1. Drug Therapy for Parkinson’s Disease

2. What is Parkinson Disease?
Slowly progressive neurodegenerative disorder
Second most common neurodegenerative disease
Alzheimer’s disease is most common
Dr. James Parkinson, originally described PD in 1817
khanacademymedicine has a series of 11 brief videos on Parkinson’s Disease (7 – 12 minutes in length)

3. Parkinsonism  Parkinson’s Disease
Parkinsonism is any condition that causes a combination of the movement abnormalities seen in Parkinson's disease — such as tremor, slow movement, impaired speech or muscle stiffness — especially resulting from the loss of dopamine–containing nerve cells (neurons).
Elsevier Inc. items and derived items © 2007 by Saunders, an imprint of Elsevier Inc.

4. A few celebrities with Parkinson’s Disease or Parkinsonism
Muhammad Ali (42)
Michael J Fox (30)
Davis Phinney (40)
Robin Williams (?)

5. Epidemiology of Parkinson’s Disease
1% of population over 60
Men > women
Mean age of onset = 60
10% are young onset, before age 50 (very early onset can occur in the 20’s)
Risk: increases with age

6. Etiology of PD Underlying cause – loss of dopaminergic neurons
NO CURE – goal of drug therapy is to maintain QOL
Genetic factors
Younger onset especially re: PD genes
Liver enzymes that metabolize pesticides
Nitrous oxide genes - smoking
Approximately 15 % of PD is familial, caused by mutations in the LRRK2, PARK2, PARK7, PINK1, or SNCA gene, or by alterations in genes that have not been identified.
Mov Disord. 2010;25 Suppl 1:S58-62

7. Pathophysiology of PD
Loss of neurons in the substantial nigra (brainstem) that produce dopamine
Motor signs developed when over half of these neurons are lost
Other brain areas affected also
Olfactory bulb
Cortex
Amygdala
Locus ceruleus
Vagal nucleus
Peripheral autonomic nervous system

10. Parkinson’s Disease
Proper function of the striatum requires a balance between the neurotransmitters dopamine and acetylcholine (ACh).
Imbalance between dopamine and ACh results from degeneration of the neurons that supply dopamine to the striatum.
GABA --- gamma-aminobutyric acid
Dopamine – excitatory or inhibitory to GABA?
Ach – excitatory or inhibitory to GABA?

11. PD: Cardinal Features T tremor (70% have this) A akinesia/bradykinesia
R cogwheel rigidity
P postural instability (later in disease)
Symptoms are asymmetric at onset
Patients may also complain of psychological disturbances, depression and impaired memory

12. Parkinson’s Disease (cont’d)
Therapeutic goals:
Improve patient’s ability to carry out activities of daily life
Drug selection and dosages are determined by extent to which PD interferes with work, dressing, eating, bathing, etc.
Remember, there is no cure
drugs provide symptomatic relief

13. Drug Therapy for PD Levodopa Levodopa/Carbidopa (Sinemet, Parcopa)
Dopamine agonists
Nonergot: pramipexole, ropinirole, apomorphine
Ergot: bromocriptine, cabergoline
COMT inhibitor: entacapone, tolcapone
MAO-B inhibitors: selegiline, rasagiline
Dopamine releaser: amantadine
Centrally acting anticholinergic drugs

14. Drug Therapy for PD (cont’d)

15. Drug Therapy for PD (cont’d)
Two major therapies
Levodopa (Dopar)
By far the most commonly used and most effective treatment for PD
Promotes synthesis of dopamine
Levodopa [Dopar]; Levodopa/Carbidopa [Sinemet]
Dopamine agonists
Less effective than Levodopa
Less likely to cause dyskinesias but can cause disturbing psychological side effects

16. Figure 21-2 Steps leading to alteration of CNS function by levodopa.
Mechanism of Action of Levodopa

17. Levodopa (Dopar) Pharmacokinetics: Oral Food delays absorption
Primarily metabolized in periphery with less than 2% entering the brain
Adverse effects:
Nausea/Vomiting
Dyskinesias
Postural hypotension
Psychosis
- Carbidopa is added to potentiate levodopa

18. Fate of levodopa in the presence and absence of carbidopa Figure 21-4
Fate of levodopa in the presence and absence of carbidopa Figure Data in the figure are extrapolated from Nutt JG, Fellman JH: Pharmacokinetics of levodopa. Clin Neuropharmacol 7:35, 1984.

