the child as well. Effective education is critical. The following issues should be addressed: Dosage size and timing Route and technique of administration Duration of treatment Drug storage The nature and time course of desired responses The nature and time course of adverse responses Written instructions should be provided to reinforce verbal instructions. For techniques of administration that are difficult, a demonstration should be made, after which the child\'s caregivers should repeat the procedure to ensure they understand. With young children, spills and spitting out are common causes of inaccurate dosing; parents should be taught to estimate the amount of drug lost and to readminister that amount, being careful not to overcompensate. When more than one person is helping medicate a child, all participants should be warned against multiple dosing. Multiple dosing can be avoided by maintaining a drug administration chart. With some disorders---especially infections---symptoms may resolve before the prescribed course of treatment has been completed. Parents should be instructed to complete the full course nonetheless. Additional strategies to promote adherence are presented in Table 9.2. TABLE 9.2 Strategies to Promote Medication Adherence in Children Strategies for Providers Prescribe drugs that can be taken once daily or less often, when possible. Consider drug costs and insurance coverage when choosing medications; discuss options with the caregiver. Use drug information sheets to reinforce verbal instructions. Give caregivers age-appropriate and condition-specific reading or coloring books to teach children Strategies for Caregivers Suggest medication reminders to avoid missed doses, such as pillboxes, calendars, computer alert systems. Recommend a reward system to prompt the child to take medication, such as stickers. Provide pleasant-tasting medication when possible. If the medication is unpalatable, consider the following: Suggest keeping it refrigerated, even if not required for storage. Administer with food to mask taste, unless contraindicated. Have the child suck on a frozen treat to decrease taste sensation before administration. Offer a treat to "get the taste out" immediately after taking the medication. Praise the child for taking the medication well. Strategies for Older Children and Adolescents Simplify medication regimens, when possible. Treat the patient with respect and develop trust. Teach and reinforce necessary skills (e.g., inhaler administration, insulin injection) to improve confidence. Provide developmentally appropriate information, games, software, and videos to reinforce teaching. Proactively address adverse effects when possible and collaborate with the patient on preferred methods to manage them when they occur. Set up networks to connect the child or adolescent with others managing similar illnesses and medication regimens. Employ an interprofessional team approach for support and encouragement Drug use among older adults (those 65 years and older) is disproportionately high. While older adults constitute only 12.8% of the US population, they consume 33% of the nation\'s prescribed drugs. The reasons for this intensive use of drugs include increased severity of illness, multiple pathologies, and excessive prescribing. Drug therapy in older adults represents a special therapeutic challenge. As a rule, older patients are more sensitive to drugs and they show wider individual variation. In addition, older adults experience more adverse drug reactions (ADRs) and drug--drug interactions. The principal factors underlying these complications are (1) altered pharmacokinetics (secondary to organ system degeneration), (2) multiple and severe illnesses, (3) multidrug therapy, and (4) poor adherence. To help ensure that drug therapy is as safe and effective as possible, individualization of treatment is essential: each patient must be monitored for desired and adverse responses, and the regimen must be adjusted accordingly. Because older adults often suffer from incurable chronic illnesses, the usual objective is to reduce symptoms and improve quality of life. Pharmacokinetic Changes in Older Adults The aging process can affect all phases of pharmacokinetics. From early adulthood on, there is a gradual, progressive decline in organ function. This decline can alter the absorption, distribution, metabolism, and excretion of drugs. As a rule, these pharmacokinetic changes increase drug sensitivity (largely from