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Pharmacologic Treatment in Alzhaeimer Disease

Pharmacologic Treatment in Alzhaeimer Disease

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TRATAMIENTO FARMACOLÓGICO DE LA ENFERMEDAD DE ALZHEIMER
UNA ACTUALIZACIÓN
TRATAMIENTO FARMACOLÓGICO DE LA ENFERMEDAD DE ALZHEIMER
UNA ACTUALIZACIÓN

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Published by: GUIMEDIC ASOCIACIÓN MÉDICA on Jun 03, 2011
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genetic predisposition and environmentalinfluences is probably responsible.
3
One of these influences may be subclinical ischemia,because patients with high blood pressure andelevated cholesterol levels tend to have anincreased risk for Alzheimer’s disease.
4
Neurofibrillary tangles are made up partly ofa protein called tau,which links togetherto form filaments.The density ofthese fila-ments within neurons in the brain is directly related to the severity ofdementia.It isunclear why tangles form,but different al-leles ofa gene are known to create forms of tau that are more likely to tangle.
3
It is alsounclear whether tangles are linked to plaqueformation.The ultimate effect ofthe tangles,however,is compromise ofmicrotubularfunction,with eventual destruction oftheneuron.Involvement ofcholinergic neurons causeslevels ofacetylcholine within synapses todecline.Levels ofacetylcholinesterase alsodrop,perhaps to compensate for the loss of acetylcholine.Activity ofanother cholin-esterase enzyme (butyrylcholinesterase)increases,and a significant portion ofacetyl-choline is metabolized by this enzyme as thedisease progresses.Eventually,the neuron isdestroyed.
T
he financial and social costs of Alzheimer’s disease are stagger-ing.In the United States,the dis-ease accounts for about $100 bil-lion per year in medical andcustodial expenses,with the average patientrequiring an expenditure ofabout $27,000 per year for medical and nursing care.In addition,80 percent ofcaregivers report stress,andabout 50 percent report depression.
1,2
Thisarticle reviews the pathophysiology of Alzheimer’s disease,evidence for the efficacy ofvarious pharmacologic treatments,andguidelines for the use ofdrug therapy inpatients with this devastating disease.
Pathophysiology
Two microscopic changes occur in the brainin Alzheimer’s disease:senile plaques developbetween neurons,and neurofibrillary tanglesdevelop within neurons.These changes arethought to be intricately related to the cause,development,and course ofthe disease.Researchers have speculated that inflamma-tion around plaques destroys neighboringneurons.Plaques,which are composed of 
-amyloid polypeptides,seem to form as aresult ofdisorders in processing
-amyloidand its precursor protein.A combination of 
Alzheimer’s disease is characterized by the development of senile plaques and neurofibril-lary tangles, which are associated with neuronal destruction, particularly in cholinergic neu-rons. Drugs that inhibit the degradation of acetylcholine within synapses are the mainstayof therapy. Donepezil, rivastigmine, and galantamine are safe but have potentially trouble-some cholinergic side effects, including nausea, anorexia, diarrhea, vomiting, and weightloss. These adverse reactions are often self-limited and can be minimized by slow drug titra-tion. Acetylcholinesterase inhibitors appear to be effective, but the magnitude of benefitmay be greater in clinical trials than in practice. The drugs clearly improve cognition, but evi-dence is less robust for benefits in delaying nursing home placement and improving func-tional ability and behaviors. Benefit for vitamin E or selegiline has been suggested, but sup-porting evidence is not strong. Most guidelines for monitoring drug therapy in patients withAlzheimer’s disease recommend periodic measurements of cognition and functional ability.The guidelines generally advise discontinuing therapy with acetylcholinesterase inhibitorswhen dementia becomes severe. (Am Fam Physician 2003;68:1365-72. Copyright© 2003American Academy of Family Physicians.)
Pharmacologic TreatmentofAlzheimers Disease:An Update
VINCENT W.DELAGARZA,M.D.,West Virginia University School ofMedicine,Morgantown,West Virginia
CLINICAL PHARMACOLOGY
Richard W. Sloan,M.D., R.PH.,coordina-tor of this series, ischairman of theDepartment of Family Medicine at York (Pa.)Hospital and clinical associate professor infamily and community medicine at the Mil-ton S. Hershey Med-ical Center, Pennsylva-nia State University,Hershey, Pa.See page 1241 for definitions of strength-of-evidence levels.
Downloaded from the
 American Family Physician
Web site at www.aafp.org/afp. Copyright© 2003 American Academy ofFamily Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved.
 
