CNS Pharmacology: Drugs for Alzheimer’s Disease

Introduction / Overview

Alzheimer’s disease (AD) represents the most common form of dementia and imposes a significant burden on patients, caregivers, and health systems worldwide. The progressive decline in cognition, memory, and functional capacity necessitates a therapeutic approach that addresses both symptomatic relief and potential disease modification. Current pharmacotherapy focuses on cholinergic enhancement, glutamatergic modulation, and, more recently, amyloid-β and tau-directed biologics. The present chapter provides a detailed analysis of these agents, including their pharmacodynamic and pharmacokinetic profiles, clinical indications, safety considerations, and special population considerations. The goal is to furnish medical and pharmacy students with a robust foundation for understanding the therapeutic landscape of AD.

Learning Objectives

• Identify the main classes of pharmacologic agents employed in AD and their chemical classifications.
• Explain the mechanisms of action underlying cholinesterase inhibition, NMDA antagonism, and monoclonal antibody therapy.
• Describe the absorption, distribution, metabolism, and excretion characteristics of commonly used AD drugs.
• Recognize the therapeutic indications, contraindications, and notable adverse effect profiles of these medications.
• Appreciate the implications of special populations, including geriatric, renal/hepatic impairment, pregnancy, and lactation, on drug selection and dosing.

Classification

1. Cholinesterase Inhibitors (ChEIs)

ChEIs are considered first-line symptomatic agents for mild to moderate AD. They are chemically diverse, yet share a common functional motif that facilitates reversible inhibition of acetylcholinesterase (AChE). The main agents include:

• Donepezil – a pyridyl derivative with a tertiary amine moiety.
• Rivastigmine – a carbamate-based compound that exhibits pseudo‑irreversible inhibition.
• Galantamine – an alkaloid that combines AChE inhibition with allosteric nicotinic receptor modulation.

2. NMDA Receptor Antagonist

Memantine, a low‑affinity uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, is approved for moderate to severe AD. It possesses a unique voltage-dependent blocking profile that preserves normal synaptic activity while attenuating excitotoxicity.

3. Amyloid‑β Targeted Monoclonal Antibodies

In the past decade, several monoclonal antibodies (mAbs) targeting amyloid‑β (Aβ) aggregates have been approved, including:

• Aducanumab – recognizes aggregated Aβ species.
• Lecanemab – binds soluble protofibrils.
• Donanemab – targets N‑terminally oxidised Aβ.
• Gantenerumab – binds full-length Aβ fibrils.

4. Tau‑Targeted Therapies

Although still largely investigational, several agents aim to reduce tau phosphorylation or aggregation, such as small‑molecule kinase inhibitors and antisense oligonucleotides.

Mechanism of Action

1. Cholinesterase Inhibitors

Central to the cholinergic hypothesis of AD is the loss of acetylcholine (ACh) due to decreased neuronal AChE activity. ChEIs competitively bind to the active site of AChE, preventing ACh hydrolysis. Donepezil and rivastigmine exhibit high specificity for AChE over butyrylcholinesterase, whereas galantamine also exerts allosteric modulation of nicotinic acetylcholine receptors, enhancing postsynaptic responsiveness. These actions collectively increase synaptic ACh concentrations, potentially ameliorating cognitive deficits.

2. NMDA Receptor Antagonist

Memantine binds within the ion channel pore of the NMDA receptor in a voltage-dependent manner, blocking excessive Ca²⁺ influx that contributes to neuronal excitotoxicity. By preferentially inhibiting over‑activated receptors while sparing normal synaptic transmission, memantine mitigates neurodegeneration without substantial cognitive side effects.

3. Amyloid‑β Targeted Monoclonal Antibodies

These antibodies are engineered to recognize specific conformations or post‑translational modifications of Aβ peptides. Upon binding, they facilitate microglial clearance via Fc receptor engagement, promote solubilization of fibrillar deposits, and reduce Aβ seeding. The net effect is a reduction in cerebral amyloid burden, which correlates with slowed cognitive decline in clinical trials.

