PARKINSON'S DISEASE

Parkinson's disease (PD) is a progressive neurological disorder that results from

degeneration of neurons in the neostriatum. This degeneration creates a shortage of
dopamine, causing the movement impairments that characterize the disease, The
condition affects about 1 to 2 percent of people over the age of 60 years and the chance of
developing PD increases as we age.
HISTORY
Parkinson's disease was first formally described in "An
Essay on the Shaking Palsy," published in 1817 by a
London physician named James Parkinson, but it has
probably existed for many thousands of years. Its
symptoms and potential therapies were mentioned in the
Ayurveda, the system of medicine practiced in India as
early as 5000 BC, and in the first Chinese medical text,
Nei Jing, which appeared 2500 years ago. In the early
1960s, scientists identified the primary problem
underlying the disease: the loss of brain cells that produce
dopamine. This discovery led to the first successful
treatment for PD and suggested ways of devising new and
even more effective therapies.
ETIOLOGY
A. Genetics
Until relatively recently, Parkinson disease was not though to be heritable, and research
was primarily focused on environmental risk factors such as viral infection or
neurotoxins, However, a positive family history was gradually perceived to be a risk
factor, a view that was confirmed last year (2003) when a candidate gene for some cases
of Parkinson disease was mapped to chromosome 4. Mutations in this gene have now
been linked to several Parkinson disease families. The product of this gene is the protein
called alpha-synucIein. The finding was published online by Neuron on October 22,
2004. The collaborative work was spearheaded by National Institute on Aging (USA),
The Institut de Biomedicina (Spain), and The Institute of Neurology in London.
B. Environmental Factors
Although the importance of genetics in PD is increasingly recognized, many researchers
still believe that environmental exposures also increase a person's risk of developing the
disease. Even when genes are a factor in the disease, as with many familial cases,
exposure to toxins or other environmental factors may influence when symptoms of the
disease appear and/or how the disease progresses.

One of the primary pieces of evidence that environmental factors play a role in the
development of PD is that the relative risk of the disease is higher in industrialized
countries than in less industrialized ones. In addition, studies have found that farmers and
other agricultural workers have an increased risk of developing PD.
Another piece of evidence comes from observations of people who have been
accidentally poisoned with the toxin MPTP (l-methyl-4-phenyl-l, 2,5,6tetrahydropyridine), a structurally similar to some pesticides, which sometimes
contaminates street drugs. Actually, is a metabolite of MPTP, produced by MAO
type B and called MPP+ that destroys dopaminergic neurons in the substantia
nigra. The result is a severe, permanent parkinsonian syndrome in affected
people. This toxin is now used to create animal models of PD.
Scientists are continuing to study environmental toxins such as pesticides and herbicides
that can cause PD symptoms in animals. Researchers supported by the NINDS and the
National Institute on Aging have shown that exposing rodents to the pesticide rotenone
can cause cellular and behavioral changes that mimic those seen in PD.
Viruses are another possible environmental trigger for PD. People who developed
encephalopathy after a 1918 influenza epidemic were later stricken with severe,
progressive Parkinson's-like symptoms. A group of Taiwanese women developed similar
symptoms after herpes virus infections. In the latter case, the symptoms were linked to a
temporary inflammation of the substantia nigra, and later disappeared. However, these
cases showed that viruses can sometimes affect the region of the brain damaged in PD.
PATHOLOGY
The pathological hallmark of PD is a loss of the pigmented, dopaminergic neurons of
the substantia nigra and the presence of an inclusion body, called the Lewy body, in
many regions of the brain. Lewy bodies are dense clumps, or aggregates, of proteins.

