Download Curs Parkinson 24.03.2014

Parkinson’s Disease
Parkinson’s Disease
 Degenerative disease of the
nervous system
 First described by James
Parkinson (1817)
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Tremor
Weakness
Propensity to bend the trunk
forward
Propensity to pass from a
walking to a ruunning pace
Senses and intelect uninjured
 1841 – paralysis agitans
(Marshall Hall)
Parkinson’s Disease
 Idiopathic Parkinson disease is observed in all
ethnic groups and all socioeconomic classes
 Incidence in afroamericans is ¼ that in whites
 In asians incidence is 1/3-1/2 that in whites
 Incidence is about 1% in population over age 65
years (1 million patients in North America)
Parkinson’s Disease
 Begins between 40 and 70 years, peak age of onset in
the sixth decade
 Incidence somewhat greater in men
 Risk for the first degree relatives about 5%
 Genetic aspects
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Evidence of striatal dysfunction in 75% of asymptomatic
monozygotic twins of Parkinson patients (pet scanning for
dopamine metabolism)
Familial cases – there was identified forms with clear
established genetic defects (less than 25% from all cases)
Progresion of Parkinsons Disease
Parkinson’s Disease
 Familial cases - earlier onset (the fourth decade) and a relatively rapid
course (10 years from onset to death)
 Mutation in the gene enconding the protein α-synuclein (main
component of the Levy body ) (crs 4q)
 Mutations of exons in Park2 gene (chr 6q) – the commonest types are
point mutations or deletions in exon 7 but abnormalities of the other 12
exons evince similar syndromes
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50% of families with early onset of parkinson disease harbor mutations in
this gene
Up to 2% of late onset cases and 18% of sporadic cases with early onset are
due to parkin mutations (Kahn et all)
 Mutations in genes park 5, 6, 7, 8, NR4A2
Parkinson’s Disease
 Lewy bodies (LB) are considered as the
histological hallmark of Parkinson's disease;
 They were first described in cholinergic
neurons of substantia innominata
("unnamed substance")
 Then described in dopaminergic neurons of
substantia nigra (pars compacta) in
association with cells depletion and
replacement gliosis
 There are two morphological types:
classical (brain stem) Lewy bodies and
cortical Lewy bodies.
 A Lewy body is composed of the protein
alpha-synuclein associated with other
proteins such as ubiquitin, neurofilament
protein and alpha B crystallin
Lewy bodies and
Lewy neurites in PD
Parkinson’s Disease : Pathophysiology

The major neuropathologic findings in Parkinson disease are a loss of
pigmented dopaminergic neurons in the substantia nigra and the
presence of Lewy bodies
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Primary neurochemical deficiency in Parkinson's disease is
the loss of dopaminergic projections of the striatum.
 There are also others pigmented an nonpigmeted neuronal
population in midbrain and lower brainstam wich are affected
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Other neurotransmitter deficiencies such as norepinephrine,
serotonin, acetilcholine and gamma amino butyric (GABA) due to
neuronal loss in locus ceruleous, lateral tegmental areas of the
brain, nucleus basalis of Meynert, raphe nuclei may contribute to
secondary symptoms
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Recent data suggests that many neurodegenerative diseases (AD, PD)
are overlaping
Loss of pigmented neurons in
substantia nigra
Normal
Parkinson Disease
Loss of pigmented neurons in substantia
nigra
 Symmetrycal activity of
striat (healthy volunteer)
 Asymmetrycal decrease
of striatal activity in a
PD patient
 Patients may follow or
not dopaminergic
therapy
Reprinted from Parkinson Study Group. Neurology. 2000;55:1540-1547.
Clinical Features
 Frequently unilateral onset, early symptoms may
be overlooked by patient or family members
Initial symptoms in patients with PD (Hoehn and Yahr)
Tremor
70%
Gait disturbance
11%
Rigidity
10%
Slowness of voluntar movement
10%
Muscular aches
8%
Loss of dexterity
7%
Handwriting disturbance (micrographia)
5%
Depression, nervousness, other psychiatric disturbance
4%
Speech disturbance
3%
Clinical Features
 Hipokynesia / bradykinesia
 Resting tremor
 Postural instability
 Rigidity
Clinical Features
 Tremor
Frequently unilateral onset
 4~6Hz frequency,
 Most conspicuous at rest, it increases at times of
emotional stress and often improves during voluntary
activity.
 Fluctuations of intensity - is aggravated by emotions or walk
 Frequency remains constant
 “Pill-rolling” or “money-counting” character
 EMG – alternating burst of activity in agonist and antagonist
muscles
 Negro’s sign (cogwheel phenomenon)
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Clinical Features
 Rigidity
 It tends to appear in the more advanced stages of the disease
 It can be felt by the palpating finger and seen as a salience of
muscle groups in active and pasive movements or even when
the patient relaxes. It affects both the extensor and flexor
groups.
