In the United States, persons 65 years of age and older are the largest users of prescription and over-the-counter (OTC) medications. Although making up only about 12% of the population, they consume about one third of all prescriptions drugs and one half of those available OTC (Beyth and Shorr, 2007). The majority (94%) regularly takes prescription medications, 46% take OTCs, and 53% take dietary supplements such as herbs (Qato et al., 2008). Although the statistics vary from study to study, the increase in number of medications with the number of years lived, and chronic conditions acquired, is consistent. The most commonly prescribed and used drugs in the ambulatory older population are cardiovascular drugs, diuretics, nonopioid analgesics, anticoagulants, and antiepileptics (Field et al., 2004). Gastrointestinal preparations and analgesics are the most-used OTC medications, followed by cough products, eye washes, and vitamins. According to a report of the Agency for Healthcare Research and Quality, Medicare beneficiaries spent about $82 billion in 2007 on medications, one fourth of this or about $19 billion, on those for cholesterol and diabetes (Agency for Healthcare Quality Research, 2010).

Pharmacological interventions can both enhance and endanger the quality and quantity of life. When medications are used inappropriately, they contribute to both morbidity and mortality in this population. Unfortunately, even when drugs are used appropriately, there are times that they may adversely affect the elder’s health and well-being. Older adults are at greater risk for polypharmacy, adverse drug events, and inappropriate drug use than are younger adults. The reasons for this are many and include increases in chronic disease and varying levels of geriatric skills of health care providers. When used with caution and care, pharmacological interventions can be used alongside nonpharmacological approaches to maximize healthy aging.

This chapter reviews the basics of pharmacokinetics and pharmacodynamics relevant to geropharmacology. Several issues are addressed with special attention to the use of psychotropic medications.

Pharmacokinetics

Pharmacokinetics is the study of the movement and action of a drug in the body. Pharmacokinetics determines the concentration of drugs in the body, which in turn determines effect. The concentration of the drug at different times depends on how the drug is taken into the body (absorption), where the drug is dispersed (distribution), how the drug is broken down (metabolism), and how the body gets rid of the drug (excretion). It is important for the gerontological nurse to understand how pharmacokinetics may differ in an older adult (Figure 9-1).

Absorption

For a drug to be effective, it must be absorbed into the bloodstream. The amount of time between the administration of the drug and its absorption depends on a number of factors, including the route of administration, bioavailability, and the amount of drug that passes through the absorbing surfaces in the body. The most common routes of administration are intravenous, oral, enteral, parenteral, transdermal, and rectal. The drug is delivered immediately to the bloodstream with intravenous administration and quickly via the parenteral, transdermal, and rectal routes. Orally and enterally administered drugs are absorbed the most slowly and primarily in the small intestine.

Drugs given orally pass through the mouth and esophagus and enter the stomach. Most solid oral drug dosage forms (e.g., tablets, capsules, powders, pills) are designed to dissolve in the stomach. Drugs given enterally (via tube) are intended for an oral administration route but mechanically bypass the mouth and potentially the stomach and duodenum. Many factors affect the rate at which a medication is dissolved. These factors include the amount of liquid in the stomach, the type of coating the tablet has, the extent of tablet compression used in making the tablet, the presence of expanders in the tablet, the solubility of the drug in the acid environment of the stomach, and the rate of peristalsis. Liquid drug dosage forms for oral use come as solutions, suspensions, tinctures, and elixirs. The presence of food in the stomach may or may not delay absorption.

There does not seem to be conclusive evidence that absorption in older adults is changed appreciably. However, we do know that diminished salivary secretion and esophageal motility may interfere with swallowing some medications, which could in turn lead to erosions if adequate fluids are not taken with the medications (Gore and Mouzon, 2006). Decreased gastric acid, common in the elderly, will retard the action of acid-dependent drugs. Delayed stomach emptying may diminish or negate the effectiveness of short-lived drugs that could become inactivated before reaching the small intestine. Some enteric-coated medications, such as enteric-coated aspirin, which are specifically meant to bypass stomach acidity, may be delayed so long in older adults that their action begins in the stomach and may produce undesirable effects, such as gastric irritation or nausea.

