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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. ( 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

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

  2. 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

  3. 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

  4. 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)

  5. 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)

  6. 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)

  7. 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

  8. How to treat deficit of dopamine? Fig 2a. Synapsis of dopaminergic nigrostriatal neurons autoreceptorss MAO B D2, D3 - receptors levodopa dopamine

  9. Fig 2b. Parkinson´s disease treatment 6 agonists MAO B 2 4 5 dopamine levodopa 1 3

  10. 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

  11. 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

  12. 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

  13. 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).

  14. 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

  15. 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)

  16. 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

  17. 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’

  18. 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

  19. 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

  20. 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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