reduced hepatic and renal drug elimination). However, it should be noted that the extent of change varies greatly among patients: pharmacokinetic changes may be minimal in patients who have remained physically fit, whereas they may be dramatic in patients who have aged less fortunately. Accordingly, you should keep in mind that age-related changes in pharmacokinetics are not only a potential source of increased sensitivity to drugs but also a potential source of increased variability. The physiologic changes that underlie alterations in pharmacokinetics are summarized in Table 10.1. TABLE 10.1 Physiologic Changes That Can Affect Pharmacokinetics in Older Adults Absorption of Drugs Increased gastric pH Decreased absorptive surface area Decreased splanchnic blood flow Decreased gastrointestinal motility Delayed gastric emptying Distribution of Drugs Increased body fat Decreased lean body mass Decreased total body water Decreased serum albumin Decreased cardiac output Metabolism of Drugs Decreased hepatic blood flow Decreased hepatic mass Decreased activity of hepatic enzymes Excretion of Drugs Decreased renal blood flow Decreased glomerular filtration rate Decreased tubular secretion Decreased number of nephrons Absorption Altered gastrointestinal absorption is not a major factor in drug sensitivity in older adults. As a rule, the percentage of an oral dose that becomes absorbed does not usually change with age. However, the rate of absorption may be slowed (because of delayed gastric emptying and reduced splanchnic blood flow). As a result, drug responses may be somewhat delayed. Gastric acidity is reduced in older adults and may alter the absorption of certain drugs. For example, some drug formulations require high acidity to dissolve, and hence their absorption may be reduced. Distribution Four major factors can alter drug distribution in older adults: (1) increased percentage of body fat, (2) decreased percentage of lean body mass, (3) decreased total body water, and (4) reduced concentration of serum albumin. The increase in body fat seen in older adults provides a storage depot for lipid-soluble drugs (e.g., propranolol). As a result, plasma levels of these drugs are reduced, causing a reduction in responses. Because of the decline in lean body mass and total body water, water-soluble drugs (e.g., ethanol) become distributed in a smaller volume than in younger adults. As a result, the concentration of these drugs is increased, causing effects to be more intense. Although albumin levels are only slightly reduced in healthy older adults, these levels can be significantly reduced in older adults who are malnourished. Because of reduced albumin levels, sites for protein binding of drugs decrease, causing levels of free drug to rise. Accordingly, drug effects may be more intense. Metabolism Rates of hepatic drug metabolism tend to decline with age. The principal reasons are reduced hepatic blood flow, reduced liver mass, and decreased activity of some hepatic enzymes. Because liver function is diminished, the half-lives of certain drugs may be increased, thereby prolonging responses. Responses to oral drugs that ordinarily undergo extensive first-pass metabolism may be enhanced because fewer drugs are inactivated before entering the systemic circulation. However, it is important to note that the degree of decline in drug metabolism varies greatly among individuals. As a result, we cannot predict whether drug responses will be significantly reduced in any particular patient. Excretion Renal function, and hence renal drug excretion, undergoes progressive decline beginning in early adulthood. Drug accumulation secondary to reduced renal excretion is the most important cause of ADRs in older adults. The decline in renal function is the result of reductions in renal blood flow, glomerular filtration rate, active tubular secretion, and number of nephrons. Renal pathology can further compromise kidney function. The degree of decline in renal function varies greatly among individuals. Accordingly, when patients are taking drugs that are eliminated primarily by the kidneys, renal function should be assessed. In older adults, the proper index of renal function is creatinine clearance, not serum creatinine levels. Creatinine levels do not adequately reflect kidney function in older adults because the source of serum creatinine---lean muscle mass---declines in parallel with the decline in kidney function. Accordingly, creatinine levels may be