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Drug treatment of Parkinson ´s disease. Prof. MUDr Jiřina Martínková, CSc 2006/2007. 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

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Drug treatment of parkinson s disease

Drug treatment of Parkinson ´s disease

Prof. MUDr Jiřina Martínková, CSc

2006/2007


Parkinson s disease
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 nigraand

  • degeneration of nerve terminalsinthe 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


Parkinsonian patients
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 withdementia


Neurodegenerative disorder
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)


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)


Fig. 1b.

Extrapyramidal motor system - Basal ganglia

Neurodegeneration, Parkinson´s disease

glutamate

motor cortex

TREMOR

RIGIDITY

Corpus striatum

glutamate

ACH

dopamine

GABA

GABA

Substantia nigra

neurodegeneration

(upraveno podle Rang-Dale, 1999)


Fig 1a
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


How to treat deficit of dopamine?

Fig 2a. Synapsis of dopaminergic nigrostriatal neurons

autoreceptorss

MAO B

D2, D3 - receptors

levodopa

dopamine


Fig 2b. Parkinson´s disease treatment

6

agonists

MAO B

2

4

5

dopamine

levodopa

1

3


How to treat deficit of dopamine
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


How to treat deficit of dopamine1
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


How to treat deficit of dopamine2
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 deficit of dopamine3
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).


How to treat deficit of dopamine levodopa l dopa
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


How to treat deficit of dopamine levodopa l dopa1
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)


How to treat deficit of dopamine4
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 deficit of dopamine mao b blockade
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’


How to treat deficit of dopamine5
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 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


How to treat excitatory function of cholinergic and glutaminergic neurons
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


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