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Pharmacology_Katzung. C. Predictable Toxic Drug Actions in the Fetus Chronic use of opioids by the mother often produces dependence in the fetus and newborn. This dependence may be manifested after delivery as a neonatal withdrawal syndrome. A less well understood fetal drug toxicity is caused by the use of angiotensinconverting enzyme inhibitors during late pregnancy. These drugs can result in significant and irreversible renal damage in the fetus and are therefore contraindicated in pregnant women. Adverse effects may also be delayed, as in the case of female fetuses exposed to diethylstilbestrol, who may be at increased risk for adenocarcinoma of the vagina after puberty. D. Teratogenic Drug Actions


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Pharmacology_Katzung. D. Teratogenic Drug Actions A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure. Thalidomide is an example of a drug that may profoundly affect the development of the limbs after only brief exposure. This exposure, however, must be at a critical time in the development of the limbs. Thalidomide-induced phocomelia occurs during the fourth through the seventh weeks of gestation because it is during this time that the arms and legs develop (Figure 59–1).


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Pharmacology_Katzung. 1. Teratogenic mechanisms—The mechanisms by which different drugs produce teratogenic effects are poorly understood and are probably multifactorial. For example, drugs may have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues. Drugs may interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus. Finally, drugs may have important direct actions on the processes of differentiation in developing tissues. For example, vitamin A (retinol) 20-38 Full term Fetal period (weeks) Embryonic period (weeks) 3816987654321 Heart CNS Eye Eye Heart Arm Leg Teeth Ear External genitalia Central nervous system Arms Eyes Legs Teeth Palate External genitalia Ear Major morphologic abnormalities Prenatal death Usually not susceptible to teratogen Brain Physiologic defects and minor morphologic abnormalities Period of dividing zygote, implantation, and bilaminar embryo Palate


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Pharmacology_Katzung. abnormalities Prenatal death Usually not susceptible to teratogen Brain Physiologic defects and minor morphologic abnormalities Period of dividing zygote, implantation, and bilaminar embryo Palate Indicates common site of action of teratogen Heart


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Pharmacology_Katzung. FIGURE 59–1 Schematic diagram of critical periods of human development. (Reproduced, with permission, from Moore KL: The Developing Human: Clinically Oriented Embryology, 4th ed. Saunders, 1988. © Elsevier.) has been shown to have important differentiation-directing actions in normal tissues. Several vitamin A analogs (isotretinoin, etretinate) are powerful teratogens, suggesting that they alter the normal processes of differentiation. Finally, deficiency of a critical substance appears to play a role in some types of abnormalities. For example, folic acid supplementation during pregnancy appears to reduce the incidence of neural tube defects (see Box, page 599).


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Pharmacology_Katzung. Continued exposure to a teratogen may produce cumulative effects or may affect several organs going through varying stages of development. Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters, may result in the fetal alcohol spectrum disorder (see Chapter 23). In this syndrome, the central nervous system, growth, and facial development may be affected.


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Pharmacology_Katzung. 2. Defining a teratogen—To be considered teratogenic, a candidate substance or process should (1) result in a characteristic set of malformations, indicating selectivity for certain target organs; (2) exert its effects at a particular stage of fetal development, eg, during the limited time period of organogenesis of the target organs (Figure 59–1); and (3) show a dose-dependent incidence. Some drugs with known teratogenic or other adverse effects in pregnancy are listed in Table 59–1. Teratogenic effects are not limited only to major malformations, but also include intrauterine growth restriction (eg, cigarette smoking), miscarriage (eg, alcohol), stillbirth (eg, cigarette smoke), and neurocognitive delay (eg, alcohol, valproic acid).


Pharmacology_Katzung

Pharmacology_Katzung. In addition to teratogenic drugs, teratogenicity can be induced by a large group of infectious pathogens, including viruses such as rubella, cytomegalovirus, herpes, and recently, Zika virus. Similarly, numerous chemicals, such as heavy metals (eg, mercury, lead) and environmental factors (eg, radiation, hyperthermia) can damage the fetus. It is important to consider these nondrug factors in the differential diagnosis of drug-induced adverse fetal effects.


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Pharmacology_Katzung. The widely cited US Food and Drug Administration (FDA) system for teratogenic potential (Table 59–2) has been an attempt to quantify teratogenic risk from A (safe) to X (definite human teratogenic risk). This system has been criticized as inaccurate and impractical. For example, several drugs have been labeled “X” despite extensive opposite human safety data (eg, oral contraceptives). Diazepam and other benzodiazepines are labeled as “D” despite lack of positive evidence of human fetal risk. The FDA has recently changed its system from the A, B, C grading system to narrative statements that summarize evidence-based knowledge about each drug in terms of fetal risk and safety.


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Pharmacology_Katzung. 3. Counseling women about teratogenic risk—Since the thalidomide disaster, medicine has been practiced as if every drug were a potential human teratogen when, in fact, fewer than 30 such drugs have been identified, with hundreds of agents proved safe for the unborn. Owing to high levels of anxiety among pregnant women—and because half of the pregnancies in North America are unplanned—every year many thousands of women need counseling about fetal exposure to drugs, chemicals, and radiation. The ability of appropriate counseling to prevent unnecessary abortions has been documented. Clinicians who wish to provide such counsel to pregnant women must ensure that their information is up-to-date and evidence-based and that the woman understands that the baseline teratogenic risk in pregnancy (ie, the risk of a neonatal abnormality in the absence of any known teratogenic exposure) is about 3%. It is also critical to address the maternal-fetal risks of the untreated condition if a medication


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Pharmacology_Katzung. the risk of a neonatal abnormality in the absence of any known teratogenic exposure) is about 3%. It is also critical to address the maternal-fetal risks of the untreated condition if a medication is avoided. Recent studies show serious morbidity in women who discontinued selective serotonin reuptake inhibitor therapy for depression in pregnancy.


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Pharmacology_Katzung. Physiologic processes that influence pharmacokinetic variables in the infant change significantly in the first year of life, particularly during the first few months. Therefore, special attention must be paid to pharmacokinetics in this age group. Pharmacodynamic differences between pediatric and other patients have not been explored in great detail but are probably important for those specific target tissues that mature at birth or immediately thereafter (eg, the ductus arteriosus). Drug absorption in infants and children follows the same general principles as in adults. Unique factors that influence drug absorption include blood flow at the site of administration, as determined by the physiologic status of the infant or child; and, for orally administered drugs, gastrointestinal function, which changes rapidly during the first few days after birth. Age after birth also influences the regulation of drug absorption. A. Blood Flow at the Site of Administration


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Pharmacology_Katzung. Absorption after intramuscular or subcutaneous injection depends mainly, in neonates as in adults, on the rate of blood flow to the muscle or subcutaneous area injected. Physiologic conditions that might reduce blood flow to these areas are cardiovascular shock, vasoconstriction due to sympathomimetic agents, and heart failure. However, sick preterm infants requiring intramuscular injections may have very little muscle mass. This is further complicated by diminished peripheral perfusion to these areas. In such cases, absorption becomes irregular and difficult to predict, because the drug may remain in the muscle and be absorbed more slowly than expected. If perfusion suddenly improves, there can be a sudden and unpredictable increase in the amount of drug entering the circulation, resulting in high and potentially toxic concentrations of drug. Examples of drugs especially hazardous in such situations are cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants.


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Pharmacology_Katzung. B. Gastrointestinal Function Significant biochemical and physiologic changes occur in the neonatal gastrointestinal tract shortly after birth. In full-term infants, gastric acid secretion begins soon after birth and increases gradually over several hours. In preterm infants, the secretion of gastric acid occurs more slowly, with the highest concentrations appearing on the fourth day of life. TABLE 59–1 Drugs with significant teratogenic or other adverse effects on the fetus. TABLE 59–2 FDA teratogenic risk categories.1 1This system has been changed as of 2014 by eliminating the A, B, C qualifications and replacing them with specific structured narratives for each drug.


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Pharmacology_Katzung. Gastric emptying time is prolonged (up to 6 or 8 hours) in the first day or so after delivery. Therefore, drugs that are absorbed primarily in the stomach may be absorbed more completely than anticipated. In the case of drugs absorbed in the small intestine, therapeutic effect may be delayed. Peristalsis in the neonate is irregular and may be slow. The fraction of drug absorbed in the small intestine may therefore be unpredictable; more than the usual amount of drug may be absorbed if peristalsis is slowed, and this could result in toxicity from an otherwise standard dose. Table 59–3 summarizes data on oral bioavailability of various drugs in neonates compared with older children and adults. An increase in peristalsis, as in diarrheal conditions, tends to decrease the extent of absorption, because contact time with the large absorptive surface of the intestine is decreased.


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Pharmacology_Katzung. Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of α-amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs. TABLE 59–3 Oral drug absorption (bioavailability) of various drugs in the neonate compared with older children and adults.


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Pharmacology_Katzung. TABLE 59–3 Oral drug absorption (bioavailability) of various drugs in the neonate compared with older children and adults. As body composition changes with development, the distribution volumes of drugs are also changed. The neonate has a higher percentage of its body weight in the form of water (70–75%) than does the adult (50–60%). Differences can also be observed between the full-term neonate (70% of body weight as water) and the small preterm neonate (85% of body weight as water). Similarly, extracellular water is 40% of body weight in the neonate, compared with 20% in the adult. Most neonates will experience diuresis in the first 24–48 hours of life. Since many drugs are distributed throughout the extracellular water space, the size (volume) of the extracellular water compartment may be important in determining the concentration of drug at receptor sites. This is especially important for water-soluble drugs (such as aminoglycosides) and less crucial for lipid-soluble agents.


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Pharmacology_Katzung. Preterm infants have much less fat than full-term infants. Total body fat in preterm infants is about 1% of total body weight, compared with 15% in full-term neonates. Therefore, organs that generally accumulate high concentrations of lipid-soluble drugs in adults and older children may accumulate smaller amounts of these agents in less mature infants.


