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Integrated Drug Structure, Action, and Therapeutics > Parkinson's Disease > Flashcards

Parkinson's Disease Flashcards

1
Q

A deficiency in substantia nigra is known as…

A

Parkinson’s Disease

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2
Q

In someone who has died of PD, what are not found in the substantial nigra?

A

The cell bodies

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3
Q

How much of brain dopamine is found in the basal ganglia?

A

80%

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4
Q

What is the most common neurogenerative motor disorder? What percent of the population does this hit after age 60? After age 85?

A

Lewy body PD. 1% and 5%, respectively.

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5
Q

What is the average age of onset of PD?

A

55-60, although 10% is <40 years

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6
Q

How much striatal dopamine loss do you have before you start noticing the symptoms?

A

70-80% due to some redundancy in the system

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7
Q

Why is there a therapeutic window for treating PD?

A

Because we don’t treat until symptoms are seen at 70-80% loss, but treatment doesn’t improve symptoms past 85% loss. The rate at which this stratal dopamine loss occurs is different for each person depending on the progression and how aggressive the onset is.

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8
Q

akinetic

A

the absence of movement

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9
Q

Bradykinesia

A

movement is slow.

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10
Q

PD is considered a what kind of kinetic disorder?

A

A hypo kinetic disorder

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11
Q

Movement disorders include:

A

Hyperkinetic - increased movement
Hypokinetic - decreased movement
Dystonia - involuntary muscle spasms leading to sustained, painful postures
Myoclonus - rapid jerking movements
Chorea - dyskinesia (dance-like flowing movements)

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12
Q

What are two major pathological characteristics of PD?

A
  1. Degeneration of the nigrostriatal pathway (dopaminergic neurons of the SNc that enervate the caudate and putamen are lost)
  2. Appearance of Lewy bodies
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13
Q

What is a major component of Lewy bodies?

A

Alpha-synuclein. Mutations in alpha-synuclein gene lead to misfolding of the protein, leaky vesicles, and then an accumulation of cytoplasmic DNA.

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14
Q

If PD seems to have been inherited, what could you look for genetically?

A

mutations in the alpha-synuclein

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15
Q

Lewy bodies are in what neurodegenerative diseases?

A

multiple system atrophy (in oligodendrocytes)
Dementia with Lewy bodies (in neurons)
PD (in neurons)

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16
Q

Is alpha-SYN found mainly in pre- or post-synaptic neurons?

A

Presynaptic terminal, used for maintaining synaptic vesicles

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17
Q

What are the clinical manifestations?

A

A. Tremor at rest
B. Bradykinesia progressing to akinesia
C. Rigidity
Also…
D. Diminished sense of smell, changes in handwriting
E. Mask-like face (later symptom)
F. Excessive salivation/swallowing difficulties
G. Depression (co-morbidity, treated separately)
H. Sleep disturbances (due to medication or muscle rigidity)
I. Anxiety
J. Dementia (30% / more advanced pts)

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18
Q

What was the main drug used to treat PD until the 1960’s?

A

Anticholinergics, for excessive drooling

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19
Q

In true PD, do the symptoms start symmetrically or asymmetrically?

A

Asymmetrically

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20
Q

What distinguishes idiopathic PD from PD from other causes?

A

asymmetry of symptoms and resting tremor. Also response to L-dopa therapy

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21
Q

What can cause symptoms of PD?

A

stroke, infection, drug-induced toxicity (DA antagonists, MPTP)

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22
Q

What hereditary forms of PD are there?

A
  1. Alpha-synuclein (familial)
  2. PARKIN (familial, juvenile and early onset)
  3. UCH-L1
  4. PINK1
  5. LRRK2
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23
Q

What gene is associated with juvenile onset PD?

A

PARK2

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24
Q

What is the three-step process of tagging a protein with UBIQUITIN?

A
  1. E1 activates UBIQUITIN
  2. E2 transports UBIQUITIN
  3. E3 ligase protein complex (PARKIN) recruits substrate and UBIQUITIN is transferred to the target protein.
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25
Q

How else is the UBIQUITIN-proteasome system implicated in PD?

A
  1. Unfolded proteins enter the 20S proteasome cylinder to be degraded
  2. Cap proteins facilitate unfolding and release Ub chain. Ubiquitin carboxy-terminal hydrolase (UCH-L1) degrades chain to free Ub. Alpha-synuclein aggregates cannot be unfolded. Thought to interfere with 26S proteasome normal function.
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26
Q

What is required to release the monomeric form of Ub?

