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Spring '14 Pharmacology > MS, Parkinson's and Alzheimers Drugs > Flashcards

MS, Parkinson's and Alzheimers Drugs Flashcards

1
Q

Alzheimer’s is a form of dementia that (does/ does not) have a distinct cause, like stroke or brain injury?

A

does not

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2
Q

Alzheimer’s causes problems in these 5 areas:

A
  1. Memory
  2. Language
  3. Judgment and Thinking
  4. Personality
  5. Perception
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3
Q

Alzheimer’s is divided into 2 general categories, they are?

A

Early onset and Late onset

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4
Q

If Alzheimer’s symptoms appear at age _______ , the diagnosis is considered early onset Alzheimers.

A

Before age 60

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5
Q

What contributes to early onset Alzheimers?

A

genetic factors

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6
Q

If symptoms of Alzheimers occur at age _________, the diagnosis is considered late onset Alzheimers.

A

after age 60

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7
Q

What is the prevalence of Alzheimers at 65 years of age?

A

5%

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8
Q

What is the prevalence of Alzheimers at age 95?

A

>90%

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9
Q

What 2 main things occur to the brain in Alzheimers pathology?

A
  1. Brain shrinkage
  2. Localized loss of neurons
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10
Q

What are the 3 hallmarks of Alzheimers?

A
  1. Decrease of cholinergic transmission
  2. Amyloid plaques (amyloid beta)
  3. Neurofibrillary tangles
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11
Q

A decrease in cholinergic transmission occurs at which two places in the brain?

A

The hippocampus and the frontal cortex

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12
Q

Because the hippocampus is affected in Alzheimers, you will see:

A

loss of memory and learning

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13
Q

Because the frontal cortex is affected in Alzheimers, you will see:

A

a loss in executive function

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14
Q

What is a neurofibrillary tangle?

A

aggregate of hyerphosphorylated tau protein

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15
Q

What is an amyloid plaque?

A

A plaque consisting of tangles of amyloid protein (insoluble fibrous protein aggregates)

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16
Q

What are the 2 main pharmacologic approaches to treating Alzheimer’s.

A
  1. Cholinesterase inhibitors
  2. NMDA receptor antagonists
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17
Q

Alzheimer’s disease inovolves a selective loss of ____________ neurons.

A

cholinergic

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18
Q

What is the purpose of cholinesterase inhibitors in brains affected by Alzheimers?

A

to restore cholinergic function

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19
Q

What do cholinesterase inhibitors do?

A

They prevent the breakdown of AcH by cholinesterases, leaving more AcH in in the neuromuscular junction

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20
Q

In the path of Acetylcholine, What happens in steps 1, 2, and 3.

A
  1. Choline 2. Acetyl CoA 3. Join to form acetylcholine
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21
Q

In the path of acetylcholine, What is happening in steps 4 and 5?

A
  1. AcH is packaged up to leave the axon, it then leaves the neuron and begins to cross the synapse 5. Acetylcholine crosses the synapse and reaches the nicotinic receptor on the receiving neuron causing a message to be sent.
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22
Q

In the path of acetylcholine, What is happening in step 6?

A

After the message has been sent, acetylcholinesterase is released into the synapse and breaks down acetylcholine, inactivating it.

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23
Q

Can cholinesterase inhibitors make up for the defect in cholinergic transmission?

A

No

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24
Q

Cholinesterase inhibitors are indicated for (mild/moderate/severe) Alzheimer’s?

A

mild to moderate

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25
Q

Do cholinesterase inhibitors improve congitive function?

A

There is a slight improvement in cognitive function

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26
Q

Do cholinesterase inhibitors halt Alzheimer’s disease?

A

Unfortunately No.

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27
Q

Give 3 examples of cholinesterase inhibitors.

A
  1. Donepezil (Aricept)
  2. Rivastigmine (Exelon)
  3. Galantamine (Razadyne)
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28
Q

By which route and how often are cholinesterase inhibitors given?

A

They are given PO and are given 1-2 x/ day

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29
Q

What are the 5 side effects of cholinesterase inhibitors?

A

nausea

diarrhea

dizziness

headache

bronchoconstriction

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30
Q

What is an NMDA receptor?

A

N-methyl-D-aspartate receptor is a glutamate receptor, which plays an important role in memory storage.

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31
Q

What does activation of the NMDA receptor do?

A

It opens an ion channel that is nonselective to cations.

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32
Q

When the NMDA receptor is activated, it opens the ion channel and ___ and ____ move into the cell, while ___ moves out.

A

Na+ and Ca++ move in and K+ moves out.

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33
Q

Activation of the NMDA receptor requires the binding of ______or ________ and the coagonist_________.