normal even though renal function is greatly reduced. Although most medication adjustments for renal problems use creatinine clearance, for a few medications the estimated glomerular filtration rate (eGFR) is used. The National Kidney Foundation offers online calculators to determine the creatinine clearance at https://www.kidney.org/professionals/KDOQI/gfr\_calculatorCoc and the eGFR at https://www.kidney.org/professionals/kdoqi/gfr\_calculator. Pharmacodynamic Changes in Older Adults Alterations in receptor properties may underlie altered sensitivity to some drugs. However, information on such pharmacodynamic changes is limited. In support of the possibility of altered pharmacodynamics is the observation that beta-adrenergic blocking agents (drugs used primarily for cardiac disorders) are less effective in older adults than in younger adults, even when present in the same concentrations. Possible explanations for this observation include (1) a reduction in the number of beta receptors and (2) a reduction in the affinity of beta receptors for beta-receptor blocking agents. Other drugs (warfarin, certain central nervous system depressants) produce effects that are more intense in older adults, suggesting a possible increase in receptor number, receptor affinity, or both. Unfortunately, our knowledge of pharmacodynamic changes in older adults is restricted to a few families of drugs. Adverse Drug Reactions and Drug Interactions ADRs are seven times more common in older adults than in younger adults, accounting for about 16% of hospital admissions among older individuals and 50% of all medication-related deaths. Most of these reactions are dose related, not idiosyncratic. Symptoms in older adults are often nonspecific (e.g., dizziness, cognitive impairment), making identification of ADRs difficult. Furthermore, older adults may be less comfortable revealing alcohol or recreational drug use because of generational taboos in some segments of society. This can confound efforts to identify the source of a new ADR-related symptom. Perhaps surprisingly, the increase in ADRs seen in older adults is often not the direct result of aging. Rather, multiple factors predispose older patients to ADRs, the most important of which follow: Drug accumulation secondary to reduced renal function Polypharmacy (treatment with multiple drugs) Greater severity of illness Presence of comorbidities Use of drugs that have a low therapeutic index (e.g., digoxin, a drug for heart failure) Increased individual variation secondary to altered pharmacokinetics Inadequate supervision of long-term therapy Poor patient adherence Most ADRs in older adults are avoidable. Measures that can reduce their incidence are presented in Box 10.1. Box 10.1 Measures to Reduce Adverse Drug Reactions in Older Adults Take a thorough drug history, including over-the-counter medications, herbal remedies, and dietary supplements Account for the pharmacokinetic and pharmacodynamic changes that occur with aging Initiate therapy with low doses and titrating upward gradually ("start low and go slow") Monitor clinical responses and plasma drug levels to provide a rational basis for dosage adjustment Employ the simplest medication regimen possible Monitor for drug--drug interactions and iatrogenic illness Periodically review the need for continued drug therapy, and discontinue medications as appropriate Encourage the patient to dispose of old medications Take steps to promote adherence Avoid drugs included in Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (the Beers list) unless benefits outweigh risks. Synthesizing information on disparate drugs that can cause harm has presented a challenge. A few lists have emerged over the years, but perhaps the most well known are the Beers List and START/STOPP criteria. Both identify drugs that are potentially inappropriate. As with all drug decisions, the provider must weigh benefits and risks. The patient's individual history must also be taken into account. For example, often patients are started on these medications well before they reach age 65. If the drugs are meeting the patient's needs and not causing problems, it would be illogical to stop them or reduce their dosage based on age alone. The Beers List identifies drugs with a high likelihood of causing adverse effects in older adults. Accordingly, drugs on this list should generally be avoided in adults older than 65 years except when the benefits are significantly greater than the risks. A