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Pharm II > PD and movement disorders > Flashcards

PD and movement disorders Flashcards

1
Q

PD occurs where?

What causes PD?

A

PD occurs in the nigrostriatal pathway (loss of dopaminergic neurons)

o Dopamine inhibits GABA and ACh promotes GABA
o In PD you have low DA which means ACh takes over the brain causing the activation of a shit ton of GABA
»This can cause tremors -anti muscarinic is the common adjunct treatment

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2
Q

Drug Induced Parkinsonism

What does it cause in the synapse?

What drugs are responsible for this ?

A

• DA depletion from neurons (Less DA in synapse) caused by certain drugs of abuse

Reserpine; tetrabenazine; deutetrabenazine
drugs used to treat HD- since HD is reverse PD

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3
Q

What drugs can cause a DA receptor blockade that could also play a role in Drug-Induced Parkinsonism?

A

Antipsychotics (EPS)
-typical&raquo_space;> atypical

Metoclopramide (Reglan) -antiemetic
-DA antagonist used in GI disorders

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4
Q

What are some motor symptoms of Parkinsons Disease?

A

Progressive; combination of: (TRAP)

  • Tremor
  • Rigidity
  • Akinesia/bradykinesia/hypokinesia
  • Postural instability
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5
Q

What are the Key features of PD’s ?

A

o Repetitive “Pill Rolling” Movement
o Persistent Tremors
o Shuffling gait, taking steps

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6
Q

What are other non-motor symptoms of parkinsons disorder?

A

o Affective disorder; personality changes
o Abnormalities of autonomic function
o Sensory complaints; fatigue
o Sleep disorders

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7
Q

What drug would you not want to give to someone with PD?

A

Cognitive decline as disease advances
o Wouldn’t want to give AChesterase because of the pathophys of parkinsons

Cholinesterase Inhibitors (AChI’s)

  • Tacrine
  • Rivastigmine
  • Galantamine
  • Donepezil
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8
Q

What are your typical first line therapy options for PD?

What are some additional therapy considerations?

A

Typical first line therapy options:
o Dopamine receptor agonist
o Dopamine replacement therapy (levodopa, oral = pre-dopamine, different then the IV dopamine)
+/- enzyme inhibitors (decrease DA breakdown)

Additional therapy considerations 
o Muscarinic receptor antagonist 
For tremors
o Pimavanserin in PD related psychosis 
o Behavioral therapy; family/social dynamic
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9
Q

Draw out the diagram the describes the process of how L-Dopa gets into the brain

A

/Users/syddearmond/Desktop/Screen Shot 2019-02-18 at 10.25.43 AM.png

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10
Q

What is the target for DA receptor agonists?

A

Target: D2 receptors in basal ganglia

o ADR’s from activation of other DA receptors

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11
Q

DA agonists compared to L-Dopa?

A

No enzyme conversion concerns (COMT/MAO)
o Better BBB transportation/penetration
o More selective DA receptor activation
o Less Response fluctuations (on/off phenomenon) and dyskinesias

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12
Q

What drug combination would be beneficial in treating advanced PD and why?

A

DA agonist often used in combination with Sinemet
o Can reduce levodopa dose requirements, response fluctuations, and adverse effects
The ^ mg of L-Dopa the ^ chance they will get side effects and exhaust efficacy to L-Dopa
• L-DOPA + DA agonist will allow you to use less L-Dopa (less GI side effects)—beneficial in advance PD disease

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13
Q

Bromocriptine (ergot or nonergot?)

What receptors does it hit?

What are its indications for use?

How is it metabolized?

A

-Ergot derivative (pergolide discontinued in US)
o Not commonly used anymore

-D2/D3/D4 agonist 
o D2: target
o D3/D4: can cause side effects 
o Older drug, less selective than non-ergot derivatives 
o Not commonly used in PD anymore

-May see drug used for various indications
o Hyperprolactinemia syndromes
»Dopamine agonist can decrease prolactin release
o Pituitary adenoma
o Cocaine withdrawal
o Alcohol dependence
o Mastalgia

Metabolized by CYP34A
o Consider drug interactions

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14
Q

Non-Ergot DA agonists

How are they used?

