Geriatric Pharmacology

Transcription

1 Geriatric Pharmacology Charles D. Ciccone, PT, PhD, FAPTA INTRODUCTION Physical therapists working with any patient population must be aware of the drug regimen used in each patient. Therapists must have a basic understanding of the beneficial and adverse effects of each medication and must be cognizant of how specific drugs can interact with various rehabilitation procedures. This idea seems especially true for geriatric patients receiving physical therapy. Older adults are generally more sensitive to the adverse effects of drug therapy, and many adverse drug reactions (ADRs) impede the patient s progress and ability to participate in rehabilitation procedures. An adequate understanding of the patient s drug regimen, however, can help physical therapists recognize and deal with these adverse effects as well as capitalize on the beneficial effects of drug therapy in their geriatric patients. The purpose of this lesson is to discuss some of the pertinent aspects of geriatric pharmacology with specifi c emphasis on how drug therapy can affect older individuals receiving physical therapy. This lesson begins by describing the pharmacologic profi le of the geriatric patient, with emphasis on why ADRs tend to occur more commonly in older adults. Specifi c ADRs that commonly occur in the older adult are then discussed. Finally, the benefi cial and adverse effects of specifi c medications are examined, along with how these medications can have an impact on the rehabilitation of older adults. PHARMACOLOGIC PROFILE OF THE GERIATRIC PATIENT Older adults are more likely than younger adults to experience an ADR, and these adverse reactions are typically more severe in older adults. 1 The increased incidence of adverse drug effects in older adults is influenced by two principal factors: the pattern of drug use that occurs in a geriatric population and the altered response to drug therapy in older adults. 2, 3 A number of other contributing factors, such as multiple disease states, lack of proper drug testing, and problems with drug education and compliance also increase the likelihood of adverse effects in older adults. The influence of each of these factors on drug response in older adults is discussed briefly here. Pattern of Drug Use in Older Adults: Problems of Polypharmacy Older adults consume a disproportionately large amount of drugs relative to younger people. 1 Adults older than age 65 years, for example, compose about 13% of the U.S. population, but they receive 34% of all prescription drugs. 3 Given that more and more of the population is reaching advanced age, it seems certain that older adults will continue to receive a disproportionate share of drugs over the next several decades. 3 A logical explanation for this disproportionate drug use is that older adults take more drugs because they suffer more illnesses. 1 Indeed, more than 80% of individuals older than age 65 years suffer from one or more chronic conditions, and drug therapy is often the primary method used to treat these conditions. 3 In a large sample of community-dwelling people age 57 to 85 years, 81% reported using at least one prescription medication, and 29% used at least five prescription medications simultaneously. 4 Drug use in certain older subpopulations is even higher, with nursing home residents and frail older patients often receiving five or more prescription medications each day. 3 Use of nonprescription (over-the-counter) products is also an important factor in geriatric pharmacology, especially among the community-dwelling older adults who have greater access to these products. 4, 5 Older adults therefore rely heavily on various prescription and nonprescription products, and medications are often essential in helping resolve or alleviate some of the illnesses and other medical complications that occur commonly in older adults. A distinction must be made, however, between the reasonable and appropriate use of drugs and the phenomenon of polypharmacy. Although sources may vary somewhat in exactly how they define this term, polypharmacy typically refers to the excessive or inappropriate use of medications. 6 Owing to the extensive use of medications in this population, older adults are often at high risk for polypharmacy. 7, 8 Polypharmacy can be distinguished from a more reasonable drug regimen by the criteria listed in Table 1. Of these criteria, the use of drugs to treat ADRs is especially important. The administration of drugs to treat drug-related reactions often creates a vicious cycle in

2 TABLE 4-1 Characteristic Characteristics of Polypharmacy in Older Adults Use of medications for no apparent reason Use of duplicate medications Concurrent use of interacting medications Use of contraindicated medications Use of inappropriate dosage Use of drug therapy to treat adverse drug reactions Patient improves when medications are discontinued Example Digoxin use in patients who do not exhibit heart failure Simultaneous use of two or three laxatives Simultaneous use of a laxative and an antidiarrheal agent Use of aspirin in bleeding ulcers Failure to use a lower dose of a benzodiazepine sedative-hypnotic Use of antacids to treat aspirin-induced gastric irritation Withdrawal of a sedative-hypnotic results in clearer sensorium ( Adapted from Simonson W: Medications and the Elderly: A Guide for Promoting Proper Use. Rockville, MD: Aspen Publications, ) which additional drugs are used to treat ADRs, thus creating more adverse effects, thereby initiating the use of more drugs, and so on ( Figure 4-1 ). 3, 9 This cycle, known also as a medication cascade effect, can rapidly accelerate until the patient is receiving a dozen or more medications. In addition to the risk of creating the vicious cycle seen in Figure 4-1, there are several obvious drawbacks to polypharmacy in older adults. Because each drug will inevitably produce some adverse effects when used alone, the number of adverse effects will begin to accumulate when several agents are used concurrently. 9 More importantly, the interaction of one drug with another (drug drug interaction) increases the risk of an untoward reaction because of the ability of one agent to modify the effects and metabolism of another drug. If many drugs are administered simultaneously, the risk of ADRs increases exponentially. 9, 10 Other negative aspects of polypharmacy are the risk of decreased patient adherence to the drug regimen 11 and the increased financial burden of using large numbers of unnecessary drugs. 