Another cellular characteristic of PD is the presence of Lewy neurites - swollen nerve

fibers containing alpha-synuclein and other proteins. The accumulation of
alphasynuclein in these nerve fibers may interfere with transmission of nerve signals
or other important neuronal functions.
PARKINSON'S DISEASE CLINICAL MANIFESTATIONS
The symptoms vary from patient to patient and not every one is affected by all of them.
In some people, the disease progresses quickly; in others it does not. The following are
the most common primary symptoms of Parkinson's disease.
Tremor: In the early stages of the disease, about 70% of people experience a slight
tremor in the hand or foot on one side of the body, or less commonly in the jaw or face. It
appears as a 'beating' or oscillating movement and is regular (4-6 beats per second).
Because tremor usually appears when the muscles are relaxed, it is called "resting
tremor." This means that the affected body part trembles when it is at rest and not
doing work and often subsides with action.
The tremor often spreads to the other side of the body as the disease progresses, but
remains most apparent on the original side of occurrence. As the disease progresses, it
increases in severity and frequency. It has also been called a "pill-rolling" tremor
because it looks like a pill being rolled between the fingers. Tremor may be the least
disabling symptom, but is often the most embarrassing to the patient.
Rigidity: Rigidity or increased muscle tone means stiffness or inflexibility of the
muscles. Rigidity can result in a decreased range of motion. For example a patient may
not swing his or her arms when walking.
Cogwheel rigidity refers to increased tone that is felt by the examiner as a ratchetlike resistance during passive range of motion.

Bradykinesia: Bradykinesia is a slowing of voluntary movement. In addition to slow

movements, a person with bradykinesia will likely also have incompleteness of
movement, difficulty in initiating movements, and arrests of ongoing movement.
Patients may begin to walk with short, shuffling steps (festination), which,
combined with other symptoms such as loss of balance, increases the incidence of
falls. They may also experience difficulty making turns or abrupt movements. They
may go through periods of "freezing," which is when the patient is stuck and finds it
difficult to stop or start walking. Bradykinesia and rigidity can occur in the facial
muscles, causing a "mask-like" expression with little or no movement of the face.
The slowness and incompleteness of movement can also affect speaking and
swallowing.
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Postural Instability: The unsteadiness with walking and turning, as well as occasional
falls in Parkinson's disease patients is due in part to the postural instability. A patient
suffering from mildly impaired postural mechanisms will recover by stepping back one
or two paces after being nudged at the sternum. After a sternal nudge, a more disabled
patient will attempt to recover by stepping backwards, however they will continue in this
fashion until they either fall or hit something (called retropulsion). An extremely disabled
patient, being extremely rigid, may fall back straight as a board, without any attempt at
recovery, When the patient reaches end-stage, they are not able to stand without
assistance.
PATHOPHYSIOLOGY
It is a chronic, progressive disease that results when nerve cells in the substantia nigra,
die or are impaired. These nerve cells produce dopamine that transmits signals from
the substantia nigra to the corpus striatum. These signals allow for coordinated
movement. When the dopamine-secreting cells in the substantia nigra die, the other
movement control centers in the brain become unregulated. When 80% of the
dopamine-producing cells in the substantia nigra are depleted, symptoms of PD develop.
In Parkinsons disease the loss of dopamine on both the Direct and Indirect Pathways in
combination with a predominance of Ach actions in interneurons results in a reduction in
the activity of VA/VL and, in turn, motor cortical neurons. This explains the hypokinetic
symptoms seen in this neurological disease.

A normally pigmented substantia

nigra is seen in the midbrain on
the right but the midbrain on the
left from the patient with
Parkinson's disease shows a pale
substantia nigra.
As the pigmented nigral cells
degenerate, the neuromelanin is
dispersed and taken up by
macrophages; thus, one of the
diagnostic
histopathologic
hallmarks
of
PD
is
DEPIGMENTATION of the
substantia nigra.

A. Dopamine
Dopamine is a natural neurotransmitter, which belongs to the wider group of
neurotransmitters: the monoamines. As you should remember a monoamine is any
molecule that contains a single amine group (-NH2). As a catecholamine besides
containing the amine group it also has a "cathechol nucleus" which is composed of a
benzene ring with two adjacent hydroxyl groups (-OH).
B. Dopaminergic Neurons
Dopamine neurons synthesize dopamine from the amino acid tyrosine, which is
converted to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase.
Dihydroxyphenylalanine is converted to dopamine by the enzyme DOPA decarboxylase
(or aromatic amino acid decarboxylase) that is found in the cytoplasm. Dopamine can be
further metabolized to norepinephrine by the enzyme dopamine--hydroxylase, in
neurons containing the enzyme.

