Parkinson's disease:Pharmacotherapy

7/28/2019 Parkinson's disease:Pharmacotherapy

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Neurodegenerative

disordersDr.Rathnakar U.P.

MD.DIH.PGDHM

MBBS. 5th Sem

8th and 18th July 2013


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Neurodegenerative disorders

Dementia

Alzheimer's disease

Extrapyramidal and movement disorders

Parkinson's disease

Huntington's disease

Motor neuron disease

Amyotrophic lateral sclerosis


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PD[Poverty of movements, tremors and rigidity]


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PD[Poverty of movements, tremors and rigidity]

Thought

Of

movement

PFCortex

Pull out a programme

Motor area

Inhibition of

information

Inhibition of

information

PD


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ACh

Glu+

GABA[-]

GABA[-]

GABA[-]

GABA[-]

DA

D1+

D2-

Thalamus

STN SNigraPC

GP-Int- Ex C.Striatum

Cortex-Purposeful

movement

CS tract-

Purposeful movement

Glu+

Glu+


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Pathophysiology of PD

Thalamus M.Cortex

Movement

Tone

S.Cord

Thalamus M.Cortex

Movement

Tone

S.Cord

Normal

PD

1.Increasedinhibition

of

thalamus

2.Reduced

excitation

of cortex

Degenaration of

dopaminergic

nigrostriatal

pathway


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ACh

Glu+

GABA[-]

GABA[-]

GABA[-]

GABA[-]

DA

D1+

D2-Thalamus

STN SNigraPC


Cortex-Purposeful

movement

CS tract-

Purposeful movement

Glu+

Glu+

123

45

6

78

9

10

1.Excitaion

2.More GABA

3.Less GABA

4. Inhibition

5.Less GABA

6.GABA&Inhi

7.Less stim.

8. GABA & Inhi.

9. Excitation

10. Movement

Dopaminergic system intact


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ACh

Glu+

GABA[-]

GABA[-]

GABA[-]

GABA[-]

DA

D1+

D2-Thalamus

STN SNigraPC


Cortex-Purposeful

movement

CS tract-

Purposeful movement

Glu+

Glu+

123

45

6

78

9

10

1.No stim.

2.No GABA

3.More GABA

4.No Inhib.

5.More GABA

6.No GABA&Inhi

7.More stim.

8.More GABA&Inhi.

9.No Stim.

10. No Mov.

PD


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Clinical features of

PDParkinson's disease (PD) is the second commonestneurodegenerative disease, exceeded only by Alzheimer'sdisease (AD).5 million persons in the world suffer from this disorder.
http://localhost/var/www/apps/conversion/tmp/scratch_15/Parkinsonian%20Gait%20Demonstration_(360p).flvhttp://localhost/var/www/apps/conversion/tmp/scratch_15/Parkinsonian%20Gait%20Demonstration_(360p).flv


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"Dopaminergic" pathology

Degeneration of dopaminergic neurons inSNc

Non-dopaminergic" pathologyOver activity cholinergic neurones, Lewy

bodies


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The Substantia Nigra in

Parkinsons Disease


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Thalamus M.Cortex

Movement

Tone

S.Cord

Thalamus M.Cortex

Movement

Tone

S.Cord

Normal

PD

1.Increasedinhibition

of

thalamus

2.Reduced

excitation

of cortex


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DA and Ach in PD

AchAch Ach

DADA DA

Normal

DA=Ach

PD

Deficiency of DA

Relative excess of Ach

Treatment PD

Dopaminergics

Anticholinergics

DAAntichlonergics


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Sites of action of drugs used to treat Parkinson's disease

Levodopa 3-MDOPADopamine

DDC COMT

Entacapone

Tolcapone

Carbidopa

Benserazide

BBBBBB

Levodopa

Dopamine 3MT

DOPAC COMTMAOB

Selegiline

Rasagiline

Tolcapone

D1 & D2

ReceptorsDA agonists

1

2 2

33

4

Anticholinergics

Trihexyphenidyl

Procyclidine

Biperiden

Antihistaminics

5

0Stupid

6

DA facilitator

Amantadine


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Drugs for PD

I.Drugs affecting brain dopaminergicsystem

1. DA precursor- Levodopa

2. DDC inhibitors-Carbidopa

3. DA agonists-

Bromocriptine

4. MAO-B inhibitors-

Selegiline5. COMT inhibitors-

Entacapone

6. DA facilitator-Amantadine

II.Drugs affecting brain cholinergicsystem

1. Central anticholinergics

Trihexyphenydyl,

procyclidine, biperiden

2. Antihistaminics

Orphenadrine,

promethazine


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Levodopa


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Levodopa - PK


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Levodopa

Pharmacological actions

CNS

1. Normal persons-no

effect

2. PD: Excellent clinicalimprovement initially-

rigidity, hypokinesia,

Tremors other non-

motor symptoms later

3. Psychosis

4. Sexual activity

CVS

1. Tachycardia

2. Postural

hypotension[centralaction]

3. Tolerance develops

EndocrineProlactin


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Levodopa

ADEs

At initiation of therapy

Nausea & vomiting

Postural hypotension

Cardiac arrhythmias

Exacerbation of angina

Alteration of taste

Prolonged therapy

Abnormal movements

[dyskinesia]-chorea,

grimacing. Worsen with time

Dose limiting

Behavioral-Anxiety-

depression-psychosis End of dose effect

On-off phenomenon[worsening and improvement in a few

minutes-progressive degeneration]


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Levodopa

DIs

Pyridoxine abolishes

the effectnot with

carbidopa]

