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Update on the Treatment of Alzheimer's Disease
Update on the Treatment of Alzheimer's Disease Drug therapy can ameliorate the behavioral manifestations of this disease. by E. Paul Larrat, MS
Program Preview The care and treatment of individuals afflicted with Alzheimer's disease (AD) have received great attention recently in the health care and lay press. Over the past decade, research efforts have significantly advanced our understanding of the disease process and provided hope for effective treatment of this degenerative illness. This article updates the pharmacist on these recent advances in AD pharmacotherapy, the resources available to health care professionals and family care givers, and future research and treatment strategies for the disease. The primary goal of this continuing education program is to provide the reader with the background necessary to positively influence the therapeutic regimen of the patient with Alzheimer's and to serve as a source of AD and dnlg therapy information.
Introduction
Given these circumstances, the pharmacist can playa critical role in providing effective and appropriate therapy for the AD patient. Successfully filling this role requires an understanding of the course of the disease, the risks and benefits of pharmacologic approaches to therapy, and sources of information and support for health care professionals, patients, and their families.
CE Credit
CE Credit: To obtai:O two (2) hours of continuing education credit for completing "Update on the Treatment of Alzheimer's Disease," complete the assessment exercise and CE registration form and return it to APhA. A certificate will be awarded if you achieve a passing grade of 7oPio or better. Pharmacists completing this article within two years of date of issue can receive credit.
"Update on the Treatment of Alzheimer's Disease" is a selfstudy continuing education program for pharmacists developed by Jhe American Pharmaceutical Association.
There has been an explosion of new knowledge about AD during the past decade. Several research initiatives have resulted in clinical drug trials that provide hope for treatment of the cognitive deficits that characterize the disease. Innovative dnlg and nondrug approaches to addressing behavioral symptoms associated with AD have been introduced. Furthermore, there has been an enhanced public awareness of and concern for the individual and societal impacts of AD. Despite these encouraging developments) medical science has not come up with a cure for this affliction or a clear understanding of its etiology. Pharmacologic treatment of Alzheimer's patients is largely confined to supportive care and amelioration of behavioral manifestations of the disease. The side effects of therapeutic agents used for these purposes often cause more harm than good. Vol. NS32, No. 9 September 1992/743
AMERICAN PHARMACY
The Disease
In the United States, the elderly represent the most rapidly growing segment of society. This growth in the aged population has placed a substantial burden on health care and social support systems because of the increase in the incidence of chronic, degenerative illnesses such as AD. Recent studies indicate that AD afflicts an estimated 10.3% of the population over age 65 and nearly half of those age 85 and older. 1 Twothirds of these individuals remain in a home setting and rely on family and community resources for their care. The cost of health care for an institutionalized AD patient has been estimated at upwards of $2,000 per month. 2 AD was first recognized early in the 20th century by Alois Alzheimer. Often considered a form of "senility," AD is
Table 1
Some Symptoms of Alzheimer's Disease Symptom
Manifestation
Memory loss
• Difficulty remembering names, places, etc. (particularly shortterm memory) • Asking the same question over and over
Disorientation to time and place
• Inability to keep appointments • Loses way even in familiar surroundings
Disorientation to person
• Misidentification of relatives and friends
Visuospatial problems
• Difficulty operating simple appliances • Difficulty finding one's way in a new environment
Language deficits
• Inability to get point across • Failure to initiate conversation • Difficulty following
instructions Calculation
• Inability to handle finances
Poor judgment
• Carelessness • Inappropriate behavior
Confusion
• Misplaces objects
Personality changes
~
Unpredictability
• Impulsive, erratic behavior
Source: Reference 32.
AMERICAN PHARMACY
Aggressiveness, mood swings
marked by an insidious and progressive decline in memory, cognition, and reasoning. Behavioral symptoms are common, with agitation being reported in approximately 80% of AD patients. Depression (40%), delusions (35%), aggression (20%), and hallucinations (16%) occur less frequently.3-6 Visuospatial abnormalities, such as environmental disorientation, have been noted to arise as the disease progresses. 7 The AD patient gradually loses verbal communication skills, as evidenced by decreased ability to relate words to objects and impaired comprehension of their verbal output. 8 Physical debilitation, sleep pattern disnlption, incontinence, and nutritional problems mark the advanced stages of the disease. The Alzheimer's patient eventually becomes bedridden and may die from unrelated causes, such as infection or cardiovascular disease. 2 ,9 Table 1 summarizes the major signs and symptoms of AD. Recent research efforts provide information about the underlying pathophysiology of this illness of dementia. The major morphologic markers of AD include: • Cortical atrophy. • Abnormal accumulation of amyloid protein plaques and aluminum in cerebral tissue. • The formation of neurofibrillary tangles. Biochemical studies indicate substantial decreases in important neurochemicals, largely related to diminished choline acetyltransferase levels. Pharmacologic treatment strategies have concentrated on dnlgs that act to augment these depleted neurochemicals. 1O Although defmitive diagnosis of the disease continues to be made at autopsy, the use of proper antemortem diagnostic criteria has been shown to be reliable 70%-90% of the time. 11 Diagnosis of AD is largely one of exclusion in that the physician attempts to nue out other causes of dementia. 12 These alternative causes of cognitive decline may be reversible or irreversible and may include depreSSion, advanced Parkinson's disease, Huntington's disease, transient ischemic attacks, infectious disease processes, and dnlg intoxication. 13 This last diagnosis is important for pharmacists to consider because many drugs have cognitive side effects and may contribute to producing reversible dementias in the elderly (see Table 2). Often, modification of the medication regimen of an individual suffering from dementia may substantially improve cognitive fimction. 14 Despite recent advances in our knowledge of the disease, the cause of AD has still not been completely elucidated. The following causal theories have been described. The Genetic Model: Individuals afflicted with Down's syndrome, a genetic disease related to an extra copy of chromosome 21, invariably develop symptoms of AD around their third decade of life. Chromosome 21 has also been identified as the site for several genes that regtuate amylOid protein synthesis. There is also evidence that several forms of AD exist, including an autosomal dominant version labeled familial Alzheimer'S disease (FAD). FAD is characterized by an early September 1992/744 Vol. NS32, No.9
onset of symptoms (often before age 50) and by more severe cognitive decline. A ftrst-degree relative of an individual with FAD appears to be at several times greater risk for developing AD than an individual without a family history of the disease. lS The Toxin Model: Several epidemiologic studies have discovered associations between AD and exogenous aluminum, such as that found in water supplies and antiperspirants. Although they have been extensively reported in the lay press, these fmdings remain controversial. At this time, there is little evidence to suggest that the use of aluminum pots, pans, or drinking containers or of aluminum-containing antacids or antiperspirants causes AD. The Trauma Model: Eight studies have investigated head injury (e.g. , from concussions, auto accidents, pugilism) as a causal explanation for AD. Three of these investigations noted a significant association between head traunla and AD; the other five did not confirm this relationship. 16 The Neurochemical Model: As previously mentioned, decreased choline acetyl transferase levels are a biochemical marker of AD. The levels of several other neurochemicals, including norepinephrine, serotonin, and somatostatin, have been observed to be diminished in AD patients. Evidence suggests that these lower levels of neurochemicals result from degenerating neurons. This enzymatic deficiency translates into decreased levels of acetylcholine at the nerve synapse. To date, most of the strategies advanced to treat AD have attempted to augment synaptic acetylcholine through a variety of mechanisms. Other Models: Several alternative causes of AD have been explored in the past, including thyroid disease , abnormal accumulation of cerebral proteins, slow-acting viruses , immlme system alterations, and decreased blood flow to the brain. For the most part, research based on these explanatory models has decreased over the past decade. 17
Table 2
Medications Kno\Nn to Cause Reversible Dementias Alcohol
Lithium carbonate
Anticholinergics
Methyldopa
Antidepressants
Propranolol
Sa rbitu rates
Reserpine
Senzodiazepines
Pharmacologic Treatment Until the late 1970s, AD was thought to be associated with an age-related decrease in blood flow to the brain. Ineffective therapeutic strategies emphasizing vasodilators such as papaverine, nylidrin, and isoxsuprine reflected this fallacious etiologic model. Although our increased lmderstanding of the pathophysiology of the disease has brought about the development of a second generation of therapeutic agents, these efforts to enhance cognitive performance in the Alzheimer's patient have largely been lmsuccessflll. Scientific research in this area has been hampered by poor clinical study design, a lack of reliable measures of disease progression, an incomplete understanding of the disease process, and the unique pharmacokinetic characteristics of the test compolmds. The intensity of research has accelerated recently, as more nmding has become available in both the private and public sectors. Although most research efforts are concentrating on compolmds that enhance cholinergic activity, several drugs with unique mechanisms are being tested. 8,18,19 (fable 3 summarizes the following treatment strategies.)
