Absorption

Drug absorption in infants and children follows the same basic principles as in adults. However, three factors tend to be especially important in children. First, the physiologic status of the infant or child determines the blood flow at the site of intramuscular (IM) or subcutaneous drug administration. Factors that may reduce blood flow to muscular or subcutaneous tissues include cardiovascular shock, vasoconstriction caused by sympathomimetic agents, or heart failure. In these conditions, there would be reduced absorption of any drugs injected intramuscularly or into subcutaneous tissues. In premature infants with little muscle mass, the blood supply to these areas and the resulting absorption are very irregular. In older children, muscle size and circulation in the muscles affect how rapidly a medication is absorbed. There is more rapid absorption from the deltoid muscle (shoulder and upper arm) than from the vastus lateralis muscle (thigh), and the slowest absorption is from the gluteal (buttock) muscles.

Compared with older children and adults, the instability or immaturity of different body processes in premature infants is a second influence on drug absorption from IM sites. For example, toxic drug levels may occur if the blood supply to muscle or subcutaneous tissues suddenly increases, leading to greater absorption of medication and increasing the amount of the drug entering the blood. With some drugs, there is only a small difference between the level of drug that is helpful and the level of drug that is toxic and harmful. We say that these drugs have a narrow therapeutic margin. Examples of these drugs are antic­onvulsants, cardiac glycosides, and aminoglycoside antibiotics. With these drugs, it would be easy for an infant to get too much medicine when absorption is variable.

A final factor in drug absorption is that the skin of premature and newborn infants has a greater ability to absorb some chemicals because of its greater hydration. That is, the outside stratum corneum of the epidermal barrier in the skin may allow more fluid to enter because the system is not well developed. The transdermal route may be used with some infants to reduce the unpredictability of some medications that are usually given orally or intramuscularly (for example, theophylline). However, transdermal dosage patches available for sale are not intended for pediatric patients and would deliver doses much higher than what is needed for infants and children. Instead, rubbing the drug into the skin, putting the drug in an oil base, or using an occlusive dressing (covering the skin on which the drug is placed by wrapping the area in plastic wrap) are all different ways that may increase the absorption of topical or skin products.

Distribution

Drug distribution is determined by two factors: (1) the chemical properties of the drug itself (for example, the molecular weight), which do not vary; and (2) the physiologic factors specific to the patient, including total body water, extracellular water, protein binding, and pathologic conditions modifying physiologic function, all of which vary widely in different patient populations.

Metabolism

The biotransformation of drugs in the body into usable substances involves chemical reactions that convert a drug to an inactive or less active compound. In general, drug metabolism in infants is much slower than that in older children and adults. Because most drug metabolism takes place in the liver, the fact that the levels of cytochrome P-450 enzymes of infants are only 50% to 70% of adult values is important in treatment of children. The amounts vary for the different enzymes, but the ability to increase production of all enzymes continues until the third or fourth year of life.

Because neonates have a decreased ability to metabolize drugs, they may be at increased risk for adverse effects as a result of slow clearance rates and prolonged half-lives, particularly when drugs must be given over long periods.

Excretion

As with metabolism, the growth and maturity of the child’s organs has an important effect on the child’s ability to excrete the end products of the drug reactions. Problems caused by the incomplete development of the renal excretion system, including glomerular filtration, tubular secretion, and tubular reabsorption, are slowly resolved as the child develops prior to birth. However, this system may still be very immature at birth and may only slowly develop to normal over the first year of life.

This process of normal development has implications for drug clearance, particularly of common drugs such as penicillin, aminoglycosides, and digoxin, for which clearance rates may fall to 17% to 34% of the adult clearance rate. If a child is sick enough to require these drugs, the glomerular filtration rate may not improve as predicted during the first weeks and months of life. This means that adjustments must be made in dosage and dosing schedules. The child will also require more careful monitoring, and dosages should be determined based on plasma drug levels determined at intervals throughout the course of therapy.

The growth spurt and the increase in adrenal steroid and sex hormone (estrogen in girls, androgens in both sexes) levels that occur before puberty affect drug response in children who are near puberty and in adolescents. The increase in male muscle mass, increase in female body fat, and stability of the body temperature in both sexes also affect adolescent drug response.

