4
Special Populations (Children and Elderly)
There is no specific chapter on the topic of pharmacotherapy of special populations (children and elderly) in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition. However, this is an important area of clinical pharmacology because the pharmacotherapy of children and the elderly requires consideration of the differences in pharmacokinetics and pharmacodynamics that can significantly affect the safety and efficacy of drugs used in these special populations. Moreover, most randomized controlled clinical trials exclude young children and the aged, which makes it difficult for the clinician to make evidence-based decisions regarding appropriate drugs and dosing regimens to use in these patients.
The content of this chapter is drawn from a variety of sources, including a number of chapters in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition including Chapters 1 to 3 in Section I: General Principles, and later chapters in which the pharmacotherapy of children or the elderly is discussed in the context of specific agents. Content regarding general principles of pharmacotherapy in these special populations is drawn from online Updates published as part of the online version of Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition related to pediatric pharmacology (specifically, The History of Pediatric Drug Therapy: Learning from Errors Not Trials and Pediatric Pharmacokinetics: Why Kids Are Not Small Adults), and from Hazzard’s Geriatric Medicine and Gerontology, 6th Edition (specifically, Chapter 8 General Principles of Pharmacology and Chapter 24 Appropriate Approach to Prescribing). Neither a Mechanisms of Action Table nor a Clinical Summary Table is included in this chapter because this information is provided for specific agents in subsequent chapters. In addition to the material provided here, Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition contains:
• Appendix II with pharmacokinetic data for a number of drugs with differences in pharmacokinetic parameters that occur in children, the aged, and individuals with specific disease states
Hazzard’s Geriatric Medicine and Gerontology, 6th Edition contains:
• Table 8-5 Changes in Pharmacokinetics and Pharmacodynamics with Aging and Suggested Dose Adjustments for Older Patients
LEARNING OBJECTIVES
Describe the important pharmacokinetic and pharmacodynamic differences between adults and children that can affect safety and efficacy of drugs used in infants and children.
Know the FDA’s role in providing information to clinicians to improve safe and effective use of drugs in young children, including breast-feeding infants.
Describe the important changes in the pharmacokinetics and pharmacodynamics of drugs that occur in older adults.
Know the classes of medications that should be avoided in older adults because of central nervous system (CNS) effects.
Know the steps that should be taken to optimize drug regimens in older adults.
PEDIATRIC PHARMACOKINETICS—ABSORPTION
• Absorption of drugs from the gastrointestinal (GI) tract is reduced in neonates and changes with maturation making prediction of medication bioavailability of orally administered drugs very difficult.
▶ Young children have higher gastric pH than adults; adult levels of gastric acidity are not reached until 3 to 7 years of age.
▶ Acid-labile drugs (eg, penicillin, ampicillin, and nafcillin) have greater bioavailability.
▶ Weak acids (eg, phenobarbital, phenytoin) are ionized in the GI tract of the neonate and young child and thus are more slowly absorbed than in adults.
▶ Weak bases (eg, penicillin, ampicillin, and erythromycin) will be more quickly absorbed than in the adult GI tract.
▶ Neonates and infants have prolonged rates of gastric emptying compared to adults, with adult rates of gastric emptying not developing until 6 to 8 months of age.
▶ Biliary function develops over the first month of life; the reduced levels of bile acid salts and pancreatic enzymes in the neonate may reduce the absorption of lipophilic drugs.
▶ β-Glucuronidase and UDP-glucuronyl transferase have higher activities in the neonate GI tract than in adults which may reduce drug absorption.
▶ The development of intestinal flora in the neonate, which depends primarily on diet, can contribute to differences in drug metabolism compared with adults.
• Dermal absorption is higher in neonates and infants due to underdeveloped stratum corneum and increased skin hydration.
• Intramuscular injections are generally avoided in neonates, infants, and children because intramuscular absorption is unpredictable due to decreased muscle tone and contraction, and variable blood flow and oxygenation.
In 1956, newborns receiving the antibiotic sulfisoxazole were found to have a high incidence of kernicterus, which leads to yellow discoloration of the brain, seizures, and death.
a. What is kernicterus and what causes it?
Kernicterus refers to the yellow discoloration of the brain that is caused by high concentrations of bilirubin in the brain. It is a condition only seen in young children and can lead to brain damage and death if not treated.
