Parkinson's disease

Anindya Banerjee
Patient Safety – Pharmacovigilance Associate
Dept of Pharmacology
NRS Medical College & Hospital , Kolkata
And
National Coordination Centre – Pharmacovigilance Program of India
Indian Pharmacopoeia Commission , Ghaziabad

Lecture Outline
• Etiology
• Incidence
• Patho-physiology
• Clinical Presentation
• Diagnosis
• Prognosis
• Treatment

Parkinson’s Disease
Parkinson’s disease , is named after James
Parkinson who in 1817 wrote a classic “shaking
palsy”a disease for which the reason is still
unknown .

• Definition :-
It is a chronic degenerative disorder that
primarily affects the neurons of the basal
ganglia.
It is a syndrome that consists of slowing down in
the initiation and execution of movement
(brady kinesia), increased muscle tone
(rigidity), tremor and impaired postural
reflexes

The famous internationally
known boxer
Mr. Mohammed Ali suffered
from this disease.
incidence:
Occurs in the age group of 60s.
Mostly men are affected than
women.

Etiology
 Parkinsonism: differing combinations of slowness of
movement (bradykinesia), increased tone/stiffness
(rigidity), tremor & loss of postural reflexes(akinetic-
rigid syndromes).
 The most common cause of parkinsonism is
idiopathic (no known cause) Parkinson's disease.
In most-may be combination of factors:
 Environmental toxins (MPTP, occasionally
pesticides):
The discovery that methyl-phenyl-
tetrahydropyridine (MPTP; A contaminant in
methylenedioxymethamphetamine ("ecstasy“))
caused severe parkinsonism in young drug users
suggests that the idiopathic disease might be due
to an environmental toxin.
 Viral infections (encephalitis lethargica)
 No strong genetic factors, but genetic influence
may be greater than previously thought. Genetic
mutations 1-2%; alpha-synuclein gene, Parkin
gene, Ubiquitin gene mutations.
 Protective factors-Both smoking and coffee
drinking have been associated with a lower risk
for PD.

PARKINSON'S DISEASE-Incidence
7
 Annual incidence 0.2/1000 & prevalence of 1.5/1000.
 Prevalence rates are similar throughout the world, except lower rates in
China /West Africa.
 Affects 1% of those over 55 years, 1.5% of people 70-79 years of age
 Generally occurs between 50-80 years
 Sex incidence is about equal.

Pathology
 There is depletion of the pigmented dopaminergic neurons in the
substantia nigra, atrophic changes in the substantia nigra& depletion of
neurons in the locus coeruleus.
 Clinical features don’t emerge until >60-80% dopamine lost.
 Compensatory changes include hyperactivity in remaining neurones
(increased transmitter turnover), increase in dopamine receptors; receptor
supersensitivity
 Other pigmented nuclei also affected (locus ceruleus and raphe). Also
cortex and other structures affected.
 Characteristic histological inclusion in affected neurons are eosinophilic
cytoplasmic inclusions in nigral cells called the Lewy Bodies.
8

Free Radicals
• Unpaired electrons that can easily react with
surrounding molecules and destroy them.
• Metabolism of dopamine by MAO produce hydrogen
peroxide.
• Glutathione normally breaks down the hydrogen
peroxide quickly.
• Reduced glutathione = loss of protection against free
radicals  cell damage

Genetic Factors
• Mutation of SNCA genes in chromosome 4.
• 2 types of alterations:
• Alanine is replaced with
threonine.
• Cause alpha-synuclein to
misfold.
• SNCA genes is
inappropriately duplicated or
triplicated.
• Extra copies of the gene lead
to an excess of alpha-
synuclein.
• Aggregate (Lewy bodies) and attract other protein.
• Clog neuron and impair the function of neuron.

