Post on 04-Jun-2018
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Dr Keli Med III lectures
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Outline
Overview
Diagnosis
Treatment
Physical Therapy
Drug Therapy
Surgery
New Research
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Overview
Second most common human
neurodegenerative disorder.
Prevalence of 1 out 272 in U.S.
Increases to 4 to 5% for ages 85 and over.
Degeneration of dopaminergic neurons in
the substantia nigra.
Dopamine
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Phothophysiology Cont
Reduction of dopamine occurs in the
basal ganglia
Dopaminergic neurones inhibit the
output of GABargic cells in the corpusstriatum
Treatment based on
Restoration of dopaminergic activity Balance of doprminergic and cholinergic
activity with antimuscarinic drugs
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Overview contd
Symptoms caused by insufficient dopamine.
3 main symptoms:
Tremors
Rigidity
Slowed motion (Bradykinesia)
Postural instability
Other symptoms include:
Dementia, sleep disturbances, depression, etc.5
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Overview contd
Common causes of chronic progressive
parkinsonism.
Exact causes still yet unknown.
Gene mutation
Toxins , unrecognised neurotoxin, oxidative
stress
Trauma
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Diagnosis
No definitive tests for PD. PET scans
can aid to determine levels of dopamine.
Difficult to diagnose, many symptoms
shared with other disorders.
Medical history and neurological tests
are conducted to diagnose.
Usually, if two of the cardinal symptoms arepresent.
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TreatmentParkinsons
Disease No cure for PD.
Treatment can be divided into two stages. Early and Later stages
Early stage Onset of symptoms, treated with physical therapy and
medications (Levodopa, dopamine agonists, etc)
Later stage
Usually after having received 5+ years of levodopatreatment.
Wearing-off and On/Off effect develops, othermedication in conjunction levodopa is commenced.
MAO-B and COMT (Catecohol o methyltransferase)inhibitors.8
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TreatmentPhysical
Therapy Regular exercise
Recommended throughout the life of disorder.
Helps maintain and improve mobility and strength.
Physical exercise aids in rigidity relief, musclestrength and flexibility, balance, etc.
Caution is advised to avoid sudden movements or
strenuous activitiesfall could result in serious
injury.
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Levodopa
Precursor of dopamine, penetrates theBBB
Its an isomer of dopa
Dopa is precursor of dopamine and
norepinephrine
D2 receptors are located post synaptically
in the striatal neurons and in the
presynapsis of substatia nigra of the basalganglia
Dopaminergic drugs stimulate mostly D2
receptors
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Kinetics Levodopa
Absorption delayed by food certain
amino acids
Peak 1-2 hrs T1/2 1-3 hrs Main met is Homovallinic acid
Only 1-3% enters the brain must be
given in large amounts Given with a dopa decarboxylase
inhibitor the plasma half life is longer
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Drug TherapyL-DOPA
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Drug TherapyL-DOPA
L-DOPA can cross blood-brain barrier, when
dopamine cannot. This led to the idea of
using L-DOPA as treatment for PD.
First used in the 1960s, with daily increasedosage program.
L-DOPA used in combination with Carbidopa
in 1967. Increases potency of L-DOPA up to 4-fold.
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Drug therapy
Used early in treatment daily dose has
to be reduced over time
Causes selective denervation some
patients become less responsive
Effects diminsh 3-4yrs of therapy ?due
to dissappearance of nigrostrial and
strial nerve tissue Early use lowers mortality of
Parkinsonism
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:Levodopa dose
Sinemet is a preparation containing
Levodopa and carbidopa
Sinemet 25mg/100mg one TID increase
accordingly 30 min before meals
Can be used with a dopa agonist
Particularly relieves bradykinesia only
1/3 patients respond well
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Drug TherapyL-DOPA
Side effects include
Psychiatric symptoms; linked to depression
Nausea and vomiting ( stimulation of emetic
center in the brain stem) in absence of carbidopain 80% case Rx antacids easy dosing, anti
emetics phenothiazines should be avoided they
reduce the antiperkinsonism effect
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Side effects
CVS
Arrythmias incidence reduced in the
presence of Carbidopa;
Tarchycardias,ventricular extrasysytoles,rare AF due to peripheral
catecholamines
Hypotension, Hypertension in massive doses,in
presence of MAO I
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Side effects
Prolonged use/ poor timing can cause
wearing-off effect the latter also knownas end of dose effect
Leads to other motor complications, such as
dyskinesia in 80% cases Include chorea, ballismus, athetosis,
dystonia, myoclonus, tics, tremor
At other times fluctuations are unrelated
to timing of doses on and off effect
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Side effects
Behaviour variety of mental effects
depression, anxiety, agitation, insomnia,
somnolense, delusions, hallucinations
night mares,due to high concetrations oflevodopa in the brain
Rx mental dx clozapine BM depression
6.254mg at bed increament as requiredolanzapine, quietipine, risperidone no
BM depression less effective
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Miscellenous side effects
Mydriasis proceeding to glaucoma
Positve coombs test with evidence of
hemolysis
Hot flushes agraavation or ppt of gout,
abnormalities of smell
Discoloration of body fluids
Priapism, urea serum transaminases,
ALP, Bilirubin
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TreatmentDrug Therapy
Dopamine Agonists
Acts directly on the dopamine receptors.
Initially was used with L-DOPA.
Today, sometimes prescribed before L-DOPA, to delay wearing-off effect and
other motor complications brought on by
prolonged use of L-DOPA.