A

UCH-L1

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27
Q

What are the accumulated mis-folded proteins called?

A

Lewy-bodies

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28
Q

What organelle is implicated with this energy crisis?

A

The mitochondria

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29
Q

Where are the Lewy bodies located?

A

In the cytoplasm, but they spread to the dendrites

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30
Q

What gene implicated in PD is also known as Dardarin?

A

Leucine Rich Repeat Kinase 2 (LRRK2)

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31
Q

What gene links idiopathic and familial PD?

A

LRRK2

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32
Q

What was discovered when LRRK2 mutations were examined in different types of patients?

A

A link was discovered between familial and idiopathic PD.

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33
Q

Of the genes implicated in PD, which is the greatest known contributor to PD?

A

LRRK2. It has multiple pathogenic mutations.

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34
Q

In a dose-response curve of kinase activity, what is the difference between a high IC50 number and a low IC50 number?

A

The lower the IC50 number, the more potent the inhibitor.

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35
Q

What is MPTP?

A

It is a pro-toxin that is converted into MPP+ by MAO-B in glia, that produces PD-like neurological effects.

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36
Q

How does MPP+ enter the neuron?

A

Via the dopamine transporter (DAT)

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37
Q

What does MPP+ bind to within the neuron?

A

Neuromelanin. Levels of melanin are high within the nigrostriatal tract.

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38
Q

What can protect against MPTP effects?

A
  1. A selective MAO-B inhibitor such as Selegiline will prevent conversion from MPTP to MPP+ (and MPDP in between)
  2. DAT inhibitors protect against neurotoxicity (bringing in bad things via the DAT)
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39
Q

What form of the chemical creating “frozen addicts” crosses the blood brain barrier?

A

MPTP

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40
Q

Where does MPP+ concentrate once it gets into the neuron? What is the primary cause of MPTP toxicity?

A

It concentrates in the mitochondria where it inhibits oxidative phosphorylation. This depletes ATP, which leads to cell death. Mitochondrial damage is the primary cause of toxicity.

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41
Q

Does MPTP produce Lewy bodies?

A

No, although it does produce irreversible damage and acute PD-like symptoms.

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42
Q

What is the pesticide hypothesis?

A

The link between environment toxins and the subsequent development of PD to account for some fraction of idiopathic PD.

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43
Q

What does the normal function of Parkin and PINK1 appear to maintain?

A

Mitochondrial function and promote clearance of dysfunctional mitochondria.

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44
Q

What was the impact of the discovery of MPTP?

A

That the focus is on the mitochondria, and how dysfunction can affect the neuron.

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45
Q

What are the autosomal dominant and autosomal recessive genetic risk factors involved in PD?

A

Dominant: LRRK2, alpha-synuclein
Recessive: Parkin, PINK1

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46
Q

What are the five nuclei in the basal ganglia?

A
  1. Caudate
  2. Putamen
  3. Globus Pallidus
  4. Subthalamic
  5. Substantia nigra
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47
Q

What nuclei form the striata?

A

caudate and putamen

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48
Q

What do the basal ganglia do?

A

They regulate the flow of information from the motor cortex to the motor neurons of the spinal cord.

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49
Q

How many types of dopamine receptors are there? Which are similar to each other?

A
  1. D1 and D5 are coupled similarly.
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50
Q

Dopamine pathway: What is the pathway of dopamine in from aa to vesicle release?

A

Dietary phenylalanine is converted to tyrosine by hepatic PH. Tyrosine is transported into the neuron and then converted to L-DOPA by tyrosine hydroxylase. AADC/AAAD catalyzes L-DOPA to dopamine. Dopamine is packaged and released from vesicles into the synaptic terminal mediated by Ca2+.

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51
Q

Dopamine pathway: what does the dopamine in the synaptic cleft do?

A

It can affect dopamine auto receptors at the presynaptic terminal, receptors at the postsynaptic terminal, or be transported by the DAT presynaptically (which terminates the DA response, has 12 domains, and is target for cocaine).

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52
Q

Dopamine pathway: After transport by DAT….

A

Once DA has been transported inside by DAT, it can be stored via VMAT2, or metabolized. Metabolism options include MAO and then COMT, or COMT and then MAO. (Remember COMT adds methyl group, MAO removes NH2 and adds O2H). Homovanillic acid (HVA) is the product of either way. DOPAC is one of the bi-products.

