Alzheimer's Medications Flashcards
1
Q
Alzheimer’s
Pathology
A
- Plaques containing β-amyloid
- Tangles containing phosphorylated tau
-
Cortical hippocampal atrophy
- Destruction of cholinergic neurons in nucleus basalis of Meynert
- May be responsible for loss of short-term memory early in the disease
- Destruction of cortical and hippocampal targets that receive cholinergic input
- Destruction of cholinergic neurons in nucleus basalis of Meynert
- Involves multiple other neurotransmitter systems including:
- Glutamate
- 5-HT
- Neuropeptides
- Possibly caused by oxidative stress, inflammation, or failure to clear the A-β-amyloid
- Chronic NSAIDs reduce the risks of Alzheimer’s, but chronic NSAIDs have their own set of adverse effects
2
Q
Alzheimer’s
Biomarker Eval
A
-
PIB-PET imaging
- Pittsburgh imaging compound-B (PIB) tracer binds to amyloid
- Imaged using PET (positron-emission tomography)
- Aggregation process starts to level off before definitive sx appear
-
Tau proteins become detached & clump into tangles
- Detected in CSF
- Also look for decreasing levels of amyloid-β
- Occurs as peptides removed from CSF to form deposits in the brain
- Together these indicate that disease process is advancing
3
Q
Mild Cognitive Impairment
Biomarker Eval
A
- MCI occurs 1-4 years before AD diagnosed b/c select neuron populations damaged or dying
- Stage can be tracked w/ volumetric MRI
- Measures shrinkage of the brain as neurons die
- Monitored w/ fluorodeoxyglucose-PET (FDG-PET) ⇒ gauges the metabolic status of neurons
4
Q
Alzheimer’s
Genetic Mutations / Risk Factors
A
-
~1% of early-onset cases due to genetic mutations
- Genetic alterations create both plaques and tangles
- Always lead to the disease
- Four genetic alterations have been identified w/ Alzheimer’s:
-
Amyloid precursor protein (APP)
- ↑ formation of A-β in general or particular type of A-β highly prone to forming deposits
-
Down’s syndrome (trisomy 21) ⇒ ↑ incidence of Alzheimer’s in middle age
- Chromosome 21 contains the APP gene
- Produce higher levels of A-β from birth
- Amyloid deposits found as early as age 12
-
Mutations in presenilin 1 and 2
- Proteins are essential for functioning of gamma-secretase
-
Variant of apolipoprotein called E4
- Protein involved in lipid metabolism
- Variant form more susceptible to both atherosclerosis and Alzheimer’s
-
Amyloid precursor protein (APP)
- Obesity in mid-life, high BP and high cholesterol are key risk factors for developing dementia within two decades
5
Q
Alzheimer’s
Developmental Treatments
A
Key is to ID pts or populations w/ genetic predisposition and tx early before sx occur
Several clinical trials for agents that could slow progression of Alzheimer’s:
-
Inhibitors of enzymes that produce amyloid-β:
- Block or modify the action of gamma secretases that cleave the amyloid precursor protein in a way that releases the amyloid-β peptides
-
Vaccines or antibodies that clear amyloid-β:
- Induce production of Ab that bind to amyloid, which facilitates the ability of microglia to eliminate the protein
- Greatly reduces amyloid plaques in animal models and pts, but, presently, it is unclear whether this prevents the memory deficits
-
Amyloid-β aggregation blockers:
- Prevent amyloid fragments from clumping to prevent damage to neurons
-
Anti-tau compounds:
- Various approaches, such as blocking production of the toxic form of the tau protein or impeding its aggregation into tangles
-
Neuroprotective agents:
- Boost natural brain chemicals that enhance the health of neurons
- In one, a gene for Nerve Growth Factor (NGF) is delivered into the brain to facilitate the production of this neuroprotective substance
6
Q
Alzheimer’s Treatment
Pharmacological Agents
A
- Agents have only a modest effect on cognition, ? clinical significance
- Cholinesterase inhibitors ⇒ mild to moderate Alzheimer’s
- NMDA antagonist ⇒ moderate to severe Alzheimer’s
7
Q
Tacrine
A
- First centrally acting cholinesterase inhibitor
- Generally not used because of significant hepatotoxicity
8
Q
Donepezil
MOA
A
- Reversible cholinesterase inhibitor
- ⊗ Cholinesterase in the CNS ⇒ ↑ acetylcholine in the cortex
- ⊗ Cholinesterase in the periphery ⇒ some of its side effects
- Because of its long half-life, it is dosed once a day
9
Q
Donepezil
Adverse Effects
A
- Most common side effects are nausea, diarrhea, headache, insomnia, anorexia and pain
- Dose related and may be transient
- Urinary incontinence may occur
10
Q
Donepezil
Contraindications
A
- Drug allergy
-
Cardiac conduction abnormalities
- May be aggravated by the drug and lead to arrhythmias and syncope
- Ulcers
- Hx of seizures, asthma and COPD
- Older pts w/ low body weight
11
Q
Donepezil
Interactions
A
- May accentuate the effect of succinylcholine
- Cytochrome p450 interactions w/ drugs like cimetidine, ketoconazole, ritonavir etc
12
Q
Galantamine
A
- ⊗ Cholinesterase in the CNS
-
⊕ Allosteric modulator of nicotinic receptors
- ? synergistic effect
- Used for Alzheimer’s w/ a CVA component
- Side effects and interactions are the same as for donepezil
13
Q
Rivastigmine
A
- ⊗ Acetylcholinesterase
-
⊗ Butyryl cholinesterase in glia
- Can also act on acetylcholine
- Cortical neuron death ⇒ gliosis ⇒ release of butyryl cholinesterase
- ⊗ ⇒ ↑ [ACh]
- GI side effects may be more severe but less of a problem w/ the skin patch
- Otherwise information is same as for Galantamine & Donepezil
14
Q
Memantine
MOA and Indications
A
- N-methyl-d-aspartate (NMDA) receptor antagonist
- Moderate to severe Alzheimer’s
- Amyloid plaques ⇒ small continuous release of glutamate ⇒ excitotoxic
- Complete ⊗ of NMDA receptors (w/ phencyclidine) ⇒ psychosis
- However, memantine only blocks “open” NMDA channels w/ a low to moderate affinity
- It also has a fast on and off time
- Blocks effects of glutamate “leak” at NMDA receptors but does not block all glutamate transmission
- May also be used for other dementias such as Huntington disease, AID related dementia, and vascular dementia
15
Q
Memantine
Adverse Effects, Contraindications, Interactions
A
- Common side effects are dizziness, constipation, confusion, headache, HTN
- Contraindications include: drug allergy, renal impairment, CV disease and hx of seizures
- Interactions:
- Raising urinary pH will reduce elimination
- Do not combine w/ other drugs that are also NMDA receptor antagonists such as amantadine, ketamine, and dextromethorphan