What agents are available?

A

Used as monotherapy in mild PD or as an adjunct to Sinemet in advanced disease
o Commonly used for restless leg syndrome

Available agents are D2/D3 agonists
o Pramipexole
o Ropinirole
o Rotigotine (Transdermal Patch)

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15
Q

DA agonists ADR’s
(Ergot and Non-Ergot)

What situations do you have to be cautious in when giving a DA agonist?

A 
Similar to Sinemet
o GI 
o Cardiovascular 
o Dyskinesias
Side effect from drug as well as progression of the disease
o Mental disturbances

Caution in:
o Psychotic illness (ESP. Schizophrenia
o Recent MI; uncontrolled HTN of refractory patients

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16
Q

Levodopa

What is it?

How does it enter into the CNS?

A

-Essentially oral dopamine replacement
o More like a “pre-dopamine”

-Enters brain via L-amino acid transporter (LAT)
o Food intake affects drug absorption
Overloads transporter

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17
Q

Is Levodopa use as monotherapy? Why or why not?

A

Rarely used as monotherapy
o Only about 1-3% of L-DOPA reaches the brain (if used as monotherapy)
o Majority is decarboxylated in periphery to DA
→ Peripheral DA adverse effects (activates CTZ)
→ → Chemotrigger zone - induces vomiting
»»»>Need for combination with enzyme inhibitor

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18
Q

What is Carbidopa?

What is its purpose?

A
  • DOPA-decarboxylase inhibitor
  • Inhibits peripheral conversion of L-DOPA to DA

-Allows more L-DOPA to be transported across BBB via LAT to be converted to DA to then activate D2 receptors in basal ganglia

NOT USED AS MONOTHERAPY

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19
Q

Comparing Levodopa alone vs, Levodopa with carbidopa

A

/Users/syddearmond/Desktop/Screen Shot 2019-02-18 at 12.43.11 PM.png

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20
Q

What is the dosing of of Sinemet?

What is the Caveat of Sinament?

A

-Typically dosed 3-4 times daily, 30-60 minutes before meals
o Compliance concerns; adherence tools
>Difficult to take a pill 3-4 times a day

-Protein may reduce levodopa entry into brain due to competition for LAT
>Might have higher or lower doses at different times of the day
»>This could allow patients to have protein meals maybe in the morning to you would need to give a higher dose with it because the protein means will end up keeping for the same transporter Sinemet is using so you want to make sure that the Sinemet is higher, so you are getting the appropriate amount of medication across your BBB

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21
Q

Are there other formulations of Sinemet?

A

Controlled-release formulation available - Still BID

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22
Q

What feature of the TRAP mnemonic does PD work on the best?

A

-Can improve all clinical features of parkinsonism with most efficacy seen in bradykinesia
o Bradykinesia goes in the akinesia category of the mnemonic TRAP
»>Sinemet works on all letters of TRAP

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23
Q

When do you see the best results with Sinemet?

What does early initiation of this medication show?/ what does long term therapy lead to?

A

Best results in first few years of treatment
o Benefit diminishes after 3-4 years of treatment
»»Why we like the non-ergot DA agonists
o Dose adjustment over time with DA-related ADR’s
o Disease progression over time

2.)Early initiation lowers mortality rate compared to DA agonists

-Long-Term therapy may lead to other difficulties like response fluctuations
»>Reason why doctor might delay treatment

24
Q

Sinemets ADR’s

A

-Nausea/vomiting (DA receptors in GI tract-in CTZ)

-Cardiovascular
o Increased peripheral catecholamine formation
o Tachycardia, ventricular abnormalities
o Hypertension

-Behavioral (depression, anxiety, etc.)

-Dyskinesias (up to 80% in chronic therapy)
o 8 plus years
o Dose-related; considerable inter-patient variation

-Response fluctuations

25
Q

What is the handwriting like with people with PD?

A

**Handwriting of people with PD shrink’s - if the Sinemet is working their handwriting doesn’t shrink**

26
Q

What is end-of-dose akinesia?

