Changes in Drug Response with Aging

Aging alters the dynamic processes that drugs undergo to produce therapeutic effects. These alterations involve the process of pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body). The processes of pharmacokinetics and pharmacodynamics and the implications for nurses caring for older adults are described in the following section.

Pharmacokinetic Changes: What the Body Does to the Drug

When a drug is taken, it begins a journey of four phases: absorption, distribution, metabolism, and excretion. What the body does to the drug during the four phases of this journey is known as pharmacokinetics. The normal physiologic changes that occur with aging can alter pharmacokinetics. This section explores those pharmacokinetic changes that occur with aging. A summary of important age-related physiologic alterations that affect pharmacokinetics is presented in Table 22–1.

Absorption refers to the movement of a drug from the site of administration to the systemic circulation. The primary alteration of absorption occurs with drugs taken orally or via feeding tubes. To be absorbed, orally administered drugs first need to enter the stomach and intestines. With aging there is decreased secretion of gastric acid, slowed gastric emptying and decreased gastrointestinal motility, decreased absorptive capacity, and decreased blood flow to the stomach and intestines (Hutchison & O’Brien, 2007). Although these effects may slow absorption of oral drugs, they do not substantially affect the amount of drug absorption that ultimately occurs; therefore age-related changes in absorption of most drugs are usually insignificant (Beers, Porter, Jones, et al, 2006; Flammiger & Maibach, 2006); however, the first dose of a new drug may take longer to take effect (Hutchison & O’Brien, 2007). Topical drugs also face barriers to absorption. Aged skin has decreased water content, a relative decrease in lipid content, and a decrease in tissue perfusion. These changes may result in impaired absorption of some medications that are administered via lotions, creams, ointments, and patches (Flammiger & Maibach, 2006).

Distribution refers to movement of the drug from the systemic circulation to the site of action. Distribution is affected by the relative amounts of total body water, fat content, and protein binding. Older adults have alterations in each of these. Total body water decreases gradually with aging. Because there is less water for dilution, this may result in a higher concentration of highly water-soluble (hydrophilic) drugs (Lilley, Harrington, & Synder, 2007). Because hydrophilic drugs have a tendency to stay within the circulation longer, this will be reflected by a higher serum drug level on laboratory studies. If the risk of toxicity is to be decreased, smaller doses of hydrophilic medications such as digoxin, lithium, atenolol, and aminoglycosides may be needed for older adults (Beers et al, 2006). Conversely, older adults have a decrease in lean body mass, so the percentage of fat content is increased in comparison with younger adults of similar weight. As a consequence of this higher proportion of fat, there will be an increase in the distribution of highly fat-soluble (lipophilic) drugs (Hutchison & O’Brien, 2007). As a result, lipophilic drugs such as benzodiazepines and certain anesthetics (e.g., halothane and thiopental) may exhibit extended effects (Hutchison & O’Brien, 2007; Lilley et al, 2007). A final area of concern regarding distribution involves drugs that are highly protein bound. Drugs of this type, such as warfarin, phenytoin, furosemide, and naproxen, tend to bind primarily to albumin, a protein in the plasma, and only become active when unbound. With age, particularly for malnourished or frail adults, albumin levels may drop. As a result of decreased sites for protein binding, the activity of highly protein-bound drugs, and any side effects caused by these drugs, may be increased (Beers et al, 2006; Hutchison & O’Brien, 2007; Lilley et al, 2007).

