Chapter 69 - Parkinson's disease Flashcards
parkinson background
- Neurological disorder.
- > = 65
- Neurons in substantia nigra die or become impaired.
- These cells produce the neurotransmitter dopamine (DA), which allows smooth, coordinated function of body muscles and movement.
- When -80% of the dopamine-producing cells are damaged, the motor symptoms of the disease appear
low dopamine causes parkinson - high dopamine causes schizophrenia (psychosis)
PD Sx
In ParkinsonDisease:
Less dopamine ➔ less instructions to the brain ➔ movement problems (called the TRAP major symptoms)
TRAP Major Symptoms:
- Tremor: when resting
- Rigidity: in legs, arms, trunk and face (mask-like face)
- Akinesia/ Bradykinesia: lack of/ slow start in movement
- Postural Instability: imbalance, falls
AdditionalSymptoms:
- Small, cramped handwriting (micrographia)
- Shuffling walk, stooped posture
- Muffled speech, drooling, dysphagia
- Depression, anxiety (psychosis in advanced disease)
- Constipation, incontinence
- Tremor: first noticeable symptom; usually starts in one hand or foot (on just one side, unilateral) and eventually spreads to both sides (bilateral).
- Resting tremor means it appears when the hand is not moving, such as when a person’s hand is resting in their lap.
Abnormal involuntary movement scale (AIMS) is used to
Measure involuntary movements from medications (Tardive dyskinesia)
Dopamine blocking drugs that can worsen PD:
■ Phenothiazines (e.g., prochlorperazine) used for nausea, agitation, psychosis,
■ Butyrophenones (e.g., haloperidol, droperidol) used for psychosis and behavior disorders or nausea
■ First and second-generation antipsychotics (e.g.,risperidone at higher doses, paliperidone); lowest risk with quetiapine
■ Metoclopramide, a renally-cleared drug that can accumulate in elderly patients
Non-motor Sx
- loss of smell (anosmia), constipation, sleep difficulties, low mood/depression and orthostasis.
What are off times or off episodes in PD?
Even with high doses of PD drugs and various combinations, the disease will progress, including extended periods of “off time.”
This is when symptoms of the disease worsen before the next dose of medication is due.
An “off” episode, with muscle stiffness, slow movements and difficulty starting movement, is one of the most frustrating aspects of living with the disease.
How to treat depression caused by PD?
- SSRI or SNRI
–> Concern: may contribute to tremor or inc risk of serotonin syndrome in patients taking other serotonergic agents - Tricyclic antidepressants, preferably the secondary amines (such as desipramine and nortriptyline), and the dopamine agonist pramipexole (reported to provide antidepressant effects), are other options.
Antipsychotic that has the lowest risk of movement disorders?
And what SE does it cause more than others?
Quetiapine is the preferred antipsychotic due to a low risk of movement disorders
but it can cause metabolic complications, including increased cholesterol and blood glucose.
Which antipsychotic has a low risk of worsening movement disorders
but has a high risk of agranulocytosis, seizures and other serious complications.
What should you monitor with it?
Clozapine
Requires frequent monitoring and reporting of white blood cells.
Pimavanserin (Nuplazid)
a 5HT2A/2C receptor inverse agonist, is FDA-approved to treat hallucinations and delusions in PD
when does NMS occur and how can you prevent it?
Rapid withdrawal of levodopa or dopamine agonists can lead to a condition similar to neuroleptic malignant syndrome (NMS),which is a life-threatening condition sometimes seen with antipsychotics.
These medications must be tapered off slowly if discontinued to prevent this condition.
Levodopa
Levodopa, a prodrug of dopamine, is the most effective agent.
why do you give carbidopa with levodopa?
What is the brand name of this combination?
Carbidopa is given with levodopa (in the combination product Sinemet) to prevent the peripheral (i.e., outside of the CNS) metabolism of levodopa, which would destroy most of the drug before it crosses the blood-brain barrier.
It is important to provide the right amount of carbidopa without causing excess side effects (see the drug table on the following page).
Initial treatment with … is sometimes better tolerated in the elderly than …
… are commonly used for initial treatment in younger patients and eventually in most patients.
Initial treatment with carbidopa/levodopa is sometimes better tolerated in the elderly than the dopamine agonists.
Dopamine agonists are commonly used for initial treatment in younger patients and eventually in most patients.
As the disease progresses, treatment will be directed at
This will require multiple therapies, such as
both reducing “off” periods and limiting dyskinesias (abnormal movement).
catechol-o-methyltransferase (COMT) inhibitors and MAO-B inhibitors.
Tremor-predominant disease in younger patients can be treated with:
Can you use these drugs for elderly? Why?
… or … are other options for initial treatment of tremor.
A centrally-acting anticholinergic.
