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Pharmacology III > Alzhiemers > Flashcards

Alzhiemers Flashcards

1
Q

What are the types of dementia?

A 
Mild Cognitive Impairment (MCI)
Alzheimer’s Disease (AD)
Vascular Dementia
Lewy Body Dementia
Parkinson’s Dementia
Frontal Lobe Dementia (Frontotemporal Dementia)
Mixed Dementia
Vascular Dementia and AD
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2
Q

What is a sudden alteration in cognitive function that can last several hours to days?

A

Delirium

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3
Q

What is delirium?

A 
Sudden alterations in cognitive function
Hours to days
Fluctuations in cognition during day
Attention span impaired
Rarely aware of cognitive deficits
Often accompanied by disturbances in sleep-wake cycle and psychomotor disturbances
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4
Q

What are the underlying pathologies associated with delirium?

A

UTI
MI
Pneumonia
Pain

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5
Q

What drugs can induce delirium?

A

Benzodiazepines, anticholinergics, antihistamines, anticonvulsants, beta blockers, sympathomimetics, lithium, diuretics

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6
Q

How is depression differentiated from dementia?

A

Short and long-term memory are selectively impaired
No progression/worsening of cognitive dysfunction
Pt usually aware of deficits (often disturbed by dysfunction)

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7
Q

What is the most common form of dementia?

A

Alzheimer’s Disease

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8
Q

What is alzheimer’s disease?

A

Neurodegenerative disease characterized by non-reversible, progressive cognitive deterioration, together with declining activities of daily living and by neuropsychiatric symptoms or behavioral changes

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9
Q

What are the risk factors for alzheimer’s disease?

A

-Age (most common being over 65)
-Dementia in close family member
-E4 allele of the ApoE gene
-History of psychiatric illness
-Other possible risk factors
Down’s Syndrome, exposure to anesthetic agents, head injury, diabetes

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10
Q

What are the genetics associated with early onset of alzheimers?

A

Almost all early-onset cases are attributable to chromosomal abnormalities
Mutations in 3 genes:
Prensilin 1 on Chromosome 21
Amyloid Precursor Protein (APP) on Chromosome 1
Presenilin 2 on Chromosome 1
Mutations lead to an increase in B-A4 peptide fragments of APP which forms neuritic plaques

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11
Q

What are the genetics associated with late onset alzheimers?

A 
Apolipoprotein E (Apo E) on Chromosome 19
May be more dependant on environmental factors
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12
Q

What family hx is associated with Alzheimer’s Disease?

A

Risk of inheriting AD may be increased four-fold

Apo E4 allele

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13
Q

What is involved with the neuropathology of Alzheimer’s Disease?

A 
Neurofibrillary tangles (NFTs) from abnormally phosphorylated tau protein
Tau essential for axonal transport- stabilizes neuron

Neurons with abnormal tau become unstable and eventually die
NFTs accumulate because not recognized as abnormal
Neuritic plaque lesions with insoluble B-amyloid peptide core
Accumulation leads to neuronal death

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14
Q

What is the pathology Alzheimer’s Disease?

A

Immune System
Glial cells, cytokines (IL-1 and IL-6), and complement cascade
Present near areas of plaque formation

Inflammation (women doesn’t really help)
Occurs secondary to neuronal degeneration

Oxidative damage by free radicals
Tx targets these free radicals

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15
Q

What is the cholinergic system of AD?

A

Multiple neuronal pathways are destroyed by plaques
Leading to shortage of Acetylcholine (this is important for memory and cognition centers)
These cholinergic pathways project to the frontal cortex and hippocampus
Areas strongly associated with memory and cognition

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16
Q

What is involved with the glutamatergic system and AD?

A
  • -Glutamate involved in neuronal pathways essential to learning & memory
  • -B-amyloid aggregation can disrupt transmission of glutamate and lead to excess stimulation of NMDA receptors
  • -Excess stimulation of NMDA receptors can lead to high intracellular Ca++ concentration and excitotoxicity -> neuronal death
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17
Q

What are the cognitive deficits in AD?

A
  • -Early symptom is loss of memory (amnesia), which usually manifests as minor forgetfulness that becomes steadily more pronounced with the progression of the illness, with relative preservation of older memories.
  • -As disorder progresses, cognitive impairment extends to domains of language (aphasia), skilled movements (apraxia), recognition (agnosia), and functions related to frontal and temporal lobes (decision-making and planning)
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18
Q

What is the average duration of AD?