Metabolism refers to the reactions that transform drugs into metabolites that can be more easily excreted. (Less commonly, metabolism will convert inactive drugs, known as prodrugs, to an active form.) Metabolism is accomplished by biochemical reactions that take place primarily in the liver via phase 1 (oxidation–reduction via the cytochrome P [CYP] 450 enzyme system) and phase 2 (glucuronidation, acetylation, or sulfation) reactions. It was once believed that there was a generalized decrease in all metabolic processes with aging. More recent research demonstrates that aging does not appear to effect phase 2 processes. Furthermore, while some isoenzymes (e.g., CYP2C19 has a role in metabolizing diazepam, naproxen, omeprazole, and propranolol) are reduced with aging, others remain unchanged, are variable, or affect only those older adults who are malnourished or frail (Hutchinson & O’Brien, 2007). In addition to the metabolic processes, the adequacy of hepatic circulation to direct drugs to the liver for metabolism must be considered. With aging there is a 35% decrease in hepatic blood flow (Hutchison & O’Brien, 2007). This is particularly relevant in regard to the role of first-pass metabolism. First-pass metabolism is a process in which a large percentage of drugs absorbed from the stomach or intestines first enters the portal circulation of the liver and is metabolized (inactivated) before reaching the systemic circulation. A decrease in hepatic blood flow can result in a decrease in the amount of a drug diverted to the liver for transformation before it enters the systemic circulation. With decreased first-pass metabolism, a greater amount of active drug enters the systemic circulation; consequently, there is an additional risk that standard doses of drugs will more likely result in toxic effects (Hutchison & O’Brien, 2007; Lilley et al, 2007). The implications of these alterations are that metabolism of some drugs may be slowed, thus leading to a prolonged drug half-life and an increased risk of drug accumulation and toxic effects; however, this cannot be generalized to all older adults. Individualization of medication regimens and close assessments for signs or symptoms of toxic effects or complications are necessary while dosing schedules are being optimized.

Excretion, the elimination of drugs from the body, occurs primarily via the kidneys. When renal function is decreased, half-life increases and drugs can accumulate to toxic levels. This has important implications for older adults because, for most, renal function decreases with aging, especially for those who have conditions such as hypertension or heart disease (Shi, Mörike, & Klotz, 2008). Because the degree of renal function varies from patient to patient, it is important to evaluate whether adequate renal function exists and, if not, to what degree it is compromised. A serum creatinine level is commonly used as a screening test for renal function; however, in older adults, the serum creatinine level may be within normal limits even when renal function is significantly compromised (Hutchison & O’Brien, 2007; Shi et al, 2008). The best indicator of renal function is the glomerular filtration rate (GFR). The most commonly used method to calculate the GFR is the Cockcroft-Gault (CG) formula; however, this may result in an inaccurate measure of GFR in older adults (Hutchison & O’Brien, 2007; Shi et al, 2008). For older adults, most experts currently recommend that laboratories use the Modification of Diet in Renal Disease (MDRD) formula to estimate GFR (Fliser, 2008; Schrier, 2008; Shi et al, 2008; Verhave, Fesler, Ribstein, et al, 2005). The prescriber can then use information gleaned from the GFR to determine whether lower doses are needed.

Nursing management associated with altered pharmacokinetics rests primarily on careful patient monitoring to assess the adequacy of the drug to achieve the desired effect and to identify any adverse effects that can create problems for the patient. Also, because altered pharmacokinetics makes the older adult particularly vulnerable to elevated levels of some drugs, the nurse will need to routinely assess the patient for signs and symptoms of drug toxicity. Each drug manifests toxicity in different ways, so it is essential that the nurse is familiar with signs and symptoms of toxicity for each drug that a patient takes so that this problem is detected in the early stages. It is also important for the nurse to know how toxicity is measured. For some drugs (e.g., digoxin), toxicity is determined directly by acquiring a serum drug level. For other drugs, toxicity is determined through diagnostic tests that evaluate drug effects; for example, warfarin toxicity is determined by an international normalized ratio (INR) or INR with prothrombin time (PT) rather than by a warfarin level. If there is evidence of toxic effects, the nurse will need to contact the prescriber promptly and then hold any subsequent dose until the prescriber has had an opportunity to evaluate the patient’s status and make any necessary adjustments in the medication.