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Pharmacology_Katzung. Another major factor determining drug distribution is drug binding to plasma proteins. Albumin is the plasma protein with the greatest binding capacity. In general, protein binding of drugs is reduced in the neonate, as seen with local anesthetic drugs, diazepam, phenytoin, ampicillin, and phenobarbital. Therefore, the concentration of free (unbound) drug in plasma is increased initially. Because the free drug exerts the pharmacologic effect, this can result in greater drug effect or toxicity despite a normal or even low plasma concentration of total drug (bound plus unbound). As an example, consider a therapeutic dose of a drug (eg, diazepam) given to a patient. The concentration of total drug in the plasma is 300 mcg/L. If the drug is 98% protein-bound in an older child or adult, then 6 mcg/L is the concentration of free drug. Assume that this concentration of free drug produces the desired effect in the patient without producing toxicity. However, if this drug is given to a preterm


Pharmacology_Katzung

Pharmacology_Katzung. mcg/L is the concentration of free drug. Assume that this concentration of free drug produces the desired effect in the patient without producing toxicity. However, if this drug is given to a preterm infant in a dosage adjusted for body weight and it produces a total drug concentration of 300 mcg/L—and protein binding is only 90%—then the free drug concentration will be 30 mcg/L, or five times higher. Although the higher free concentration may result in faster elimination (see Chapter 3), this concentration may be quite toxic initially.


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Pharmacology_Katzung. Some drugs compete with serum bilirubin for binding to albumin. Drugs given to a neonate with jaundice can displace bilirubin from albumin. Because of the greater permeability of the neonatal blood-brain barrier, substantial amounts of bilirubin may enter the brain and cause kernicterus. This was in fact observed when sulfonamide antibiotics were given to preterm neonates as prophylaxis against sepsis. Conversely, as the serum bilirubin rises for physiologic reasons or because of a blood group incompatibility, bilirubin can displace a drug from albumin and substantially raise the free drug concentration. This may occur without altering the total drug concentration and would result in greater therapeutic effect or toxicity at normal concentrations, as has been shown with phenytoin.


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Pharmacology_Katzung. The metabolism of most drugs occurs in the liver (see Chapter 4). The drug-metabolizing activities of the cytochrome P450 super-family and the conjugating enzymes are substantially lower (50– 70% of adult values) in early neonatal life than later. The point in development at which enzymatic activity reaches adult levels depends on the specific enzyme system in question. Glucuronide formation reaches adult values (per kilogram body weight) between the third and fourth years of life. Because of the neonate’s decreased ability to metabolize drugs, many drugs have slow clearance rates and prolonged elimination half-lives in early life. If drug doses and dosing schedules are not altered appropriately, this immaturity predisposes the neonate to adverse effects from drugs that are metabolized by the liver. Table 59–4 demonstrates how TABLE 59–4 Comparison of elimination half-lives of various drugs in neonates and adults.


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Pharmacology_Katzung. TABLE 59–4 Comparison of elimination half-lives of various drugs in neonates and adults. neonatal and adult drug elimination half-lives can differ and how the half-lives of phenobarbital and phenytoin decrease as the neonate grows older. The process of maturation must be considered when administering drugs to this age group, especially in the case of drugs administered over long periods. Another consideration for the neonate is whether or not the mother was receiving drugs (eg, phenobarbital) that can induce early maturation of fetal hepatic enzymes. In this case, the ability of the neonate to metabolize certain drugs will be greater than expected, and one may see less therapeutic effect and lower plasma drug concentrations when the usual neonatal dose is given. During toddlerhood (12–36 months), the metabolic rate of many drugs exceeds adult values, often necessitating larger doses per kilogram than later in life.


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Pharmacology_Katzung. The glomerular filtration rate is much lower in newborns than in older infants, children, or adults, and this limitation persists during the first few days of life. Calculated on the basis of body surface area, glomerular filtration in the neonate is only 30–40% of the adult value. The glomerular filtration rate is even lower in neonates born before 34 weeks of gestation. Function improves substantially during the first week of life. At the end of the first week, the glomerular filtration rate and renal plasma flow have increased 50% from the first day. By the end of the third week, glomerular filtration is 50–60% of the adult value; by 6–12 months, it reaches adult values (per unit surface area). Subsequently, during toddlerhood, it exceeds adult values, often necessitating larger doses per kilogram than in adults, as described previously for drug-metabolic rate. Therefore, drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of


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Pharmacology_Katzung. kilogram than in adults, as described previously for drug-metabolic rate. Therefore, drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of life.


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Pharmacology_Katzung. Penicillins, for example, are cleared by preterm infants at 17% of the adult rate based on comparable surface area and 34% of the adult rate when adjusted for body weight. The dosage of ampicillin for a neonate less than 7 days old is 50–100 mg/kg/d in two doses at 12-hour intervals. The dosage for a neonate over 7 days old is 100–200 mg/kg/d in three doses at 8-hour intervals. A decreased rate of renal elimination in the neonate has also been observed with aminoglycoside antibiotics (kanamycin, gentamicin, neomycin, and streptomycin). The dosage of gentamicin for a neonate less than 7 days old is 5 mg/kg/d in two doses at 12-hour intervals. The dosage for a neonate over 7 days old is 7.5 mg/ kg/d in three doses at 8-hour intervals. Total body clearance of digoxin is directly dependent upon adequate renal function, and accumulation of digoxin can occur when glomerular filtration is decreased. Since renal function in a sick infant may not improve at the predicted rate during the first


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Pharmacology_Katzung. adequate renal function, and accumulation of digoxin can occur when glomerular filtration is decreased. Since renal function in a sick infant may not improve at the predicted rate during the first weeks and months of life, appropriate adjustments in dosage and dosing schedules may be very difficult. In this situation, adjustments are best made on the basis of plasma drug concentrations determined at intervals throughout the course of therapy.


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Pharmacology_Katzung. Although great focus is naturally concentrated on the neonate, it is important to remember that toddlers may have shorter elimination half-lives of drugs than older children and adults, due probably to increased renal elimination and metabolism. For example, the dose per kilogram of digoxin is much higher in toddlers than in adults. The mechanisms for these developmental changes are still poorly understood. Special Pharmacodynamic Features in the Neonate


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Pharmacology_Katzung. The appropriate use of drugs has made possible the survival of neonates with severe abnormalities who would otherwise die within days or weeks after birth. For example, administration of indomethacin (see Chapter 36) causes the rapid closure of a patent ductus arteriosus, which would otherwise require surgical closure in an infant with a normal heart. Infusion of prostaglandin E1, on the other hand, causes the ductus to remain open, which can be lifesaving in an infant with transposition of the great vessels or tetralogy of Fallot (see Chapter 18). An unexpected effect of such infusion has been described when the drug caused antral hyperplasia with gastric outlet obstruction as a clinical manifestation in 6 of 74 infants who received it. This phenomenon appears to be dose-dependent. Neonates are also more sensitive to the central depressant effects of opioids than are older children and adults, necessitating extra caution when they are exposed to some narcotics (eg, codeine) through


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Pharmacology_Katzung. are also more sensitive to the central depressant effects of opioids than are older children and adults, necessitating extra caution when they are exposed to some narcotics (eg, codeine) through breast milk.


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Pharmacology_Katzung. At birth, the function of drug transporters may be very low; for example, P-glycoprotein, which pumps morphine from the blood-brain barrier back to the systemic circulation. Low-level function of P-glycoprotein at birth can explain why neonates are substantially more sensitive than older children to the central nervous system depressant effects of morphine.


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Pharmacology_Katzung. The form in which a drug is manufactured and the way in which the parent dispenses the drug to the child determine the actual dose administered. Many drugs prepared for children are in the form of elixirs or suspensions. Elixirs are alcoholic solutions in which the drug molecules are dissolved and evenly distributed. No shaking is required, and unless some of the vehicle has evaporated, the first dose from the bottle and the last dose should contain equivalent amounts of drug. Suspensions contain undissolved particles of drug that must be distributed throughout the vehicle by shaking. If shaking is not thorough each time a dose is given, the first doses from the bottle may contain less drug than the last doses, with the result that less than the expected plasma concentration or effect of the drug may be achieved early in the course of therapy. Conversely, toxicity may occur late in the course of therapy, when it is not expected. This uneven distribution is a potential cause of


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Pharmacology_Katzung. of the drug may be achieved early in the course of therapy. Conversely, toxicity may occur late in the course of therapy, when it is not expected. This uneven distribution is a potential cause of inefficacy or toxicity in children taking phenytoin suspensions. It is thus essential that the prescriber know the form in which the drug will be dispensed and provide proper instructions to the pharmacist and patient or parent.


Pharmacology_Katzung

Pharmacology_Katzung. Adherence (formerly called compliance) may be more difficult to achieve in pediatric practice than otherwise, since it involves not only the parent’s conscientious effort to follow directions but also such practical matters as measuring errors, spilling, and spitting out. For example, the measured volume of “teaspoons” can vary from 2.5 to 7.8 mL. The parents should obtain a calibrated medicine spoon or syringe from the pharmacy as these devices improve the accuracy of dose measurements and simplify administration of drugs to children.


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Pharmacology_Katzung. When evaluating adherence, it is often helpful to ask if an attempt has been made to give a further dose after the child has spilled half of what was offered. The parents may not always be able to say with confidence how much of a dose the child actually received. The parents must be told whether or not to wake the infant for its every-6-hour dose day or night. These matters should be discussed and made clear, and no assumptions should be made about what the parents may or may not do. Nonadherence frequently occurs when antibiotics are prescribed to treat otitis media or urinary tract infections and the child feels well after 4 or 5 days of therapy. The parents may not feel there is any reason to continue giving the medicine even though it was prescribed for 10 or 14 days. This common situation should be anticipated so the parents can be told why it is important to continue giving the medicine for the prescribed period even if the child seems to be “cured.”


Pharmacology_Katzung

Pharmacology_Katzung. Practical and convenient dosage forms and dosing schedules should be chosen to the extent possible. The easier it is to administer and take the medicine and the easier the dosing schedule is to follow, the more likely it is that adherence will be achieved.