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53
Q

What is the direct pathway from the basal ganglia to the motor cortex?

A

substantia nigra –> striatum –> substantia nigra –> thalamus –> cortex

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54
Q

What is the indirect pathway from the basal ganglia to the motor cortex?

A

substantia nigra –> striatum –> globus pallidus –> subthalamic –> substantia nigra –> thalamus –> cortex

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55
Q

Is D1 receptor activating or inhibitory?

A

Activating

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56
Q

Is D2-like receptors activating or inhibitory?

A

Inhibitory

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57
Q

If the normal direct or indirect pathways are working, what happens to the cortex?

A

It has a normal activating signal from the thalamus.

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58
Q

If the normal direct or indirect pathways have a loss of dopamine, what happens to the cortex?

A

The thalamus is inhibited from sending a signal to the cortex.

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59
Q

Does the loss of dopamine have the same effect on the direct and indirect pathways?

A

Both pathways inhibit the cortex, although the effect is unequal. The indirect pathway seems to actively inhibit the motor cortex stimulation. The difference allows drug design ideas.

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60
Q

What is the goal of medication therapy for PD?

A

Treat symptoms, not alter disease. Maintain functional mobility.

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61
Q

What are the four strategies?

A
  1. Replace DA
  2. Mimic dopamine action
  3. Inhibit breakdown of DA
  4. Modulate GABA (via anti-muscarinic agents)
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62
Q

What is the single most effective agent is PD treatment?

A

L-Dopa therapy

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63
Q

How is L-dopa given?

A

In mono therapy, only 1-3% enters CNS. Would have to give 2-8 g/day to reach therapeutic levels. Usually given with decarboxylase inhibitor such as carbidopa, to inhibit AAAD reactions in the periphery. (In periphery, L-Dopa would be converted into dopamine and not enter the CNS). This way, more can enter CNS.

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64
Q

What are the side effects of L-dopa from? Therapeutic effects?

A

Therapeutic effects and side effects are both from DA

65
Q

What are two main things to consider when using L-dopa therapy?

A
  1. Avoid starting too early

2. Manage icky side effects associated with dopamine

66
Q

If a carboxylase inhibitor is used to block AAAD, what reaction does it drive instead?

A

Conversion of L-dopa to DA in the CNS (as well as COMT in periphery)

67
Q

Does carbidopa act centrally or in the periphery?

A

In the periphery

68
Q

Carbidopa/levodopa

A 
Fixed proportions (1:10, 1:4)
levodopa formulation
start low to avoid desensitization
69
Q

Sinemet

A

CR formulation of levodopa

Increased 1/2 life can help end-of-dose reactions/on-off effects

70
Q

Parcopa

A

ODT formulation of levodopa

Helps with swallowing difficulties

71
Q

What are end-of-dose reactions?

A

Same as traditional wearing off
symptoms come back between doses
Akinesia

72
Q

What did the addition of carbidopa do?

A

Allowed massive reduction in dose

73
Q

What does L-dopa therapy do for a patient?

A

Acute response is dramatic
Pt. can return to normal lifestyle for a time (5-8 years)
Eventual failure may be due to desensitization + drug-induced side effects (refractory) or progression of disease
3 classic symptoms improve

74
Q

What are the 3 symptoms that improve with L-dopa therapy?

A

Bradykinesia shows greatest improvement
Some improvement in rigidity
Tremor improves less favorably

75
Q

Adverse effects of L-dopa therapy?

A
  1. GI effects (D2 receptors in chemoreceptor zone in brain stem triggered)
  2. Cardiovascular effects (D1 receptors cause vasodilation, B1 receptors cause low incidence of arrhythmia, NE release enhanced)
  3. Dystonia (primary or secondary, painful cramps)
  4. Dyskinesia (drug induced, usually tolerated)
  5. On/off phenomenon (sign of becoming refractory, not related to end-of dose)
  6. Behavioral effects (usually affects those at advanced stage: depression, hallucinations, mood-changes)
76
Q

GI effects of L-dopa therapy

A

Worse without carbidopa (80% vs. 20%)
Nausea, vomiting, severe loss of appetite
DA activates D2 receptors in chemoreceptor trigger zone( in brain stem, responsible for mechanical vomiting)
Tolerance to this should develop, management strategies such as small doses and with food help
Elevated liver enzymes