12 Polypharmacy can occur in older adults for a number of reasons. In particular, physicians may rely on drug therapy to accomplish goals that could be achieved More drugs administered Drug side effects seen as symptoms Increased illness in older adults Older adults need/take more drugs Increased risk of side effects FIGURE 1 Vicious cycle of drug administration that can lead to polypharmacy in the older adult. through nonpharmacologic methods; that is, it is often relatively easy to prescribe a medication to resolve a problem in the older adult even though other methods that do not require drugs could be used. For instance, the patient who naps throughout the day will probably not be sleepy at bedtime. It is much easier to administer a sedative-hypnotic agent at bedtime rather than institute activities that keep the patient awake during the day and allow nocturnal sleep to occur naturally. In some cases, the patient may also play a contributing role toward polypharmacy. Patients may obtain prescriptions from various practitioners, thus accumulating a formidable list of prescription medications. Older individuals may receive medications from friends and family members who want to share the benefits of their prescription drugs. Some older adults may also use over-the-counter and self-help remedies to such an extent that these agents interact with one another and with their prescription medications. Polypharmacy can be prevented if the patient s drug regimen is reviewed periodically and any unnecessary or harmful drugs are discontinued. 13, 14 Also, new medications should only be administered if a thorough patient evaluation indicates that the drug is truly needed in that patient. 15 When several physicians are dealing with the same patient, these practitioners should make sure that they communicate with one another regarding the patient s drug regimen. 16 Physical therapists can play a role in preventing polypharmacy by recognizing any changes in the patient s response to drug therapy and helping to correctly identify these changes as drug reactions rather than disease symptoms. In this way, therapists may help prevent the formation of the vicious cycle illustrated in Figure 4-1. Altered Response to Drugs There is little doubt that the response to many drugs is affected by age and that the therapeutic and toxic effects of any medication will be different in an older adult than in a younger individual. Alterations in drug response in older adults can be attributed to differences in the way the body handles the drug (pharmacokinetic changes) as well as differences in the way the drug affects the body

3 (pharmacodynamic changes). 17 The effects of aging on drug pharmacokinetics and pharmacodynamics are discussed briefly here. Pharmacokinetic Changes. Pharmacokinetics is the study of how the body handles a drug, including how the drug is absorbed, distributed, metabolized, and excreted. Several changes in physiological function occur as a result of aging that alter pharmacokinetic variables in older adults. The principal pharmacokinetic changes associated with aging are summarized in Figure 4-2 and are discussed briefly here. The effects of aging on pharmacokinetics has been the subject of extensive research, and the reader is referred to several excellent reviews for more information on this topic Drug Absorption. Several well-documented changes occur in gastrointestinal (GI) function in the older adult that could potentially affect the way drugs are absorbed from the GI tract. Such changes include decreased gastric acid production, decreased gastric emptying, decreased GI blood flow, diminished area of the absorptive surface, and decreased intestinal motility. 18, 20 The effect of these changes on drug absorption, however, is often inconsistent; that is, aging does not appear to significantly alter the absorption of most orally administered drugs. This may be due in part to the fact that the aforementioned changes may offset one another. For instance, factors that tend to decrease absorption (e.g., decreased GI blood flow, decreased absorptive surface area) could be counterbalanced by factors that allow the drug to remain in the gut for longer periods (decreased GI motility), thus allowing more time for absorption. Hence, altered drug absorption does not appear to be a major Drug Administration Absorption Altered gastrointestinal function due to: Gastric acid Stomach emptying Body H 2 O Body fat Hepatic Metabolism Altered due to: Liver mass Liver blood flow Enzyme activity Distribution Altered due to: Absorbing area Motility Lean body mass Plasma proteins Renal Excretion Altered due to: Kidney mass Kidney blood flow Tubular function in nephron FIGURE 2 Summary of the physiological effects of aging that may alter pharmacokinetics in older adults. factor in determining pharmacokinetic changes in older adults. Drug Distribution. After a drug is absorbed into the body, it undergoes distribution to various tissues and body fluid compartments (e.g., vascular system, intracellular fluid, and so forth). Drug distribution may be altered in older adults because of several physiological changes such as decreased total body water, decreased lean body mass, increased percentage body fat, and decreased plasma protein concentrations. 17, 18, 21 Depending on the specifi c drug, these changes can affect how the drug is distributed in the body, thus potentially changing the response to the drug. For instance, drugs that bind to plasma proteins (e.g., aspirin, warfarin) may produce a greater response because there will be less drug bound to plasma proteins and more of the drug will be free to reach the target tissue. Drugs that are soluble in water (e.g., alcohol, morphine) will be relatively more concentrated in the body because there is less body water in which to dissolve the drug. Increased percentages of body fat can act as a reservoir for lipid-soluble drugs, and problems related to drug storage may occur with these agents. Hence, these potential problems in drug distribution must be anticipated, and dosages must be adjusted accordingly in older individuals. Drug Metabolism. The principal role of drug metabolism (biotransformation) is to inactivate drugs and create water-soluble by-products (metabolites) that can be excreted by the kidneys. Although some degree of drug metabolism can occur in tissues throughout the body, the liver is the primary site for metabolism of most medications. Several distinct changes in liver function occur with aging that affect hepatic drug metabolism. The total drug-metabolizing capacity of the liver decreases with age because of a reduction in liver mass, a decline in hepatic blood flow, and decreased activity of drug-metabolizing enzymes. 