Documentos de Académico
Documentos de Profesional
Documentos de Cultura
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
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Pharmacology
I.
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Pharmacology
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
3. Additional therapies
a.
b.
II.
Carbidopa-levodopa
A. Mechanism of action
1. Carbidopa-levodopa combination
a.
b.
c.
Pharmacology
c.
d.
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.
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Pharmacology
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.
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Pharmacology
V.
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
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
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