Alzheimer's Disease: Managing Unique Pharmacotherapy Needs

Background

Alzheimer’s disease (AD) is a form of dementia accounting for approximately 60% to 80% of dementia cases. Although it may affect patients in different ways, it is most commonly associated with a gradual worsening of the ability to remember new information. It is a progressive disorder with treatments that, at best, result in modest improvement. Although it is not a normal part of the aging process, advanced age is the greatest risk factor. As the US population ages, life expectancy increases, and the baby boom generation reaches retirement age, the number of cases of AD is expected to increase from 4.7 million in 2010 to 8.4 million by 2030.¹

Types of Dementia

Although AD is the most common type of dementia, there are other types, and each type is associated with distinct symptom patterns and brain abnormalities. Recent studies show that mixed dementia is more common than previously thought. The most common types and their characteristics are presented in Table 1.¹

Treatment

There are no treatments that stop the progression of AD. Primary goals of treatment should focus on improving the quality of life and maximizing functional performance by enhancing cognition, mood, and behavior. Nonpharmacologic treatment options should be utilized and include activities such as scheduled toileting to help with urinary incontinence, and graded assistance with activities of daily living to promote increased independence. Music, walking, light exercise, family presence, and pet therapy may help patients with problem behaviors.²

Pharmacologic therapy should first focus on optimizing treatment of comorbid conditions and avoiding medications that may impair cognitive function, such as anticholinergic medications, benzodiazepines, and sedatives.³

There are several FDA-approved medications for treatment of AD. These include the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, and the N-methyl-D-aspartate receptor antagonist (NMDA) memantine.²

It is believed that in AD, accumulation of beta-amyloid plaques outside the neurons and accumulation of an abnormal form of the protein tau inside neurons harms information transfer at the synapses in neural tissues. This accumulation harms neuron-to-neuron communication, blocks transport of nutrients to the neuron, and contributes to cell death.¹ This process leads to a loss of cholinergic neurons in the brain and a decreased level of acetylcholine. Acetylcholinesterase inhibitors increase acetylcholine levels in the synapses and boost cholinergic neurotransmission in the forebrain regions to compensate for the loss of functioning brain cells.⁴ They are approved for the treatment of mild or moderate AD, with donepezil also approved for severe AD. Only 10% to 25% of patients taking acetylcholinesterase inhibitors show modest global improvement, but many have less rapid cognitive decline. Side effects include nausea, vomiting, diarrhea, dyspepsia, anorexia, weight loss, leg cramps, bradycardia, syncope, insomnia, and agitation. Adverse effects increase with higher dosages.^1-3

The NMDA memantine is thought to be neuroprotective by preventing excessive glutamate activation of NMDA receptors. It has been shown to have modest efficacy in moderate to severe AD as monotherapy or when combined with donepezil. Side effects include confusion, dizziness, constipation, and headache.^2-3,5 Acute Care Considerations

In 2008, there were 780 hospital stays per 1000 Medicare beneficiaries 65 years and older for patients with dementia compared with 234 hospital stays for those without dementia. The most common reasons for hospitalization include syncope, fall and trauma (26%), ischemic heart disease (17%), gastrointestinal disease (9%), pneumonia (6%), and altered mental status (5%). Average annual per-person payments for inpatient hospital stay in 2008 were $10,748 for Medicare beneficiaries 65 years and older with dementia versus $4321 for those without dementia.¹ Approximately 25% of all hospitalized patients over 75 years have dementia as a secondary diagnosis.⁷ This group of patients represents a significant challenge in managing costs and preventing adverse events during their hospitalization. The pharmacist can play a key role in recognizing medication-related adverse events and preventing future problems.

Syncope

Syncope, fall, and trauma are the most common reasons for hospital admission in dementia patients.¹ It is important to recognize these causes to prevent future occurrences, and the pharmacist should play a role in recognizing any possible medication relationship. The alpha blockers doxazosin, prazosin, and terazosin; tricyclic antidepressants; and the antipsychotic medications chlorpromazine, thioridazine, and olanzapine are associated with an increased risk of orthostatic hypotension and bradycardia, and their avoidance is recommended by the 2012 Beers committee list when syncope is suspected.⁸ In addition, all of the acetylcholinesterase inhibitors can cause syncope, and their discontinuation should be considered if their risks outweigh the marginal benefits observed or the dementia has progressed past the point of additional benefit.² Drugs that increase fall risk include anticonvulsants, antipsychotics, benzodiazepines, nonbenzodiazepine hypnotics, tricyclic antidepressants, and selective serotonin reuptake inhibitors. These medications should also be avoided unless safer alternatives are not available.⁸