77
Q

Cardiovascular effects of L-dopa therapy

A

Related to DA conversion in periphery
Orthostatic hypotension is caused by DA at D1 receptors in mesenteric, renal, and coronary beds = vasodilation
DA = positive inotropic effect on myocardium, low rate of arrhythmias (benefits usually outweighs risks even in patients with heart disease)
Enhances release of NE

78
Q

Dystonia as a result of L-dopa therapy

A

Complex symptom
Can be secondary (drug-induced caused by L-dopa therapy: low or high dose) or primary (it’s own disorder often seen in early-onset PD that responds to DOPA, also originating in basal ganglia)
Painful, prolonged contractions/involuntary cramps beginning in one body region
Managed by changing (usually increase) DOPA levels, anticholinergics, botulinum toxin, PT

79
Q

Dyskinesia related to L-dopa therapy

A

Occurs in 80% of its over time
Related to dose, varies in intensity
After prolonged use (5-6 years) or within 6 months if high doses are used initially
Involuntary movements of the face, neck, tongue, hands, limbs induced by L-dopa
Choreothetosis - uncontrolled writhing movements
Possibly due to excessive DA receptor activation
Exacerbated by L-dopa plus carbidopa over just L-dopa alone
Usually tolerated, can lower dose but positive effects go away
Diphasic dyskinesia: occurs when levels are rising or falling. rigidity or involuntary movements
Peak-dose dyskinesia: most common - correlates with peak dose. Chorea form: less disabling

80
Q

On-off phenomenon as SE of L-dopa therapy

A

Unrelated to end-of-dose
Related to duration of treatment
Mobile patient can become akinetic (off) over a period of hours (freezing) and alternates with dyskinesia (on)
Common in patients that respond well to L-dopa
Can use ER formulation/apomorphine (1st gen DA agonist)
Sign of becoming refractory to L-dopa therapy

81
Q

Behavioral effects of L-dopa therapy

A

Depression, restlessness, anxiety, confusion, insomnia, vivid dreams/nightmares, hallucinations, personality and mood changes
Due to excessive DA in CNS (cortex and limbic)
More common in L-dopa plus carbidopa over L-dopa alone
Treatment: Reduce/withdraw medication or use atypical antipsychotics with low D2 receptor affinity

82
Q

How do you manage complications of L-dopa therapy?

A

ER formulations
Drug holiday (3-21 days, 60% people improve, doesn’t help on/off phenomenon, risk of conditions)
DA agonist
COMT inhibitor

83
Q

What conditions are at a higher risk of contraction due to drug holidays from L-dopa therapy?

A

Pneumonia, venous thrombosis, pulmonary embolism, depression

84
Q

What does current therapy favor the early use of? What does this decrease the risk of? What are other benefits?

A

DA agonists alone in mono therapy (later can use with L-dopa).
Decreases risk of developing dyskinesias
Does not require enzymatic conversion or a functional nigrostrial pathway

85
Q

What two DA receptor agonists are most widely used?

A
  1. Ropinerole
  2. Pramipexole
    Both 2nd gen
86
Q

What other DA agonists are there?

A

Bromocriptine (1st gen)
Pergolide (withdrawn due to fibrotic changes in heart valves related to 5HT2B)
Rotigotine (transdermal patch, D3 agonist)
Apomorphine (D4 receptor affinity, adrenergic receptors, and is rescue therapy via SQ injection. SE’s require anti-emetic)

87
Q

What class of dopamine receptors do ropinirole and pramipexole have affinity for?

A

Greater affinity for D2. D3 >D2, low affinity for D1.

88
Q

What are the adverse effects of the 2nd generation DA agonists?

A

Nausea and vomiting, postural hypotension, dyskinesia’s, impulse control, severe fatigue and sudden somnolence (associated with traffic accidents)

89
Q

What is restless leg syndrome and is it related to PD?

A

Sleep disorder
Not clearly linked to PD
Neuro condition linked to desire to move legs, creeping sensations, itching, burning
Unknown cause
Risk factors include pregnancy, fatigue, diabetic neuropathy
Better if you move, returns when you sit/lie down

90
Q

What meds can you use to treat restless leg?

A

Ropinirole 0.25-4mg/day
Pramipexole 0.125-0.75mg/day
Rotigotine transdermal patch
Also BDZ’s, opioids, anticonvulsants

91
Q

What do COMT inhibitors do for PD patients?