A

requires glutamate or aspartate and the coagonist glycine

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34
Q

The flux of ____ is the critical ionic flow that enhances synaptic plasticity and memory function.

A

Ca++

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35
Q

In cells damaged by Alzheimer’s there is an excess of ___________.

A

glutamate

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36
Q

What will an excess of glutamate do to neurons?

A

excessive gluatamate binds to NMDA receptors creating a chronic exposure of neurons to calcium which can speed up cell damage.

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37
Q

What do NMDA receptor antagonists do?

A

They block glutamate from attaching to NMDA receptor which prevents ionic flow through the channel including calcium, preventing damage to neurons by overexposing them to calcium.

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38
Q

Name an NMDA receptor antagonist?

A

Memantine (Namenda)

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39
Q

Memantine (Namenda) is used to treat _________ (mild/moderate/severe) cases of Alzheimer’s.

A

moderate to severe

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40
Q

Is there any clinical benefit to using Namenda (Memantine)?

A

There are only very modest benefits.

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41
Q

Name 10 side effects of Namenda (Memantine).

A
  1. Dizziness
  2. Headache
  3. Fatigue
  4. Sedation
  5. Hypertension
  6. Rash
  7. Diarrhea
  8. Weight gain
  9. Urinary frequency
  10. Anemia
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42
Q

Name the receptor in this picture.

A

NMDA receptor

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43
Q

What is excitotoxicity?

A

Pathological process in which nerve cells are damaged and killed by excessive stimulation by neurotransmitters.

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44
Q

What is synaptic plasticity?

A

a general term used to describe long-term changes in synaptic connectivity and efficacy, following physiological alterations in neuronal activity (as in learning and memory)

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45
Q

What does memantine do to plastic processes?

A

It improves them

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46
Q

What are the 2 ways memantine works?

A
  1. Blocks leaky channels to help prevent calcium related excitotoxicity
  2. Blocking leaky channels helps reduce background noise which makes signals relatively stronger
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47
Q

Do NMDA antagonists or cholinesterase inhibitors stop Alzheimer’s?

A

No, they do not cure or stop the progression of the disease.

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48
Q

What is APP?

A

Amyloid precursor protein

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49
Q

Amyloid beta protein makes the ____________.

A

amyloid beta plaque

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50
Q

In the non-amyloidogenic pathway, APP protein gets cleaved by ___________ and no amyloid Beta protein is formed.

A

alpha secretase, once cleaved gamma secretase forms the correct protein.

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51
Q

In the amyloidogenic pathway, __________ cleaves the amyloid precursor protein, and gamma secretase then makes the ___________.

A

Beta secretase; amyloid beta 40/42

52
Q

Amyloid beta 40/42 proteins make _________.

A

amyloid plaques

53
Q

Are the amyloid beta plaques the cause of the disease process?

A

The plaques themselves are not thought to be harmful. It is most likely the soluble derivatives of the amyloid beta plaque that cause cognitive deficits, rather than the plaques themselves.

54
Q

Early onset Alzheimers disease is heavily due to ____________________.

A

genetic factors.

55
Q

Many mutations associated with Alzheimer’s disease increase the amount of:____________.

A

amyloid beta

56
Q

When looking at the genes for Alzheimers, most of the mutations are clustered around __________ sites.

A

secretase

57
Q

What is the ApoE gene?

A

It encodes for a protein that facilitates the clearance of amyloid beta.

58
Q

The more ApoE you have, the more ________ of amyloid beta occurs.

A

clearance

59
Q

Carrying the ApoE genotype tells us what?

A

It is a significant risk factor for developing Alzheimers.

60
Q

What sort of risk for Alzheimers occurs in people who have the ApoE2 gene?

A

These people tend to have a lower risk of Alzheimers. There is some protective behaviors in this gene.

61
Q

What sort of risk for Alzheimers occurs in people who have the ApoE3 gene?

A

This gene is associated with a normal/ average risk of disease.

62
Q

What sort of risk for Alzheimers occurs in people who have the ApoE4 gene?

A

These folks are at an increased risk of getting Alzheimers.

63
Q

If you have one copy of an ApoE4 gene your risk for developing Alzheimers is?

A

you have a 3 fold increase in risk.

64
Q

If you have 2 copies of the ApoE4 gene, what is your risk for developing Alzheimers?

A

You have a 12-15 fold increased risk of developing the disease.

65
Q

What is the role of Tau proteins in normal neurons?

A

Tau proteins help stabilize the microtubules of normal neurons.

66
Q

What happens to Tau proteins in Alzheimer’s disease?

A

The Tau protein becomes hyperphosphorylated and can no longer function, it falls away from the microtubule and no longer supports it. The microtubule subunit falls apart and the Tau proteins aggregate in clumps.