Parkinson’s Disease-Patho-physiology
11
 Basal Ganglia
 Controls movement
 Dopamine
 Inhibitory neurotransmitter in the
basal ganglia
 Acetylcholine
 Excitatory neurotransmitter in the
basal ganglia
 Without dopamine, inhibitory
influences are lost and excitatory
mechanisms are unopposed 
 Neurons of basal ganglia are over
stimulated 
 Excess muscle tone, tremors &
rigidity

Parkinson’s Disease-Clinical features:
The classical syndrome:
 Tremors
 Rigidity
 Bradykinesia
These may be absent initially, when non-specific
symptoms of tiredness, aching limbs, mental
slowness, depression & small handwriting
(micrographia) may be noticed.
Although parkinsonian features are initially unilateral,
gradual bilateral involvement is the rule. A resting
tremor in an upper limb being a common
presenting feature.
12

 Resting tremor, may remain the
predominant symptom for some years.
 with activity
 h tremor when…
 Walking
 Anxious
 Sensation of heat
 Calorie burning!
Resting 4-6 Hz
Usually first in fingers/thumb, may also affect the legs, mouth & tongue.
Coarse, complex movements, flexion/extension of fingers
Abduction/adduction of thumb
Supination/pronation of forearm
May affect arms, legs, feet, jaw, tongue
Intermittent, present at rest & when distracted
Diminished on action
Postural 8-10 Hz
Less obvious, faster, finer amplitude
Present on action or posture, persists with movement
13
Parkinson’s Disease-Clinical features: Tremors

14
Parkinson’s Disease-Clinical features: Rigidity
Cogwheel type, mostly upper limbs -
Rigidity with superimposed tremor, felt as
tigthness/stiffness of muscles, Ratchet-like
(catch-release-catch release like
movement.
 Plastic (leadpipe) type, mostly legs
 Stiffness
 Neck
 Trunk
 Shoulders
 Posture
 Head bowed
 Body bent forward
 Arms flexed
 Thumbs turned into palms
 Knees bent (slightly)

 Paul Marie Louis Pierre Richer (1849-1933) was a French anatomist, physiologist, sculptor and
anatomical artist. Paul Richer was an assistant to Jean-Martin Charcot at the Salpêtrière. In
1880, Jean-Marie Charcot completed a full clinical description of Parkinson's Disease. The
symptoms were depicted by Paul Richer in drawings and a statuette of people with
Parkinson's Disease. Along with a photograph, these are the first known depictions of
Parkinson's Disease
15
Parkinson’s Disease-Clinical features: Rigidity

 Bradykinesia may develop gradually.
 Bradykinesia: Slowed ability to start and continue
movements, and impaired ability to adjust the body's
position.
 The word bradykinesia is logically derived from two Greek
roots: bradys, slow + kinesis, movement = slow movement,
slow motion, slow moving
 Slow movement
 Akinesia
 Loss of movement
 Esp face Expressionless face(poker/masked-face)
 Slow speech-softer & indistinct
 Dysphonia
 Dysphagia
 Drooling
Slowness in initiating or repeating movements -Most have
difficulty with rapid fine movements, as slowness of gait
&difficulty with tasks as fastening buttons, shaving or writing
(micrograpia).
16
Parkinson’s Disease-Clinical features: Bradykinesia

 Asymmetrical Gait
Slow to start walking
Shortened stride
Stiff legged gait-rigidity comes
through on one side, therefore
difficult clearing swinging on one
side
Rapid, small steps, tendency to run
(festination)
Reduced arm swing (usually
unilateral)
Impaired balance on turning
Leads with head and shoulders
 Fall forward down turned
posture-Postural righting
reflexes are impaired early, but
falls tend not to occur until later.
17
Parkinson’s Disease-Clinical features: Abnormal Gait/posture

Additional information to read later Clinical features:
There are a number of abnormalities on neurological examination:
 Muscle strength / reflexes remain normal, plantar responses are flexor.
 There is a paucity of facial expression (hypomimia) & the blink reflex may be
exaggerated & fail to habituate (glabellar tap sign).
 Eye movements are normal to standard clinical testing, provided allowance
is made for the normal limitation of upward gaze with age.
 Sensation is normal & intellectual abilities are not affected initially.
 As the disease progresses, 1/3 develop cognitive impairment.
 PD commonly associated with other features; loss of smell, depression,
dementia, autonomic dysfunction, sleep disturbance- due to involvement of
other non-dopaminergic structures as disease progresses.
18

PARKINSON'S DISEASE
DIAGNOSIS
19

Investigations:
 The diagnosis is made clinically, as there is no diagnostic test for Parkinson's
disease.
 Imaging (CT or MRI) of the head may be needed if there are any features
suggestive of pyramidal, cerebellar or autonomic involvement, or the
diagnosis is otherwise in doubt (e.g to exclude stroke).
20
[18F]dopa PET and β-CIT SPECT images.
[18F]dopa PET uptake in the putamen
is reduced in PD.