Pharmacologic Therapy
While no drug has been shown to completely protectneurons,agents that inhibit the degradation ofacetyl-choline within the synapse are the mainstay oftreatmentfor Alzheimer’s disease.Cholinesterase/acetylcholines-terase inhibitors are the only agents approved by the U.S.Food and Drug Administration for the treatment of Alzheimer’s disease.Other drugs have been studied,buttheir use remains controversial.
ACETYLCHOLINESTERASEINHIBITORS
The cholinesterase inhibitor tacrine (Cognex) is usedrarely because ofpotential liver toxicity and the need forfrequent laboratory monitoring.The acetylcholinesteraseinhibitors donepezil (Aricept),rivastigmine (Exelon),andgalantamine (Reminyl) have been proved effective in clin-ical trials.
Table 1
5-7
compares the pharmacologic charac-teristics ofthe three acetylcholinesterase inhibitors andprovides dosing and cost information.All three drugs have a low incidence ofserious reactions,but they commonly have cholinergic side effects such as nau-sea,anorexia,vomiting,and diarrhea.Tolerance to these sideeffects often develops.However,iftherapy with an acetyl-cholinesterase inhibitor is interrupted for more than severaldays,the drug should be restarted at the lowest dosage andretitrated,because ofrenewed susceptibility to side effects.Instruments that measure cognition,behavior,andfunctional ability have shown that acetylcholinesteraseinhibitors are beneficial in patients with Alzheimer’s dis-ease.While these instruments are discussed in greaterdetail elsewhere,
8
the most commonly used scales are sum-marized in
Table 2
.
9-15
Although clinical trials have shown that treatment withacetylcholinesterase inhibitors delays nursing home place-ment and improves cognition and functional ability,thesebenefits may not apply to all patients with Alzheimer’s dis-ease.For example,patients might be excluded from a studifthey have significant coexisting illnesses with symptomsthat could be confused with drug side effects.Conse-quently,the study population might consist ofpatientswho are more likely to respond to the drug.Nonetheless,it is safe to conclude that patients who tol-erate and respond to acetylcholinesterase inhibitors willexperience modest cognitive improvements.In fact,deteri-oration ofcognition will be delayed by one year in about 20percent oftreated patients (as measured by a seven-pointimprovement on the Alzheimer’s Disease Assessment Scale,Cognitive Section).
5,6,16
[Reference 16—Evidence level A,randomized controlled trial]
Table 3
5-7,16-23
summarizes evi-dence for the benefits ofacetylcholinesterase inhibitors.1366
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Side effects of acetylcholinesterase inhibitorsinclude nausea, anorexia, vomiting, and diarrhea.Tolerance to these side effects often develops.
TABLE 1
Acetylcholinesterase Inhibitors Used in the Treatment of Alzheimer’s Disease
Target MinimumDrugPharmacologic actionsDosagedosage*therapeutic dosage
Cost 
Donepezil Acetylcholinesterase Start at 5 mg once daily, taken at 10 mg once 5 mg daily$142(Aricept)
5
inhibitorbedtime; after 6 weeks, increase dailyto 10 mg once daily.Rivastigmine Acetylcholinesterase Start at 1.5 mg twice daily, taken with 6 mg twice 3 mg twice $134(Exelon)
6
inhibitorfood; at 2-week intervals, increase dailydailyButyrylcholinesterase each dose by 1.5 mg, up to ainhibitordosage of 6 mg twice daily.Galantamine Acetylcholinesterase Start at 4 mg twice daily with food; 12 mg twice 8 mg twice $130(Reminyl)
7
inhibitorat 4-week intervals, increase dailydaily§Nicotinic receptor each dose by 4 mg, up to aactionsdosage of 12 mg twice daily.
*—Manufacturer’s recommendation on the dosage that produces the best results.
—The lowest dosage at which a statistically significant improvement in cognition over placebo was noted.
—Estimated cost to the pharmacist for one month of therapy at the target dosage based on average wholesale prices (rounded to the nearest dollar) in Red book. Montvale, N.J.: Medical Economics Data, 2003. Cost to the patient will be higher, depending on prescription filling fee.
§
—This dosage can be used in patients with moderate hepatic or renal disease; galantamine is not recommended for use in patients with severehepatic or renal disease.Information from references 5 through 7.
 
