2013 pu ns 23 antiparkinsonian agents
TRANSCRIPT
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
1/25
Anti-Parkinsonian Agents
Class: JC3 2013/2014
Course: Neuroscience
Code: NS 23
Lecturer: Dr Brian KirbyDate: 10thOctober 2013
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
2/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
3/25
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]
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
4/25
Brain areas involved in PD
Basal Ganglia: Substantia nigra:
Thalamus:
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
5/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
6/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
7/25
Substantia nigra (pigmented)
Pathology of Parkinsons disease
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
8/25
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
9/25
Pathophysiology
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
10/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
11/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
12/25
L-dopa
Dopamine
DA receptor
Tyrosine
Synthesis of dopamine
Dopamine metabolised by
MAO-B and COMT
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
13/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
14/25
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)
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
15/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
16/25
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?
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
17/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
18/25
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?
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
19/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
20/25
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?
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
21/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
22/25
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?]
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
23/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
24/25
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
-
7/25/2019 2013 PU NS 23 Antiparkinsonian Agents
25/25
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