These facts about the drug-metabolizing system in pediatric (infants through adolescents) patients are important to remember in looking at a child’s sensitivity to medication. For example, infants and children require a total daily digoxin dose that is approximately twice that of an adult on a basis of the ratio of weight to dose. It is thought that this increased requirement for digoxin is the result of a greater binding strength of the child’s developing myocardial digoxin receptors for digitalis derivatives. Variations in the development of drug receptors may make a neonate very sensitive to anesthetics such as curare but resistant to other anesthetics such as succinylcholine.

Adverse Reactions

The risk for drug-drug interactions and adverse effects is increased in very ill children and infants. Children may be exposed to drugs in three major ways: (1) transplacentally, when the drug is given to the mother during pregnancy and delivery; (2) receiving the drug as a result of direct administration; and (3) getting the drug through breast milk if the mother has taken the drug. Fetal exposure to drugs through the placenta and neonatal exposure through breast milk share a common characteristic: These are the only stages in life in which one is exposed to and affected by drugs given to another person, the mother.

The number of adverse reactions in pediatric patients is unknown. Because young children are vulnerable, their diseases are often complex, their drug therapy is often complicated, and adverse drug reactions are unavoidable or hard to assess. However, studies have generally found that rates of adverse reactions in children are equal to those in adults. The rate may be as high as 5.8% of drugs administered to children, although the rate is higher if the child is hospitalized rather than at home. Adverse drug reactions may have a large and immediate, delayed, or long-term effect on the child’s neurologic and somatic development.

With younger children, it may be difficult to tell whether the child is having an adverse reaction, is just experiencing symptoms of the underlying illness, or is having a paradoxic reaction to a drug (e.g., hyperactive behavior with antihistamines or chloral hydrate, sleepiness with stimulants such as Ritalin). Over-the-counter preparations (particularly antihistamines and adrenergic drugs found in various cough syrups, cold remedies, decongestants, and nose drops) may also provoke adverse reactions in pediatric patients, and many of these medications have now been banned for this age group. A broad spectrum of reactions may be seen, varying from minor hypersensitivity reactions to more serious problems, including alterations in growth, damage to anatomic or physiologic systems, and numerous other problems.

Absorption

The overall importance of changes in the absorption of drugs with aging is not completely clear. There may be some delay in the absorption process. Physiologic changes that affect the GI tract include a reduction in acid output, so there is a more alkaline environment, which may affect drugs that require an acid medium for absorption. Reductions in blood flow, enzyme activity, gastric emptying, and bowel motility may increase the delay in absorption of some drugs, although they probably have little if any effect on the extent of absorption. Compounds such as iron, calcium, and certain vitamins that depend on active transport mechanisms for absorption may be affected by the decreased blood flow in the aging patient’s GI tract.

Distribution

The distribution of drugs in the body may also be affected by the aging process and is linked to the chemical makeup of the agent involved. There is a decline in total body water and lean body mass with aging that may result in less movement or distribution of water-soluble drugs into some tissues. If the dose of these drugs is not decreased, the patient may develop higher serum concentrations, leading to an increased effect or toxicity. Thus the usual rule is to start drugs using a low dose and then increase the dose slowly in older adult patients. Drugs that are distributed into body water or lean body mass include digoxin, cimetidine, lithium, gentamicin, meperidine, phenytoin, and theophylline.

The distribution of fat-soluble drugs may also be changed by the aging process. With aging, there is usually a decrease in lean body mass but an increase in total body fat. Thus, lipid-soluble drugs may be stored in larger amounts in fat tissues and remain in the body for a longer time. Diazepam, chlordiazepoxide, flurazepam, thiopental, antipsychotics, and some antidepressants are lipid-soluble drugs that may require a lower dose and slow increases if used in the older adult population.

Another important concern that may exist with older adult patients is a decrease in serum proteins such as albumin. Albumin is the most common protein that binds to various acidic drugs, and a large decrease in albumin may result in a greater amount of unbound drug that may circulate freely. Highly protein-bound drugs that tend to bind quickly to albumin include phenytoin, warfarin, naproxen, theophylline, phenobarbital, and some antidepressants.

Excretion

Kidney, or renal, function is the single most important factor that causes adverse drug reactions. Studies show that renal function varies with aging. Biologic changes in the aging kidney include decreases in the number of nephrons; decreases in renal blood flow, glomerular filtration, and tubular secretion rate; and an increase in the number of damaged glomeruli. In addition, damage to the arterial walls of blood vessels and lowered cardiac output reduce the amount of blood that flows to the kidneys by 40% to 50% between the ages of 25 and 65. The result of these changes may be a decrease in excretion of creatinine, which is reported to decrease 10% for each decade (10 years) after age 40 years.

