DRUG TREATMENT OF PARKINSON S DISEASE. Mr. D.Raju, M.pharm, Lecturer

DRUG TREATMENT OF PARKINSON S DISEASE Mr. D.Raju, M.pharm, Lecturer

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

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 dopamine ACH GABA GABA Substantia nigra (upraveno podle Rang-Dale, 1999)

Fig. 1b. Extrapyramidal motor system - Basal ganglia Neurodegeneration, Parkinson s disease motor cortex glutamate TREMOR RIGIDITY Corpus striatum ACH glutamate dopamine GABA GABA Substantia nigra neurodegeneration (upraveno podle Rang-Dale, 1999)

How to treat deficit of dopamine? Fig 2a. Synapsis of dopaminergic nigrostriatal neurons autoreceptorss MAO B levodopa D 2, D 3 - receptors dopamine

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

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).

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

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)

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

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? 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