Pharmacological Intervention of Alzheimer's Disease

 SUSHRUT -A Magazine of Pharmaceutical Sciences

Volume 1, Issue 1, August 2024, Pages 5-7

Pharmacological Intervention of Alzheimer's Disease

➧ 
August, 2024 ➧ A Magazine of Pharmaceutical Sciences ➧ ¹Department of Pharmaceutical Sciences, Usha Martin University, Ranchi, Jharkhand-835103, India ➧ Volume 1

Several prescription drugs are approved by the U.S. Food and Drug Administration (FDA) for Alzheimer’s disease to help either manage the symptoms of or to treat the disease. Most FDA-approved drugs work best for people in the early or middle stages of Alzheimer’s. There are currently no known interventions that will cure Alzheimer’s. Alzheimer’s researchers continue to explore a variety of innovative approaches to treat symptoms as well as underlying disease processes. In ongoing clinical trials, they are developing and testing several new possible interventions. These include additional immunotherapy and other drug therapies, cognitive training, diet, and physical activity. While our era offers much more in the way of therapeutics for AD, it is clear that more work still needs to be done.

: Alzheimer’s disease, Dementia, Pharmacologic Therapy

Introduction

Alzheimer's disease (AD) first characterized by Alois Alzheimer in 1907 is a gradually progressive dementia affecting both cognition and behavior. Patients eventually lose cognitive, analytical, and physical functioning and the disease is ultimately fatal. AD is defined by both neuropathologic and clinical criteria. Neuropathologically AD destroys neurons in the cortex and limbic structures of the brain, particularly the basal forebrain, amygdala, hippocampus, and cerebral cortex. These areas are responsible for higher learning, memory, reasoning, behavior, and emotional control [1].

Non-pharmacologic Therapy

Sleep disturbances, wandering, urinary incontinence, agitation, and aggression should be managed with behavioral interventions whenever possible. On initial diagnosis, the patient and caregiver should be educated on the course of illness, available treatments, legal decisions, changes in lifestyle that will be necessary with disease progression, and other quality-of-life issues. The Alzheimer’s Association recommends staying physically, mentally and socially active, adopting a low-fat/low-cholesterol diet rich in dark vegetables and fruit, and managing body weight. Managing blood pressure, cholesterol, and blood sugar may reduce the risk of developing AD and may prevent the worsening of dementia in patients with AD. Current pharmacotherapeutic interventions are primarily symptomatic attempts to improve or maintain cognition. Successful treatment reflects a decline of less than 2 points each year on

the MMSE (Mini Mental Score Examination) score[2]

Pharmacologic Therapy

Cholinesterase Inhibitors such as Donepezil, rivastigmine, and galantamine are indicated in mild to moderate AD, while donepezil is also indicated in severe AD. The most frequent adverse effects are mild to moderate Gastro-intestinal symptoms (nausea, vomiting, and diarrhea), urinary incontinence, dizziness, headache, syncope, bradycardia, muscle weakness, salivation, and sweating. Abrupt discontinuation can cause worsening of cognition and behavior in some patients. Donepezil (Aricept) is a piperidine derivative with specificity for inhibition of acetylcholinesterase rather than butyrylcholinesterase. Rivastigmine has central activity at acetylcholinesterase and butyrylcholinesterase sites, but low activity at these sites in the periphery. Galantamine is a cholinesterase inhibitor that also has activity as a nicotinic receptor agonist. Tacrine was the first cholinesterase inhibitor approved for the treatment of AD, but it has been replaced by safer drugs which are better tolerated3

.

Other Drugs

Memantine (Namenda) blocks glutamatergic neurotransmission by antagonizing N-methylD -aspartate receptors, which may prevent excitotoxic reactions. It is used as monotherapy, and data suggest that when it is combined with a cholinesterase inhibitor, there is improvement in cognition and activities of daily living. It is indicated for treatment of  moderate to severe AD. It is not metabolized by the liver, but is primarily excreted unchanged in the urine (half-life of elimination = 60 to 80 hours). It is usually well tolerated, and side effects include constipation, confusion, dizziness, hallucinations, headache, cough, and hypertension. It is initiated at 5 mg/day and increased weekly by 5 mg/day to the effective dose of 10 mg twice daily. Dosing must be adjusted in patients with renal impairment. Recent trials do not support the use of Estrogen to prevent or treat cognitive decline. Evidence related to the role of vitamin E in preventing AD is mixed, and conclusions cannot be drawn at this time. Because of a significant incidence of side effects and a lack of compelling evidence, non-steroidal anti-inflammatory drugs are not recommended for treatment or prevention of AD. There is interest in the use of lipid-lowering agents, especially the 3- hydroxy-3-methylglutaryl coenzyme A–reductase inhibitors, to prevent AD. Pravastatin and lovastatin, but not simvastatin, were associated with a lower prevalence of AD. Further study is needed before these agents can be recommended for this use. Pharmacotherapy of Non-cognitive Symptoms Pharmacotherapy is aimed at treating psychotic symptoms, inappropriate or disruptive behavior, and depression. General guidelines include use of reduced doses, monitor closely, titrate dosage slowly, document carefully and periodically attempt to reduce medication in minimally symptomatic patients.

Antipsychotics

Antipsychotic medications have traditionally been used to treat disruptive behaviors and psychosis in AD patients. A meta-analysis showed that 17% to 18% of dementia patients showed a modest treatment response to atypical antipsychotics. Adverse events included somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased risk of death. Typical antipsychotics may also be associated with a small increased risk of death, as well as more severe extrapyramidal effects and hypotension. Eg; Haloperidol, Olanzapine, Quetiapine, Risperidone, Ziprasidone

Antidepressants

Depression and dementia have many symptoms in common, and the diagnosis of depression can be difficult, especially later in the course of AD. Eg; Citalopram, Escitalopram, Fluoxetine, Paroxetine, Sertraline. Treatment with a selective serotonin reuptake inhibitor is usually initiated in depressed patients with AD. Paroxetine causes more anticholinergic side effects than the other selective serotonin reuptake inhibitors. Venlafaxine may also be used. Although probably equally effective, the tricyclic antidepressants are usually avoided because of anticholinergic side effects [4].

Conclusion

Treating the symptoms of Alzheimer’s can help provide people with comfort, dignity, and independence for a longer period of time and also assist their caregivers. A number of drugs have been approved for the treatment of Alzheimer’s disease (AD) and a larger number are being studied as possible therapies. The current mainstays of the pharmacotherapy of AD are the cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. They collectively have acceptable tolerability and proven but modest efficacy.

References and Bibliography

1. https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-factsheet.
2. Li, X., Ji, M., Zhang, H. et al. Non-drug Therapies for Alzheimer’s Disease: A Review. Neurol Ther 12, 39–72 (2023). https://doi.org/10.1007/s40120-022-00416-x.
3. Hogan DB. Progress update: Pharmacological treatment of Alzheimer's disease. Neuropsychiatr Dis Treat. 2007; 3(5): 569-78.
4. Small GW, Rabins PV, Barry PP et al. Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA. 1997; 278:1363-71.