Bilirubin is a yellow pigment that is the breakdown product of heme, 80% of which originates from circulating hemoglobin and 20% from other heme-containing proteins such as the CYPs. Bilirubin is hydrophobic, associates with serum albumin, and must be metabolized further by glucuronidation to assure its elimination. The failure to efficiently metabolize bilirubin by glucuronidation leads to elevated serum levels and a clinical symptom called hyperbilirubinemia or jaundice. High levels of free bilirubin in the plasma can enter the brain causing kernicterus.
b. How did sulfisoxazole lead to kernicterus in these newborns?
Bilirubin is metabolized by glucuronosyl transferase (UGT1A1) and the glucuronidated bilirubin is excreted in the urine. Infants have limited expression of glucuronosyl transferase and thus cannot efficiently metabolize bilirubin. Sulfisoxazole displaces bilirubin from plasma proteins, thus increasing the free fraction of bilirubin in the plasma and enhancing the movement of bilirubin into the brain. Moreover, infants also have an immature BBB, which allows more of the free bilirubin to cross into and damage the brain.
c. What other infant drug toxicities have resulted from low glucuronosyl transferase expression in newborns?
In 1959, gray baby syndrome was described in premature infants receiving the antibiotic chloramphenicol. This syndrome was caused by chloramphenicol accumulation and resulted in hypothermia, vomiting, acidosis, hypotension, cyanosis, a characteristic gray color, and death in some infants. Because of immature glucuronosyl transferase, infants cannot metabolize chloramphenicol to the inactive chloramphenicol glucuronate. Infants also have reduced renal capacity and diminished renal excretion of chloramphenicol and its metabolites also contributed to the accumulation of the drug in these children.
d. What other drugs have altered metabolism in children because of immature phase 2 metabolic enzymes?
Morphine is metabolized by glucuronosyl transferase to the 20-fold more active metabolite, 6-glucuronide morphine. Thus, higher serum concentrations of morphine are required for infants to obtain effective analgesia.
PEDIATRIC PHARMACOKINETICS—DISTRIBUTION
• Volume of distribution (V) is important in children due to age-related changes in body composition.
▶ Premature infants have a higher percentage of body weight that is water (85% total body water) than term infants (75% total body water).
▶ Adult total body water (55%) is reached by 12 years of age.
▶ The V of drugs that distribute in total body water and extracellular fluid are higher for infants than adults.
• Body fat increases with age and development.
▶ Premature infants do not have appreciable body fat compared to term infants (16% body fat).
▶ Drugs that are fat soluble have lower V in infants and children than adults.
▶ Premature infants have increased membrane permeability allowing easier access of drugs into compartments such as the CNS.
▶ Infants have an immature blood-brain barrier (BBB), which allows toxic substances to more readily cross into and damage the brain.
• Protein binding, both α1-acid glycoprotein and albumin, are decreased in the neonate.
▶ Serum albumin concentrations do not reach adult levels until 1 year of age.
▶ Neonatal serum albumin is 80% of that in adults and has decreased binding affinity for many drugs.
▶ Bilirubin and free fatty acids are present in higher concentrations in neonates and compete with some drugs that bind to albumin (see Case 4-1).
▶ The reduced plasma protein binding of drugs results in a larger fraction of free drug in neonatal serum and thus greater drug effect.
An 83-year-old man has occasional pain from mild osteoarthritis. He also has hypertension and is overweight.
a. What are the considerations in using a nonsteroidal anti-inflammatory drug (NSAID; Chapter 22) to treat this patient’s arthritis symptoms?
Epidemiologic and clinical studies have demonstrated an association between NSAID use and GI bleeds and renal impairment in older persons. The effects of NSAIDs on renal function increase salt and water retention, which will contribute to this patient’s hypertension. Age generally is correlated with an increased probability of developing serious adverse reactions to NSAIDs (see Chapter 22), and caution is warranted such as choosing a lower starting dose for elderly patients.
