Parkinson’

Parkinson’s Disease Huntington’

Huntington’s Disease

Drug Treatments
for
Neurodegeneration Alzheimer’
Alzheimer’s Disease

Dr. Darren Scully

Medicine Phar30060

Email: darren.scully@ucd.ie

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
• metabolic precursor of DA
• DA not coss BBB. Levodopa transported into
brain & converted to DA
• But, large doses of levodopa required as
usually broken down in periphery
• “on-off phenomenon”: v short t1/2, therefore
plasma levels drop suddenly Æ causes sudden
immobility etc.
• Dyskinesia possibility Æ overstimulation of
DA-R
Not used with:
• non-selective MAO-I: causes excess DA in
periphery
• Pyridoxine: increases peripheral DA
breakdown
• Antipsychotics: block DA-R
Carbidopa
• used in combo with Levodopa
• not cross BBB
Amantadine
• anti-retroviral used to treat influenza
• exact mechanism unknown. Recent research
suggests either stimulates DA release at
surviving neurons or inhibit uptake of DA at
synapses
• may improve tremor & rigidity when used with
levodopa
• only effective for few weeks but may be more
effective than anticholinergics
• Restlessness, confusion, skin rash, peripheral
oedema
Neural Transplantation??
Bromocriptine
• used in conjunction with Levodopa
• allow reduction in levodopa dosage
Æ reduce long-term levodopa s/e
• also used to treat hyperprolactinemia
• s/e: hallucinations, delerium,
vomiting, postural hypotension,
cardiac arrythmia, erythromelalgia
• Dyskinesia possibility Æ
overstimulation of DA-R
Selegiline
• selective I MAO-B
• decreases DA metabolism in
periphery Æ increase DA in brain
• in combo with levodopa
• s/e: hypertensive crisis at high dose
Benztropine
• reduce cholinergic output from
striatum
• lot less efficacious than levodopa
• adjunct therapy
• s/e as a result of parasympathetic
response: sedation, dry mouth,
constipation etc.
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)

8
 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

11