By: Anureet Kaur, PharmD Candidate c/o 2024 

Alzheimer’s disease (AD) is an epidemic. Currently, the neurodegenerative disorder holds the title of the seventh leading cause of death in the United States (U.S.), disproportionately affecting older adults.¹ The National Institute on Aging reports that the number of people with AD doubles about every five years beyond the age of 65 years.² While AD is not a normal part of aging, age-related changes in the brain may increase the risk of disease. Ongoing research also suggests that vascular conditions, lack of social engagement, diet, and genetics may play a role in disease progression.²

The probable pathophysiology of AD is twofold; proposed mechanisms involve an accumulation of abnormal plaques as well as the formation of neurofibrillary tangles in the brain. In the healthy brain, naturally occurring beta-amyloid proteins are broken down by enzymes. In the brain of a person with AD, abnormal levels of beta-amyloid protein clump together to form insoluble plaques that collect between neurons and disrupt cell function.³ Furthermore, in the healthy brain, tau proteins bind to and stabilize microtubules to support neurons. Abnormal chemical changes in those with AD cause tau to misfold. This creates tangles inside neurons, disrupting normal synaptic communication.⁴ These two mechanisms cause a variety of neurotransmitter deficits, with loss of acetylcholine being one of the most notable.⁴ Acetylcholine carries messages from the brain to nerve cells; thus, its deficiency may lead to memory loss, confusion, and delusions.⁵

Four clinical phases of AD are currently recognized. The pre-clinical stage is distinguished by mild memory loss with no decline in performance of daily living activities.⁵ The mild stage is when several symptoms start to develop including poor memory, disorientation of place and time, depression, and decreased concentration.⁵ The moderate stage is when the disease spreads to other areas of the brain, leading to a subsequent loss of control, increased memory loss, and issues with reading, writing, and speaking. Agitation, paranoia, and delusion become more prominent during this period as well.⁵ Lastly, the severe stage comprises of significant cognitive, neuropsychiatric, and functional deterioration. By this phase, the disease has spread to the entire cortex of the brain. The patient loses the ability to perform basic tasks such as speaking, walking, and swallowing. Complications from the severe stage can contribute to the patient’s death.⁵

Despite the significant public health issue it poses, treatments for AD are limited. The mainstay of therapy for this disease includes three cholinesterase inhibitors (ChEIs) and one N-methyl-D-aspartate receptor antagonist (NMDA). These drugs do not alter the course of the disease, but rather work to control symptoms of AD.⁵ 

Current guidelines recommend initiating AD treatment with any of the ChEIs as opposed to an NMDA antagonist. Choice of ChEI therapy is individualized based on patient preference, drug interactions, affordability, and ease of use. The major mechanism behind cholinesterase inhibitors involves restoration of the cholinergic pathway by inhibiting acetylcholinesterase, the enzyme responsible for acetylcholine hydrolysis. There are 3 drugs in this class: Aricept (donepezil), Exelon (rivastigmine), and Razadyne (galantamine). These medications are typically well tolerated by patients, but some common side effects of nausea, vomiting, and diarrhea have been observed. Syncope, bradycardia, atrial arrhythmias, and myocardial infarction are other less common, yet significant side effects. Due to its cardiovascular effects, a contraindication to ChEI use is a heart rate below 50 beats per minute.⁴

Donepezil is the leading choice of therapy for those with AD. This medication is available in a variety of formulations: a(n) standard oral tablet, oral dissolving tablet, oral solution, and transdermal patch. All of donepezil’s dosage forms are approved for use in any stage of AD, unlike rivastigmine and galantamine.⁴ Another advantage of donepezil is that it only requires once-a-day dosing due to its extensive half-life of 70 hours. Patients are generally initiated on 5 mg daily, for both oral and transdermal formulations. The dose may be titrated to 10 mg after 4 to 6 weeks based on clinical response.⁶ Patients should be advised to take oral formulations of donepezil in the evening due to their tendency to cause significant dizziness and irregular heartbeat.⁶ However, this drug, like other ChEIs, has also been reported to cause sleep disturbances – in patients experiencing such side effects, it may be recommended to take the dose in the morning instead.⁴

