Neurodegenerative

Question 0

Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne) are what drug class?

Answer 0

Cholinesterase Inhibitors

Question 1

Alzheimers leads to deficits in cholinergic signaling, what will this do?

Answer 1

Cholinergic neuron loss in hippocampus (memory and learning) and frontal cortex (executive function)
Decreases in choline acetyltransferase activity, acetylcholine amount, acetylcholinesterases, choline transport, and nicotinic acetylcholine receptor expression

Question 2

What is the cholinesterase inhibitors mechanism of action?

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

Answer 2

Prevents action of acetylcholinesterase, thereby increasing acetylcholine concentrations in the synapse

Question 3

Effects and side effects of cholinesterase inhibitors?

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

Answer 3

Effects: slight improvement in cognitive function, indicated for mild to moderate Alzheimers but does not halt the disease
Side effects: nausea, diarrhea, dizzy, headache, bronchocontriction

Question 4

What class of drug is Memantine (Namenda)?

Answer 4

NMDA Receptor Antagonist

Question 5

What are the indications and side effects of Memantine (Namenda) - NMDA receptor antagonists?

Answer 5

Indications: moderate to severe Alzheimers, has modest benefits
Side effects: dizzy, headache, fatigue, sedation, hypertension, rash, diarrhea, weight gain, urinary frequency, anemia

Question 6

What are the two possible mechanisms of action of Memantine (Namenda)?

Answer 6

1. Blocking leaky channels help reduce calcium-induced excitotoxicity
2. Blocking leaky channels help reduce background noise, making signals stronger

Question 7

What are two protein aggregates that are seen in patient’s with Alzheimers that future treatments may be able to focus on?

Answer 7

Amyloid plaques (amyloid beta): Block synthesis, promote clearance, block plaque aggregation formation
Neurofibrillary tangles (hyperphosphorylated tau): block aggregation of Tau

Question 8

What are two ways that Amyloid-beta can be processed?

Answer 8

Amyloidogenic: APP (Amyloid Precursor Protein) gets cleaved by beta-secretase followed by gamma-secretase and the aggregates form plaque **Hallmark of Alzheimers
Nonamyloidogenic: APP gets cleaved by alpha-secretase followed by gamma-secretase, no Amyloid-beta is formed

Question 9

What is the ApoE gene? What is the risk factor difference between ApoE2, ApoE3, and ApoE4?

Answer 9

ApoE gene encodes for a protein that facilitates clearance of Amyloid-beta
ApoE2: low risk for Alzheimers
ApoE3: normal risk for Alzheimers
ApoE4: increased risk (x3) for Alzheimers

Question 10

What is Tau protein? What happens to it in Alzheimers? How are Neurofibrillary tangles formed?

Answer 10

Tau protein is in normal neurons in the microtubules
It becomes hyperphosphorylated in Alzheimers
Proteins become tangled and form Neurofibrillary tangles which correlates with neuronal death

Question 11

What is Parkinson’s disease?

Answer 11

A movement disorder occurring mostly in the elderly, genetic risk factors but no obvious cause
Characterized by dyskinesias (difficulty of movement), muscle rigidity, tremor at rest, cognitive impairments, depression

Question 12

What does the basal ganglia consist of and what is its function?

Answer 12

Basal Ganglia: striatum, globus pallidus, subthalamic nuclei, substantia nigra
Function: starts purposeful movement and suppresses unwanted movement

Question 13

What two neurotransmitters must be balanced in order for controlled movement? Which is decreased in Parkinsons?

Answer 13

Dopamine and Acetylcholine

Dopamine in the Striatum is decreased in Parkinsons

Question 14

Which classes of drugs are effective for Parkinsons? How do they work?

Answer 14

Dopaminergic agents: increase dopamine in the striatum and mimic dopamine (dopamine agonists), ex: Pramipexole and ropinirole
Anticholinergic agents: prevent cholinergic inhibition of dopamine release

Question 15

How does Levodopa work?