20, 22 As a result, drugs that undergo inactivation in the liver will remain active for longer periods because of the general decrease in the hepatic metabolizing capacity seen in older adults. Drug Excretion. The kidneys are the primary routes for drug excretion from the body. Drugs reach the kidney in either their active form or as a drug metabolite after biotransformation in the liver. In either case, it is the kidney s responsibility to fi lter the drug from the circulation and excrete it from the body via the urine. With aging, declines in renal blood flow, renal mass, and function of renal tubules result in a reduced ability of the kidneys to excrete drugs and their metabolites. 23, 24 These changes in renal function tend to be one of the most important factors affecting drug pharmacokinetics in older adults, and reduced renal function should be taken into account whenever drugs are prescribed to these individuals. 17, 21 The cumulative effect of the pharmacokinetic changes associated with aging is that drugs and drug metabolites often remain active for longer periods, thus prolonging

4 drug effects and increasing the risk for toxic side effects. This is evidenced by the fact that drug half-life (the time required to eliminate 50% of the drug remaining in the body) is often substantially longer in an older individual versus a younger adult. 25 For example, the half-life of certain medications such as the benzodiazepines (e.g., diazepam [Valium], chlordiazepoxide [Librium]) can be increased as much as fourfold in older adults. 26 Obviously, this represents a dramatic change in the way the older adult s body deals with certain pharmacologic agents. Altered pharmacokinetics in older adults must be anticipated by evaluating changes in body composition (e.g., decreased body water, increased percentages of body fat) and monitoring changes in organ function (e.g., decreased hepatic and renal function) so that drug dosages can be adjusted and ADRs minimized in older 17, 18 individuals. Finally, it should be noted that the age-related pharmacokinetic changes described here vary considerably from person to person within the geriatric population. 19 These changes are, however, considered part of the normal aging process. Any disease or illness that affects drug distribution, metabolism, or excretion will cause an additional change in pharmacokinetic variables, thus further increasing the risk of ADRs in older 20, 23 adults. Pharmacodynamic Changes. Pharmacodynamics is the study of how drugs affect the body, including systemic drug effects as well as cellular and biochemical mechanisms of drug action. Changes in the control of different physiological systems can influence the systemic response to various drugs in older adults. 27, 28 For instance, deficits in the homeostatic control of circulation (e.g., decreased baroreceptor sensitivity, decreased vascular compliance) may change the response of older adults to cardiovascular medications. Other age-related changes, such as impaired postural control, decreased visceral muscle function, altered thermoregulatory responses, and declines in cognitive ability, can alter the pharmacotherapeutic response as well as the potential side effects that may occur when various agents are administered to the older adult. 28 The degree to which systemic drug response is altered will vary depending on the magnitude of these physiological changes in each individual. In addition to these systemic changes, the way a drug affects tissues on a cellular level may be different in the older adult. Most drugs exert their effects by first binding to a receptor that is located on or within specific target cells that are influenced by each type of drug. This receptor is usually coupled in some way to the biochemical machinery of the target cell, so that when the drug binds to the receptor, a biochemical event occurs that changes cell function in a predictable way ( Figure 4-3 ). For instance, binding of epinephrine (adrenaline) to 1- receptors on myocardial cells causes an increase in the activity of certain intracellular enzymes, which in turn causes an increase in heart rate and contractile force. 1 3 Drug Receptor Biochemical event Target cell 2 Coupling mechanism FIGURE 4-3 Potential sites for altered cellular responses in older adults. Changes may occur (1) in drug-receptor affinity, (2) in the coupling of the receptor to an intracellular biochemical event, and (3) in the cell s ability to generate a specific biochemical response. Similar mechanisms can be described for other drugs and their respective cellular receptors. The altered response to certain drugs seen in older adults may be caused by one or more of the cellular changes depicted in Figure 4-3. For instance, alterations in the drug receptor attraction (affinity) could help explain an increase or decrease in the sensitivity of the older adult to various medications. 17, 27 Likewise, changes in the way the receptor is linked or coupled to the cell s internal biochemistry have 29, 30 been noted in certain tissues as a function of aging. Finally, the actual biochemical response within the cell may be blunted because of changes in subcellular structure and function that occur with aging. 27 Age-related declines in mitochondrial function, for example, could infl uence how the cell responds to various medications. 31, 32 Changes in cellular activity, however, vary according to the tissue and the drugs that affect that tissue. Although some tissues might be more sensitive to certain drugs (e.g., increased sensitivity of CNS tissues to psychotropics and opioids), other tissues may be less responsive (e.g., decreased sensitivity of the cardiovascular system to -adrenergic agents). 17 Age-related changes in cellular response must therefore be considered according to each tissue and the specific drugs that affect that tissue. Consequently, pharmacodynamics may be altered in older adults as a result of systemic physiological changes acting in combination with changes in drug responsiveness that occur on a cellular or even subcellular level. These pharmacodynamic changes along with the pharmacokinetic changes discussed earlier help explain why the response of a geriatric individual to drug therapy often differs from the analogous response in a younger individual.

