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Drug Therapy for Parkinson’s Disease

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Presentation on theme: "Drug Therapy for Parkinson’s Disease"— Presentation transcript:

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

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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


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