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Pharmacology

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

DRUGS FOR PARKINSONS DISEASE


Drug Classes and Drugs to consider
Combination DA agonists
Carbidopalevodopa

COMT
Inhibitors

Bromocriptine Entacapone
Pramipexole Tolcapone

MAO-B
Inhibitors

Anticholinergics Others

Rasagiline

Benztropine

Amantadine

Goal
To enable you to apply your knowledge of the pharmacology of the various classes of
drugs used in the treatment of Parkinsons disease.

Learning Objectives
Mechanism of action
Explain the molecular mechanism of action of each drug in each drug class.
Pharmacokinetics
Describe the routes of administration of the drugs
Describe the catabolism of L-DOPA and dopamine
Adverse effects and drug interactions
Describe the principal adverse effects of the drugs of each class, as appropriate
Describe the clinically important drug interactions of the drugs of each class, as
appropriate
Therapeutic uses
Outline the use of these drugs in the treatment of Parkinsons Disease.
Drug list and pronunciation
Entacapone
en TA ka pone
Amantadine
a MAN ta deen
Levodopa
lee voe DOE pa
Benztropine
BENZ troe peen
Pramipexole pra mi PEKS ole
Bromocriptine broe moe KRIP teen
Rasagiline
ra SA ji leen
Carbidopa
kar bi DOE pa
Tolcapone
TOLE ka pone
Outline
I.
Pathophysiology of Parkinsons
Disease relevant to pharmacology
A. Dopaminergic terminal
B. Neural mechanism of
parkinsonism
C. Overview of drug therapy
II. Carbidopa-levodopa
III. Dopamine agonists-Bromocriptine,
pramipexole

IV. COMT inhibitors-Entacapone,


tolcapone
V. MAO-B inhibitors-Rasagiline
VI. Anticholinergics-Benztropine
VII. Amantadine
VIII. Summary of treatment of Parkinsons
Disease

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Pharmacology

I.

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

Pathophysiology of Parkinsons Disease relevant to pharmacology


A. Dopaminergic terminal
1. Tyrosine is the precursor of
all catecholamines. It is taken
up by dopaminergic nerves
via an amino acid transporter
(AAT)
2. Dopamine (DA) is
synthesized in the cytoplasm
and transported into
secretory vesicles.
3. Upon nerve cell stimulation,
DA is released into the
synaptic cleft, where the
neurotransmitter can
stimulate postsynaptic dopamine receptors. D1 and D2 receptors are important
in brain regions involved in Parkinsons disease (see below). Stimulation of D2
receptors is largely responsible for reducing rigidity and bradykinesia.
4. DA is transported out of the synaptic cleft by the selective, Na+-coupled
dopamine transporter (DAT).
5. Cytoplasmic DA is re-transported into secretory vesicles or degraded by
monoamine oxidase (MAO).
B. Neural mechanism of Parkinsonism
1. Normal (refer to figure on left below)
Both direct and indirect pathway neurons in the putamen receive inputs from
the nigrostriatal dopaminergic system (dotted arrow) and from cortical
glutamatergic systems (solid arrow), process these inputs in the context of
local cholinergic influences (ACh), and transmit a GABAergic output (not
shown).

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Pharmacology

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

2. Parkinsons disease (refer to figure on right above)


Degeneration of dopaminergic neurons in the substantia nigra results in
understimulation of the direct (movement-enabling) pathway and
underinhibition of the indirect (movement-inhibiting) pathway. The net result is
inhibition of movement. Dotted gray arrows indicate decreased activity
caused by understimulation, and thick black arrow indicates increased activity
caused by underinhibition.
C. Overview of Drug Therapy
1. The salient pathophysiologic feature of Parkinsons Disease is the
progressive loss of dopamine from the nigrostriatal tracts in the brain
2. Drug therapy is aimed at replenishing the supply of dopamine. This is
accomplished through one, or a combination, of the following methods (refer
to figure and text below):
a.

Administering exogenous dopamine in the form of a precursor, levodopa


(L-DOPA)

b.

Inhibiting the major metabolic pathways that are responsible for the
degradation of levodopa and its metabolites.
i. Aromatic L-amino acid decarboxylase (AAD) inhibitors (e.g.,
carbidopa)
ii. Catechol-O-methyltransferase (COMT)-inhibitors (e.g., entacapone,
tolcapone)
iii. Monoamine oxidase type B (MAO-B) inhibitors (e.g. rasagiline)
Stimulating dopamine receptors within the corpus striatum through the
use of dopamine agonists (e.g., pramipexole, bromocriptine) [not shown]

c.