Investigations:
Causes of parkinsonism:
 Toxins (manganese, CO poisoning), CNS infs, structural
lesions, metabolic disorders, other neurologic disorders.
 Most are rare& suggested by atypical features, history or
exam.
Routinely needed to consider 2 alternative diagnoses:
 Drug-induced parkinsonism
 “Parkinsonism-plus” syndromes: parkinsonian features
with other neurological signs atypical of parkinson
disease.
21

Drug-induced parkinsonism:
 Important because it is reversible, although may require weeks or
months after discontinuation.
 Dopamine antagonists;neuroleptic agents (HALPERIDOL), atypical
neuroleptic agents, antiemetic drugs, CCB (flunarizine ,cinnarizine).
 Amiodarone, valproic acid,lithium,by uncertain mechanisms.
 Dopamine antagonists also exacerbate Parkinson’s disease& should
be avoided, if possible, in the treatment of patients with the
disease.
22

Additional information to read later
Parkinson-plus syndromes:
23

Features suggesting other conditions include:
 Falls or dementia early in the course of the disease
 Symmetric parkinsonism
 Wide-based gait
 Abnormal eye movements
 Babinski signs
 Marked orthostatic hypotension
 Urinary retention
 Development of marked disability within 5 ys after the onset.
 Responds poorly to antiparkinsonians, have a worse prognosis
than idiopathic PD.
 Neurologic consult needed if the clinical features suggest
other diagnosis.
24
Additional information to read later
Parkinson-plus syndromes:

PARKINSON'S DISEASE PROGNOSIS
25

Prognosis:
Variable& depends partly on the age of onset.
If symptoms start in middle life, the disease is
usually slowly progressive & likely to shorten
lifespan because of the complications of
immobility & tendency to fall.
 Onset after 70 is unlikely to shorten life or
become severe.
26

PARKINSON'S DISEASE
TREATMENT
27

Current pharmacological therapies –
symptomatic treatment
28
 Levodopa to replace dopamine L-DOPA + peripheral-acting dopa-
decarboxylase inhibitor to improve L-dopa availability in the CNS,
e.g. benserazide, entacapone.
 D1 and D2 receptor agonists e.g. Apomorphine, bromocriptine,
pergolide - favoured early in L-dopa-sparing pharmacotherapeutic
approaches
 MAOB inhibitors e.g. selegiline
 COMT (catechol-O-methyl-transferase) inhibitors: e.g Entacapone
 Amantadine – dopamine releaser, reuptake inhibitor?
 Anticholinergic drugs (Muscarinic receptor antagonists) e.g.

L-DOPA (LEVODOPA)
29
 L-3,4-hydroxyphenylalaninine (L-DOPA) a precursor of dopamine.
Although the number of dopamine-releasing terminals in the striatum
is diminished in Parkinson's disease, remaining neurons can be driven
to produce more dopamine by administering its precursor, L-DOPA. D-
DOPA is not active as a pro-drug.
 Well absorbed from gut, but > 90% is decarboxylated to dopamine
peripherally in GIT& blood vessels & only a small proportion reaches
the brain (dopamine does not readily cross BBB). Therefore combined
with peripheral decarboxylase inhibitor that does not cross the blood-
brain barrier along with L-DOPA. 2 peripheral decarboxylase inhibitors,
carbidopa & benserazide, are available as combination preparations
with levodopa, as Sinemet & Madopar, respectively.
L-DOPA

 The initiation of levodopa should be delayed until there is significant
disability, since there is concern regarding long-term side-effects.
 Some suggest to initiate treatment with a dopamine agonist or a slow-
release levodopa to minimise or delay the onset of long-term side-effects.
 90% of patients show improvement of rigidity and bradykinesia and (to a
lesser extent) tremor. 20% restored to normal motor function
 The initial dose is 50 mg 8-hourly, increased if necessary.
The total levodopa dose may be increased to over 1000 mg/day, but should
be kept as low as possible.
 Effective on a 3x/day regime with smooth control even though
phamacological T1/2 = 90min i.e biological T1/2 >> pharmacological T1/2
initially.
30
L-DOPA (LEVODOPA): dose/therapeutic
effects

L-DOPA (LEVODOPA): unwanted effects
31
Acute effects (tend to disappear over first few weeks):
The peripheral conversion of levodopa is responsible for the
high incidence of side-effects if used alone.
 Nausea and anorexia, hypotension, psychological effects
(confusion, insomnia, euphoria, inappropriate behaviours,
nightmares, hallucinosis, psychosis) Reduced by the use of
a peripheral dopamine antagonist as domperidone.

