Exam 2: Neurodegenerative Disease Therapies

Question 1

Early vs. late onset AD:

Answer 1

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

Question 2

Two main pathologies of AD:

Answer 2

Brain atrophy

Protein aggregation

Question 3

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

Answer 3

Hippocampus

Frontal cortex

Question 4

Five aspects of ACh signaling that are decreased in AD:

Answer 4

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

Question 5

Two types of protein aggregation in AD:

Answer 5

Amyloid plaques

Neurofibrillary tangles

Question 6

Two classes of drug tx for AD:

Answer 6

Cholinesterase inhibitors

NMDA receptor antagonists

Question 7

Three examples of cholinesterase inhibitors:

Answer 7

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

Question 8

MoA of cholinesterase inhibitors:

Answer 8

Prevents action of acetylcholinesterase, thus increasing ACh in the synapse

Question 9

Indications for cholinesterase inhibitors:

Answer 9

Mild to moderate AD

Question 10

Side effects of cholinesterase inhibitors:

Answer 10

N/V
Diarrhea
Dizziness
Headache
Bronchoconstriction

Question 11

Efficacy of cholinesterase inhibitors:

Answer 11

Slight improvements

Does not halt disease

Question 12

Example of NMDA receptor antagonist:

Answer 12

Memantine (Namenda)

Question 13

Indications for NMDA receptor antagonist:

Answer 13

Moderate to severe AD

Question 14

Efficacy of NMDA receptor antagonist:

Answer 14

Very modest benefits

Question 15

MoA of NMDA receptor antagonist:

Answer 15

Blocks “leaky” channels to reduce Ca2+ induced excitotoxicity

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

Question 16

Two types of amyloid precursor protein processing:

Answer 16

Amyloidogenic

Nonamyloidogenic

Question 17

Non-amyloidogenic pathway:

Answer 17

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

Question 18

Amyloidogenic pathway:

Answer 18

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

Question 19

Effect of Aβ plaques on cognition:

Answer 19

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

Question 20

Gene that encodes Aβ-clearing protein:

Answer 20

ApoE

Question 21

ApoE genotype that increases AD risk:

Answer 21

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

Question 22

State of tau proteins that causes their dysfunction:

Answer 22

Hyperphosphorylated

Question 23

Three ways Aβ can be targeted in future drug therapies:

Answer 23

Block Aβ synthesis
Promote Aβ clearance
Block plaque formation

Question 24

Four parts of the basal ganglia:

Answer 24

GSSS
Globus pallidus
Striatum
Subthalamic nuclei
Substantia nigra

Question 25

Functions (2) of basal ganglia:

Answer 25

Start purposeful movement | Suppress unwanted movement

Question 26

Mechanism of PD:

Answer 26

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

Question 27

Two classes of drugs for PD:

Answer 27

Dopaminergic agents | Anticholinergic agents

Question 28

Efficacy of Levodopa:

Answer 28

80% show improvement, 20% regain near-normal motor function Efficacy wears off after 2-3 years

Question 29

MoA of Levodopa:

Answer 29

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

Question 30

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

Answer 30

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

Question 31

Side effects of Levodopa:

Answer 31

Acute: nausea, anorexia, hypotension, psychosis Chronic: dyskinesias, on-off effect Other: dysrhythmias, adrenergic stimulation

Question 32

Drug interactions with Levodopa:

Answer 32

Nonselective MAOIs (can cause overload of dopamine, norepi)

Question 33

MoA of carbidopa:

Answer 33

Peripheral decarboxylase inhibitor

Question 34

MoA of entacapone:

Answer 34

COMT inhibitor

Question 35

Examples of dopamine agonists:

Answer 35

Pramipexole | Ropinirole

Question 36

Receptors targeted by pramipexole/ropinirole:

Answer 36

D2/D3

Question 37

Efficacy of pramipexole/ropinirole:

Answer 37

Highly effective

Question 38

Side effects of pramipexole/ropinirole:

Answer 38

Hallucinations Compulsive behaviors (Think mania - dopamine overload)

Question 39

MoA of selegiline:

Answer 39

MAO-B inhibitor; decreases dopamine degradation | Not involved in norepi metabolism

Question 40

MoA of amantadine:

Answer 40

Enhances dopamine release into synapse

Question 41

Example of anticholinergic drug for PD:

Answer 41

Benztropine

Question 42

MoA of benztropine:

Answer 42

Blockage of muscarinic receptors, which relieves inhibition of dopaminergic neurons

Question 43

Side effects of benztropine:

Answer 43

Impaired vision Urinary retention Dry mouth Constipation

Question 44

Lewy bodies are:

Answer 44

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

Question 45

Anesthetic considerations for memantine:

Answer 45

Clearance reduced in alkaline urine

Question 46

Anesthetic considerations for cholinesterase inhibitors:

Answer 46

Prolongs succinylcholine; creates resistance to non-depolarizing NMBs

Question 47

Anesthetic considerations for anticholinergic drugs:

Answer 47

Side effects, especially HR Avoid drugs that impact cholinergic tone (TCAs) or increase HR

Question 48

Anesthetic considerations for amantadine:

Answer 48

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

Question 49

Anesthetic considerations for levodopa/carbidopa:

Answer 49

*Must* recieve q6-12 hours, even intra-op (via NG tube) Assess for side effects: dysrhythmias, adrenergic stimulation, hypotension, GI

Question 50

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

Answer 50

Assess for side effects: CV, hypotension, pleuropulmonary fibrosis

Question 51

Anesthetic considerations for selegiline:

Answer 51

Avoid ephedrine and meperidine! Extreme caution with vasoactive medications Titrate NMBs, sedatives, diuretics, etc carefully