Topic Discussion During Internal Medicine Rotation

1. 1
Accumulation of
alpha synucelin in
the SN
ROS generation and
Loss of DA neurons
(-) direct pathway
(+) indirect pathway
DISINHIBITION OF
MOVEMENT
Background and Epidemiology
Pathophysiology
Anna Sandler
Parkinson’s Disease
PharmD Candidate, 2023
 Parkinson’s Disease (PD): Neurodegenerative disease with bradykinesia + other features
 Loss of dopaminergic (DA) neurons in the substantia nigra (SN)
 Affects 1-2 people/1000 people; 1% affected > 60 years old
 Men > women
 Genetic predisposition: 5-10%
Etiology:
Environmental,
Genetic, Alpha-
synuclein
accumulation
Thalamus
Striatum
GP
SN
DA
Movement
Striatum
Thalamus
GP
SN
Movement
DA
Direct Pathway Indirect Pathway

2. 2
Psychtoic
Mood,
Cognition
Non-
motor
sx
Sensory
Sleep
Autonomic
1: Exclusion can also be done by seeing whether a patient has a clear response to Levodopa treatment, which is not well seen
with overlapping syndromes. Imaging studies can also help exclude bleeding, stroke, or massive lesions.
2: Typical /first generation antipsychotics are most implicated such as haloperidol and fluphenazine. Prokinetics drugs include
metoclopramide, and valproic acid has been implicated in inducing parkinsonism with long-term use.
 No treatments have
been shown to be
disease-modifying or to
be neuroprotective
 Diagnosis based on clinical symptoms (sx) and exclusion1
o Other conditions: Lew body disease, multiple
system atrophy
o Iatrogenic2
: Antipsychotics, CCBs, antiepileptics, and
Li
 Cardinal features: Bradykinesia + Tremor and/or rigidity
o Late manifestation: Gait disturbance
 Other features due to deposition of alpha-synuclein in other
brain areas
Treatment overview
 Hallucinations
 Impulse control
 Depression
 Anxiety
 Impaired
judgement
 GI
disturbances
 Sexual
dysfunction
 Restless legs syndrome
 REM behavior sleep
disorder
Non-pharmacologic Non-motor symptoms
Motor symptoms
Managing side
effects/resistance
Diagnosis and Clinical Presentation
Individualize

3. 3
Drug/Class Dosing Pearls, Adverse Effects (AEs), Monitoring
Dopamine
precursor
Carbidopa-
levodopa
(Sinemet,
Parcopa)
Initial: 25/100 mg IR ½ tab BID-TID
Titrate over several weeks to full tab TID
as tolerated
Take with meals or snack to avoid nausea
Superior effects on PD motor sx and qol > other drugs
Higher rate of adverse effects: dyskinesias
Should not be abruptly stopped d/t withdrawl concern
AEs/Monitoring: Nausea, somnolence,orthostatic
hypotension (OH) headache (HA) (early, non-serious),
delusions, agitation (older patients, serious), impulse-
control disorders, LFTs, BUN, SCr, CBC, s/sx of
peripheral neuropathy
MAOBis:
Selegiline
Rasagiline
Safinamide
Selegiline: 5 mg PO BID
Rasagiline: 0.5 mg PO once daily
increased to 1 mg daily as tolerated
Safinamide: 50 mg once daily titrated to
100 mg once daily
AEs/monitoring: Nausea, HA, confusion, hallucinations,
falls, insomnia dyskinesia, hypertensive crisis4
Avoid with TCAs or SSRIs, washout period of 14 days
required, Safinamide usually as adjunct to levodopa to
help w/ motor fluctuations
Amantadine IR: 100 mg PO BID or TID
ER: 100 mg daily
Can be used as monotherapy (if tremor present)5
AEs/monitoring: Livedo reticularis and ankle edema,
rarely tx-limiting, renal function, mental status, BP
Managing motor symptoms
 Therapy may not be needed
 Pharmacological options:
o Monoamine Oxidase type B
inhibitor (MAOBi)
o Amantadine
o Levodopa (L-dopa)
o Anticholinergic
Mild
</= 65 y/o
 Dopamine
agonist (DA)
 L-dopa
Maintaining Independence in Everyday Life with Non-Pharmacological Treatments
 Nutrition
o At risk of malnutrition due to increased metabolic demands and taste alterations
o No consensus on a specific diet but certain recommendations: high fiber, hydration,
protein restriction?3
>65 y/o
 L-dopa>
DA
3: Dietary protein restriction may be needed in advanced disease with motor fluctuations; competition with other amino
acids may interfere with the absorption of Levodopa.
4: Doses of selegiline > 10 mg/day place patients at higher risk of a hypertensive crisis, impulse control disorders are more
common in older patients with advanced , the serious AEs
5: Can be used as monotherapy in younger patients in PD, particularly when tremor is prominent, also useful in managing
dyskinesias and off-time
 Exercise and Physical Therapy
o Regular aerobic exercise: Walking, swimming, tai
chi
o Resistance training
o Balance training
o May slow motor progression and improve non-
motor symptoms
Moderate-severe
 L-dopa preferred at any
age
Mild-moderate
Age
Motor sx management: Drug Table

