Parkinson’
Parkinson’s Disease Huntington’
Huntington’s Disease
Drug Treatments
for
Neurodegeneration Alzheimer’
Alzheimer’s Disease
Dr. Darren Scully
Medicine Phar30060
Email: [email protected]
Objectives
Comprehend treatments for 3 neurodegenerative diseases
Observe that diseases are neurodegenerative but the
treatments only palliate not cure disease state
Lecture Content
1. Parkinson’s Disease
2. Huntington’s Disease
3. Alzheimer’s Disease
1
Treatment of Neurodegenerative Disorders
Treatment Treatment
Begins Ends
Cognitive ability
Normal progression
Symptomatic treatment
Disease modification
Time
Parkinson’s Disease
2
Parkinson’s Disease
Hypokinetic disorder
striatum
muscle
ACh
GABA
GPe
dopamine
GABA cortex
Parkinson’s
STN
disease
Glu
Glu
GABA thalamus
pc pr
substantia nigra
Aim:
Aim
To re-establish the balance between dopamine and acetylcholine in basal ganglia
Method:
Method
Increase dopamine
Reduce cholinergic output
Parkinson’s Disease: DA precursor
levodopa
Therapy L-dopa
Key:
DDC inhibitor
DA: dopamine DDC
carbidopa metabolites
DDC: dopa decarboxylase
DA-R(D2): D2 dopamine receptor DA
Ach: acetylcholine
ACh-R (m) : muscarinic
MAOB
acetylcholine receptor
DA MAOB inhibitor
stimulate DA release selegiline
amantadine
DA agonist
DA
bromocriptine
apomorphine
DA-R(D2)
ACh
ACh
Ach-R
(m) inhibition
anticholinergics excitation
benztropine
3
Levodopa Bromocriptine
• metabolic precursor of DA • used in conjunction with Levodopa
• DA not coss BBB. Levodopa transported into • allow reduction in levodopa dosage
brain & converted to DA Æ reduce long-term levodopa s/e
• But, large doses of levodopa required as • also used to treat hyperprolactinemia
usually broken down in periphery • s/e: hallucinations, delerium,
• “on-off phenomenon”: v short t1/2, therefore vomiting, postural hypotension,
plasma levels drop suddenly Æ causes sudden cardiac arrythmia, erythromelalgia
immobility etc. • Dyskinesia possibility Æ
• Dyskinesia possibility Æ overstimulation of overstimulation of DA-R
DA-R
Not used with: Selegiline
• non-selective MAO-I: causes excess DA in • selective I MAO-B
periphery • decreases DA metabolism in
• Pyridoxine: increases peripheral DA periphery Æ increase DA in brain
breakdown • in combo with levodopa
• Antipsychotics: block DA-R • s/e: hypertensive crisis at high dose
Carbidopa
• used in combo with Levodopa
• not cross BBB
Amantadine Benztropine
• anti-retroviral used to treat influenza • reduce cholinergic output from
• exact mechanism unknown. Recent research striatum
suggests either stimulates DA release at • lot less efficacious than levodopa
surviving neurons or inhibit uptake of DA at • adjunct therapy
synapses • s/e as a result of parasympathetic
• may improve tremor & rigidity when used with response: sedation, dry mouth,
levodopa constipation etc.
• only effective for few weeks but may be more
effective than anticholinergics
• Restlessness, confusion, skin rash, peripheral
oedema
Neural Transplantation??
4
Huntington’s Disease
Huntington’s Disease
Hyperkinetic disorder
striatum Huntington’s
disease
muscle
ACh
GABA
GPe
GABA cortex
dopamine
STN
Glu
Glu
GABA thalamus
pc pr
substantia nigra
5
Huntingtin Aggregation
High levels of glutamine repeats lead to protein aggregation – intracellular inclusions
Genetic – single defect on chromosome 4
Dysregulation of proteasome system and mitochondrial anomalies
Excitotoxicity and oxidative stress
GABAergic agonist – eg. baclofen
Normal Huntingtin Mutant Huntingtin
Alzheimer’s Disease
6
Treatment of Alzheimer’
Alzheimer’s disease
Most treatment strategies, to date, are based on the cholinergic hypothesis
of cognitive dysfunction in Alzheimer’s disease:
- depressed acetylcholine synthesis arising from reduced acetylcholine
activity and choline precursor uptake
- reduced acetylcholine release
Strategies employed included:
- precursor replacement with choline, phosphatidylcholine from
which choline is released. This strategy is generally ineffective as only
1% of administered choline is incorporated into acetylcholine, the rest is
diverted into alternative metabolic pathways
- acetylcholine agonism was found to be ineffective in clinical trials
- inhibition of acetylcholine degradation with acetylcholinesterase inhibitors
is modestly effective
Acetycholinesterase inhibitors
Action
Potential 1.