19. Levodopa/Carbidopa (Sinemet, Parcopa)
Provides dopamine precursor to brain
Regular and continuous release (CR) forms. CR form is 30% less bioavailable and has less predictable kinetics
Half life min. – but stays in brain longer in newer onset/younger patients
Later on, brain can’t store dopamine so need more frequent dosing
Side effects:
Nausea/vomiting, orthostatic hypotension, drowsiness, dyskinesias, hallucinations

20. Dyskinesias due to Levodopa/Carbidopa
Dyskinesia are choreatic (writhing) movements of the limbs and trunk – begin in 40-50% of cases after 5yrs, % by 10yrs
Occur at various times
End-of-dose wearing off
Delayed “on” on “no-on” effect
Unpredictable on/off symptoms
Sudden “off” periods
Peak dose dyskinesias
Therapeutic window decreases over time

21. COMT Inhibitor (Entacapone)
Mechanism of action:
Entacapone inhibits COMT in the periphery
Prolongs half-life of levodopa in blood and availability of levodopa to the brain
Decreases production of levodopa metabolites
In clinical trial, increased T1/2 of levodopa by 50%-75%, delayed “wearing off” and extended “on” times
Doses: 200mg tablet, fixed-dose combination with levo/carbi [Stalevo]
Side effects: vomiting, diarrhea, constipation, yellow- orange discoloration of the urine

22. Question for you . . .
Why not just give dopamine as a pharmacologic treatment?

23. Dopamine Agonists
Five drugs available on the market: 3 nonergot, 2 ergot
Pramipexole [Mirapex]
Ropininole [Requip]
Apomorphine [Apokyn]
Bromocriptine [Parlodel]
Cabergoline [Dostinex]
 Mechanisms of action
Direct activation of dopamine receptors
 Used in patients with mild  mod symptoms

24. Dopamine Agonists (cont’d)
First line drug therapy for motor symptoms
Oral or transdermal route
Side Effects: Nausea, Dizziness, somnolence, hallucinations, dyskinesias (less than carbi/levo), orthostatic hypotension

25. Monoamine oxidase B inhibitors
Can be used in patients with mild motor symptoms with/without levodopa.
MOA: Inhibit MAO-B inactivation preventing dopamine breakdown in the striatum
Drugs/doses: Selegiline, Eldepryl 5mg, Zelapar (ODT) mg, Emsam (patch) 6, 9, 12mg/24h
Side effects: Hypertensive crisis, atrial fibrillation, diarrhea, headache
ODT: orally disintegrating tablet

26. Nonmotor Symptoms Management
Treatment based on patient symptoms
Autonomic: constipation, urinary incontinence, drooling, orthostatic hypotension, cold intolerance, and erectile dysfuntion
Sleep disturbances: EDS, PLMS, insomnia
Depression: 50% of PD patients
Dementia: 40% of PD patients
Psychosis: caused by PD drugs
EDS: excessive daytime sleepiness
PLMS: periodic limb movements of sleep

27. Non-Pharmacologic Treatment options
Surgery:
Patients with advanced PD
Deep Brain Stimulation (DBS), Pallidotomy, Cell implant
Exercise:
Tai chi and yoga
Lower stress, more relaxed, increased energy, balance, and flexibility
Diet
Positive attitude

28. Nursing Implications Involve family members in medicating outpatients
Levodopa
taken with food to avoid nausea/vomiting
avoid high-protein meals
inform – benefits may be delayed for weeks to months
Minimize adverse effects by teaching