4. 4
Drug/Class Dosing Pearls, Clinical Trials, Adverse effects (AEs)
DAs:
Pramipexole,
ropinirole,
rotigotine
Pramipexole: 0.125 mg TID (IR), increase by 0.125
mg every 5-7 days or 0.375 mg daily at bedtime
(ER), titrated by 0.375 mg increments to max 1.5-
4.5 mg
Ropinirole: 0.25 mg TID (IR), gradually increase by
0.25 mg/week for 4 weeks (max: 3 mg/day), or 2
mg daily at bedtime (ER), titrate by 2 mg
increments to max of 24 mg
Rotigotine: Once daily TD patch, 2mg/24 hours
and titrated weekly by 2mg/24 hour increments
to max of 6 mg/24 hours
AEs/Monitoring: nausea, vomiting, renal
function, OH, confusion, hallucinations,
peripheral edema, impulse control
disorders
Start low and go slow, do not abruptly
stop treatment
Anticholinergics6
:
Trihexyphenidyl
Benztropine
Trihexylphenidyl: 0.5mg-1 mg PO BID, gradully
increased to 2mg daily
Benztropine: 0.5-2 mg BID
AEs/monitoring: dry mouth, blurred
vision, constipation, tachycardia,
intraocular pressure
Sometimes useful as monotherapy for
patients </= 65 y/o who have tremor, w/h
significant bradykinesiaor gait disturbance.
Can also be added in those unresponsive
to L-dopa or DAs.
Gradually d/c to avoid exacerbation of PD
Side effect Management Other notes
Nausea Additional carbidopa
Add domperidone or PRN
Ondansetron or trimethobenzamide
Orthostasis May need to d/c or lower reduce anti-
hypertensive medication
Taper or withdraw the less-effective
therapies prior to reducing L-dopa
Impulse control disorders
(ICDs)
Persistent: Cognitive behavioral
therapy?
Education’
Reduce dose until ICD resolves
Most commonly associated with DAs
Risk factors: younger age, male, comorbid
anxiety and depression
Managing side effects/resistance to treatment
Motor sx management: Drug Table continued
No benefit of catechol-O-
methyltransferase (COMT)
inhibitors as initial therapy!7
Rescue DA: Apomorphine
6: DA depletion can lead to cholinergic sensitivity, resulting in exacerbation of PD sx by cholinergic drugs. Thus, anticholinergic
drugs may be useful in PD, especially younger patients who have disturbing tremors.
7: The STRIDE-PD trial demonstrated that the combination of levodopa-carbidopa with entacapone (LCE) resulted in an increased
frequency of dyskinesias compared to levodopa-carbidopa monotherapy (LC); frequency at week 134: 42% versus 32%; p=0.02

5. 5
Side effect Management Other notes
Wearing off  Initial increases in levodopa dose
 Smaller but more frequent doses
 Add COMT inhibitors, DA or MAOBi
 Rescue therapy with apomorphine
 Longer-acting formulations
 Protein avoidance and/or taking med
on empty stomach 40-60 min before or
60-90 min after a meal
 Save greater protein content for the
evening
 Dose increases may lead to or
worsen dyskinesias
 Doses in the evening may fail
d/t failure to reach therapeutic
threshold
 Use of a MAO B inhibitor may
help prolong the half-life of DA
in the brain
 Obtain baseline EKG before
starting apomorphine
Peak-dose
dyskinesia
 Reduce levodopa dose
 Administer more frequently
 Use amantadine
 Clozapine in refractory dyskinesia
 Extensive monitoring required with
clozapine: ANC, WBC,
Unpredictable
off periods
 Document and diaries
 Avoid protein around drug
administration
Failure of on
response
 Avoid protein around drug
administration
 Add a dose of levodopa one hour
before the usual failure of “on” time
 Avoid Metoclopramide due to
dopamine receptor block!
Off period
dystonia
 Take CR levodopa before bed time if
occurs in the morning
 Take levodopa or DA during the night or
first thing in the morning
 Use apomorphine rescue injection
 Monitor supine and standing BP
and pulse, s/sx hemolytic anemia,
OH, and mental status changes
with apomorphine