Pharmacodynamic Changes: What the Drug Does to the Body

The physiologic alterations associated with aging can also alter how the older adult responds to drugs. Pharmacodynamics, what the drug does to the body, is the term used to explain the body’s response to a drug. As people age, pharmacodynamics is altered by the number of receptors and their affinity for drugs, as well as by alterations in response to receptor stimulation (Shi et al, 2008). As a result, drug sensitivity may be either increased (e.g., increased sedative effects of benzodiazepines) or decreased (e.g., decreased bronchodilator response to beta agonists such as albuterol). In both respects, the altered sensitivity is unrelated to the drug level. Furthermore, the bodily processes that maintain homeostasis become less effective; consequently, the older adult may be less able to tolerate the effects and side effects of certain drugs. As with nursing actions related to pharmacokinetics, it is imperative that the nurse assess responses to drugs so that therapy can be adjusted, if needed, to improve patient outcomes.

Medications and Quality of Life

In addition to weighing drugs in terms of benefit versus risk, it is also important to weigh them in terms of desired versus undesired outcomes. It is natural to assume that a drug is appropriate if it achieves the desired outcome. For example, if an antihypertensive drug such as atenolol adequately maintains blood pressure within normal parameters or if a prokinetic drug such as metoclopramide promotes adequate gastric emptying to decrease gastroesophageal reflux, then they would generally be perceived as appropriate drugs. On the other hand, if the atenolol caused erectile dysfunction or if the metoclopramide caused tardive dyskinesias, the patient’s quality of life may be lessened to a greater extent than the benefit provided by the drug.

Medications may have various detrimental effects on cognition, emotion, ambulation, continence, and other essential functions. These negative effects on an older patient’s quality of life must be carefully considered as part of pharmacologic therapy. Some patients may prefer to endure a condition rather than suffer an adverse effect. Generally, other drugs or interventions can be used instead. If one uses the earlier example, an angiotensin-converting enzyme inhibitor (ACEI) will be less likely to cause erectile dysfunction than the beta blocker, and the patient’s gastroesophageal reflux may be managed by drugs that decrease acidity. For this reason, if a patient refuses a medication, rather than simply charting a medication as refused, the nurse should elicit the patient’s perspective so that a more appropriate intervention can be implemented. When other options are not advisable, it is generally important to honor patient values. Management that is patient-centered in such a way that it considers the patient’s beliefs and goals regarding quality of life to be tantamount to those of the provider is necessary to ensure optimal outcomes.

Pharmacologic Contributors to Risk

A number of factors can increase the risk of poor outcomes for older adults who require pharmacologic therapy. Among the most important risk factors are drug interactions, polypharmacy, and substance abuse.

Drug Interactions

Drugs may interact with other drugs and with food. Some drugs may even interact with diseases. It is important for the nurse to be aware of potential interactions so that harmful patient outcomes can be avoided.

Drug–drug interactions occur in a variety of ways. Perhaps the most common interaction is the result of altered metabolism via the CYP450 hepatic enzyme system. Some drugs have the ability to induce or inhibit the activity of various CYP isozymes, which results in speeding up or slowing down biotransformation of drugs metabolized by the affected set of isoenzymes. If the biotransformation is accelerated, the drug affected will be inactivated prematurely; whereas, if the biotransformation is decelerated, the drug may accumulate to toxic levels. Drugs may also interact indirectly through opposing or antagonistic actions. For example, in the patient who has both asthma and hypertension, a beta-blocker given to control hypertension may oppose the actions of a beta-agonist given to dilate airway passages. Drugs may also interact chemically. This is more readily seen in intravenous (IV) solutions in which incompatible drugs may crystallize when mixed; however, it may also occur when certain oral drugs are taken together. Table 22–2 lists examples of significant drug–drug interactions.