C. Dopamine Receptor Subtypes

There are five types of dopamine

receptors. These are Dl, D2, D3, D4, and
D5 .
Dl, and D2 receptors are found in the
corpus striatum.

All of these receptor subtypes work

through the G-protein-linked receptor.
Once activated the Dl and Ds receptors
activate adenylyl cyclase leading to the
production
of
cyclic
adenosine
monophosphate (cAMP). The D2, D3,
and D4 receptors, on the other hand,
inhibit adenylyl cyclase leading to a
decrease
of
cyclic
adenosine
monophosphate (cAMP).

THE CORTICOSPINAL TRACT

Movement in the human body is
produced by the motor cortex. From
there, the motor pathway, also called
pyramidal tract or the corticospinal
tract, leaves.
The motor impulses originate in the
giant pyramidal cells or Betz cells
(upper motor neurons) The axons of
these cells pass in the depth of the
cerebral cortex, then through the
corona radiata, internal capsule,
midbrain and medulla oblongata.
Is in the latter where the majority of
fibers decussate to the opposite side
and descends in the white matter of
the lateral funiculus of the spinal cord
on the opposite side. Fibers for the extremities pass 100% to the opposite side.
The fibers of the corticospinal tract terminate in the anterior horn of the grey matter of
the spinal cord. There, the lower motor neurons of the corticospinal cord are located.
Peripheral motor nerves carry the motor impulses from the anterior horn to the
voluntary muscles.

THE BASAL GANGLIA

However,
the
pyramidal
system is modulated by the
"extrapyramidal"
circuit,
which includes:

The Substantia Nigra

Striatum
Subthalamic Nucleus
Globus Pallidus
The Thalamus.

There are two important pathways through which striatal information reaches Globus
Pallidum Internal (GPi) - the direct pathway and the indirect pathway. These two
pathways have opposite effects on motor activity.
DIRECT PATHWAY
The cortical projections to the striatum
use
the
excitatory
transmitter
glutamate. When they are activated,
these cortical projections excite striatal
neurons. This excitatory input is
enough to turn on the striatal cell. This
striatal cell uses the inhibitory
transmitter GABA and its axon passes
to, and inhibits, a cell in GPi. The cells
in GPi that project to the motor
thalamus (VA/VL) also use GABA. So,
the cortical signal excites striatal
neurons, which results in more
inhibition from striatum to GPi. More
inhibition of GPi means less inhibition
of motor thalamus. Since the motor
thalamus receives less inhibition, the
VA/VL cells will increase their firing.
This decrease in inhibition is called disinhibition. Though not the same as
direct excitation, it similarly leads to an increase in activity.

So the end result of cortical excitatory input to striatal neurons at the head of the
direct pathway is INCREASED FIRING OF VA/VL NEURONS AND IN TURN
MOTOR CORTEX. This results in increased activity in the corticospinal tract and
eventually the muscles. REMEMBER, THE DIRECT PATHWAY TURNS UP
MOTOR ACTIVITY.

INDIRECT PATHWAY

In the indirect pathway, cortical fibers

excite striatal neurons that project to GPe.
The increased activity of the GABAergic
striatal neurons decreases activity in GPe.
The GABAergic cells in GPe inhibit cells
in the subthalamic nucleus, so the decrease
in activity in GPe results in less inhibition
of cells in the subthalamic nucleus. That is,
subthalmic neurons are disinhibited and
increase their activity. The return
projection from the subthalamic nucleus to
GPi is excitatory, so the increased activity
in the subthalamic nucleus results in more
excitation to cells in GPi.

Thus, the end result of actions of the indirect loop is an increase in activity of the
GABAergic cells in GP (internal) that project to VA/VL or an INCREASE in
INHIBITION of the thalamic neurons. The Indirect Pathway turns DOWN the
motor thalamus and, in turn, motor cortex. Thus, THE INDIRECT PATHWAY
TURNS UP MOTOR ACTIVITY.

