Alzheimer's Disease: Slowing Down the Course

Mary M. Barna, PharmD, and Francis L. Hughes, PharmD, BCPS
Published Online: Sunday, March 1, 2009

Drs. Barna and Hughes are both clinical assistant professors in the Department of 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 an incurable, irreversible, and progressive neurologic disease and is the most common cause of dementia. According to the US Census 2000, it was estimated that nearly 4.5 million Americans had AD. As the baby boom generation of the United States ages, the prevalence of this debilitating disease, primarily associated with advancing age, is projected to triple to affect an estimated 13.2 million individuals by 2050.1 The National Center for Health Statistics data indicate that AD surpassed diabetes to become the sixth leading cause of death in the United States in 2006, with an estimated 72,914 Americans succumbing to this disease.2 The growing incidence of AD in the United States represents a mounting public health problem and mandates that clinicians have a strong understanding of both the disease and various treatment modalities.

Pathophysiology

The current cause of AD is not fully known, but the amyloid cascade hypothesis is the leading hypothesis describing the pathogenesis of AD. It states that an imbalance exists between the production and clearance of â-amyloid peptide (a peptide produced during normal cell metabolism) in the brain.3 The accumulation of â-amyloid peptide causes damage to the neurons through multiple mechanisms including inflammation, production of neuritic plaques and neurofibrillary tangles, and neuron toxicity due to excessive stimulation of the N-methyl-D-aspartate (NMDA) receptor by glutamate. Damage to neurons leads to the depletion of neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, causing the clinical manifestations of AD.4

AD currently has no cure, and pharmacologic therapy focuses on regulation of neurotransmittors, not on halting or preventing the underlying cause of the disease. Therefore, nonpharmacologic behavioral interventions are the mainstay of therapy for patients and families living with AD. Behavioral modification, simplification of demands and tasks, increased physical activity, and education and counseling for family members are important components of a multidisciplinary approach to caring for the AD patient. Pharmacologic interventions can help to slow the progression of the disease, reduce symptoms, and improve quality of life. Both therapeutic modalities are often used in conjunction with each other because of the profound effects of AD on the patient as well as family members and caregivers.

Counseling the Caregiver

Because nonpharmacologic treatments are the mainstay of caring for the patient with AD, the pharmacist plays a pivotal role in reinforcing important counseling points with family members and caregivers. Education for the AD patient's caregiver has shown to improve caregiver satisfaction, knowledge, and confidence. It also has been known to potentially delay nursing home placement, although it has no effect on disease severity or patient outcome.5

Behavioral modification strategies, including limiting wardrobe choices and accessories, encouraging showering instead of bathing because of ease, and eliminating unnecessary furniture that could pose an environmental hazard and increase the patient's risk of fall, are important interventions to minimize harm to the patient. Confrontation and aggression can often be avoided by simplifying tasks and demands. Brain exercises and increasing physical activity may increase cerebral blood flow and oxygen consumption, resulting in improvements in cognition. Ultimately, the caregiver should be reminded that sudden declines in mentation should be referred to a health care provider for management.

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 Disease Progression

The American College of Physicians and the American Academy of Family Physicians recently published a clinical practice guideline with recommendations for pharmacologic treatment in the AD patient. The document emphasizes an individualized approach to choosing to initiate pharmacologic therapy, based on evaluating the patient's benefits and risks of treatment. Further, because of limited clinical trial evidence comparing the efficacy of available therapeutic agents, drug therapy selection should be based on ease of use, adverse effect profile, patient tolerability, and cost of medication.6

Cholinesterase Inhibitors

For patients with mild-to-moderate AD, cholinesterase inhibitors are the agents with the strongest evidence of efficacy in treating cognitive symptoms, according to the American Association for Geriatric Psychiatry.7 Because a primary pathology of AD is a deficiency in acetylcholine, agents in this category exert their pharmacologic effect by inhibiting the enzyme acetylcholinesterase, reducing the hydrolysis of acetylcholine and subsequently increasing levels of acetylcholine available in the synaptic space. Four agents in this category have been approved by the FDA: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). No strong clinical evidence exists indicating that one agent is superior in efficacy to another. Due to complex dosing and safety concerns, however-specifically the risk of causing hepatoxicity- tacrine is generally not recommended for routine use.