Pharmacology_Katzung

Pharmacology_Katzung. Consistent with their ability to comprehend and cooperate, children should also be given some responsibility for their own health care and for taking medications. This should be discussed in appropriate terms both with the child and with the parents. Possible adverse effects and drug interactions with over-thecounter medicines or foods should also be discussed. Whenever a drug does not achieve its therapeutic effect, the possibility of non-adherence should be considered. There is ample evidence that in such cases parents’ or children’s reports may be grossly inaccurate. Random pill counts and measurement of serum concentrations may help disclose nonadherence The use of computerized pill containers, which record each lid opening, has been shown to be very effective in measuring adherence.


Pharmacology_Katzung

Pharmacology_Katzung. Because many pediatric doses are calculated—eg, using body weight—rather than simply read from a list, major dosing errors may result from incorrect calculations. Typically, tenfold errors due to incorrect placement of the decimal point have been described. In the case of digoxin, for example, an intended dose of 0.1 mL containing 5 mcg of drug, when replaced by 1.0 mL— which is still a small volume—can result in a fatal overdose. Different strategies have been developed to prevent these potentially fatal errors. For drugs with narrow therapeutic windows (eg, digoxin, insulin, potassium), independent double-checking of dose and volume calculations is widely practiced. A good rule for avoiding such “decimal point” errors is to use a leading “0” plus decimal point when dealing with doses less than “1” and to avoid using a zero after a decimal point (see Chapter 65).


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Pharmacology_Katzung. remember that, compared with breast-feeding, formula feeding is associated with higher infant morbidity and mortality in all Despite the fact that most drugs are excreted into breast milk in socioeconomic groups. amounts too small to adversely affect neonatal health, thousands Most drugs administered to lactating women are detectable in of women taking medications do not breast-feed because of breast milk. Fortunately, the concentration of drugs achieved in fears of harming the baby and misperception of risk. Unfortu-breast milk is usually low (Table 59–5). Therefore, the total amount nately, physicians often contribute to this bias. It is important to the infant would receive in a day is substantially less than what TABLE 59–5 Drugs often used during lactation and possible effects on the nursing infant.


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Pharmacology_Katzung. TABLE 59–5 Drugs often used during lactation and possible effects on the nursing infant. would be considered a “therapeutic dose.” If the nursing mother must take medications and the drug is a relatively safe one, she should optimally take it 30–60 minutes after nursing and 3–4 hours before the next feeding. In some cases this may allow time for drugs to be partially cleared from the mother’s blood, and the concentrations in breast milk will be relatively low. Most antibiotics taken by nursing mothers can be detected in breast milk. Tetracycline concentrations in breast milk are approximately 70% of maternal serum concentrations and present a risk of permanent tooth staining in the infant. Isoniazid rapidly reaches equilibrium between breast milk and maternal blood. The concentrations achieved in breast milk are high enough so that signs of pyridoxine deficiency may occur in the infant if the mother is not given pyridoxine supplements.


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Pharmacology_Katzung. Most sedatives and hypnotics achieve concentrations in breast milk sufficient to produce a pharmacologic effect in some infants. Barbiturates taken in hypnotic doses by the mother can produce lethargy, sedation, and poor suck reflexes in the infant. Chloral hydrate can produce sedation if the infant is fed at peak milk concentrations. Diazepam can have a sedative effect on the nursing infant, but, most importantly, its long half-life can result in significant drug accumulation.


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Pharmacology_Katzung. Opioids such as heroin, methadone, and morphine enter breast milk in quantities potentially sufficient to prolong the state of neonatal narcotic dependence if the drug was taken chronically by the mother during pregnancy. If conditions are well controlled and there is a good relationship between the mother and the physician, an infant could be breast-fed while the mother is taking methadone. She should not, however, stop taking the drug abruptly; the infant can be tapered off the methadone as the mother’s dose is tapered. The infant should be watched for signs of narcotic withdrawal. Although codeine has been believed to be safe, a case of neonatal death from opioid toxicity revealed that the mother was an ultra rapid metabolizer of cytochrome 2D6 substrates, producing substantially higher amounts of morphine. Hence, polymorphism in maternal drug metabolism may affect neonatal exposure and safety. A subsequent case-control study has shown that this situation is not rare. The FDA has


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Pharmacology_Katzung. amounts of morphine. Hence, polymorphism in maternal drug metabolism may affect neonatal exposure and safety. A subsequent case-control study has shown that this situation is not rare. The FDA has published a warning to lactating mothers to exert extra caution while using painkillers containing codeine. More recent research has also shown that blood-brain barrier levels of P-glycoprotein are lower at birth, allowing more morphine to penetrate into the brain, than later in infancy and childhood. This can explain sedation in breast-fed neonates even when there is no genetic variability in CYP2D6.


Pharmacology_Katzung

Pharmacology_Katzung. Minimal use of alcohol by the mother has not been reported to harm nursing infants. Excessive amounts of alcohol, however, can produce alcohol effects in the infant. Nicotine concentrations in the breast milk of smoking mothers are low and do not produce effects in the infant. Very small amounts of caffeine are excreted in the breast milk of coffee-drinking mothers. Lithium enters breast milk in concentrations equal to those in maternal serum. Clearance of this drug is almost completely dependent upon renal elimination, and women who are receiving lithium may expose the infant to relatively large amounts of the drug. Radioactive substances such as iodinated 125I albumin and radioiodine can cause thyroid suppression in infants and may increase the risk of subsequent thyroid cancer as much as tenfold.


Pharmacology_Katzung

Pharmacology_Katzung. Radioactive substances such as iodinated 125I albumin and radioiodine can cause thyroid suppression in infants and may increase the risk of subsequent thyroid cancer as much as tenfold. Breast-feeding is contraindicated after large doses and should be withheld for days to weeks after small doses. Similarly, breastfeeding should be avoided in mothers receiving cancer chemotherapy or being treated with cytotoxic or immunomodulating agents for collagen diseases such as lupus erythematosus or after organ transplantation.


Pharmacology_Katzung

Pharmacology_Katzung. Because of differences in pharmacokinetics in infants and children, simple proportionate reduction in the adult dose may not be adequate to determine a safe and effective pediatric dose. The most reliable pediatric dose information is usually that provided by the manufacturer in the package insert. However, such information is not available for the majority of products, even when studies have been published in the medical literature, reflecting the reluctance of manufacturers to label their products for children. Recently, the FDA has moved toward more explicit expectations that manufacturers test their new products in infants and children. Still, most drugs in the common formularies, eg, Physicians’ Desk Reference, are not specifically approved for children, in part because manufacturers often lack the economic incentive to evaluate drugs for use in the pediatric market.


Pharmacology_Katzung

Pharmacology_Katzung. Most drugs approved for use in children have recommended pediatric doses, generally stated as milligrams per kilogram or per pound. In the absence of explicit pediatric dose recommendations, an approximation can be made by any of several methods based on age, weight, or surface area. These rules are not precise and should not be used if the manufacturer provides a pediatric dose. When pediatric doses are calculated (either from one of the methods set forth below or from a manufacturer’s dose), the pediatric dose should never exceed the adult dose. The current epidemic proportions of childhood obesity calls for a fresh and careful look at pediatric drug dosages. Studies in adults indicate that dosing based on per-kilogram body weight may constitute overdosing, because in obese subjects, drugs are distributed based on lean body weight. Surface Area, Age, & Weight


Pharmacology_Katzung

Pharmacology_Katzung. Surface Area, Age, & Weight Calculations of dosage based on age or weight (see below) are conservative and tend to underestimate the required dose. Doses based on surface area (Table 59–6) are more likely to be adequate. Age (Young’s rule): Weight (somewhat more precise is Clark’s rule): TABLE 59–6 Determination of drug dosage from surface area.1 1For example, if adult dose is 1 mg/kg, dose for 3-month-old infant would be 0.18 mg/kg or 1.1 mg total. Reproduced, with permission, from Silver HK, Kempe CH, Bruyn HB: Handbook of Pediatrics, 14th ed. Originally published by Lange Medical Publications. © 1983 by the McGraw-Hill Companies, Inc. Despite these approximations, only by conducting studies in children can safe and effective doses for a given age group and condition be determined. Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th ed. Wolters Kluwer/Lippincott Williams & Wilkins, 2015.


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Pharmacology_Katzung. Briggs GG, Freeman RK, Yaffe SJ: Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th ed. Wolters Kluwer/Lippincott Williams & Wilkins, 2015. de Wildt SN et al: Ontogeny of midazolam glucuronidation in preterm infants. Eur J Clin Pharmacol 2010;66:165. Gavin PJ, Yogev R: The role of protease inhibitor therapy in children with HIV infection. Paediatr Drugs 2002;4:581. Hansten PD, Horn JR: Drug Interactions, Analysis and Management. Facts & Comparisons. [Quarterly.] International Liaison Committee on Resuscitation: The International Liaison Committee on Resuscitation (ILCOR) consensus on science with treatment recommendations for pediatric and neonatal patients: pediatric basic and advanced life support. Pediatrics 2006;117:e955. Iqbal MM, Sohhan T, Mahmud SZ: The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. J Toxicol Clin Toxicol 2001;39:381.


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Pharmacology_Katzung. Iqbal MM, Sohhan T, Mahmud SZ: The effects of lithium, valproic acid, and carbamazepine during pregnancy and lactation. J Toxicol Clin Toxicol 2001;39:381. Ito S: Drug therapy for breast feeding women. N Engl J Med 2000;343:118. Kearns GL et al: Developmental pharmacology—drug disposition, action and therapy in infants and children. N Engl J Med 2003;349:1157. Koren G, Nordeng H: Antidepressant use during pregnancy: The benefit-risk ratio. Am J Obstet Gynecol 2012;207:157. Koren G, Pastuszak A: Prevention of unnecessary pregnancy terminations by counseling women on drug, chemical, and radiation exposure during the first trimester. Teratology 1990;41:657. Koren G, Pastuszak A, Ito E: Drugs in pregnancy. N Engl J Med 1998; 338:1128. Koren G et al: Sex differences in the pharmacokinetics and bioequivalence of the delayed-release combination of doxylamine succinate-pyridoxine hydrochloride: Implications for pharmacotherapy in pregnancy. J Clin Pharmacol 2013;53:1268.