A

Block the activation of peripheral COMT produced by carbidopa inhibition of AAAD.
Blocks COMT in the CNS
Makes DA more available
Tend to be add-on to L-dopa therapy

92
Q

What are the COMT inhibitors?

A
  1. Tolcapone (both periphery and CNS)
  2. Entacapone (just periphery, much safer)
  3. Stalevo (levodopa, carbidopa, entacapone)
93
Q

What are the adverse effects of COMT inhibitors?

A

Diarrhea, fatigue, sleep disorders, anxiety, nausea, dizziness, hallucinations, confusion

94
Q

What does tolcapone require?

A

Liver function tests, it is toxic

95
Q

What are MAO-B inhibitors?

A

Drugs that inhibit the reaction from dopamine to DOPAC.

96
Q

What is responsible for the majority of dopamine metabolism in the striatum?

A

MAO-B

97
Q

What are the two oral MAO-B inhibitors?

A
  1. Selegiline

2. Rasagilene

98
Q

When are MAO-B inhibitors given?

A

In early PD as monotherapy

In combo with L-dopa

99
Q

Which is safer, Selegiline or Rasagilene?

A

Rasagilene. Selegiline is metabolized to amphetamine which enhances dopamine release but gives anxiety, insomnia (but not abuse). Rasagilene is 5X more potent without the amphetamine side effects. Low tyramine diet recommended.

100
Q

What are MAO-B inhibitors contraindicated with?

A

SSRI’s and tricyclic antidepressants in the increased risk or serotonin syndrome.

101
Q

Where are MAO B located?

A

Inside the presynaptic terminal on the outside of mitochondria.

102
Q

Why is tyramine bad?

A

It is normally metabolized by MAO A. When that is inhibited, tyramine builds up and raise blood pressure, inducing a hypertensive crisis. Tyramine is sympathomimetic -increases NE release and effect.

103
Q

What are some other approaches to controlling PD?

A
  1. Muscarinic ACh receptor antagonists
  2. Amantadine
  3. Droxidopa
  4. Experimental surgical procedures
104
Q

What do muscarinic ACh receptor antagonists do for PD patients?

A

Targets the indirect pathway
Used prior to L-dopa discovery
Useful for improving tremor, sialorrhea
Acts primarily on cholinergic receptors in the striatum (all 5 subtypes present)
Useful in younger patients (<70) and early PD
Adverse effects: drowsiness, blurred vision, dry mouth, constipation, mental confusion
Contraindicated in older PD patients or those showing mental confusion.

105
Q

What are the ACH receptor antagonists?

A
  1. Benzotropine
  2. Trihexphenidyl
    Have modest activity in PD
106
Q

What does amantadine do in PD?

A

Antiviral drug
May facilitate DA release
Anticholinergic
Weak NMDA antagonist (blocks receptors normally activated by glutamate)
Useful in treating L-dopa induced dyskinesia in advanced PD
Used to delay L-dopa therapy in early PD

107
Q

What does droxidopa do to help PD patients?

A

Helps with non-motor symptoms of PD
Pro-drug of NE
Used for neurogenic orthostatic hypotension

108
Q

What are the bad things about droxidopa?

A

SE’s: dizziness, nausea, confusion, exacerbation of heart problems
Increased risk of supine hypertension
Interaction: high dose carbidopa may block effectiveness

109
Q

Naltrexone

A

May be useful in impulse control

110
Q

Rivastigmine & donezipil

A

Cognitive symptoms/dementia in PD

111
Q

What are some experimental surgical procedures used in PD?

A

(used for drug refractory cases)

  1. Ablative surgery (target lesions in thalamus. 80% reduction in arm tremor)
  2. Deep brain stimulation (goal is to reduce/retitrate drugs to gain better symptom control/relief of dyskinesia. Electrical stimulation of thalamic nuclei).
112
Q

What are the two rating scales in PD?

A
  1. Unified Parkinson’s Disease Rating Scale (UPDRS) - out of 195 points
  2. Modified Hoehn and Yahr scale (stages I-V)
113
Q

What stage of PD would someone be in if they had bilateral involvement, but no impairment in balance?

A

Stage II

114
Q

What stage of PD would someone be in if they needed assistance to walk and even live?

A

Stage IV

115
Q

What stage of PD would someone be in if they had unilateral involvement and inconvenient symptoms but not disabling?

