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Advanced Pharmacology > Neurology Pt 1 Alzheimers and Parkinson's > Flashcards

Neurology Pt 1 Alzheimers and Parkinson's Flashcards

1
Q

Goals of Therapy

  • Improve _ _ _
  • Improve or slow the loss of ____/_____
  • Maintain and maximize independent ______
  • Minimize _ _ of drug therapy
A
  • QOL
  • memory/cognition
  • function
  • AE

NO CURE =(

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2
Q

2) Decarboxylase Inhibitors

(1)

A

Carbidopa

  • always used with levodopa (Sinemet)
  • NOT ACTIVE ALONE
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3
Q

Cholinesterase Inhibitors Adverse Effects

  • Donezepil:
  • Galantamine:
  • Rivastagmine:
  • ALL (3) - (_____ titrate dose)
  • ____cardia, d_____, s______
  • Urinary ______
  • Hyper______, sw_______
A
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4
Q

Adverse effects of too much _______ activity include hyperhidrosis, increased urinary frequency, dyspepsia, lacrimation

A

Acetycholine

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5
Q

Which of the following agents is selective in its inhibitory properties when given at low doses and should be avoided with dietary products high in tyramine content?

  • Carbidopa
  • Levodopa
  • Amantadine
  • Selegiline
A

Selegiline

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6
Q

Risk Factors

(3)

A
  1. Age
  • Natural loss of DA neurons of the corpus striatum (70-80% loss)
    • ​Terminal of DA neuron degenerates
    • Lewy bodies form in the soma of DA neuron which results in protein degradation amongst others
  1. Environmental exposures (amphetamine and cocaine use)
  2. Hereditary
  • Chromosomal mutations
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7
Q

6) Acetylcholine Receptor Antagonists

(2)

A

Benztropine (Cogentin)

Trihexyphenidyl (Artane)

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8
Q

Cholinergic Crisis Signs and Symptoms

What is it?

  • S
  • L
  • U
  • D
  • G
  • E
A

To much Ach from inactivity of AchE enzyme that usually breaks it down

  • Salivation
  • Lacrimation
  • Urination
  • Defecation
  • Gastric upset
  • Emesis
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9
Q

COMT Inhibitors

Agents (3)

A
  • Tolcapone
  • Entacapone
  • Opicapone
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10
Q

Acetylcholine Receptor Antagonists

AE

A

(Anticholinergic)

  • Sedation, depression, confusion
  • Dry mouth, blurred vision, constipation, urinary retention
  • Patients often find them difficult to tolerate
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11
Q

Neurotransmitters and Receptors cont.

  • Gaba-primary inhibitory transmitter*
  • Glutamate-primary excitatory transmitter*
A
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12
Q

Alzheimer’s Disease

Characterized by?

A

Acetylcholine Deficiency

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13
Q

Memantine (Namenda)

Adverse Effects

A
  • Constipation
  • HA, confusion, dizziness, hallucinations
  • HTN
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14
Q

Neurotransmitters and Receptors cont.

A
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15
Q

Pharmacologic Targets

_____ and _______ function depend on the coordinated ____ of _____ and ______

How to treat?

1) _____ Dopamine
2) _____ Acetylcholine

A

Motor, Cognitive, interaction, Dopamine, Acetylcholine

1) Increase
2) Decrease

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16
Q

Parkinson’s Disease

What’s the issue?

A

Lack of Dopamine

Goal: Increase Dopamine

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17
Q

COMT Inhibitors

AE (5)

A
  • Hepatotoxicity (tolcapone)- requires LFT monitoring (rarely used)
  • Orthostatic hypotension
  • Diarrhea
  • Hallucinations
  • Brown-orange urine discolation (almost exclusively w entacapone* - something unique about this drug)
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18
Q

Memantine

Indication

A

Moderate to severe Alzheimer’s disease

  • often used in combination with cholinesterase inhibitor
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19
Q

Acetylcholine Receptor Antagonists

MOA

A

Competes with Ach at muscarinic receptors (anticholinergic)

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20
Q

Carbidopa

  • Always give in combination with ______ (_____)
  • Titrate dose ____ up to __ mg of carbidopa daily
    • Reduce incidence of peripheral conversion = reduced _ _
  • Wearing off Phenomenon, what is it?
A
  • Levodopa (Sinemet)
  • Slowly, 75
    • AE
  • Loss of efficacy over time (proven effective for 2-5 yrs) OR Fluctuation in response to meds occurs over time and may need higher doses