Amantadine or a selective monoamine oxidase (MAO) inhibitor are other options for initial treatment of tremor.
The considerable side effects of these drugs make them difficult to use in elderly patients; the Beers criteria for potentially inappropriate medication use in older adults recommends to “avoid” use.
Do u use selective or non selective MAO I in PD?
And which one do you use in depression and why are they CI for PD?
For PD, selective MAO inhibitors are used; the non-selective inhibitors that are used for depression are contraindicated with dopaminergic drugs because they would block drug metabolism.
… can be useful to help with dyskinesias, in addition to tremor.
Amantadine
… treats severe freezing episodes that usually occur in more advanced disease, but it requires subcutaneous (SC) administration, has worrisome side effects and provides increased movement for just about an hour.
Apomorphine
… is a newer drug indicated for orthostatic hypotension, which can affect PD patients.
Droxidopa (Northern)
DOPAMINE REPLACEMENT DRUGS & AGONISTS + MOA
1) Carbidopa/levodopa:
MOA: levodopa is a precursor of dopamine. Carbidopa inhibits dopa decarboxylase nz metabolism of levodopa.
2) COMT inhibitors:
MOA: increase the duration of action of levodopa; inhibit the enzyme catechol-O-methyltransferase (COMT) to prevent peripheral conversion of levodopa. COMT inhibitors should only be used with levodopa.
3) Dopamine agonists:
MOA: act similar to dopamine at the dopamine receptor.
4) Dopamine agonist injection for advanced disease:
Indication: A “rescue”movement drug for “off”periods
Carbidopa/ Levodopa Brand names + doses
- Sinemet IR,
DOSE: 25/100 mg PO TID (Carbi must be 70-100 mg/day)
-Sinemet CR Tablets:
DOSE: 50/200 PO BID (double the IR)
Can be cut in half - do not crush or chew
- Rytary: ER capsule
DOSE: start at 23.75/95 mg PO TID if levodopa-naive; take whole or sprinkle on a small amount of applesauce - Duopa: Enteral suspension given via J-tube
- lnbrija: Levodopa capsule for oral inhaler, used as needed for symptoms during off periods
DOSE: lnbrija: 84 mg (2 capsules) inhaled up to 5 times daily as needed,
max dose: 420 mg/day
Titrate cautiously
CARBIDOPA/ LEVODOPA CI
- Non-selective MAO inhibitors within 14 days, (cz they block drug metabolism)
- Narrow angle glaucoma
CARBIDOPA/ LEVODOPA SE
- Can cause brown, black or dark discoloring of urine, saliva or sweat and can discolor clothing
- Positive Coombs test: discontinue drug (hemolysis risk)
- Unusual sexual urges, priapism
- inc uric acid
- Nausea
- Dizziness, orthostasis,
- Dyskinesias, dystonias (occasional, painful),
- Hallucinations, psychosis, confusion
- Xerostomia (dry mouth)
Rytary: suicidal ideation and attempts
Duopa: GI complications
Dose of carbidopa required to inhibit dopa decarboxylase
70-100 mg/day
1) Long-term use of carbi/levo can lead to …
2) DDI/DFI: Separate from:
3) Should it be tapered?
4) Duopa cassettes storage?
1) Fluctuations in response and dyskinesias
2) oral iron and high protein foods
3) Do not discontinue abruptly; must be tapered
4) Store in freezer, thaw in refrigerator prior to dispensing (good for12 weeks upon refrigeration)
List COMT inhibitor drugs + brand names
- Entacapone (Comtan)
- Opicapone (Ongentys)
- Tolcapone (Tasmar)
- Entacapone + Carbidopa/ Levodopa (Stalevo)
why is tolcapone (Tasmar) rarely used?
due to hepatotoxicity
opicapone (ongentys) dose & when do we need to dec dose?
50 mg POQHS
Dose dec needed in liver disease
Entacapone (Comtan) dose
max dose?
200 mg PO with each dose of carbidopa/levodopa
(max= 1,600 mg/day)
stalevo (carbidopa + levodopa + entacapone) dose
carbidopa/levodopa in a ratio of 1:4 with 200 mg of entacapone in each tablet
(example: 12.5/50/200 mg)
dec in levodopa dose of … % is usually necessary when adding on a COMT inhibitor
which SE can occur earlier with COMT inhibitors?
dec in levodopa dose of 10-30% is usually necessary when adding on a COMT inhibitor
Dyskinesias can occur earlier with COMT inhibitors
Why do we add Carbidopa? Entacapone?
Carbidopa: to prevent peripheral conversion of levo
Entacapone: to increase duration of action (also prevents peripheral conversion of levo)
Pramipexole
brand names + doses
how is it eleminated and when should you inc/ dec dose?
