2013 PU NS 23 Antiparkinsonian Agents

7/25/2019 2013 PU NS 23 Antiparkinsonian Agents

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Anti-Parkinsonian Agents

Class: JC3 2013/2014

Course: Neuroscience

Code: NS 23

Lecturer: Dr Brian KirbyDate: 10thOctober 2013


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Learning outcomes

NS23: Antiparkinsonian Agents

Relationship of treatment to pathophysiology of

Parkinson's disease

L-dopa therapy and its adverse effects

Dopamine agonists

MAO-B inhibitors

COMT inhibitors


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Parkinson

s disease

Progressive neurodegenerative disorder ofextrapyramidal motor system

Disorder of basal ganglia function: caudate nucleus

& putamen [striatum]

Primarily a disorder of the elderly, but can present

earlier

Also parkinsonism: post-encephalitic; drug-induced

[seeAntipsychotics]; neurotoxic [MPTP, Mn, CO]


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Brain areas involved in PD

Basal Ganglia: Substantia nigra:

Thalamus:


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Symptoms

Slowness/poverty of

voluntary movement:

bradykinesia/akinesia

Muscular rigidity: lead-

pipe or cog-wheel

Tremor at rest

Abnormal posture

Shuffling gait/hesitancy

Blank facial expression

Speech impairment

Inability to perform

skilled tasks


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Neuropathology

Parkinsons disease [PD] is a dopamine [DA] deficiency

disorder

DA neurons in substantia nigra pigmented [black] due to

neuromelanin; nigrostriatal DA pathway projects to striatum

Pathologically, in PD there is:

Loss of pigmented cells in zona compacta of substantia

nigra in midbrain

Degeneration of DA cell bodies in substantia nigra

Loss of DA from striatum; also from regions of limbic

system and frontal cortex innervated by DA


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Substantia nigra (pigmented)

Pathology of Parkinsons disease


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Pathophysiology


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Dopamine depletion

Reduced pigmentation correlates with depletion of dopamine

Brain Area Normal PD

Putamen 3.57 0.23

Caudate nucleus 3.5 0.32

Globus Pallidus 0.3 0.14

Substantia nigra 0.46 0.07

Hypothalamus 0.02 0


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Treatment of Parkinson

s disease

Symptomatic treatments

DA replacement therapy Levodopa [L-dopa]

DA receptor agonists

Bromocriptine, ropinirole Monoamine oxidase [MAO]-B inhibitors

Selegiline

Catechol-O-methyltransferase [COMT]

inhibitors Entacapone

Older treatments: (a) Muscarinic antagonists

(b) Amantadine


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L-dopa

Dopamine

DA receptor

Tyrosine

Synthesis of dopamine

Dopamine metabolised by

MAO-B and COMT


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Levodopa (L-dopa)

1stline treatment - most effective therapy L-dopa is inactive

Must be transported to brain and converted to

DA by aromatic aminoacid decarboxylase[AAAD]

Aminoacid system transports L-dopa to brain

L-dopa DopamineAAAD

But AAAD found in many tissues


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Decarboxylation of L-dopa in peripheral tissues

diminishes bioavailability, as DA cannot cross blood

brain barrier [BBB]

effectiveness, peripheral S/Es

Solution: combine L-dopa with an AAAD inhibitor thatdoes not cross BBB, e.g. carbidopa

Peripheral conversion to DA

Brain entry at a lower dose

Therapeutic activity

Peripheral S/Es

Now: L-dopa = L-dopa + carbidopa

Levodopa (L-dopa)


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DA synthesis in presence and absence of

carbidopa

dopa

Peripheraltissue

GI tract

Side effects

GI tractperipheral

tissueSide effects

--dopa

dopa

dopamine

DA receptor

Tyrosine

1. L-dopa

2. L-dopa +carbidopa


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Therapeutic effectiveness of L-dopa

Initially, 80% of patients show improvement

rigidity, bradykinesia; less so tremor

After 3-5 years

1/3 retain benefit

1/3 slowly lose benefit

1/3 rapidly lose benefit

Loss of effectiveness: natural progression of disease oremergence of side effects?


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Side effects of L-dopa

L-dopa dyskinesia

Fluctuations in clinical state

Nausea, vomiting

stimulation of DA receptors in CTZ

Mental disturbances: psychosis

stimulation of DA receptors in limbic regions/cortex?

Hypotension, cardiac arrhythmias

Endocrine: decreased release of prolactin


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L-dopa dyskinesia

Abnormal involuntary movement of limbs, trunk andorofacial regions

Following 2+ years of treatment

Initially at peak blood levels

disappear at dose, but rigidity returns

Later, unrelated to blood level

may be no movement without dyskinesia

Continuing disease - receptor denervation and upregulation,orpharmacological sensitisation?


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Fluctuations in clinical state:

on-off

effects

50% of patients after 5 years of therapy

Variable transitions from lack of movement [off]to normal movement or dyskinesia [on]

End-of-dose akinesia Progressive shortening of L-dopa action

Give more frequent, smaller L-dopa doses

On-offeffects

rapid fluctuations less related to timing

Continuous release formulations of L-dopa


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DA receptor agonists

DA agonists at D2/3

receptors

Bromocriptine, ropinirole

Possibility that continuing loss of DA nerve terminals limitslong-term effect of L-dopa

DA agonists do not require intact DA neurons

Efficacy L-dopa; long half-life

Early treatment - delays use of L-dopa

Later treatment - for on-offeffects

Side effects: similar to L-dopa

Nausea/vomiting; prolactin

Mental disturbances. Less dyskinesia?

Hypotension; sleep?


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MAO-B inhibitors

Rationale MAO-B deaminates DA in humans

Selective MAO-B inhibitor selegiline

Reduces breakdown of DA

Therapeutic benefit in PD

Potentiates L-dopa

Small reduction in L-dopa dosage

Controversy over retardation of disease progressionvssymptomatic treatment


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COMT inhibitors

Rationale COMT inactivates L-dopa and DA

Selective COMT inhibitor entacapone

Reduces breakdown of L-dopa and DATherapeutic benefit in PD

Potentiates L-dopa [peripheral > central]

Moderate reduction in L-dopa dosage

Improves motor fluctuations [dyskinesia?]


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Learning outcomes

NS24: Antiparkinsonian drugs

Relationship of treatment to pathophysiology of

Parkinson's disease

L-dopa therapy and its adverse effects

Dopamine agonists

MAO-B inhibitors

COMT inhibitors


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Other treatments

Additional anti-parkinsonian drugs

Dopamine agonists

Apomorphine s.c., with an antiemetic agent

Pramipexole

Ropinirole

MAO-B inhibitorRasagiline

Pharmacological Research

Neuroprotection; Adenosine antagonists; glutamate antagonists

Non-drug treatments

Surgery: Lesioning; stem cell transplantation; deep brain stimulation


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Further reading

Lees AJ, Hardy J, Revesz T. Parkinson

s disease. Lancet 2009; 373: 2055-66.

Calabresi P, Di Filippo M, Ghiglieri V, Tambasco N, Picconi B. Levodopa-

induced dyskinesias in patients with Parkinsons disease. Lancet

Neurology 2010; 9: 1106-17.

Goodm an & Gi lmans The Pharmaco logic al Basis o f Therapeut ics.

Rang & Dales Pharmacology

2013 PU NS 23 Antiparkinsonian Agents

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