THE EFFECT OF THE DOPAMINERGIC NIGROSTRIATAL PROJECTION

ON MOTOR ACTIVITY
Dopamine is produced by
cells in the pars compacta of
the substantia nigra (SNc).
Nigrostriatal axon terminals
release dopamine into the
striatum. Dopamine has an
excitatory effect upon cells
in the striatum that are part
of the Direct Pathway. This
is
via
D1
receptors.
Dopamine has an inhibitory
effect upon striatal cells
associated with the Indirect
Pathway. This is via D2
receptors.

In other words, the direct pathway (which turns up motor activity) is excited by
dopamine while the indirect pathway (which turns down motor activity) is inhibited.
BOTH OF THESE EFFECTS LEAD TO INCREASED MOTOR ACTIVITY.

THE EFFECT OF THE CHOLINERGIC STRIATAL INTERNEURONS ON

MOTOR ACTIVITY
ACh in the striatum is derived
from a population of giant, aspiny
cholinergic
interneurons.
Although they represent less than
2% of the total neuronal
population of the striatum, these
large cells have an extensive
network of processes, enabling
them to affect activity throughout
the striatum. Activation of
midbrain
dopamine
neurons
switches their activity to a
bursting firing pattern, a phasic
pattern of bursts of action
potentials. The consequence is
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substantially greater dopamine release in the striatum. Burst firing of dopamine neurons
is accompanied by silencing of the cholinergic interneurons, so ACh release ceases when
dopamine release increases. This coordinated reciprocal response, relies on nigrostriatal
inputs to the striatum.

The cholinergic actions inhibit striatal cells of the direct pathway and excite striatal
cells of the indirect pathway through M1 receptors.
Thus the effects of ACh are OPPOSITE the effects of dopamine on the direct and
indirect pathways.
ACh INHIBITS THE DIRECT AND EXCITES THE INDIRECT PATHWAY
IN PARKINSONS DISEASE THE LOSS OF DOPAMINE ON BOTH THE
DIRECT AND INDIRECT PATHWAYS RESULTS IN A PREDOMINANCE OF
ACH ACTIONS IN INTERNEURONS.
THIS RESULTS IN DECREASED MOTOR ACTIVITY

PARKINSONS DISEASE TREATMENT

There are several symptomatic treatments for people with Parkinson's including
medication, surgery, and physical therapy. The degree of success of each treatment varies
among individuals, as does the length of time the treatment option remains effective.
PHARMACOLOGICAL TREATMENT

Increasingthe
thedopaminergic
dopaminergic
activity
Increasing
activity
Treatment is addressed to restore this balance either by increasing the availability of
BASED ON
PD
PATHOPHYSIOLOGY
WHAT
Decreasing
the
cholinergic
activity
Decreasing
cholinergic
activity
dopamine
or reducing thethe
activity
of acetylcholine.

PHARMACOLOGICAL APPROACH WOULD YOU TAKE?

Treatment
of
Treatment
of
Parkinsonism
Parkinsonism

Parkinsonism
Parkinsonism

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I. LEVODOPA
If Parkinson's disease is primarily a dopamine deficient disease, the obvious strategy for
treatment is to replenish dopamine. However, dopamine DOES NOT CROSS THE
BLOOD-BRAIN BARRIER.
L-DOPA, the immediate precursor of dopamine does cross the blood-brain barrier and
in the brain is CONVERTED TO DOPAMINE BY THE ENZYME DOPA
DECARBOXYLASE.
Traditionally, levodopa has been used as the first-line therapy that alleviates signs and
symptoms of Parkinson's disease and reverses disability. It is usually the most effective
on average of all drugs for symptoms of PD, especially for bradykinesia or rigidity.
If levodopa is used alone, large does are required in order to ensure that a sufficient
amount enters the brain and is converted to dopamine (remember that significant amounts
of L-DOPA are peripherally metabolized to dopamine). This problem is alleviated with
the addition of carbidopa.