 Rigidity and cogwheel feature can be elicited or enhanced by
having the patient engage the the opposite limb in a motor task
requiring some degree of concentration
 In the muscle of the trunk, postural hypertonuspredominates
in yhe flexor groups and confers on the patient the
characteristic flexed posture
 Muscle aches (back, neck, shoulders, hips)
Clinical Features
 Bradykinesia – slowness in initiation and execution of a movement
 Hypokinesia – reduced frequency and amplitude of movement
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Infrequency of blinking (associated with widening of the palpebral fissures –
stelwag sign), infrequency of swallowing, slowness of chewing,
Limited capacity to make postural adjustments
Absence of arm swing in walking, lack of small “movements of cooperation”
Difficulty in executing two motor acts simultaneously, alternating
movements become progressively impeded and finally are blocked
completely or adopt the the rhythm of the patient alternating tremor
Micrographia: small, tremulous, cramped handwriting (Charcot)
“hypokinetic dysarthria” (Caekebeke): voice softens, speech seems hurried,
monotonous and mumbling
 Kinesis paradoxica – in the excitement of some unusual
circumstance, the patient is capabil of brief but remarkably effective
movement
Clinical Features
 Gait disturbance
 Walking is shuffled, the patient frequently loses balance,
walking forward and backward may seem to be “chasing” the
body’s center of gravity with a series of short steps in order to
avoid falling (festination)
 Defence and righting reactions are faulty
 Falls occur surprisingly infrequently given the degree of
postural instability
 Gait is typically improved by sensory guidance, as by holding
yhe patient at the elbow
 Obstacles such as door tresholds causes the patient to”freeze”
in place
Clinical Features
 Dementia – 10-15% of oatients (Mayeux)
 Incidence increases with advancing age aproaching 65 percent
in patients above 80 years of age
 Sometimes associated with lesions in white matter
 Hypersalivation (failure to swallow with normal
frequency), seborheea, excessive sweating
 Other involuntary movements (dystonias)
Compensatory changes in dopaminergic synapse in PD
Uncom penste
Adaptative capacity
100%
80%
60%
40%
Compensate
(no simptoms)
20%
Mild simptomatology
0%
Important simptomatology
 Presynaptic:
 Hiperactivity of
restant dopaminergic
neurons (increasing of
dopamine turnover)
 Postsynaptic
 Increasing of
receptor’s sensitivity
for dopamine
Most symptoms do not appear until striatal DA levels decline by at least
70-80%.
Treatment of Parkinson’s Disease
Stimulating the
release of
dopamine
(amantadine)
Increasing the synthesis
of dopamine (levodopa)
Inhibiting the catabolism of
dopamine (MAO B and COMT
inhibitors)
Stimulating the
dopamine receptor
sites directly (agonists)
Drug Therapy Against Parkinson
Disease
D1
PRESYNAPTIC
D2
POSTSYNAPTIC
Inhibata de Tolcapone
decarboxylase
Levodopa
Dopamine
Dopamine
MAO-B
decarboxylase
Levodopa
Inhibited by
Carbidopa,
Benserazide
COMT
Inhibited by
Entacapone
, Tolcapone
MAO-B
inhibitors
(Selegiline)
Deaminated
metabolites
Inhibitori de MAO B
Deaminated
metabolites
MAO-B
Levodopa
3-Ο methyl dopa methoxytyramine
MAO-B
COMT
3-Ο methyl dopa
Homovanillic
acid
MAO-B
BBB
Intestinal wall
Levodopa metabolism
Deaminate
d
metabolites
L-Dopa therapy
 Action:
 L Dopa fairly effective in eliminating most of the symptoms of Parkinson disease
bradykinesia > rigidity > tremor
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L Dopa less effective in eliminating postural instability, shuffling gait, dysarthria,
vegetative disturbance meaning other neurotransmitters are involved in Parkinson
disease
Decrease of action: frequently after 3-5 years motor fluctuations and dyskinesias may
occur
Delivers to restant neurons in substantia nigra the substrate for dopamine sinthesis
 Drugs:
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L-Dopa andBenserazide: Madopar 125/250 tb., 62,5/125 cps., Madopar LT tb.
(125mg), Madopar 125 Depot-Kapseln;
L-Dopa and Carbidopa: NacomR 100/250 tb., Nacom retard 100/200 tb.; Isicom
100/250 tb., StriatonR 200 tb.
Effects of chronic levodopa
administration
End-of-dose
wearing-off effect
On/off oscillations
Freezing during
movement
Dose failure (drug
resistance)
Dyskinesia at peak
dose
Complications of long-term therapy with L-dopa
 Motor Fluctuations:
 beneficial effects of levodopa last a few hours and then
diminish: "wearing-off"
 Rapid and unpredictablechange from a state of relative
freedomof symptoms to one of complete immobility: "on-off"
 Off-period dystonia and early morning dystonia : painful
contractions of ankle muscles
 “Delayed on” : long interval between administration of pill
and onset of on effect
 “No on” : no response to l-dopa administration
 "freezing“ phenomenon
Motor complications of long-term therapy with
L-dopa
 Dyskinesias (choreic, athetosic, dystonic, balistic
movements)
 “peak-dose” dyskinesia (choreic movement)
 “end-of-dose" dyskinesia (dystonic aspect)
 diphasic dyskinesia (choreic and balistic
movements)
Almost always dyskinesias are combined with on-off fluctuations
Catechol-O-methyltransferase inhibitors (COMT)
 Action: inhibits metabolisation of L-Dopa to 3-Ο
methyl dopa in peripheral tissues (Tolcapone acts in
periphery and also centraly, Entacapone only in
periphery )
 Increases the duration of effect of levodopa dose
 Drugs :
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Entacapone (Comtan) tb. 200mg;
Tolcapone (Tasmar) tb. 100/200mg;
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Hepatic toxicity
 STALEVO – combination 1:4:8 of carbidopa, levodopa
and entacapone (tablets 50, 100 and 150 mg)
Inhibitors of Monoamine Oxidase B (MAO-B)
 Action: inhibits the metabolic breakdown of dopamine.
