Parkinson's Disease Therapeutics

Question 1

Stages of Disease

Answer 1

Stage 1 (unilateral; symptoms not disabling; tremor in one limb but no posture or facial expression changes)

Stage 2 (bilateral; slowed speech, decreased posture and abnormal gait; no balance impairment)

Stage 3 (Worsening; significant posture and balance problems; bradykinesia; mild to moderate disability)

Stage 4 (rigidity and bradykinesia; needs walking assistance; unable to live alone; severe disability)

Stage 5 (Unable to stand or walk; constant care)

Question 2

Somatic Non-motor symptoms of PD

Answer 2

Sweating, hypotension, constipation, overactive bladder, seborrheic dermatitis, soft voice, decreased facial expression, decreased on arm swing (first side involved), decreased sense of smell and rapid eye movement disorder

Question 3

Behavioral PD symptoms

Answer 3

Depression, anxiety, psychosis (visual hallucinations usually pleasant; delusions/paranoia), dementia (increased risk because of hallucinations)

Question 4

Parkinson’s Medications provide control for _________ years

Answer 4

4-6

Question 5

In PD, health related quality of life is largely determined by ______________________

Answer 5

non-motor features

Question 6

Factors contributing to rapid progression of PD

Answer 6

Older age at onset, male with initial gate difficulty/postural instability, decreased response to L-DOPA, psychosis

Question 7

Factors contributing to milder PD progression

Answer 7

Tremor only major sign at initial diagnoses, good response to L-DOPA

Question 8

Essential tremor vs PD

Answer 8

In essential tremor, tremor is only symptom (PD presents with rigidity, tremor, balance, falling, slowness of movement, etc.)

In essential tremor, tremor occurs when hands are in use (resting tremor in PD)

In essential tremor, hands, head and voice impacted (no head or voice in PD)

In essential tremor, alcohol reduces tremor (no effect in PD)

Question 9

Pharmacologic options for PD

Answer 9

Dopamine precursor (L-DOPA - carbidopa; Sinemet CR)

1st Generation Dopamine Agonists (Bromocriptine, Apomorphine)

2nd Gen (Pramipexole, Ropinerole, Rotigotine Patch)

MAO-B Inhibitors (Selegiline, Rasagiline)

COMT Inhibitors (Tolcapone, Entacapone)

Antiviral NMDA (Amantadine)

Anticholinergics (Benztropine, Trihexyphenidyl)

Question 10

Levodopa/Carbidopa

Answer 10

First line (wait until symptoms are disabling)

Greatest benefit with fewest ADE in short term (most effective for bradykinesia then tremor and rigidity; not effective for instability or freezing)

TID to QID; titrated q 3 day then switch to CR BID-QID

Best use in stage 2-5 or as initial treatment in older person

Question 11

Levodopa-Carbidopa Side Effects

Answer 11

Nausea, insomnia, akathisia, dyskinesias, confusion, elevated liver enzymes, postural hypotension, visual hallucinations

On-off phenomenon (freezing off period to dyskinetic movement on period) –> unrelated to dose time, sign of becoming refractory

Question 12

L-DOPA Induced Dyskinesia

Answer 12

Occurs afte 5-6 years or early in therapy (6 months) if high doses are used initially

Off-period dystonia (painful feet spasms when LDOPA levels are low)

Diphasic dyskinesia (occurs when levels are rising or falling; rigidity or involuntary movement with muscles of lower limbs)

Peak-Dose dyskinesia (most common form; correlates with peak plateau plasma levels and impacts upper limbs, head, trunk and respiratory muscles)

Question 13

Treatment for L-DOPA Side Effects

Answer 13

End of dose wearing off (increase frequency or change to CR; add COMT or MAO inhibitor; dopamine agonist)

Delayed onset (take on empty stomach, use ODT or IR form; avoid taking with high protein food/drink; crush tablet and take with water only)

Start hesitation/Freezing (increase dose; add DA or MAO-B inhibitor; Physical therapy)

Peak Dose Dyskinesia (use smaller doses more frequently; add amantadine)