CARBIDOPA enhances the amount of dopamine available to the brain and

thereby allows the dose of L- DOPA to be decreased and consequently a less
incidence of its side effects.
It does so because it INHIBITS THE ENZYME DOPA DECARBOXYLASE
ONLY IN THE PERIPHERY SINCE IT CANNOT CROSS THE BLOOD-BRAIN
BARRIER (therefore it does not compromise the desired metabolism of L-DOPA
to dopamine in the brain).
It also shortens the time need it for the process of gradually increasing toe
levodopa dose to achieve maximal effects by several weeks because it substantially
decreases levodopa-induced nausea and vomiting.

11

Significant amounts of L-DOPA are peripherally metabolized to dopamine by the

enzyme DOPA DECARBOXYLASE.
This is the cause of L-DOPA side effects such as:
NAUSEA, VOMITING: Seen in up to 80 % of patients when levodopa is used
ALONE!!! DOPAMINE STIMULATES THE EMETIC CENTER LOCATED IN
THE BRAINSTEM (WHICH IS OUTSIDE OF THE BLOOD BRAIN BARRIER)
Tolerance develops after several months.
POSTURAL HYPOTENSION: Dopamine receptors are also found in the
periphery such as in arteries which cause vasodilation.
CARDIAC ARRHYTHMIAS: D4 receptors are found in the atria and their
activation cause increased myocardial contractility and cardiac output.
ANXIETY AND AGITATION AND HALLUCINATIONS: are CENTRAL effects
of dopamine and are caused by levodopa REGARDLESS OF WHETHER
CARBIDOPA IS ADDED TO LEVODOPA TREATMENT and is related to the
levels of dopamine.
Therefore, CARBIDOPA DOES NOT DECREASE
ADVERSE REACTIONS DUE TO CENTRAL EFFECTS OF LEVODOPA. By
permitting more levodopa to reach the brain, adverse CNS effects, including
dyskinesias, will occur at lower dosages and sooner during therapy with Carbidopa
and Levodopa extended-release than with levodopa alone.
Conversion of Levodopa to dopamine in the periphery by the enzyme dopa
decarboxylase is facilitated by pyridoxine (Vit B6). THEREFORE
PHARMACEUTICALS WHICH CONTAIN VITAMINE B6 MAY DECREASE
THE EFFECTS OF LEVODOPA.

12

PARKINSONS DISEASE PROGRESSION AND BRAIN

DOPAMINE LEVELS REFLECTING PLASMA LEVODOPA LEVELS

Most
patients
initially
respond well to levodopa
(the honeymoon period).
This is because early in the
disease there are still
sufficient
dopaminergic
neurons, which can store
dopamine, derived from
levodopa administration.
These neurons work as a
buffer against fluctuating
levodopa concentrations.

Progressive degeneration
of striatal terminal results
in a reduced striatal
dopamine and therefore,
the buffering capacity of
these
neurons
is
diminished.
Motor
response becomes more
dependent on fluctuations
in
synaptic
dopamine
concentrations.

Over a period of 5 to 15
years, disabling motor
response fluctuation and
dyskinesias appear which
pose a major management
problem.

13

"WEARING-OFF FLUCTUATIONS

The "wearing-off phenomenon, an increasingly shortened benefit period following each

dose of levodopa, is the most common type of motor fluctuation seen in Parkinson's
disease patients. Linked to nigrostriatal system degeneration, it is regular and
predictable and occurs 2 to 4 hours following a levodopa dose. It is believed to be due to
levodopa's relatively short plasma elimination half-life (about 1.5 hours). Patients may
present with sensory, psychiatric, autonomic and motor fluctuations.
Strategies for managing "wearing-off' phenomena focus on adjusting the medication
dose for optimal effect. Patients with short-duration responses often respond well to the
adjunctive therapy with a dopamine agonist. Prolonged-release levodopa preparations
may be substituted in part or totally for the immediate-release levodopa. Carbidopa,
levodopa and entacapone (Stalevo) is a combination tablet for patients who experience
signs and symptoms of end-of-dose "wearing-off".

