Exam 2: Neurodegenerative Disease Therapies Flashcards Preview

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Flashcards in Exam 2: Neurodegenerative Disease Therapies Deck (51):
1

Early vs. late onset AD:

Early before age 60 (strong genetic implication); late after age 60

2

Two main pathologies of AD:

Brain atrophy
Protein aggregation

3

Parts of the brain that experience cholinergic neuron loss in AD:

Hippocampus
Frontal cortex

4

Five aspects of ACh signaling that are decreased in AD:

1. Choline acetyltransferase activity (production of ACh)
2. ACh amount
3. ACh-ases
4. Choline transport
5. Nicotinic ACh receptor expression

5

Two types of protein aggregation in AD:

Amyloid plaques
Neurofibrillary tangles

6

Two classes of drug tx for AD:

Cholinesterase inhibitors
NMDA receptor antagonists

7

Three examples of cholinesterase inhibitors:

Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne)

8

MoA of cholinesterase inhibitors:

Prevents action of acetylcholinesterase, thus increasing ACh in the synapse

9

Indications for cholinesterase inhibitors:

Mild to moderate AD

10

Side effects of cholinesterase inhibitors:

N/V
Diarrhea
Dizziness
Headache
Bronchoconstriction

11

Efficacy of cholinesterase inhibitors:

Slight improvements
Does not halt disease

12

Example of NMDA receptor antagonist:

Memantine (Namenda)

13

Indications for NMDA receptor antagonist:

Moderate to severe AD

14

Efficacy of NMDA receptor antagonist:

Very modest benefits

15

MoA of NMDA receptor antagonist:

Blocks "leaky" channels to reduce Ca2+ induced excitotoxicity

Intracellular Ca2+ reduction means less background noise, making nerve signals relatively stronger

16

Two types of amyloid precursor protein processing:

Amyloidogenic
Nonamyloidogenic

17

Non-amyloidogenic pathway:

APP protein gets cleaved by α-secretase then γ-secretase, no Aβ formed

18

Amyloidogenic pathway:

APP get cleaved by β-secretase then γ-secretase; Aβ40/42 formed

19

Effect of Aβ plaques on cognition:

Unclear; likely soluble derivatives that are problematic, not plaques themselves

20

Gene that encodes Aβ-clearing protein:

ApoE

21

ApoE genotype that increases AD risk:

ApoE4
One copy: 3-fold risk
Two copies: 12-15-fold risk

22

State of tau proteins that causes their dysfunction:

Hyperphosphorylated

23

Three ways Aβ can be targeted in future drug therapies:

Block Aβ synthesis
Promote Aβ clearance
Block plaque formation

24

Four parts of the basal ganglia:

GSSS
Globus pallidus
Striatum
Subthalamic nuclei
Substantia nigra

25

Functions (2) of basal ganglia:

Start purposeful movement
Suppress unwanted movement

26

Mechanism of PD:

Loss of dopaminergic neurons (70%+) from substantia nigra

27

Two classes of drugs for PD:

Dopaminergic agents
Anticholinergic agents

28

Efficacy of Levodopa:

80% show improvement, 20% regain near-normal motor function

Efficacy wears off after 2-3 years

29

MoA of Levodopa:

Dopamine precursor

Converted to dopamine in both the periphery and brain - dopamine does not cross BBB though!

30

Barrier to end-organ distribution of Levodopa and method of overcoming it:

Most is converted to dopamine in the periphery and will not cross BBB

Given along with carbidopa (1st) and entacapone (when carbidopa effectiveness wanes) to inhibit the enzymes that convert Levodopa to dopamine in the blood

31

Side effects of Levodopa:

Acute: nausea, anorexia, hypotension, psychosis

Chronic: dyskinesias, on-off effect

Other: dysrhythmias, adrenergic stimulation

32

Drug interactions with Levodopa:

Nonselective MAOIs (can cause overload of dopamine, norepi)

33

MoA of carbidopa:

Peripheral decarboxylase inhibitor

34

MoA of entacapone:

COMT inhibitor

35

Examples of dopamine agonists:

Pramipexole
Ropinirole

36

Receptors targeted by pramipexole/ropinirole:

D2/D3

37

Efficacy of pramipexole/ropinirole:

Highly effective

38

Side effects of pramipexole/ropinirole:

Hallucinations
Compulsive behaviors

(Think mania - dopamine overload)

39

MoA of selegiline:

MAO-B inhibitor; decreases dopamine degradation

(Not involved in norepi metabolism)

40

MoA of amantadine:

Enhances dopamine release into synapse

41

Example of anticholinergic drug for PD:

Benztropine

42

MoA of benztropine:

Blockage of muscarinic receptors, which relieves inhibition of dopaminergic neurons

43

Side effects of benztropine:

Impaired vision
Urinary retention
Dry mouth
Constipation

44

Lewy bodies are:

Alpha-syneuclein protein aggregates found in PD neurons; unclear if harmful or beneficial

45

Anesthetic considerations for memantine:

Clearance reduced in alkaline urine

46

Anesthetic considerations for cholinesterase inhibitors:

Prolongs succinylcholine; creates resistance to non-depolarizing NMBs

47

Anesthetic considerations for anticholinergic drugs:

Side effects, especially HR

Avoid drugs that impact cholinergic tone (TCAs) or increase HR

48

Anesthetic considerations for amantadine:

Rule-out CHF side effect
Identify anticholinergic-like side effects

49

Anesthetic considerations for levodopa/carbidopa:

*Must* recieve q6-12 hours, even intra-op (via NG tube)

Assess for side effects: dysrhythmias, adrenergic stimulation, hypotension, GI

50

Anesthetic considerations for synthetic dopamine agonists (pramipexole/ropinirole):

Assess for side effects: CV, hypotension, pleuropulmonary fibrosis

51

Anesthetic considerations for selegiline:

Avoid ephedrine and meperidine! Extreme caution with vasoactive medications

Titrate NMBs, sedatives, diuretics, etc carefully