TABLE 22–2

COMMON DRUG–DRUG INTERACTIONS IN OLDER ADULTS

DRUG–DRUG COMBINATION	POTENTIAL EFFECT
Warfarin and aspirin	Increased risk of bleeding
Warfarin and chloral hydrate	Increased risk of toxicity
Digitalis and quinidine	Increased risk of toxicity
Cimetidine and propranolol	Decreased clearance, increased bradycardia
Thiazides and longer acting antidiabetics	Increased risk of hypoglycemia
Levodopa and clonidine	Decreased antiparkinsonian effect
Diuretics and NSAIDs	Renal impairment
Lithium and diuretics	Increased risk of toxicity
Lovastatin (Mevacor) and gemfibrozil (Lopid)	Toxic liver effect
Prednisone and barbiturates	Decreased steroid effect
St. John’s wort and pseudoephedrine	Increased blood pressure
Ginkgo with aspirin	Increased bleeding risk

NSAIDs, Nonsteroidal antiinflammatory drugs.

Drug–food interactions are less common than drug–drug interactions but still increase risk. The metabolism or effect of certain drugs can be altered when combined with certain foods. For example, potentially dangerous interactions can occur when certain drugs are taken with grapefruit juice. This occurs because a chemical found in grapefruit juice inhibits metabolism by 3A4 isoenzymes of the CYP450 enzyme system. The 3A4 isoenzymes are responsible for first-pass metabolism of a large number of drugs; therefore, as a result of inhibited metabolism, drugs normally metabolized by 3A4 isoenzymes, such as calcium channel blockers, may accumulate to high or even toxic levels. Some drugs may affect drug levels in other ways. For example, some laxatives may cause rapid transit of an orally administered drug through the gastrointestinal system so that it is not adequately absorbed. See Table 22–3 for examples (Kiani & Imam, 2007).

TABLE 22–3

COMMON DRUG–FOOD INTERACTIONS IN OLDER ADULTS

FOOD	DRUG	POTENTIAL EFFECT
Caffeine	Theophylline	Increased potential for toxicity
Fatty food	Griseofulvin	Increased absorption of drug
Blue cheese	Penicillin	Antagonistic action
Fiber	Digoxin	Absorption of drug into fiber, reducing drug action
Vitamin K foods: cabbage, greens, egg yolk, fish, rice	Warfarin	Decreased effect of drug, inhibiting anticoagulation
Food	Many antibiotics	Reduced absorption rate of drug
Mineral oil	Fat-soluble vitamins	Fat-soluble vitamins dissolve in oil; deficiency possible
Tyramine foods: aged cheese, wines, pickled herring, chocolate	Monoamine oxidase (MAO) inhibitors (phenelzine [Nardil], tranylcypromine [Parnate]), St. John’s wort	May precipitate hypertensive crisis
Vitamin B6 supplements	Levodopa-carbidopa	Reverses antiparkinsonian effect
Grapefruit juice	Cisapride, calcium channel blockers, quinidine	Altered metabolism and elimination can increase concentration of drug
Citrus juice	Calcium channel blockers	Gastric reflux exacerbated

Drug–disease interactions may exacerbate patient conditions and hinder healing. These drugs are generally contraindicated in patients with coexisting underlying disease. For example, 13% of African American men and 20% of African American women are carriers of the gene that can cause a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G6DP). If a patient with this deficiency takes certain drugs such as sulfonamides or aspirin, erythrocyte hemolysis can occur (Lilley et al, 2007). Table 22–4 lists examples of drug–disease interactions.

TABLE 22–4

COMMON DRUG–DISEASE INTERACTIONS IN OLDER ADULTS

DISEASE	DRUG	POTENTIAL EFFECT
Atrophic gastritis	Aspirin, NSAIDs	GI hemorrhage
Sinus or atrioventricular note disease	Digitalis, verapamil	Bradycardia
Venous insufficiency	Calcium channel blockers or beta-blockers	Edema, intermittent claudication
Cataracts	Corticosteroids	Accelerated cataract formation
Unstable bladder	Diuretics	Incontinence
Prostatic hypertrophy	Anticholinergics	Urinary retention
Parkinson’s disease	Metoclopramide, neuroleptics	Parkinson’s syndrome
Renal impairment	NSAIDs, contrast material, aminoglycosides	Acute renal failure
Chronic obstructive pulmonary disease	Beta-blockers, opiates	Bronchoconstriction, respiratory depression
Hypokalemia	Digitalis	Cardiac toxicity
Osteopenia	Corticosteroids	Fracture risk
Orthostatic hypotension	Diuretics, psychotropics, antihypertensives	Increased fall risk
Depression	Central-acting antihypertensives, alcohol, antianxiety drugs, corticosteroids	Exacerbation of depression