Cholinergic Enhancers Three distinct groups of cholinergic enhancers are currently in various stages of clinical study, including several in Phase III clinical trials. These include acetylcholine precursors that augment acetylcholine synthesis and release (e.g., choline, lecithin, DuP 996), cholinesterase inhibitors that prevent the breakdown of acetylcholine in the synapse (e.g., physostigmine, tetrahydroaminoacridine [THA, tacrine], velnacrine maleate), and postsynaptic receptor agonists (e.g., bethanechol, arecoline). Some of these compounds have limited use because of their marginal efficacy and variable sideeffect profile. Furthermore, several drugs in this class of cholinergic enhancers either cannot be orally administered or have extremely short half-lives. The Food and Drug Administration is currently reviewing protocols for expanded access to some of the more promising compounds, such as THA and velnacrine maleate, before granting marketing approval. 20 ,21 Recently, THA became the first such product granted expanded access approval.
Phospholipids Some modest improvements in cognitive nlnction have been noted in several European trials of compounds that enhance neural membrane function. One such compound, lecithin, is available in the United States as a nutritional supplement and has been studied concurrently with other cognitive enhancers, with equivocal results.
Source: Reference 33.
Vol. NS32, No.9 September 1992/745
AMERICAN PHARMACY
ACE I"n hibitors During clinical trials that studied the antihypertensive effects of the angiotensin-converting enzyme (ACE) inhibitor, captopril, the mental status of study subjects was noted to have improved. Several large studies now in progress may further elucidate this interesting side effect of the drug.
Calcium Antagonists There is an expanding body of evidence showing that increased calcium influx is intimately involved in the mechanism of brain cell death. Also, altered calcium metabolism has been associated with age-related declines in acetylcholine activity. Modest improvements in cognition have been observed in one study of the calcium antagonist, nimodipine.
Currently, several multicenter studies are exploring this mode of cognitive treatment.
Monoamine Oxidase-B Inhibitors Monoamine oxidase-B acts to catalyze a reaction that deactivates certain neurotransmitters. A by-product of this biochemical process is hydrogen peroxide, a compound thought to be involved in the deterioration of neuronal cells related to AD. The monoamine oxidase-B enzyme is present in higher levels 'in the aged brain. Selegiline acts as a selective inhibitor of monoamine oxidase-B in low doses but appears to be ineffective at higher doses. s Studies involving treatment of Alzheimer's patients with selegiline have noted improvements in the behavioral and cognitive symptoms of AD.
Neuropeptides Table 3
Investigation al R esearch Strategies for A lzheimer's Disease Therapeutic Class
Drugs
Cholinergic enhancers
Choline Phosphatidylcholine (lecithin) DuP 996 Acetylcholine Physostig mine Tacrine (Cognex)
Several neuropeptides, such as adrenocorticotropic hormone, vasopressin, and thyrotropin-releasing hormone, playa role in the release and function of acetylcholine. Although research is ongoing, the practical use of most of these compounds is hampered by their inactivation upon oral administration.
Opioid Antagonist s A recent report on a double-blind, placebo-controlled, multicenter crossover study failed to support previous claims that the opioid antagonist, naloxone, was effective in controlling the cognitive impairment associated with AD. 22
Velnacrine maleate (Mentane) Arecoline
N ootropics
Bethanechol
The only medication labeled for use as a treatment for AD is ergoloid mesylates, a compound thought to improve neuronal metabolism and neurotransmitter activity. The dnlg has been commonly used in elderly and demented elderly populations for many years. Although numerous research efforts have shown favorable results with ergoloid mesylates therapy in AD, recent clinical trials have questioned the compound's efficacy and usefulness. 23 Oxiracetam and piracetam have been extensively studied for their nootropic effects; however, there is little evidence to support their efficacy in the treatment of AD.
Phospholipids
Lecithin
ACE inhibitors
Captopril (Capoten)
Calcium antagonists
Nimodipine (Nimotop) Sabeluzole
Monoamine oxidase-B inhibitors Neuropeptides
Selegiline (Eldepryl) Adrenocorticotropic hormone Vasopressin
Opioid antagonists
Naloxone (Narcan)
Nootropics
Ergoloid mesylates (Hydergine)
Other
Acetyl-L-carnitine (Alcar)
Source: References 4, 8, 18.
