Alzheimer's Medications

Question 1

Alzheimer’s

Pathology

Answer 1

• 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
• 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

Question 2

Alzheimer’s

Biomarker Eval

Answer 2

• 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

Question 3

Mild Cognitive Impairment

Biomarker Eval

Answer 3

• 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

Question 4

Alzheimer’s
Genetic Mutations / Risk Factors

Answer 4

• ~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
• Obesity in mid-life, high BP and high cholesterol are key risk factors for developing dementia within two decades

Question 5

Alzheimer’s

Developmental Treatments

Answer 5

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

Question 6

Alzheimer’s Treatment
Pharmacological Agents

Answer 6

• Agents have only a modest effect on cognition, ? clinical significance
• Cholinesterase inhibitors ⇒ mild to moderate Alzheimer’s
• NMDA antagonist ⇒ moderate to severe Alzheimer’s

Question 7

Tacrine

Answer 7

• First centrally acting cholinesterase inhibitor
• Generally not used because of significant hepatotoxicity

Question 8

Donepezil

MOA

Answer 8

• 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

Question 9

Donepezil

Adverse Effects

Answer 9

• Most common side effects are nausea, diarrhea, headache, insomnia, anorexia and pain
  
  • Dose related and may be transient
• Urinary incontinence may occur

Question 10

Donepezil

Contraindications

Answer 10

• 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

Question 11

Donepezil

Interactions

Answer 11

• May accentuate the effect of succinylcholine
• Cytochrome p450 interactions w/ drugs like cimetidine, ketoconazole, ritonavir etc

Question 12

Galantamine

Answer 12

• ⊗ 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

Question 13

Rivastigmine

Answer 13

• ⊗ 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

Question 14

Memantine

MOA and Indications

Answer 14

• 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

Question 15

Memantine

Adverse Effects, Contraindications, Interactions

Answer 15

• 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

Question 16

Vitamin E

Answer 16

Many physicians will prescribe Vit E for antioxidant properties

Question 17

Dementia/Behavioral Disorders
Non-Pharmacological Approaches

Answer 17

• Exercise and CV health may slow progression (Metformin)
• Support the caregiver
• Behavioral approaches such as distraction or close–ended questions
• Environmental modification
• Developing and maintaining routines
• Sensory intervention - touch, music or pet therapy

Question 18

Dementia

Behavioral Changes

Answer 18

• Psychotic features tend to present later including hallucinations, delusions, and delusional misidentifications
• Non-psychotic behaviors might include agitation, wandering, and aggression
• The goal of therapy should be to reduce these behaviors, not eliminate them

Question 19

Behavioral Changes of Dementia

Pharmacological Treatment

Answer 19

• Atypical antipsychotics ⇒ first line therapy in these pts
  
  • Better tolerated and less extrapyramidal side effects
  • Monitor for tremor, rigidity, and dystonia
  • Used once daily at night to take advantage of the sedative effects
  • Quetiapine is least likely to increase symptoms in Parkinson’s pts
• Typical antipsychotics (ex. Haloperidol) ⇒ used at low doses for short periods to manage delirium and acute agitation
  
  • Then the patient should be switched to an atypical
• Anticonvulsants ⇒ used when the psychosis leads to aggressive behavior
  
  • Second line agents when the patient does not respond to antipsychotics
  • Either valproic acid or carbamazepine can be used
• Antidepressants (ex. SSRIs) ⇒ used for depression
  
  • Avoid tricyclics
• Benzodiazepines ⇒ not first line therapy for anxiety in these pts, but they are commonly used
  
  • May worsen the behavior because of amnesia and disinhibition
  • Used only to manage acute symptoms
  • Use benzodiazepines w/ short half-lives and no active metabolites

Recent study suggested that antipsychotic drugs overused in dementia pts

Increase death risk of the patient