Story time: Carbidopa is that friend you bring to the grocery when you are super hungry to stop you from grabbing too much food and not getting to your destination> always have carbidopa by your side bc it inhibits dopamine breakdown in periphery

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21
Q

Signs and Symptoms of Alzheimers

  • Difficulty performing ____ t____
  • Difficulty r_____ and w______
  • Loss of _______
  • D_____, D______, A_______
A
  • basic tasks
  • reading, writing
  • memory
  • Delusions, Depression, Agitation
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22
Q

MN was recently started on a new medication in addition to her Levodopa/carbidopa/entacopone (Stalevo). Since initation she has been experiencing dry mouth, trouble urinating and constipation. From the information provided, which of the following agents is most likely the cause of her newly experienced side effects?

  • Ropinorole (Requip)
  • Benztropine (Cogentin)
  • Donepezil (Aricept)
  • Pimavanserin (Nuplazid)
A

Benztropine (Cogentin)

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23
Q

Presentation

  • ________ Symptoms
    • ________ (slow/lack of movements)
    • Muscular _______ (e.g. cogwheel)
    • ______ tremor (e.g pill rolling)
    • ______ instability
    • ____ (e.g shoulder shrugs)
  • Dys______
  • Loss of _____
  • A_______
A
  • Extrapyramidal
    • Bradykinesia
    • Muscular Rigidity
    • Resting tremor
    • Postural instability
    • Tics
  • Dystonia voice changes
  • Loss of Smell
  • Anxiety
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24
Q

Medications Used in the Treatment of Parkinson’s Disease

(7)

A
  1. Dopaminergic agents (think replacement)
  2. Decarboxylase Inhibitor
  3. Caetchol O methyl transferase (COMT) inhibitors
  4. MAO-B Inhibitors
  5. Dopamine receptor agonists (NOT ON EXAM)
  6. Acetylcoline receptor antagonists
  7. Adenosine A2A receptor antagonist (NOT ON EXAM)
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25
Q

3) COMT Inhibitors

(3)

A

Entacapone (Comtan)

Tolcapone (Tasmar

Opicapone (Ongentys)

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26
Q

Acetylcholine Receptor Antagonists

Admin

A

Always used as adjunctive

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27
Q

Three histopathological hallmarks can impair neurotransmitter function of ________ leading to _____ deficits

    1. 3.
A

Acetylcholine, memory

  1. Beta-amyloid-rich senile plaques (lots of ongoing research)
  2. Neuritic plaques and neurofibrillary tangles
  3. Neuronal degeneration
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28
Q

Interactive Case

CD is a 68 yo F who presents to your clinic after hearing you were the expert in PD pharmacology. She has been taking Levodopa/carbidopa for 6 months. She complains of N/V and believes it is because she is taking too many pills (plus her friend said Carbidopa always made her sick). She asks if it would be okay to just take levodopa?

What is your response?

A

ABSOLUTELY NOT

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29
Q

Interactive Case

  • AB is a 73 yo M with PMH of HTN, HLD, DM, progressive loss of memory, difficulty reading, and most recently depression and agitation
  • He is diagnosed with Alzheimer’s Disease and referred to you for management
  • You decide to prescribe Donepezil (Aricept)
A

Alzheimers is deficiency in acetycholine

Donepezil = cholinesterase inhibitor

AE: SLUDGE

Galanatmine -> weight gain? switched to aricept

30
Q

Memantine (Namenda)

Route

A

Oral

  • Available as combination with donepezil (Namzaric) which is also given PO
31
Q

Memantine

Drug Interactions

A

No CYP 450 drug interactions

32
Q

Monamine Oxidase (MAO) Inhibitors

Agents (3)

A

Selegiline

Rasagiline

Safinamide

33
Q

Medications Used in the Tx of Alzheimer’s

2 classes, 5 agents

A
  • Cholinesterase Inhibitors
    • ​Donepezil (Aricept)
    • Rivastigmine (Exelon)
    • Galantamine (Razadyne)
  • ​NMDA receptor Antagonist
    • ​Memantine (Namenda)​
  • Combination
    • ​Donepezil + Memantine (Namzaric)

  • Not many tx options unfortunately*
  • Aricept and Memantine most common*
  • Onset: takes about 2-4 wks for these drugs to kick in*
34
Q

Neurotransmitters and Receptors

  • Serotonin is responsible for a myriad of things*
  • Notice there are so many different receptors*
  • ex) dopamine has like 4 receptors
A
35
Q

Where do CNS drugs primarily work?