WHILE CARBIDOPA REDUCES THE SIDE EFFECTS OF LEVODOPA,

ENTACAPONE EXTENDS THE TIME LEVODOPA IS ACTIVE IN THE BRAIN

14

"ON-OFF" FLUCTUATIONS
The "on-off' phenomenon is characterized by sudden, unpredictable shifts between
undertreated and overtreated states. These motor shifts appear to be an indirect result of
the destruction of presynaptic dopamine terminals resulting from fluctuation transmitter
levels. During the off period the patient becomes immobile or unable to perform
activities of daily living (e.g., inability to rise from a chair, to speak. or to walk).
Because they are sudden and unpredictable, "on-off' responses are very difficult to treat.
The addition of or increased dosage of a dopamine agonist or larger doses of levodopa
can be tried; however, most pharmacologic interventions that improve the" on" time will
also increase dyskinesias.
LEVODOPA AND HIGH PROTEIN MEALS
Large neutral amino acid transporter (LNNAs) is a heterodimeric membrane transport
protein that preferentially transports the essential amino acids tyrosine, tryptophan,
phenylalanine, leucine, isoleucine, histidine, methionine and threonine. This transporter
is mainly expressed in the blood brain barrier and in the gut. All of the LNNAs compete
for places on the same carrier system for movement into the brain and gut. Levodopa
crosses the gut and the blood brain barrier using this transporter.

Patients should be advised to TAKE LEVODOPA ON AN EMPTY STOMACH.

It is recommended to REDUCE DIETARY PROTEIN OR ADJUST MEAL
TIMES (an hour before or after) to prevent competition with transport, which may
lead to reduced therapeutic effect of the drug.

WHEN PRESCRIBING LEVODOPA PATIENTS SHOULD BE

ADVISED OF:

The risk of HYPERTENSIVE CRISIS IF MAOIs ARE GIVEN

CONCOMITANTLY

THOSE RECEIVING ANTIPSYCHOTIC TREATMENT SHOULD NOT

BE PRESCRIBED LEVODOPA TO TREAT THE EXTRAPYRAMIDAL
EFFECTS since L-DOPA enhances dopamine and therefore its interaction
with D2 receptors in the mesolimbic and mesocortical pathways. These
receptors' blockade is the base of antipsychotic's mechanism of action and
therefore, their efficacy could be compromised.

Metoclopramide DECREASES L-DOPA efficacy.

15

II. DOPAMINE AGONISTS

Dopaminergic agonists can be divided into ERGOT DAs such as BROMOCRIPTINE
(Parlodel) and NON-ERGOT DAs, PRAMIPEXOLE (Mirapex), ROPINIROLE
(Requip), and APOMORPHINE (Apokyn). Dopamine agonists are effective for all
features of the disease, but are not generally as effective as levodopa. Their used is being
recommended as monotherapy or as adjunct therapy early in the disease, particularly in
younger patients.

DAs VERSUS LEVODOPA

They ACT DIRECTLY AT DOPAMINE RECEPTORS and therefore

metabolic conversion to an active moiety, as in the case of levodopa, is not
required.

They do not undergo oxidation and thus AVOID THE GENERATION OF

FREE RADICALS THAT MAY CONTRIBUTE TO NEURONAL
DEGENERATION. This is being currently investigated to demonstrate a
potential neuroprotective role of these drugs in PD.

THE LONGER HALF-LIFE OF THESE DRUGS CAUSE FEWER

MOTOR COMPLICATIONS as they are able to provide continuous
stimulation of striatal dopamine receptors and reduce the frequency of doses
required to maintain adequate drug levels.

Unlike levodopa, DAs do not require carrier-mediated transport for

gastrointestinal absorption or entry into the brain and thus DIETARY
RESTRICTIONS ARE NOT REQUIRED

Their use is ASSOCIATED WITH MORE HALLUCINATIONS,

SOMNOLENCE, AND EDEMA THAN WITH LEVODOPA THERAPY.

