7: Pharmacologic Issues Across the Lifespan
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)- Name three physiologic pharmacokinetic issues affecting drug response in neonates and infants.
- Discuss the pharmacologic variables associated with each pediatric age group (neonate, infant, and child).
- Name the four considerations for increasing medication compliance for the elderly.
- Describe the physiologic changes in pregnancy that may affect the absorption, distribution, metabolism, and excretion of medications.
- Summarize the Pregnancy and Lactation Rule endorsed by the Food and Drug Administration (FDA).
7.0 Overview
Pharmacokinetic and pharmacodynamic processes vary with age. These differences are due to the normal physiologic changes that occur over a normal lifespan, especially in infants and older people. A critical difference across the lifespan is the amount of total body water, which changes with age and condition.
Figure 7.0: Total Body Water by Age and Condition. (CC-BY 4.0; Riley Cutler)
7.1 Neonates, Infants, Children
Drug treatment for neonates (less than one month of age) and infants (less than one year of age) is complicated by the lack of evidence in this age group. Instead, data from adult clinical trials is applied to determine dosing and efficacy. The dose-response relationship may change in the first few weeks after birth, making it a challenge to establish guidelines.
7.1.1 Absorption
Some physiologic changes associated with the first few months of life that affect absorption include a higher-than-normal gastric pH. In neonates and pediatric patients, the stomach's acid-producing cells are immature until around the age of one to two years. They also experience prolonged and irregular gastric emptying until 6-8 months of age.
7.1.2 Distribution
Changes that affect distribution include lower adipose tissue, decreased plasmin albumin, and higher total body water. The developing blood–brain barrier allows more drugs to enter the brain.1
7.1.3 Metabolism
The developing liver in neonates and infants produces decreased levels of microsomal enzymes. This may decrease the ability to metabolize medications, necessitating lower drug doses. As an infant’s liver matures and liver metabolism increases, the infant may require higher doses of medications. Age (in weeks) is important when prescribing for neonates and infants, as liver function may change weekly. Hepatic function reaches maturity at about two years old.
7.1.4 Elimination
Neonates, infants, and children have immature kidneys with decreased glomerular filtration, reabsorption, and tubular secretion. As a result, medications are not cleared as efficiently from the body. Dosing for most medications used to treat infants and pediatric patients is commonly based on weight in kilograms, and a smaller dose is usually prescribed. In addition, pediatric patients may have higher levels of free circulating medication than anticipated and may become toxic quickly.
7.2 Overview of Older Adults
The rationale use of drugs in persons over 65 years of age is complicated by physiologic changes, increased incidence of chronic disease and co-morbidities, and polypharmacy. Financial issues, limited resources, and poor nutritional status may all influence an older adult’s ability to comply.
Cardiac output starts declining by 1% at about age 30, and in older people, there is a redistribution of blood flow favoring the brain, heart, and kidneys. Lean body mass declines with age, and total body water decreases. Plasma albumin levels may decrease, especially in the poorly nourished. Glomerular filtration rate and plasma renal blood flow steadily decline with aging.
7.2.1 Absorption
As a natural result of aging, older adults will experience decreased blood flow to tissues within the GI tract. In addition, changes in the gastric pH may alter the absorption of certain medications. Older adult patients may also experience variations in available plasma proteins, which can impact drug levels of highly protein-bound medications. Consideration must also be given to using subcutaneous and intramuscular injections in older patients experiencing decreased cardiac output. Decreased drug absorption of medications can occur when peripheral circulation is reduced. Finally, as adults age, they often have less body fat, resulting in reduced absorption of drugs from transdermal patches that require adequate subcutaneous fat stores for proper absorption.
7.2.2 Distribution
The aging adult patient will experience a decrease in total body water, muscle mass, and serum albumin while total body fat increases. As these parameters change with aging, the volume of distribution (Vd) of a drug may be affected. Recall that Vd is the volume of total body fluid into which a drug appears to distribute after it reaches equilibrium or steady state. In older adults, lipid-soluble drugs such as diazepam and lidocaine have a larger Vd, whereas water-soluble drugs such as acetaminophen and ethanol have a smaller Vd. Serum albumin often also decreases, resulting in more active free drug within the body. This is one reason why many older adult patients require lower medication levels. Be aware that a person who has taken medication for a chronic condition for many years may need a dosage adjustment as they age.
7.2.3 Metabolism
Hepatic metabolism may significantly decline in older adults. As a result, dosages should be adjusted according to the patient’s liver function and anticipated metabolic rate. First-pass metabolism is also decreased with aging; therefore, older adults may have higher “free” circulating drug concentrations and be at higher risk for side effects and toxicities.