Answer 15

Levodopa is a dopamine precursor, it is converted to dopamine. It is first line therapy for Parkinsons although the effectiveness of therapy wears off in a couple years (due to neurodegeneration)

Question 16

What meds are given with Levodopa to help it reach the brain in a small enough dose to not cause problems in the periphery?

Answer 16

Levodopa is given with Carbidopa (peripheral decarboxylase inhibitor) and entacapone (COMT inhibitor) because Levodopa is degraded by decarboxylases and COMT
When effectiveness wanes, Entacapone is added

Question 17

Levodopa side effects?

Answer 17

Dyskinesias (involuntary movements), “on-off” effect (fluctuations between hypokinesia and improvements)
Acute side effects that disappear in a few weeks include N/V, anorexia, hypotension, psychosis (schizophrenia-like symptoms)

Question 18

What is the main drug interaction with Levodopa?

Answer 18

Non-selective MAOI’s cause an overload of dopamine and norepinephrine leading to peripheral side effects

Question 19

What do Pramipexole and ropinirole do?

Answer 19

They are dopamine agonists, they mimic dopamine in the striatum
They are selective D2/D3 receptors, highly effective, fewer side effects than dopamine agonists that hit D1/D2 receptors, although they may cause hallucinations or compulsive behaviors

Question 20

What is Selegiline?

Answer 20

MAO-B inhibitor, decreases dopamine degradation

It does not have unwanted effects of MAOI’s, not involved in NE metabolism

Question 21

What is Amantadine do?

Answer 21

It is a synthetic antiviral that enhances dopamine release into the synapse

Question 22

How do anticholinergic drugs work for Parkinsons? Hint: they are also muscarinic receptor antagonists

Answer 22

Since muscarinic receptors inhibit dopamine release, by blocking these receptors, more dopamine can be released
Muscarinic receptors are present in stratum where they inhibit dopamine release from dopamine neurons
Example: Benztropine

Question 23

Side effects of anticholinergic drugs?

Answer 23

Dry mouth, constipation, impaired vision, urinary retention

Question 24

What are Lewy bodies?

Answer 24

Found in Parkinsons, they are protein aggregates composed of alpha-synuclein protein. Alpha-synuclein function is unclear.

Question 25

Anesthetic considerations: Memantine (NMDA receptor antagonist)

Answer 25

Clearance can be reduced by increasing urinary pH, be careful with bicarb

Question 26

Anesthetic considerations: Cholinesterase inhibitors- Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne)

Answer 26

Prolong succinylcholine

Relative resistance to non-depolarizing muscle relaxants

Question 27

Anesthetic considerations: Anticholinergic drugs (Example: Benzotropine)

Answer 27

Assess for anticholinergic side effects (increased HR)

Avoid drugs that impact cholinergic tone (TCA) or increase side effects (HR), if possible

Question 28

Anesthetic considerations: Amantadine

Answer 28

Evaluate for anti-cholinergic like side effects, rule-out congestive heart failure side effect

Question 29

Anesthetic considerations: Levodopa and decarboxylase inhibitors (Carbidopa)

Answer 29

Must receive every 6-12 hours. Administer 20 min pre-op and intra-op per NG (to avoid loss of effect, neuromuscular/respiratory failure)
Assess for side effects: cardiac dysrhythmias, adrenergic stimulation, orthostatic hypotension, GI

Question 30

Anesthetic considerations: Synthetic dopamine agonists (Example: pramipexole and ropinirole)

Answer 30

Assess for side effects: CV, hypotension, pleuro-pulmonary fibrosis

Question 31

Anesthetic considerations: Selegine (MAO-B)

Answer 31

Avoid ephedrine, meperidine (demerol). Use caution with vasoactive medications
Pronounced effect with neuromuscular blockers, sedatives, diuretics (titrate carefully)