5 Other Factors That Increase the Risk of Adverse Drug Reactions in Older Adults In addition to the pattern of drug use and the altered response to drugs seen in older adults, several other factors may contribute to the increased incidence of ADRs seen in these individuals. Several of these additional factors are presented here. Presence of Multiple Disease States. The fact that older people often suffer from several chronic conditions greatly increases the risk of ADRs. 1 The presence of more than one disease (comorbidity) often necessitates the use of several drugs, thus increasing the risk of drug drug interactions. Even more important is the fact that various diseases and illnesses usually alter the pharmacokinetic and pharmacodynamic variables discussed earlier. For instance, the age-related changes in hepatic metabolism and renal excretion of drugs are affected to an even greater extent if liver or kidney disease is present. Many older patients suffer from diseases that further decrease function in both of these organs as well as cause diminished function in other physiological systems. The involvement of several organ systems, combined with the presence of several different drugs, makes the chance of an ADR almost inevitable in older adult patients with multiple disease states. Lack of Proper Drug Testing and Regulation. The Food and Drug Administration (FDA) is responsible for monitoring the safety and efficacy of all drugs marketed in the United States. The FDA requires all drugs to undergo extensive preclinical (animal) and clinical (human) trials before they receive approval. With regard to older adults, some question has been raised about the evaluation of drugs in geriatric individuals prior to FDA approval. It has been recognized that an adequate number of patients older than age 65 years should be included at various stages of the clinical testing, especially for drugs that are targeted for problems that occur primarily in older adults (e.g., dementia, Parkinson's disease, and so forth). 33 It is unclear, however, whether efforts to increase drug testing in geriatric subjects have been successful in providing improved information about drug safety in older adults. 34, 35 Clinical trials, for example, may lack adequate numbers of older subjects, especially subjects who are older than age 75 years. 36 Additional efforts on the part of the FDA and the drug manufacturing companies may be necessary to help reduce the risk of adverse effects through better drug testing. There also has been concern that many drugs are overprescribed and misused in older adults. This concern seems especially true for certain classes of psychotropic agents (e.g., antipsychotics, sedative-hypnotic agents). 37 Fortunately, efforts have been made to institute government regulations and guidelines that limit the use of these medications. 38 It is hoped that enforcement of existing regulations and development of guidelines for other types of drugs will reduce the incidence of inappropriate drug use in older adults. Problems with Patient Education and Nonadherence to Drug Therapy. Even the most appropriate and wellplanned drug regimen will be useless if the drugs are not taken as directed. Patients may experience an increase in adverse side effects, especially if drugs are taken in excessive doses or for the wrong reason. 39 Conversely, older patients may stop taking their medications, resulting in a lack of therapeutic effects and a possible increase in disease symptoms. The fact that older patients often neglect to take their medications is one of the most common types of drug nonadherence. 39, 40 Many factors can disrupt the older individual s adherence (compliance) to drug therapy. A decline in cognitive function, for example, may impair the older person s ability to understand instructions given by the physician, nurse practitioner, or pharmacist. This can hamper the ability of the geriatric patient to take drugs according to the proper dosing schedule, especially if several medications are being administered, with a different dosing schedule for each medication. 9, 41 Other factors such as poor eyesight may limit the older person s ability to distinguish one pill from another, and arthritic changes may make it difficult to open certain childproof containers. Some patients may fail to adhere to drug therapy because they feel that their medications are simply not effective; that is, they fail to see any obvious benefit from the drugs. 41, 42 The older adult may also stop taking a medication because of an annoying but unavoidable side effect. 40 For instance, older patients with hypertension may refuse to take a diuretic because this particular medication increases urinary output and may necessitate several trips to the bathroom in the middle of the night. To encourage patient self-adherence, it must be realized that these annoying side effects are not trivial and can represent a major source of concern to the patient. Hence, health care professionals should not dismiss these complaints but should make an extra effort to help the patient understand the importance of adhering to the drug regimen whenever such unavoidable side effects are present. Use of Inappropriate Medications. Because of the physiological changes described earlier, certain medications pose an especially high risk for ADRs in older adults. To identify these medications, an expert panel developed criteria and compiled a specific list of medications that should probably be avoided in people older than age 65 years. 43 These criteria and the related list are known commonly as the Beers criteria (or Beers list) because they were created originally by geriatrician Mark Beers. The Beers criteria/list has been updated periodically to indicate medications that should be avoided and thus help improve geriatric prescribing. 44, 45 Hopefully, physicians and pharmacists can refer to this list to avoid use of these drugs in older adults, thereby reducing the risk of serious adverse effects in this population. Additional Factors. Other factors, including poor diet, excessive use of over-the-counter products, cigarette