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Pharmacology_Katzung. Madadi P et al: Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: A case control study. Clin Pharmacol Ther 2009;85:31. Namouz-Haddad S, Koren G: Fetal pharmacotherapy 2: Fetal arrhythmia. J Obstet Gynaecol Can 2013;35:1023. Pauwels S, Allegaert K: Therapeutic drug monitoring in neonates. Arch Dis Child 2016;101:377. Peled N et al: Gastric-outlet obstruction induced by prostaglandin therapy in neonates. N Engl J Med 1992;327:505. SickKids Drug Handbook and Formulary 2015/2016. The Hospital for Sick Children, Toronto. Tetelbaum M et al: Back to basics: Understanding drugs in children: Pharmacokinetic maturation. Pediatr Rev 2005;26:321. Van Lingen RA et al: The effects of analgesia in the vulnerable infant during the perinatal period. Clin Perinatol 2002;29:511. Special Aspects of Geriatric Pharmacology Bertram G. Katzung, MD, PhD


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Pharmacology_Katzung. Special Aspects of Geriatric Pharmacology Bertram G. Katzung, MD, PhD A 77-year-old man comes to your office at his wife’s insistence. He has had documented moderate hypertension for 18 years but does not like to take his medications. He says he has no real complaints, but his wife remarks that he has become much more forgetful lately and has almost stopped reading the newspaper and watching television. A Mini-Mental State Examination reveals that he is oriented as to name and place but is unable to give the month or year.


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Pharmacology_Katzung. Society has traditionally classified everyone over 65 as “elderly,” but most authorities consider the field of geriatrics to apply to persons over 75—even though this too is an arbitrary definition. Furthermore, chronologic age is only one determinant of the changes pertinent to drug therapy that occur in older people. In addition to the chronic diseases of adulthood, the elderly have an increased incidence of many conditions, including Alzheimer’s disease, Parkinson’s disease, and vascular dementia; stroke; visual impairment, especially cataracts and macular degeneration; atherosclerosis, coronary and peripheral vascular disease, and heart failure; diabetes; arthritis, osteoporosis, and fractures; cancer; and incontinence. As a result, the need for drug treatment is great in this age group. And as the average life span approaches (and in some countries, already exceeds) 80, this need will increase dramatically.


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Pharmacology_Katzung. When all confounders are accounted for, age itself is still the strongest risk factor for cardiovascular and neurodegenerative diseases and most forms of cancer. Research into the molecular basis of aging has answered a few questions and opened many more. It has long been known that caloric restriction alone can prolong the life span of animals, including mammals. Some evidence suggests He cannot remember the names of his three adult children or three random words (eg, tree, flag, chair) for more than 2 minutes. No cataracts are visible, but he is unable to read standard newsprint without a powerful magnifier. Why doesn’t he take his antihypertensive medications? What therapeutic measures are available for the treatment of Alzheimer’s disease? How might macular degeneration be treated?


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Pharmacology_Katzung. that calorically restricted mice also remain healthier for a longer time. Drugs that mimic caloric restriction have been shown to increase lifespan in the nematode Caenorhabditis elegans, as well as other species, including mice. Metformin and rapamycin each increase life span in these species when given alone and appear to have synergistic effects when given together. Sirtuins, a class of endogenous protein deacetylase enzymes, may be linked to life span in some species, but activators (such as resveratrol) of certain sirtuins have not been shown to prolong life in mice. Assuming that safer alternatives to metformin or rapamycin can be found, should everyone over the age of 40 or 60 years take such a drug? Few would maintain that a simple increase in the years of life—life span—is desirable unless accompanied by an increase in the years of healthy life—“health span.” Provocative research suggests that variables such as telomere length on chromosomes may predict prospective life span


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Pharmacology_Katzung. unless accompanied by an increase in the years of healthy life—“health span.” Provocative research suggests that variables such as telomere length on chromosomes may predict prospective life span and that proteins in the blood of young animals may “rejuvenate” older animals, but these studies provide no guidance regarding the current treatment of diseases in older patients.


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Pharmacology_Katzung. Important changes in responses to some drugs occur with increasing age in many individuals. For other drugs, age-related changes are minimal, especially in the “healthy old.” Drug usage patterns also change as a result of the increasing incidence of disease with age and the tendency to prescribe heavily for patients in nursing homes. General changes in the lives of older people have significant effects on the way drugs are used. Among these changes with advancing age are the increased incidence of several simultaneous diseases, nutritional problems, reduced financial resources, and—in some patients—decreased dosing adherence (also called compliance) for a variety of reasons. The health practitioner should be aware of the changes in pharmacologic responses that may occur in older people and should know how to deal with these changes. Finally, dependent elders are sometimes abused physically or financially by caregivers at home or in nursing homes, and the health practitioner should


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Pharmacology_Katzung. and should know how to deal with these changes. Finally, dependent elders are sometimes abused physically or financially by caregivers at home or in nursing homes, and the health practitioner should investigate abuse as a cause of nonadherence, as well as bruises, dehydration, and other morbidities.


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Pharmacology_Katzung. In the general population, measurements of functional capacity of most of the major organ systems show a decline beginning in young adulthood and continuing throughout life. As shown in Figure 60–1, there is no “middle-age plateau” but rather a linear decrease beginning no later than age 45. However, these data reflect the mean and do not apply to every person above a certain age; approximately one third of healthy subjects have no age-related decrease in, for example, creatinine clearance up to the age of 75. Some of these changes result in altered pharmacokinetics. FIGURE 60–1 Effect of age on some physiologic functions. (Adapted, with permission, from Kohn RR: Principles of Mammalian Aging. Copyright copy; 1978 by Prentice-Hall, Inc. Used by permission of Pearson Education, Inc.) CHAPTER 60 Special Aspects of Geriatric Pharmacology 1059


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Pharmacology_Katzung. CHAPTER 60 Special Aspects of Geriatric Pharmacology 1059 For the pharmacologist and the clinician, the most important of these is the decrease in renal function. Other changes and concurrent diseases may alter the pharmacodynamic characteristics of particular drugs in certain patients. A. Absorption There is little evidence of any major alteration in drug absorption with age. However, conditions associated with age may alter the rate at which some drugs are absorbed. Such conditions include altered nutritional habits, greater consumption of nonprescription drugs (eg, antacids and laxatives), and changes in gastric emptying, which is often slower in older persons, especially in older diabetics. B. Distribution


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Pharmacology_Katzung. Compared with young adults, the elderly have reduced lean body mass, reduced body water, and increased fat as a percentage of body mass. Some of these changes are shown in Table 60–1. There is usually a decrease in serum albumin, which binds many drugs, especially weak acids. There may be a concurrent increase in serum orosomucoid (α-acid glycoprotein), a protein that binds many basic drugs. Thus, the ratio of bound to free drug may be significantly altered. As explained in Chapter 3, these changes may alter the appropriate loading dose of a drug. However, since both the clearance and the effects of drugs are related to the free concentration, the steady-state effects of a maintenance dosage regimen should not be altered by these factors alone. For example, the loading dose of digoxin in an elderly patient with heart failure should be reduced (if used at all) because of the decreased apparent volume of distribution. The maintenance dose may have to be reduced because of reduced


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Pharmacology_Katzung. in an elderly patient with heart failure should be reduced (if used at all) because of the decreased apparent volume of distribution. The maintenance dose may have to be reduced because of reduced clearance of the drug.


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Pharmacology_Katzung. C. Metabolism The capacity of the liver to metabolize drugs declines with age for some, but not all, drugs. Animal studies and some clinical studies have suggested that certain drugs are metabolized more slowly TABLE 60–1 Some changes related to aging that affect pharmacokinetics of drugs. TABLE 60–2 Effects of age on hepatic clearance of some drugs.


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Pharmacology_Katzung. in the elderly; some of these drugs are listed in Table 60–2. The greatest changes are in phase I reactions, ie, those carried out by microsomal P450 systems. There are much smaller changes in the ability of the liver to carry out conjugation (phase II) reactions (see Chapter 4). Some of these changes may be caused by decreased liver blood flow (Table 60–1), an important variable in the clearance of drugs that have a high hepatic extraction ratio. In addition, there is a decline with age of the liver’s ability to recover from injury, eg, that caused by alcohol or viral hepatitis. Therefore, a history of recent liver disease in an older person should lead to caution in dosing with drugs that are cleared primarily by the liver, even after apparently complete recovery from the hepatic insult. Finally, malnutrition and diseases that affect hepatic function—eg, heart failure—are more common in the elderly. Heart failure may dramatically alter the ability of the liver to metabolize drugs by


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Pharmacology_Katzung. Finally, malnutrition and diseases that affect hepatic function—eg, heart failure—are more common in the elderly. Heart failure may dramatically alter the ability of the liver to metabolize drugs by reducing hepatic blood flow. Similarly, severe nutritional deficiencies, which occur more often in old age, may impair hepatic function.


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D. Elimination

Pharmacology_Katzung. D. Elimination


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Pharmacology_Katzung. Because the kidney is the major organ for clearance of drugs from the body, the age-related decline of renal functional capacity is very important. A decline in creatinine clearance (Clcr)—the usual measure of estimated glomerular filtration rate (eGFR)—occurs in about two thirds of the population. It is important to note that this decline is not reflected in an equivalent rise in serum creatinine because the production of creatinine is also reduced as muscle mass declines with age; therefore, serum creatinine alone is not an adequate measure of renal function. The practical result of this change is marked prolongation of the half-life of many drugs, and the possibility of accumulation to toxic levels if dosage is not reduced in size or frequency. Dosing recommendations for the elderly often include an allowance for reduced renal clearance. If only the young adult dosage is known for a drug that requires renal clearance, a rough correction can be made by using the Cockcroft-Gault


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Pharmacology_Katzung. often include an allowance for reduced renal clearance. If only the young adult dosage is known for a drug that requires renal clearance, a rough correction can be made by using the Cockcroft-Gault formula to estimate the GFR and multiplying the recommended young adult dosage by eGFR/100. The Cockcroft-Gault formula is applicable to patients age 40 through 80:


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Pharmacology_Katzung. For women, the result should be multiplied by 0.85 (because of reduced muscle mass). It must be emphasized that this estimate is, at best, a population estimate and may not apply to a particular patient. If the patient has normal renal function (up to one third of elderly patients), a dose corrected on the basis of this estimate will be too low—but a low dose is initially desirable if one is uncertain of the renal function in any patient. Simple online calculators using the more modern MDRD (Modification of Diet in Renal Disease) formula are available, eg, http://nkdep.nih.gov/ lab-evaluation/gfr-calculators.shtml.