3.
NT ACh Rec
2.
4.
NT
Steps of neurotransmission Inhibits acetylcholinesterase
1. Electrical message (action potential)
2. Neurotransmitter synthesis and release
3. Neurotransmitter receptor interaction
4. Neurotransmitter degradation/clearance
ACh: Achetylcholine
7
Acetylcholinesterase Inhibitors
physostigmine
CH3
O C N CH3 - can provide some mild transitory improvements but
H
O duration of action is too short
N N
CH3 CH3
tacrine NH2
- can enhance some measures of memory
performance but is hepatotoxic and can cause nausea,
vomiting and cramps
N
H3C O galantamine
O - exerts some beneficial effects. Exhibits dual mode of
action by inhibiting acetylcholinesterase and directly
OH acting on nicotinic receptors
N
H3C
Acetylcholinesterase Inhibitors
Donepezil (Aricept)
Rivastigmine (Exelon)
Galanthamine (Reminyl)
Alzheimer’s Disease Assessment Scale (ADAS-cog)
Galanthamine (4.1) > Rivastigmine (3.8) > Donepezil (2.8)
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Dual Cholinesterase Inhibition
Me NMe2
N O
Et Me
O
Rivastigmine
Brain AchE decreases (99%-65%) but BuChE increases (1%-35%)
with AD disease progression
Rivastigmine has the dual action of inhibiting both AchE and
BuChE
Clinical Therapeutics 26 2004 615
Placebo
Rivastigmine
(6-12mg/day)
2 Rivastigmine
1
(1-4mg/day)
Projected placebo
Mean change from baseline
0
Actual Placebo
-1
-2
-3
-4
Patients
-5 respond
-6
-7
-8
-9
12 18 26 38 44 52
Study week
Eur Neurol 44;2000, 236
9
Acetylcholinesterase Inhibitors
Donepezil:
- reversible and selective AchEI
- piperidine derivative
- exhibits minimal peripheral acetylcholinesterase activity
- peak plasma concentrations occur in 3-4h
- long plasma half life that allows for once-daily dosing regimen
- 96% plasma protein bound and elimination half time is 70h
- 50% excreted unchanged in urine, rest by P450 system
Galantamine:
- reversible AchEI
- enhances response of nicotinic receptors to acetylcholine
Rivastigmine:
- relatively selective pseudo-irreversible AchEI
- 10h duration of action
- in rats, exhibits preferential AchE inhibition in cortex and hippocampus
- exhibits minimal peripheral adverse effects on heart and skeletal muscle
Tacrine:
- non-selective reversible AchEI
- 2-4h plasma half-life
- absorption declines with food intake
- elevates serum liver enzyme levels in approximately 30% of patients
NMDA receptor antagonism
NH2HCl
Memantine
non-competitive, low-to-moderate affinity NMDA antagonist
strong voltage-dependency but rapid unblocking kinetics leads to prevention of
pathological but not physiological actions of NMDA receptors
approved for the treatment of moderate-to-severe dementia of the Alzheimer type
adverse reactions are mild and can include agitation, urinary incontinence, insomnia,
diarrhoea, dizziness, headache and hallucinations
Lancet Neurology 2 2003 503
Nature Reviews Drug Discovery 3 2004 109
10
Cholinesterase inhibition NMDA receptor antagonism
Pros Pros
Approved for treatment of mild- Approved for treatment of
to-moderate AD moderate-to-severe AD
Low incidence of serious side- Combination with ChEIs shown
effects to be beneficial
Cons Cons
Cholinergic side effects Conflicting efficacy data in
mild-to-moderate AD
High non-responder rate
Provide only modest
symptomatic relief
Limited data showing evidence
for prolonged duration of effect
Adjunct therapy for behavioural/pschological
symptoms in Alzheimer’
Alzheimer’s disease
Class Endpoint evaluated Outcome
Typical neuroleptics psychosis/agitation
haloperidol good
thiothixene fair
Atypical neuroleptics psychosis/agitation
risperidone good
olanzepine good
quetiapine fair
Serotonin agonists irritability/agitation
trazadone fair
paroxetine fair
depression
citalopram poor
sertraline fair
fluoxetine none
Cholinesterase inhibitors psychosis/agitation
donepezil fair
Expert Rev. Neurotherapeutics 1 (2001) 70
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