Delirium

Delirium and agitation are 2 of the more difficult inpatient complications to treat. Delirium occurs in 11% to 42% of hospitalized patients and can affect patients at any age. However, two-thirds of cases of hospitalized delirium occur in patients with underlying cognitive impairment.⁹ Major surgery has been associated with a 44% incidence of postoperative delirium in elderly patients.¹⁰ Delirium is much easier to prevent than treat. Prevention strategies include removing medications that may cause delirium, such as anticholinergics, narcotic medications, and sedative-hypnotics; correcting electrolyte abnormalities; treating pain; and implementing reorientation strategies that focus on maintaining the sleep-wake cycle.⁹ Treatment strategies should first focus on finding and treating the cause of the delirium, whether it is pain, medications, infection, dehydration, or severe illness.^7,9 Nonpharmacological strategies such as reorientation, use of sitters or volunteers to engage in conversation, spending time out of bed, and exercise should also be attempted. If nonpharmacological approaches fail, pharmacologic treatment may be appropriate. Acute agitation may be treated using low dose risperidone or other atypical antipsychotics.² It is important to note that atypical antipsychotic medications have been associated with an increased risk of death and cerebrovascular events in the treatment of dementia, so their use should ideally be short term and reserved for incidents when the agitation causes the patient to be a danger to themselves or others.^2,11 Benzodiazepines should be avoided due to paradoxical confusion that may worsen the agitation.

Diabetes

Diabetes is a significant coexisting medical condition in hospitalized patients with dementia. In 2009, there were approximately 835 hospital stays per 1000 Medicare beneficiaries with diabetes and dementia versus 474 per 1000 diabetic beneficiaries without dementia.¹ Cross sectional studies have shown an association between hyperglycemia and cognitive dysfunction. There is also emerging evidence regarding the dangers of hypoglycemia in this population. Hypoglycemia has been linked to cognitive dysfunction in a bidirectional fashion. Cognitive impairment increases the subsequent risk of hypoglycemia, and history of severe hypoglycemia has been linked to incidence of dementia.¹² The American Diabetes Association recently published a consensus report regarding treatment of diabetes in older adults with new hemoglobin A1C goals. Patients with mild to moderate cognitive impairment now have a goal A1C of less than 8%, and patients with severe cognitive impairment should have a goal of less than 8.5%.¹² Another issue has been the increased reliance on sliding scale insulin. One study has shown that 83% of long term care residents started on sliding scale insulin were still treated by sliding scale alone 6 months later.¹³ Sliding scale insulin has been shown to increase the risk of hypoglycemia without improvement in hyperglycemia management and should be avoided if possible, regardless of care setting.⁸ The pharmacist should encourage treatment of diabetes with scheduled medications when appropriate and avoid the use of sliding scale insulin as monotherapy in the inpatient setting.

Conclusion

Dementia is a progressive disorder accounting for significant morbidity and health care expenditures. Treatment should be centered on patients’ specific health care goals, taking into consideration other comorbid conditions. The pharmacist is well positioned to provide expert medical advice and treatment regarding initial therapeutic choice and management of dementia’s complications.

J. Ronald Davis, PharmD, is a clinical pharmacy specialist at UNC Health Care and is part of the inpatient geriatrics team on the acute care of the elderly unit at UNC Hospitals

References

1. Alzheimer’s Association. 2014 Alzheimer’s disease facts and figures. Alzheimer’s Dementia. 2014;10:e47-e92.

2. Ruben DB, Herr KA, Pacala JT, Pollack BG, Potter JF, Semla PT, eds. Geriatrics at Your Fingertips. 16th ed. New York, NY: American Geriatrics Society; 2014.

3. American Geriatrics Society. A guide to dementia diagnosis and treatment. American Geriatrics Society website. http://dementia.americangeriatrics.org/. Accessed November 2014.

4. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondzic AM, Vasic VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacolol. 2013;11(3):315-335.

5. Nygaard HB. Current and emerging therapies for Alzheimer’s disease. Clin Ther. 2013;35(10):1480-1489.

6. Namenda XR [package insert]. St Louis, MO: Forest Pharmaceuticals, Inc; 2014.

7. Weitzel T, Robinson S, Barnes MR, et al. The special needs of the hospitalized patient with dementia. Medsurg Nursing. 2011;20(1):13-18.

8. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60(4):616-631.

9. Miller MO. Evaluation and management of delirium in hospitalized older patients. Am Fam Physician. 2008;78(11):1265-1270.

10. Robinson TN, Raeburn CD, Tran ZV, Angles EM, Brenner LA, Moss M. Postoperative delirium in the elderly. Ann Surg. 2009;249(1):173-178.

11. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo controlled trials. JAMA. 2005; 294(15):1934-1943.

12. Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults: a consensus report. J Am Geriatr Soc. 2012;60(12):2342-2356.

13. Pandya N, Thompson S, Sambamoorthi U. The prevalence and persistence of sliding scale insulin use among newly admitted elderly nursing home residents with diabetes mellitus. J Am Med Dir Assoc. 2008;9(9):663-669.