Once a drug has been administered orally (or enterally), it may be absorbed directly into the bloodstream from the stomach (e.g., alcohol), but usually passes dissolved into the duodenum or small intestine. The small intestine has a large surface area and is efficient at absorption. Slowed intestinal motility, frequently seen with aging, can increase the contact time and increase drug effect because of prolonged absorption, significantly increasing the risk for adverse reactions or unpredictable effects.

The drug passes from the small intestine into the network of veins surrounding it, known as the portal system, and into the liver, where it may undergo metabolism (see below). Drugs that are extensively metabolized as they pass through the liver are said to have a large first-pass effect. Drugs with a significant first-pass effect usually require much larger oral doses than the same drug given by injection. In normal aging, both liver mass and blood flow are significantly decreased, resulting in reductions in the metabolism rate with potential but unknown implications for the older adult.

With sublingual and rectal administration, the drug is absorbed through the mucous membrane directly into the systemic circulation. Drying of the mouth, a common side effect of many of the medications taken by older adults, may reduce or delay buccal absorption. Rectal administration may be useful when the patient cannot tolerate oral medications.

Nurses working with older adults are usually familiar with the transdermal drug delivery system (TDDS) because of its long use for the topical application of nitroglycerin; the drug was dispersed in an oil-based cream, placed on a piece of paper (measured by the centimeter), and taped to the skin. The system has developed significantly and is now used for many fat-soluble drugs, usually a medication-impregnated patch (e.g., estrogen, clonidine, nicotine, fentanyl, nitroglycerin). This route overcomes any first-pass problems, is more convenient, acceptable, and reliable than other routes, especially in the outpatient setting and for some persons with cognitive disorders. Ideally the TDDS provides for a more constant rate of drug administration and eliminates concern about gastrointestinal absorption variation, gastrointestinal intolerance, and drug interaction. It is indicated when a slow, timed-release delivery into the tissue and ultimately the bloodstream is desired. The skin must be intact, the patch must remain in place for the designated amount of time, and the previous patch must be removed before a new one is applied. For the elder who is either underweight or overweight, dosing may be unreliable. The characteristic thinning, dryness, and roughness of older skin also may affect absorption of the intended dose. The risk for an allergic reaction to the patch is increased with the normal immune changes with aging.

Distribution

The systemic circulation transports a drug throughout the body to receptors on the cells of the target organ, where a therapeutic effect is initiated. The organs of high blood flow (e.g., brain, kidneys, lungs, liver) rapidly receive the highest concentrations. Distribution to organs of lower blood flow (e.g., skin, muscles, fat) generally occurs more slowly and results in lower concentrations of the drug in these tissues. Circulatory disease, such as peripheral vascular disease, can affect drug distribution.

Lipophilic (fat-soluble) drugs pass through capillary membranes more easily than do hydrophilic (water-soluble) drugs, resulting in more rapid tissue distribution and a greater volume of distribution. Lipophilic drugs concentrate in adipose tissue to a greater extent than in the vasculature or other tissues. As adipose tissue nearly doubles in healthy older men and increases by one half in older women, the risk for accumulation and potentially fatal overdoses is increased. Drugs that are highly lipid soluble are stored in the fatty tissue, thus extending and possibly increasing the drug effect, depending on the level of adiposity (Masoro and Austed, 2003). In contrast, decreased body water in normal aging leads to higher serum levels of water-soluble drugs, such as digoxin, ethanol, and aminoglycosides. This can result in a higher relative volume of lipophilic drugs (e.g., diazepam, lorazepam) and a decreased relative volume of hydrophilic drugs (e.g., cimetidine, morphine) (Burchum, 2011).

Distribution also depends on the availability of plasma protein in the form of lipoproteins, globulins, and especially albumin. Some drugs are bound to protein for distribution. Normally, a predictable percentage of the absorbed drug is inactivated as it is bound to the protein. The remaining free drug is available in the bloodstream for therapeutic effect when an effective concentration is reached in the plasma.