  • 1) Supplementing the NT*
  • ex) deficiency in norepi, give norepi*
A
36
Q

PD Associated Psychosis

  • ~20-50% of pts with PD develop _______
    • Manifested by visual _____
    • ____ disease vs. _____?
  • Intrinsic Disease: Dopamine deficiency can __-regulate ____ function -> p____ and h_____ (visual)
  • ADE: _______ concentrations of dopamine may also cause psychosis
  • First drug approved to treat hallucinations and delusions of PD
A
  • Psychosis
    • hallucinations
    • Intrinsic vs. Adverse drug effects (ADE)
  • up, 5-HT, psychosis, hallucinations
  • Supratherapeutic
  • 2 reasons for psychosis in PD: intrinsic, ADE*
  • Overcompensation of Serotonin is the cause of the psychosis (not the dopamine)*
  • But not always the case. So we have to investigate if pt experienced after adding a new drug.? Or have they had this disease for awhile and been on drugs for awhile? that might be more intrinsic*
37
Q

Levodopa

  • Always combined with _____
    • Examples of combined formulations
A
  • Carbidopa
    • Sinemet, Sinemet CR, Parcopa ODT
    • Rytary (new formulation that has advanced control release to reduce motor fluctuations, less frequently dosed, can be opened and sprinkled unlike sinemet (not interchangeable with), expensive/should not be first line)
38
Q

Pimavanserin (Nuplazid)

  • MOA:
  • ____ data to support clinical benefit (1/4 trials)
  • Serious adverse affects
    • worsening ______, ___ prolongation, d____
  • Boxed Warning:
  • Cause of death _____ (cardiac, respiratory, infectious)
  • Use with _____ and _____ closely
  • Investigate whether _______ are an _ _
    • Increased _______ can also cause hallucinations
A
  • Selectively blocks serotonin (5-HT)
  • Limited
    • hallucinations, QTC, death
  • Increased mortality in elderly patients with dementia related psychosis (all antipsychotics)
  • unclear
  • caution, monitor
  • hallucinations, AE
    • dopamine

  • All antipsychotics have increased mortality, but causes are unclear…*
  • So with that -> USE CAUTION if your going to prescribe if you see pt has QTC prolongation or psychosis “I don’t think its safe for the pt”*
39
Q

Cholinesterase Inhibitors

Agents

Routes

A

Donepezil (Aricept) - oral, ODT

Rivastigmine (Exelon) - oral, transdermal patch

Galantamine (Razadyne) - oral

Oral disintegrating tablet since alot of older adults have trouble swallowing

40
Q

1) Dopaminergic agents

(2)

A
  • Levodopa (L-DOPA)
  • Amantadine (Symmetrel)
41
Q

Background

  • Degenerative disease of the _____ ______, resulting in gradual decline in _____, ______, and _____ functioning
  • Severe loss (~80%) of dopaminergic neurons of the substantia nigra
    • Presence of _____ _____ (intracellular inclusions)
    • Creates _______ of acetylcholine and dopamine
  • __ treatment = progresses to an ______ state (5-10 yrs)
  • Mortality due to ______ (aspiration pneumonia, clotting disorders, etc)
A
  • basal ganglia, motor, autonomic, cognitive
    • Lewy bodies
    • imbalance
  • No, akinetic
  • imobility
  • Occurs when you have about 80% loss of dopaminergic neurons**​*
  • Due to Lewy Bodies that block transmission of neuro signals*
  • Homeostasis of acetylcholine and dopamine messed up*
  • IMMOBILITY*-**All the effects usually secondary to immobility*
42
Q

Neuron

  • Building block of the CNS
    • Process/transmit information
  • Classified based on f_____, l_____, and n______ released
  • Form dendritic trees - receive from other neurons and transmit to cell body =
  • Cell body =
  • Carries signal from cell body eventually to synapse =
  • Junction of neurons where NT are released to interact with receptors or other neurons
    • ultimately stimulates channels that allow _____ and ______ allowing for necessary communication/processes
A
  • function, location, neurotransmitter
  • Dendrites
  • Soma
  • Axons
  • Synapse
    • ​opening, closing
43
Q

Levodopa

AE (4)