A

Relates to dosing times
-Wearing-off reaction
»>Overtime you might get symptoms at the end of the dose as it wears off might need to increase dose
»>Dose-time related

27
Q

What is On/Off phenomenon?

How do you treat the off?

A

On/Off phenomenon
o Typically unrelated to dosing time

o On: improved mobility, often marked dyskinesia
(involuntary muscle movements)

o Off: marked akinesia (absence of movement) - if severe consider treatment
»>Apomorphine injection (potent DA agonist)—don’t use consistently, use for refractory akinesia only
o Less incidence with more continuous DA exposure
Intraduodenal; intrajejunal; drug delivery system - low levels of DA continuous 24 hours a day (like a diabetes pump)

28
Q

Dr. Thumar Black board answer to On/off phenomenon vs. End-of-dose akinesia

A

Both situations manifest with similar symptoms (i.e. akinesia) and both are related to either/both diminishing levodopa effect (at stable dose) or progressed Parkinson’s disease.

In practice, it is relatively easier to recognize and manage end-of-dose akinesia via Sinemet interval/dose adjustments than it is to recognize/manage a true on/off phenomenon. A dose increase is not always the answer; sometimes we can shorten the interval between doses or otherwise may need to both increase the dose and shorten the interval (with regard to managing end-of-dose akinesia).

Sometimes the on/off phenomenon is initially interpreted as end-of-dose akinesia, with Sinemet dosing/intervals adjusted accordingly, only to realize minimal to no improvement from the Sinemet change; as such, addition of another agent to Sinemet is typically the next step (with potential opportunity to reduce levodopa dose upon addition of new med).

Apomorphine is reserved for more severe situations of akinesia (can be used in either situation) as a sort of “quick fix” when a dose adjustment and/or addition of a new med would not relieve the severe akinesia swiftly enough.

29
Q

Carbidopa specifically inhibits ?

Over time what can this cause

A

Carbidopa’s inhibitory effect on DOPA decarboxylase may “rev-up” other metabolic pathways for levodopa SUCH AS: COMT; MAO-B
o Body sense higher [Levodopa] and tries to compensate by metabolizing it via COMT/MAO-B

30
Q

What does Catechol-O-Methyltransferase (COMT) do?

What issues can it cause in the periphery?

A

Central dopamine metabolism
>Breaks down Dopamine to become metabolite (3-MT)

Peripheral L-Dopa metabolism
>Breakdowns L-Dopa to metabolite (3-OMD)

Peripheral conversion to 3-OMD which competes with L-DOPA for LAT sites
>More competition may reduce Sinemet clinical efficacy**

31
Q

What is monoamine oxidase?

A

An enzyme in the body that breaks down catecholamines in the body such as epinephrine, norepinephrine, serotonin and dopamine

32
Q

What two types of MAO’s does the body have?

What is MAO-B caveat?

A
  • MAO-A breaks down NE/5HT (primarily)
  • MAO-B is more selective to breaking down DA (centrally)

MAO-B at high doses will become less selective and can break down NE

33
Q

What is the deal with eating foods rich in tyramine and taking a MAOI?

A

So if you eat foods high in tyramine (natural amino acid -precursor to NE) MAO will breakdown the NE. If you are taking a MAOI then you are inhibiting this conversion and will have an increase in NE which can lead to hypertensive crisis

34
Q

What COMT inhibitor’s agents are available? benefits/risks to each drug?

A

Tolcapone (Tasmar)
o Inhibits central AND peripheral COMT
o Central COMT inhibition =no added clinical benefit in trials
o Linked to hepatotoxicity

Encatcapone
o Inhibits peripheral COMT only
»>Allows a lower dose (mg’s) of the levodopa

35
Q

What is the name of the drug that has combined a COMT inhibitor and Sinemet?

What COMT inhibitor is it/what are the benefits?

A

Levodopa/carbidopa/entacapone– (Stalevo)
>Might be used in response fluctuation cases or moderate case of PD
>Less pill burden -“3 pills in one”
>Often allows/ requires lower levodopa dose which is beneficial because ADRs are related to increased levels of Levodopa

36
Q

Selegiline

A

o Irreversible MAO-B inhibitor; dietary restrictions by formulation/dose
o Metabolized to amphetamine derivatives

37
Q

Rasagiline

A

o Irreversible MAO-B inhibitor; less dietary restrictions than selegiline

38
Q

Safinamide

A

o Reversible inhibitor; less dietary restrictions than selegiline

39
Q

At High doses MAO-B inhibitors might become?

