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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
GP-Int- Ex C.Striatum
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
GP-Int- Ex C.Striatum
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).flv7/28/2019 Parkinson's disease:Pharmacotherapy
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Pathophysiology of PD
"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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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
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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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