AMERICAN PHARMACY
Behavioral Management Since we have yet to develop an effective regimen for treating the pathologic aspects of AD, we must rely on both drug and nondrug approaches for the management of its signs and September 19921746 Vol. NS321, No.9
symptoms. Commonly, therapeutic agents are used to treat the aggression, depression, sleep disturbances, anxiety, and psychotic problems associated with the disease. Although the therapeutic alternatives available for these conditions are numerous, the choice of an optimal agent for the Alzheimer's patient must be made with a clear understanding of therapy goals, the side-effect profile of the medications involved, and the impact of the dnlg on the underlying disease. The goals of behavioral management of the AD patient include the following: • The therapy regimen should alleviate the behavioral manifestations (target symptoms) of AD. Since many of the psychiatric problems associated with AD have signs and symptoms common to other diseases, it is of great importance that an accurate diagnosis of the patient's condition be made by a qualified medical practitioner and that the individual's dnlg regimen be tailored to that diagnosis. • The patient should be kept ambulatory and interactive with his or her environment. Overreliance on regimens that emphasize psychotropic drugs has been associated with a decline in the cognitive and physical health of the AD patient. 24, 25 • Medications that can have a negative impact on the course of AD should be avoided. For example, many of the psychotropic agents commonly used in patients with dementia have potent anticholinergic effects that may cause further depletion of acetylcholine stores; these should be used with caution and care. • The effectiveness of the therapeutic regimen should be assessed on a regular basis and necessary adjustments made. Functional assessment instruments, such as Activities of Daily Living (ADL) scales, may be useful for measuring changes in patient functioning. • N ondrug alternatives and adjunctive supportive therapy should be incorporated into the treatment plan whenever possible. 3
Psychoactive Medications Psychoactive medications used in the elderly patient with dementia may be classified into antipsychotics for the treatment of psychotic symptoms such as paranoia and hallucinations, antidepressants for the treatment of depression, and sedative/hypnotics for the amelioration of sleep disturbances and anxiety. Antipsychotics
The agitated and aggressive behaviors associated with AD are commonly treated with antipsychotic agents. In general, these agents have been fOlmd to be moderately effective in relieving severe behavioral problems such as hostility, aggression, hallucinations, and paranoia. This class of drugs usually does not effectively manage cognitive deficits, nonaggressive verbal behaviors, or pacing and wandering. 3 Since the sideVol. NS32, No.9 September 1992/747
effect profile of these compounds can have a substantial negative influence on the course of the disease, care must be taken in choosing an appropriate agent and in assessing its impact on the patient. The antipsychotic family of drugs can be divided into highpotency and low-potency agents. The high-potency group, which includes haloperidol and thiothixene, generally causes fewer sedation and anticholinergic side effects than the lower potency alternatives. However, the incidence of extrapyramidal symptoms is higher for these drugs and may limit their usefulness. 26 Lower potency antipsychotics, including thioridazine and chlorpromazine, may be beneficial to patients who can tolerate the anticholinergic side effects of these drugs. As a result of pharmacokinetic changes in drug distribution and elimination and changes in receptor sensitivity in the elderly, these patients are at greater risk for the harmful side effects of psychotropic agents. Of special concern is the orthostatic hypotension produced by these drugs, which may result in falls and injury in the frail patient. This is particularly true of the elderly AD patient. Generally, the recommended dose of antipsychotic agents for the older patient is half that used for the nonelderly patient. The AD patient appears to benefit from even lower doses (see Table 4). Since the half-life of these agents may be extended in the elderly, less-frequent dosing may be indicated. Care should be taken to increase or lower the dose slowly. Ideally, the goal is to use the lowest possible dose that provides relief from the target behavioral problems. Frequent reconsideration of the need for drug therapy and regular reassessment of the patient's progression are warranted. Antidepressants
Depression is often an unrecognized and untreated symptom in the AD patient. When carefully used, antidepressants can help mitigate some of the signs and symptoms of depression, such as lethargy, weight loss or gain, social withdrawal, and other mood changes. 3 Antidepressants tend to have long half-lives and are dependent on the liver and kidneys for their metabolism and excretion. Since age-related changes in hepatic and renal function may prolong the action of these agents, the dose range for elderly patients is usually half the usual dose. Laboratory monitoring of plasma drug concentrations may be useful in maintaining an optimal therapy regimen. The dose of the medication should be titrated upward over the course of several weeks and an adequate (six- to eight-week) trial period should be allowed. Side effects of most antidepressants include sedation, cardiac disturbances, orthostatic hypotension, and anticholinergic actions. Tertiary amines, such as amitriptyline, imipramine, trimipramine, and clomipramine, are generally not recommended for treatment of depression in the Alzheimer's patient because these medications tend to cause more severe side effects than the other classes of antidepresAMERICAN PHARMACY
For treatment of anxiety, buspirone represents an alternative for patients who cannot tolerate the side effects of the benzodiazepines. Dosing begins at 5 mg three times a day and may be increased to 10 mg three times a day. 28 When switching a patient from a benzodiazepine to buspirone, a period of a few weeks should be allowed during which both medications are given. This will allow buspirone to reach effective levels before complete discontinuation of the benzodiazepine occurs.29 Alternatives for the treatnlent of sleep disturbances include chloral hydrate, diphenhydramine, and hydroxyzine. The last two agents are generally inappropriate for use in the AD patient because of their potent anticholinergic effects. (See Table 6.)
sants and because of the availability of suitable alternatives. As with the antipsychotic agents, the choice of the appropriate antidepressant should include a consideration of the anticholinergic potential of the drug. Newer compounds, such as trazodone and fluoxetine, exhibit fewer anticholinergic effects. Monoamine oxidase inhibitors, which produce little anticholinergic activity or sedation, may also be an effective alternative to traditional tricyclic antidepressant therapy. (See Table 5). Sedative/Hypnotics
Sleep disturbances and anxiety common to the AD patient are often treated with sedativelhypnotics, especially the benzodiazepines. The side effects of these agents may be particularly troublesome to the elderly patient, and they should be used for short-term therapy only. Since benzodiazepine elimination times are substantially prolonged in the elderly, the use of compounds with short half-lives , such as triazolam , lorazepam, and oxazepam, may be more appropriate. A major concern of the use of these dnlgs in the elderly patient with dementia is their propensity for causing increased confusion and sedation. Antegrade memory loss is more commonly seen when administering benzodiazepines that have a low volume of distribution, i.e. , triazolam, lorazepam, and alprazolam. 27
Nondrug Alternatives The side effects of medications used for the treatment of behavioral symptoms of AD often offset their therapeutic benefits. Recently, there has been an increased recognition of the importance of nondrug treatlnent in modifying behavioral problems. Sleep disturbances often diminish when the patient is kept active during the day. Temporary agitational situations may be resolved by employing distractional techniques with the AD patient. Table 4
Compa rison of Selected Antipsychotic M edicati o n s Drug Parameters
Chlorpromazine
Haloperidol
1,600
100
250
500
800
60
800
50
125
250
400
30
400
15
60
125
Age < 65 Age
~
65
Patients with Dementia
Loxapine
Mesoridazine
Thioridazine
Thiothixene
15
Anticholinergic
++++
+
+++
++++
++++
++
Sedative
+++
++
+++
+++
++++
++
Extrapyramidal
+
+++
++
+
+
+++
Orthostatic Hypotension
++++
++
+++
+++
++++
+
Gilles de la Tourette's syndrome Huntington's disease Organic mental syndrome (including dementia) with behavior symptoms such as • Hallucinations • Delusions • Paranoia • Psychomotor agitation • Hiccups, nausea, vomiting, or pruritus Sources: References 2, 27, 34.
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Many long-term care facilities have taken a more organized approach to caring for the Alzheimer's patient by creating special care units that emphasize activity and behavior modification programs, one-on-one nursing care, and group therapy. These facilities attempt to integrate these programs with the patient's drug therapy regimen in order to maintain the patient at a high fimctional level and to slow the progressive mental decline associated with the disease. This approach has been documented to have a positive impact on patient care and on medication utilization and cost. 14
in the treatment of behavioral problems, experimental treatments for the disease, and referral sources for in-home care. The pharmacist can also playa key role in providing home health care support. Environmental changes in the home that reduce the possibility of injury to the patient should be recommended to the care giver. Since caring for an AD patient is a highly stressful responsibility, the pharmacist should be supportive, patient, and understanding when cOlmseling a family care giver. Unfortunately, the care giver can expect his or her loved one to progressively lose filnction and to eventually require around-the-clock care. The pharmacist must recognize the intense emotional problems and family stresses that are inherent in the care of the AD patient in the home setting and respond in an appropriate and caring manner. In the institutional setting, the pharmacist can take an active part in ensuring effective and rational therapy for the AD patient that minimizes severe side effects and maintains the patient at an optimal level of functioning. Several studies have reinforced the need for more comprehensive education of professional care givers in the area of psychotropic medication;30,31 the pharmacist is well prepared to discharge this responsibility.