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Pharmacology_Katzung. If a precise measure is needed, a standard 12or 24-hour creatinine clearance determination should be obtained. As indicated above, nutritional changes alter pharmacokinetic parameters. A patient who is severely dehydrated (not uncommon in patients with stroke or other motor impairment) may have an additional marked reduction in renal drug clearance that is completely reversible by rehydration. The lungs are important for the excretion of volatile drugs. As a result of reduced respiratory capacity (Figure 60–1) and the increased prevalence of active pulmonary disease in the elderly, the use of inhalation anesthesia is less common and intravenous agents more common in this age group. (See Chapter 25.)


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Pharmacology_Katzung. It was long believed that geriatric patients were much more “sensitive” to the action of many drugs, implying a change in the pharmacodynamic interaction of the drugs with their receptors. It is now recognized that many—perhaps most—of these apparent changes result from altered pharmacokinetics or diminished homeostatic responses. Clinical studies have supported the idea that the elderly are more sensitive to some sedative-hypnotics and analgesics. In addition, some data from animal studies suggest actual changes with age in the characteristics or numbers of a few receptors. The most extensive studies suggest a decrease in responsiveness to β-adrenoceptor agonists. Other examples are discussed below.


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Pharmacology_Katzung. Important homeostatic control mechanisms appear to be blunted in the elderly. Since homeostatic responses are often significant contributors to the overall response to a drug, these physiologic alterations may change the pattern or intensity of drug response. In the cardiovascular system, the cardiac output increment required by mild or moderate exercise is successfully provided until at least age 75 (in individuals without obvious cardiac disease), but the increase is the result primarily of increased stroke volume in the elderly and not tachycardia, as in young adults. Average blood pressure goes up with age (in most Western countries), but the incidence of symptomatic orthostatic hypotension also increases markedly. It is thus particularly important to check for orthostatic hypotension (>20 mm Hg drop in systolic blood pressure on standing) on every visit. Similarly, the average 2-hour postprandial blood glucose level increases by about 1 mg/ dL for each year of age above 50.


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Pharmacology_Katzung. (>20 mm Hg drop in systolic blood pressure on standing) on every visit. Similarly, the average 2-hour postprandial blood glucose level increases by about 1 mg/ dL for each year of age above 50. Temperature regulation is also impaired, and hypothermia is poorly tolerated by the elderly.


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Pharmacology_Katzung. Major changes in the conditions of daily life accompany the aging process and have an impact on health. Some of these (eg, forgetting to take one’s pills) are the result of cognitive changes associated with vascular or other pathology. One of the most important changes is the loss of a spouse. Others relate to economic stresses associated with greatly reduced income and, frequently, increased expenses due to illness.


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Pharmacology_Katzung. The half-lives of many benzodiazepines and barbiturates increase by 50–150% between ages 30 and 70. Much of this change occurs during the decade from 60 to 70. For some of the benzodiazepines, both the parent molecule and its metabolites (produced in the liver) are pharmacologically active (see Chapter 22). The age-related decline in renal function and liver disease, if present, both contribute to the reduction in elimination of these compounds. In addition, an increased volume of distribution has been reported for some of these drugs. Lorazepam and oxazepam may be less affected by these changes than the other benzodiazepines. In addition to these pharmacokinetic factors, it is generally believed that the elderly vary more in their sensitivity to the sedative-hypnotic drugs on a pharmacodynamic basis as well. Among the toxicities of these drugs, ataxia and other stability impairments lead to increased falls and fractures.


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Pharmacology_Katzung. The opioid analgesics show variable changes in pharmacokinetics with age. However, the elderly are often markedly more sensitive to the respiratory effects of these agents because of age-related changes in respiratory function. Therefore, this group of drugs should be used with caution until the sensitivity of the particular patient has been evaluated, and the patient should then be dosed appropriately for full effect. Opioids are not as effective in chronic pain syndromes as they are for acute pain, eg, fracture pain (see Chapter 31). Unfortunately, studies show that opioids are consistently underutilized in patients who require strong analgesics for CHAPTER 60 Special Aspects of Geriatric Pharmacology 1061 chronic painful conditions such as cancer. Good pain management plans are readily available (see Morrison, 2006; Rabow and Pantilat, 2011).


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Pharmacology_Katzung. CHAPTER 60 Special Aspects of Geriatric Pharmacology 1061 chronic painful conditions such as cancer. Good pain management plans are readily available (see Morrison, 2006; Rabow and Pantilat, 2011). The traditional antipsychotic agents (phenothiazines and halo peridol) have been very heavily used (and often misused) in the management of a variety of psychiatric conditions in the elderly.


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Pharmacology_Katzung. The traditional antipsychotic agents (phenothiazines and halo peridol) have been very heavily used (and often misused) in the management of a variety of psychiatric conditions in the elderly. There is no doubt that they are useful in the management of schizophrenia in old age, and also in the treatment of some symptoms associated with delirium, dementia, agitation, combat iveness, and a paranoid syndrome that occurs in some geriatric patients (see Chapter 29). However, they are not fully satisfactory in these geriatric conditions, and dosage should not be increased on the assumption that full control is possible. There is no evi dementia, and on theoretical grounds the antimuscarinic effects of the phenothiazines might be expected to worsen memory impair ment and intellectual dysfunction (see below).


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Pharmacology_Katzung. Much of the apparent improvement produced by these drugs in effects. When a sedative antipsychotic is desired, a phenothiazine such as thioridazine is appropriate. If sedation is to be avoided, haloperidol or a second generation (atypical) antipsychotic is more appropriate. Haloperidol has increased extrapyramidal toxicity, however, and should be avoided in patients with preexisting extra- pyramidal disease. The phenothiazines, especially older drugs such as chlorpromazine, often induce orthostatic hypotension because of their α-adrenoceptor-blocking effects. They are even more prone to do so in the elderly. Dosage of these drugs should usually be started at a fraction of that used in young adults. The second generation antipsychotic agents (clozapine, olanzapine, quetiapine, risperi done, aripiprazole) do not appear to be significantly superior to the effects. Evidence supporting the benefits of olanzapine is somewhat stronger than that for the other second generation agents.


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Pharmacology_Katzung. Lithium is often used in the treatment of mania in the aged. Because it is cleared by the kidneys, dosages must be adjusted appropriately and blood levels monitored. Concurrent use of thiazide diuretics reduces the clearance of lithium and should be measurement of lithium blood levels.


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Pharmacology_Katzung. Psychiatric depression is thought to be underdiagnosed and undertreated in the elderly. The suicide rate in the over-65 age group (twice the national average) supports this view. Unfor tunately, the apathy, flat affect, and social withdrawal of major depression may be mistaken for senile dementia. Clinical evidence suggests that the elderly are as responsive to antidepressants (of all types) as younger patients but are more likely to experience adverse effects. This factor along with the reduced clearance of some of these drugs underlines the importance of careful dos ing and strict attention to the monitoring of toxic effects. Some to tricyclic antidepressants because the SSRIs have fewer auto nomic adverse effects. If a tricyclic is to be used, a drug with reduced antimuscarinic effects should be selected, eg, nortriptyline or desipramine (see Table 30–2).


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Pharmacology_Katzung. Alzheimer’s disease (AD) is characterized by progressive memory impairment, dementia, and cognitive dysfunction, and may lead to a completely vegetative state, resulting in early death. Prevalence increases with age and may be as high as 20% in individuals over 85, although long-term epidemiologic studies suggest that the overall prevalence of dementia has decreased in the USA and Europe over the last 15–30 years (see Langa 2017). The annual cost of dementia in the United States is estimated at $150–$215 billion annually. Both familial and sporadic forms have been identified. Early onset of Alzheimer’s disease is associated with several gene defects, including trisomy 21 (chromosome 21), a mutation of the gene for presenilin-1 on chromosome 14, and an abnormal allele, ε4, for the lipid-associated protein, ApoE, on chromosome 19. Unlike the common forms (ApoE ε2 and ε3), the ε4 form strongly correlates with the formation of amyloid β deposits (see below).


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Pharmacology_Katzung. Pathologic changes include increased deposits of amyloid beta (Aa) peptide in the cerebral cortex, which eventually forms extracellular plaques and cerebral vascular lesions, and intraand interneuronal fibrillary tangles consisting of the tau protein (Figure 60–2). There is a progressive loss of neurons, especially cholinergic neurons, and thinning of the cortex. An inflammatory process involving the NLRP3 inflammasome appears to contribute to this pathology, and anti-inflammatory nonsteroidal anti-inflammatory drugs (NSAIDs), eg, mefenamic acid, reverse some of the markers of Alzheimer’s disease in animal models. The loss of cholinergic neurons results in a marked decrease in choline acetyltransferase and other markers of cholinergic activity. Patients with Alzheimer’s disease are often exquisitely sensitive to the central nervous system toxicities of drugs with antimuscarinic effects. Some evidence implicates excess excitation by glutamate as a contributor to neuronal death. In


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Pharmacology_Katzung. exquisitely sensitive to the central nervous system toxicities of drugs with antimuscarinic effects. Some evidence implicates excess excitation by glutamate as a contributor to neuronal death. In addition, abnormalities of mitochondrial function may contribute to neuronal death.


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Pharmacology_Katzung. Many methods of treatment of Alzheimer’s disease have been explored (Table 60–3). Much attention has been focused on the cholinomimetic drugs because of the evidence of loss of cholinergic neurons noted earlier. Monoamine oxidase (MAO) type B inhibition with selegiline (l-deprenyl) has been suggested to have some beneficial effects. One drug that inhibits N-methyld-aspartate (NMDA) glutamate receptors is available (see below), and “ampakines,” substances that facilitate synaptic activity at glutamate AMPA receptors, are under intense study. Some evidence suggests that lipid-lowering statins are beneficial. So-called cerebral vasodilators are ineffective.


