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Alzheimer Dementia: Starting, Stopping Drug Therapy

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Alzheimer Dementia: Starting, Stopping Drug Therapy REVIEW CME CREDIT LUKE D. KIM, MD, FACP, CMD RONAN M. FACTORA, MD, FACP, AGSF Assistant Professor of Medicine, Cleveland Clinic Lerner Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, College of Medicine of Case Western Reserve University, Cleveland, OH; Center for Geriatric Medicine, Medicine Cleveland, OH; Center for Geriatric Medicine, Medicine Institute, Cleveland Clinic Institute, Cleveland Clinic Alzheimer dementia: Starting, stopping drug therapy ABSTRACT lzheimer disease is the most common A form of dementia. In 2016, an estimated Alzheimer disease is the most common type of dementia. 5.2 million Americans age 65 and older had Two classes of cognition-enhancing drugs are approved Alzheimer disease. The prevalence is project- to treat the symptoms, and both have provided modest ed to increase to 13.8 million by 2050, includ- benefi t in clinical trials. Psychotropic drugs are sometimes ing 7 million people age 85 and older.1 used off-label to treat behavioral symptoms of Alzheimer Although no cure for dementia exists, sev- disease. All these medications should be continuously eral cognition-enhancing drugs have been ap- evaluated for clinical effi cacy and, when appropriate, proved by the US Food and Drug Administra- discontinued if the primary benefi t—preservation of cog- tion (FDA) to treat the symptoms of Alzheimer nitive and functional status and a reduction in behaviors dementia. The purpose of these drugs is to associated with dementia—is no longer being achieved. stabilize cognitive and functional status, with a secondary benefi t of potentially reducing be- KEY POINTS havioral problems associated with dementia. In 2016, an estimated 5.2 million Americans age 65 and ■ CURRENTLY APPROVED DRUGS older had Alzheimer disease; by 2050, the prevalence is expected to be 13.8 million. Two classes of drugs are approved to treat Alz- heimer disease: cholinesterase inhibitors and an N-methyl-d-aspartate (NMDA) receptor Cognitive enhancers (cholinesterase inhibitors and an antagonist (Table 1). N-methyl-D-aspartate receptor antagonist) have shown modest effi cacy in preserving cognitive function. Cholinesterase inhibitors The cholinesterase inhibitors act by revers- When evaluating therapy with a cognitive enhancer, prac- ibly binding and inactivating acetylcholines- titioners need to consider the potential adverse effects, terase, consequently increasing the time the neurotransmitter acetylcholine remains in the especially gastrointestinal effects with cholinesterase synaptic cleft. The 3 FDA-approved cholines- inhibitors. terase inhibitors are donepezil, galantamine, and rivastigmine. Tacrine, the fi rst approved Discontinuation should be considered when the demen- cholinesterase inhibitor, was removed from tia reaches the advanced stage and the initial intended the US market after reports of severe hepatic purpose of these drugs is no longer achievable. toxicity.2 The clinical effi cacy of cholinesterase in- hibitors in improving cognitive function has been shown in several randomized controlled trials.3–10 However, benefi ts were generally modest, and some trials used questionable Dr. Factora has disclosed stock ownership in Pfi zer, Inc. methodology, leading experts to challenge the doi:10.3949/ccjm.85a.16080 overall effi cacy of these agents. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 85 • NUMBER 3 MARCH 2018 209 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. ALZHEIMER DRUGS TABLE 1 Cognitive enhancers approved for Alzheimer disease Proprietary name Drug (date approved) Indications Formulations Cholinesterase inhibitors Donepezil Aricept (1996), Mild to moderate Tablets, disintegrating tablets generics available disease (5–10 mg), moderate to severe disease (10–23 mg) Rivastigmine Exelon (2000), Mild to moderate Tablets, oral solution, transdermal patch generics available disease Galantamine Razadyne (2001), Mild to moderate Immediate-release tablets, oral solution, generics available disease extended-release tablets N-methyl-D-aspartate receptor antagonist Memantine Namenda (2003), Moderate to severe Tablets, oral solution generics available disease Combination drug Donepezil + Namzaric (2014), Moderate to severe Extended-release capsules memantine generics available disease All 3 drugs are approved for mild to mod- In December 2014, the FDA approved a No novel drug erate Alzheimer disease (stages 4–6 on the capsule formulation combining donepezil and for Alzheimer Global Deterioration Scale; Table 2)11,12; only memantine to treat symptoms of Alzheimer donepezil is approved for severe Alzheimer dis- dementia. However, no novel