GI, Gastrointestinal; NSAIDs, nonsteroidal antiinflammation drugs.

Education is an essential component of any risk prevention program. Nurses should provide patients with information regarding the risk of potentially dangerous interactions among the drugs they are taking. It may also be helpful to provide the patient with a list of acceptable over-the-counter drugs for common problems such as mild pain or constipation. A “safe over-the-counter medication list” may be a useful tool for health care providers to review with patients before completing the office visit (Table 22–5).

TABLE 22–5

A SAFE LIST FOR OVER-THE-COUNTER MEDICATIONS

IF YOU HAVE	GENERALLY AVOID OVER- THE-COUNTER MEDICINES CONTAINING	EXAMPLES	BECAUSE	SAFER ALTERNATIVES
Asthma or lung disease	Ephedrine Epinephrine Extra theophylline Pseudoephedrine Caffeine	Bronkaid Primatene Bronkaid Sudafed NoDoz, DeWitt’s pills	May cause insomnia, nervousness, irregular heartbeats, especially when taking prescription asthma medicines	Ask your doctor
	Aspirin/salicylates (if you have aspirin allergy)	Ecotrin	May cause allergic reaction (e.g., wheezing, itching, hives)	Acetaminophen (Tylenol)
	NSAIDs (if you have aspirin allergy)	Nuprin
Blood clots (and are taking blood thinners) NSAIDs	Aspirin/salicylates	Ecotrin, Vanquish, Alka-Seltzer, Pepto-Bismol	May cause bleeding	Acetaminophen, Kaopectate
	Nuprin	May cause bleeding
Heart problems (high blood pressure, heart failure, abnormal heartbeat)	Sodium, salt Phenylpropanolamine Ephedrine Epinephrine/pseudoephedrine Caffeine	Alka-Seltzer, antacids Dexatrim Bronkaid Primatene Sudafed NoDoz	May worsen your condition	Acetaminophen, nasal sprays, nonmedicated throat lozenges
Diabetes	Liquid or syrups containing alcohol or sugar	Emetrol, many cough or cold syrups	May alter blood sugar	Sugar-free, sugarless, or alcohol-free liquids
	Phenylpropanolamine	Dexatrim	May increase blood sugar	Nonmedicated nose sprays, throat lozenges
	Ephedrine	Acutrim
	Epinephrine	Bronkaid, Primatene
	Aspirin/salicylates	Ecotrin, Pepto-Bismol	May decrease blood sugar if taking oral diabetes pills to lower sugar	Kaopectate, acetaminophen
Seizures	Aspirin/salicylates		May change levels of prescription seizure medicines	Acetaminophen
	Antihistamines (depressant medicine)	Benadryl, Unisom	May add to drowsiness caused by prescription seizure medicines	Ask your doctor
	Theophylline	Bronkaid Ecotrin	May change levels of prescription seizure medicine
Stomach ulcers	Aspirin/salicylates	Nuprin	May worsen your ulcers	Acetaminophen
	NSAIDs Theophylline	Bronkaid	May have more side effects from theophylline if taking certain prescription ulcer medicines	Ask your doctor

These are general suggestions and should be discussed with your doctor. He or she may want to change this list or may add suggestions to fit your individual needs. Always read the label on nonprescription (over-the-counter) medicines before purchasing and have a pharmacist assist you if you are not sure what choice to make.

NSAFDs, Nonsteroidal antiinflammatory drugs.

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