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Pharmacology_Katzung. FIGURE 60–2 Some processes involved in Alzheimer’s disease. From the left: Mitochondrial dysfunction, possibly involving glucose utilization; synthesis of protein tau and aggregation in filamentous tangles; synthesis of amyloid beta (Aβ) and secretion into the extracellular space, where it may interfere with synaptic signaling and accumulates in plaques. (Reproduced, with permission, from Roberson ED, Mucke L: 100 years and counting: Prospects for defeating Alzheimer’s disease. Science 2006;314:781. Reprinted with permission from AAAS.) TABLE 60–3 Some potential strategies for the prevention or treatment of Alzheimer’s disease. Aβ, amyloid beta; IL, interleukin; PERK, protein kinase RNA-like ER kinase; PPAR-γ, peroxisome proliferator-activated receptor-gamma.


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Pharmacology_Katzung. Tacrine (tetrahydroaminoacridine, THA), a long-acting cholinesterase inhibitor and muscarinic modulator, was the first drug shown to have any benefit in Alzheimer’s disease. Because of its hepatic toxicity, tacrine has been replaced in clinical use by newer cholinesterase inhibitors: donepezil, rivastigmine, and galantamine. These agents are orally active, have adequate penetration into the central nervous system, and are much less toxic than tacrine. Although evidence for the benefit of cholinesterase inhibitors (and memantine; see below) is statistically significant, the amount of benefit is modest and does not prevent the progression of the disease. The cholinesterase inhibitors cause significant adverse effects, including nausea and vomiting, diarrhea, and other peripheral cholinomimetic effects. These drugs should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine; see Chapter 4). Preparations available are


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Pharmacology_Katzung. effects. These drugs should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine; see Chapter 4). Preparations available are listed in Chapter 7.


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Pharmacology_Katzung. Excitotoxic activation of glutamate transmission via NMDA receptors has been postulated to contribute to the pathophysiology of Alzheimer’s disease. Memantine binds to NMDA receptor channels in a use-dependent manner and produces a noncompetitive blockade. CHAPTER 60 Special Aspects of Geriatric Pharmacology 1063 Its modest efficacy in moderate-to-severe Alzheimer’s disease is similar to or smaller than that of the cholinesterase inhibitors. In contrast, a small study of memantine in Alzheimer’s disease in persons with Down syndrome found no benefit. However, this drug may be better tolerated and less toxic than the cholinesterase inhibitors. Combina tion therapy with both memantine and one of the cholinesterase inhibitors has produced mixed results. Memantine is available as Namenda in 5 and 10 mg oral tablets.


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Pharmacology_Katzung. Namenda in 5 and 10 mg oral tablets. Recent research has focused on amyloid beta, because the char acteristic plaques consist mostly of this peptide. Unfortunately, two anti-amyloid antibodies, solanezumab and bapineuzumab, both failed to improve cognition or slow progression in recent clinical trials. Verubecestat, an inhibitor of beta-site amyloid pre cursor protein cleaving enzyme (BACE1), reduces the production of amyloid β. This drug showed safety in an early clinical trial, and longer-term phase 3 trials for efficacy are under way. Another effort suggests that the accumulation of filamentous tangles of tau protein is a critical component of neuronal damage in Alzheimer’s and several other neurodegenerative conditions. Accumulation of tau appears to be associated with dissociation from microtubules in neurons, which has stimulated interest in drugs that inhibit microtubule disassembly, such as epothilone-D.


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Pharmacology_Katzung. Blood pressure, especially systolic pressure, increases with age in Western countries and in most cultures in which salt intake is high. In women, the increase is more marked after age 50. Although often ignored in the past, clinicians now believe that hypertension should be treated in the elderly. In fact, more aggressive treatment of hypertension is one factor that may contribute to the reported decline in the incidence of dementia.


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Pharmacology_Katzung. The basic principles of therapy are not different in the geriatric age group from those described in Chapter 11, but the usual cautions regarding altered pharmacokinetics and blunted compensatory mechanisms apply. Because of its safety, nondrug therapy (weight reduction in the obese and moderate salt restriction) should be encouraged. Thiazides are a reasonable first step in drug therapy. The hypokalemia, hyperglycemia, and hyperuricemia caused by these agents are more relevant in the elderly because of the higher prevalence in these patients of arrhythmias, type 2 diabetes, and gout. Thus, use of low antihypertensive doses— rather than maximum diuretic doses—is important. Calcium channel blockers are effective and safe if titrated to the appropriate response. They are especially useful in patients who also have atherosclerotic angina (see Chapter 12). Beta blockers are potentially hazardous in patients with obstructive airway disease and are considered less useful than calcium


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Pharmacology_Katzung. in patients who also have atherosclerotic angina (see Chapter 12). Beta blockers are potentially hazardous in patients with obstructive airway disease and are considered less useful than calcium channel blockers in older patients unless chronic heart failure is present. Angiotensin-converting enzyme inhibitors are also considered less useful in the elderly unless heart failure or diabetes is present. The most powerful drugs, such as minoxidil, are rarely needed. Every patient receiving antihypertensive drugs should be checked regularly for orthostatic hypotension because of the danger of cerebral ischemia and falls.


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Pharmacology_Katzung. Heart failure is a common and particularly lethal disease in the elderly. Fear of this condition is one reason why physicians overuse cardiac glycosides in this age group. The toxic effects of digoxin are particularly dangerous in the geriatric population, since the elderly are more susceptible to arrhythmias. The clearance of digoxin is usually decreased in the older age group, and although the volume of distribution is often decreased as well, the half-life of this drug may be increased by 50% or more. Because the drug is cleared mostly by the kidneys, renal function must be considered in designing a dosage regimen. There is no evidence that there is any increase in pharmacodynamic sensitivity to the therapeutic effects of the cardiac glycosides; in fact, animal studies suggest a possible decrease in therapeutic sensitivity. On the other hand, there is probably an increase in sensitivity to the toxic arrhythmogenic actions. Hypokalemia, hypomagnesemia, hypoxemia (from pulmonary


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Pharmacology_Katzung. decrease in therapeutic sensitivity. On the other hand, there is probably an increase in sensitivity to the toxic arrhythmogenic actions. Hypokalemia, hypomagnesemia, hypoxemia (from pulmonary disease), and coronary atherosclerosis all contribute to the high incidence of digitalis-induced arrhythmias in geriatric patients. The less common toxicities of digitalis such as delirium, visual changes, and endocrine abnormalities (see Chapter 13) also occur more often in older than in younger patients.


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Pharmacology_Katzung. The treatment of arrhythmias in the elderly is particularly challenging because of the lack of good hemodynamic reserve, the frequency of electrolyte disturbances, and the high prevalence of significant coronary disease. The clearances of quinidine and procainamide decrease and their half-lives increase with age. Disopyramide should probably be avoided in the geriatric population because its major toxicities—antimuscarinic action, leading to voiding problems in men; and negative inotropic cardiac effects, leading to heart failure—are particularly undesirable in these patients. The clearance of lidocaine appears to be little changed, but the half-life is increased in the elderly. It is recommended that the loading dose of this drug be reduced in geriatric patients because of their greater sensitivity to its toxic effects.


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Pharmacology_Katzung. Recent evidence indicates that many patients with atrial fibrillation—a very common arrhythmia in the elderly—do as well with simple control of ventricular rate as with conversion to normal sinus rhythm. Measures (such as anticoagulant drugs) must be taken to reduce the risk of thromboembolism in chronic atrial fibrillation.


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Pharmacology_Katzung. Several age-related changes contribute to the high incidence of infections in geriatric patients. A reduction in host defenses in the elderly is manifested in the increase in both serious infections and cancer. This may reflect an alteration in T-lymphocyte function. In the lungs, a major age and tobacco-dependent decrease in mucociliary clearance significantly increases susceptibility to infection. In the urinary tract, the incidence of serious infection is greatly increased by urinary retention and catheterization in men. Preventive immunizations should be maintained: influenza vaccine should be given annually, tetanus toxoid every 10 years, and pneumococcal and zoster vaccines once.


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Pharmacology_Katzung. Since 1940, the antimicrobial drugs have contributed more to the prolongation of life than any other drug group because they can compensate to some extent for this deterioration in natural defenses. The basic principles of therapy of the elderly with these agents are no different from those applicable in younger patients and have been presented in Chapter 51. The major pharmacokinetic changes relate to decreased renal function; because most of the β-lactam, aminoglycoside, and fluoroquinolone antibiotics are excreted by this route, important changes in half-life may be expected. This is particularly important in the case of the aminoglycosides, because they cause concentrationand time-dependent toxicity in the kidney and in other organs. The half-lives of gentamicin, kanamycin, and netilmicin are more than doubled. The increase may be less marked for tobramycin.


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Pharmacology_Katzung. Osteoarthritis is a very common disease of the elderly. Rheumatoid arthritis is less exclusively a geriatric problem, but the same drug therapy is usually applicable to both types of disease. The basic principles laid down in Chapter 36 and the properties of the anti-inflammatory drugs described there apply fully here.


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Pharmacology_Katzung. The nonsteroidal anti-inflammatory agents (NSAIDs) must be used with special care in geriatric patients because they cause toxicities to which the elderly are very susceptible. In the case of aspirin, the most important of these is gastrointestinal irritation and bleeding. In the case of the newer NSAIDs, the most important is renal damage, which may be irreversible. Because they are cleared primarily by the kidneys, these drugs accumulate more rapidly in the geriatric patient and especially in the patient whose renal function is already compromised beyond the average range for his or her age. A vicious circle is easily set up in which cumulation of the NSAID causes more renal damage, which causes more cumulation. There is no evidence that the cyclooxygenase (COX)-2 selective NSAIDs are safer with regard to renal function. Elderly patients receiving high doses of any NSAID should be carefully monitored for changes in renal function.


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Pharmacology_Katzung. Corticosteroids are extremely useful in elderly patients who cannot tolerate full doses of NSAIDs. However, they consistently cause a doseand duration-related increase in osteoporosis, an especially hazardous toxic effect in the elderly. It is not certain whether this drug-induced effect can be reduced by increased calcium and vitamin D intake, but it would be prudent to consider these agents (and bisphosphonates if osteoporosis is already present, see Qaseem reference) and to encourage frequent exercise in any patient taking corticosteroids. Glaucoma is more common in the elderly, but its treatment does not differ from that of glaucoma of earlier onset. Management of glaucoma is discussed in Chapter 10.