Rivastigmine is available as a(n) oral capsule, oral solution, and transdermal patch. Both oral formulations of rivastigmine are approved for mild and moderate AD, while the transdermal patch is only approved for severe cases.⁴ Oral formulations are dosed twice daily due to the drug’s short half-life of 1.5 hours. They should be taken with meals to mitigate gastrointestinal (GI) side effects. The oral solution may be mixed in water, cold fruit juice, or soda, and stored at room temperature for up to 4 hours before administration.⁷ Initial oral dosing is 1.5 mg twice daily and may be increased by 3 mg daily every 2 weeks based on tolerability for a maximum recommended daily dose of 12 mg. Initial transdermal dosing is one 4.6 mg/24-hour patch applied daily. After a minimum of 4 weeks, the clinician may increase the dose to 9.5 mg/24 hour as tolerated and continue to titrate to a maximum dose of 13.3 mg/24-hour patch. In contrast to other ChEIs, rivastigmine carries a distinct low body weight warning – for patients weighing less than 50 kilograms, close monitoring for toxicity, which can manifest as excessive nausea and vomiting, is advised.⁷

In contrast to the other ChEIs, galantamine is only available in oral formulations including a standard tablet, solution, and extended-release capsule. Given its short half-life of 7 hours, regular release oral formulations are dosed twice daily. The drug should be taken with meals to avoid GI side effects like other ChEIs.Galantamine oral solution can also be mixed with water, cold fruit juice, or soda; however, unlike rivastigmine, this medication must be administrated right away after mixing.⁹ The regular-release tablet or solution is initiated at 4 mg twice daily for 4 weeks and, if tolerated, doubled every 4 weeks to a maximum of 24 mg daily in 2 divided doses. The extended-release capsule is initiated at 8 mg once daily for 4 weeks. The dose may be doubled every 4 weeks to a maximum of 24 mg daily as a single dose.⁸ Renal and hepatic dosing is necessary for both rivastigmine and galantamine. Lastly, interruptions in ChEI therapy for 3 or more days require retitration.⁴

Memantine’s mechanism of action differs from the aforementioned AD drugs. It is a partial antagonist of NMDA receptors which cause neuronal loss when overactivated.¹⁰ The drug is indicated for use in moderate and severe AD. It can be used as monotherapy and in conjunction with a ChEI, to enhance therapeutic response and mitigate GI side effects. Common adverse events of memantine include headache, constipation, confusion, and dizziness.⁴ Similar to donepezil, memantine has an extensive half-life of 60 to 80 hours, allowing for once-a-day initial dosing. The medication is available as a tablet, oral solution, and extended-release capsule. Immediate-release preparations are initiated at 5 mg once daily and increased by 5 mg every week as tolerated to a target maximum dose of 20 mg/day. Extended-release capsules are initiated at 7 mg once daily and increased by 7 mg every week as tolerated to a target maximum dose of 28 mg once daily. Renal and hepatic dosing is necessary.⁴ Unlike the other oral solutions, memantine oral solution cannot be mixed with other liquids; however, capsules may be opened, and contents may be sprinkled into applesauce to aid in administration.⁴

AD is a complex condition to manage – an interprofessional approach is recommended to improve quality of life and achieve therapeutic outcomes. Pharmacists can contribute to this process by considering factors such as comorbidities and patient preferences as they personalize medication regimens with ChEIs and NMDA antagonists. Although current options are limited and may only provide symptomatic relief, there appears to be a promising future for AD therapy. The Food and Drug Administration recently approved two new medications that may potentially delay decline from dementia. AD is currently a challenging condition to deal with, but with the proper care and pharmacological therapy, there is potential to better manage the disease.

References

1. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023;19(4):1598-1695. doi:10.1002/alz.13016
2. What Causes Alzheimer’s Disease? National Institute on Aging. Reviewed December 24, 2019. https://www.nia.nih.gov/health/what-causes-alzheimers-disease.
3. Sheppard O, Coleman M. Alzheimer’s Disease: Etiology, Neuropathology and Pathogenesis. In: Huang X, ed. Alzheimer’s Disease: Drug Discovery. Brisbane (AU): Exon Publications; December 18, 2020.
4. Zimmerman KM, Peron EP, Crouse EL, Sargent LJ, Hobgood SE. Alzheimer Disease. In: DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition. McGraw Hill; 2023. Accessed November 12, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=267240515
5. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules. 2020;25(24):5789. doi:10.3390/molecules25245789
6. Aricept (donepezil hydrochloride) [package insert]. Woodcliff Lake, NJ: Eisai Co., Ltd.; Revised 2018.
7. Exelon (rivastigmine tartrate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Revised 2018.
8. Razadyne® (galantamine hydrobromide) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Revised 2021.
9. Galantamine Hydrobromide (galantamine hydrobromide solution) [package insert]. Berkeley Heights, NJ: Hikma Pharmaceuticals USA Inc.; Revised 2022.
10. Folch J, Busquets O, Ettcheto M, et al. Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. J Alzheimers Dis. 2018;62(3):1223-1240. doi:10.3233/JAD-170672

Published by Rho Chi Post