Bromocriptine is a dopamine agonist. It directly stimulates postsynaptic dopamine D2

receptors within the corpus striatum. It also has Dl antagonist activity. It is administered
orally. Pramipexole and Ropinirole are selective D2 agonists.

16

The ERGOT-DAs have been linked to FIBROTIC REACTIONS AFFECTING

CARDIAC VALVE, PULMONARY, AND RETROPERITONEAL SOFT
TISSUES.
DOPAMINERGIC DRUGS have the potential to induce sudden and irresistible
drowsiness leading to sudden onset of sleep (SLEEP ATTACKS). These episodes
have the potential to cause serious accidents e.g. vehicle accidents.
DEVELOPMENT OF COMPULSIVE BEHAVIOR MANIFESTED AS
PATHOLOGIC GAMBLING, BINGE EATING, COMPULSIVE SHOPPING,
AND HYPERSEXUALITY. This is most likely to occur in younger onset PD
patients and those with family history of alcohol abuse.
Other side effects with these drugs, which are frequent and related to dopamine
include nausea, postural hypotension, somnolence, and psychosis.
III. APOMORPHINE

Although chemically related to morphine, APOMORPHINE LACKS any

ANALGESIC ACTIONS or risk for causing dependence OR ADDICTION. It is
classified as a dopaminergic agonist.
The unique role that apomorphine can offer for PD is the RAPID "RESCUE" IT
OFFERS A PD PATIENT FROM AN UNDERMEDICATED OR "FROZEN"
STATE.
Apomorphine does not relieve all features or symptoms of PD (such as imbalance).
Apomorphine needs to be administered by a subcutaneous injection. It has a very
rapid onset of action (10-15 min).
The first injection of apomorphine should be administered at the doctors office to
determine the correct dose, train the patient to self-injection and TO MONITOR
FOR HYPOTENSION.
IT MUST BE TAKEN WITH AN ANTIEMETIC drug because, when taken alone,
it causes severe nausea and vomiting. IT MUST NOT BE TAKEN WITH THE
5HT3 ANTAGONISTS (ONDANSETRON AND SIMILAR DRUGS), because the
combination of apomorphine and these drugs can lead to very low blood pressure
and loss of consciousness.

17

IV. AMANTADINE (Symmetrel)

Amantadine is an antiviral agent that was discovered serendipitously when a patient who
was given the drug to treat influenza experienced a remission in her tremor, rigidity, and
bradykinesia.

It
augments
dopamine
release from presynaptic
nerve terminals.

It may be used as monotherapy in patients with early Parkinson's disease, or as adjunct

therapy to levodopa. It is also used in combination with L-DOPA to treat L-DOPArelated dyskinesias
It is relatively safe and the major concern with its use is that doses need to be reduced in
patients with renal impairment since it is mainly excreted through the kidneys.

One of its side effects includes

LIVEDO RETICULARIS, a mottled
reticulated vascular pattern that
appears like a lace-like purplish
discoloration of the skin.

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V. MONOAMINE OXIDASE (MAO) INHIBITORS

Monoamine oxidase-B inhibitors (e.g., SELEGILINE, RASAGILINE) are used for the
treatment of early-stage Parkinsons disease. They block the breakdown of dopamine to
dihydroxyphenylacetic acid in the brain, resulting in an increased supply of dopamine.
As a result, inhibition of MAO-B can increase the dopaminergic response without
requiring an increase in levodopa dosage.
Selegiline (Deprenyl or Eldepryl) has a mild therapeutic effect. It also has mild
antidepressant activity that offers modest direct symptomatic benefit for PD.
SELEGILINE is METABOLIZED TO AMPHETAMINE and methamphetamine
metabolites,
which
may
induce
SLEEP
DISTURBANCES
AND
HALLUCINATIONS in susceptible patients.
RASAGILINE, a second-generation MAO-B inhibitor, is distinguished from
selegiline by its LACK OF AMPHETAMINE METABOLITES.