A
  • N/V (Antacid 30-60min before may help)
  • Orthostatic hypotension, Sedation
  • Depression, Delirium, Paranoia, Delusions, Hallucinations (CNS effects associated with long-term use)
  • Motor fluctuations (end of dose wearing off: peak-pose dyskinesa)

Breakthrough dyskinesia

44
Q
  • Dopamine in the periphery =
  • Goal is to get levodopa to the?
  • 2 enzymes that break down down in the periphery (2)
A
  • Does nothing and wreaks havoc
  • Brain
  • COMT, Decarboxylase
45
Q

Memantine (Namenda)

MOA

A

NMDA (glutamate receptor) antagonist

  • Attenuates (reduces) excitotoxic effects of glutamate (neuroprotective)
  • Glutamate is very excitatory but very neurotoxic as well*
46
Q

Cholinesterase Inhibitors

  • May _____ deterioration of ______ function
    • Preserves m_____, l_____, a______
  • Does not effect:
A
  • slow, cognitive
    • memory, learning, attention
  • underlying degenerative process
47
Q

Cholinesterase Inhibitors

Drug Interactions

A

Anticholinergic drugs (drugs that block cholinergic receptors)

Donepezil is a minor substrate of CYP3A4

  • Anticholinergic = blocks acetylcholine receptors*
  • Know that its a minor substrate, will not question on enzymes*
48
Q

MAO Inhibitors

  • Selegiline/Rasagiline are selective for MAO-B at __ doses
    • Enhances and prolongs effects of _____
    • At high doses it starts to inhibit ____
  • Safinamide (Xadago) - ____ selective MAO-B inhibitor
A
  • low
    • ​dopamine
    • MOA-A
  • more
  • Given at very low doses* is V efficacy*
  • Safinamide most recently approved*
49
Q

Cholinesterase Inhibitors

MOA

A

Selectively inhibits cholinesterase (enzyme that hydrolyzes (inactivates) Ach) in the CNS

  • Increases Ach concentrations in the cerebral cortex
50
Q

Levodopa

  • What is it?
  • Metabolized by what in the peripheral tissue?
  • If given as a monotherapy, what happens?
  • Always give it with?
A
  • Biosynthetic precursor of dopamine
    • Increases concentration of dopamine in the brain
  • Decarboxylase and Catechol-O-methyl transferase (COMT)
  • Less than 1% reaches the brain (always need decarboxylase inhibitor and often also needs COMT-inhibitor)
  • ALWAYS give in combo with carbidopa

  • What dopamine itself causes - GI upset*
  • Too much dopamine = depression, delirium, paranoia, hallucinations -> makes sense bc in schizophrenia they have too much dopamine*
51
Q

Pathophysiology

  • ___ receptors impacted
    • _____ _____ -*> protein degradation -> terminal degredation
A
  • D2
  • -* Lewy Bodies
52
Q

4) MAO-B Inhibitors

(3)

A

Safinamide (Xadago)

Selegline (Eldepryl)

Rasagline (Azilect)

53
Q

Acetylcholine Receptor Angagonists

Favorable effects (2)

A

Helps reduce tremor (too much Ach creates the famous parkinson TREMOR*)

Favorable effects on rigidity and bradykinesia

54
Q

Cholinesterase Inhibitor Adverse Effects

  • D
  • U
  • M
  • B
  • E
  • L
  • S
A
  • Diarrhea
  • Urination
  • Miosis
  • Bronchospasm
  • Emesis
  • Lacrimation
  • Salivation
55
Q

Goals of Therapy

  • Improve ____ and _ _ _
  • Prevent long term ______, minimize _____ disability
  • Slow disease _______
  • Maximize ___ therapy and minimize _ _
A
  • symptoms, QOL
  • complications, functional
  • progression
  • drug, AE
56
Q

Voltage vs. Ligand Gated Channels

  • Voltage - ____ mediated
    • Primarily located on the initial segment of the axon as well as axon itsself (___ action potential)
  • Ligand - ______ mediated
    • Ligand (inotropic) receptor - _____ opens
    • Metabotropic receptor - engages _-protein to produce ______ messanger (_____-gated)
      • Calcium-___synaptic-____ channel function
      • Potassium-___synaptic-____ opening of channel
A
  • ion
    • fast
  • neurotransmitter
    • directly
    • G, second, voltage
      • pre, inhibit
      • post, slow

  • Voltage such as Na, Ca, K*
  • Ligand more neurotransmitter based*
57
Q

Dopamine (DA)