VITAMINE
Vitamin E,an antioxidant,is thought to mitigate theinflammatory effects ofplaque formation in the brain.Invitro,vitamin E protects nerve cells from the effects of 
-amyloid,but it does not protect against other centralnervous system diseases such as Parkinson’s disease,inwhich oxidation is thought to play a part in neuronaldestruction.
24
The argument for the use ofvitamin E comes from theAlzheimer’s Disease Cooperative Study,
25
which evaluatedthe effects of10 mg ofselegiline once daily and/or 1,000 IUofvitamin E twice daily as treatments for Alzheimer’s dis-ease.The researchers concluded that these agents delayeddisability and nursing home placement but not deteriora-tion ofcognitive function.The study population appearedto be highly selected:the subjects were younger but hadmore severe dementia than control patients and were nottaking psychoactive medication.Consequently,there havebeen questions about whether the results ofthe study areapplicable to a clinical setting.A recent Cochrane review
26
concluded that after adjust-ing for differences between patient groups in theAlzheimer’s Disease Cooperative Study,there was insuffi-cient evidence to recommend vitamin E.The Cochranereview also found weak evidence ofside effects associatedwith the use ofvitamin E.The risks may be higher in thegeneral population,in which many patients withAlzheimer’s disease also have serious coexisting illnesses.
SELEGILINE
A number ofstudies have examined evidence for theuse ofselegiline (Eldepryl),a selective monoamine oxi-dase inhibitor,in the treatment ofAlzheimer’s disease.Most ofthese studies have shown some improvement incognition,behavior,and mood,but little evidence of 
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TABLE 2
Scales Used in the Management of Alzheimer’s Disease
ScalePurposeDescriptionCompletion timeComments
Mini-Mental State Measures cognitionAssesses orientation, 5 to 10 minutesScore decreases about 2 toExamination
9
registration, attention, 3 points per year in patientsrecall, and language with Alzheimer’s disease.on a 30-point scaleRequires minimal training toadminister; useful in clinicalpracticeAlzheimer’s Disease Measures cognitionAssesses cognitive domains 20 to 45 minutesScore decreases by 6 to 12 pointsAssessment Scale, with an 11-item, 70-point per year in patients withCognitive Section
10
scaleAlzheimers disease.Requires significant training toadminister; a research instrumentGlobal Impressions*
11,12
Quantifies an overall Assesses cognitive domains, 10 to 30 minutesRequires a consistent andperception of behavior, and self care on systematic interview at each visitchangea scale of 1 (marked Requires moderate training toimprovement) to 7 (very administer; most useful inmuch worse); often used researchwith caregiver inputNeuropsychiatric Measures disturbed Assesses severity and 10 to 20 minutesUseful in research; in clinicalInventory
13
behaviorsfrequency of 12 symptoms practice, it may be more useful(e.g., agitation, irritability, to use a “global” approach todepression, hallucinations); assess disturbed behaviors.also measures caregiverdistressPhysical Self-Maintenance Measures ability to Assesses six basic tasks and 10 minutesRequires minimal training toScale and Instrumental accomplish basic eight areas of higher administer; useful in clinicalActivities of Daily Living
14
and instrumental functioning on a scale practicetasksof 1 to 5Functional Activities Quantifies disabilityScores functional capacity 5 to 10 minutesEasy to completeQuestionnaire
15
on a scale of 1 (normal)to 7 (severely incapacitated)
*—As measured by the Clinician Interview-Based Impression of Change
11
or the Clinical Global Impression of Change.
12
Information from references 9 through 15.

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