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CHAPTER 28
Pharmacologic Management
of Parkinson disease (PD)
2
Overview of Parkinson's Disease
• PD is a progressive neurological disorder of muscle
movement, characterized by combination of rigidity,
bradykinesia, resting tremor, and postural instability
• It generally affects the elderly and is estimated to afflict
more than 1% of individuals over the age of 65
• PD is correlated with destruction of dopaminergic neurons
in the substantia nigra with a consequent reduction of
dopamine actions in the corpus striatum-parts of the
brain's basal ganglia system that are involved in motor
control
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Overview of Parkinson's Disease
• Thus, the normal modulating inhibitory influence of
dopamine on cholinergic neurons in the neostriatum is
significantly diminished, resulting in overproduction or a
relative over-activity of acetylcholine by the stimulatory
neurons
• This triggers a chain of abnormal signaling, resulting in
loss of the control of muscle movements
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Connection to
muscle
through motor
cortex and
spinal cord
_
STIMULATORY
Ach NEURONE
+
NEOSTRIATUM
Cell death
results in
less
dopamine
release in
the
neostriatu
m
SUBSTANTIA
NIGRA
_
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Strategy of treatment
• Since
there is no cure for PD, the aim of
pharmacological therapy is to provide symptomatic
relief
• This
is obtained re-establishing the correct
dopamine/acetylcholine balance through the use of
drugs that either increase dopaminergic actions or
antagonizing the excitatory effect of cholinergic
neurons
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Drugs Used in Parkinson's Disease
• Drugs used in Parkinson’s disease include:
1) Levodopa
2) Dopamine agonists
3) Monoamine oxidase (MAO) inhibitors
4) Cathechol-O-methyl transferase (COMT(
inhibitors
5) Anticholinergic agents
6) Amantadine
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Levodopa
• Levodopa is the single most effective agent in the
•
•
•
•
•
treatment of PD
It is immediate metabolic precursor of DA
Levodopa is itself largely inert
levodopa, as an a.a, is transported into the brain by a.a
transport systems
Therapeutic and adverse effects of levodopa result from
its decarboxylation to dopamine
Oral levodopa is absorbed rapidly from the small
intestine by the transport system for aromatic amino acids
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Aromatic Amino Acid
Decarboxylase
Dopamine
DOPA
Tyrosine
Hydroxylase
Tyrosine
H+
DA
DOPAC
Uptake 1
HVA
DA
HVA
Uptake 2
Dopamine receptor
HVA
DA
3MT
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Levodopa
• Certain a.as from ingested food can compete with
levodopa for absorption from gut & for transport from
blood to brain
• About 1–3% of administered levodopa actually enters the
brain unaltered; the remainder is metabolized
extracerebrally, predominantly by decarboxylation to
dopamine, which does not penetrate the BBB
• It is combined with a peripheral dopa decarboxylase
inhibitor (e.g. carbidopa)
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Carbidopa
• A dopa decarboxylase inhibitor that does not
cross the BBB
• Carbidopa
diminishes the metabolism
levodopa in the GIT and peripheral tissues:
of
a. Increases the availability of levodopa to the CNS
b. Lowers the dose of levodopa needed by about 10-
fold
c. Decreases the severity of the side effects arising
from peripherally formed dopamine
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Levodopa
(Clinical use)
• Levodopa is widely used for treatment of all types of PD
except those associated with antipsychotic drug
therapy
• Levodopa substantially reduces the severity of all the
signs and symptoms of PD in the first few years of
treatment
• Patients then typically experience a decline in response
during the third to fifth year of therapy (progression of the
disease and the loss of striatal dopamine nerve terminals)
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Levodopa
ADRs
A. Gastrointestinal tract (GIT)
• Anorexia, nausea, and vomiting (likely due to dopamine’s
stimulation of the CTZ)
• Minimized by taking the drug in divided doses, with or
immediately after meals, and by increasing the total daily
dose very slowly
• When levodopa is given in combination with carbidopa,
adverse GIT effects are much less frequent & patients
can tolerate proportionately higher doses
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Levodopa
ADRs
B. Cardiovascular effects
• Cardiac arrhythmias: caused by increased catecholamine
formation peripherally
• Postural hypotension as a result of the peripheral
decarboxylation of levodopa and release of dopamine into
the circulation
• Incidence can be reduced if levodopa is taken in
combination with Carbidopa
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Levodopa
ADRs
C. Dyskinesias
• Occur in up to 80% of patients receiving levodopa within 2