The healthy elder shows either no or only an insignificant change in plasma binding proteins. However, albumin may be significantly reduced in those with malnutrition, an acute illness, or a long-standing chronic condition, common among those in need of skilled care at home or in long-term care settings. Unpredictable concentrations of drug are especially dangerous in those with narrow therapeutic windows such as salicylates, lorazepam, diazepam, chlorpromazine, phenobarbital, or haloperidol. Basic drugs (e.g., lidocaine, propranolol) will show increased protein binding and less effect, and acidic drugs (e.g., warfarin, phenytoin) will show decreased protein binding and greater effect because of decreased plasma albumin (Burchum, 2011). This is especially relevant to nurses working with medically fragile elders, such as in the acute care setting.

Metabolism

Some drugs exert their therapeutic effect in their absorbed form, whereas others must be metabolized first. Metabolism is the process wherein the chemical structure of the drug is converted to a metabolite that is more easily used and excreted. This process is called biotransformation. A drug will continue to exert a therapeutic effect as long as it remains either in its original state or as an active metabolite or metabolites. Active metabolites retain the ability to have a therapeutic effect and have the same or more chance of adverse effects as the original structure. For example, the metabolites of acetaminophen (Tylenol) can cause liver damage with doses above 4 g in 24 hours; extra strength tablets are commonly used at doses of 1 gram per tablet. The duration of drug action is determined by the metabolic rate and is measured in terms of half-life, that is, the length of time 50% of the drug/metabolites is/are active.

Metabolism occurs in two phases—phase I (oxidative) and phase II (conjugative). Conjugation reactions primarily convert drugs and their metabolites to glucuronides. Glucuronides are very hydrophilic and are more readily excreted in the urine or bile. The oxidative metabolizing enzymes are known as the cytochrome P450 (CYP450) monooxygenase system. The human CYP450 system is composed of about 50 isoforms (e.g., CYP3A3/4), each of which can perform a specific chemical reaction (Wilkinson, 2001). These isoforms metabolize the parent compound by adding or subtracting a part of the drug molecule (e.g., adding an oxygen atom or subtracting a methyl group), thereby changing the molecule into a more hydrophilic (polar) compound. Eight to ten of these isoforms are responsible for the majority of all drug metabolism.

Several of the metabolizing enzymes (CYP450 isoforms) show genetic differences. It has been found that people from different global regions tend to metabolize at different levels of efficiency: there are poor metabolizers, normal metabolizers, rapid metabolizers, and ultrarapid metabolizers (Box 9-1). Although differences in metabolism are important with any class of drugs, they are of particular note in relation to psychotropic and pain medications addressed elsewhere in this chapter.

BOX 9-1

Focus on Genetics

Drug Metabolism

As knowledge of the genome explodes, so does our ability to consider the possibility of what has come to be called “personalized medicine.” Included in this is consideration of someday selecting medications and formulations consistent with the metabolic enzymes specific to the individual, which should optimize therapeutic effect while minimizing or eliminating any untoward effects. Cytochrome P450 refers to a group of enzymes found primarily in the liver and responsible for the metabolism and excretion of the majority of drugs. Four phenotypic categories of persons relative to the speed of P450 metabolism have been identified. Someone who is a “poor” or “slow” metabolizer will excrete more slowly and therefore can achieve the same therapeutic effect with a low dose of a medication compared with the high dose needed by a “rapid” or even “ultrarapid” metabolizer. Among persons from the regions of northern Europe, 5% to 10% are poor metabolizers. This contrasts with persons from parts of Asia and Africa, among whom only 1% are poor metabolizers.

Data from Tiwari AK, Souza RP, Müller DJ: Pharmacogenetics of anxiolytic drugs, Journal of Neural Transmission 116:667, 2009.