Creatinine is a muscle by-product, and almost all of it is removed by the kidney, making it an excellent marker to measure kidney function (or renal clearance). A drug’s creatinine clearance rate is the amount of blood from which a drug is cleared per unit of time. Although creatinine clearance is used to measure renal function, it is important to note that it is only an estimate. A number of formulas can be used to determine the creatinine clearance rate, but the results may not be very accurate. Creatinine clearance can be assessed more accurately by collecting urine for 24 hours and directly measuring the amount of creatinine in it, although this may be difficult to do. However, any method of estimating creatinine clearance may not be accurate in older adult patients, who have very little muscle mass and produce very little creatinine. In addition to the normal slowing of kidney function that may occur with aging and be made worse by disease, problems leading to dehydration can also affect renal function and make the decision about how much drug to give the older adult patient even more complex.

The important factors to remember when caring for older adult patients who are taking drugs that will be excreted from the kidneys is that each patient may respond a little differently to the drug. The dosage ordered should have been adjusted based on the best creatinine clearance estimates, and low doses or longer intervals between doses are the norm if it is believed some kidney damage might be present. Drugs that depend on the kidneys for elimination include many antibiotics, some antivirals, antineoplastics, antifungals, analgesics, and many cardiac drugs.

Other kidney changes that occur with aging include a decrease in the ability of the kidney to remove only chemicals and not fluid (renal concentrating ability) and a tendency for the kidney to hold onto sodium (sodium conservation), which may affect patients on high-dose diuretics.

Adverse Reactions

Many older adults with chronic illnesses are required to take medications daily. These drugs are helpful in controlling disease, but they also present a very real hazard to older adult patients. Approximately 90% of older adults have adverse reactions to drugs, and 20% of these reactions require hospitalization. As many as 30,000 people may die each year as a result of adverse drug reactions.

Because many older adult patients take several drugs, interactions among these different drugs may also cause problems for them. These patients may see several specialists, each of whom may prescribe different medications. If the specialists don’t know about all the different drugs a patient may be taking at the same time, the patient may be at risk from combining drugs that have adverse interactions with each other.

All drugs have some risk or hazard, but the medications most dangerous to the older adult patient are tranquilizers, sedatives, and other drugs that alter the mind and change what the patient thinks he or she sees, or cause the patient to become dizzy or lose balance. Diuretics and cardiac drugs such as digitalis also pose special dangers and must be given with caution and careful observation of how the patient responds. Older adult patients may become dehydrated easily, thus allowing the amount of drug in the blood to increase. This places them at greater risk for side effects and toxicity with normal dosages. Results of research show there is also a high rate of alcohol use among many older people, both living at home and in nursing homes. Thus we are now becoming aware that drug-alcohol interactions are a serious concern in this age group.

Laboratory tests should be ordered regularly to look at kidney and liver function, and the nurse should look for side effects and signs of toxicity at every visit or encounter in the hospital or nursing home–entering the room in the hospital or long term care facility, passing the resident in the hall, greeting the resident in the dining room. If the nurse notices signs or symptoms of toxic reactions or adverse effects of drugs or observes behavior that might be a side effect, this should be reported immediately to the registered nurse. These signs and symptoms include changes in level of mental function, increased fatigue, restlessness, irritability, depression, weakness, dizziness, headache, and disorientation. These problems may interfere with appetite, balance, and energy, leading to dehydration, weight loss, falls, and immobility (not being able to move around). It is important to see that these often mild symptoms may be caused by drugs and should not simply be ignored as “typical” older adult behavior. For example, an older adult who becomes confused might have a urinary infection.

Patient Teaching Considerations

Some older persons may require special teaching about how to take their prescription medications and about the danger of taking nonprescription drugs at the same time. Failure of older adult patients to follow their medication plan, or regimen, may be because of many reasons: the cost of the drug, difficulty in getting it from a pharmacy, poor memory, lack of desire to take the drug regularly, depression, and feelings of being overwhelmed by the responsibility of taking care of themselves. These things all contribute to older adult patients failing to follow a medication regimen. In some cases, arthritis or another disease that causes physical disability may make it difficult to open bottle lids or use an inhaler. Poor eyesight may make it hard to draw up insulin or read the dose accurately. Many older patients also diagnose each other’s health problems and share medications, which may make it very difficult for the nurse to evaluate the effects of prescribed medications in a particular patient. Patients who struggle to pay for their medicines may cut pills in half or skip doses without realizing it may prevent the drug from helping them.