A

Stage I

116
Q

What stage of PD would someone be in if they were unable to walk or stand, required constant nursing care, and were restricted to a bed or wheelchair?

A

Stage V

117
Q

What stage of PD would someone be in if they had significant problems with posture imbalance and bradykinesia, and were restricted in activities?

A

Stage III

118
Q

What is usually the initial symptoms?

A

Resting tremor in an upper extremity

Initial asymmetry

119
Q

As PD progresses, what symptoms also progress?

A

Bradykinesia
Rigidity
Gait difficulty
Ataxia (freezing)

120
Q

What symptom doesn’t usually arrive until later?

A

Posture imbalance

121
Q

What are some somatic non-motor symptoms of PD?

A 
Sweating in strange places
Hypotension
Constipation
Overactive bladder
Seborrheic dermatitis
Soft voice
Decreased facial expression
Decreased arm swing on first involved side
Decreased sense of smell
Rapid eye movement
122
Q

What are some behavioral non-motor symptoms of PD?

A

Depression
Anxiety
Psychosis (visual hallucinations and delusions)
Dementia (hallucinations increase risk for dementia w/i a few years)

123
Q

What are the treatment goals of PD therapy?

A

Lessen progression of motor symptoms

Lessen non-motor symptoms

124
Q

What are some risk factors for more rapid progression of motor decline, cognitive decline, and dementia risk?

A

Older age at onset
Male with initial gate difficulty
Decreased response to levodopa
Psychosis

125
Q

What are some signs that you may have milder progression of PD?

A

Tremor only major sign at initial diagnosis

Good response to levodopa

126
Q

Essential tremor or PD: tremor is only symptom.

A

Essential tremor

127
Q

Essential tremor or PD: tremor occurs at rest

A

PD

128
Q

Essential tremor or PD: shaking or quivering voice.

A

Essential tremor

129
Q

Essential tremor or PD: tremor when active

A

Essential tremor

130
Q

Essential tremor or PD: alcohol reduces the tremor.

A

Essential tremor

131
Q

What are the 1st gen dopamine agonists?

A
  1. Bromocriptine

2. Apomorphine

132
Q

What forms do PD meds come in?

A 
All sorts:
transdermal patches - 2nd gen DA
tablets 
ODT - dopamine precursor
Injectables
Abdominal pump
Solution
133
Q

What is the first line agent for PD? When do you use it?

A

Levodopa/Carbidopa. Use when symptoms begin to disable. Stages II-V, or in older patients initially.

134
Q

How is Levodopa/Carbidopa dosed?

A

TID-QID, titrated q 3 days, then switch to CR BID-QID.

135
Q

What can you do if you notice “wearing off” during your levodopa/carbidopa therapy?

A 
Increase frequency of dose
Change to CR
Add MAO-I
Add COMT inhibitor
Add dopamine agonist
136
Q

What do you do if you notice that there is no “on” response, or it is slow?

A

Take on empty stomach, or with water only
Use ODT or IR formulation
Avoid taking especially with high protein food/drink
Crush and take with glass of water

137
Q

What do you do if you notice “freezing” occurring, or hesitation with beginning movement?

A

Increase dose
Add DA
Add MAO
Add PT

138
Q

What do you do if you notice peak dose dyskinesia?

A

Use smaller doses more frequently
Add amantadine
Deal with it - its not disabling

139
Q

Where is dystonia pain often located?

A

In the feet

140
Q

What are the contributors to hallucinations or psychosis in PD therapy?

A 
Medications for PD:
Amantadine
COMT inhibitors
DA
Levodopa
Anticholinergic medications:
Oxybutynin
Tolterodine
Benztropine
Diphenhydramine
141
Q

What can you do if you are experiencing psychosis/hallucination side effects?

A

Reduce or withdraw medication (anticholinergics first, then PD meds)
Atypical antipsychotics with low D2 affinity (clozapine, olanzapine, quetiapine, risperidone)

142
Q

What is Pimvanserin?

A

New drug for PD psychosis
Works at 5HT2a and 5HT2c
Minimal action at D2, muscarinic, histaminergic or adrenergic receptors
More psychosis = better results w/ drug
Serious risks: increased risk of death, QT prolongation, bradycardia, hypokalemia, falls, nausea, constipation, UTI’s, etc.