pharmacologic disease has ease. Rivastigmine has an added indication for treatment for Alzheimer disease has been ap- been approved treating mild to moderate dementia associated proved since 2003. Furthermore, recently Pfi z- since 2003 with Parkinson disease. Cholinesterase inhibi- er announced a plan to eliminate 300 research tors are often used off-label to treat other forms positions aimed at fi nding new drugs to treat of dementia such as vascular dementia, mixed Alzheimer disease and Parkinson disease.15 dementia, and dementia with Lewy bodies.13 ■ CONSIDERATIONS WHEN STARTING NMDA receptor antagonist COGNITIVE ENHANCERS Memantine, currently the only FDA-approved NMDA receptor antagonist, acts by reducing Cholinesterase inhibitors neuronal calcium ion infl ux and its associated Adverse effects of cholinesterase inhibitors are excitation and toxicity. Memantine is approved generally mild and well tolerated and subside for moderate to severe Alzheimer disease. within 1 to 2 weeks. Gastrointestinal effects are common, primarily diarrhea, nausea, and Combination therapy vomiting. They are transient but can occur in Often, these 2 classes of medications are pre- about 20% of patients (Table 3). scribed in combination. In a randomized con- Other potential adverse effects include trolled trial that added memantine to stable bradycardia, syncope, rhabdomyolysis, neu- doses of donepezil, patients had signifi cantly roleptic malignant syndrome, and esophageal better clinical response on combination ther- rupture. Often, the side-effect profi le helps de- apy than on cholinesterase inhibitor mono- termine which patients are appropriate candi- therapy.14 dates for these medications. 210 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 85 • NUMBER 3 MARCH 2018 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. KIM AND FACTORA TABLE 2 Alzheimer disease: Severity, associated symptoms, and recommended treatment Dementia category Global Deterioration Scale (stages 1–7) Medications Not demented 1 No cognitive impairment No indication for cognitive enhancers 2 Very mild decline: age-associated cognitive impairment 3 Mild cognitive impairment, minor neurocognitive decline Mild dementia 4 Decreased knowledge of current and recent events Cholinesterase inhibitors Decreased ability to travel, handle fi nances, and manage basic activities of daily living Moderate 5 Unable to recall a major relevant aspect of their current life, Cholinesterase inhibitors dementia an address or telephone number of many years, or the names with or without an NMDA of close family members receptor antagonist Basic activities of daily living begin to be impaired Severe dementia 6 Occasionally forgets the name of the spouse or caregiver on whom Cholinesterase inhibitor he or she is entirely dependent (donepezil) with or without an NMDA receptor Unaware of all recent events and experiences in their lives antagonist Most basic activities of daily living impaired Advanced 7 Cannot speak or walk, has incontinence and diffi culty swallowing No randomized controlled dementia trials in stage 7 NMDA = N-methyl-D-aspartate Based on information in references 11 and 12. As expected, higher doses of donepezil (23 Bradycardia risk. Patients with signifi cant mg vs 5–10 mg) are associated with higher bradycardia or who are taking medications rates of nausea, diarrhea, and vomiting. that lower the heart rate may experience a Dosing. The cholinesterase inhibitors worsening of their bradycardia or associated should be slowly titrated to minimize side ef- symptoms if they take a cholinesterase inhibi- fects. Starting at the lowest dose and main- tor. Syncope from bradycardia is a signifi cant taining it for 4 weeks allows suffi cient time for concern, especially in patients already at risk transient side effects to abate. Some patients of falls or fracture due to osteoporosis. may require a longer titration period. As the dose is escalated, the probability of NMDA receptor antagonist side effects may increase. If they do not sub- The side-effect profi le of memantine is gener- side, dose reduction with maintenance at the ally more favorable than that of cholinesterase next lower dose is appropriate. inhibitors. In clinical trials, it has been bet- Gastrointestinal effects. Given the ad- ter tolerated with fewer adverse effects than verse gastrointestinal effects associated with placebo, with the exception of an increased this class of medications, patients experienc- incidence of dizziness, confusion, and delu- ing signifi cant anorexia and weight loss should sions.16,17 generally avoid cholinesterase inhibitors. Caution is required when treating patients However, the rivastigmine patch, a transder- with renal impairment. In patients with a mal formulation, is an alternative
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