partial listing of these drugs appears in Table 10.2. The full list, updated in 2019, is available online at https://onlinelibrary.wiley.com/doi/pdf/10.1111/jgs.15767. TABLE 10.2 Some Drugs to Generally Avoid in Older Adults Drugs Reason for Concern Alternative Treatments Analgesics Indomethacin (Indocin) Ketorolac (Toradol) Chronic use of non- --COX-2 selective NSAIDs (e.g., ibuprofen, aspirin \>325 mg/day) Risk of GI bleeding and acute renal failure. Indomethacin is more prone to affect the CNS than other NSAIDs. Mild pain: acetaminophen, codeine, COX-2--selective inhibitors if no heart failure risk, short-term use of low-dose NSAIDs Meperidine (Demerol) Not effective at usual doses, risk for neurotoxicity, confusion, delirium Moderate to severe pain: morphine, oxycodone, hydrocodone Tricyclic Antidepressants, First Generation Amitriptyline Clomipramine (Anafranil) Doxepin (\>6 mg/day) Imipramine (Tofranil) Anticholinergic effects (constipation, urinary retention, blurred vision), risk for cognitive impairment, delirium, syncope SSRIs with shorter half-life, (e.g., paroxetine, sertraline, fluvoxamine), SNRIs, or other antidepressants Antihistamines, First Generation Chlorpheniramine (Chlor-Trimeton, Teldrin, Chlor-Tripolon ) Diphenhydramine (Benadryl) Hydroxyzine (Vistaril, Atarax ) Promethazine (Phenergan) Anticholinergic effects (constipation, urinary retention, blurred vision), sedation, orthostatic hypotension Second-generation antihistamines, such as cetirizine (Zyrtec), fexofenadine (Allegra), or loratadine (Claritin) Antihypertensives, α-Adrenergic Blocking Agents α1 blockers (e.g., doxazosin \[Cardura\], prazosin \[Minipress\], terazosin \[Hytrin\]) High risk for orthostatic hypotension and falls; less dangerous drugs are available Thiazide diuretic, ACE inhibitor, beta-adrenergic blocker, calcium channel blocker Sedative-Hypnotics Barbiturates (e.g., butalbital \[component of Fiorinal\], phenobarbital, secobarbital \[Seconal\]) Physical dependence; compared with other hypnotics, higher risk for falls, confusion, cognitive impairment Short-term zolpidem (Ambien), zaleplon (Sonata), or eszopiclone (Lunesta) Low-dose ramelteon (Rozerem) or low-dose doxepin Nonpharmacologic interventions (e.g., cognitive behavioral therapy) Benzodiazepines, both short acting (e.g., alprazolam \[Xanax\], lorazepam \[Ativan\]) and long acting (e.g., chlordiazepoxide \[Librium\], diazepam \[Valium\]) Sedation, cognitive impairment, risk for falls, delirium risk Low-dose ramelteon (Rozerem) or low-dose doxepin Nonpharmacologic interventions (e.g., cognitive behavioral therapy) Drugs for Urge Incontinence Oxybutynin (Ditropan) Tolterodine (Detrol) Anticholinergic effects, urinary retention, confusion, hallucinations, sedation Behavioral therapy (e.g., bladder retraining, urge suppression) Muscle Relaxants Carisoprodol (Soma) Cyclobenzaprine Metaxalone (Skelaxin) Methocarbamol (Robaxin) Anticholinergic effects, sedation, cognitive impairment; may not be effective at tolerable dosage Antispasmodics, such as baclofen (Lioresal) Nonpharmacologic interventions (e.g., exercises, proper body mechanics) Proton Pump Inhibitors (chronic use exceeding 8 weeks) Esomeprazole (Nexium) Lansoprazole (Prevacid) Omeprazole (Prilosec) Increased risk for Clostridium difficile infection, decreased bone integrity, and fractures Histamine-2 receptor antagonists (e.g., famotidine (Pepcid), ranitidine (Zantac)) Nonpharmacologic interventions (e.g., deleting foods that increase gastric acidity, such as high-fat foods, and deleting substances that lower esophageal sphincter pressure such as alcohol) ACE, Angiotensin-converting enzyme; CNS, central nervous system; COX-2, cyclooxygenase-2; GI, gastrointestinal; NSAIDs, nonsteroidal antiinflammatory drugs; SNRI, serotonin/norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. Adapted from American Geriatrics Society 2019 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019; 674--694. (Note: The original document lists many drugs in addition to those in this table.) STOPP stands for Screening Tool of Older People\'s potentially inappropriate Prescriptions. Like the Beers List, STOPP criteria also identify drugs that may be dangerous if prescribed for older adults. It has an advantage of also considering the economic costs of drug therapy. Additionally, when combined with the Screening Tool to Alert doctors to Right Treatment (START), the set can be used to promote the selection of appropriate treatment in addition to the