Lecture 43 - Pharmacotherapy of Parkinson's Disease Flashcards
Disease Progression
Slow developing and progressive disease
- Develops over 5-10 years with an increase in motor symptoms
- Cognitive symptoms may present after several years of PD
- Life expectancy after diagnosis (~15 years) can be similar to general population
must have bradykinesia (cardinal sign) for diagnosis
Clinical Presentation: motor symptoms
Motor Symptoms
- Tremor
- Bradykinesia
- Rigidity
- Parkinsonian gait
Clinical Presentation: non-motor symptoms
- Anxiety, depression
- Constipation
- Dementia
- Insomnia
- Orthostatic hypotension
- Psychosis/delirium
- Sexual dysfunction
Assessment of Disease
Unified Parkinson’s Disease Rating Scale (UPDRS)
- Standardized rating scale to assess signs/symptoms of PD - Scale scores from 0-4 to assess 42 domains for PD severity
- Higher UPDRS score = worse PD symptoms
Clinical assessment
- Observation of motor symptoms
- Impact of disease on quality of life (QOL)
Goals of Therapy
- Minimize/manage motor and non-motor symptoms
- Maintain highest quality of life (QOL) possible
- Preserve activities of daily living (ADLs)
- Minimize/manage adverse drug reactions
Non-pharmacologic Therapy
- Exercise/physical therapy
- Nutritional counseling
- Occupational therapy
- Psychotherapy/support groups
- Speech therapy
Pharmacologic Therapy – Initial Treatment
1st line: rule out drug induced PD, (drugs that block dopamine: antipsychotics, promethazine, anti-emetics), dopamine precursor (introduce potential risks, can progress disease/cause more dyskinesias), dopamine agonists, MAO-B inhibitor
2nd line: COMT inhibitors, amantadine
Treatment initiation
- For most, initiate with Levodopa (Dopamine Precursor) - generally start with IR
- Dopamine agonist may be used as initial treatment if age <60 years and higher risk for dyskinesia
- Avoid dopamine agonists as initial treatment if:
- age >70 years, or
- those with history of ICD, or
- cognitive impairment, or
- excessive daytime sleepiness, or
- hallucinations
In general, initiate with IR > CR - In general, initiate with lowest effective dose to delay adverse effects or dyskinesias
- Efficacy with Motor Symptoms: Levodopa/Carbidopa > DA > MAOB-I
Dopamine Precursor
levodopa (carbidopa/levodopa)
1st line for initial PD therapy and throughout course, most effective monotherapy for motor sx (gold standard), adjunctive therapy with dopamine agonists and other agents
Dopamine precusor SE
N/V
LD motor fluctuations/dyskinesias
hallucinations
Dopamine precursor
↑ absorption with empty stomach, but food ↓ nausea
Starting dose: 25/100 mg CD/LD PO BID-TID with meals
Maintenance: Frequency can increase as needed (5-6x/day) or switch to CR/XR forms
Titrate dose to balance efficacy and side effects
- Limit nausea/vomiting and motor fluctuations
LD motor fluctuations
wearing off: before next dosing interval, signs of motor symptoms
freezing: inability to move sue to insufficicnet or fluctuating DA levels
delayed onset: therapeutic benefits delayed
peak-dose dyskinesias: involuntary body movement caused by high DA levels
Management of LD motor fluctuations
wearing off: increase CD/LD dose or frequency; add DA agonist, MAOI, or COMTI; XR CD/LD
freezing: increase CD/LD dose or frequency; add DA agonist, (apomorphine); add ODT CD/LD
delayed onset: take CD/LD on empty stomach; ODT CD/LD; avoid CR/XR CD/LD
peak-dose dyskinesias: add amantadine; decrease dose of DA or CD/LD
deep brain stimulation
Dopamine agonists
Non-ergot
-Pramipexole (Mirapex®)
-Ropinirole (Requip®)
-Rotigotine (Neupro®)
-Apomorphine (Apokyn® injection and SL film)
Ergot
-Bromocriptine (Parlodel®)
-Cabergoline (Dostinex®)
Dopamine agonists place in therapy
Non-ergot DA agonists first-line for initial PD therapy
Minimize LD motor fluctuations
Ergots used rarely due to toxicity
Treatment: off (Apomorphine)
Dopamine agonsits SE
Nausea/ vomiting
Sudden onset sleep/EDS
Hallucinations
Impulse control disorder (ICD)
Edema
Orthostatic hypotension
$$$$
Dopamine agonists clinical pearls
Starting doses:
- pramipexole IR 0.125 mg PO
TID; ER 0.375 mg PO daily
- ropinirole IR 0.25 mg PO
TID; ER 2 mg PO daily