32
 Slowly developing unwanted effects, motor fluctuations.
 Late deterioration despite levodopa occurs after 3-5 years in 1/3-1/2.
manifests as fluctuation in response; of 2 types:
 End-of-dose deterioration due to progression of the disease& loss of capacity
to store dopamine, often can be improved by dividing the levodopa into
smaller but more frequent doses, or by converting to a slow-release
preparation
 ‘On-off' phenomenon: More complex fluctuations present as sudden,
unpredictable changes in response, in which periods of severe parkinsonism
alternate with dyskinesia&agitation,is difficult to treat, but sometimes SC
apomorphine (a dopamine agonist) are helpful to 'rescue' the patient rapidly.

33
 Slowly developing unwanted effects, motor fluctuations.
 Develop in most patients after 3-5years on L-dopa, esp if young, high
dose
 Involuntary movements, sp orofacial dyskinesias, limb &axial
dystonias,occasionally depression, hallucinations& delusions.
Involuntary movements (dyskinesia), can be violent; may occur as a
peak-dose phenomenon, or as a biphasic phenomenon (during build-up
& wearing-off phases). Management is difficult, but again involves
modifying the way levodopa is administered (reduce dose) to obtain
constant levels in the brain & use of alternatives, particularly dopamine
agonists. Thought to be related to the short phamacological T1/2 of L-
dopa causing pulsatile stimulation of the striatum and eventual
disordered basal ganglia output.
 Dopamine dysregulation syndrome (DDS) dysfunction of the reward
system, characterized by self-control problems such as addiction to
medication, gambling, or hypersexuality.

Optimization of PD pharmacological treatment
34
Now aim to prolong the pharmacological dopaminergic
stimulation of the striatum to limit the development of motor
fluctuations
 In younger patients, preference is given to neuroprotective and
L-DOPA sparing therapies.
 L-DOPA should only be started to help overcome significant
disability. In young (<65) aim to avoid L-DOPA for as long as
possible (although all patients eventually need it) and tend to
use long-acting (t1/2 8+hrs) dopamine agonists initially.
 L-DOPA plus…
 Peripheral COMT inhibitors, e.g. entacapone
 MAOB inhibitors, e.g. selegiline; may retard progression of
disease
 D1 and D2 receptor agonists

Anticholinergic therapy
35
Redressing the balance between dopaminergic and cholinergic neurons
appears to be some compensation for the overall deficit in dopamine
function
 Highest content of brain ACh is in the striatum
 ACh release is strongly inhibited by dopamine (D2 receptors)
 Cholinergic hyperactivity due to lack of dopamine contributes to hypokinesia,
rigidity and tremor (mainly via over-stimulation of the indirect pathway)

 Muscarinic receptor antagonists (anticholinergic’s)
 These have a useful effect on tremor & rigidity, but do not help bradykinesia.
 They can be prescribed early in the disease before bradykinesia is a problem,
but should be avoided in elderly patients in whom they cause
confusion/dementia/hallucinations.
 Other side-effects include dry mouth, blurred vision, difficulty with
micturition / constipation.
 Many anticholinergics are available-, trihexyphenidyl (benzhexol; 1-4 mg 8-
hourly) , orphenadrine (50-100 mg 8-hourly).
36
TrihexyphenidylOrphenadrine
Anticholinergics therapy

Amantadine
 While the mechanism of action of amantadine in the treatment of PD is not
known, it is believed to release brain dopamine from nerve endings making
it more available to activate dopaminergic receptors.
 This has a mild, usually short-lived effect on bradykinesia, but may be used
early in the disease before more potent treatment is needed.
 The dose is 100 mg 8- or 12-hourly.
 Side-effects include nausea, dizziness (lightheadedness) and insomnia,
livedo reticularis (a mottled reticulated vascular pattern that appears like a
lace-like purplish discoloration of the lower extremities), peripheral oedema,
confusion, seizures.
37
Adantadine