6 smoking, and consumption of various other substances (e.g., caffeine, alcohol), may help contribute to the increased risk of adverse drug effects in older adults. 3,46-48 These factors must be taken into consideration when a prescription drug program is implemented for older individuals. For instance, it must be realized that the older adult with a protein-defi cient diet may have extremely low plasma protein levels, thus further altering drug pharmacokinetics and increasing the risk of an adverse drug effect. It is therefore important to consider all aspects of the lifestyle and environment of the older adult that may affect drug therapy in these individuals. COMMON ADVERSE DRUG REACTIONS IN OLDER ADULTS An ADR is any unwanted and potentially harmful effect caused by a drug when the drug is given at the recommended dosage. 9 Listed here are some of the more common ADRs that may occur in older adults. Of course, this is not a complete list of all the potential ADRs, but these are some of the responses that physical therapists should be aware of when dealing with geriatric patients in a rehabilitation setting. Gastrointestinal Symptoms Gastrointestinal problems such as nausea, vomiting, diarrhea, and constipation are among the most commonly 49, 50 occurring adverse drug reactions in older adults. These reactions can occur with virtually any medication, and GI symptoms are especially prevalent with certain medications such as the opioid (narcotic) and nonopioid (nonsteroidal anti-infl ammatory drugs [NSAIDs]) analgesics. Although these symptoms are sometimes mild and transient in younger patients, older individuals often require adjustments in the type and dosage of specific medications that cause gastrointestinal problems. Sedation Older adults seem especially susceptible to drowsiness and sleepiness as a side effect of many medications. In particular, drugs that produce sedation as a primary effect (e.g., sedative-hypnotics) as well as drugs with sedative side effects (e.g., opioid analgesics, antipsychotics) will often produce excessive drowsiness in older adults. Confusion Various degrees of confusion ranging from mild disorientation to delirium may occur with a number of medications, such as antidepressants, narcotic analgesics, and drugs with anticholinergic activity. 51, 52 Confusion can also indicate that certain drugs, such as lithium and digoxin, are accumulating and reaching toxic levels in the body. Older individuals who are already somewhat confused may be more susceptible to drugs that tend to further increase confusion. Depression Symptoms of depression (e.g., intense sadness and apathy, as described elsewhere in this text) may be induced in older adults by certain medications. Drugs such as barbiturates, antipsychotics, alcohol, and several antihypertensive agents (e.g., clonidine, reserpine, propranolol) have been implicated in producing depression as an 53, 54 ADR in older adults. Orthostatic Hypotension Orthostatic (postural) hypotension is typically described as a 20-mmHg or greater decline in systolic blood pressure or a 10-mmHg or greater decline in diastolic blood pressure that occurs when an individual assumes a more upright posture (e.g., moving from lying to sitting or from sitting to standing). 55 Owing to the fact that many older adults are relatively sedentary and have diminished cardiovascular function, these individuals tend to be more susceptible to episodes of orthostatic hypotension, even without the influence of drug therapy. 55, 56 A number of medications, however, augment the incidence and severity of this blood pressure decline. 57, 58 In particular, drugs that tend to lower blood pressure (e.g., antihypertensives, antianginal medications) are a common cause of orthostatic hypotension in older adults. Orthostatic hypotension often leads to dizziness and syncope, because blood pressure is too low to provide adequate cerebral perfusion and oxygen delivery to the brain. Hence, orthostatic hypotension may precipitate falls and subsequent injury (e.g., hip fractures, other trauma) in older individuals. 58 Because older patients are especially susceptible to episodes of orthostatic hypotension during certain rehabilitation procedures (e.g., gait training, functional activities), physical therapists should be especially alert for this ADR. Fatigue and Weakness Strength loss and muscular weakness may occur for a number of reasons in response to drug therapy. Some agents, such as the skeletal muscle relaxants, may directly decrease muscle contraction strength, whereas other drugs, such as the diuretics, may affect muscle strength by altering fluid and electrolyte balance. Older individuals who are already debilitated will be more susceptible to strength loss as an ADR. Dizziness and Falls Drug-induced dizziness can be especially detrimental in older adults because of the increased risk of loss of balance and falling. Problems with dizziness result from

7 drugs that produce sedation or from agents that directly affect vestibular function. Examples of such agents include sedatives, antipsychotics, opioid analgesics, and antihistamine drugs Dizziness may also occur secondary to drugs that cause orthostatic hypotension (see previous discussion). Drug-induced dizziness and increased risk of falling may be especially prevalent in older adults who already exhibit balance problems, and physical therapists should be especially alert for these ADRs in these individuals. Anticholinergic Effects Acetylcholine is an important neurotransmitter that controls function in the central nervous system and also affects peripheral organs such as the heart, lungs, and GI tract. A number of drugs exhibit anticholinergic side effects, meaning that these agents tend to diminish the response of various tissues to acetylcholine. In particular, antihistamines, antidepressants, and certain antipsychotics tend to exhibit anticholinergic side effects. Ace-tylcholine affects several diverse physiological systems throughout the body, and drugs with anticholinergic effects are therefore associated with a wide range of ADRs. Drugs with anticholinergic effects may produce central nervous system effects, such as confusion, nervousness, drowsiness, and dizziness. Peripheral anticholinergic effects include dry mouth, constipation, urinary retention, tachycardia, and blurred vision. Older adults seem to be more sensitive to anticholinergic effects, possibly because of the fact that acetylcholine infl uence has already started to diminish as a result of the aging process. In any event, physical therapists should be aware that a rather diverse array of potentially serious ADRs may arise from drugs with anticholinergic properties. Extrapyramidal Symptoms Drugs that produce side effects that mimic extrapyramidal tract lesions are said to exhibit extrapyramidal symptoms. Such symptoms include tardive dyskinesia, pseudoparkinsonism, akathisia, and other dystonias. Antipsychotic medications are commonly associated with an increased risk of extrapyramidal symptoms. The problem of extrapyramidal symptoms as an antipsychotic ADR is presented in more detail later in this lesson. DRUG CLASSES COMMONLY USED IN OLDER ADULTS: IMPACT ON PHYSICAL THERAPY This section provides a brief overview of drug therapy in older adults. Included are some of the more common groups of drugs that are prescribed to older adults. For each group, the principal clinical indication or indications are listed, along with a brief description of the mechanism of action of each type of drug. The primary adverse effects and any specifi c concerns for physical therapy in older patients receiving these drugs are also discussed. Examples of typical drugs found in each of the major groups are indicated in several tables in this section. For additional information about specifi c agents listed here, the reader can refer to one of the sources listed at the end of this lesson Psychotropic Medications Psychotropic drugs include a variety of agents that affect mood, behavior, and other aspects of mental function. As a group, older adults exhibit a high incidence of psychiatric disorders. 