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Pharmacology_Katzung. Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly in the developed world. Two forms of advanced AMD are recognized: the neovascular “wet” form, which is associated with intrusion of new blood vessels in the subretinal space, and a more common “dry” form, which is not associated with abnormal vascularization. Although the cause of AMD is not known, smoking is a documented risk factor, and oxidative stress has long been thought to play a role. On this premise, antioxidants have been used to prevent or delay the onset of AMD. Proprietary oral formulations of vitamins C and E, β-carotene, zinc oxide, and cupric oxide are available. Some include the carotenoids lutein and zeaxanthin, and omega-3 long-chain polyunsaturated fatty acids. Evidence for the efficacy of these antioxidants is modest.


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Pharmacology_Katzung. In advanced neovascular AMD, treatment has been moderately successful. This form of AMD can now be treated with laser photo-therapy or with antibodies against vascular endothelial growth factor (VEGF). Two antibodies are available—bevacizumab (Avastin, used off-label) and ranibizumab (Lucentis)—as well as aflibercept (Eylea, a decoy protein receptor that binds VEGF) and the oligopeptide pegaptanib (Macugen). Aflibercept is also approved for the treatment of diabetic macular degeneration. These agents are injected into the vitreous for local effect. Ranibizumab is extremely expensive. Other agents that bind VEGF are under study.


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Pharmacology_Katzung. The relation between the number of drugs taken and the incidence of adverse drug reactions (ADRs) has been well documented. In long-term care facilities, in which a high percentage of the population is elderly, the average number of prescriptions per patient varies between 6 and 8. Studies have shown that the percentage of patients with adverse reactions increases from about 10% when a single drug is being taken to nearly 100% when 10 drugs are taken. Thus, it may be expected that about half of patients in long-term care facilities will have recognized or unrecognized ADRs at some time. Patients living at home may see several different practitioners for different conditions and accumulate multiple prescriptions for drugs with overlapping actions. It is useful to conduct a “brown bag” analysis in such patients. The brown bag analysis consists of asking the patient to bring to the practitioner a bag containing all the medications, supplements, vitamins, etc, that he or she is currently


Pharmacology_Katzung

Pharmacology_Katzung. in such patients. The brown bag analysis consists of asking the patient to bring to the practitioner a bag containing all the medications, supplements, vitamins, etc, that he or she is currently taking. Some prescriptions will be found to be duplicates, and others unnecessary. The total number of medications taken can often be reduced by 30–50%.


Pharmacology_Katzung

Pharmacology_Katzung. The overall incidence of ADRs in geriatric patients is estimated to be at least twice that in the younger population. Reasons for this high incidence include errors in prescribing on the part of the practitioners and errors in drug usage by the patient. Practitioner errors sometimes occur because the physician does not appreciate the importance of changes in pharmacokinetics with age and age-related diseases. Some errors occur because the practitioner is unaware of incompatible drugs prescribed by other practitioners for the same patient. For example, cimetidine, an H2-blocking drug heavily prescribed (or recommended in its over-the-counter form) to the elderly, causes a higher incidence of untoward effects (eg, confusion, slurred speech) in the geriatric population than in younger patients. It also inhibits the hepatic metabolism of many drugs, including phenytoin, warfarin, β blockers, and other agents. A patient who has been taking one of the latter agents without untoward effect


Pharmacology_Katzung

Pharmacology_Katzung. It also inhibits the hepatic metabolism of many drugs, including phenytoin, warfarin, β blockers, and other agents. A patient who has been taking one of the latter agents without untoward effect may develop markedly elevated blood levels and severe toxicity if cimetidine is added to the regimen without adjustment of dosage of the other drugs. Additional examples of drugs that inhibit liver microsomal enzymes and lead to adverse reactions are described in Chapters 4 and 66.


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Pharmacology_Katzung. Patient errors may result from nonadherence for reasons described below. In addition, they often result from use of nonprescription drugs taken without the knowledge of the physician. As noted in Chapters 63 and 64, many over-the-counter agents and herbal medications contain “hidden ingredients” with potent pharmacologic effects. For example, many antihistamines contained in over-the-counter drugs have significant sedative effects and are inherently more hazardous in patients with impaired cognitive function. Similarly, their antimuscarinic action may precipitate urinary retention in geriatric men or glaucoma in patients with a narrow anterior chamber angle. If the patient is also taking a metabolism inhibitor such as cimetidine, the probability of an adverse reaction is greatly increased. A patient taking an herbal medication containing gingko is more likely to experience bleeding while taking low doses of aspirin.


Pharmacology_Katzung

Pharmacology_Katzung. The quality of life in elderly patients can be greatly improved and life span can be prolonged by the intelligent use of drugs. However, the prescriber must recognize several practical obstacles to compliance. The expense of drugs can be a major disincentive in patients receiving marginal retirement incomes who are not covered or inadequately covered by health insurance. The prescriber must be aware of the cost of the prescription and of cheaper alternative therapies. For example, the monthly cost of arthritis therapy with newer NSAIDs may exceed $100, whereas that for generic ibuprofen and naproxen, two older but equally effective NSAIDs, about $20.


Pharmacology_Katzung

Pharmacology_Katzung. Nonadherence may result from forgetfulness or confusion, especially if the patient has several prescriptions and different dosing intervals. A survey carried out in 1986 showed that the population over 65 years of age accounted for 32% of drugs prescribed in the USA, although these patients represented only 11–12% of the population at that time. Since the prescriptions are often written by several different practitioners, there is usually no attempt to design “integrated” regimens that use drugs with similar dosing intervals for the several conditions being treated. Patients may forget instructions regarding the need to complete a fixed duration of therapy when a course of anti-infective drug is being given. The disappearance of symptoms is often regarded as the best reason to halt drug taking, especially if the prescription was expensive.


Pharmacology_Katzung

Pharmacology_Katzung. The disappearance of symptoms is often regarded as the best reason to halt drug taking, especially if the prescription was expensive. Nonadherence may also be deliberate. A decision not to take a drug may be based on prior experience with it. There may be excellent reasons for such “intelligent” noncompliance, and the practitioner should try to elicit them. Such efforts may also improve compliance with alternative drug regimens, because enlisting the patient as a participant in therapeutic decisions increases the motivation to succeed.


Pharmacology_Katzung

Pharmacology_Katzung. Some errors in drug taking are caused by physical disabilities. Arthritis, tremor, and visual problems may all contribute. Liquid medications that are to be measured “by the spoonful” are especially inappropriate for patients with any type of tremor or motor disability. Use of a dosing syringe is essential in such cases. Because of decreased production of saliva, older patients often have difficulty swallowing large tablets. “Childproof” containers are often “elder-proof” if the patient has arthritis. Cataracts and macular degeneration occur in a large number of patients over 70. Therefore, labels on prescription bottles should be large enough for the patient with diminished vision to read or should be color-coded if the patient can see but can no longer read. Because of impaired hearing, even carefully delivered instructions regarding drug use may not be understood by the patient; written instructions may be helpful.


Pharmacology_Katzung

Pharmacology_Katzung. Drug therapy has considerable potential for both helpful and harmful effects in the geriatric patient. The balance may be tipped in the right direction by adherence to a few principles: 1. Take a careful drug history. The disease to be treated may be drug-induced, or drugs being taken may lead to interactions with drugs to be prescribed. 2. Prescribe only for a specific and rational indication. Do not prescribe omeprazole for “dyspepsia.” Expert guidelines are published regularly by national organizations and websites such as UpToDate.com. 3. Define the goal of drug therapy. Then start with small doses and titrate to the response desired. Wait at least three half-lives (adjusted for age) before increasing the dose. If the expected response does not occur at the normal adult dosage, check blood levels. If the expected response does not occur at the appropriate blood level, switch to a different drug. 4.


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Pharmacology_Katzung. 4. Maintain a high index of suspicion regarding drug reactions and interactions. Know what other drugs the patient is taking, including over-the-counter and botanical (herbal) drugs. 5. Simplify the regimen as much as possible. When multiple drugs are prescribed, try to use drugs that can be taken at the same time of day. Whenever possible, reduce the number of drugs being taken. American College of Cardiology Foundation Task Force: ACCF/AHA 2011 Expert consensus document on hypertension in the elderly. J Am Coll Cardiol 2011;57:2037. American Geriatrics Society 2015 Beers Update Expert Panel: American Geriatrics use in older adults. J Am Geriatr Soc 2015;63:2227. Ancolli-Israel S, Ayalon L: Diagnosis and treatment of sleep disorders in older adults. Am J Geriatr Psychiatry 2006;14:95. Aronow WS: Drug treatment of systolic and diastolic heart failure in elderly persons. J Gerontol A Biol Med Sci 2005;60:1597.


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Pharmacology_Katzung. Aronow WS: Drug treatment of systolic and diastolic heart failure in elderly persons. J Gerontol A Biol Med Sci 2005;60:1597. Blackburn EH, Epel ES, Liu J: Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 2015; 350:1193. Calcado RT, Young NS: Telomere diseases. N Engl J Med 2009;361:2353. Chatap G, Giraud K, Vincent JP: Atrial fibrillation in the elderly: Facts and management. Drugs Aging 2002;19:819. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31. Dergal JM et al: Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic. Drugs Aging 2002;19:879. Docherty JR: Age-related changes in adrenergic neuroeffector transmission. Auton Neurosci 2002;96:8. Drugs for cognitive loss and dementia. Treat Guidel Med Lett 2013;11:95.


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Pharmacology_Katzung. Docherty JR: Age-related changes in adrenergic neuroeffector transmission. Auton Neurosci 2002;96:8. Drugs for cognitive loss and dementia. Treat Guidel Med Lett 2013;11:95. Epstein NU et al: Medication for Alzheimer’s disease and associated fall hazard: A retrospective cohort study from the Alzheimer’s disease neuroimaging initiative. Drugs Aging 2014;31:125. Ferrari AU: Modifications of the cardiovascular system with aging. Am J Geriatr Cardiol 2002;11:30. Gandy S: Lifelong management of amyloid-beta metabolism to prevent Alzheimer’s disease. N Engl J Med 2012;367:864. Guarente L: Sirtuins, aging, and medicine. N Engl J Med 2011;364:2235. Hubbard BP, Sinclair DA: Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 2014;35:146. Jager RD, Mieler WF, Miller JW: Age-related macular degeneration. N Engl J Med 2008;358:2606.