 Selegiline: Deprenyl tb. 5mg;
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Stimulatory amphetaminic effect
selectively inhibits monoamine oxidase B which metabolizes dopamine,
but does not inhibit monoamine oxidase a which metabolizes
norepinephrine and serotonin
 Rasagiline (Azilect) 1 mg/day
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rapidly absorbed, reaching peak plasma concentration in approximately 1
hour.
Monotherapy in early stages and combined with Levodopa in advanced
stages of disease (beneficial effects on dopaminergic motor dysfunction.)
There are some data wich suggests un possible neuroprotective efect
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Early use of rasagiline may delay the progression of symptoms
Patients treated early with rasagiline have a lower functional decline
comparative with those patients who takes rasagiline with a delay of 6 months
Dopamine agonists
 Action: the direct influence of the D1 and D2
receptor, dopamine independently
different half-lives
 Generics and preparations:
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Bromocriptine, Cabergolin; Lisurid;
Pergolid; α-dihidroergocriptine:
Ropinirol: Requip cp
0,25/0,5/1/2/5mg;
Ropinirol retard cp 2/4/8 mg
Pramipexol: cp0,125/0,25/1mg.
Dopamine agonists
 Effective even in
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monotherapy - postponing
the need to introduce
levodopa with 12-36 months
Symptomatic benefit less
than levodopa
Delay / Reduce motor
complications
May delay disease
progression
Have a sparing effect of
levodopa
Start with a low dose and
slowly increase
• Titrate to therapeutic efficacy
o pramipexole 1.5-4.5 mg/day
o ropinirole 3-24 mg/day
o bromocriptina 7.5-30
mg/day
o pergolide 1.5-4.5 mg/day
 Acute side effects: nausea,
dizziness, drowsiness,
confusion
 Not affected by dietary protein
intake
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NMDA antagonists
 Low affinity blocker of the NMDA receptor channel,
increases the release of dopamine, blocks up the
dopamine reuptake and cholinergic effects
 Amantadine: 100mg cp
 Modest effects on tremor, hypokinesia and postural
symptoms
 May cause edema, worsen heart failure, exaggerate
cognitive impairment disorders ,worsen the
glaucoma
Anticolinergics
 Action: central and peripheral muscarinic receptor
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blockade
Clinical action especially on tremor and rigidity
Cognitive side effects, hallucinations, prostatic
obstruction
The effect is cumulative and occurs after several days of
dosing.
Dose titrated up to the best into balance between
effectiveness and side effects
Generics and preparations:
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Benzatropin: Cogentinol cp. 2mg;
Biperiden: Akineton cp. 2mg,
Trihexiphenidil: Artane cp. 2/5mg, Artane retard
Deep Brain Stimulation in Parkinsons Disease
 In Parkinson's disease, the rest tremor seems to be caused by a
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neuronal group located in the thalamus and basal ganglia
downloading signals synchronous
Under physiological conditions, these neurons download signals in a
chaotic mode
It acts as a pacemaker and enables the premotor cortex, the motor
cortex area, and the additional motor
Stimulation of thalamic / subthalamic with high frequency (high
frequency periodic pulse - 4100 Hz) suppresses the activity of peace
maker, and consequently the peripheral tremor
It was approved by FDA in 2002
Cost: £ 25-30000
Deep Brain Stimulation in Parkinsons Disease
 Thalamic stimulation has a favorable effect
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on tremor especially =>seems to be
particularly useful in patients with essential
tremor
Pallidal stimulation is effective on
dyskinesias, improves rigidity, increases
periods "on", has minimal effect or worsens
bradykinesia
Subthalamic stimulation is effective on
tremor, rigidity, bradykinesia.
Could improve stability, walking, states
"freezing"
Requires lower stimulation intensities
(longer use)
Continuous Dopaminergic stimulation - DUODOPA
 The concept of continuous dopaminergic stimulation
reprezents a new trend in the PD pharmacology
 The fundamental theory behind this concept consists in
the fact that physiological striatal dopaminergic
stimulation is constant and that the oral therapy with
levodopa cand replace this constant stimulation in a
intermitent and non pysiological way
 This pulsatile stimulation of the dopaminergic receptors
is belived to contribute to the development of the motor
fluctuations, which are common after a few years of
levodopa treated PD patients and can affect the quality
of life
Levodopa – Duodenal Infusion
“Bypass“stomach area
L-dopa infused
directly in
duoden/jejuni