  • Catecholamine, synthesized in dopaminergic neurons from tyrosine
  • DA receptors ( __ total, grouped into D_ and D_)
    • D1 - _____ synthesis of cyclic AMP (_____)
    • D2 - _____ synthesis of cyclic AMP, suppresses CA currents, activate K currents (_____)
  • ​Neostriatum of the basal ganglia regulates flow of information from the _____ cortex to the motor neurons of the _____ cord
A
  • 5, D1, D2
    • stimulate, excitatory
    • inhibit, inhibitory
  • cerebral, spinal

5 diff dopamine receptors - 2 types

58
Q

Central Nervous System

  • _____ and _____ cord
  • Integrates _____ information and generates ______ output
  • Billions of _______ and surrounding _____ cells
  • _______ are responsible for the flow of information
  • ___________- chemicals relay, amplify, and modulate signals
    • Excitatory or Inhbitory
A
  • brain, spinal
  • sensory, motor
  • neurons, glial
  • Neurons
  • Neurotransmitters
59
Q

COMT Inhibitors

How is it given?

A

Used in combination with levodopa/carbidopa to enhance its effectiveness and manage wearing off

Entacapone combined with Levodopa/Carbidopa (Stalevo)

Combo of all three is so common that we have Stalevo

60
Q

Carbidopa

MOA

A

Decarboxylase Inhibitor

  • Inhibits conversion of levodopa to dopamine in peripheral tissues (thereby decreasing GI and CV effects)
  • Increases amount of levodopa in the brain
61
Q

Acetylcholine (Ach)

  • Neurotransmitter responsible for _____ contraction (n____ receptors) and ________ component of the autonomic nervous system (_______ receptors)
  • Central Nervous System
    • Assists in: l____, m_____, neuro_____, c______
  • Peripheral Nervous System
    • _____ relaxation, skeletal and _____ contraction
A
  • muscle (nicotinic), parasympathetic (muscarinic)
  • learning, memory, neuroplasticity, concentration
  • Cardiac, muscle
62
Q

Cholinesterase Inhibitors

Indication

A

For mild to moderate disease

63
Q

COMT Inhibitors

MOA

A

Inhibits peripheral metabolism of levodopa through inhibition of Catechol-O-methyl transferase (COMT)

64
Q

Acetylcholine Receptor Antagonists

Agents (2)

A

Benztropine

Trihexyphenidyl

65
Q

MOA Inhibitors

Interactions (2)

A
  • At high doses (which should be avoided in PD), MAO-A can be inhibited
  • Avoid foods/drinks high in tyramine (eg aged cheese, smoked meat, red wines, others)
    • Reduction in tyramine catabolism -> hypertensive crisis

Tyramine also targets monoamine oxidase - so if you give someone these inhibitors it can cause a buildup of tyramine -> HTN crisis

66
Q

MAO Inhibitors

MOA

A

Irreversibly inhibits the monamine oxidase (MAO) enzyme system

  • MAO-A - catabolize Serotonin and Norepinephrine
  • MAO-B - catabolize Dopamine
  • 2 subtypes: breaks down diff neurotransmitters, we’re focusing on MAO-B*
  • MAO B inhibitors prevent breakdown of dopamine*
67
Q

MOA Inhibitors

Admin

A

As a class, always used as adjunctive therapy

  • NOT GIVEN AS MONOTHERAPY*
  • more refractory disease of parkinsons, this drug has really fallen out of favor dt the adverse effects*
68
Q

Pharmacological Considerations

  • Cholinergic pathways are damaged -> ____ of Ach transmission
  • Overstimulation of _____ receptor by ______ -> neuronal damage
  • Inhibition of ________ receptors -> impairs cognition
A
  • loss
  • NMDA, glutamate

- nicotinic

Perhaps inhibiting glutamate will prevent further progression of disease

69
Q

MAO Inhibitors

AE (3)

A
  • Augments levodopa toxicities (dyskinesias, psychiatric symptoms)
  • Nausea, dizziness, orthostatic hypotension, hallucination, insomnia
  • Serotonin syndrome with other serotinergic agents esp bc a lot of times given with antidepressants
70
Q

What is Alzheimers?

Accounts for __-__% of dementia

A

A progressive degenerative disease ultimately resulting in cerebral atrophy

50-75%

71
Q

Primary risk factors for Alzheimers

A

Age and Family Hx

  • Cerebral trauma, Vascular disease

Advanced Pharmacology (14 decks)

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