NSAIDs are labeled with a black box warning related to cardiovascular risks and are specifically contraindicated following coronary artery bypass graft (CABG) surgery. Patients at increased risk of cardiovascular disease or thrombosis are likely to be particularly prone to cardiovascular adverse events while on NSAIDs. This includes patients with rheumatoid arthritis as the relative risk of myocardial infarction is increased in these patients compared to patients with osteoarthritis or no arthritis. The risk appears to be related to factors influencing drug exposure, such as dose, t1/2, degree of COX-2 selectivity, potency, and treatment duration. Thus, the lowest possible dose should be prescribed for the shortest possible period.
b. What are the alternatives to NSAIDs in this patient?
Alternative approaches should be considered before NSAIDs are prescribed for indications such as osteoarthritis in elderly patients. Possible non-pharmacologic approaches, such as gentle exercise and weight reduction, may be beneficial alternatives to treatment with NSAIDs.
When pharmacologic therapy is required, a drug therapy with a less-adverse event profile, such as acetaminophen, should be used.
PEDIATRIC PHARMACOKINETICS—EXCRETION
• Infants and small children have reduced renal function (20-40% of adult function).
• Adult filtration rates are not reached until approximately 3 years of age.
• Reduced renal function in children is due to:
▶ Reduced glomerular filtration rate (GFR)
▶ Tubular cell immaturity
▶ Reduced nephron length
▶ Reduced solute gradient
▶ Decreased responsiveness to antidiuretic hormone
• Even when normalized for body surface area, renal plasma flow, glomerular filtration, tubular secretion, tubular reabsorption, and the concentrating and acidifying functions of the kidney are low compared with adults.
• Renal clearance of drugs excreted almost entirely by glomerular filtration (eg, aminoglycosides and vancomycin) will change in a manner that corresponds to maturation of renal function.
• Premature infants have lower filtration rates and are slow to develop the renal capacity that term neonates will have developed by 1 week of age.
▶ Premature infants require lower doses, longer dosing intervals, or both to maintain the same steady-state plasma concentrations as the full-term infant.
• Excretion of drugs that depend on tubular secretion (eg, penicillins, sulfonamides, furosemide, and chloramphenicol) has reduced rates of clearance in the neonate.
A 90-year-old woman develops symptoms of a cold and buys an over-the-counter cold medication at the grocery store. The medication contains diphenhydramine, acetaminophen, and phenylephrine. She takes the recommended adult dose but soon after taking the medication she becomes very confused and disoriented.
a. What is likely causing the signs of confusion?
Diphenhydramine is a first-generation antihistamine that is a common ingredient in over-the-counter cold and allergy medications (see Chapter 21). This agent is able to cross the BBB where it has significant anticholinergic effects, including confusion and somnolence. The elderly have reduced BBB function and are also at a higher risk of adverse drug effects when taking drugs that have anticholinergic properties.
b. What symptoms are associated with strong anticholinergic drugs in older patients?
In the elderly, drugs with strong anticholinergic properties are associated with adverse effects such as confusion, dry mouth, dry eyes, urinary retention, constipation, and postural hypotension.
c. What other drugs have strong anticholinergic properties that should be avoided in elderly patients?
The 2012 Beers Criteria (see Side Bar POTENTIALLY INAPPROPRIATE MEDICATIONS FOR THE ELDERLY) lists the following medications with strong anticholinergic properties that should be avoided in older adults.
First-generation antihistamines, as a single agent or as part of a combination product (see Chapter 21):
Brompheniramine
Carbinoxamine
Chlorpheniramine
Clemastine
Cyproheptadine
Dexchlorpheniramine
Diphenhydramine (oral)
Doxylamine
Hydroxyzine
Promethazine
Triprolidine
Antispasmodics (see Chapter 6)
Belladonna alkaloids
Clidinium-chlordiazepoxide
Dicyclomine
Hyoscyamine
Propantheline
Scopolamine
Antiarrhythmics (see Chapter 18)
Disopyramide
Tertiary tricyclic antidepressants (TCAs), alone or in combination (see Chapter 8)
Amitriptyline
Chlordiazepoxide-amitriptyline
Clomipramine
Doxepin more than 6 mg/d
Imipramine
Perphenazine-amitriptyline
Trimipramine
Antipsychotics (see Chapter 8)
Thioridazine
Mesoridazine
Skeletal muscle relaxants (see Chapter 9)
Carisoprodol
Chlorzoxazone
Cyclobenzaprine
Metaxalone
Methocarbamol
Orphenadrine
PEDIATRIC PHARMACKINETICS—METABOLISM
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