avoidance of inappropriate treatment. The article detailing START/STOPP criteria is available at https://academic.oup.com/ageing/article/44/2/213/2812233. Promoting Adherence Between 26% and 59% of older adult patients fail to take their medicines as prescribed. Some patients never fill their prescriptions, some fail to refill their prescriptions, and some don\'t follow the prescribed dosing schedule. Nonadherence can result in therapeutic failure (from underdosing or erratic dosing) or toxicity (from overdosing). Of the two possibilities, underdosing with resulting therapeutic failure is by far (90%) the more common. Problems arising from nonadherence account for up to 10% of all hospital admissions, and their management may cost more than \$100 billion a year. Multiple factors underlie nonadherence to the prescribed regimen (Box 10.2). Among these are forgetfulness; failure to comprehend instructions (because of intellectual, visual, or auditory impairment); inability to pay for medications; and use of complex regimens (several drugs taken several times a day). All of these factors can contribute to unintentional nonadherence. However, in most cases (about 75%), nonadherence among older adults is intentional. The principal reason given for intentional nonadherence is the patient\'s conviction that the drug was simply not needed in the dosage prescribed. Unpleasant side effects and expense also contribute to intentional nonadherence. Box 10.2 Factors That Increase Risk for Poor Adherence in Older Adults Multiple chronic disorders Multiple prescription medications Multiple doses per day for each medication Drug packaging that is difficult to open Multiple prescribers Changes in the regimen (addition of drugs, changes in dosage size or timing) Cognitive or physical impairment (reduction in memory, hearing, visual acuity, color discrimination, or manual dexterity) Living alone Recent discharge from hospital Low literacy Inability to pay for drugs Personal conviction that a drug is unnecessary or the dosage too high Presence of side effects Several measures can promote adherence, including the following: Simplifying the regimen so that the number of drugs and doses per day is as small as possible Explaining the treatment plan using clear, concise, verbal and written instructions Choosing an appropriate dosage form (e.g., a liquid formulation if the patient has difficulty swallowing) Requesting that the pharmacist label drug containers using a large print size and provide containers that are easy to open by patients with impaired dexterity (e.g., those with arthritis) Suggesting the use of a calendar, diary, or pill counter to record drug administration Asking the patient if he or she has access to a pharmacy and can afford the medication Enlisting the aid of a friend, relative, or visiting health care professional Monitoring for therapeutic responses, adverse reactions, and plasma drug levels However, it must be noted that the benefits of these measures will be restricted primarily to patients whose nonadherence is unintentional. Unfortunately, these measures are generally inapplicable to the patient whose nonadherence is intentional. For these patients, intensive education may help. Considerations for End-of-Life Care End-of-life care poses a set of different concerns regarding the choice of drugs to best meet the needs of older patients. Priority treatment varies as goals shift from disease prevention and management to the provision of comfort measures. Drugs that were once considered important in care (e.g., drugs for cholesterol management) may no longer be relevant and can be discontinued. Drugs that were once considered inappropriate due to patient age (e.g., sedatives) may need to become a predominant feature of care. Table 10.3 explores medication considerations and choices for concerns that patients sometimes encounter near the end of life. Additional information is available at https://www.cancer.gov/about-cancer/advanced-cancer/caregivers/planning/last-days-hp-pdq\#section/\_7. The National Academy of Medicine\'s report Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life addresses multiple concerns of dying patients and their families, and is available at http://www.nap.edu/read/18748/chapter/1. TABLE 10.3 Pharmacological Considerations for End-of-Life Care Problems Considerations Drug Choice Constipation Constipation may be opioid-induced; an order for opioids should be accompanied by an order to treat constipation. Stimulants