Neuro 1_3: Carrier: Parkinson's

Front 1

Parkison't Dz is d/t? characterized by?

Back 1

Characterized by resting tremor, rigidity, bradykinesia and postural instability
Results from degeneration of dopaminergic neurons in the basal ganglia

Front 2

Parkinson's Tx strategies aim to maintain dopamine levels in the brain by...

Back 2

Maintain dopamine levels in brain
Increasing synthesis
Inhibiting breakdown
Increasing release
Simulate dopamine
Other treatments
Surgical procedures

Front 3

What s Levodopa (L-dopa)?

Back 3

Biosynthetic precursor of dopamine
Given with carbidopa to inhibit the conversion of L-dopa to dopamine in peripheral tissues
L-dopa + carbidopa = Sinemet

Front 4

what does carbidopa inhibit?

Back 4

Inhibits dopa decarboxylase in the periphery only to prevent conversion of L-dopa to dopamine so that more L-dopa will reach the brain to be converted into dopamine.

Front 5

Can L-dopa reverse the effects of Parkinson's?

Back 5

Does not stop the progression of PD
Effective in relieving all PD clinical features
Specifically bradykinesia
Best results obtained in the first few years
Daily dose needs to be reduced over time
To avoid side effects not present initially
Patients become less responsive
May be lost completely

Front 6

L-dopa SEs?

Back 6

GI – Anorexia/Nausea/Vomiting
~80% of patients
Vomiting d/t stimulation of the chemoreceptor trigger zone (brainstem) and tolerance can develop to L-dopa
Anti-emetics are NOT given as they may exacerbate the parkinsonism
(most antiemetics are dopamine antagonists)

Front 7

How can patients tolerate more L-dopa?

Back 7

L-dopa + carbidopa – reduced GI distress
Patients can tolerate higher doses

Front 8

What causes HTN with L-dopa?

Back 8

In presence of nonselective monoamine oxidase inhibitors, sympathomimetics or large doses of L-dopa
Remember, carbidopa decreases peripheral effects

Front 9

What happens when patients take L-dopa for long periods?

Back 9

Dyskinesias
Up to 80% of patients receiving L-dopa for long periods
Choreoathetosis of the face and distal extremities is most common

Front 10

Are behavioral SEs mor common with L-dopa alone or L-dopa + Carbidopa?

Back 10

More common in L-dopa + carbidopa
Depression, anxiety, agitation, delusions, hallucinations, somnolence
Several atypical antipsychotics can be given to counteract
Clozapine, olanzapine, quetiapine and risperidone

Front 11

What is the on-off phenomenon? How do you treat it?

Back 11

Fluctuations in response to L-dopa
“off” periods marked by akinesia which alternate with “on” periods of improved mobility but marked dyskinesia
Off periods can be treated with SubQ apomorphine

Front 12

Does a drug holiday relieve the symptoms of "on-off pnenomenon"?

Back 12

No, but it does improve response to L-dopa. Drug is discontinued for 3-21 days.

Front 13

What does pyridoxine do to L-dopa? What is it?

Back 13

it's vit B6... it enhances the peripheral breakdown of L-dopa (in the absence of carbidopa)

Front 14

What do monoamine oxidase A inhibitors do to L-dopa?

Back 14

At the same time or within 2 weeks causes
Hypertensive crisis
Elevated BP, vascular damage to the kidney, headache, mental confusion
Note, MAO B inhibitors are usually okay.

Front 15

What are the contraindications for L-dopa?

Back 15

Psychotic patients – exacerbates mental disturbances
Angle-closure glaucoma (increased IOP)
History of melanoma/undiagnosed skin lesions
L-dopa precursor to skin melanin  malignant melanoma

Front 16

Selegiline
Rasagiline

Back 16

Monoamine Oxidase Inhibitors
Monoamine oxidase B (MAO-B) metabolizes dopamine

Front 17

Tolcapone
Entacapone

Back 17

Catechol-O-Methyl Transferase Inhibitors
Catechol-O-methyltranferase (COMT) metabolizes L-dopa in periphery and brain
More active when dopa decarboxylase is inhibited
Increases levels of 3-O-methyldopa (3OMD)
Elevated 3OMD associated with poor response to L-dopa

Front 18

Which is more potent, Selgiline or Rasagiline? Which one can be monotherapy?

Back 18

Rasagiline
Monotherapy for early symptomatic treatment
Adjunctive therapy in advanced disease
Selagiline is adjunctive only

Front 19

What happens when patients on Selagiline/Rasagiline take meperidine, tricyclics/SSRIs a/o Tyramine?

Back 19

Serotonin crisis- excessive stimulation of the CNS and CV system.
Meperidine, antodpressants and tyramine are CIs for MAO-B inhibitors

Front 20

Why is tyramine a CI for MAO-B inhibitors?

Back 20

Tyramine is metabolized by monoamine oxidase; MAO inhibitor can cause excess levels of tyramine: elevated BP and others

Front 21

What competes with L-dopa to cross BBB with the L-amino acid transporter?

Back 21

3-OMD: 3-O-methyldopa; competes with L-dopa to cross the BBB; high levels of 3-OMD means less L-dopa is getting across the BBB.
COMT is in periphery and brain, MAO-B is in the brain only.

Front 22

Which COMT inhibitor decreases metabolism of L-dopa in the periphery only?

Back 22

Entacapone: Decreases metabolism of L-dopa in the periphery
Tolcapone: Decreases metabolism in BOTH periphery and CNS

Front 23

Why use a COMT inhibitor?