Because of the high level of variability in metabolism from individual to individual, it is difficult to ascribe decreased drug-metabolizing capability to increased age. Studies have shown no decrease in either conjugative metabolism or CYP450 system function as a result of age. However, with aging, liver activity, mass, and volume and blood flow are diminished, with resultant decreases in hepatic exposure. Drugs that do not undergo significant first-pass metabolism are not affected by the aging liver, but those that undergo extensive first-pass metabolism may exhibit decreased metabolism, increased bioavailability, and a decreased rate of biotransformation (Beyth and Shorr, 2007).

Excretion

Drugs and their metabolites are excreted in sweat, saliva, and other secretions but primarily through the kidneys. They are excreted either unchanged or as metabolites. A few drugs are eliminated through the lungs, as unreabsorbed metabolites in bile and feces, or in breast milk. Very small amounts of drugs and metabolites can also be found in hair, sweat, saliva, tears, and semen.

Renal drug excretion occurs when the drug passes through the kidneys; it involves glomerular filtration, active tubular secretion, and passive tubular reabsorption. Glomerular filtration depends on both the rate and the extent of protein binding of the drug. The process involves passive filtration, and only unbound drugs are filtered. Because kidney function declines in many older persons, so does the ability to excrete or eliminate drugs in a timely manner. The glomerular filtration rate, renal plasma flow, tubular function, and reabsorptive capacity decline. The significantly decreased glomerular filtration rate leads to prolongation of the half-life of drugs eliminated through the renal system, resulting in more opportunities for accumulation and potential toxicity or other adverse events. Although renal function cannot be estimated on the basis of the serum creatinine level, it can be approximated by calculating creatinine clearance. There are a number of online ways to calculate creatinine clearance (e.g., see Chapter 8 or http://www.nephron.com/cgi-bin/CGSIdefault.cgi). The doses of many drugs eliminated through the renal system are based on the patient’s measured or estimated creatinine clearance. Reductions in dosages for drugs eliminated through the renal system (e.g., allopurinol, vancomycin) are needed when the creatinine clearance is reduced (see also Chapter 4).

Pharmacodynamics

Pharmacodynamics refers to the physiological interactions between a drug and the body, specifically, the chemical compounds introduced into the body and receptors on the cell membrane. Receptors are generally specifically configured cellular proteins that, because of their shape and ionic charge, bind to specific chemicals in the medications. The receptor protein has a specific shape that fits the chemical molecule, like a glove to a hand, with complementary ionic charges. When the chemical binds to the receptor, the therapeutic effect is initiated (e.g., nerve conduction and enzyme inhibition).

Drugs are usually similar in configuration to chemicals occurring naturally in the body, such that they bind to the same receptor sites. When a drug binds to the receptor sites, it may initiate the same physiological action as the natural chemical (agonist) or it may simply occupy the receptor sites and, in doing so, block the ability of the body chemical’s usual physiological process (antagonist) depending on desired therapeutic effect. Although the drugs are designed to bind to specific receptor sites for specific purposes, usually they will attach to various other types of receptors as well. The physiological effects that occur as a result of binding to the unplanned types may produce unwanted side effects.

The older a person gets, the more likely he or she will have altered and unreliable pharmacodynamics. Although it is not always possible to explain or predict the alteration, several are known. Those of special note in the elderly are related to drugs with anticholinergic side effects (Box 9-2), which significantly increase the risk for accidental injury and associated with geriatric syndromes. Baroreceptor reflex responses decrease with age. This causes increased susceptibility to positional changes (orthostatic hypotension) and volume changes (dehydration). Age-related increases in sympathetic nervous system activity occur as a result of decreased myocardial sensitivity to catecholamines (e.g., norepinephrine, epinephrine) (Hämmerlein et al., 1998). A decreased responsiveness of the α-adrenergic system results in decreased sensitivity to β-agonists and β-antagonists (β-blockers). Because of the decreased effectiveness of β-blockers and increased sensitivity to diuretics, thiazide diuretics and not β-blockers are recommended for first-line treatment of hypertension in the elderly (Beyth and Shorr, 2007).