143
Q

What drug class is associated with SE’s of impulse control issues such as gambling, hyper sexuality, binge eating and other compulsive behaviors?

A

The 2nd generation dopamine agonists, such as pramipexole and ropinerole.
Reduction in dose usually helps or removes issue

144
Q

When do you use 2nd generation DA’s?

A

In younger patients with good cognition (delay use of L-dopa or reduce dose of L-dopa)
Useful in all stage of disease (mono therapy or adjunct therapy)
May reduce frequency of off periods
Delay dyskinesias
Impulse control and sleep attacks (especially pramipexole)

145
Q

What are the 2nd gen DA’s, and what is their usual dosing?

A

Pramipexole 0.125 - 1.5mg TID, or SR dosed QD (up to 4.5mg/day)
Ropinirole 0.25 - 1mg TID, or SR QD (up to 24 mg/day)
Rotigotine patch 2-6mg/day

146
Q

Which dopamine agonist is ergot derived?

A

Bromocriptine (1st gen)
Not used because it increases risk of pulmonary fibrosis
Less effective for PD
High risk of motor complications

147
Q

Rasagiline

A

MAO-B inhibitor
0.5-1mg/day
Adjunct with levodopa or DA in stages II-V
May delay need for increased levodopa doses
Mono therapy early in disease has mild benefit only
Hypertensive crisis, tyramine interactions, impulse control disorders, drug interactions

148
Q

Selegiline

A

MAO-B inhibitor
10mg/day or 2.5mg/day ODT
Adjunct with levodopa or DA in stages II-V
May delay need for increased levodopa doses
Mono therapy early in disease has mild benefit only
Insomnia, confusion, psychosis in elderly
Drug interactions with antidepressants

149
Q

Tolcapone

A

COMT inhibitor
100mg TID
Not used much in US because of liver issues
Requires liver monitoring

150
Q

Entacapone

A

COMT inhibitor
200mg w/ each dose of levodopa up to 8 doses/day
hypotension, syncope, fibrotic complications, hallucinations, orange color to urine, increased melanoma risk

151
Q

What do COMT inhibitors do?

A

They act as a useful adjunct to Levodopa for motor fluctuations
Allows L-dopa to work longer
“dopa extenders” of 1-2 hours
Useful when dopa is nearing “end-of-dose”
Not for initial PD or as add-on without motor complications

152
Q

Stalevo

A

COMT inhibitor
used pretty often
combination levodopa/carbidopa/entacapone

153
Q

Amantadine

A

100-400mg/day IR (BID-TID) or new ER
mildly helps bradykinesia, rigidity, tremor in I-IV stages
Mono therapy or adjunct to L-dopa/DA
tolerance develops, may need drug holiday
May be useful in treating L-dopa dyskinesia
SE’s: peripheral edema, psychosis, hallucinations, nightmares, confusion (can be scary for patient)

154
Q

Benztropine

A

Anticholinergic agent
0.5-2mg BID
Don’t use in elderly or dementia patients
Used as 2nd line for tremor early in PD or for younger patients
Mono therapy or adjunct
Lots of SE’s: confusion, hallucinations, sedation, tachycardia, constipation, dry mouth, decreased cognition and memory

155
Q

Trihexyphenidyl

A

Anticholinergic agent
0.5-2mg BID
Don’t use in elderly or dementia patients
Used as 2nd line for tremor early in PD or for younger patients
Mono therapy or adjunct
Lots of SE’s: confusion, hallucinations, sedation, tachycardia, constipation, dry mouth, decreased cognition and memory

156
Q

What are risk factors of progression in PD to dementia?

A

Older age
Greater severity of motor symptoms
Cognitive impairment
Hallucinations prior to dementia diagnosis
Postural instability and gait akinesia (freezing)

157
Q

When does cognitive impairment usually set in for dementia PD?

A

about 8 years or so after onset of motor features

Onset of dementia within 1 year after motor symptoms suggests Lewy body dementia

158
Q

Is dementia in PD always Lewy body dementia? What percentage of PD patients have dementia?

A

No. Could also be Alzheimer’s dementia, but usually occurs later. Lewy body can occur in those with and without PD.
Dementia in PD ranges from 20-40% with PD increasing risk for dementia 2-6 fold.

159
Q

What has been developed regarding LRRK2 activity?

A

Brain permeable inhibitors of LRRK2 activity as a molecular tool.

Integrated Drug Structure, Action, and Therapeutics (20 decks)

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