05[1]. Neurodegeneration

8/8/2019 05[1]. Neurodegeneration

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Drug Treatmentsfor

Neurodegeneration

ParkinsonParkinsons Diseases Disease

AlzheimerAlzheimers Diseases Disease

HuntingtonHuntingtons Diseases Disease

Dr. Darren ScullyMedicine Phar30060

Email: [email protected]

ObjectivesObjectives

Comprehend treatments for 3 neurodegenerative diseases

Observe that diseases are neurodegenerative but thetreatments only palliate not cure disease state

1. Parkinsons Disease

2. Huntingtons Disease

3. Alzheimers Disease

Lecture ContentLecture Content


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Cognitiveability

Time

TreatmentBegins

TreatmentEnds

Normal progression

Disease modification

Symptomatic treatment

Treatment of Neurodegenerative DisordersTreatment of Neurodegenerative Disorders



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striatum

substantia nigra

cortex

muscle

dopamine

Parkinsonsdisease

pc pr

ACh

thalamus

Glu


AimAim:To re-establish the balance between dopamine and acetylcholine in basal ganglia

MethodMethod:Increase dopamineReduce cholinergic output

GABA

Glu

GABA

GPe

STN

GABA

Hypokinetic disorder

ACh

ACh

DA

L-dopa

DA

DDC

DA

DA-R(D2)

inhibition

Ach-R(m)

excitation

metabolites

MAOB

ParkinsonParkinsons Disease:s Disease:

TherapyTherapyDA precursor

levodopa

DDC inhibitorcarbidopa

MAOB inhibitorselegilinestimulate DA releaseamantadine

DA agonistbromocriptineapomorphine

anticholinergicsbenztropine

DDC: dopa decarboxylase

DA: dopamine

DA-R(D2): D2 dopamine receptor

ACh-R (m) : muscarinicacetylcholine receptor

Ach: acetylcholine

Key:Key:


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Levodopa metabolic precursor of DA DA not coss BBB. Levodopa transported intobrain & converted to DA

But, large doses of levodopa required asusually broken down in periphery

on-off phenomenon: v short t1/2, thereforeplasma levels drop suddenly causes suddenimmobility etc. Dyskinesia possibility overstimulation ofDA-R

Not used with: non-selective MAO-I: causes excess DA inperiphery Pyridoxine: increases peripheral DAbreakdown

Antipsychotics: block DA-R

Carbidopa used in combo with Levodopa not cross BBB

Bromocriptine

used in conjunction with Levodopa allow reduction in levodopa dosage reduce long-term levodopa s/e also used to treat hyperprolactinemia s/e: hallucinations, delerium,vomiting, postural hypotension,cardiac arrythmia, erythromelalgia Dyskinesia possibilityoverstimulation of DA-R

Selegiline selective I MAO-B decreases DA metabolism inperiphery increase DA in brain in combo with levodopa

s/e: hypertensive crisis at high dose

Amantadine anti-retroviral used to treat influenza exact mechanism unknown. Recent researchsuggests either stimulates DA release atsurviving neurons or inhibit uptake of DA atsynapses

may improve tremor & rigidity when used withlevodopa only effective for few weeks but may be moreeffective than anticholinergics Restlessness, confusion, skin rash, peripheraloedema

Benztropine reduce cholinergic output fromstriatum

lot less efficacious than levodopa adjunct therapy

s/e as a result of parasympathetic

response: sedation, dry mouth,constipation etc.

Neural Transplantation??