Akathisia  Take CR levodopa or DA before bed
Persistent
tremor
 Add on amantadine or anticholinergic
 Deep brain stimulation if persists
despite maximal therapy
Managing Motor fluctuations and dyskinesias8 of levodopa
 Motor fluctuations: Motor fluctuations consist of on and off periods
 Wearing off: Emergence of PD sx as levodopa diminishes
 Unpredictable Off: No relationship between time of dose and
appearance of off episode
 Failed response: Lack of a response following dose of levodopa
8: Due to the progressive nature of PD, presynaptic neurons actually start failing to store and release levodopa after enzymatic
conversion to dopamine, resulting in a shorter half-life. Pulsatile stimulation of dopamine receptors may also be involved in the
narrow therapeutic window. Other contributing factors include: reduced intestinal absorption due to poor gastric emptying,
competition from dietary protein, and slow intestinal transit times.
Avoid CR formulations in
severe/complex dyskinesia
patterns

6. 6
Symptom Management Other notes
Erectile dysfunction  Sildenafil
Depression  SNRI or SSRI, TCA if patients
do not improve
 Sertraline, Paroxetine,
venlafaxine
 Monitor: QTc especially if risk
factors, exacerbation of motor
symptoms or comorbid sleep
disorders
 Caution SSRIs and exacerbation of
motor symptoms
Psychosis  Potentially reducing doses of
anti-PD drugs
 Quetiapine or clozapine in
low doses > other
antipsychotics
 Counsel on risk of stroke, MI, death
Dementia  Cholinesterase inhibitors
 Rivastigmine
 Donepezil
 Memantine
Anxiety  SSRIs, SNRIs, buspirone
 Citalopram, sertraline
 Psychotherapy
Managing the non-motor symptoms of PD

7. 7
References:
1. Shin HW, Chung SJ. Drug-Induced Parkinsonism. J Clin Neurol. 2012;8(1):15.
doi:10.3988/jcn.2012.8.1.15
2. Kwok JYY, Kwan JCY, Auyeung M, et al. Effects of Mindfulness Yoga vs Stretching and
Resistance Training Exercises on Anxiety and Depression for People With Parkinson Disease:
A Randomized Clinical Trial. JAMA Neurol. 2019;76(7):755-763.
doi:10.1001/jamaneurol.2019.0534
3. Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without
entacapone in early Parkinson disease: The STRIDE-PD study. Ann Neurol. 2010;68(1):18-
27. doi:10.1002/ana.22060
4. Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder
society evidence-based medicine review: Update on treatments for the motor symptoms of
Parkinson’s disease: Treatment of Motor Symptoms in PD. Mov Disord. 2018;33(8):1248-
1266. doi:10.1002/mds.27372
5. Zafar S, Yaddanapudi SS. Parkinson Disease. In: StatPearls. StatPearls Publishing; 2022.
Accessed August 23, 2022. http://www.ncbi.nlm.nih.gov/books/NBK470193/
UpToDate Links:
https://www.uptodate.com/contents/management-of-nonmotor-symptoms-in-parkinson-
disease?search=parkinsons%20disease%20non%20motor%20symptoms&source=search_resu
lt&selectedTitle=1~150&usage_type=default&display_rank=1
https://www.uptodate.com/contents/initial-pharmacologic-treatment-of-parkinson-
disease?search=parkinsons%20disease%20adult&source=search_result&selectedTitle=2~150
&usage_type=default&display_rank=2
https://www.uptodate.com/contents/medical-management-of-motor-fluctuations-and-dyskinesia-
in-parkinson-
disease?search=motor%20symptom%20fluctuations%20parkinsons&source=search_result&s
electedTitle=2~150&usage_type=default&display_rank=2

8. 8
Picture Links:
https://chroniccareeps.com/parkinsons-disease
https://www.researchgate.net/figure/Coronal-section-of-the-basal-ganglia-and-associated-regions-
permission-line-to-come_fig5_265497846
https://www.google.com/search?q=parkinson%27s+disease+clinical+presentation&rlz=1C1CHBF_enUS9
78US978&source=lnms&tbm=isch&sa=X&ved=2ahUKEwidr-
67zN35AhUGGDQIHaa8C6cQ_AUoAXoECAIQAw&biw=767&bih=700&dpr=1.25#imgrc=OaUTQJoGLyGew
M
https://healthjade.com/lewy-body-dementia/
https://scienceofparkinsons.com/tag/substantia-nigra/