Back 23

Selective COMT inhibitors
Prolongs L-dopa activity
May be useful in patients taking L-dopa and experiencing fluctuations
More prolonged “on-time”

Front 24

What drug can produce orange urine?

Back 24

Entacapone

Front 25

Why does Tolcapone have a black box warning?

Back 25

Tolcapone – increased liver hepatotoxicity
Signed consent in the US

Front 26

What is Stalevo?

Back 26

L-dopa + carbidopa + entacapone
Simplifies drug regimen
If patient is stable on appropriate doses

Front 27

What is Amantadine?

Back 27

Antiviral with antiparkinson properties
UNKNOWN mechanism of action
MAY enhance dopaminergic function:
-Synthesis
-Release- from remaining dopaminergic neurons
-Reuptake

Front 28

amantadine clinical use?

Back 28

Less potent than L-dopa
Benefits are short-lived
Treatment lasts only weeks
Reduces bradykinesia, rigidity, and tremor

Front 29

What anti-parkinson drug causes Livedo reticularis?

Back 29

amantadine
Livedo reticularis: purple mottling of the skin; goes away with discontinuation

Front 30

What is the advantage of dopamine receptor agonists?

Back 30

Unlike L-dopa:
Do not require enzymatic conversion
Have no toxic metabolites
Do not compete with other substances to actively cross into blood and the BBB
Have fewer AE
Lower incidence of response fluctuations and/or dyskinesias

Front 31

What is the Tx strategy for dopamine receptor agonists?

Back 31

Initially – L-dopa + carbidopa started then a dopamine receptor agonist added
Dose of agonist is increased over time
Depends on response and tolerance
Later – When L-dopa treatment produces end-of-dose akinesia, “on-off” phenomenon, or lack of response to L-dopa

Front 32

what are the older dopamine receptor agonists?

Back 32

Ergot alkaloids:
Bromocriptine- D2; hyperprolactinemia
Pergolide- D1 & D2; withdrawn in U.S.

Front 33

What are the newer dopamine agonists?

Back 33

Non-Ergots
Pramipexole
Ropinirole

Front 34

Pramipexole

Back 34

Specific for the D3 receptor
Can be used effectively as monotherapy
Mild PD
As adjunctive therapy
Advanced PD to lower L-dopa dose/smooth out fluctuations
May reduce AFFECTive symptoms of PD
Renal impairment may require dose adjustments
Ropinirole

Front 35

Ropinirole

Back 35

Selective for D2 receptor

Front 36

Dopamine Receptor Agonists – Adverse Effects

Back 36

GI
Anorexia/N/V - take with meals
Cardiovascular
Postural hypotension – at initiation
Dyskinesias – reversed by reducing dose
Mental Disturbances – more severe than with L-dopa
Somnolence (newer, non-ergot agents), SUDDEN SLEEP ATTACKS!!!, confusion, hallucinations, delusions, etc…

Front 37

Dopaminergic dysregulation syndrome

Back 37

Seen with L-dopa and DOPAMINERGIC AGONISTS
-Compulsive use of dopaminergic drugs in male patients
--Leads to cyclical mood disorders (hypomania/manic), tolerance and impulse control disorders (hypersexuality and pathological gambling)

Front 38

Other PD treatments: Apomorphine

Back 38

SubQ injection – quickly into blood and brain
Effect seen ~10 min and lasts for ~2 hours
Potent dopamine agonist
Temporary relief of off-periods of akinesia in patients on dopamine therapy
Adverse effects – nausea; pretreatment with an antiemetic (trimethobenzamide)

Front 39

Other PD treatments – Acetylcholine Blockers

Back 39

Ex: BENZTROPINE MESYLATE, biperiden, orphenadrine, procyclidine, TRIHEXYPHENIDYL
Treatment starts low and increases until benefit or adverse effects seen
Improve the tremor and rigidity
Little effect on bradykinesia

Front 40

Other PD treatments – Surgical procedures

Back 40

Ablative surgery
-Thalamotomy or posteroventral pallidotomy– to alleviate conspicuous tremor
Deep-Brain Stimulation
-Thalamus – relieves tremor
-Subthalamic nucleus or globus pallidus internus – clinical fluctuation in advanced PD
Transplantation of dopaminergic tissue
-Controversial effects

Front 41

Parkinson's: Dopamine, ACh, GABA

Back 41

Front 42

How do you prevent an acute dystonic attack from drug-induced dyskinesias?

Back 42

Typical (1st generation) Antipsychotics:
-Haloperidol or fluphenazine
Metoclopramide (anti-emetic)
To prevent an acute dystonic attack:
Benztropine, diphenhydramine, trixhexyphenidyl, diazepam

Front 43

Drug-induced Dyskinesias: Tardive Dyskinesia

Back 43

Offending drug should be tapered off, if clinically possible
-Switch to Atypical antipsychotic (2nd generation)
-Reducing the dopamine receptor blocker often worsens the dyskinesia
Treat with drugs that interfere with dopamine signaling:
-EX: Reserpine, tetrabenazine, trixhexyphenidyl
-EX: Phenothiazines, butyrophenones (both as a last resort)

Front 44

What is resltess leg syndrome and how do you treat it?

Back 44

Characterized by unpleasant, creeping discomfort
Occur when relaxed (sitting or laying down) →urge to move
Treatment:
Dopamine agonists (ropinirole, pramipexole)

Front 45

Which pateitns can you start on a dopamine agonist, older or younger?

Back 45

younger

Front 46

If Sinemet begins to “wear-off”, what drug can be added to the treatment plan?

Back 46

Sinemet: L-dopa + Carbidopa
you can add Entecapone... SEs might occur from additional L-dopa to the brain= dyskinesias and stuff