A

7-10 years

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19
Q

What stage of AD is no congnitive impairment?

A

Stage 1

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20
Q

What stage of AD is very mild cognitive decline?

A

Stage 2

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21
Q

What stage of AD is mild cognitive decline?

A

Stage 3

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22
Q

What stage of AD is moderate cognitive decline?

A

Stage 4

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23
Q

What stage of AD is moderately severe cognitive decline?

A

Stage 5

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24
Q

What stage of AD is severe cognitive decline?

A

Stage 6

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25
Q

What stage of AD is very severe cognitive decline?

A

Stage 7

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26
Q

What do the initial stages of AD involve?

A

Initial stages include cognitive deficits and neuropsychiatric symptoms

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27
Q

What do the final stages of AD involve?

A

Final stages of disease often result in placement in long-term care
Lose ability to eat, walk, or communicate

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28
Q

What are the events that generally result in death of AD patients in the final stages of the dz?

A

Choking
Aspiration
Infection

29
Q

How is AD diagnosed?

A

Made on basis of history, clinical observation, memory tests and intellectual functioning over weeks or months; blood tests and neuroimaging (PET and SPECT scans) to R/O alternative diagnoses
No medical tests available to diagnose conclusively pre-mortem

30
Q

What score on the MMSE is considered mild to moderate AD?

A

10-26 on MMSE

31
Q

What score on the MMSE is considered to be moderate to severe AD?

A

3-14 on MMSE

32
Q

What are the proposed txs suggested to delay AD progression?

A

Vitamin E

Selegiline

33
Q

Vitamin E

A

Recommended that every AD patient go on vit E that is the initial tx
Recent meta-analyses suggest that high-dose Vit E (>400 IU/day) may increase all-cause mortality
Recommendation: If used, dose </= 400 IU/day

34
Q

Selegiline

A

Improvements similar to vitamin E in 1 study

Recommendation: Not recommended as adjunctive tx

35
Q

What are the proposed treatments to prevent AD?

A

Estrogen

NSAIDS

36
Q

Estrogen

A

The Women’s Health Initiative Memory Study
4500 women aged 65+
Assess incidence of dementia and MCI taking placebo or estrogen + progesterone
Study didn’t support a role for estrogen in treating sx of AD
Ongoing clinical trials are being conducted for possible preventative treatment role
Recommendation: Use only in pts who have another medical reason for HRT

37
Q

NSAIDS

A

Epidemiologic studies indicate lower incidence of AD or higher MMSE scores
Evidence of delaying disease onset and progression, slowed rate of cognitive impairment
2 years of exposure necessary for protective effect
Mixed results regarding efficacy once AD has begun
Safety profile limits use
Recommendation: Do not use as treatment at this time

38
Q

When should lipid lowering agents be used in patients with AD?

A

If they have a lipid problem not just to tx alzheimers

39
Q

What should be used to tx mild AD?

A

Donepezil, galantamine, rivastigmine, tacrine* or memantine

+ Vitamin E

40
Q

What should be used to tx moderate to severe AD?

A

Donepezil, galantamine, rivastigmine or tacrine* alone OR donepezil in combination with memantine
+ Vitamin E
* tacrine no longer used due to hepatotoxicity

41
Q

What can be used to evaluate medication response in AD?

A

MMSE

ADAS-COG

42
Q

What is shown on MMSE to evaluate med response in AD?

A

Average expected decline in AD is 2-4 points per year in an untreated patient
Halting progression or improvement over a 6-12 month time period during clinical trials would be considered response

43
Q

What is shown on ADAS-Cog to evaluate med response in AD?

A

Average expected decline is 4pts at 6 months and 7pts at 1 year
Halting progression or improvement at 6 months or longer considered response

44
Q

What is the primary goal for the treatment of AD?

A

Primary goal is to maintain patient functioning for as long as possible and symptomatically treat cognitive symptoms

45
Q

What is the secondary goal for the tx of AD?

A

Secondary goal is to treat the psychiatric and behavioral sequelae

46
Q

What is used to treat mild to moderate AD?

A

Cholinesterase inhibitors

47
Q

What is used to treat moderate to severe AD?

A

Memantine +/- cholinesterase inhibitor

donepezil

48
Q

What are the cholinesterase inhibitors?