The Pharmacist's Role The pharmacist can play an important role in the care and treatment of the AD patient primarily by serving as a source of information, expertise, and support for both family and professional care givers. In community pharmacy practice, the pharmacist should be prepared to provide information to the family of the AD patient about the medication employed
Table 5
Compariso n of Selected A ntidepressant M e d ications Maximum Daily Dose (mg) Medication
Ages 12-64
Age ~65
Side Effects Anticholinergic
Sedative
Antiadrenergic
Amitripty line
300
150
++++++
+++++
+++++
Desipramine
300
150
++
+
+
Doxepin
300
150
+++
++++++
++++
40
20
+
+
+
Nortriptyline
150
75
++
++
+
Trazodone
600
300
+
+++
++++
Fluoxetine
Summary The research and clinical experience of the past decade have provided a wealth of new knowledge about the causes of AD and the treatment of individuals afflicted with this progressive, irreversible illness. Public awareness of the costs of the disease has increased both at a national level and at
Source: References 2, 27, 34.
Table 6
Comparison of Selected Sedative/Hvpnotic Medications Maximum Daily Dose (mg) Medication
Ages 12-64
Alprazolam Chlordiazepoxide Diazepam
4
Age
Drug Profile
~65
Effect Onset
Metabolites
T 1/2 (hr) (nonaged)
2
Intermediate
Active
11-15
100
40
Intermediate
Activ e
6-30
60
20
Ra p id
Act ive
20-50
Lorazepam
6
3
Intermed iate
Inactiv e
10-20
Oxazepam
90
60
Int ermediate
Inact ive
5-1 0
Temazepam
30
15
Intermediate
Inactive
10
Sources: References 2, 27, 28, 34.
Vol. NS32, No.9 September 1992/749
AMERICAN PHARMACY
a family and individual level. Despite these advances, the care and treatment of the AD patient are complex in that the risks of therapy often outweigh benefits. The pharmacist can play a key role by ensuring rational therapy, providing professional support to AD care givers , and serving as a source of information in both the ambulatory and institutional patient settings.
References 1. Evans 0, Fukenstein H, Albert M, et al. Prevalence of Alzheimer's disease in a community population of older persons. JAMA. 1989;
262(18):2551- 6. 2. Kahn N, Stoudemire A. Behavioral and pharmacologic management of patients with Alzheimer's disease. Georgia Med J. 1990;79:287- 94. 3. Jeste 0, Krull A. Behavioral problems associated with dementia: diagnosis and treatment. Geriatrics. 1991;46(11):28-34. 4. Burns A, Jacoby R, Levy R. Psychiat ric phenomena in Alzheimer's disease: I. Disorders of thought content. Br J Psychiatr. 1990;157:72-6. 5. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease: IV. Disorders of behaviour. Br J Psychiatr. 1990;157:86-94.
Sources of Information
6. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease: III. Disorders of mood. Br J Psychiatr. 1990;157:81-6.
Organiz ations
7. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease II. Disorders of perception. Br J Psychiatr. 1990;157:76-81.
Alzheimer 's Association-National (800) 621-0379 Provides information about research efforts, an autopsy network, local chapter contacts, and national intervention and advocacy programs. Alzheimer's Association-Local Chapter In the Yellow Pages of the phone directory under "Associations" A chapter's telephone help line is an excellent resource for local support groups, respite care programs, day care services, homemaker programs, medical referrals, crisis intervention, legal services, and nursing home placements. State or Local Office on Aging In government section of phone directory Provides information and access to many government-sponsored programs, including Medicare, Medicaid, protective services, senior centers, Social Service, and other entitlement programs. Books
Care ofAlzheimer's Patients: A Manualfor Nursing Home Staff, by L. Gwyther. Chicago: American Health Care Association; 1985. Understanding Alzheimer's Disease, by M. Aronson. New York: Charles Scribner's Sons; 1988. Confronting Alzheimer's Disease, by A. Kalicki. Washington, DC: Rynd Communications; 1987. The 36-Hour Day, by N. Mace and P. Rabins. Baltimore: Johns Hopkins University Press; 1981. Periodicals
AD Newsletter (published quarterly, available from the Alzheimer's Association). Journal ofAlzheimer's Disease and Related Dementias, (published six times a year, Prime National Publishing Corp. , Weston, MA, $ 29/year).
8. Theesen K, Boyd J. Dementia of the Alzheimer's type: an update. JAm Soc Consult Pharm. 1990;5(9):535-40. 9. Katzman R. Alzheimer's disease. N Engl J Med. 1986;314:964-73. 10. Giacobini E, Becker R. Present progress and future development in the therapy for Alzheimer's disease. In: Iqbal K, Wisniewski H, Winblad B, eds. Alzheimer's Disease and Related Disorders, vol. 317. New York: Alan R. Liss, Inc; 1988:1121-54. 11. Small G, Greenberg D. Biologic markers, genetics, and Alzheimer's disease. Arch Gen Psychiatr. 1988;45:945-7.
12. McKhann G, Drachman 0, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group. Neurology. 1984;34:939-44. 13. National Institutes of Health. Differential diagnosis of dementing diseases. JAMA. 1987;258(23):3411-6. 14. Larrat E, Anderson J, Laureau M, et al. Alternative care of Alzheimer residents in long-term care facilities: effects on drug use. J Am Soc Consult Pharm. March 1989;4:149-57. 15. Bauwens S. Alzheimer's Disease. Lawrence, Kans: Pharmat, 1987;13:1-14. 16. Rocca W, Amaducci L. The etiology of Alzheimer's disease: an epidemiologic point of view. Neurobiol Aging. 1989;10:440-1. 17. Wurtman RJ. Alzheimer's disease. Sci Am. January 1985;62-87. 18. Levy R. Are drugs targeted at Alzheimer's disease useful? Br Med J. 1990:300:1131-2. 19. Byrne E, Arie T. Insufficient evidence of worthwhile benefit. Br Med J. 1990;300:1132- 3. 20. Hoechst-Roussel willing to make velnacrine available under expanded access. The Pink Sheet. FDC Rep. July 22,1991;53:8. 21. Cognex expanded access availability should await start of new clinical trials, FDA advisory cmte. recommends. The Pink Sheet. FDC Rep. July 22, 1991;53:6-8. 22. Henderson V, Roberts E, Wimer C, et al. Multicenter trial of naloxone in Alzheimer's disease. Ann Neurol. 1989;25:404-6.
23. Thompson T, Filley C, Mitchell W, et al. Lack of efficacy of Hydergine in patients with Alzheimer's disease. N Engl J Med. 1990;323(7):445-8. 24. Beers M, Avorn J, Soumerai S, et al. Psychoactive medication use in intermediate-care facility residents. JAMA. 1988;260:3016-20. 25. Riesenberg D. Drugs in the institutionalized elderly: time to get it right? JAMA. 1988;260:3054. 26. Devanand 0, Sackeim H, Brown R, et al. A pilot study of haloperidol treatment of psychosis and behavioral disturbance in Alzheimer's disease. Arch Neurol. 1989;46:854-7.
27. McDonald W, Ranga Rama Krishnan K. Pharmacologic management of the symptoms of dementia. AFP. 1990;42(1):123-32. 28. Dunagan W, Ridner M. Manual of Medical Therapeutics. Boston: Little, Brown & Co; 1989. 29. Rakel R. Antianxiety agents: how to use them, what to avoid. Consultant. June 1989:75-85. 30. Mace L, Sherman 0, Coons D. Antipsychotic drugs in the nursing home: some evaluative guidelines. Am J Alzheimer's Care. September/October 1990:36-40. 31. Soumerai S. Suboptimal psychoactive medication use in elderly nursing home residents. WeI/come Trends in Pharmacy. March 1989:2- 5. 32. Aronson M. Understanding Alzheimer's Disease. New York: Charles Scribner's Sons; 1988. 33. Fujimoto-Thompson 0 , Shimomura S. Alzheimer's disease (primary
AMERICAN PHARMACY
Septe mber 1992/750 Vol. NS32, No.9
Program Preview The care and treatment of individuals afflicted with Alzheimer's disease (AD) have received great attention recently in the health care and lay press. Over the past decade, research efforts have significantly advanced our understanding of the disease process and provided hope for effective treatment of this degenerative illness. This article updates the pharmacist on these recent advances in AD pharmacotherapy, the resources available to health care professionals and family care givers, and future research and treatment strategies for the disease. The primary goal of this continuing education program is to provide the reader with the background necessary to positively influence the therapeutic regimen of the patient with Alzheimer's and to serve as a source of AD and dnlg therapy information.