- rotigotine 2 mg patch
applied to the skin Q24H
-apomorphine 2 mg SC
injection prn up to 5 x daily or 10 mg SL Film up to 5 x daily
Advantages
- Fewer motor fluctuations
- Long-acting formulations
MAO-B inhibitors
Rasagiline (Azilect®)
Selegiline (Eldepryl®)
Safinamide (Xadago®)
MAO-B inhibitors place in therapy
First line for mild symptoms
Second-line for adjunctive therapy
Manage LD motor fluctuations
Adjunctive for PD depression
MAO-B inhibitors SE
Nausea/ vomiting
Headache
Insomnia (selegiline)
Hypotension/ Hypertension
MAO-B inhibitors clinical pearls
Starting doses:
- rasagiline 0.5 mg PO daily
- selegiline 5 mg PO BID
- safinamide 50 mg PO daily
Dietary restrictions (tyramine-rich foods)
Risk of serotonin syndrome with drug-drug interactions
serotonergic antidepressants
dextromethorphan serotonergic opioids
COMT inhibitors
Entacapone (Comtan®)
(also co- formulated with CD/LD as Stalevo®)
Opicapone (Ongentys®)
Tolcapone (Tasmar®)
COMT inhibitors place in therapy
In combination to manage symptom fluctuation (wearing off)
COMT inhibitors SE
Nausea/vomiting
Brown/orange urine discoloration (entacapone)
Hepatotoxicity (tolcapone use limiting side effect)
COMT inhibitors clinical pearls
In early PD, no benefit of COMT inhibitors with CD/LD compared to CD/LD alone
Starting dose:
- entacapone 200 mg PO with
each CD/LD dose
- tolcapone 100 mg PO TID
- opicapone 50 mg po QHS
Amantadine place in therapy
Management of LD motor fluctuations
Modest Effect in controlling motor symptoms, but rarely used monotherapy (tremor)
Amantadine SE
Insomnia
Confusion/ Hallucinations
Livedo Reticularis
Amantadine clinical pearls
Utility limited due to cognitive side effects
Usually reserved CD/LD peak dose dyskinesias
Starting dose:
- amantadine 100 mg PO BID
Anticholinergics
Benztropine (Cogentin®)
Trihexyphenidyl (Artane®)
Anticholinergies place in therapy
Management of tremor-dominant symptom in patients < 65 years old
Anticholinergics SE
Confusion/ dementia
Blurry vision
Urinary retention
Dry mouth
Constipation
Anticholinergic clinical pearls
Starting doses:
- benztropine 0.5 mg PO QHS - trihexyphenidyl 1 mg PO
daily
Use limited by confusion and anti-muscarinic side effects
- Avoid if > 65 years old
Monitoring
- Evaluate motor symptoms
- Assess for side effects related to pharmacotherapy
- Identify medications which can worsen PD: dopamine antagonists, antipsychotics
Patient Education
- Stress importance of adherence and timing of medication administration to patient/caregiver
◦ Make rescue plan
◦ Multiple formulations/schedule options to personalize care - Pros/Cons of taking medications with food
- Report side effects and symptoms to healthcare provider
- Support group and education referral
Deep Brain Stimulation
Elective surgical procedure offered after maximizing pharmacotherapy
May allow for reduction of treatments and reduction in adverse events
Risks: infection, device malfunction, headache, tingling of face or limbs (during stimulation), cost
Treatment of Non-motor Symptoms: constipation
Evaluate for meds causing constipation
Increase fluid intake, physical activity
Stool softeners/laxatives or probiotics may be effective
Treatment of Non-motor Symptoms: insomnia
Non-pharmacologic counseling
Melatonin
avoid: benzodiazepines (diazepam, lorazepam, oxazepam)
Treatment of Non-motor Symptoms: orthostatic hypotension
Non-pharmacologic counseling
Midodrine, Droxidopa
Medical equipment to stabilize patients
Treatment of Non-motor Symptoms: anxiety, depression
Cognitive behavioral therapy (or other non-pharmacologic approach)
Selective serotonin reuptake inhibitor (SSRI)
Serotonin-norepinephrine reuptake inhibitor (SNRI)
AVOID: benzodiazepines
CAUTION: tricyclic antidepressant (TCA)
Treatment of Non-motor Symptoms: dementia
Cholinesterase inhibitor (donepezil, rivastigmine)
AVOID: anticholinergics, benzodiazepines, antihistamines, sedatives
Treatment of Non-motor Symptoms: psychosis/delirium
Reduce PD medication doses (if appropriate)
Pimavanserin: new(ish) antipsychotic for PD psychosis
Atypical antipsychotics (clozapine, quetiapine)
AVOID: haloperidol, olanzapine, paliperidone, risperidone