67
Q

Clumps of Tau proteins are known as:_____________.

A

Neurofibrillary tangles.

68
Q

Neurofibrillary tangles are correlated with:___________.

A

Neuronal death

69
Q

Future Alzheimers drugs aimed at treating amyloid beta proteins will possibly do what?

A
  • block synthesis of amyloid beta
  • promote clearance of amyloid beta
  • block plaque formation
70
Q

Future Alzheimers drugs aimed at treating Tau proteins will hopefully do what?

A

Block aggregation of Tau proteins

71
Q

Name 3 common characteristics of someone with Parkinson’s disease?

A
  1. Repetitive ‘pill rolling’ movement
  2. Persistent tremors
  3. Shuffling gait (small steps)
72
Q

What is Parkinson’s disease?

A

a movement disorder occuring mostly in the elderly.

73
Q

What causes Parkinson’s disease?

A

Caused mostly by environmental factors, but may have some genetic risk factors.

74
Q

Parkinson’s is characterized by which 5 traits?

A
  1. Dyskinesias: difficulty with movement
  2. Muscle rigidity
  3. Tremor at rest
  4. Difficulty starting movement, difficulty stopping movement once started.
  5. Cognitive impairments; depression (depression is thought to be part of the disease process itself and not a response to living with the disease)
75
Q

What part of the brain does Parkinson’s affect?

A

The basal ganglia

76
Q

Name the 4 parts of the basal ganglia thought to be affected in Parkinson’s disease.

A
  1. Striatum
  2. Globus Pallidus
  3. Subthalamic nuclei
  4. Substantia nigra
77
Q

What is the function of the basal ganglia?

A

to start purposeful movement and suppress unwanted movement.

78
Q

The balance of which 2 neurotransmitters result in controlled movement?

A

Dopamine and Acetylcholine

79
Q

In Parkinson’s disease, which neurotransmitter is out of balance?

A

There is reduced dopamine in the striatum.

80
Q

By the time Parkinson’s symptoms appear, there has already been a ______ % loss of dopamine neurons.

A

70% loss of dopamine neurons from substantia nigra to striatum before symptoms occur.

81
Q

In the brain without Parkinson’s, what is the balance of dopamine to acetylcholine?

A

They are balanced

82
Q

In the brain with Parkinson’s, what is the balance of dopamine to acetylcholine?

A

There is a depletion of dopamine and a significant imbalance in the dopamine/ acetylcholine ratio

83
Q

What drug is considered the first line therapy for Parkinson’s?

A

Levodopa (L-dopa)

84
Q

What do dopaminergic agents do for brains affected by Parkinson’s?

A

They increase the amount of dopamine in the striatum. (increased delivery or decreased degradation). Dopaminergics mimic the effects of dopamine (dopamine agonists)

85
Q

What do anticholinergic agents do for the brain affected by Parkinson’s?

A

prevent cholinergic inhibition of dopamine.

86
Q

Of patients receiving L-dopa for Parkinson’s, __% of patients show improvement and ___% of patients re-gain near normal motor function.

A

80% improve, 20% regain motor function.

87
Q

Does L-dopa stop the progression of Parkinson’s?

A

No, it helps with the symptoms but does not halt the progression of the disease.

88
Q

Does L-dopa remain an effective therapy for long term use in Parkinson’s?

A

No, the effectiveness wears off over time (2-3 years). This is probably due to advanced neurodegeneration.

89
Q

What is Levodopa?

A

It is a dopamine precursor.

90
Q

In what parts of the body does L-dopa convert to dopamine?

A

In the brain and in the periphery

91
Q

In effect, L-dopa provides dopamine to the:

A

striatum

92
Q

Levodopa is degraded by __________ and ___________ into dopamine.

A

decarboxylases and catecholamine O- methyl transferase (COMT)

93
Q

Does dopamine cross the blood-brain barrier?

A

No

94
Q

Because dopamine does not cross the blood-brain barrier what does this mean for L-dopa that is converted to dopamine in the periphery?

A

It means that despite large doses of L-dopa, only small amounts of dopamine will reach the brain

95
Q

Do large amounts of dopamine from L-dopa conversion, cause problems in the periphery?

A

Yes

96
Q

What can be done to L-dopa to decrease the amount of it that is converted to dopamine in the periphery?

A

You can dose levidopa with Carbidopa (peripheral decarboxylase inhibitor) and entacapone (COMT inhibitor). This will allow the same amount of dopamine to reach the brain but requires a much smaller dose of L-dopa.

97
Q

Is entacapone (COMT inhibitor) given routinely with Levidopa?

A

No. Entacapone is usually added when the effectivenessof Levidopa/ Carbidopa wanes.