65, 66 Psychotropic drugs are therefore commonly used in older individuals and are also associated with a high incidence of adverse effects that can have an impact on rehabilitation. 66 The major groups of psychotropic drugs are listed in Table 4-2, and pertinent aspects of each group are discussed here. Sedative-Hypnotic and Antianxiety Agents. Sedativehypnotic drugs are used to relax the patient and promote a relatively normal state of sleep. Antianxiety drugs are intended to decrease anxiety without producing excessive sedation. Insomnia and disordered sleep may occur in older individuals concomitant to normal aging or in response to medical problems and lifestyle changes that occur with advanced age. 67, 68 Likewise, medical illness, depression, and other aspects of aging may result in increased feelings of fear and apprehension in older adults. 69, 70 Hence, use of sedative-hypnotic and antianxiety drugs is commonly encountered in older adults. Historically, a group of agents known as the benzodiazepines have been the primary drugs used to promote sleep 71, 72 and decrease anxiety in older adults (see Table 4-2 ). Benzodiazepines exert their beneficial effects by increasing the central inhibitory effect of the neurotransmitter -aminobutyric acid (GABA). 73 This increase in GABAmediated inhibition seems to account for the decreased anxiety and increased sleepiness associated with these drugs. Despite their extensive use, benzodiazepines are associated with several problems, especially when administered to older adults. When treating insomnia, for example, residual or hangover effects may occur, producing drowsiness and sluggishness the morning after a sedative-hypnotic is used. These effects seem especially prevalent if a relatively longacting benzodiazepine, such as chlordiazepoxide, diazepam, or flurazepam, is administered to an older patient. 74 Physical therapists should be especially aware of the possibility of residual effects of sedative-hypnotic drugs when scheduling older patients for rehabilitation first thing in the morning. Other potential adverse effects include anterograde amnesia, in which patients have lapses in short-term memory for the period immediately preceding drug administration, and rebound insomnia, in which sleeplessness increases when the drug is discontinued. 74

8 TABLE 2 Common Examples Group Generic Name Trade Name Sedative-Hypnotic Agents Benzodiazepines Estazolam Flurazepam Temazepam Triazolam Others Eszopiclone Ramelteon Zaleplon Zolpidem ProSom Dalmane Restoril Halcion Lunesta Rozerem Sonata Ambien Antianxiety Agents Benzodiazepines Chlordiazepoxide Diazepam Lorazepam Librium Valium Ativan Azapirones Buspirone BuSpar Antidepressants Tricyclics MAO * inhibitors Second-generation agents Antipsychotics Conventional agents Second generation (atypical antipsychotics) * MAO, monoamine oxidase. Psychotropic Drug Groups Amitriptyline Imipramine Isocarboxazid Phenelzine Bupropion Escitalopram Fluoxetine Maprotiline Paroxetine Sertraline Venlafaxine Chlorpromazine Haloperidol Prochlorperazine Thioridazine Clozapine Olanzapine Quetiapine Risperidone Elavil, Endep Norfranil, Tofranil Marplan Nardil Wellbutrin Lexapro Prozac Ludiomil Paxil Zoloft Effexor Thorazine Haldol Compazine Mellaril Clozaril Zyprexa Seroquel Risperdal Use of benzodiazepines to treat sleep disorders can also result in problems associated with addiction if these drugs are used indiscriminately for prolonged periods (4 weeks or longer). 75, 76 These problems include the need to progressively increase dosage to achieve beneficial effects (tolerance) and the onset of withdrawal symptoms when the drug is discontinued (physical dependence). Clearly, benzodiazepines can help the older patient cope with occasional sleep disturbances, but these drugs should be used at the lowest possible dose and for only short periods while trying to fi n d n o n p h a r m a c o l o g i c m e t h o d s ( e. g., c o u n s e l i n g a n d decreased caffeine use) to deal with the patient s insomnia. 72, 76, 77 Benzodiazepines are also associated with specific adverse responses when used to treat anxiety in older adults. As previously described, these agents can cause tolerance and physical dependence when used for prolonged periods. Likewise, sedation and cognitive impairment are possible side effects when benzodiazepines are used to treat anxiety in older adults. 68 Physical therapists should therefore realize that the use of benzodiazepines in older patients is a two-edged sword. Decreased anxiety may enable the patient to be more relaxed and cooperative during rehabilitation, but any benefits will be negated if the patient experiences significant psychomotor slowing and is unable to remain alert during the therapy session. In order to treat insomnia and anxiety more effectively in older adults, several newer strategies have been explored. Regarding sleep disorders, nonbenzodiazepine agents such as eszopiclone, zolpidem, and zaleplon are 72, 78, 79 now available (see Table 4-2 ). Although these newer drugs also affect the GABA receptor, they appear to bind somewhat more selectively to this receptor than the benzodiazepines. Moreover, these newer drugs tend to produce fewer residual effects, such as the hangover effect, and may be less likely to cause tolerance and dependence. 78, 80 In addition, ramelteon (Rozerem) is a drug that stimulates CNS melatonin receptors, and this drug may also be effective in promoting sleep in older adults with less risk of residual effects and addiction. 81, 82 Hence, several new options are now available to treat sleep disorders in older adults, and many patients are being prescribed these newer drugs instead of the more traditional benzodiazepines. Regarding treatment of anxiety, agents known as the azapirones (e.g., buspirone) have been developed. 