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Pharmacology

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

3. Additional therapies
a.

b.

II.

Anticholinergics (e.g., benztropine) counterbalance the negative effects of


the relative increase in acetylcholine activity and improve tremor
symptoms.
Amantadine, an antiviral agent, has antiparkinsonian activity through
modulation of dopamine release in the striatum, anticholinergic
properties, and blocking NMDA glutamate receptors.

Carbidopa-levodopa
A. Mechanism of action
1. Carbidopa-levodopa combination
a.
b.
c.

In the periphery, levodopa is metabolized to dopamine by the enzyme


aromatic amino acid (dopa) decarboxylase
Carbidopa is an inhibitor of dopa decarboxylase which does not cross the
blood brain barrier
Combining levodopa with carbidopa enhances the amount of dopamine
available to the brain and allows the dose of levodopa to be decreased

2. Levodopa is transported across the blood-brain barrier by an amino acid


transporter system. Once in the brain, levodopa is converted to dopamine
primarily in presynaptic terminals.
3. Dopamine is released from the terminals to stimulate dopamine receptors, D2
being the important receptor in treating Parkinsons disease.
B. Administration and elimination
1. Levodopa is absorbed in the proximal duodenum by an amino acid
transporter system.
2. When peripheral conversion to dopamine is blocked by carbidopa, the main
route of metabolism is by COMT.
C. Adverse effects
1. CNS: Anxiety, agitation, insomnia or sleepiness, nightmares, euphoria or
depression, confusion, delusions, hallucinations, personality changes
2. GI: Anorexia, nausea and vomiting, weight loss
3. Cardiovascular: Postural hypotension
4. Motor complications
a.
b.

During initial therapy there is marked improvement. Over time, however,


the effectiveness of levodopa declines.
As patients continue on levodopa therapy, they require more drug to
produce a clinically significant improvement in symptoms (tolerance).
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Pharmacology

Drugs for Parkinsons Disease

c.

d.

John L. Szarek, Ph.D.

They develop alternating periods of freezing and increased rigidity (off


periods) with periods of normal or even dyskinetic movement (on
periods).
i. On periods occur shortly after the administration of
levodopa/carbidopa, when a large bolus of dopamine is delivered to
the striatum.
ii. Off periods occur as plasma levels of levodopa decline
Eventually patients with end-stage Parkinsons disease experience either
mobility with severe dyskinesias or complete immobility.

D. Drug interactions
1. Competition for absorption sites in the small bowel from dietary amino acids
can reduce the absorption of levodopa. Competition can also occur at the
level of the blood-brain barrier
2. Nonspecific inhibitors of MAO (e.g., phenelzine) markedly accentuates the
actions of levodopa and may precipitate life-threatening hypertensive crisis
(Levodopa is converted to dopamine and subsequently norepinephrine.
MAOIs inhibit the degradation of dopamine.)
E. Clinical use
All patients will require levodopa treatment at some point. Levodopa remains the
most effective therapy for Parkinsons disease, and should be initiated as soon
as other therapies are unable to control parkinsonian symptoms effectively.
III.

Dopamine agonistsBromocriptine, pramipexole


A. Mechanism of action
1. The dopamine agonists work by directly stimulating postsynaptic dopamine
receptors within the corpus striatum; Stimulation of D2 receptors is largely
responsible for reducing rigidity and bradykinesia
2. Drugs
a.
b.

Bromocriptine is an ergot alkaloid that is an agonist at D2 receptors and a


partial antagonist at D1 receptors
Pramipexole is a nonergot agonist that has selective activity at D2
receptors and little or no activity at D1 class sites

B. Administration and elimination


Bromocriptine and pramipexole are administered orally

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Pharmacology

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

C. Adverse effects
1. Similar to those mentioned above for carbidopa-levodopa
2. Impulse-control disorder, manifested by pathologic gambling, excessive
shopping, binge eating or hypersexuality
D. Clinical uses in Parkinsons Disease
1. Dopamine agonists or levodopa can be used as initial therapy for Parkinsons
disease. In younger patients (e.g., age <65 years) with milder disease, a
dopamine agonist can be used as a first-line agent which will delay the
introduction of levodopa
2. Dopamine agonists can be used with carbidopa-levodopa in patients who are
refractory or experience on-off effects.
IV.