7.2.4 Elimination
Kidney and liver function often decreases with age, leading to reduced medication excretion. Subsequently, medication may have a prolonged half-life with a greater potential for toxicity from elevated circulating drug levels. Two important principles need to be applied to dosing for older people. First, most elderly patients do not have “normal” renal function despite having a serum creatinine level that appears normal. Second, most elderly persons require a dose adjustment for a medication or drug metabolite eliminated through the kidneys. Smaller doses of medications are often recommended for older patients because of these factors, commonly called “start low and go slow.”
7.3 Overview of Pregnancy and Breastfeeding
Drug use during pregnancy is common: many people take at least one medication. Indications may include pregnancy-related issues such as nausea, constipation, and pre-eclampsia, or chronic conditions such as epilepsy and asthma. When drugs are used during pregnancy, there is a risk to the fetus as well. However, most drugs are not tested during pregnancy, and the risk to the fetus remains unknown. Therefore, the provider should initiate a shared decision approach and weigh the risks and benefits.
For some chronic conditions, such as asthma, the risk to the fetus is clearly greater when the pregnant person stops the asthma medications. The incidence of stillbirth is high among pregnant persons who do not take medications for asthma. Note that due to the lack of data from clinical trials, evidence for the medication safety and risk is derived from histories of women who have delivered children with and without congenital disabilities.
During pregnancy, changes in the kidney, liver, and GI tract affect drug disposition. These changes may be associated with a specific trimester. During the third trimester, renal blood flow doubles, causing an increase in glomerular filtration and an accelerated clearance of drugs, such as lithium, that are eliminated by this process.
In December 2014, the FDA passed the Pregnancy and Lactation Labeling Rule (PLLR). This rule supersedes the Pregnancy Risk Categories and was enacted on June 30, 2015. By 2020, all drugs will cease using lettered categories. The PLLR requires labeling for (1) pregnancy, (2) lactation, and (3) females and males of reproductive potential. More information is available at fda.gov [fda.gov] [www.fda.gov] under pregnancy and lactation labeling resources.
From a pharmacological perspective, the greatest concern during pregnancy is exposing the fetus to a teratogen. A teratogen is any substance, organism, or physical agent that causes a permanent malformation of an embryo. The risk is dependent upon the dose of the drug and the time during gestation at which the exposure occurred. In general, clinicians should assume all drugs cross the placenta and may reach the fetus.
7.3.1 Absorption
Hormonal changes and abdominal pressure as the uterus expands may affect absorption. Gastric tone and motility slow during pregnancy, requiring a longer time to absorb drugs. This may require a reduction in drug dose.
7.3.2 Distribution
The increase in blood volume and decrease in plasma proteins in a pregnant person cause dilution of drug levels. In addition, increased cardiac output and plasma volume alter regional blood flow. Blood flow to the uterus, kidneys, and skin is increased. Changes in lipid levels may alter distribution, especially in the third trimester. Fat-soluble drugs readily distribute into breast milk.
7.3.3. Metabolism
Drug metabolism may increase during pregnancy, requiring a higher dose for certain drugs, such as anticonvulsants. Carbamazepine, phenytoin, and valproic acid may require higher doses during pregnancy.
7.3.4 Elimination
Blood flow through the kidneys is increased by the third trimester by over 50%. Because drug excretion rates are increased, medication doses may need to be adjusted.
7.4 Lactation
A large number of drugs are secreted into breast milk, but few are contraindicated. The potential effects of drugs on the infant are influenced by the amount of drug that reaches the infant’s circulation. Some drugs may not be absorbed or may be destroyed in the infant’s GI system. General recommendations for pharmacotherapy during lactation are: (1) postponing therapy until the infant is weaned, (2) administering the medication immediately after breastfeeding to maximize time in between feedings, (3) prescribing medications with a short half-life to reduce the drug exposure to the infant, (4) avoiding breastfeeding when the medication is at its peak, (5) selecting medications with high protein-binding properties as they are less likely to be secreted into breast milk, and (6) avoiding herbals and supplements that have not been reviewed with a provider.
References:
Fernandez, E., Perez, R., Hernandez, A., Tejada, P., Arteta, M., & Ramos, J. T. (2011). Factors and mechanisms for pharmacokinetic differences between the pediatric population and adults. Pharmaceutics, 3(1), 53–72. NA [doi.org]
This chapter, titled Pharmacologic Issues Across the Lifespan, is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Karen Vuckovic from Introduction to Pharmacology by Carl Rosow, David Standaert, & Gary Strichartz (MIT OpenCourseWare) via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request. Figures by Riley Cutler.