Other common side effects associated with all of these agents are significant gastrointestinal adverse reactions, including nausea, vomiting, anorexia, and weight loss. To minimize the risk of these unwanted side effects, common strategies include starting with the lowest doses, using a slow titration schedule, using alternative dosage forms (ie, transdermal patch), and taking medications with food. Refer to the Table for a comparison of available dosage forms, dosing, and titration schedules for the various agents.

NMDA Antagonist

Memantine (Namenda) is currently the only available NMDA antagonist approved for the treatment of moderateto- severe AD. Memantine is thought to exert its pharmacologic effect by binding to glutamate receptors to attenuate glutaminergic excitotoxicity and provide symptomatic improvements in memory and daily function. Memantine dosing information can be found in the Table. Memantine is generally well tolerated, although common side effects include dizziness, headache, hallucinations, confusion, and constipation. Because memantine is not hepatically metabolized, it is unlikely to be associated with significant hepatic drug–drug interactions. Still, caution should be taken with concomitant administration of other medications likely to have an effect at the NMDA receptor, such as dextromethorphan.

Memantine can be used as monotherapy, or in combination with the cholinesterase inhibitors, to slow the progression of AD. Results of clinical trials in patients with moderate-to-severe AD have shown the combination of memantine plus cholinesterase inhibitor may have a modest effect on improving cognition, slowing the decline in activities of daily living, and reducing the frequency of the development of new behavioral symptoms when compared with placebo.8 The decision to combine agents of these 2 classes should be patient specific.

Medications to Control Behavioral Symptoms

Behavioral symptoms, including depression, social withdrawal, and mood change, occur early in the course of AD, whereas agitation, irritability, and anxiety become more pronounced as the disease progresses.9 Atypical antipsychotics such as olanzapine (Zyprexa) and risperidone (Risperdal) have shown comparable efficacy in treating behavioral symptoms in patients with AD.10 These agents are preferred over conventional antipsychotics due to a lower risk of extrapyramidal side effects.4 Approximately 20% of patients receiving olanzapine and risperidone discontinued treatment, because of adverse effects, including sedation and extrapyramidal side effects, which may offset any benefit of these medications. 10 In addition, current atypical antipsychotics have a black box warning advising against using in patients with dementia-related psychosis because of a potential increased risk of death.11-13

It is important that health care professionals carefully evaluate the risks and benefits associated with using antipsychotic medications in managing patients with AD. Carbamazepine (Tegretol) and valproic acid (Depakote) also may be useful in managing behavioral symptoms. 4

Selective serotonin reuptake inhibitors are preferred for the management of depression in patients with AD. Tricyclic antidepressants have significant anticholinergic adverse effects and should be avoided.9 Short-acting benzodiazepines can be useful for managing nonpsychosis-related agitation in patients with AD; however, long-term use should be avoided due to the potential for sedation and impaired cognition.9

Conclusion

AD is a growing public health concern. Pharmacists can play an active role in counseling patients and caregivers on realistic outcome expectations, medication costs, and potential adverse effects from both pharmacologic and nonpharmacologic therapies. Pharmacists also can proactively identify concomitant medications that may affect cognitive function, such as sedatives and medications with anticholinergic adverse effects, as well as recommend alternative therapies.

References

  1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer's disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60(8):1119-1122.
  2. Heron MP, Hoyert DL, Xu J, Scott C, Tejada-Vera B. Deaths: preliminary data for 2006. Natl Vital Stat Rep. 2008;56(16):4.
  3. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet. 2006;368(9533):387-403.
  4. Cummings JL. Alzheimer's disease. N Engl J Med. 2004;351(1):56-67.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Beier MT. Treatment strategies for the behavioral symptoms of Alzheimer's Disease: focus on early pharmacologic intervention. Pharmacotherapy. 2007;27(3):399-411.
  10. 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.
  11. Zyprexa [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2008.
  12. Seroquel [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2008.
  13. Risperdal [prescribing information]. Titusville, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc; 2008.


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