Introduction
Given these circumstances, the pharmacist can playa critical role in providing effective and appropriate therapy for the AD patient. Successfully filling this role requires an understanding of the course of the disease, the risks and benefits of pharmacologic approaches to therapy, and sources of information and support for health care professionals, patients, and their families.
CE Credit
CE Credit: To obtai:O two (2) hours of continuing education credit for completing "Update on the Treatment of Alzheimer's Disease," complete the assessment exercise and CE registration form and return it to APhA. A certificate will be awarded if you achieve a passing grade of 7oPio or better. Pharmacists completing this article within two years of date of issue can receive credit.
"Update on the Treatment of Alzheimer's Disease" is a selfstudy continuing education program for pharmacists developed by Jhe American Pharmaceutical Association.
There has been an explosion of new knowledge about AD during the past decade. Several research initiatives have resulted in clinical drug trials that provide hope for treatment of the cognitive deficits that characterize the disease. Innovative dnlg and nondrug approaches to addressing behavioral symptoms associated with AD have been introduced. Furthermore, there has been an enhanced public awareness of and concern for the individual and societal impacts of AD. Despite these encouraging developments) medical science has not come up with a cure for this affliction or a clear understanding of its etiology. Pharmacologic treatment of Alzheimer's patients is largely confined to supportive care and amelioration of behavioral manifestations of the disease. The side effects of therapeutic agents used for these purposes often cause more harm than good. Vol. NS32, No. 9 September 1992/743
AMERICAN PHARMACY
The Disease
In the United States, the elderly represent the most rapidly growing segment of society. This growth in the aged population has placed a substantial burden on health care and social support systems because of the increase in the incidence of chronic, degenerative illnesses such as AD. Recent studies indicate that AD afflicts an estimated 10.3% of the population over age 65 and nearly half of those age 85 and older. 1 Twothirds of these individuals remain in a home setting and rely on family and community resources for their care. The cost of health care for an institutionalized AD patient has been estimated at upwards of $2,000 per month. 2 AD was first recognized early in the 20th century by Alois Alzheimer. Often considered a form of "senility," AD is
Table 1
Some Symptoms of Alzheimer's Disease Symptom
Manifestation
Memory loss
• Difficulty remembering names, places, etc. (particularly shortterm memory) • Asking the same question over and over
Disorientation to time and place
• Inability to keep appointments • Loses way even in familiar surroundings
Disorientation to person
• Misidentification of relatives and friends
Visuospatial problems
• Difficulty operating simple appliances • Difficulty finding one's way in a new environment
Language deficits
• Inability to get point across • Failure to initiate conversation • Difficulty following
instructions Calculation
• Inability to handle finances
Poor judgment
• Carelessness • Inappropriate behavior
Confusion
• Misplaces objects
Personality changes
~
Unpredictability
• Impulsive, erratic behavior
Source: Reference 32.
AMERICAN PHARMACY
Aggressiveness, mood swings
marked by an insidious and progressive decline in memory, cognition, and reasoning. Behavioral symptoms are common, with agitation being reported in approximately 80% of AD patients. Depression (40%), delusions (35%), aggression (20%), and hallucinations (16%) occur less frequently.3-6 Visuospatial abnormalities, such as environmental disorientation, have been noted to arise as the disease progresses. 7 The AD patient gradually loses verbal communication skills, as evidenced by decreased ability to relate words to objects and impaired comprehension of their verbal output. 8 Physical debilitation, sleep pattern disnlption, incontinence, and nutritional problems mark the advanced stages of the disease. The Alzheimer's patient eventually becomes bedridden and may die from unrelated causes, such as infection or cardiovascular disease. 2 ,9 Table 1 summarizes the major signs and symptoms of AD. Recent research efforts provide information about the underlying pathophysiology of this illness of dementia. The major morphologic markers of AD include: • Cortical atrophy. • Abnormal accumulation of amyloid protein plaques and aluminum in cerebral tissue. • The formation of neurofibrillary tangles. Biochemical studies indicate substantial decreases in important neurochemicals, largely related to diminished choline acetyltransferase levels. Pharmacologic treatment strategies have concentrated on dnlgs that act to augment these depleted neurochemicals. 1O Although defmitive diagnosis of the disease continues to be made at autopsy, the use of proper antemortem diagnostic criteria has been shown to be reliable 70%-90% of the time. 11 Diagnosis of AD is largely one of exclusion in that the physician attempts to nue out other causes of dementia. 12 These alternative causes of cognitive decline may be reversible or irreversible and may include depreSSion, advanced Parkinson's disease, Huntington's disease, transient ischemic attacks, infectious disease processes, and dnlg intoxication. 13 This last diagnosis is important for pharmacists to consider because many drugs have cognitive side effects and may contribute to producing reversible dementias in the elderly (see Table 2). Often, modification of the medication regimen of an individual suffering from dementia may substantially improve cognitive fimction. 14 Despite recent advances in our knowledge of the disease, the cause of AD has still not been completely elucidated. The following causal theories have been described. The Genetic Model: Individuals afflicted with Down's syndrome, a genetic disease related to an extra copy of chromosome 21, invariably develop symptoms of AD around their third decade of life. Chromosome 21 has also been identified as the site for several genes that regtuate amylOid protein synthesis. There is also evidence that several forms of AD exist, including an autosomal dominant version labeled familial Alzheimer'S disease (FAD). FAD is characterized by an early September 1992/744 Vol. NS32, No.9
onset of symptoms (often before age 50) and by more severe cognitive decline. A ftrst-degree relative of an individual with FAD appears to be at several times greater risk for developing AD than an individual without a family history of the disease. lS The Toxin Model: Several epidemiologic studies have discovered associations between AD and exogenous aluminum, such as that found in water supplies and antiperspirants. Although they have been extensively reported in the lay press, these fmdings remain controversial. At this time, there is little evidence to suggest that the use of aluminum pots, pans, or drinking containers or of aluminum-containing antacids or antiperspirants causes AD. The Trauma Model: Eight studies have investigated head injury (e.g. , from concussions, auto accidents, pugilism) as a causal explanation for AD. Three of these investigations noted a significant association between head traunla and AD; the other five did not confirm this relationship. 16 The Neurochemical Model: As previously mentioned, decreased choline acetyl transferase levels are a biochemical marker of AD. The levels of several other neurochemicals, including norepinephrine, serotonin, and somatostatin, have been observed to be diminished in AD patients. Evidence suggests that these lower levels of neurochemicals result from degenerating neurons. This enzymatic deficiency translates into decreased levels of acetylcholine at the nerve synapse. To date, most of the strategies advanced to treat AD have attempted to augment synaptic acetylcholine through a variety of mechanisms. Other Models: Several alternative causes of AD have been explored in the past, including thyroid disease , abnormal accumulation of cerebral proteins, slow-acting viruses , immlme system alterations, and decreased blood flow to the brain. For the most part, research based on these explanatory models has decreased over the past decade. 17
Table 2
Medications Kno\Nn to Cause Reversible Dementias Alcohol
Lithium carbonate
Anticholinergics
Methyldopa
Antidepressants
Propranolol
Sa rbitu rates
Reserpine
Senzodiazepines
Pharmacologic Treatment Until the late 1970s, AD was thought to be associated with an age-related decrease in blood flow to the brain. Ineffective therapeutic strategies emphasizing vasodilators such as papaverine, nylidrin, and isoxsuprine reflected this fallacious etiologic model. Although our increased lmderstanding of the pathophysiology of the disease has brought about the development of a second generation of therapeutic agents, these efforts to enhance cognitive performance in the Alzheimer's patient have largely been lmsuccessflll. Scientific research in this area has been hampered by poor clinical study design, a lack of reliable measures of disease progression, an incomplete understanding of the disease process, and the unique pharmacokinetic characteristics of the test compolmds. The intensity of research has accelerated recently, as more nmding has become available in both the private and public sectors. Although most research efforts are concentrating on compolmds that enhance cholinergic activity, several drugs with unique mechanisms are being tested. 8,18,19 (fable 3 summarizes the following treatment strategies.)
