Parkinson's Disease Pharmacotherapy (L10)

PD is largely a clinical diagnosis based on motor and non-motor symptoms (bradykinesia ± rigidity and/or resting tremor)

response to __________ is supportive of diagnosis, but not required

levodopa

drugs that can worsen PD

anti_______ or prokinetic dopamine blockers (metoclopramide, prochlorperazine, and promethazine)

anti_______ dopamine blockers (haloperidol and risperidone)

emetic, psychotic

________________ provides the greatest symptomatic motor benefit and is appropriate for many patients

carbidopa/levodopa

__________ therapies should be selected according to the specific problem: wearing off, OFF episodes, dyskinesia, or residual symptoms

adjunct

PD pharm therapy improves symptoms by increasing __________ (primary treatment), directly stimulating __________ receptors, prolong levodopa effects, and modifying glutamatergic, adenosine, or _______ signaling

dopamine, dopamine, choline

PD pharm therapy improves symptoms by increasing dopamine (primary treatment), directly stimulating dopamine receptors, prolong levodopa effects, and modifying glutamatergic, adenosine, or choline signaling

always start _______ and go ________

low, slow

when to initiate PD treatment

Levodopa: preferred when greater ________ symptom relief is needed or adverse-effect vulnerability limits other options

motor

when to initiate PD treatment

______________: preferred when greater motor symptom relief is needed or adverse-effect vulnerability limits other options

Levodopa

when to initiate PD treatment

dopamine agonist: _________ (age) patients with mild symptoms (lower risk of hallucinations, sleepiness, orthostasis, and decreased impulse control)

young

when to initiate PD treatment

_____________: younger patients with mild symptoms (lower risk of hallucinations, sleepiness, orthostasis, and decreased impulse control)

dopamine agonist

_________ is the precursor for dopamine in the dopaminergic neuron

L-DOPA

Selegiline, Rasagiline, and Safinamide are all ____________ (class)

MAO-B inhibitors (decrease dopamine breakdown)

Ropinirole, Pramipexole, Rotigotine, and Apomorphine are all __________ (class)

dopamine agonists (increase dopamine in the synaptic cleft at D1 and D2 receptors)

Entacapone, Opicapone and Tolcapone are all _____________ (class)

COMT inhibitors (decrease L-dopa breakdown)

Carbidopa-Levodopa: Carbidopa _______ cross the BBB and Levodopa _______ cross the BBB

does not, does

Carbidopa/Levodopa: gold standard for Levodopa therapy

__________ is the dopamine precursor

Levodopa

Carbidopa/Levodopa: gold standard for Levodopa therapy

Carbidopa blocks ___________ conversion of levodopa to hep reduce ADEs from ____________ converted dopamine

peripheral (AEs ex: hypotension, tachycardia, N/V)

Carbidopa/Levodopa: gold standard for Levodopa therapy

____________ blocks peripheral conversion of levodopa to hep reduce ADEs from peripherally converted dopamine (hypotension, tachycardia, N/V)

carbidopa

Carbidopa/Levodopa: gold standard for Levodopa therapy

most effective symptomatic therapy which improves ___________, ________, and ________ (motor symptoms)

bradykinesia, rigidity, tremor

Carbidopa/Levodopa: gold standard for Levodopa therapy

disadvantages: motor fluctuations and __________

dyskinesia (unwanted/unexpected movements)

Carbidopa/Levodopa formulations and clinical role

IR tablet: initial therapy and flexible titration

ER tablet: longer coverage or selected motor fluctuations

Carbidopa/Levodopa/__________: given to prevent metabolism of L-Dopa in the periphery

Entacapone (COMT inhibitor)

Carbidopa/Levodopa formulations and clinical role

IR tablet: initial therapy and flexible titration

ER tablet: longer coverage or selected motor fluctuations

Inhaled levodopa: _________ treatment for intermittent OFF episodes

rescue

Carbidopa/Levodopa formulations and clinical role

IR tablet: initial therapy and flexible titration

ER tablet: longer coverage or selected motor fluctuations

_________ levodopa: rescue treatment for intermittent OFF episodes

inhaled

Carbidopa/Levodopa formulations and clinical role

IR tablet: initial therapy and flexible titration

ER tablet: longer coverage or selected motor fluctuations

intestinal _________: for advanced PD with refractory motor fluctuations

suspension

Carbidopa/Levodopa formulations and clinical role

IR tablet: initial therapy and flexible titration

ER tablet: longer coverage or selected motor fluctuations

___________ monotherapy: additional peripheral decarboxylase inhibition if needed (i.e. if the levodopa is causing too many peripheral SEs)