typically cause some degree of abdominal cramping. Drugs specifically formulated for opioid-induced constipation (i.e., methylnaltrexone) are very expensive and may not be warranted if other interventions are effective. Increased fiber may cause constipation if there is insufficient fluid intake First-line choices are osmotic laxatives (e.g., lactulose, polyethylene glycol). Stimulants with stool softener (e.g., senna with docusate) are second-line choices if abdominal cramping is a concern; otherwise, they may be given as a first-line choice. For those who cannot swallow, bisacodyl rectal suppositories or enemas can provide relief. Methylnaltrexone may be used for refractory opioid-induced constipation Delirium Delirium may be a manifestation of pain. Delirium may be a manifestation of opioid-induced neurotoxicity. Benzodiazepines may cause a paradoxical agitation but may be helpful if delirium is related to alcohol withdrawal or as an adjunct to antipsychotics. Underlying causes (constipation, urinary retention, infection) should be treated, if identified Treat with antipsychotics such as haloperidol or olanzapine. Benzodiazepines such as midazolam may be helpful short term to supplement antipsychotics for acute episodes of delirium. Consider adding analgesics (or evaluate adequacy of currently prescribed analgesics). For patients taking opioids (e.g., morphine), changing to a different opioid (e.g., fentanyl) has been helpful. Dyspnea Dyspnea may or may not be associated with hypoxemia. Management should consider severity of associated manifestations (e.g., profound fatigue exacerbated by respiratory effort). Bronchodilators may increase anxiety which can further worsen sensation of shortness of breath Oxygen therapy is indicated if hypoxemia is present. Opioids are a first-line drug choice. Glucocorticoids are often helpful, if not contraindicated. Consider bronchodilators only if dyspnea is associated with bronchospasm Fatigue Dexamphetamine has only short-term benefit due to tolerance; one study showed that benefit did not extend past 8 days Methylphenidate has demonstrated improvement in some studies Nausea and vomiting Management should be tailored to the underlying cause Chemotherapy or radiation-induced N/V: 5-HT3 receptor antagonists (e.g., ondansetron) or neurokinin1 receptor antagonist (e.g., aprepitant) or glucocorticoid (e.g., dexamethasone). Metoclopramide is recommended first line for N/V due to gastroparesis, liver failure and unknown causes. Haloperidol, a dopamine receptor antagonist, is often effective in relieving N/V of unknown causes and is first line for N/V due to bowel obstruction and renal failure. Glucocorticoids may be helpful in treating N/V secondary to brain tumors and bowel obstructions. For N/V of unknown cause, metoclopramide may be supplemented with 5HT3-receptor antagonists or dopamine receptor antagonists Pain Pain associated with conditions such as cancer is often intractable. Concerns about addiction are generally irrelevant at this stage of life, so highly addictive drugs may be employed. Opioids undergo hepatic metabolism and most undergo renal excretion. As organ failure occurs, opioids may accumulate to toxic levels. TCAs have adverse effects and drug--drug interactions that create complications when used for neuropathic pain Fentanyl is the drug of choice for severe pain in patients with renal and/or hepatic dysfunction. Methadone is a drug of choice for patients with renal dysfunction but without hepatic dysfunction. Schedule medication around the clock rather than prn. Gabapentin or pregabalin are recommended for management of neuropathic pain. SSRIs and SNRIs also may be helpful Respiratory secretions "Death Rattle" Accumulation of secretions in the airway occurs as the patient nears death (within 2 weeks or less) and ineffective cough progresses to loss of cough reflex and pooling of secretions. Suctioning may be inadequate to relieve this problem. Expert opinion is divided regarding whether treatment is warranted. Many believe that the death rattle does not cause patient distress, but it can be upsetting to families If drug therapy is desired, anticholinergics are often effective in decreasing secretions. Glycopyrrolate is the anticholinergic of choice due to decreased CNS adverse effects. Some studies have indicated that hyoscyamine is a good choice for this purpose CNS, Central nervous system; N/V, nausea and vomiting; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants.