Alzheimer's Disease: Slowing Down the Course

Drs. Barna and Hughes are both clinical assistant professors in the Departmentof Pharmacy Practice and Administration at Ernest Mario School of Pharmacy,Rutgers—The State University of New Jersey in Piscataway, New Jersey.

Alzheimer's disease (AD) is anincurable, irreversible, and progressiveneurologic disease andis the most common cause of dementia.According to the US Census 2000,it was estimated that nearly 4.5 millionAmericans had AD. As the babyboom generation of the United Statesages, the prevalence of this debilitatingdisease, primarily associated withadvancing age, is projected to triple toaffect an estimated 13.2 million individualsby 2050.¹ The National Centerfor Health Statistics data indicate thatAD surpassed diabetes to become thesixth leading cause of death in theUnited States in 2006, with an estimated72,914 Americans succumbingto this disease.² The growing incidenceof AD in the United States representsa mounting public health problem andmandates that clinicians have a strongunderstanding of both the disease andvarious treatment modalities.

Pathophysiology

The current cause of AD is not fullyknown, but the amyloid cascade hypothesisis the leading hypothesis describingthe pathogenesis of AD. It states that animbalance exists between the productionand clearance of â-amyloid peptide(a peptide produced during normal cellmetabolism) in the brain.³ The accumulationof â-amyloid peptide causesdamage to the neurons through multiplemechanisms including inflammation,production of neuritic plaques andneurofibrillary tangles, and neuron toxicitydue to excessive stimulation of theN-methyl-D-aspartate (NMDA) receptorby glutamate. Damage to neurons leadsto the depletion of neurotransmitters,such as acetylcholine, norepinephrine,and serotonin, causing the clinical manifestationsof AD.⁴

AD currently has no cure, and pharmacologictherapy focuses on regulationof neurotransmittors, not on halting orpreventing the underlying cause of thedisease. Therefore, nonpharmacologicbehavioral interventions are the mainstayof therapy for patients and familiesliving with AD. Behavioral modification,simplification of demands and tasks,increased physical activity, and educationand counseling for family membersare important components of a multidisciplinaryapproach to caring for the ADpatient. Pharmacologic interventionscan help to slow the progression of thedisease, reduce symptoms, and improvequality of life. Both therapeutic modalitiesare often used in conjunction witheach other because of the profoundeffects of AD on the patient as well asfamily members and caregivers.

Counseling the Caregiver

Because nonpharmacologic treatmentsare the mainstay of caring for the patientwith AD, the pharmacist plays a pivotalrole in reinforcing important counselingpoints with family members and caregivers.Education for the AD patient'scaregiver has shown to improve caregiversatisfaction, knowledge, and confidence. It also has been known to potentiallydelay nursing home placement,although it has no effect on diseaseseverity or patient outcome.⁵

Behavioral modification strategies,including limiting wardrobe choicesand accessories, encouraging showeringinstead of bathing because of ease,and eliminating unnecessary furniturethat could pose an environmental hazardand increase the patient's risk offall, are important interventions to minimizeharm to the patient. Confrontationand aggression can often be avoided bysimplifying tasks and demands. Brainexercises and increasing physical activitymay increase cerebral blood flowand oxygen consumption, resulting inimprovements in cognition. Ultimately,the caregiver should be reminded thatsudden declines in mentation shouldbe referred to a health care provider formanagement.

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Summary of Pharmacologic Agents Used in the Treatment of Alzheimer's Disease

Agent

Dosage Forms Available

Starting Dose and Schedule

Effective Daily Dose

Titration

Donepezil (Aricept; Aricept ODT)

Tablets; ODT

5-10 mg once daily in the evening with or without food

5-10 mg

5 mg over 4-6 weeks

Galantamine (Razadyne; Razadyne ER)

Tablets and oral solution (immediate release); capsules (ER)

4 mg twice a day with food (immediate release); 8 mg once daily in the morning, preferably with food (ER)

16-24 mg

8 mg every 4 weeks

Rivastigmine (Exelon; Exelon Patch)

Capsules and oral solution; transdermal patch

1.5 mg twice a day (oral formulations); 4.6 mg/24 hours (transdermal patch)

6-12 mg (oral formulations); 9.5 mg (transdermal patch)

3 mg every 2 weeks (oral formulations); 9.5 mg/24 hours after 4 weeks (transdermal patch)

Memantine (Namenda)

Tablets and oral solution

5 mg once a day

5-20 mg

5 mg every week

Medications to Slow DiseaseProgression

The American College of Physiciansand the American Academy of FamilyPhysicians recently published a clinicalpractice guideline with recommendationsfor pharmacologic treatment in theAD patient. The document emphasizesan individualized approach to choosingto initiate pharmacologic therapy, basedon evaluating the patient's benefits andrisks of treatment. Further, because oflimited clinical trial evidence comparingthe efficacy of available therapeuticagents, drug therapy selection shouldbe based on ease of use, adverse effectprofile, patient tolerability, and cost ofmedication.⁶

