Drug treatment of Parkinson

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Drug treatment of Parkinson s disease

• Prof. MUDr Jirina Martínková, CSc
• 2006/2007

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PARKINSON S DISEASE

• (parkinsonism) is a neurodegenerative disorder
• which affects t h e b a s a l g a n g l i a
  -
• and is associated with
• a loss of dopaminergic neurons
• in the substantia
  nigra and
• degeneration of nerve terminals in the striatum
• PARKINSON S SYNDROME
• is the adverse effect of antipsychotic agents
• due to D2-receptor blockade in the basal ganglia
• Its acute form is reversible

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Parkinsonian patients

• suffer from
• - tremor at rest
• which tend to diminish during voluntary activity
• muscle rigidity, detectable as an increased
  resistance in passive limb movement
• suppression of voluntary movements hypokinesis
• Parkinsonian patients walk with a characteristic
  shuffling gait. They find it hard to start, and
  once in progress they cannot quickly stop or
  change direction.
• Degenerative process also affects other parts of
  the brain
• PD is commonly associated with dementia

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Neurodegenerative disorder

• The damage is caused by
• EXCITOTOXICITY
• OXIDATIVE STRESS
• APOPTOSIS /NECROSIS OF NEURONS
• EXCITOTOXICITY is due to
• release of a high amount of glutamate
• intracellular Ca 2 overload
• activation of NMDA, AMPA and metabotropic
• 
  receptors
• activation of proteases and lipases (causing
  membrane
• 
  damage)

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Fig. 1a.
Extrapyramidal motor system - Basal ganglia
motor cortex
glutamate
MOVEMENT
Corpus striatum
glutamate
ACH
dopamine
GABA
GABA
Substantia nigra
(upraveno podle Rang-Dale, 1999)
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Fig. 1b.
Extrapyramidal motor system - Basal
ganglia Neurodegeneration, Parkinsons disease
glutamate
motor cortex
TREMOR RIGIDITY
Corpus striatum
glutamate
ACH
dopamine
GABA
GABA
Substantia nigra
neurodegeneration
(upraveno podle Rang-Dale, 1999)
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Fig. 1a
In normal conditions acetylcholine release from
the striatum (cholinergic neurons) is strongly
inhibited by dopamine (depleted from the
nigrostriatal neurons). Joint GABA-ergic neurons
then opposite excitatory function of glutamate
neurones connected to the motor cortex.
Fig.
1b Neurodegeneration of the dopaminergic neurons
(Subs.nigra) loss of dopamine (the striatum)
leads to both hyperactivity of these cholinergic
striatal neurons blockade of GABA-ergic cells
(Subst.nigra). The result is an increase in
excitatory activity of glutamate the motor
cortex muscle rigidity, tremor,
hypokinesia
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How to treat deficit of dopamine?
Fig 2a. Synapsis of dopaminergic nigrostriatal
neurons
autoreceptorss
MAO B
D2, D3 - receptors
levodopa
dopamine
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Fig 2b. Parkinsons disease treatment
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agonists
MAO B
2
4
5
dopamine
levodopa
1
3
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How to treat deficit of dopamine?

• INCREASE IN DOPAMINERGIC ACTIVITY
• (1) dopamine precursors (replacement of dopamine)
• (2) MAO-B blockade
• (3) increase in dopamine release
• (4) blockade of amine neuronal reuptake
• (5) dopamine receptors agonists
• How to treat excitatory function of cholinergic
  and glutaminergic neurons?
• MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS

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How to treat deficit of dopamine?

• INCREASE IN DOPAMINERGIC ACTIVITY
• (1) dopamine precursors (replacement of dopamine)
• (2) MAO-B blockade
• (3) increase in dopamine release
• (4) blockade of amine neuronal reuptake
• (5) dopamine receptors agonists
• (6) presynaptic autoreceptor blockade

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How to treat deficit of dopamine?

• INCREASE IN DOPAMINERGIC ACTIVITY
• (1) dopamine precursors (replacement of dopamine)
• (2) MAO-B blockade
• (3) increase in dopamine release
• (4) blockade of amine neuronal reuptake
• (5) dopamine receptors agonists

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How to treat deficit of dopamine?

• Levodopa (L-DOPA) the first-line drug

Dopa decarboxylase
Levodopa dopamine
Dopamine does not penetrate the blood-brain
barrier. DOPA conversion to dopamine in the
periphery, which would cause troublesome adverse
effects is largely prevented by the
decarboxylase inhibitor. Since the inhibitor
does not penetrate the blood-brain barrier,
decarboxylation occurs rapidly within the brain
(95 of the levodopa dose).
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How to treat deficit of dopamine? Levodopa
(L-DOPA)

• About 80 of parkinsonian patients show initial
  improvement with levodopa, particularly of
  rigidity and hypokinesia, and about 20 are
  restored virtually to normal motor function. Some
  symptoms (cognitive decline, dysphagia) are not
  improved.
• W i t h t i m e the effectiveness of
  levodopa gradually declines
• it reflects the natural
  progress of disease
• receptor
  down-regulation

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How to treat deficit of dopamine? Levodopa
(L-DOPA)

• Adverse effects (type A)
• dyskinesia - involuntary writhing movements
  develop in the majority
• of patients within 2
  years of starting levodopa therapy
• affect the face and limbs
• are dose-dependent (disappear if the dose is
  reduced)
• on-off effect rapid fluctuation in clinial
  state
• where hypokinesia
  and rigidity
• suddenly worsen (for anything from a few minutes
  to a few hours) and then improve again (probably
  the fluctuations reflect the changing plasma
  levodopa concentration)
• Others
• nausea and anorexia, hypotension,
• by increase dopamine activity in the
  brain----schizophrenia-like syndrome with
  delusions and hallucinations
• confusion, disorientation, insomnia (in 20 of
  patients)

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How to treat deficit of dopamine?

• INCREASE IN DOPAMINERGIC ACTIVITY
• (1) dopamine precursors (replacement of dopamine)
• (2) MAO-B blockade
• (3) increase in dopamine release
• (4) blockade of amine neuronal reuptake
• (5) dopamine receptors agonists

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How to treat deficit of dopamine?MAO-B blockade

• Selegiline
• a selective inhibitor for MAO-B, which
  prediminates
• in dopamine containing regions
  in the CNS
• MAO-B inhibition
• protects dopamine from intraneuronal degradation
• lacks the adverse peripheral effects of
  non-selective MAO
• 
  inhibitors used to treat depression
• does not provoke the cheese reaction

Combination of levodopa selegilin is more effective in relieving symptoms and prolonging life
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How to treat deficit of dopamine?

• INCREASE IN DOPAMINERGIC ACTIVITY
• (1) dopamine precursors (replacement of dopamine)
• (2) MAO-B blockade
• (3) increase in dopamine release
• (4) blockade of amine neuronal reuptake
• (5) dopamine receptors agonists

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How to treat deficit of dopamine? dopamine
receptors agonists-increase in dopamine release-
blockade of amine neuronal reuptake

• potent agonists at dopamine D2 receptors in the
  CNS
• bromocriptine derived from the ergot alkaloids
• lisuride and pergolide
• amantadine increases dopamine release, activates
  D2 receptors
• less active, more tolerated

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How to treat excitatory function of cholinergic
and glutaminergic neurons?

• MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS
• atropine
• action is more limited (than that od levodopa)
• tremor is more diminished than rigidity or
  hypokinesia
• Adverse effects (type A- troublesome peripheral
  action)
• dry mouth, constipation, impaired vision, urinary
  retention
• benzatropine has less peripheral effect in
  relation to their central effect than does
  atropine