MAOB inhibitors: Selegiline
 Selegiline and rasagiline belong to a class of drugs called monoamine
oxidase inhibitors (MAOIs). They slow the breakdown of dopamine in the
brain. They have a fairly mild anti-Parkinsonian effect in their own right.
 There has been some doubt as to its safety, but this is also controversial and
the subject of ongoing research.
 The usual dose is 5-10 mg in the morning.
 Selegiline has an amphetamine-like metabolite (by-product). This means it
can cause insomnia and hallucinations in some people.
 In the periphery MAOA breaks down dietary tyramine (found in cheeses,
smoked meats, fish, red wine, etc.) – if you also block MAOA, will get
tachycardia, hypertension, vomiting, headache)
38
Selegiline

COMT (catechol-O-methyl-transferase) inhibitors:
 Entacapone prevents COMT from metabolizing L-DOPA into 3-
methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the periphery,
which does not easily cross the blood brain barrier (BBB).
Pharmacologically, entacapone is somewhat similar to carbidopa
or benserazide.
 Entacapone (200 mg with each dose of levodoa) prolongs the
effects of each dose & reduces motor fluctuations when used with
levodopa.
 This allows the levodopa dose to be reduced & given less
frequently.
39Entacapone

Dopamine receptor agonists :
• More easily administered drugs include bromocriptine (D2 receptor agonist,
mild D1 receptor antagonist); pergolide (D1/D2 receptor agonist, more
potent and longer acting)
• These drugs are less powerful than levodopa in controlling features of
parkinsonism, but they are much less likely to cause dose fluctuations or
dyskinesia, though they will certainly exacerbate the latter once these have
developed. Side-effects include nausea, vomiting, confusion and
hallucinations.
• Orally administered; The dose of bromocriptine is 1 mg initially, increased to
2.5 mg 8-hourly, up to 30 mg/day.
• Pergolide dose starts at 50 μg, increased to 250 μg 8-hourly, possibly to
3000 μg/day.
• Dopamine agonists derived from ergot (e.g. pergolide / cabergoline) have
recently been associated with the development of cardiac fibrosis-fibrotic
reactions/ thickening of heart valves, so most are screened with echo, chest
X-ray / renal function tests before commencing therapy&every 6 months
40
Bromocriptine Pergolide

Dopamine receptor agonists :Apomorphine
 Apomorphine given alone causes marked vomiting & has to be administered
parenterally.
 The vomiting can be overcome by the concomitant use of the anti-sickness
drug domperidone, & parenteral administration achieved through
continuous subcutaneous infusion from a portable pump, or direct injection
as needed.
 This requires considerable nursing support but, if used correctly, can be very
useful.
41
Apomorphine

Treatment In Malaysia
Decision pathway for the initiation of medication

Additional information to read later: Alternative
treatment approaches
Surgery :
 Stereotactic thalamotomy can be used to treat tremor, though this is needed
relatively infrequently because of the medical treatments available.
 Other stereotactic lesions are currently undergoing evaluation, in particular
pallidotomy to help in the management of drug-induced dyskinesia.
 Implantation of dopamine rich fragments of brain
into the striatum
 Implantation of stem cells
 Midbrain neurones transplanted into the striatum
 Immortalised neuronal precursor cells
Physiotherapy& rehab:
Patients at all stages of Parkinson's disease benefit from physiotherapy, which
helps reduce rigidity& corrects abnormal posture.
Speech therapy may help in cases where dysarthria & dysphonia interfere
with communication.
 Gene therapy
 Transfection of tyrosine hydroxylase gene into the brain 43

 Neural tissue transplants--
Researchers are studying ways to
implant neural tissues from fetal
pigs into the brain to restore the
degenerate area. In a clinical trial
conducted in part at Boston
University School of Medicine,
three patients out of 12
implanted with the pig tissues
showed significant reduction in
symptoms.
 Genetic engineering--Scientists
are modifying the genetic code
of individual cells to create
dopamine-producing cells from
other cells, such as those from
the ski

Conclusion
• Patient has idiopathic Parkinson’s disease
• There is no cure but therapies are available
• Treatments aim to:
 Prevent clinical progression
 Improvement of parkinsonism
 Delay of motor complications
• Complications: choking, falls and side effects of drugs
• Prognosis: normal life expectancy for treated patients

Parkinson's disease

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