Dopamine Agonist
- Mirapex IR
DOSE: start with 0.125 mg PO TID, titrate weekly to max of 1.5 mg TID
(IR formulation also approved for restless legs syndrome (RLS)) - Mirapex ER
DOSE: start with 0.375 (IR x3) mg PO DAILY, titrate weekly to max of 4.5 mg daily
DEC dose if CrCI < 50 ml/min (90% renally excreted)
Ropinirole
- Requip XL:
DOSE: start with 2 mg PO daily, titrate weekly to max of
24 mg daily - Requip IR:
DOSE: start with 0.25 mg PO TID, titrate weekly to max of 8 mgTID
IR formulation also approved for RLS
CYP450 1A2 substrate; caution with CYP1A2 inhibitors
Rotigotine
how to apply?
warning?
Dopamine agonist
Neupro Patch
DOSE: start with 2 mg/24 hrs (early PD)
Max dose; 8 mg/24 hours
Also approved for RLS
- Apply once daily at the same time each day to the stomach, thigh, hip, side of the body, shoulder or upper arm;
- Do not use the same site for at least 14 day
- Remove the patch before an MRI;
- Do not apply a heat source over the patch;
- Avoid if sensitivity/allergy to sulfites
Warning:
application site (skin) reactions
SE:
hyperhidrosis
What is Bromocriptine?
is another drug in the dopamine agonist class;
no longer recommended
Warning with Pramipexole (Mirapex)
- postural deformity (e.g., bent spine, dropped head),
- rhabdomyolysis
Warnings + SE with dopamine agonists
- Somnolence (including sudden daytime sleep attacks)
- Orthostasis
- Hallucinations
- Dyskinesias
- Impulse control disorders
- Dizziness,
- Nausea, vomiting,
- Dry mouth,
- Peripheral edema,
- Constipation
Why do we titrate with dopamine agonists?
A slow titration (no more than weekly) is required due to orthostasis, dizziness, sleepiness; do not discontinue abruptly
Apomorphine
1) Brand
2) Indication
3) Dose
4) CI
5) SE
6) Monitoring?
7) What to give for emesis prevention?
1) Apokyn, Kynmobi
2) Apomorphine treats severe freezing episodes that usually occur in more advanced disease , has worrisome side effects and provides increased movement for just about an hour.
3) DOSE
Injection:
- Start with 0.2 ml (2 mg) SC PRN (up to Sx/day); titrate by 1 mg every few days
- Max single dose: 0.6 ml (6mg)
- Lasts 4S-90 minutes
- Must be started with a test dose in a medical office
Sublingual film:
- 10-30 mg PRN; max of 5 doses/day
4) CI: Do not use with SHT-3 antagonists (e.g.,ondansetron) due to severe hypotension and loss of consciousness
5) SE:
Severe nausea/vomiting, hypotension, yawning, dyskinesias, somnolence, dizziness, QT prolongation
Sublingual film: dry mouth, tongue pain
6) Monitor supine and standing blood pressure
7) For emesis prevention, give trimethobenzamide (Tigan) 300 mg PO TIO, or a similar antiemetic, started 3 days prior to the initial dose
DDI with sinmet
■ Contraindicated with non-selective MAO inhibitors (a two-week separation is required).
■ Iron and protein-rich foods can dec absorption.
■ Do not use with dopamine blockers, which will worsen Parkinson symptoms (e.g.,phenothiazines, metoclopramide).
MOA of amantadine
Blocks dopamine reuptake into presynaptic neurons and increases dopamine release from presynaptic fibers.
Primarily used to treat dyskinesias associated with peak dose of carbidopa/levodopa.
Amantadine brand names + doses
- Amantadine IR:
DOSE: 100 mg PO BID - Osmolex ER:
DOSE: 137 mg PO daily, increase after 1 week to
274 mg daily - Gocovri (ER):
DOSE: 129 mg daily, increase weekly to max dose of 322 mg daily - Dec dose in renal impairment
- eGFR < 15 ml/min/1.73 m’: ER products contraindicated
Amantadine Warning, SE, Notes
WARNINGS
Somnolence (including falling asleep without warning during activities of daily living), compulsive behaviors, psychosis (hallucinations, delusions, paranoia)
SIDE EFFECTS
Dizziness, orthostatic hypotension, syncope, insomnia, abnormal dreams, dry mouth, constipation
Cutaneous reaction called livedo reticularis (reddish skin mottling - can require drug discontinuation)
NOTES
Gocovri is indicated for the treatment of dyskinesia in patients receiving levodopa-based therapy
SelectiveMAO-B inhibitors MOA:
Block the breakdown of dopamine which increases dopaminergic activity.
Primarily used as adjunctive treatment to carbidopa/levodopa;
Rasagiline has an indication for monotherapy.