COMT inhibitors-Entacapone, tolcapone


A. Mechanism of action
Entacapone and tolcapone are selective and reversible COMT inhibitors which
increase the amount of levodopa available for transport across the bloodbrain
barrier. Tolcapone inhibits COMT in the periphery and in the CNS.
B. Administration
1. Entacapone is usually given with every administration of carbidopa/levodopa
2. Tolcapone is dosed three times daily
C. Adverse effects
1. Similar to those mentioned above for carbidopa-levodopa
2. Tolcapone is associated with liver failure thus liver function needs to be
monitored. It is recommended for use only in patients taking levodopa who
are experiencing motor fluctuations and are not responding adequately to, or
are not appropriate candidates for, other adjunctive therapy. Because of the
risks for hepatotoxicity associated with tolcapone, entacapone is the preferred
COMT inhibitor.
D. Clinical use
Inhibiting COMT improves and prolongs the response to levodopa as measured
by an increase in the amount of time spent on and a decrease in the daily
levodopa dosage.

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Pharmacology

V.

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

MAO-B inhibitors-Rasagiline
A. Mechanism of action
1. Two types of MAO enzymes exist: type A (MAO-A) oxidatively deaminates
catecholamines, such as serotonin, norepinephrine, and tyramine, and
MAO-B is responsible for the metabolism of dopamine.
2. Rasagiline is an MAO inhibitor that irreversibly inhibits MAO type B in the
brain preventing destruction of endogenous and exogenously administered
dopamine.
B. Adverse effects
Similar to those mentioned above for carbidopa-levodopa
C. Clinical use
1. Monotherapy in early disease delays initiation of levodopa treatment
2. Adjunctive therapy with levodopa in advanced disease permits use of lower
doses of levodopa.

VI.

Anticholinergics-Benztropine
A. Mechanism of action
In Parkinsons disease, the loss of dopamine-producing neurons results in a loss
of the balance that normally exists between acetylcholine and
dopamine-mediated neurotransmission. The anticholinergic agents work by
blocking the excitatory neurotransmitter acetylcholine in the striatum, thereby
minimizing the effect of the relative increase in cholinergic sensitivity.
B. Adverse effects
1. Peripheral effects, such as dry mouth, blurred vision, constipation, urinary
retention, and increased intraocular pressure
2. Central nervous system effects can include confusion, impairment of recent
memory, hallucinations, and delusions
C. Clinical use
1. Treatment of tremors in early disease and in younger patient with preserved
cognitive function
2. Adjunct to levodopa/carbidopa therapy

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Pharmacology

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

VII. Amantadine
A. Mechanism of action
1. An antiviral agent which has antiparkinsonian activity
2. The mechanism of action of amantadine is not entirely understood
a. Augments dopamine release from presynaptic nerve terminals and
possibly inhibits dopamine reuptake into storage granules.
b. Anticholinergic effects
c. Antagonist at N-methyl-D-aspartate (NMDA) receptors
B. Adverse effects
1. Neuropsychiatric complaints, which include dizziness, confusion,
disorientation, depression, nervousness, irritability, insomnia, nightmares, and
hallucinations.
2. Livedo reticularis
a. A rose-colored mottling of the skin, usually involving the lower extremities
b. Persists until therapy is discontinued
c. Caused by local release of catecholamines, which cause vasoconstriction
and alter the permeability of cutaneous blood vessels.
C. Clinical use
The main role of amantadine in the treatment of PD appears limited to add-on
therapy for treating levodopa-induced dyskinesias.

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Pharmacology

Drugs for Parkinsons Disease

John L. Szarek, Ph.D.

VIII. Summary of treatment for Parkinsons Disease


A. Levodopa combined with carbidopa remains the most effective symptomatic
treatment for Parkinsons disease. Dopamine agonists, the next most effective
drugs after levodopa in decreasing symptoms, can be used alone before the
introduction of levodopa, or as an adjunct to levodopa; the non-ergot drugs are
preferred.
B. Dopamine agonists may be
used as initial therapy in
younger patients with
Parkinsons disease and
levodopa as the initial
treatment in older patients
who may be more
vulnerable to the adverse
cognitive effects of the
agonists.
C. Addition of a
peripherally-acting COMT
inhibitor or an MAO-B
inhibitor to levodopa can
reduce motor fluctuations in
patients with advanced
disease.
D. Anticholinergics or amantadine can be a useful addition to levodopa for control of
tremor and drooling, or dyskinesia, respectively.
E. Direct brain stimulation (DBS) represents an treatment option in PD patients to
improve motor function and to reduce motor fluctuations, dyskinesia, and
medication usage.

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