Cholinergic Enhancers Three distinct groups of cholinergic enhancers are currently in various stages of clinical study, including several in Phase III clinical trials. These include acetylcholine precursors that augment acetylcholine synthesis and release (e.g., choline, lecithin, DuP 996), cholinesterase inhibitors that prevent the breakdown of acetylcholine in the synapse (e.g., physostigmine, tetrahydroaminoacridine [THA, tacrine], velnacrine maleate), and postsynaptic receptor agonists (e.g., bethanechol, arecoline). Some of these compounds have limited use because of their marginal efficacy and variable sideeffect profile. Furthermore, several drugs in this class of cholinergic enhancers either cannot be orally administered or have extremely short half-lives. The Food and Drug Administration is currently reviewing protocols for expanded access to some of the more promising compounds, such as THA and velnacrine maleate, before granting marketing approval. 20 ,21 Recently, THA became the first such product granted expanded access approval.
Phospholipids Some modest improvements in cognitive nlnction have been noted in several European trials of compounds that enhance neural membrane function. One such compound, lecithin, is available in the United States as a nutritional supplement and has been studied concurrently with other cognitive enhancers, with equivocal results.
Source: Reference 33.
Vol. NS32, No.9 September 1992/745
AMERICAN PHARMACY
ACE I"n hibitors During clinical trials that studied the antihypertensive effects of the angiotensin-converting enzyme (ACE) inhibitor, captopril, the mental status of study subjects was noted to have improved. Several large studies now in progress may further elucidate this interesting side effect of the drug.
Calcium Antagonists There is an expanding body of evidence showing that increased calcium influx is intimately involved in the mechanism of brain cell death. Also, altered calcium metabolism has been associated with age-related declines in acetylcholine activity. Modest improvements in cognition have been observed in one study of the calcium antagonist, nimodipine.
Currently, several multicenter studies are exploring this mode of cognitive treatment.
Monoamine Oxidase-B Inhibitors Monoamine oxidase-B acts to catalyze a reaction that deactivates certain neurotransmitters. A by-product of this biochemical process is hydrogen peroxide, a compound thought to be involved in the deterioration of neuronal cells related to AD. The monoamine oxidase-B enzyme is present in higher levels 'in the aged brain. Selegiline acts as a selective inhibitor of monoamine oxidase-B in low doses but appears to be ineffective at higher doses. s Studies involving treatment of Alzheimer's patients with selegiline have noted improvements in the behavioral and cognitive symptoms of AD.
Neuropeptides Table 3
Investigation al R esearch Strategies for A lzheimer's Disease Therapeutic Class
Drugs
Cholinergic enhancers
Choline Phosphatidylcholine (lecithin) DuP 996 Acetylcholine Physostig mine Tacrine (Cognex)
Several neuropeptides, such as adrenocorticotropic hormone, vasopressin, and thyrotropin-releasing hormone, playa role in the release and function of acetylcholine. Although research is ongoing, the practical use of most of these compounds is hampered by their inactivation upon oral administration.
Opioid Antagonist s A recent report on a double-blind, placebo-controlled, multicenter crossover study failed to support previous claims that the opioid antagonist, naloxone, was effective in controlling the cognitive impairment associated with AD. 22
Velnacrine maleate (Mentane) Arecoline
N ootropics
Bethanechol
The only medication labeled for use as a treatment for AD is ergoloid mesylates, a compound thought to improve neuronal metabolism and neurotransmitter activity. The dnlg has been commonly used in elderly and demented elderly populations for many years. Although numerous research efforts have shown favorable results with ergoloid mesylates therapy in AD, recent clinical trials have questioned the compound's efficacy and usefulness. 23 Oxiracetam and piracetam have been extensively studied for their nootropic effects; however, there is little evidence to support their efficacy in the treatment of AD.
Phospholipids
Lecithin
ACE inhibitors
Captopril (Capoten)
Calcium antagonists
Nimodipine (Nimotop) Sabeluzole
Monoamine oxidase-B inhibitors Neuropeptides
Selegiline (Eldepryl) Adrenocorticotropic hormone Vasopressin
Opioid antagonists
Naloxone (Narcan)
Nootropics
Ergoloid mesylates (Hydergine)
Other
Acetyl-L-carnitine (Alcar)
Source: References 4, 8, 18.