A

• Dose-independent MAO-B selectivity (may inhibit MAO-A at high doses)

40
Q

DDI’s and ADR’s of MAO-B?

A

• Drug Interactions (risk of serotonin syndrome with SSRI’s)
• Often allows /requires lower levodopa dose
o ADR’s related to increased levels of levodopa

41
Q

What is the benefit of using Antimuscarinics in PD?

A

(benztropine, trihexyphenidyl)
o Relieve tremor/rigidity (little effect on bradykinesia)
o Recall ADR profile from fall semester; cautious use in elderly
 Can cause impaired cognition, constipation, fall risk

42
Q

What is the benefit of using Apopmorphine in PD?

A

o Potent DA receptor agonist used as “rescue” from off-periods of akinesia during on/off phenomenon
o Injection—clinical benefit seen within 10 mins
o Significant nausea limits regular clinical use

43
Q

What is the benefit of using Pimavanserin in PD?

A

• Atypical antipsychotic – for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis ONLYYYYY
o Primarily targets 5HT2A and 5HT2C
 Focus more on serotonin receptors and less on DA
 This drug is only indicated for parkinsons compared to other Atypicals
o Possible QT prolongation
 Greater than 500 millieseconds

44
Q

What are tremors?

A

Tremor
• Rhythmic oscillatory movements; seen in PD
o Can be from disease and/or drug therapy
o May require dose/therapy adjustments
o Usually dose-dependent effect if drug related

45
Q

What is restless leg syndrome? and How do you treat it?

A

• Unpleasant, creeping discomfort that arises deep within legs and occasionally arms
• Symptoms occur when relaxed, especially lying/sitting down; may delay onset of sleep
• Treatment considerations:
o D2-agonists (non-ergot)
o Gabapentin (less common)

46
Q

What is HD?

A

• Autosomal dominant inherited disorder
o Usually begins in adult hood
o Over-activity of DA nigrostriatal pathways(DA inhibits GABA) + GABA neuron degeneration
→ Reduced/Impaired GABA activity – two things that inhibit GABA

47
Q

What drugs are used to treat HD?

A
  • Resperine
  • Tetrabenazine
  • Deutetrabenazine
48
Q

Resperine

A

o Recall: inhibits VMAT to reduce reuptake of catecholamines (used to use in treatment of HTN)
o Also binds to and destroys catecholamine storage vesicles, not allowing them to be stored resulting in sympathetic dysfunction

49
Q

Tetrabenazine

A

o More selective than reserpine for dopamine
o Depletes pre-synaptic DA stores; also mildly antagonizes D2 receptors
o Less ADRs than reserpine
o Indicated for the treatment of chorea associated with HD

50
Q

Deutetrabenazine (Austedo)

A

o VMAT-2 inhibitor

→ Doesn’t even allow DA to be stored to begin with

51
Q

Outside of PD, tremors can be?

A

normal/physiologic, disease-related, or drug-induced

52
Q

Treatment options for tremors?

A 
Treatment considerations:
o	Benztropine (also for EPS dystonia/psuedoparkinsonism)
o	Propranolol (also for EPS akathisia) -antagonize beta-2 receptors in the brain
53
Q

The Chorea in HD is directly related to?

A

Chorea related to imbalance of DA, ACh, and GABA in basal ganglia -involuntary jerky movements

54
Q

What symptoms are key features of HD?

A

• Progressive chorea and dementia (big abnormal movements)

55
Q

How are HD symptoms alleviated in regards to drugs?

A

• Alleviated by drugs that impair DA neurotransmission or block receptors

56
Q

What are the ADR’s of Resperine?

A

o Many ADR’s (also affects NE and 5HT): hypotension, depression, sedation, diarrhea, nasal congestion

*Not really used in practice today

Pharm II (12 decks)

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