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striatum

substantia nigra

cortex

muscle

dopamine

pc pr

ACh

thalamus

GABA

Glu

GABA

GPe

STN

GABA

Glu

Huntingtonsdisease


Hyperkinetic disorder


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HuntingtinHuntingtin AggregationAggregation

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

Mutant HuntingtinNormal Huntingtin

AlzheimerAlzheimers Diseases Disease


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Treatment of AlzheimerTreatment of Alzheimers diseases disease

Most treatment strategies, to date, are based on the cholinergic hypothesisof cognitive dysfunction in Alzheimers disease:

- depressed acetylcholine synthesis arising from reduced acetylcholineactivity 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 isdiverted into alternative metabolic pathways

- acetylcholine agonism was found to be ineffective in clinical trials- inhibition of acetylcholine degradation with acetylcholinesterase inhibitorsis modestly effective

AcetycholinesteraseAcetycholinesterase inhibitorsinhibitors

AChNT Rec

ActionPotential 1.

2.

3.

TN

4.

Steps of neurotransmission1. Electrical message (action potential)2. Neurotransmitter synthesis and release3. Neurotransmitter receptor interaction4. Neurotransmitter degradation/clearance

ACh: Achetylcholine

Inhibits acetylcholinesterase


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N

NH2tacrine

N

O

O

H3C

H3C

OH

galantamine

O C NH

CH3

O

CH3CH3

CH3

N N

physostigmine

AcetylcholinesteraseAcetylcholinesterase InhibitorsInhibitors

- can provide some mild transitory improvements butduration of action is too short

- can enhance some measures of memoryperformance but is hepatotoxic and can cause nausea,vomiting and cramps

- exerts some beneficial effects. Exhibits dual mode ofaction by inhibiting acetylcholinesterase and directlyacting on nicotinic receptors


Donepezil (Aricept)Rivastigmine (Exelon)

Galanthamine (Reminyl)

Alzheimers Disease Assessment Scale (ADAS-cog)

Galanthamine (4.1) > Rivastigmine (3.8) > Donepezil (2.8)


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Me

NMe2

ONEt

Me

O

Rivastigmine

Dual Cholinesterase InhibitionDual Cholinesterase Inhibition

Brain AchE decreases (99%-65%) but BuChE increases (1%-35%)

with AD disease progression

Rivastigmine has the dual action of inhibiting both AchE andBuChE

Clinical Therapeutics 26 2004 615

Patientsrespond

12 18 26 38 44 52

2

1

0

-1

-2

-3

-4

-5

-6

-7

-8

-9

Study week

Meanchangefromb

aseline

Eur Neurol 44;2000, 236

Placebo

Projected placebo

Actual Placebo

Rivastigmine(6-12mg/day)

Rivastigmine(1-4mg/day)


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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

Lancet Neurology 2 2003 503

Nature Reviews Drug Discovery 3 2004 109

NH2HClMemantine

NMDA receptor antagonismNMDA receptor antagonism

non-competitive, low-to-moderate affinity NMDA antagonist

strong voltage-dependency but rapid unblocking kinetics leads to prevention ofpathological 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


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ProsApproved for treatment of mild-to-moderate AD

Low incidence of serious side-effects

ConsCholinergic side effects

High non-responder rate

Provide only modestsymptomatic relief

Limited data showing evidencefor prolonged duration of effect

ProsApproved for treatment ofmoderate-to-severe AD

Combination with ChEIs shownto be beneficial

ConsConflicting efficacy data inmild-to-moderate AD

NMDA receptor antagonismCholinesterase inhibition

Adjunct therapy forAdjunct therapy for behavioural/pschologicalbehavioural/pschological

symptoms in Alzheimersymptoms in Alzheimers diseases disease

Endpoint evaluated OutcomeClass

Typical neuroleptics

haloperidolthiothixene

psychosis/agitation

goodfair

Atypical neuroleptics

good

fair

good

risperidone

olanzepine

quetiapine

Serotonin agonists

trazadone

paroxetine

citalopramsertraline

fluoxetine

depression

irritability/agitation

psychosis/agitation

fair

fair

poor

none

Cholinesterase inhibitorsdonepezil

fair

psychosis/agitationfair

Expert Rev. Neurotherapeutics 1 (2001) 70

05[1]. Neurodegeneration

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