Patients eating foods rich in

tyramine while on drugs, which
irreversibly inhibit MAOA
enzyme may be at risk to
develop hypertensive crisis and
in some cases, death.
This is because they prevent the
metabolism of tyramine in the
small intestine, liver and
endothelium by monoamine
oxidase A and B. This can lead
to presence of tyramine in the
circulation.
Once tyramine reaches the
adrenergic neurons, it displaces
noradrenaline from the synaptic
vesicles.
(Because of the
inhibition of MAO tyramine and noradrenaline will not be degraded by MAOA in the
nerve terminal). Noradrenaline, which is then released into the synaptic cleft will be free
to interact with adrenergic receptors (e.g. 1 causing vasoconstriction and increased in the
peripheral vascular resistance and 1 causing increased cardiac output with consequent
increased in blood pressure.

19

In theory, because MAOB is present in the BRAIN BUT NOT IN ADRENERGIC

NEURONS, THE CHEESE REACTION IS NOT SEEN WITH IRREVERSIBLE
MAOB INHIBITORS, except at higher doses, which cause the selectivity of these
inhibitors to be lost.
However, selectivity of these drugs for MAO B may not be absolute even at the
recommended daily and caution should be exercised.

The cheese reaction is a MEDICAL EMERGENCY requiring immediate treatment.

Acute elevation in BP >180/120 mmHg leading to end-organ damage can start between
10 minutes and 2 hours after meal.
VI. COMT INHIBITORs
Levodopa is extensively metabolized in the periphery to 3-0-methyldopa (3-0MD) by
catechol-O-methyltransterase (COMT). COMT thereby reduces the amount of levodopa
available for conversion to dopamine. COMT inhibitors such as tolcapone and
entacapone increase the bioavailability of levodopa while maintaining more stable plasma
concentrations, and therefore enhance the efficacy of levodopa therapy.

CARBIDOPA, LEVODOPA AND ENTACAPONE (STALEVO) is a relatively new

combination tablet for patients who experience signs and symptoms of END-OFDOSE "WEARING-OFF".
WHILE CARBIDOPA REDUCES THE SIDE EFFECTS OF LEVODOPA,
ENTACAPONE EXTENDS THE TIME LEVODOPA IS ACTIVE IN THE
BRAIN.
TOLCAPONE is only used for more advanced patients, WHEN OTHER DRUGS
HAVE FAILED, because of concerns for LIVER TOXICITY.

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ANTICHOLINERGIC DRUGS
Anticholinergic agents were commonly used as initial therapy, especially in cases where
tremor was predominant. These agents have been used to treat PD since 1867, when it
was discovered that symptoms were improved by the belladonna derivative, scopolamine.
These drugs remained the mainstay of treatment until the late 1960s when amantadine
and levodopa were introduced.

The usefulness of these agents is limited by their PERIPHERAL (DRY MOUTH,

URINARY RETENTION, BLURRED VISION, CONSTIPATION) AND
CENTRAL ADVERSE EFFECTS (IMPAIRED MEMORY AND COGNITION,
CONFUSION, DELIRIUM, SOMNOLENCE, AND HALLUCINATIONS).
Co-existing diseases and conditions, such as GASTROINTESTINAL DISEASE,
BLADDER NECK OBSTRUCTION, GLAUCOMA, AND CARDIAC DISEASE,
also place patients at risk, and use of drugs with anticholinergic side effects should
generally be avoided.
Although most of these effects are mild and tolerable, serious consequences can
occur. For example, death can result from ileus of the bowel if not detected in time.

RELEVANT INFORMATION
The FDA has warned that there is an INCREASED RISK FOR MELANOMA IN
PATIENTS WITH PARKINSON'S DISEASE. Although the cause is unknown, factors
may include the disease itself and medication use.
Because drugs used in the
treatment of Parkinsons
disease may activate a
malignant melanoma, these
drugs should not be used in
patients with suspicious,
undiagnosed skin lesions or a
history of melanoma.
PERIODIC
SKIN
EXAMINATIONS SHOULD
BE
PERFORMED
TO
MONITOR
FOR
MELANOMAS.

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1
2

PARKINSONS DRUGS SUMMARY

Ropinirole
Amantadine

LIKE
PHARMACOLOGY!!!

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