carbidopa

starting dose: carbidopa/levodopa IR 25/100mg, 1 tablet PO ______ times daily

titrate by 1 tablet every 1-2 days

three (TID)

starting dose: carbidopa/levodopa IR 25/100mg, 1 tablet PO three times daily

titrate by 1 tablet every _________

1-2 days

starting dose: carbidopa/levodopa IR 25/100mg, 1 tablet PO three times daily

usual max dose: carbidopa 200mg/day and levodopa 2000mg/day (not a hard cutoff tho)

dosing >_____ times a day may be necessary

carbidopa 70-100mg per day required to inhibit dopamine decarboxylase

4

starting dose: carbidopa/levodopa IR 25/100mg, 1 tablet PO three times daily

usual max dose: carbidopa 200mg/day and levodopa 2000mg/day (not a hard cutoff tho)

dosing >4 times a day may be necessary

carbidopa _______mg per day required to inhibit dopamine decarboxylase

100

starting dose: carbidopa/levodopa IR 25/100mg, 1 tablet PO three times daily

titrate by 1 tablet every 1-2 days

titration is based on balance of _________ and ___________

efficacy and side effects

carbidopa/levodopa is best taken (and best absorbed) when taken _________ food

without (i.e. take on an empty stomach for best absorption)

carbidopa/levodopa is best taken (and best absorbed) when taken on and empty stomach (can take w/ food if GI upset occurs, just be aware absorption will decrease)

space out high ________ meals and ________ supplements by 2 hours (large amino acids compete with levodopa for transport across the gut and BBB)

protein, iron

carbidopa/levodopa ADEs: _________ hypotension, dizziness, __________, _________ control disorders, and __________/ psychosis/ suicidal ideation

orthostatic, dyskinesia, impulse, hallucinations (not to be confused with symptoms of peripheral L-dopa conversion: N/V, tachycardia, anorexia)

carbidopa/levodopa: addressing motor fluctuations

wearing off: symptoms _________ before the next _____________ (signs of motor symptoms arise)

return, dosing interval

carbidopa/levodopa: addressing motor fluctuations

_________ _____: symptoms return before the next dosing interval (signs of motor symptoms arise)

wearing off (happens just as drug reserve in body is running out/ right before the next dose)

carbidopa/levodopa: addressing motor fluctuations

wearing off: symptoms return before the next dosing interval (signs of motor symptoms arise)

solution: increase ___________ OR consider addition of _________ or _________

frequency, MAO-B or COMT inhibitors

carbidopa/levodopa: addressing motor fluctuations

_________ on: therapeutic benefits are _________

delayed (happens right after dose is taken when drug is still accumulating up in the body)

carbidopa/levodopa: addressing motor fluctuations

delayed on: therapeutic benefits are delayed

solution: take drug ___________ OR change the formulation

on empty stomach (so it gets absorbed quicker)

carbidopa/levodopa: addressing motor fluctuations

peak-dose dyskinesia: __________ body movement caused by too high of __________ level

involuntary, dopamine

carbidopa/levodopa: addressing motor fluctuations

___________ ___________: involuntary body movement caused by too high of dopamine level

peak-dose dyskinesia

carbidopa/levodopa: addressing motor fluctuations

peak-dose dyskinesia: involuntary body movement caused by too ________ of dopamine level

high

carbidopa/levodopa: addressing motor fluctuations

peak-dose dyskinesia: involuntary body movement caused by too high of dopamine level

solution: __________ dose OR consider addition of _____________

reduce, Amantadine

dopamine agonist: really the only advantage of these over Carbidopa/Levodopa is that the 1st-episode of ___________ is delayed

dyskinesia

dopamine agonists: may be used as __________ for early symptoms in selected patients

monotherapy

dopamine agonists

may be used as monotherapy for early symptoms in selected patients

may be added to __________ to reduce “wearing OFF” time

levodopa

dopamine agonists

may be used as monotherapy for early symptoms in selected patients

may be added to Levodopa to reduce _____ ________

OFF time

dopamine agonists

may be used as monotherapy for early symptoms in selected patients

may be added to Levodopa to _________ “wearing OFF time”

reduce

dopamine agonists: AEs

-N/V, constipation, dry mouth

-hallucinations

-sudden onset of _______

-________ control

-dizziness, orthostatic hypotension, peripheral edema

sleep, impulse (new or worsening gambling, hypersexuality, compulsive shopping, binge eating)

adverse effects of _____________

-N/V, constipation, dry mouth

-hallucinations

-sudden onset of sleep

-impulse control

-dizziness, orthostatic hypotension, peripheral edema

dopamine agonists (Pramipexole or Ropinirole)

dopamine agonists

___________ is dosed PO TID (or ER tablet daily) and must be renally adjusted if CrCl is <50 mL/min

Pramipexole

dopamine agonists

Pramipexole is dosed PO TID (or ER tablet daily) and must be __________ adjusted if __________

renally, CrCl <50

dopamine agonists

___________ is dosed PO TID (or ER tablet daily) and is a major CYP1A2 substrate (caution with inducers like omeprazole, smoking) (caution with inhibitors like ciprofloxacin, cimetidine)