BOX 9-2 Potential Anticholinergic Effects

Issues in Medication Use

Polypharmacy

Polypharmacy has been defined in many ways: as simply the use of multiple medications, or as the use of multiple medications for the same problem (Planton and Edlund, 2010). Either way, it is extremely common among older adults and a source of potential morbidity and mortality. Steinman and Hanlon (2010) reported that nearly 20% of community-living adults at least 65 years of age took 10 or more medications, and this number is significantly higher among those living in long-term care settings. In a study of 1002 disabled older women living in the community, 60% were taking at least 5 different medications and almost 12% were taking at least 10, when OTCs and prescription medications were combined (Crentsil et al., 2010). Simple polypharmacy may be necessary if the patient has multiple chronic conditions, even if the provider is following evidence-based guidelines, and especially when no “double-dipping” of medications is possible. Or it may occur unintentionally, especially if an existing drug regimen is not considered when new prescriptions are given, or any number of the thousands of OTC preparations and supplements are added to those prescribed. Polypharmacy is exacerbated by the combination of a high use of specialists and a reluctance of prescribers to discontinue potentially unnecessary drugs that have been prescribed by someone else; therefore treatments are continued longer than necessary (Randall and Bruno, 2006). When communication between patients, nurses, and other health care providers and caregivers becomes fragmented the risk for duplicative medications, inappropriate medications, potentially unsafe dosages, and potentially preventable interactions is accentuated. The two major concerns with polypharmacy are the increased risk for drug interactions and the increased risk for adverse events.

Drug Interactions

The more medications a person takes, either prescribed or OTC, the greater the possibility that one or more of them will interact with each other, a dietary supplement, or other herbal preparation. The more chronic conditions one has, the more likely that a medication for one condition will affect the body in such a way as to influence the other. When two or more medications are given at the same time or closely together, the drugs may potentiate one another (i.e., when given together the drugs have stronger effects than when given alone) or antagonize each other (i.e., when given together one or more of the drugs become ineffective).

Drug–Supplement Interactions

These interactions represent only a small fraction of the many real and potential nutritional supplement–drug interactions. Because of inadequate labeling requirements, drug interactions may not be listed on the product labels of these supplements. Patients, prescribers, and nurses administering medications need to be aware of the potential interactions of the herbal preparation or nutritional supplement used to the extent possible (Table 9-1) (see also Chapter 10).

TABLE 9-1

POTENTIAL INTERACTIONS BETWEEN HERBS AND CONVENTIONAL DRUGS *

HERB	CONVENTIONAL DRUG	COMMENTS
Ginkgo leaf	Acetylsalicylic acid	Ginkgo combined with acetylsalicylic acid,^† rofecoxib,^† or warfarin^† has been associated with bleeding reactions; ginkgo alone has also been associated with bleeding (case reports). Coma was reported in a patient with Alzheimer’s disease who took ginkgo leaf with trazodone^†
	Rofecoxib
	Warfarin
	Trazodone
Hawthorn leaf or flower	Digitalis glycosides	Because hawthorn may exert digitalis-like inotropic effects, it is prudent to monitor persons taking this herb in addition to digitalis glycosides closely
St. John’s wort	5-Aminolevulinic acid	A phototoxic reaction occurred in a patient simultaneously exposed to 5-aminolevulinic acid and St. John’s wort^†; in clinical studies, pretreatment with St. John’s wort decreased the area under the curve for amitriptyline (and its active metabolite nortriptyline), digoxin, indinavir, midazolam, phenprocoumon, and the active metabolite of simvastatin (simvastatin hydroxy acid)^‡; case reports have associated St. John’s wort with reduced levels of cyclosporine (sometimes with transplant rejection), tacrolimus,^† and theophylline^†; with increased oral clearance of nevirapine; and with reduced effects of phenprocoumon^† and warfarin; lethargy and grogginess were reported in a patient taking St. John’s wort and paroxetine,^† and the serotonin syndrome has been reported in users of sertraline (case reports); St. John’s wort alone has been associated with serotonin syndrome-like events (case reports)
	Amitriptyline
	Cyclosporine
	Digoxin
	Indinavir
	Midazolam
	Nevirapine
	Paroxetine
	Phenprocoumon
	Sertraline
	Simvastatin
	Tacrolimus
	Theophylline
	Warfarin
Asian ginseng root	Phenelzine	Mania has been reported in a patient taking ginseng and phenelzine^†; Asian ginseng alone has also been associated with mania^†
	Warfarin	A patient taking ginseng and warfarin had a decreased international normalized ratio^†
Garlic bulb	Ritonavir	Two brief case reports describe gastrointestinal toxic effects in patients taking garlic and ritonavir
	Saquinavir	In a clinical study, the area under the curve for saquinavir decreased by 51% in patients taking garlic for 20 days; it returned to 65% of baseline after a 10-d washout period
	Warfarin	A brief case report described an increased clotting time in two patients taking warfarin and garlic; garlic alone has also been associated with bleeding (case reports)
Kava rhizome	Alprazolam, cimetidine, terazosin	Lethargy and disorientation were reported in a patient receiving this triple-drug regimen^†
Yohimbe bark	Centrally active antihypertensive agents	Yohimbine (a major alkaloid in yohimbe bark) may antagonize guanabenz and the methyldopa metabolite through its α₂-adrenoceptor antagonistic properties
	Tricyclic antidepressants	In clinical studies, tricyclic antidepressants increased the sensitivity to the autonomic and central adverse effects of yohimbine