years of starting levodopa therapy
• Are excessive and abnormal choreiform/ involuntary
movements of the limbs, hands, trunk, and tongue
• The development of dyskinesias is dose-related that
occur most often
concentration is high
when
the
plasma
levodopa
• There is considerable individual variation in the dose
required to produce them
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Levodopa
ADRs
E. Fluctuations in Response
• Certain fluctuations in clinical response to levodopa occur
with increasing frequency as treatment continues
I. Wearing-off phenomenon/ end-of-dose akinesia:
• Related to the timing of levodopa intake
• Each dose of levodopa effectively improves mobility for a
period of time (1–2 hrs), but rigidity and akinesia return
rapidly at the end of the dosing interval
• Increasing the dose and frequency of administration can
improve this situation
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Levodopa
ADRs
E. Fluctuations in Response
II. On-off phenomenon
• Fluctuations in response are unrelated to timing of doses
• Patients fluctuate rapidly between being “off,” having no
beneficial effects from their medications, and being “on”
but with disabling dyskinesias
• Can be reduced by: *using a sustained-release
formulation, **division of the total daily dose into more
frequently administered portions, ***coadministration of
COMT inhibitors or ****selegline, and *****regulation of
dietary protein intake
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Levodopa
ADRs
F. Behavioral Effects
• Depression, anxiety, agitation, insomnia, somnolence,
confusion,
delusions,
hallucinations,
nightmares,
euphoria, and other changes in mood or personality
• More common in patients taking levodopa in combination
with carbidopa
• The use the “atypical” antipsychotic agents (e.g.,
clozapine), which are effective in the treatment of
psychosis but do not cause or worsen parkinsonism
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Drug Interactions of levodopa
• Pyridoxine
(vitamin B6): increase extracerebral
metabolism of levodopa and may prevent its therapeutic
effect unless carbidopais is also taken
• Nonspecific MAO inhibitors (e.g. phenelzine):
• Accentuates
the actions of levodopa and may
precipitate life-threatening hypertensive crisis
• MAO inhibitors must be discontinued at least 14 days
before levodopa is administered
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Levodopa
• Contraindications
Psychotic patients
2) Angle-closure glaucoma1
1)
• Careful management in patients with:
a) History of cardiac arrhythmias or recent cardiac
infarction
b) Active peptic ulcer must be managed carefully
c) History of melanoma or with suspicious undiagnosed
skin lesions2
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Monoamine Oxidase Inhibitors
• Two
types of monoamine oxidase have been
distinguished in the nervous system (MAO-A and MAO-B)
• The isoenzyme MAO-B is the predominant form in the
striatum and is responsible for most of the oxidative
metabolism of dopamine in the brain
• Blockade of dopamine metabolism makes more dopamine
available for stimulation of its receptors
• Selective MAO-B Inhibitors: Selegiline & Rasagiline
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Monoamine Oxidase Inhibitors
• Neither selegiline nor rasagiline should be taken by
patients receiving meperidine
agitation, and hyperthermia)
(stupor,
rigidity,
• They should be used with care in patients receiving
TCAs or SSRIs b/c of the theoretical risk of acute
toxic interactions of the serotonin syndrome type *
• ADEs:
o Most related to the increased levels of dopamine
o Anxiety, insomnia (selegline)
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Catechol-O-Methyltransferase Inhibitors
• Normally, the methylation of levodopa by catechol-O-
methyltransferase (COMT) to 3-O-methyldopa is a
minor pathway for levodopa metabolism
• However, when peripheral dopamine decarboxylase
activity is inhibited by carbidopa, a significant
concentration of 3-O-methyldopa is formed that
competes with levodopa for active transport into the
CNS
• Selective COMT inhibitors: tolcapone & entacapone
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Effect of entacapone on dopa concentration in the central nervous system (CNS). COMT = catechol-Omethyltransferase
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Catechol-O-Methyltransferase Inhibitors
• Entacapone is generally preferred: tolcapone has
both central & peripheral effects, whereas effect of
entacapone is peripheral
• ADRs:
o Increased levodopa exposure
o Orange discoloration of urine
o Hepatoxicity (tolcapone)
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Dopamine Receptor Agonists
• Dopamine agonists may delay the need to employ levodopa
therapy in early PD and may decrease the dose of levodopa in
advanced Parkinson's disease
• Dopamine receptor agonists:
Ergot derivatives e.g. bromocriptine
2. Non-ergot derivatives e.g. apomorphine, pramipexole,
ropinirole, and rotigotine
1.