AMERICAN PHARMACY
Behavioral Management Since we have yet to develop an effective regimen for treating the pathologic aspects of AD, we must rely on both drug and nondrug approaches for the management of its signs and September 19921746 Vol. NS321, No.9
symptoms. Commonly, therapeutic agents are used to treat the aggression, depression, sleep disturbances, anxiety, and psychotic problems associated with the disease. Although the therapeutic alternatives available for these conditions are numerous, the choice of an optimal agent for the Alzheimer's patient must be made with a clear understanding of therapy goals, the side-effect profile of the medications involved, and the impact of the dnlg on the underlying disease. The goals of behavioral management of the AD patient include the following: • The therapy regimen should alleviate the behavioral manifestations (target symptoms) of AD. Since many of the psychiatric problems associated with AD have signs and symptoms common to other diseases, it is of great importance that an accurate diagnosis of the patient's condition be made by a qualified medical practitioner and that the individual's dnlg regimen be tailored to that diagnosis. • The patient should be kept ambulatory and interactive with his or her environment. Overreliance on regimens that emphasize psychotropic drugs has been associated with a decline in the cognitive and physical health of the AD patient. 24, 25 • Medications that can have a negative impact on the course of AD should be avoided. For example, many of the psychotropic agents commonly used in patients with dementia have potent anticholinergic effects that may cause further depletion of acetylcholine stores; these should be used with caution and care. • The effectiveness of the therapeutic regimen should be assessed on a regular basis and necessary adjustments made. Functional assessment instruments, such as Activities of Daily Living (ADL) scales, may be useful for measuring changes in patient functioning. • N ondrug alternatives and adjunctive supportive therapy should be incorporated into the treatment plan whenever possible. 3
Psychoactive Medications Psychoactive medications used in the elderly patient with dementia may be classified into antipsychotics for the treatment of psychotic symptoms such as paranoia and hallucinations, antidepressants for the treatment of depression, and sedative/hypnotics for the amelioration of sleep disturbances and anxiety. Antipsychotics
The agitated and aggressive behaviors associated with AD are commonly treated with antipsychotic agents. In general, these agents have been fOlmd to be moderately effective in relieving severe behavioral problems such as hostility, aggression, hallucinations, and paranoia. This class of drugs usually does not effectively manage cognitive deficits, nonaggressive verbal behaviors, or pacing and wandering. 3 Since the sideVol. NS32, No.9 September 1992/747
effect profile of these compounds can have a substantial negative influence on the course of the disease, care must be taken in choosing an appropriate agent and in assessing its impact on the patient. The antipsychotic family of drugs can be divided into highpotency and low-potency agents. The high-potency group, which includes haloperidol and thiothixene, generally causes fewer sedation and anticholinergic side effects than the lower potency alternatives. However, the incidence of extrapyramidal symptoms is higher for these drugs and may limit their usefulness. 26 Lower potency antipsychotics, including thioridazine and chlorpromazine, may be beneficial to patients who can tolerate the anticholinergic side effects of these drugs. As a result of pharmacokinetic changes in drug distribution and elimination and changes in receptor sensitivity in the elderly, these patients are at greater risk for the harmful side effects of psychotropic agents. Of special concern is the orthostatic hypotension produced by these drugs, which may result in falls and injury in the frail patient. This is particularly true of the elderly AD patient. Generally, the recommended dose of antipsychotic agents for the older patient is half that used for the nonelderly patient. The AD patient appears to benefit from even lower doses (see Table 4). Since the half-life of these agents may be extended in the elderly, less-frequent dosing may be indicated. Care should be taken to increase or lower the dose slowly. Ideally, the goal is to use the lowest possible dose that provides relief from the target behavioral problems. Frequent reconsideration of the need for drug therapy and regular reassessment of the patient's progression are warranted. Antidepressants
Depression is often an unrecognized and untreated symptom in the AD patient. When carefully used, antidepressants can help mitigate some of the signs and symptoms of depression, such as lethargy, weight loss or gain, social withdrawal, and other mood changes. 3 Antidepressants tend to have long half-lives and are dependent on the liver and kidneys for their metabolism and excretion. Since age-related changes in hepatic and renal function may prolong the action of these agents, the dose range for elderly patients is usually half the usual dose. Laboratory monitoring of plasma drug concentrations may be useful in maintaining an optimal therapy regimen. The dose of the medication should be titrated upward over the course of several weeks and an adequate (six- to eight-week) trial period should be allowed. Side effects of most antidepressants include sedation, cardiac disturbances, orthostatic hypotension, and anticholinergic actions. Tertiary amines, such as amitriptyline, imipramine, trimipramine, and clomipramine, are generally not recommended for treatment of depression in the Alzheimer's patient because these medications tend to cause more severe side effects than the other classes of antidepresAMERICAN PHARMACY
For treatment of anxiety, buspirone represents an alternative for patients who cannot tolerate the side effects of the benzodiazepines. Dosing begins at 5 mg three times a day and may be increased to 10 mg three times a day. 28 When switching a patient from a benzodiazepine to buspirone, a period of a few weeks should be allowed during which both medications are given. This will allow buspirone to reach effective levels before complete discontinuation of the benzodiazepine occurs.29 Alternatives for the treatnlent of sleep disturbances include chloral hydrate, diphenhydramine, and hydroxyzine. The last two agents are generally inappropriate for use in the AD patient because of their potent anticholinergic effects. (See Table 6.)
sants and because of the availability of suitable alternatives. As with the antipsychotic agents, the choice of the appropriate antidepressant should include a consideration of the anticholinergic potential of the drug. Newer compounds, such as trazodone and fluoxetine, exhibit fewer anticholinergic effects. Monoamine oxidase inhibitors, which produce little anticholinergic activity or sedation, may also be an effective alternative to traditional tricyclic antidepressant therapy. (See Table 5). Sedative/Hypnotics
Sleep disturbances and anxiety common to the AD patient are often treated with sedativelhypnotics, especially the benzodiazepines. The side effects of these agents may be particularly troublesome to the elderly patient, and they should be used for short-term therapy only. Since benzodiazepine elimination times are substantially prolonged in the elderly, the use of compounds with short half-lives , such as triazolam , lorazepam, and oxazepam, may be more appropriate. A major concern of the use of these dnlgs in the elderly patient with dementia is their propensity for causing increased confusion and sedation. Antegrade memory loss is more commonly seen when administering benzodiazepines that have a low volume of distribution, i.e. , triazolam, lorazepam, and alprazolam. 27
Nondrug Alternatives The side effects of medications used for the treatment of behavioral symptoms of AD often offset their therapeutic benefits. Recently, there has been an increased recognition of the importance of nondrug treatlnent in modifying behavioral problems. Sleep disturbances often diminish when the patient is kept active during the day. Temporary agitational situations may be resolved by employing distractional techniques with the AD patient. Table 4
Compa rison of Selected Antipsychotic M edicati o n s Drug Parameters
Chlorpromazine
Haloperidol
1,600
100
250
500
800
60
800
50
125
250
400
30
400
15
60
125
Age < 65 Age
~
65
Patients with Dementia
Loxapine
Mesoridazine
Thioridazine
Thiothixene
15
Anticholinergic
++++
+
+++
++++
++++
++
Sedative
+++
++
+++
+++
++++
++
Extrapyramidal
+
+++
++
+
+
+++
Orthostatic Hypotension
++++
++
+++
+++
++++
+
Gilles de la Tourette's syndrome Huntington's disease Organic mental syndrome (including dementia) with behavior symptoms such as • Hallucinations • Delusions • Paranoia • Psychomotor agitation • Hiccups, nausea, vomiting, or pruritus Sources: References 2, 27, 34.
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September 1992/748 vol. NS32, No. 9
Many long-term care facilities have taken a more organized approach to caring for the Alzheimer's patient by creating special care units that emphasize activity and behavior modification programs, one-on-one nursing care, and group therapy. These facilities attempt to integrate these programs with the patient's drug therapy regimen in order to maintain the patient at a high fimctional level and to slow the progressive mental decline associated with the disease. This approach has been documented to have a positive impact on patient care and on medication utilization and cost. 14
in the treatment of behavioral problems, experimental treatments for the disease, and referral sources for in-home care. The pharmacist can also playa key role in providing home health care support. Environmental changes in the home that reduce the possibility of injury to the patient should be recommended to the care giver. Since caring for an AD patient is a highly stressful responsibility, the pharmacist should be supportive, patient, and understanding when cOlmseling a family care giver. Unfortunately, the care giver can expect his or her loved one to progressively lose filnction and to eventually require around-the-clock care. The pharmacist must recognize the intense emotional problems and family stresses that are inherent in the care of the AD patient in the home setting and respond in an appropriate and caring manner. In the institutional setting, the pharmacist can take an active part in ensuring effective and rational therapy for the AD patient that minimizes severe side effects and maintains the patient at an optimal level of functioning. Several studies have reinforced the need for more comprehensive education of professional care givers in the area of psychotropic medication;30,31 the pharmacist is well prepared to discharge this responsibility.
The Pharmacist's Role The pharmacist can play an important role in the care and treatment of the AD patient primarily by serving as a source of information, expertise, and support for both family and professional care givers. In community pharmacy practice, the pharmacist should be prepared to provide information to the family of the AD patient about the medication employed
Table 5
Compariso n of Selected A ntidepressant M e d ications Maximum Daily Dose (mg) Medication
Ages 12-64
Age ~65
Side Effects Anticholinergic
Sedative
Antiadrenergic
Amitripty line
300
150
++++++
+++++
+++++
Desipramine
300
150
++
+
+
Doxepin
300
150
+++
++++++
++++
40
20
+
+
+
Nortriptyline
150
75
++
++
+
Trazodone
600
300
+
+++
++++
Fluoxetine
Summary The research and clinical experience of the past decade have provided a wealth of new knowledge about the causes of AD and the treatment of individuals afflicted with this progressive, irreversible illness. Public awareness of the costs of the disease has increased both at a national level and at
Source: References 2, 27, 34.