98
Q

List some side effects of Levidopa.

A
  • Involuntary movements (dyskinesias)
  • On/Off effect (fluctuations between hypokinesia and improvements)
  • Acute side effects like: nausea, anorexia, hypotension, psychosis (shizophrenia like symptoms with excess dopamine) Note: acute symptoms usually disappear after a few weeks.
99
Q

What adverse drug reaction can occur in patients taking MAO-I and L-dopa?

A

An overload of dopamine and norepinephrine can occur causing hypertension.

100
Q

What do dopamine agonists do?

A

They mimic dopamine at the striatum

101
Q

Name 2 dopamine agonists used to treat Parkinson’s.

A
  • Pramiprexole
  • Ropinirole
102
Q

Dopamine agonists like pramiprexole and ropinirole are selective for which receptors?

A

D2/D3

103
Q

Are dopamine agonists like pramiprexole and ropinirole effective?

A

Yes, these are highly effective.

104
Q

Pramiprexole and ropinirole have fewer side effects than the old dopamine agonists. Which side effects are specifically improved?

A

less nausea and vomiting

105
Q

The old dopamine agonists, before pramiprexole and ropinirole affected which receptors?

A

D1/D2

106
Q

Name 2 possible side effects of pramiprexole and ropinirole.

A
  • hallucinations
  • compulsive behaviors like gambling, eating, etc.
107
Q

Name 2 Parkinson’s drugs used to increase dopamine at the synapse.

A

Selegiline and Amantadine

108
Q

How does Selegiline work?

A

It is a MAO-B inhibitor. It decreases dopamine degradation. It does not have the unwanted effects of nonselective MAO-I’s

109
Q

What is MAO-B?

A

It breaks down dopamine and is not involved with norepinephrine metabolism.

110
Q

How does Amantadine work?

A

It enhances dopamine release into the synapse.

111
Q

Name an anticholinergic agent used to treat Parkinson’s.

A

Benztropine

112
Q

What is Benzotropine?

A

A muscarinic receptor antagonist

113
Q

What do muscarinic receptors have to do with dopamine?

A

Muscarinic receptors are present in the striatum where they inhibit dopamine release from dopamine neurons.

114
Q

How would blockade of muscarinic receptors help in Parkinson’s?

A

The blockade of muscarinic receptors relieves the inhibition of dopaminergic neurons and the end result is more dopamine release.

115
Q

What are the side effects of Benzotropine (muscarinic receptor blocker)?

A
  • dry mouth
  • constipation
  • impaired vision
  • urinary retention
116
Q

Do any of the therapies for Parkinson’s cure or halt the progression of the disease?

A

No

117
Q

What are Lewy bodies?

A

Lewy bodies are protein aggregates found in the brains of people affected by Parkinson’s.

118
Q

What are Lewy bodies composed of?

A

Protein aggregates of alpha- synuclein protein

119
Q

What is the function of alpha synuclein protein?

A

It is not known

120
Q

What is the function of Lewy bodies?

A

They may function at synapes or ER-Golgi trafficking, but little is known for sure.

121
Q

What are the anesthetic concerns for patients taking memantine?

A

Clearance can be reduced by increasing urinary pH, so be careful when using bicarbonate.

122
Q

What are the anesthetic concerns in patients taking cholinesterase inhibitors

A
  • prolongation of succinylcholine
  • relative resistance to non-depolarizing muscle relaxants
123
Q

What are the anesthetic concerns with patients taking anticholinergic drugs?

A
  • assess for anticholinergic side effects (especially heart rate)
  • Avoid drugs that impact cholinergic tone (TCAs) or increased side effects (HR) if possible.
124
Q

What are the anesthetic concerns in patients taking amantadine?

A
  • evaluate for anti-cholinergic like side effects, rule out CHF side effect.
125
Q

What are the anesthetic concerns in patients taking levodopa and decarboxylase inhibitors?

A
  • They must receive them Q6-12 hours (Administer 20 minutes pre/op and intraop via NG to avoid sudden loss of effect and neuromuscular/ respiratory failure
  • Assess for side effects. cardiac dysrhythmias, adrenergic stimulation, orthostatic hypotension, GI
126
Q

What are the anesthetic concerns in patients taking synthetic dopamine agonists?

A
  • assess for side effects: CV- hypotension,
    pleuropulmonary fibrosis
127
Q

What are the anesthetic concerns in patients taking Selegiline (MAO type B)?

A
  • avoid ephedrine, meperidine
  • use extreme caution with vasoactive medications
  • Pronounced effect with neuromuscular blockers, sedative agents, diuretics, etc. (titrate carefully)

Spring '14 Pharmacology (6 decks)

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