Antipsychotics abolishthe effect

Domperidone prevents

vomiting without loss of

th.effect

Anti HTNves-Postural

hypotension

Atropine-enhance

therapeutic effect at low

doses of levodopa. May

retard absorption


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PERIPHERAL

DECARBOXYLASE INHIBITORS

[Carbidopa & Benserazide]

Benefits

Do not cross BBB

t1/2

Dose of l.dopa reduced Side effects less

No pyridoxine reversal

On-off effect is less

Respond better

Unchanged/worsened

Involuntary movements

Behavior

Sleepy

Postural hypotension

Co-CareldopaCarbidopa:levodopa=10:100mg

LevodopaDopamine

DDC

Carbidopa

Benserazide


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Dopamine agonists

[Bromocriptine, Ropinirole, Pramipexole]

Ropinirole, Pramipexole

D2/D3 agonists

Supplementary

Monotherapy-early PD

Neuroprotective????

Oral

Also in restless leg

syndrome

Has replaced

bromocriptine


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MAO-B inhibitors[Selegiline, Rasagiline]

Selegiline

No hypertensive

reactions[low doses]

Early cases alone Adjuant to L.dopa

Reduces the dose

Metabolized amphetamine

CI in epileptics,insomnia[ADE]

DI-pethidine

Rasagiline

Five times potent

No amphetamine

Longer acting

Neuroprotective?????


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COMT Inhibitors[Entacapone, Tolcapone]

Entacapone

Only peripheral action

Prolongs action-l.dopa

Used to smoothen the

effect of L.dopa in on-

off

Not in early PD Yellow orange-urine

Not hepatotoxic

Tolcapone

Similar to entacapone

Crosses BBB

Central action not v.imp

Hepatotoxic


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Amantadine

Antiviral

Increases synthesis &

release of DA

Anticholinergic

Glutamate antagonist

DA facilitator

Mild cases alone

Combined with L.dopa

Bluish discolration

around ankle[lividreticularis]


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Centrally acting

anticholinergics

Restore Ach/ DA

balance in striatum

Tremor is benefitted

more than rigidity Less effective than

L.dopa

Cheap, less side effects Atropine like side

effects

Trihexyphenidil

Procyclidine

Biperiden

Orphenadrine

Promethazine


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Treatment strategies in PD

Pharmacotherapy only when disease

interferes with daily life

Selegiline/+anticholinergics

Younger pt with severe disease-

Levodopa/+anticholinergics/+Amantadine

More than 70-L.dopa

Anticholinergics avoided in older pts and

with dementia


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PD-Other measures

1. Surgical Measures

Thalamotomy or pallidotomy

2. Brain Stimulation High-frequency stimulation of the

subthalamic nuclei or globus pallidus

internus

3. Gene Therapy


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HD

Underactivity of neurons containing GABA

and acetylcholine

Overactivity of DA


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Huntington's disease

There is no cure for Huntington disease

Progression cannot be halted

Treatment is purely symptomatic

Relative underactivity of neurons containing

GABA and acetylcholine

Tetrabenazine, a drug that interferes with the vesicular storage ofbiogenic amines


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Motor neuron disease

[Amyotrophic lateral sclerosis]

Spasticity

Excessive stimulation of glutamate

receptors [excitotoxicity]

Riluzole - Blocks the release of glutamate

Retards progression

Other muscle relaxants - Baclofen,Tizanidine


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Alzheimers disease

Progressive cognitive deficit

Cholinergic deficit due to atrophy and

degeneration of subcortical cholinergic

neurons

Tt-Anticholinesterases

Galantamine, rivastigmine, donepezil

Memantine NMDA receptor antagonist


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Multiple sclerosis

Demyelination

Disease modifying drugs

Natalizumab

Fingolimod

Carbamazepine-symptomatic


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Other drugs

CNS stimulants

Cognitive enhancers

(Cerebroactive drugs)


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CNS stimulants

Convulsants: Strychnine, Picrotoxin,

Bicuculline, Pentylenetetrazol (PTZ)

Analeptics: Doxapram

Psychostimulants:Amphetamines,

Methylphenidate, Atomoxetine, Modafinil,

Cocaine, Caffeine


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CNS stimulants

*Amphetamines

Dextroamphetamine, Metamphetamine

Higher central:peripheral activity

Release NA from adrenergic neurons inthe brain

Attention Deficit Hyperkinetic Disorder

improve attention span and behaviour

Methylphenidate, Atomoxetine


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*CNS stimulants

Modafinil: Narcolepsy, sleep apnoea

Caffeine: Apnoea in premature infants


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Cognitive enhancers

(Cerebroactive drugs)

Heterogenous group of drugs developed

for use in dementia and other cerebral

disorders.

Cholinergic activators-Rivastigmine

Piracetam, Pyritinol (Pyrithioxine),

Dihydroergotoxine (Codergocrine),

Piribedil, Ginkgo biloba


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Cognition enhancers

Piracetam

Nootropic - a drug that selectively

improves efficiency of higher telencephalic

integrative activities

[Learning and memory]

May reduce blood viscosity

Promoted for

cognitive impairment and dementia in

the elderly

mental retardation in children


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Cognition enhancers

Pyretinol - claimed to activate cerebral

metabolism, improve regional blood flow

Dihydroergotoxine - semisynthetic

ergot alkaloid having adrenergic blocking

property

Ginkgo biloba - have PAF antagonisticaction

prevent cerebral impairment in MID.
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Parkinson's disease:Pharmacotherapy

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