4. Tau‑Targeted Therapies

By inhibiting glycogen synthase kinase‑3β or cyclin‑dependent kinase 5, kinase inhibitors reduce tau hyperphosphorylation, thereby limiting microtubule destabilization and neurofibrillary tangle formation. Antisense oligonucleotides downregulate tau mRNA expression, decreasing protein synthesis. These approaches target a downstream pathological cascade distinct from amyloidopathy.

Pharmacokinetics

1. Absorption

Donepezil is well absorbed orally, with a bioavailability of approximately 100 %. Rivastigmine, administered via transdermal patch or oral solution, achieves steady-state concentrations over 48 h. Galantamine is absorbed orally, but its bioavailability is reduced in the presence of proton pump inhibitors. Memantine shows high oral bioavailability (~60 %) and rapid absorption. Monoclonal antibodies are administered intravenously; their absorption is limited to the circulation, and they exhibit a biphasic elimination profile.

2. Distribution

All ChEIs cross the blood–brain barrier (BBB) by passive diffusion, achieving therapeutic central nervous system (CNS) concentrations. Memantine is moderately lipophilic, allowing efficient BBB penetration. Monoclonal antibodies, due to their large molecular size, rely on FcRn-mediated transcytosis for CNS entry, resulting in low brain-to-plasma ratios (~0.5–1 %).

3. Metabolism

Donepezil undergoes hepatic cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) oxidation, producing inactive metabolites. Rivastigmine is hydrolyzed by pseudo‑cholinesterase, bypassing hepatic metabolism. Galantamine is mainly metabolized by CYP2D6 and CYP3A4. Memantine is not significantly metabolized and is eliminated unchanged. Monoclonal antibodies undergo proteolytic catabolism into peptides and amino acids, independent of hepatic or renal pathways.

4. Excretion

Donepezil metabolites are excreted via feces (≈ 60 %) and urine (≈ 20 %). Rivastigmine’s hydrolysis products are excreted renally. Galantamine and its metabolites are primarily eliminated through the kidneys. Memantine is predominantly cleared by renal excretion (≈ 70 %). Monoclonal antibodies exhibit a half‑life of 10–20 days, with clearance driven by proteolytic degradation.

5. Half-Life and Dosing Considerations

Donepezil has a terminal half-life of ~70 h, allowing once-daily dosing. Rivastigmine patch is applied twice weekly, whereas the oral formulation is taken twice daily. Galantamine’s half-life is ~7–10 h, necessitating twice-daily dosing. Memantine’s half-life is ~60 h, permitting once-daily administration. Monoclonal antibodies are dosed every 2–4 weeks, with weight-based adjustments for certain agents.

Therapeutic Uses / Clinical Applications

1. Approved Indications

• ChEIs – Indicated for mild, moderate, and severe AD, with rivastigmine also approved for Parkinsonian dementia and Lewy body dementia.
• Memantine – Indicated for moderate to severe AD, often in combination with ChEIs.
• Aducanumab, Lecanemab, Donanemab, Gantenerumab – Indicated for early to moderate AD with biomarker-confirmed amyloid pathology.

2. Off-Label Uses

While off-label use of ChEIs for vascular dementia or mixed dementia is common, evidence remains limited. Memantine is sometimes employed in frontotemporal dementia, though data are sparse. Monoclonal antibodies are rarely used off-label due to stringent biomarker requirements and cost considerations.

Adverse Effects

1. Cholinesterase Inhibitors

Common effects include nausea, vomiting, diarrhea, anorexia, insomnia, muscle cramps, and bradycardia. Serious reactions, though infrequent, encompass arrhythmias, severe hypotension, and cholinergic crisis. The black box warning for rivastigmine highlights potential for life-threatening bradycardia and gastrointestinal complications.

2. Memantine

Side effects are generally mild, comprising dizziness, headache, confusion, constipation, and insomnia. Rare but serious events such as seizures or neuropsychiatric exacerbation may occur, particularly when combined with other CNS depressants.