70 These agents appear to decrease anxiety by directly stimulating serotonin receptors in certain parts of the brain (dorsal raphe nucleus) rather than by increasing GABA-mediated inhibition like the benzodiazepines. 83 More importantly, azapirones such as buspirone do not cause sedation, do not impair cognition and psychomotor function, and appear to have a much lower potential for the patient developing tolerance and physical dependence than traditional agents such as the benzodiazepines. 83 Likewise, certain antidepressants are currently regarded as effective treatments for anxiety disorders in older adults. In particular, antidepressants such as escitalopram and paroxetine selectively affect serotonin activity (see later), and these drugs may also be effective in treating anxiety. 84, 85 Certain patients have symptoms of depression combined with anxiety, and these drugs certainly seem like a good option for these patients. It appears, however, that these antidepressants may also be effective in treating anxiety even in the absence of depression. 70 Treatment of anxiety has therefore evolved to where agents such as the azapirones and certain antidepressants may be used in favor of benzodiazepines. These

9 newer options seem to be better tolerated in older adults and continue to be used increasingly in the treatment of various forms of anxiety in older adults. 70 Antidepressants. Depression is the most common form of mental illness in the general population as well as the most commonly observed mental disorder in older adults. 69, 86 Feelings of intense sadness, hopelessness, and other symptoms may occur in older adults after a specific event (e.g., loss of a spouse, acute illness) or in response to the gradual decline in health and functional status often associated with aging. Drug therapy may be instituted to help resolve these symptoms, along with other nonpharmacologic methods, such as counseling and behavioral therapy. There are several distinct groups of antidepressant medications: tricyclics, monoamine oxidase (MAO) inhibitors, and the newer second-generation drugs (see Table 4-2 ). All antidepressant drugs share a common goal to increase synaptic transmission in central neural pathways that use amine neurotransmitters such as norepinephrine, dopamine, or 5-hydroxytryptamine (serotonin). The rationale is that symptoms of depression are due to an imbalance in the activity of certain central amine neurotransmitter pathways, especially pathways where serotonin receptors regulate dopamine activity in the brain. 87 Drugs that overstimulate these receptors bring about a compensatory decrease (downregulation) in the number of functioning receptors, thereby restoring the balance of amine neurotransmitters in the brain. 88 As receptor sensitivity stabilizes, the clinical symptoms of depression appear to be resolved. A primary focus in treating depression in older adults has been identifying which agents produce the best effects with the least side effects. 89, 90 In the past, tricyclic antidepressants were often the drugs of choice, though these drugs tend to produce anticholinergic and other side effects (see the following discussion). Certain second-generation drugs, however, appear to be as effective as the tricyclics but may be better tolerated in older adults. In particular, agents such as fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) have been advocated as drugs of choice in older adults because they generally have fewer severe side effects than other antidepressants. 89, 91 These agents are known collectively as selective serotonin reuptake inhibitors (SSRIs) because they tend to preferentially affect CNS synapses that use serotonin as a neurotransmitter rather than affect synapses using other amine transmitters, such as norepinephrine or dopamine. Considerable debate still exists, however, and optimal use of SSRIs and other antidepressants in older adults remains under investigation. 89, 92 Antidepressants produce various side effects, depending on the particular type of drug. As indicated earlier, tricyclic antidepressants produce anticholinergic effects and may cause dry mouth, constipation, urinary retention, and central nervous system (CNS) symptoms such as confusion, cognitive impairment, and delirium. Tricyclics also cause sedation and orthostatic hypotension, and these drugs can produce serious cardiotoxic effects after overdose. 93 Monoamine oxidase inhibitors also produce orthostatic hypotension and tend to cause insomnia. Side effects associated with the second-generation drugs vary depending on the specific agent. As previously noted, certain effects that are particularly troublesome in older adults (i.e., sedation, anticholinergic effects, orthostatic hypotension) tend to occur less frequently with the SSRIs. SSRIs, however, have a greater tendency to cause other bothersome effects, such as GI irritation and upper 89, 94 GI bleeding. Physical therapists should be aware that antidepressants may help improve the patient s mood and increase the patient s interest in physical therapy. Certain side effects, however, such as sedation and confusion, may impair the patient s cognitive ability and make it difficult for some older patients to participate actively in rehabilitation procedures. Hence, selection of drugs that minimize these effects may be especially helpful. Therapists should also be aware that some patients may respond fairly rapidly to the antidepressant effects of these drugs; that is, some patients receiving SSRIs experience benefi cial effects within 1 week after beginning drug treatment. 95 Other patients, however, may take 6 or more weeks from the onset of drug therapy until an improvement occurs in the depressive symptoms. This substantial time lag is critical because the patient may actually become more depressed before mood begins to improve. Therapists should therefore look for signs that depression is worsening, especially during the first few weeks of antidepressant drug therapy. A suspected increase in depressive symptoms should be brought to the attention of the appropriate member of the health care team (e.g., physician or psychologist). Treatment of Bipolar Disorder. Bipolar disorder, known also as manic depression, is a form of mental illness characterized by mood swings from an excited, hyperactive state (mania) to periods of apathy and dysphoria (depression). Although the cause of bipolar disorder is unknown, this condition responds fairly well to the drug lithium. It is not exactly clear how lithium prevents episodes of manic depression, but this drug may prevent the excitable, or manic, phase of this disorder, thus stabilizing disposition and preventing the mood swings characteristic of this 96, 97 disease. It is important to be aware of older patients taking lithium to treat manic depression because this drug can rapidly accumulate to toxic levels in these individuals. 98 Lithium is an element and cannot be degraded in the body to an inactive form. The body must therefore rely solely on renal excretion to eliminate this drug. Because renal function is reduced in older adults, the elimination of this drug is often impaired. Accumulation of lithium beyond a certain level results in lithium toxicity. 98 Symptoms of mild lithium toxicity include a metallic taste in