Question 14

Lillipuition hallucinations

Answer 14

PD see tiny people (could be medication OR disease related)

Question 15

Major contributors for psychosis/hallucinations in PD

Answer 15

Amantadine, COMT inhibitors, dopamine agonists, levodopa

Anticholinergic medications (oxybutynin, tolterodine, benzotropine, diphenhydramine)

Question 16

Psychosis/Hallucination Treatment in PD

Answer 16

Reduce or withdraw anticholinergics, then anti-PD meds

Clozapine, olanzapine, quetiapine and risperidone (antipsychotics)

Question 17

Pimvanserin

Answer 17

New drug for PD psychosis

Works at Serotonin receptors (5HT2a, 5HT2c) with minimal action at D2, muscarinic, histaminergic or adrenergic receptors

Those with more severe psychosis showed better results with drug

Serious risks (risk of death 2.38x greater with 34 mg compared with placebo; QT prolongation, bradycardia, hypokalemia, falls, severe nausea, constipation, UTIs, fatigue, worsening of hallucinations)

Question 18

Pramipexole and Ropinerole have both been known to cause _________________

Answer 18

impulse control and compulsive behavior issues (hypersexuality, gambling, shopping, binge eating)

Reduction in dose will usually help

Question 19

Second Generation DA

Answer 19

Pramipexole, Ropinirole, Rotigotine patch

Used in younger patients with good cognition to delay LDOPA

Useful in all stages; may delay dyskinesias or reduce frequency of off periods

Impulse control issue, hypersexuality, gambling and shopping

Sleep attacks during day, abrupt onset (pramipexole reported the most)

Question 20

Bromocroptine

Answer 20

DA NOT USED

Ergot derivative with increased risk of pulmonary fibrosis

Less effective in PD

Higher risk of motor complications

Question 21

MAOB Inhibitors

Answer 21

Rasagiline, Selegiline (comes in ODT)

Adjunct with LDOPA or DA in stages 2-4 (not useful in stage 5)

Selegiline SE (insomnia, confusion, psychosis in elderly)

Rasagiline (more hypertensive crisis and tyramine interactions than selegiline, impulse control disorders)

Drug interactions with antidpressants are concern

Question 22

COMT Inhibitors

Answer 22

Tolcapone, Entacapone, Stalevo

Most useful adjunct to LDOPA for motor fluctuations

Allows LDOPA to work longer (1-2 hours)

Useful when LDOPA end of dose wearing off occurs

Not for initial PD, or add-on to LDOPA when no motor complications (Tolcapone has serious liver issues; Entacapone has hypotension, syncope, fibrotic complications, hallucinations, orange colored urine and increased risk in melanoma)

Question 23

Amantadine

Answer 23

Mildly helps bradykinesia, rigidity and tremor in stages 1-4 monotherapy or adjunct to LDOPA, dopamine agonists)

Tolerance develops and may need drug holiday

May be useful in treating LDOPA dyskinesias

SE (peripheral edema, psychosis, hallucinations, nightmares and confusion)

Question 24

Anticholinergic Agents

Answer 24

Benztropine, Trihexyphenidyl

Used as 2nd line for tremor alone or with other agents

SE (decreased cognition and memory, confusion, hallucinations, constipation, urinary retention, dry mouth, blurred vision, sedation, tachycardia)

Don’t use in elderly or dementia patients

Question 25

Risk factors for PD to progress to PD Dementia

Answer 25

Older age, greater severity of motor symptoms, cognitive impairment, hallucinations prior to dementia diagnosis, and greater postural instability and gait disturbance

Question 26

Dementia in PD

Answer 26

Ranges from 20-40% with PD increasing dementia risk 2-6 fold

Cognitive impairment typically occurs 8 years or more after onset

Dementia onset within 1 year of onset of motor features suggests Lewy body dementia

Alzheimer’s also common but later; Lewy body dementia can be diagnosed in those without PD

Question 27

Anticholinergic Toxicity Mnemonic

Answer 27

Blind as a bat
Dry as a bone 
Hot as a hare 
Red as a beet
Mad as a hatter