Parkinson

Question 1

Parkinson’s

Answer 1

Progressive nervous system disease
Starts gradually
Movement disorder
◦ Bradykinesia
◦ Muscle rigidity
◦ Resting tremors
◦ Postural instability
Pathology
◦ Extensive deterioration of neurons within basal ganglia of the brain
◦ Dopamine loss
◦ Increased cholinergic activity

Question 2

Therapeutic goals

Answer 2

◦ Ideal treatment that reverses neuronal degeneration or prevents further
degeneration does not exist
◦ The goal is to improve the patient’s ability to carry out the activities of daily life
◦ Drug selection and dosages are determined by the extent to which PD interferes
with work, dressing, eating, bathing, and other activities of daily living

Question 3

Therapeutic Drug Class Alternatives

Answer 3

Dopaminergics
Dopamine Agonists
MAO B inhibitors
Glutamate antagonist (amantadine)
Anticholinergics
Catechol‐O‐Methyltransferase

Question 4

Dopaminergics - Options

Answer 4

◦ Levodopa (Dopar, Larodopa)
◦ Levodapa‐carbidopa(Sinemet, Sinemet DR, Madopar)
◦ Duodopa (continuous to small intestine)

Question 5

Dopaminergics clinical indications

Answer 5

◦ Most effective for tremors and rigidity

◦ Also used: postencephalitic and PD associated with cerebral ateriosclerosis

Question 6

Levadopa Pharmacokinetics and

Pharmacodynamics - Conversion

Answer 6

Conversion of levodopa to dopamine
◦ Restores normal balance between excitation and inhibition of neurons
◦ Carbifdopa enhances concentration of levodopa to reach brain
Absorption in gut, hampered by food
Biotransformed in liver
Short ½ life, requires frequent dosing
Renally eliminated, breast milk also.

Question 7

Levadopa SE

Answer 7

◦ N&V most common

◦ Other: dry mouth, difficulty swallowing, worsening hand tremors, numbness, syncope, sudden sleep

Question 8

Levadopa Long Term Therapy

Answer 8

◦ Dyskinesia, on‐off phenomenon, psychiatric manifestations, cardiac arrhythmia

Question 9

Levadopa Contraindications

Answer 9

◦ Concurrent MAOIs, uncontrolled HTN, narrow angle glaucoma, malignant melanoma
◦ CVD, Renal, liver disease, PUD, asthma/COPD, adrenergic therapy, Pregnance Cat D, BF, children < 12

Question 10

Levadopa Prescription and Monitoring

Answer 10

Frequency of dosing patient dependent
◦ 75mg carbidopa needed to achieve full decarboxylation
Target dose
◦ Smallest dosage necessary to control symptoms and decrease disability
Monitoring
◦ Periodic CBC, LFTs, renal studies
May interfere with urine glucose and ketone tests

Question 11

Dopamine Agonists - Options

Answer 11

◦ Bromocriptine (Parlodel)  
◦ Pergolide (Permax)
◦ Rotigotine (patch)
◦ Apomorphine (IV/IM) Ropinirole (Requip CR)
◦ Pramipexole (Mirapex)

Question 12

Dopamine Agonists - Clinical Indications

Answer 12

◦ Idiopathic and encephalic PD, restless legs
◦ Adjunct to levodopa
◦ Cannot be discontinued abruptly
◦ Require 3x a day dosing

Question 13

Dopamine Agonists - PK/PD

Answer 13

◦ Pramipexole no hepatic metabolism

Question 14

Dopamine Agonists SE

Answer 14

◦ Orthostatic hypotension, GI disturbance, less dyskinesia, drowsiness, insomnia
◦ Dyspnea, angina, arrhythmias, orthostosis possible (esp. in hot environs), compulsive behaviors

Question 15

Dopamine Agonists - Interacions

Answer 15

Pergolide

Question 16

Monamine Oxidase B Inhibitors - Options

Answer 16

◦ Selegiline (Eldepryl)
◦ Rasegeline (Agilect, Zelipar)
◦ Safinamide

Question 17

Monamine Oxidase B Inhibitors - Clinical Indications

Answer 17

◦ Adjunct to Levodopa

◦ Most effective early stages, early onset

Question 18

Monamine Oxidase B Inhibitors - MOA

Answer 18

◦ Selegiline:
◦ blocks MAO‐B; neuroprotective properties?
◦ May be monotherapy; dose twice daily
◦ Amphetamine metabolites
◦ Rasegiline:
◦ Prolongs survival of dopamine neurons; neuroprotective properties?

Question 19

Monamine Oxidase B Inhibitors SE

Answer 19

Nause, dry mouth, constipation, confusion, hallucinations, lightheadedness, drug/food interactions

Question 20

Monamine Oxidase B Inhibitors - Seleginie

Answer 20

◦ Side effects similar to levodopa
◦ Cautious use of doses of 10mg/d
◦ Caution: PUD, arrhythmia, TDK, psychosis

Question 21

Monamine Oxidase B Inhibitors - Rasegiline

Answer 21

◦ SE similar to levodopa in combo
◦ May exacerbate dyskinesia
◦ Interactions TCAs. Selegiline: CNS toxicity, death

Question 22

Glutamate Antagonist - Clinical indications

Answer 22

◦ Clinical Indications
◦ Limited efficacy, rarely prescribed initially, adjunct
◦ Effects short‐lived and mild
◦ Has stimulatory effect for some
◦ Especially useful if tremors prominent

Question 23

Glutamate Antagonist - MOA

Answer 23

◦ Reduces drug‐induced dyskinesias without worsening other symptoms

Question 24

Glutamate Antagonist - SE

Answer 24

SE: peripheral edema, skin mottling, confusion; toxic SE more common older adults