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Pharmacology_Katzung. Jager RD, Mieler WF, Miller JW: Age-related macular degeneration. N Engl J Med 2008;358:2606. Japp D et al: Mineralocorticoid receptor antagonists in elderly patients with heart failure: a systematic review and meta-analysis. Age Ageing 2017; 46:18. Kelly AS, Morrison RS: Palliative care for the seriously ill. N Engl J Med 2015;373:747. Kennedy BK, Pennypacker JK: Drugs that modulate aging: the promising yet difficult path ahead. Translat Res 2013;163:1. Kirby J et al: A systematic review of the clinical and cost-effectiveness of memantine in patients with moderately severe to severe Alzheimer’s disease. Drugs Aging 2006;23:227. Lachs MS, Pillemer KA: Elder abuse. N Engl J Med 2015;373:1947. Lamming DW et al: Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012;335:1638. Langa KM et al: A comparison of the prevalence of dementia in the United States in 2000 and 2012. JAMA Intern Med 2017;177:51.


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Pharmacology_Katzung. Levey AS et al: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Int Med 2006;145:247. Lipska KJ et al: Polypharmacy in the aging patient. A review of glycemic control in older adults with type 2 diabetes. JAMA 2016;315:1034. Mangoni AA: Cardiovascular drug therapy in elderly patients: Specific age-related pharmacokinetic, pharmacodynamic and therapeutic considerations. Drugs Aging 2005;22:913. Moreno JA et al: Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 2013;5:206ra138. Morrison LJ, Morrison RS: Palliative care and pain management. Med Clin N Am 2006;90:983. Palmer AM: Neuroprotective therapeutics for Alzheimer’s disease: Progress and prospects. Trends Pharmacol Sci 2011;32:141. Press D, Alexander M: Treatment of dementia. www.uptodate.com 2014;topic 5073.


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Pharmacology_Katzung. Press D, Alexander M: Treatment of dementia. www.uptodate.com 2014;topic 5073. Qaseem A et al: Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Int Med 2017;doi: 10.7326/M15-1361. Qato DM et al: Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 2008;300:2867. Rabow MW, Pantilat SZ: Palliative care and pain management. In: Papadakis MA, McPhee SJ, (editors): Current Medical Diagnosis & Treatment 2017, McGraw-Hill, 2017. Roberson ED, Mucke L: 100 years and counting: Prospects for defeating Alzheimer’s disease. Science 2006;314:781. Satizabal CL et al: Incidence of dementia over three decades in the Framingham Heart Study. N Engl J Med 2016;374:523. Sawhney R, Sehl M, Naeim A: Physiologic aspects of aging: Impact on cancer management and decision making, part I. Cancer J 2005;11:449.


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Pharmacology_Katzung. Sawhney R, Sehl M, Naeim A: Physiologic aspects of aging: Impact on cancer management and decision making, part I. Cancer J 2005;11:449. Staskin DR: Overactive bladder in the elderly: A guide to pharmacological management. Drugs Aging 2005;22:1013. CHAPTER 60 Special Aspects of Geriatric Pharmacology 1067 Steinman MA, Hanlon JT: Managing medications in clinically complex elders. JAMA 2010;304:1592. Teixeira A et al: Management of acute heart failure in elderly patients. Arch Cardiovasc Dis 2016;109:422. Vaillaint GE: Aging Well. Little, Brown, 2002. Vandenberghe R et al: Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther 2016;8:18. Vik SA et al: Medication nonadherence and subsequent risk of hospitalisation and mortality among older adults. Drugs Aging 2006;23:345. Wright JT Jr et al: A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103.


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Pharmacology_Katzung. Wright JT Jr et al: A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103. This patient has several conditions that warrant careful treat-ment. Hypertension is eminently treatable; the steps described in Chapter 11 are appropriate and effective in the elderly as well as in young patients. Patient education is critical in combating his reluctance to take his medications. Alzheimer’s disease may respond to one of the anticholinesterase agents (donepezil, rivastigmine, galantamine). Alternatively, memantine may be tried. Unfortunately, age-related macular degeneration (the most likely cause of his visual difficulties) is not readily treated, but the “wet” (neovascular) variety may respond well to one of the drugs currently available (bevacizumab, ranibizumab, pegaptanib). However, these therapies are expensive. Dirk B. Robertson, MD & Howard I. Maibach, MD


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Pharmacology_Katzung. Dirk B. Robertson, MD & Howard I. Maibach, MD A 43-year-old woman presents with a complaint of worsen-ing rosacea. She initially responded to once-daily topical metronidazole 0.75% gel with excellent clearing of the papulopustular component of her acne rosacea. Recently, she has noted increasing persistent facial erythema. What therapeutic options are available? Diseases of the skin offer special opportunities to the clinician. In particular, the topical administration route is especially appropriate for skin diseases, although some dermatologic diseases respond as well or better to drugs administered systemically.


Pharmacology_Katzung

Pharmacology_Katzung. The general pharmacokinetic principles governing the use of drugs applied to the skin are the same as those involved in other routes of administration (see Chapters 1 and 3). Although often depicted as a simple three-layered structure, human skin is a complex series of diffusion barriers (Figure 61–1). Quantitation of the flux of drugs and drug vehicles through these barriers is the basis for pharmacokinetic analysis of dermatologic therapy, and techniques for making such measurements are rapidly increasing in number and sensitivity. Major variables that determine pharmacologic response to drugs applied to the skin include the following: 1. Regional variation in drug penetration: For example, the scrotum, face, axilla, and scalp are far more permeable than the forearm and may require less drug for equivalent effect. 2.


Pharmacology_Katzung

Pharmacology_Katzung. Regional variation in drug penetration: For example, the scrotum, face, axilla, and scalp are far more permeable than the forearm and may require less drug for equivalent effect. 2. Concentration gradient: Increasing the concentration gradient increases the mass of drug transferred per unit time, just as in the case of diffusion across other barriers (see Chapter 1). Thus, resistance to topical corticosteroids can sometimes be overcome by use of higher concentrations of drug. 3. Dosing schedule: Because of its physical properties, skin acts as a reservoir for many drugs. As a result, the “local half-life” may be long enough to permit once-daily application of drugs with short systemic half-lives. For example, once-daily application of corticosteroids appears to be just as effective as multiple applications in many conditions.


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Pharmacology_Katzung. 4. Vehicles and occlusion: An appropriate vehicle maximizes the ability of the drug to penetrate the outer layers of the skin. In addition, through their physical properties (moistening or drying effects), vehicles may themselves have important therapeutic effects. Occlusion (application of a plastic wrap to hold the drug and its vehicle in close contact with the skin) is extremely effective in maximizing efficacy. Skin reacts to many systemic medications with a variety of symptom-generating responses. In addition, some dermatologic medications themselves cause skin reactions. The major types of reactions are summarized in Table 61–1. Topical medications usually consist of active ingredients incorporated in a vehicle that facilitates cutaneous application. Important considerations in vehicle selection include solubility of the active Metabolized ? Basement membrane Metabolized ? zone Drug binds to receptor Drug binds to receptor


Pharmacology_Katzung

Pharmacology_Katzung. Metabolized ? Basement membrane Metabolized ? zone Drug binds to receptor Drug binds to receptor FIGURE 61–1 Schematic diagram of percutaneous absorption. (Redrawn from Orkin M, Maibach HI, Dahl MV: Dermatology. Appleton & Lange, 1991.) agent in the vehicle; the rate of release of the agent from the vehicle; the ability of the vehicle to hydrate the stratum corneum, thus enhancing penetration; the stability of the therapeutic agent in the vehicle; and interactions, chemical and physical, of the vehicle, stratum corneum, and active agent.


Pharmacology_Katzung

Pharmacology_Katzung. Depending upon the vehicle, dermatologic formulations may be classified as tinctures, wet dressings, lotions, gels, aerosols, powders, pastes, creams, foams, and ointments. The ability of the vehicle to retard evaporation from the surface of the skin increases in this series, being least in tinctures and wet dressings and greatest in ointments. In general, acute inflammation with oozing, vesiculation, and crusting is best treated with drying preparations such as tinctures, wet dressings, and lotions, whereas chronic inflammation with xerosis, scaling, and lichenification is best treated with more lubricating preparations such as creams and ointments. Tinctures, lotions, gels, foams, and aerosols are convenient for application to the scalp and hairy areas. Emulsified vanishing-type creams may be used in intertriginous areas without causing maceration. Emulsifying agents provide homogeneous, stable preparations when mixtures of immiscible liquids such as oil-in-water creams


Pharmacology_Katzung

Pharmacology_Katzung. Emulsifying agents provide homogeneous, stable preparations when mixtures of immiscible liquids such as oil-in-water creams TABLE 61–1 Local cutaneous reactions to topical medications. are compounded. Some patients develop irritation from these agents. Substituting a preparation that does not contain them or using one containing a lower concentration may resolve the problem. Topical antibacterial agents may be useful in preventing infections in clean wounds, in the early treatment of infected dermatoses and wounds, in reducing colonization of the nares by staphylococci, in axillary deodorization, and in the management of acne vulgaris. Efficacy of antibiotics in these topical applications is not uniform. The general pharmacology of the antimicrobial drugs is discussed in Chapters 43–51.


Pharmacology_Katzung

Pharmacology_Katzung. Some topical anti-infectives contain corticosteroids in addition to antibiotics. There is no convincing evidence that topical corticosteroids inhibit the antibacterial effect of antibiotics when the two are incorporated in the same preparation. In the treatment of secondarily infected dermatoses, which are usually colonized with streptococci, staphylococci, or both, combination therapy may prove superior to corticosteroid therapy alone. Antibiotic-corticosteroid combinations may be useful in treating diaper dermatitis, otitis externa, and impetiginized eczema.