^*The full version of this table is available from the National Auxiliary Publications Service (NAPS). (See NAPS document no. 05609 for 33 pages of supplementary material. To order, contact NAPS, c/o Microfiche Publications, 248 Hempstead Turnpike, West Hempstead, NY 11552.) Interactions associated with multiple herb therapies are not included. Case reports do not always provide adequate evidence that the remedy in question was labeled correctly. As a result, it is possible that some of the interactions reported for a specific herb were actually due to a different, unidentified botanical or to another adulterant or contaminant.

^†A single case was reported without reference to previous cases.

^‡With the exception of phenprocoumon, these drugs are all substrates for cytochrome P450 3A, P-glycoprotein, or both.

From de Smet PA: Herbal remedies, New England Journal of Medicine 347:2048, 2002.

Drug–Food Interactions

Foods may interact with drugs, producing increased, decreased, or variable effects. Foods can bind to drugs, affecting their absorption. For example, calcium in dairy products will bind levothyroxine, tetracycline, and ciprofloxacin, greatly decreasing their absorption; lovastatin absorption is increased by a high-fat, low-fiber meal. Grapefruit juice contains substances that inhibit CYP3A4-mediated metabolism in the gut (Byrd and Luther, 2010). Blood levels of amiodarone, lovastatin, simvastatin, and buspirone are greatly increased when the drugs are taken on the same day as grapefruit (Greenblatt et al., 2001). Certain foods antagonize the therapeutic action of a drug. The vitamin K in leafy green vegetables antagonizes the anticoagulant effects of warfarin (Burchum, 2011) (Table 9-2). It is recommended that patients taking warfarin ingest a consistent amount of greens to avoid variations in coagulability. Spironolactone, prescribed for end-stage heart failure, increases potassium (K⁺) reabsorption by the renal tubule. If a patient ingests a diet high in potassium (e.g., KCl salt substitute, molasses, oranges, bananas) while taking spironolactone or other potassium-sparing agents, toxic K⁺ levels can quickly occur.

TABLE 9-2

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	Oil-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

From Meiner SE: Gerontologic Nursing, ed 3, St. Louis, MO, 2011, Mosby.

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Nov 6, 2016 | Posted by admin in NURSING | Comments Off

Issues in Medication Use

Polypharmacy

Nurse Key

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Geropharmacology

Geropharmacology

Pharmacokinetics

Absorption

Distribution

Metabolism

Excretion

Pharmacodynamics

Drug Interactions

Drug–Supplement Interactions

Drug–Food Interactions

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