Question 25

Anticholinergics - Options

Answer 25

◦ Trihexyphenidyl (Broflex, Artane, Agitane) ◦ Benztropine (Cogentin)antipsychotic drug‐induced PD) ◦ Orphenadrine (Disipal) ◦ Procyclidine (Kemadrin, Arpicolin)

Question 26

Anticholinergics - Clinical Inidcations

Answer 26

◦ Early in early onset, tremor but little rigidity or bradykinesia, drooling, EPS ◦ Not in older adults or those with dementia; BPH, Closed angle glaucoma

Question 27

Specifics - MOA

Answer 27

◦ Inhibit acetylcholine at muscarinic receptors | ◦ Restore cholinergic‐dopaminergic balance

Question 28

Specifics - SE

Answer 28

◦ Worse in older adults | ◦ Dry mouth, constipation, urinary retention, tachycardia,palpitations, impaired sweating

Question 29

Specifics - Interactions

Answer 29

◦ Antipsychotics, antihistamines, antidepressants

Question 30

Catechol‐O‐Methyltransferase (COMT) - Options

Answer 30

◦ Entacopone (Comtan) | ◦ Tolcapone (Tasmar)+

Question 31

Catechol‐O‐Methyltransferase (COMT) - Clinical Indications

Answer 31

◦ Adjunct to levodopa | ◦ Ineffective when given alone

Question 32

Catechol‐O‐Methyltransferase (COMT) - MOA

Answer 32

◦ Higher sustained serum levels of dopamine

Question 33

Catechol‐O‐Methyltransferase (COMT) - SE

Answer 33

◦ Due to increased dopaminergic stimulation | ◦ Tolcapone: dsykinesia, hallucinations, confusion, N, orthostatic hypotension. Entacopone: N, dyskinesia

Question 34

Therapeutic Goals

Answer 34

Ideal treatment that reverses neuronal degeneration or prevents further degeneration does not exist The goal is to improve the patient’s ability to carry out the activities of daily life Drug selection and dosages are determined by the extent to which PD interferes with work, dressing, eating, bathing, and other activities of daily living

Question 35

Management Strategies

Answer 35

Consider ◦ Patient age ◦ Signs and symptoms ◦ Stage of Disease ◦ Degree of functional disability ◦ Level of physical activity and productivity ◦ Shared decision‐making ◦ The effect of disease on the dominant hand ◦ The degree to which the disease interferes with work, activities of daily living, or social and leisure function ◦ The presence of significant bradykinesia or gait disturbance ◦ Patient values and preferences regarding the use of medications

Question 36

MAO‐B Inhibitors - Patients at any age

Answer 36

◦ Patients at any age with very early PD and minimal signs and symptoms who are looking for a small amount of benefit

Question 37

Glutamate Antagonists (Amantadine) - fast facts

Answer 37

◦ Patients with PD and mild symptoms, particularly when tremor is prominent ◦ Well‐tolerated in younger patients

Question 38

Anticholinergics fast facts

Answer 38

◦ Patients with PD who are ≤65 years of age and have disturbing tremor but do not have significant bradykinesia or gait disturbance ◦ Patients with more advanced disease who have persistent tremor despite treatment with levodopa or DA

Question 39

Initial Treatment Progressive Disease ≤ | 65 Years Mild to Moderate

Answer 39

Levodopa or levodopa‐carbidopa first line for many ◦ Tailor to individual Progressive disease usually requires more than monotherapy with dopamine agonist after a few years Debate over the potential neuroprotective vs. neurotoxic effects of levodopa remains unresolved

Question 40

Initial Treatment Progressive Disease > | 65 Years Mild to Moderate

Answer 40

Levodopa recommended for older adult ◦ DAs are not well tolerated in older adults and those with cognitive dysfunction ◦ Levodopa is more effective for improving motor function and quality of life Debate over the potential neuroprotective vs. neurotoxic effects of levodopa remains unresolved

Question 41

Moderate to Severe Disease Any Age

Answer 41

Levodopa preferred ◦ L‐dopa main precursor of dopamine synthesis Most effective drug for symptomatic treatment of PD Superior effects on: ◦ Motor function ◦ Activities of daily living ◦ Quality of life

Question 42

Titration and Maintenance

Answer 42

Titrate up slowly Maintain levodopa at lowest effective dose Add adjunct therapy based on age, symptoms Monitor for side effects Lower dose of levodopa if side effects increasing Monitor for drug interactions Monitor renal and liver status

Question 43

On‐Off Phenomenon

Answer 43

A switch between mobility and immobility in levodopa‐treated patients Occurs as an end of‐dose or “wearing off” worsening of motor function Or, much less commonly, as sudden and unpredictable motor fluctuations

Question 44

Non‐Motor Symptoms

Answer 44

``` 90% of patients develop nonmotor symptoms (e.g., autonomic disturbances, depression, dementia, psychosis) Autonomic symptoms ◦ Constipation, urinary incontinence, drooling, orthostatic hypotension, and cold intolerance Sleep disturbance ◦ Excessive daytime sleepiness ◦ Periodic limb movements of sleep ◦ Insomnia ```

Question 45

Parkinsonism‐Hyperpyrexia Syndrome

Answer 45

Rare occurrence Sudden withdrawal or dose reduction of antiparkinson medication Or when switching from 1 drug to another ◦ Most common drugs: Levodopa, dopamine agonist, rare amantadine Management ◦ Replace antiparkinson medications ◦ Formuations: oral, NG, IV, infusion, transdermal Severe symptoms: admit