10 the mouth, fi ne hand tremor, nausea, and muscular weakness and fatigue. These symptoms increase as toxicity reaches moderate levels, and other CNS signs such as blurred vision and incoordination may appear. Severe lithium toxicity may cause irreversible cerebellar damage, and prolonged lithium neurotoxicity can lead to 98, 99 coma and even death. Hence, physical therapists working with older patients who are taking lithium must continually be alert for any signs of lithium toxicity. This idea is especially important if there is any change in the patient s health or activity level that might cause an additional compromise in lithium excretion. In addition to lithium, several other medications can be used to help treat bipolar disorder. In particular, antipsychotic medications such as quetiapine and olanzapine can help stabilize mood, especially during the acute manic phase of this disorder. 97 Likewise, aripiprazole (Abilify) is a relatively new antipsychotic that has shown promise in treating acute manic episodes and in the long term or maintenance of bipolar disorder. 100 The neurochemistry of these newer antipsychotics is addressed in the next section. Antipsychotics Antipsychotic medications are often used to help normalize behavior in older adults. Psychosis is the term used to describe the more severe forms of mental illness that are characterized by marked thought disturbances and altered perceptions of reality. 101 Aggressive, disordered behavior may also accompany symptoms of psychosis. In older adults, psychotic-like behavior may occur because of actual psychotic syndromes (e.g., schizophrenia, severe paranoid disorders) or may be associated with various forms of dementia. 101, 102 In any event, antipsychotic drugs may be helpful in improving behavior and compliance in older patients. Further, antipsychotic drugs are often characterized as either conventional or second-generation (atypical) agents (see Table 2 ). Conventional agents have been on the market for some time, and they tend to produce different side effects than the newer, second-generation antipsychotic drugs (see later). Regardless of their classifi cation, these drugs all share a common mechanism in that they impair synaptic transmission in central dopamine pathways. 103 It is theorized that psychosis may be due to increased central dopamine infl uence in cortical and limbic system pathways. Antipsychotic drugs are believed to reduce this dopaminergic infl uence, thus helping to decrease psychotic-like behavior. Some secondgeneration antipsychotics also appear to strongly block serotonin receptors, with a more moderate effect on dopamine receptors. 103, 104 This simultaneous effect on serotonin and dopamine may explain why these newer agents exert antipsychotic effects with less risk of certain side effects (see later). Antipsychotic drugs are associated with several annoying but fairly minor side effects, such as sedation and anticholinergic effects (e.g., dry mouth, constipation). Orthostatic hypotension may also occur, especially within the fi rst few days after drug treatment is initiated. A more serious concern with antipsychotic drugs is the possibility of extrapyramidal side effects. 105, 106 As discussed earlier in this lesson, motor symptoms that mimic lesions in the extrapyramidal tracts are a common ADR associated with these medications, especially in older adults. 105 For instance, patients may exhibit involuntary movements of the face, jaw, and extremities (tardive dyskinesia), symptoms that resemble Parkinson's disease (pseudoparkinsonism), extreme restlessness (akathisia), or other problems with involuntary muscle movements (dystonias). 107 Early recognition of these extrapyramidal signs is important because they may persist long after the antipsychotic drug is discontinued, or these signs may even remain permanently. This fact seems especially true for drug-induced tardive dyskinesia, which may be irreversible if antipsychotic drug therapy is not altered when these symptoms fi rst appear. 106 Fortunately, newer agents such as clozapine and risperidone are less likely to produce extrapyramidal symptoms than older or more conventional agents (see Table 4-2 ). As indicated earlier, these newer drugs are often classifi ed as second-generation or atypical antipsychotics because of their reduced risk of certain side 104 effects. Although tardive dyskinesia and other motor side effects can still occur with newer agents, especially at higher doses, the incidence of these problems 107 is lower than more conventional drugs. Secondgeneration an-tipsychotics, however, may produce other serious problems such as cardiovascular toxicity, weight gain, and metabolic disturbances that resemble diabetes melli 107, 108 tus. The use of antipsychotic drugs may have benefi cial effects on rehabilitation outcomes because patients may become more cooperative and less agitated during physical therapy. Therapists should be especially alert for the onset of any extrapyramidal symptoms because of the potential that these symptoms may result in long-term or permanent motor side effects. Therapists should realize, however, that antipsychotics may sometimes be used inappropriately in older adults. 38, 109 These medications are approved to help control certain psychotic-related symptoms, including behavioral problems such as aggression and severe agitation. These drugs, however, should not be used indiscriminately as tranquilizers to control all unwanted behaviors in older adults. As indicated earlier, government regulations have been instituted to help decrease the inappropriate and unnecessary use of these medications in older adults. 102 Treatment of Dementia. Dementia is a term used to describe a fairly global decline in intellectual function, with marked impairments in cognition, speech, personality, and other skills. 110 Some forms of dementia may be