Download Parkinson`s disease

Parkinson's disease
Parkinson's disease
• A chronic CNS disorder characterized by
slowness and poverty of purposeful
movements, muscular rigidity and tremor
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Tremor at rest
Rigidity
Hyperkinesias
Bradykinesia
Postural Instability
Difficulty in stopping, starting and turning while
walking
Epidemiology
• Incidence increases with age
• Approximately affects 1% world wide
• Age of onset for men and women and
incidence is equal
• Prevalence increases with age
Etiology
• Cause of Parkinson’s is not known
• Characterized by neuronal cell loss and
associated presence of inclusion bodies
(Lewy bodies) in degenerate neurons
• In PKD there is progressive degeneration of
Substantia nigra neurons that have
dopaminergic neurons
Pathophysiology
o
Acetylcholine V/s Dopamine
Stages of Parkinson’s
• Based on the severity of the disease
– Stage I – Unilateral involvement
– Stage II – Bilateral or midline; no
impairment
of balance
– stage III – Bilateral involvement
– Stage IV – Fully developed, severely
disabled
– Stage V – Confined bed or chair unless
aided
• Diagnosis is based on the presence of tremor,
rigidity and bradykinesia, either together or
alone.
• Many factors influence therapeutic decisionmaking, including the degree of confidence in
the diagnosis, functional and social disability,
age and the psychological and neurological
condition of the patient.
Rationale for drug use
• Provide symptomatic relief.
• No agent has been proven to slow progression
of disease.
• Treatment does not alter progression and
individual response can be variable, such as in
benign tremulous Parkinson’s disease where the
tremor may respond poorly, but usually
progresses very slowly.
Pharmacological Management
Early Parkinson’s disease
• It might be appropriate not to treat mild
disease if symptoms are not causing disability
or handicap.
• While levodopa is the most efficacious
treatment,
a
dopamine
agonist
may
sometimes be given alone in young patients
(less than 50 years of age).
• Anticholinergic agents can also be the initial
treatment in young patients with tremordominant disease.
• levodopa+benserazide 50mg/12.5mg orally,
3 times daily, after meals, increase to
100mg/25mg 3 times daily over 1 to 2
weeks, depending on response
OR
• levodopa+carbidopa 50mg/12.5mg orally, 3
times daily, after meals, increase to
100mg/25mg 3 times daily over 1 to 2
weeks, depending on response.
• An increase in the total daily dose and the
frequency of dosing is eventually necessary
in most patients.
• In some patients, higher doses are
necessary to control symptoms adequately.
• Dietary factors such as a high protein meal
can impair the response to an individual
dose.
• Levodopa taken without food often the
response to each dose is more rapid.
Additional therapy
• The dopamine agonists, bromocriptine,
cabergoline and pergolide, are not as effective as
levodopa and are usually used in conjunction with
levodopa.
• They may help reduce motor fluctuations and
have the advantage of enabling the dose of
levodopa to be lowered with a consequent
lessening of the drug-induced dyskinesias.
• They should be used cautiously in the elderly
because of possible acute psychotic reactions
bromocriptine 2.5mg orally, twice daily, up to 15mg twice daily
OR
cabergoline 0.5mg orally, daily, up to 5mg once daily. Increase
in increments of 0.5 to 1mg weekly up to optimal dose
OR
pergolide 0.05mg orally, twice daily, up to 1.5mg 3 times daily.
Entacapone 200mg orally initially, with each dose of levodopa. (Usual
effective daily dose is 800 to 1400mg)
Tremor
• In young patients, an anticholinergic agent
may be added to produce better control of
tremor.
• benztropine 1 to 2mg orally, daily, up to 2mg twice
daily OR
• benzhexol 2mg orally, 2 or 3 times daily, up to 5mg 3
times daily OR
• biperiden 1mg orally, 2 times daily, up to 2mg, 3 to 4
times daily
• Very occasionally higher doses are beneficial
• hallucinations and confusion, especially in the elderly,
so restrict their use
Advanced Parkinson’s disease
• Management is often difficult in these patients and
clinical experience is helpful with choice of
medication, dose and frequency of administration
• most develop new symptoms as a result of disease
progression and complications of therapy
• new symptoms as a result of disease progression
and complications of therapy
– isolated dose failures, delayed effect of a particular dose,
end of dose failure, rapid fluctuations not necessarily
related to dose, dyskinesias (peak dose or off time),
dystonia and freezing.
Drug
Usual dosage
Adverse effects
Dopaminergic
levodopa+bense 100/25 to 250mg/62.5mg 3
razide
times daily
levodopa+carbid 100/25 to 250mg/50mg 3
opa
times daily
nausea and vomiting