Cholinesterase Inhibitors

For patients with mild-to-moderate AD,cholinesterase inhibitors are the agentswith the strongest evidence of efficacyin treating cognitive symptoms, accordingto the American Association forGeriatric Psychiatry.⁷ Because a primarypathology of AD is a deficiency in acetylcholine,agents in this category exerttheir pharmacologic effect by inhibitingthe enzyme acetylcholinesterase, reducingthe hydrolysis of acetylcholine andsubsequently increasing levels of acetylcholineavailable in the synaptic space.Four agents in this category have beenapproved by the FDA: tacrine (Cognex),donepezil (Aricept), rivastigmine (Exelon),and galantamine (Razadyne). Nostrong clinical evidence exists indicatingthat one agent is superior in efficacyto another. Due to complex dosing andsafety concerns, however-specificallythe risk of causing hepatoxicity-tacrine is generally not recommendedfor routine use.

Other common side effects associatedwith all of these agents are significantgastrointestinal adverse reactions,including nausea, vomiting, anorexia,and weight loss. To minimize the risk ofthese unwanted side effects, commonstrategies include starting with the lowestdoses, using a slow titration schedule,using alternative dosage forms (ie,transdermal patch), and taking medicationswith food. Refer to the Table for acomparison of available dosage forms,dosing, and titration schedules for thevarious agents.

NMDA Antagonist

Memantine (Namenda) is currently theonly available NMDA antagonist approvedfor the treatment of moderateto-severe AD. Memantine is thought toexert its pharmacologic effect by bindingto glutamate receptors to attenuateglutaminergic excitotoxicity and providesymptomatic improvements in memoryand daily function. Memantine dosinginformation can be found in the Table.Memantine is generally well tolerated,although common side effects includedizziness, headache, hallucinations, confusion,and constipation. Because memantineis not hepatically metabolized, it isunlikely to be associated with significanthepatic drug–drug interactions. Still, cautionshould be taken with concomitantadministration of other medications likelyto have an effect at the NMDA receptor,such as dextromethorphan.

Memantine can be used as monotherapy,or in combination with thecholinesterase inhibitors, to slow theprogression of AD. Results of clinical trialsin patients with moderate-to-severeAD have shown the combination ofmemantine plus cholinesterase inhibitormay have a modest effect on improvingcognition, slowing the decline in activitiesof daily living, and reducing thefrequency of the development of newbehavioral symptoms when comparedwith placebo.⁸ The decision to combineagents of these 2 classes should bepatient specific.

Medications to Control BehavioralSymptoms

Behavioral symptoms, including depression,social withdrawal, and moodchange, occur early in the course ofAD, whereas agitation, irritability, andanxiety become more pronounced asthe disease progresses.⁹ Atypical antipsychoticssuch as olanzapine (Zyprexa)and risperidone (Risperdal) haveshown comparable efficacy in treatingbehavioral symptoms in patientswith AD.¹⁰ These agents are preferredover conventional antipsychotics dueto a lower risk of extrapyramidal sideeffects.⁴ Approximately20% of patientsreceiving olanzapine and risperidonediscontinued treatment, because ofadverse effects, including sedation andextrapyramidal side effects, which mayoffset any benefit of these medications.¹⁰ In addition, current atypical antipsychoticshave a black box warningadvising against using in patients withdementia-related psychosis because of apotential increased risk of death.^11-13

It is important that health care professionalscarefully evaluate the risks andbenefits associated with using antipsychoticmedications in managing patientswith AD. Carbamazepine (Tegretol) andvalproic acid (Depakote) also may beuseful in managing behavioral symptoms.⁴

Selective serotonin reuptake inhibitorsare preferred for the managementof depression in patients with AD.Tricyclic antidepressants have significantanticholinergicadverse effects andshould be avoided.⁹ Short-acting benzodiazepinescan be useful for managingnonpsychosis-related agitation in patientswith AD; however, long-term useshould be avoided due to the potentialfor sedation and impaired cognition.⁹

Conclusion

AD is a growing public health concern.Pharmacists can play an active role incounseling patients and caregivers onrealistic outcome expectations, medicationcosts, and potential adverse effectsfrom both pharmacologic and nonpharmacologictherapies. Pharmacists alsocan proactively identify concomitantmedications that may affect cognitivefunction, such as sedatives and medicationswith anticholinergic adverseeffects, as well as recommend alternativetherapies.

References

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• Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1154-1166.
• Qaseem A, Snow V, Cross JT, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2008;148(5):370-378.
• American Association for Geriatric Psychiatry Web site. AAGP Position Statement: Principles of Care for Patients With Dementia Resulting From Alzheimer Disease. www.aagponline.org/prof/position_caredmnalz.asp. Accessed December 17, 2008.
• Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004;291(3):317-324.
• Beier MT. Treatment strategies for the behavioral symptoms of Alzheimer's Disease: focus on early pharmacologic intervention. Pharmacotherapy. 2007;27(3):399-411.
• Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med. 2006;355(15):1525-1538.
• Zyprexa [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2008.
• Seroquel [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2008.
• Risperdal [prescribing information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2008.