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PHARMACOLOGICAL MANAGEMENT THERAPEUTIC AGENTS IN

OF PARKINSON DISEASE PARKINSONISM
Parkinson’s Disease
• Parkinson disease is a movement disorder
characterized by resting tremor,
bradykinesia, rigidity, and postural
instability
• In Parkinson disease, there is a slow,
progressive degeneration of certain
dopamine secreting neurons in the basal
ganglia

Basal Ganglia
• basal ganglia include the caudate nucleus,
putamen, globus pallidus, lentiform
nucleus, and substantia nigra
• basal ganglia are primarily involved in the
control of motor activities
• medications used to treat these movement
disorders exert their effects by interacting
with basal ganglia structures
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• During this period, the patient is gradually

removed from all anti Parkinson
medication for 3 days to 3 weeks while
under close medical supervision
• The purpose of the holiday is to allow the
body to recover from any toxicity or
tolerance that may have developed because
of prolonged use of levodopa at relatively
high dosages
• Drug holidays are done with the hope that
levodopa can eventually be resumed at a
lower dosage and with better results
• Despite these potential benefits, drug
holidays are no longer used routinely
because of their potential risk to the patient
• Advanced stages of Parkinson disease,
discontinuing the anti-Parkinson
medications even temporarily results in
severe immobility, which can lead to
problems such as venous thrombosis,
pulmonary embolism, pneumonia, and
other impairments that could increase
morbidity and mortality
• Drug holidays may still be used on a limited
basis in a few select patients with Parkinson
disease, but this intervention is not used
routinely at the present time
OTHER DRUGS USED TO TREAT
PARKINSON DISEASE DOPAMINE
Problems and Adverse Effects of Levodopa AGONISTS
Therapy
Dopamine Agonists
• Gastrointestinal
• Dopamine agonists have serious side
• Cardiovascular
effects that prevent their clinical use
• Dyskinesia
• Dopamine agonists have traditionally been
• Behavioral problems used in conjunction with levodopa,
• Diminished response to levodopa especially in patients who have begun to
• Fluctuations in Response to Levodopa experience a decrease in levodopa effects,
➢ End of dose akinesia or in those who experience problems such
➢ On and off phenomenon as end-of-dose akinesia and the on-off
LEVODOPA Holiday effect
• Drug holidays are sometimes used in the • Dopamine agonists can also be used alone
patient who has become refractory to the in the early stages of mild to-moderate
beneficial effects of levodopa or has had a parkinsonism, thus providing an alternative
sudden increase in adverse side effects • if other anti-Parkinson drugs (including
levodopa) are poorly tolerated
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• Dopamine agonists may help normalize
endogenous dopamine activity, thus having
a neuroprotective effect on substantia nigra
neurons
• Dopamine agonists could produce such a
neuroprotective effect by providing
continuous stimulation of dopamine
receptors and preventing the free radical-
induced damage that is associated with
abnormal dopamine synthesis and
breakdown
Anticholinergic Drugs
• Drugs that limit acetylcholine transmission
are used to help alleviate the symptoms of
Parkinson disease, especially tremors and
rigidity
• Anticholinergic drugs are fairly
nonselective, however, and they tend to
produce a wide variety of side effects
because they block acetylcholine receptors
in various tissues throughout the body (see
below)
• When used alone, anticholinergics are
usually only mildly to moderately
successful in reducing symptoms and they
are typically used in conjunction with
levodopa or other anti-Parkinson drugs to
obtain optimal results
• Anticholinergics are associated with many
side effects including mood change,
confusion, hallucinations, drowsiness, and
cardiac irregularity, blurred vision, dryness
of the mouth, nausea/ vomiting,
constipation, and urinary retention.
Amantadine
• Amantadine (Symmetrel) was originally
developed as an antiviral drug, and its
ability to reduce parkinsonian symptoms
was discovered by chance
• Amantadine appears to work by blocking
the Nmethyl- D-aspartate (NMDA)
receptor in the brain, thereby inhibiting the
effects of excitatory amino acids such as
glutamate
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• This suggests that excitatory
neurotransmitters play a role in motor
complications associated with advanced
Parkinson disease
• The primary adverse effects associated with
amantadine are orthostatic hypotension,
CNS disturbance (e.g., depression,
confusion, hallucinations), and patches of
skin discoloration on the lower extremities
(livedo reticularis) • Side effects are
relatively mild compared to those of other
anti-Parkinson drugs and are usually
reversed by altering the drug dosage
Selegiline
• Selegiline (Deprenyl, Eldepryl) is a drug
that potently and selectively inhibits the
monoamine oxidase type B (MAOB)
enzyme
• This enzyme is responsible for breaking
down dopamine by inhibiting this enzyme,
selegiline prolongs the local effects of
dopamine at CNS synapses
• Selegiline can be used alone in the early
stages of Parkinson disease to prolong the
effects of endogenous dopamine produced
within the basal ganglia
• Selegiline may also be combined with
levodopa therapy because selegiline
prolongs the action of dopamine and allows
the reduction of parkinsonism symptoms
using a relatively low dose of levodopa
Catechol-O-Methyltransferase Inhibitors
• A relatively new group of drugs including
entacapone (Comtan) and tolcapone
(Tasmar) were developed to enhance the
effects of levodopa
• These drugs inhibit an enzyme known as
catechol-O-methyltransferase (COMT)
• This enzyme converts levodopa to an
inactive metabolite known as 3-
methyldopa; hence, these drugs are referred
to as COMT inhibitors
• By preventing levodopa conversion in
peripheral tissues, more levodopa is
available to reach the brain and exert
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beneficial effects. Hence, these drugs are

used as an adjunct to levodopa therapy to
provide better therapeutic effects using
smaller doses of levodopa
• Adding COMT inhibitor to Levodopa
therapy may also reduce fluctuations in the
response to levodopa, and prolong the
periods of levodopa effectiveness (“on”
time) with shorter periods of
unresponsiveness (“off ” time)
• The primary problem associated with
COMT inhibitors is an initial increase in
dyskinesias which may be due to the fact
that the COMT inhibitor is allowing more
levodopa to reach the brain, and that the
levodopa dosage needs to be lowered
accordingly
• Other side effects include nausea, diarrhea,
dizziness, and muscle pain/cramps