A 
Tacrine (Cognex) – no longer clinically used (hepatotoxicity)
Donepezil (Aricept)- oral
Galantamine (Reminyl)- oral
Rivastigmine (Exelon)- oral or patch
No P450 interactions with metabolite
49
Q

What is the goal of cholinesterase inhibitors?

A

To slow down rate of decline NOT USED TO CURE

50
Q

Cholinesterase inhibitors- MOA

A

Augment cholinergic transmission at remaining synapses

51
Q

Donepezil (Aricept®)- MOA

A

Long acting, selective for AChE, reversible inhibitor

52
Q

Donepezil (Aricept®)- indications

A

Mild, moderate, and severe Alzheimer’s dementia

53
Q

Donepezil (Aricept®)- pharmacokinetics

A

Metabolized by CYP 2D6 and 3A4
Minimal risk of clinically significant drug-interactions
Partial renal elimination

54
Q

What is the drug of choice of the cholinersterase inhibitors for AD?

A

Donepezil

55
Q

Rivastigmine (Exelon®)- MOA

A

Selective for AChE (G1)

Pseudo-irreversible, non-competitive

56
Q

Rivastigmine (Exelon®)- indications

A

Mild to moderate Alzheimer’s dementia

Mild to moderate Parkinson’s dementia

57
Q

Rivastigmine (Exelon®)- pharmacokinetics

A

Not significantly metabolized by CYP450 (avoids a lot of drug interactions)
Low probability of drug-drug interactions
Available as 2mg/ml oral solution

58
Q

Galantamine (Razadyne®)- MOA

A

Reversible, competitive inhibitor of AChE

Also stimulates nicotinic receptor sites (risk additional side effects)

59
Q

Galantamine (Razadyne®)- indications

A

Mild to moderate Alzheimer’s dementia

60
Q

Galantamine (Razadyne®)- pharmacokinetics

A 
Available as a once daily ER tablet
8mg daily with food
Available as 2mg/ml oral solution
Metabolized by CYP450  2D6 and 3A4
Avoid in patients with renal or liver impairment
61
Q

Cholinesterase inhibitors- Side effects

A 
N/V
Diarrhea
Anorexia
Dizziness
Dyspepsia
Agitation
62
Q

What should you be cautious with for cholinesterase inhibitors?

A

Bradycardia
Monitor carefully in pts on concomitant medications that decrease heart rate
Ulcers
Increased gastric acid secretion (may need prophylaxis)
COPD or Asthma
bronchoconstriction
Exaggerate succinylcholine neuromuscular blockade during anesthesia
The patient may require different dosing.
Anticholinergic medications will negate effects of cholinesterase inhibitors
A lot of drugs that they patient cant take cuz it will stop this drug from working.

63
Q

Memantine (Namenda®)- MOA

A

NMDA receptor antagonist
Moderate-affinity noncompetitive receptor antagonist
Shows neuroprotective effects, slows rate of memory loss in vascular and Alzheimer’s dementia. No evidence of prevention or slowed neurodegeneration in AD

64
Q

Memantine (Namenda®)- indications

A

moderate to severe AD (MMSE 3-14)

65
Q

Memantine (Namenda®)- dose reductions

A

Dose reductions in pts with renal impairment is recommended
CrCl 40-60 ml/min 5mg twice daily
Up to 80% excreted unchanged in urine
Partially eliminated by tubular secretion
Alkaline conditions reduce clearance (80% at pH = 8)
Carbonic anhydrase inhibitors and sodium bicarbonate

66
Q

Memantine (Namenda®)- drug interactions

A

Minimal CYP-450 metabolism
Use caution with other NMDA-antagonists (amantadine (used for parkinsons), ketamine (anesthetic), dextromethorphan(cough syrup OTC))

67
Q

Memantine (Namenda®)- Side effects

A

Agitation, insomnia, diarrhea, urinary incontinence, UTI

68
Q

What can be used as combination therapy in AD?

A

Memantine + Donezepil
Vitamin E
Often recommended as adjunctive treatment because of antioxidant properties
Potential effectiveness and favorable side effect profile
Doses of no greater than 400 International Units / day

69
Q

What is the treatment for behavioral and psychological sx of dementia (BPSD)?

A

-Should begin with nonpharmacologic but may also include antipsychotic and/or antidepressants
-No medications are approved to treat Behavioral and Psycological Symptoms of Dementia (BPSD)
-Use low doses of antipsychotics in patients with dementia
Risperidone, olanzipine

Pharmacology III (19 decks)

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