Table 6
Comparison of Selected Sedative/Hvpnotic Medications Maximum Daily Dose (mg) Medication
Ages 12-64
Alprazolam Chlordiazepoxide Diazepam
4
Age
Drug Profile
~65
Effect Onset
Metabolites
T 1/2 (hr) (nonaged)
2
Intermediate
Active
11-15
100
40
Intermediate
Activ e
6-30
60
20
Ra p id
Act ive
20-50
Lorazepam
6
3
Intermed iate
Inactiv e
10-20
Oxazepam
90
60
Int ermediate
Inact ive
5-1 0
Temazepam
30
15
Intermediate
Inactive
10
Sources: References 2, 27, 28, 34.
Vol. NS32, No.9 September 1992/749
AMERICAN PHARMACY
a family and individual level. Despite these advances, the care and treatment of the AD patient are complex in that the risks of therapy often outweigh benefits. The pharmacist can play a key role by ensuring rational therapy, providing professional support to AD care givers , and serving as a source of information in both the ambulatory and institutional patient settings.
References 1. Evans 0, Fukenstein H, Albert M, et al. Prevalence of Alzheimer's disease in a community population of older persons. JAMA. 1989;
262(18):2551- 6. 2. Kahn N, Stoudemire A. Behavioral and pharmacologic management of patients with Alzheimer's disease. Georgia Med J. 1990;79:287- 94. 3. Jeste 0, Krull A. Behavioral problems associated with dementia: diagnosis and treatment. Geriatrics. 1991;46(11):28-34. 4. Burns A, Jacoby R, Levy R. Psychiat ric phenomena in Alzheimer's disease: I. Disorders of thought content. Br J Psychiatr. 1990;157:72-6. 5. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease: IV. Disorders of behaviour. Br J Psychiatr. 1990;157:86-94.
Sources of Information
6. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease: III. Disorders of mood. Br J Psychiatr. 1990;157:81-6.
Organiz ations
7. Burns A, Jacoby R, Levy R. Psychiatric phenomena in Alzheimer's disease II. Disorders of perception. Br J Psychiatr. 1990;157:76-81.
Alzheimer 's Association-National (800) 621-0379 Provides information about research efforts, an autopsy network, local chapter contacts, and national intervention and advocacy programs. Alzheimer's Association-Local Chapter In the Yellow Pages of the phone directory under "Associations" A chapter's telephone help line is an excellent resource for local support groups, respite care programs, day care services, homemaker programs, medical referrals, crisis intervention, legal services, and nursing home placements. State or Local Office on Aging In government section of phone directory Provides information and access to many government-sponsored programs, including Medicare, Medicaid, protective services, senior centers, Social Service, and other entitlement programs. Books
Care ofAlzheimer's Patients: A Manualfor Nursing Home Staff, by L. Gwyther. Chicago: American Health Care Association; 1985. Understanding Alzheimer's Disease, by M. Aronson. New York: Charles Scribner's Sons; 1988. Confronting Alzheimer's Disease, by A. Kalicki. Washington, DC: Rynd Communications; 1987. The 36-Hour Day, by N. Mace and P. Rabins. Baltimore: Johns Hopkins University Press; 1981. Periodicals
AD Newsletter (published quarterly, available from the Alzheimer's Association). Journal ofAlzheimer's Disease and Related Dementias, (published six times a year, Prime National Publishing Corp. , Weston, MA, $ 29/year).
8. Theesen K, Boyd J. Dementia of the Alzheimer's type: an update. JAm Soc Consult Pharm. 1990;5(9):535-40. 9. Katzman R. Alzheimer's disease. N Engl J Med. 1986;314:964-73. 10. Giacobini E, Becker R. Present progress and future development in the therapy for Alzheimer's disease. In: Iqbal K, Wisniewski H, Winblad B, eds. Alzheimer's Disease and Related Disorders, vol. 317. New York: Alan R. Liss, Inc; 1988:1121-54. 11. Small G, Greenberg D. Biologic markers, genetics, and Alzheimer's disease. Arch Gen Psychiatr. 1988;45:945-7.
12. McKhann G, Drachman 0, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group. Neurology. 1984;34:939-44. 13. National Institutes of Health. Differential diagnosis of dementing diseases. JAMA. 1987;258(23):3411-6. 14. Larrat E, Anderson J, Laureau M, et al. Alternative care of Alzheimer residents in long-term care facilities: effects on drug use. J Am Soc Consult Pharm. March 1989;4:149-57. 15. Bauwens S. Alzheimer's Disease. Lawrence, Kans: Pharmat, 1987;13:1-14. 16. Rocca W, Amaducci L. The etiology of Alzheimer's disease: an epidemiologic point of view. Neurobiol Aging. 1989;10:440-1. 17. Wurtman RJ. Alzheimer's disease. Sci Am. January 1985;62-87. 18. Levy R. Are drugs targeted at Alzheimer's disease useful? Br Med J. 1990:300:1131-2. 19. Byrne E, Arie T. Insufficient evidence of worthwhile benefit. Br Med J. 1990;300:1132- 3. 20. Hoechst-Roussel willing to make velnacrine available under expanded access. The Pink Sheet. FDC Rep. July 22,1991;53:8. 21. Cognex expanded access availability should await start of new clinical trials, FDA advisory cmte. recommends. The Pink Sheet. FDC Rep. July 22, 1991;53:6-8. 22. Henderson V, Roberts E, Wimer C, et al. Multicenter trial of naloxone in Alzheimer's disease. Ann Neurol. 1989;25:404-6.
23. Thompson T, Filley C, Mitchell W, et al. Lack of efficacy of Hydergine in patients with Alzheimer's disease. N Engl J Med. 1990;323(7):445-8. 24. Beers M, Avorn J, Soumerai S, et al. Psychoactive medication use in intermediate-care facility residents. JAMA. 1988;260:3016-20. 25. Riesenberg D. Drugs in the institutionalized elderly: time to get it right? JAMA. 1988;260:3054. 26. Devanand 0, Sackeim H, Brown R, et al. A pilot study of haloperidol treatment of psychosis and behavioral disturbance in Alzheimer's disease. Arch Neurol. 1989;46:854-7.
27. McDonald W, Ranga Rama Krishnan K. Pharmacologic management of the symptoms of dementia. AFP. 1990;42(1):123-32. 28. Dunagan W, Ridner M. Manual of Medical Therapeutics. Boston: Little, Brown & Co; 1989. 29. Rakel R. Antianxiety agents: how to use them, what to avoid. Consultant. June 1989:75-85. 30. Mace L, Sherman 0, Coons D. Antipsychotic drugs in the nursing home: some evaluative guidelines. Am J Alzheimer's Care. September/October 1990:36-40. 31. Soumerai S. Suboptimal psychoactive medication use in elderly nursing home residents. WeI/come Trends in Pharmacy. March 1989:2- 5. 32. Aronson M. Understanding Alzheimer's Disease. New York: Charles Scribner's Sons; 1988. 33. Fujimoto-Thompson 0 , Shimomura S. Alzheimer's disease (primary
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