Ropinirole

dopamine agonists

Ropinirole is dosed PO TID (or ER tablet daily) and is a major CYP_____ substrate (caution with inducers like omeprazole, smoking) (caution with inhibitors like ciprofloxacin, cimetidine)

1A2

dopamine agonists

___________ is a 2mg/24-hour patch that can be applied once daily at the same time to different sites

Rotigotine

dopamine agonists

Rotigotine is a 2mg/24-hour _________

patch

dopamine agonists

___________ is a 2mg/0.2mL subQ PRN rescue treatment

AEs: hypotension, N/V (pre-treat with anti-emetic)

Apomorphine

dopamine agonists

Apomorphine is a 2mg _________ PRN rescue treatment

AEs: hypotension, N/V (pre-treat with anti-emetic)

subQ

dopamine agonists

Apomorphine is a 2mg/0.2mL subQ PRN _________ treatment

AEs: hypotension, N/V (pre-treat with anti-emetic)

rescue

COMT-inhibitors work by increasing duration of action of _________ by blocking enzymatic breakdown of _________ to inactive metabolites (3-OMD)

levodopa

___________ work by increasing duration of action of levodopa by blocking enzymatic breakdown of levodopa to inactive metabolites (3-OMD)

COMT-inhibitors (Entacapone and Opicapone)

COMT-inhibitors are used as _________ therapy only (adjunct or mono)

adjunct (to Levodopa)

COMT-inhibitors are used as adjunct therapy only

____________: 200mg PO with each dose of carbidopa/levodopa (TID-QID)

___________: 50mg PO once daily at bedtime

Entacapone, Opicapone

MAO-B inhibitors work by blocking the breakdown of __________ into inert compounds

dopamine (does not work on L-dopa)

MAO-B inhibitors work by blocking the breakdown of dopamine into inert compounds

they are used as adjunct therapy with __________ to decrease “wearing OFF” time and improve the wearing off of symptoms

carbidopa/levodopa

MAO-B inhibitors work by blocking the breakdown of dopamine into inert compounds

they are used as adjunct therapy with carbidopa/levodopa to decrease ____ ________ and improve the wearing off of symptoms

OFF time

MAO-B inhibitors work by blocking the breakdown of dopamine into inert compounds

ADEs: ____ _________ (may exacerbate psychosis in patients with psychiatric disorders) and may exacerbate SEs of ________

CNS depression, levodopa

______________ work by blocking the breakdown of dopamine into inert compounds

ADEs: CNS depression (may exacerbate psychosis in patients with psychiatric disorders) and may exacerbate SEs of levodopa

MAO-B inhibitors (Selegiline, Rasagiline, Safinamide)

______________ have a limited role in treating tremor-prominent PD (consider in younger patients without cognitive impairment)

anticholinergics (Benztropine or Trihexyphenidyl)

anticholinergics have a limited role in treating _________-prominent PD (consider in younger patients without cognitive impairment)

tremor

_______________ is an NMDA-receptor antagonist that is primary used to remedy levodopa-induced dyskinesia

Amantadine

Amantadine is an NMDA-receptor antagonist that is primary used to remedy _________-induced dyskinesia

levodopa

_______________ (like Istradefylline) block the indirect pathway in the basal ganglia (=reduce the suppression of movement) and therefore decrease bradykinesia

used as adjunct to levodopa in patients experiencing “OFF” episodes (not used as monotherapy)

A2A antagonists

PD _________ is treated the same as any other patient with ________ (if medication is required, select therapy with minimal motor-symptom worsening effects like Pimavanserin, Quetiapine, Clozapine)

psychosis

monitoring PD treatment

efficacy: tremors, bradykinesia, rigidity, activities of daily living, and QOL

if these are not getting better we can increase the ______ or increase the _________

dose, frequency

monitoring PD treatment

levodopa: assess wearing-off symptoms, delayed-on symptoms, and ___________

dyskinesia

monitoring PD treatment

________: assess wearing-off symptoms, delayed-on symptoms, and dyskinesia

levodopa

monitoring PD treatment: drug-specific

____________: assess sleep attacks, impulse control disorders, and hallucinations

dopamine agonist