Transcript Parkinson`s disease

Drug Therapy for Parkinson’s Disease
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
• http://healthtalkonline.org/peoplesexperiences/nerves-brain/parkinsons-disease/topics
• khanacademymedicine has a series of 11 brief videos
on Parkinson’s Disease (7 – 12 minutes in length)
https://www.youtube.com/watch?v=3n8UjH9h_8I&list=
PLbKSbFnKYVY0gSY9_6d4iVKk-p6sfHoA7
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.
A few celebrities with
Parkinson’s Disease or Parkinsonism
Muhammad Ali (42)
Michael J Fox (30)
Davis Phinney (40)
Robin Williams (?)
Epidemiology of Parkinson’s Disease
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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
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.
http://ghr.nlm.nih.gov/condition/parkinson-disease
Mov Disord. 2010;25 Suppl 1:S58-62
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
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Olfactory bulb
Cortex
Amygdala
Locus ceruleus
Vagal nucleus
Peripheral autonomic nervous system
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?
PD: Cardinal Features
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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
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
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
Drug Therapy for PD (cont’d)
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
Mechanism
of Action of
Levodopa
Figure 21-2
Steps leading to
alteration of
CNS function by
levodopa.
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
Fate of
levodopa in
the presence
and absence
of carbidopa
Figure 21-4.
Data in the figure
are extrapolated
from Nutt JG,
Fellman JH:
Pharmacokinetics of
levodopa. Clin
Neuropharmacol
7:35, 1984.
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 90-120 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
Dyskinesias due to Levodopa/Carbidopa
• Dyskinesia are choreatic (writhing) movements of the
limbs and trunk – begin in 40-50% of cases after 5yrs,
80-100% 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
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, yelloworange discoloration of the urine
Question for you . . .
Why not just give dopamine as a
pharmacologic treatment?
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
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
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)
1.25-2.5mg, Emsam (patch) 6, 9, 12mg/24h
• Side effects: Hypertensive crisis, atrial fibrillation,
diarrhea, headache
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
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
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