3. Monoclonal Antibodies

Infusion-related reactions (IRI) are common, manifesting as fever, chills, rash, and hypotension. Amyloid-related imaging abnormalities (ARIA), notably ARIA-E (edema) and ARIA-H (haemorrhage), pose significant risks, necessitating routine MRI monitoring. Rare severe hypersensitivity reactions and thromboembolic events have been reported.

4. Tau-Targeted Therapies

Preclinical data suggest neuroinflammation, off-target kinase inhibition, and cognitive worsening as potential adverse events, though definitive safety profiles remain under investigation.

Drug Interactions

1. Cholinesterase Inhibitors

Donepezil is metabolized by CYP3A4 and CYP2D6; inhibitors (e.g., ketoconazole, fluoxetine) may increase plasma levels, while inducers (e.g., rifampin, carbamazepine) may reduce efficacy. Rivastigmine’s hydrolysis is unaffected by CYP enzymes, but caution is advised when co-administered with anticholinergic drugs. Galantamine metabolism is influenced by CYP2D6 polymorphisms; potent inhibitors such as fluoxetine can elevate plasma concentrations.

2. Memantine

Minimal CYP involvement reduces interaction potential. However, concurrent use with other NMDA antagonists (e.g., ketamine) may potentiate CNS depression. Memantine is contraindicated with strong CYP2D6 inducers, which can lower its plasma levels.

3. Monoclonal Antibodies

Co-administration with drugs that increase the risk of ARIA (e.g., anticoagulants, antiplatelet agents) should be avoided. Interactions with immunosuppressants may alter antibody clearance, though data are limited.

4. Contraindications

Contraindicated in patients with severe hepatic impairment (for donepezil and galantamine), severe renal dysfunction (for memantine), or known hypersensitivity to any component of the formulation.

Special Considerations

1. Pregnancy and Lactation

ChEIs and memantine lack robust human data; current recommendations advise avoidance during pregnancy and lactation unless benefits outweigh risks. Monoclonal antibodies are contraindicated due to potential placental transfer and limited safety data.

2. Pediatric Use

AD is exceedingly rare in children; pharmacologic interventions are not indicated outside clinical trials. Pediatric pharmacokinetics differ markedly, and data are insufficient.

3. Geriatric Considerations

Polypharmacy, altered pharmacokinetics, and increased sensitivity to adverse effects necessitate careful dose titration and monitoring. Cognitive decline may mask drug-induced sedation or confusion.

4. Renal Impairment

Memantine dosing requires adjustment in patients with creatinine clearance <30 mL/min. Rivastigmine can be used without dose modification; however, renal clearance of its metabolites may accumulate in severe impairment.

5. Hepatic Impairment

Donepezil should be avoided in severe hepatic impairment (Child‑Pugh C). Galantamine dosing may need adjustment in moderate hepatic dysfunction. Rivastigmine remains safe due to minimal hepatic metabolism.

Summary / Key Points

• Cholinesterase inhibitors and memantine constitute the cornerstone of symptomatic therapy for AD, targeting cholinergic deficits and glutamatergic excitotoxicity, respectively.
• Monoclonal antibodies represent a paradigm shift toward disease modification, though their safety profile necessitates vigilant monitoring for ARIA.
• Pharmacokinetic variability, especially related to CYP polymorphisms and organ dysfunction, underscores the need for individualized dosing.
• Adverse effect profiles differ among agents; gastrointestinal disturbances predominate with ChEIs, while infusion reactions and ARIA are unique to mAbs.
• Special populations—including pregnant women, the elderly, and those with renal or hepatic impairment—require tailored therapeutic strategies to balance efficacy and safety.

Clinical pearls include initiating ChEIs at the lowest effective dose, titrating slowly to mitigate gastrointestinal toxicity, and employing routine imaging for patients on amyloid‑targeted biologics. The evolving therapeutic landscape necessitates ongoing appraisal of emerging evidence to optimize patient outcomes in Alzheimer’s disease.

References

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