(initially), involuntary
movements, psychosis,
postural hypotension,
constipation
Dopamine agonists
bromocriptine
5 to 15mg 2 times daily
cabergoline
0.5 to 5mg daily
pergolide
0.05 to 1.5mg 3 times daily
neuropsychiatric,

postural hypotension,
erythromelalgia, fibrosis
(pleuro, pulmonary,
retroperitoneal)
COMT inhibitors
200mg with each dose of
levodopa
potentiation of

levodopa adverse
effects, diarrhoea
benztropine
1 to 2mg 2 times daily
benzhexol
2mg 2 or 3 times daily
biperiden
1 to 2mg 1 to 4 times daily
neuropsychiatric,

dry mouth, urinary
retention, constipation,
blurred vision, postural
hypotension
entacapone
Anticholinergics
Others
apomorphine
complex individualized
nausea,

schedule, see Pharmacological neuropsychiatric,
management of advanced
injection site reaction
Parkinson’s disease
selegiline
2.5 to 5mg 1 or 2 times daily
insomnia,

neuropsychiatric
amantadine
100mg 2 times daily
neuropsychiatric,

nightmares, livedo
reticularis, ankle oedema
Levodopa
• Improves bradykinesia and rigidity more
consistently than tremor
• First line treatment for most people,
especially the elderly and people with
cognitive impairment
• Long term use is associated with increased
motor fluctuations (end-of-dose failure and
on-off effect), dyskinesias and dystonias
Bromocriptine, Cabergoline and
Pergolide
• Improve bradykinesia and rigidity, but are less
effective than levodopa
• May cause confusion and hallucinations more
commonly than levodopa, especially in elderly
or demented people, and in high doses
• Combination of dopamine agonists with
levodopa allows a reduction in levodopa dosage
and improves motor fluctuations.
Bromocriptine, Cabergoline and
Pergolide
• Cabergoline or bromocriptine used as
monotherapy in early disease may delay the
onset of motor fluctuations and dyskinesias
and may be preferred as first line treatment
in younger patients
• Cabergoline or bromocriptine used as
monotherapy in early disease may delay the
onset of motor fluctuations and dyskinesias
and may be preferred as first line treatment
in younger patients.
Bromocriptine, Cabergoline and
Pergolide
• Long term use as monotherapy is limited
– as adverse effects associated with the high doses needed
– risk of retroperitoneal and pleuropulmonary fibrosis
– gradual loss of efficacy
• Pergolide is marketed for use only as an adjunct to levodopa
• Efficacy and safety of dopamine agonists seem broadly
similar.
• Cabergoline has a longer duration of action than
bromocriptine and pergolide and can be given once daily.
Selegeline
• Selectively inhibits monoamine oxidase type B
• May be used as monotherapy in early disease to delay
the need for levodopa and as adjunct to levodopa in
later disease to reduce motor fluctuations
• Evidence for its effectiveness is inconclusive
• TWO previous studies found an increased mortality
associated with selegiline use
• But not confirmed in a recent meta-analysis of the use
of monoamine oxidase type B inhibitors in early
Parkinson's disease
Amantadine
• Antiviral
drug
with
dopaminergic
and
anticholinergic activity and also acts as a Nmethyl-D-aspartate (NMDA) antagonist
• More effective than anticholinergic drugs for
akinesia and rigidity, but less effective for tremor
• Some loss of efficacy after 3–6 months
• May be used as monotherapy in early disease or
later as adjunctive treatment to alleviate druginduced dyskinesias
Apomorphine
• Dopamine agonist
• Start treatment in hospital under specialist
supervision
• Administer by SC injection or continuous
infusion
• Useful in people severely disabled by motor
fluctuations refractory to conventional treatment
• May allow a reduction in levodopa dosage
• Highly emetogenic and requires pretreatment
with domperidone to reduce nausea
Entacapone
• Inhibits catechol-O-methyltransferase (COMT) in
peripheral tissues and prolongs the clinical
response to levodopa
• May be used as an adjunct to levodopa in patients
with motor fluctuations
• It increases duration of motor improvement ('on'
time), but also increases levodopa-induced
dyskinesias and GI adverse effects
• The dose of levodopa may need reduction
Entacapone
• There are limited data available for
treatment with controlled release
formulations of levodopa
• The first COMT inhibitor to be licensed
(tolcapone) was deregistered because of
severe hepatic reactions
• There is no evidence to date of any hepatic
adverse effects of entacapone
Anticholinergics
• Include benzhexol, benztropine, biperiden and
orphenadrine
• Modest effect on tremor, but little effect on rigidity
and bradykinesia
• May be used as monotherapy in early disease when
tremor is predominant, or as adjunctive treatment in
patients inadequately controlled by levodopa
• Used infrequently because of the incidence of
adverse effects and relatively poor efficacy.
Anticholinergics
• Avoid use in the elderly and those with
cognitive impairment
• Adverse effects include dry mouth,
constipation, urinary retention, blurred
vision, aggravation of glaucoma and
psychiatric adverse effects (confusion,
memory loss, hallucinations)
• Withdraw slowly to avoid precipitating a
cholinergic crisis
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