• The differences between the ergot derivatives and the newer/
non-ergot agents reside primarily in their adverse effects,
tolerability, and speed of titration
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Dopamine Receptor Agonists
ADRs
A. Gastrointestinal tract effects:
• Anorexia, N & V: can be minimized by taking the
medication with meals
• Constipation, dyspepsia, and symptoms of reflux
• Bleeding from peptic ulceration
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Dopamine Receptor Agonists
ADRs
B. Cardiovascular effects:
• Postural hypotension common at the initiation of therapy
especially with the ergot derivatives
• Dose-related painless digital vasospasm with the ergot
derivatives
• Cardiac arrhythmias (discontinuation)
• Peripheral edema
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Dopamine Receptor Agonists
ADRs
C. Dyskinesias: reversed by reducing the total dose of
dopaminergic drugs
D. Mental Disturbances
• Include confusion, hallucinations, delusions, and other
psychiatric reactions which are more common and severe
with dopamine receptor agonists than with levodopa
• Disappear on withdrawal
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Dopamine Receptor Agonists
ADRs
E. Miscellaneous Adverse Effects (ergot derivatives)
o Headache
o Nasal congestion
o Increased arousal
o Pulmonary infiltrates
o Pleural & retroperitoneal fibrosis
o Erythromelalgia (red, tender, painful, swollen feet &,
occasionally, hands, at times associated with arthralgia)
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Dopamine Receptor Agonists
Contraindications
1. History of psychotic illness
2. Recent myocardial infarction
3. Active peptic ulceration
4. Peripheral vascular disease (ergot derivatives)
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Acetylcholine-Blocking Drugs
• Centrally
acting
antimuscarinic
drugs
include:
benzotropine
mesylate,
biperiden,
orphenadrine,
procyclidine, & trihexphenidyl
• Their efficacy in PD is likely due to the ability to block
muscarinic receptors in the striatum
• Are much less efficacious than levodopa and thus are
most commonly used during the early stages of the
disease or as an adjunct to levodopa therapy
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Acetylcholine-Blocking Drugs
ADRs
• The adverse effects of these drugs are a result of their
anticholinergic properties (CNS & peripheral effects)
1. CNS: mental confusion, delirium, and hallucinations
2. Peripheral: constipation, urinary retention, and blurred
vision through cycloplegia, sinus tachycardia, & dry
mouth
• Are contraindicated in patients with glaucoma, prostatic
hyperplasia, or pyloric stenosis
Amantadine
• An antiviral agent used for the prophylaxis and treatment
of influenza A
• Its MOA in parkinsonism is unclear. However it may:
a. Potentiate dopaminergic function by influencing the
synthesis, release, or reuptake of dopamine
b. Has anticholinergic properties
c. Block NMDA glutamate receptors
d. Antagonize the effects of adenosine at adenosine A2A
receptors, which are receptors that may inhibit D2
receptor function
• Benefits are short-lived, often disappearing after only few
weeks
Amantadine
ADRs
1) CNS: headache, restlessness, depression, irritability,
2)
3)
4)
5)
6)
7)
8)
insomnia, agitation, excitement, hallucinations, &
confusion
Acute toxic psychosis & convulsions (overdosage)
Livedo reticularis
Peripheral edema
HF
Postural hypotension
Anticholinergic: urinary retention, constipation, and dry
mouth
GI disturbances: anorexia & nausea
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Livedo reticularis