Pramipexole
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Dopamine
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Dopamine agonists
Do not require enzymatic conversion
No toxic met
Do not compete for transport into blood
and BBB
May have less AE
Lower incidence of drug fluctuations and
dyskinesia of long term use
Allows lower dose of Sinemet
Alternatives to sinemet
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Drug Therapy - DOPA agonists
Triggers dopamine receptors in place of
depleted dopamine neurotransmitters.
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Bromocriptine
D2 agonist
Peaks 1-2 hrs oral adm, 7.5mg30mg
built over 2-3 months by 2.5 mg every 2
weeks
Pergoline
Egort derivative
Stimulates D1D2 receptors
Effective than Bromo
Dose 3mg Od start at 0,05mg then
increase weekly
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Pramipexole,
Pramipexole
D3 receptor agonist
Effective as monotheapy, permits
reduction of levodopa, smoothens
fluctutations
May reduce mood disorders
Dose 0.125mg TID, double weekly thenby 0.75mg upto 0.5mg to 1.5mg TID
caution in renal dx
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Ropinirole
A nonegoline drivative
Pure D2 agonist
Effective as monothearapy
Dose 0,25mg TID then increase weekly
at 0.75mg tiil week 4 then by 1,5mg may
have interactions with drugs met by
CYP1A2
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Drug TherapyDOPA
agonistsAdverse side effects
GI N, Anorexia,V,C,bleeding form PU
esophegeal reflux
Mental disturbances dizziness,hallucinations, confusion, dikinesia
CVS hypotension, painless digital
vasospams, arrrythmias, edema
Sleep attacks
Permax (pergolide) pulled after direct link
to fibrosis of cardiac valves that can lead to
death. Unavailable in U.S. since 2007.32
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Other side effects
dopamine agonists Headache, increased arousal,
pulmonary infiltrates, pleural and
retroperitoneal fibrosis, athralgia, pain in
the extremities
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Monoamine Oxidase B
(MAOB) Inhibitors Delays or reduces breakdown of dopamine by
MAO-B selective inhibitor
Used as monotherapy or in conjunction with
L-DOPA, it can reduce the dosage of L-DOPA by15%.
Selegeline
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Mono amine oxidase
enzymes MAO A breaks down serotonin and
norepinephrine
MAO B metabolizes DOPAMINE
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Drug therapyMAO-B
Inhibitors MAO-B is an enzyme that metabolizes
dopamine.
From the breakdown of dopamine,
hydrogen peroxide is produced, which theoxidative stress can damage
dopaminergic neurons in the substantia
nigra. (Possibly neuroprotective) MAO-B inhibitor delays or reduces the
metabolism of dopamine.
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Dose side effects MAO
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Dose, side effects MAO
Inhibitors
5mg with BF and 5mg at lunch to avoidinsomnia
C/I not with Meperidine, TA, SRIs
Side effects of L-DOPA may be
enhanced by selegeline.
Nausea and dizziness
Rasagiline
A MAO I
More potent than selegiline
May be neuroprotective38
C t h l
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Catechol o
Methyltransferase Involved with Levodopa met
It increases levels of 3- O methyl dopa
which is associated with poor
therapeutic response to Levodopa
3-OMD competes with levodopa for
active carrier mechanism that controls
its transport across the intestinalmucosa and the BBB
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TreatmentDrug Therapy
Catechol O-Methyl Transferase (COMT)
Inhibitors (Tolcapone, entacapone
less hepatotoxic)
Mainly used in combination with L-DOPA, itincreases the half-life of L-DOPA.
Delays wearing-off effect of L-DOPA ,
response fluctuations,and other motor
complications such as dyskinesia
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Tolcapone(Tasmar)
D th COMT
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Drug therapyCOMT
Inhibitors COMT catalyses methylation of L-DOPA.
Addition of COMT inhibitor along with L-
DOPA and carbidopa prolongs the half-life
of L-DOPA and increases the amount inthe CNS.
This increases on time for L-DOPA.
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COMT I AE Tasmarare hepatotoxic.
N,Diarrhea and sleep disturbances
Relate to increased levodopa exposure
dyskinesia confusion rx lower the dose by
30% after 48 hrs
Abdominal pain,orthostatic hypotension,
sleep disturbances, orange discoloration of
urine Tolcapone associated with liver enzymes
requires monitoring and consent before
administration
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T t t D Th
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TreatmentDrug Therapy
Amantadine Amantadine
Antiviral agent.
MOA
May pontetiate doperminergic
function by influencing synthesis,
release, or reuptake of dopermine
and release of dopermine formperipheral stores
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Amatadine Kinetics Use
Peaks at 1-4hrs on oral adm T1/2 2-4
hrs
Use
Known to aid in reducing dyskinesia.,rigidity,tremor
Effects are shortlived less potent than
Levodopa
Dose 100mg BID or TID
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Amantadine AE
Restlessness, depression, irritability,
insomnia, agitation,excitement,
hallucination confusion
Over dose acute psychosis
Sometimes Livedo retiularis
Edema which responds to diuretics
Headache, HF,hypotension,Anorexia,N,constipation, dry mouth
Not be given in HF, seizures
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A t l h li bl ki
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Acetylcholine blocking
drugs
Anticholinergics Improve tremors and stiffness no effects on
bradykinesia
Includes benztropine, biperiden,
orphenadrine, procyclidine, trihexyphenidyl Cause drowsiness, mental slowness
,constipation, restlessneslltion,dry mouth,
N,V, poor vision, arrythmias,
Withdrawal should be slow
C/I not given in prostatic hyperplasia,
obstructive GI disease, angle closure
glaucoma, with TA , adverse effects are ppt47
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Livedo reticularis
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Treatment - Surgery
Before commerciality of levodopa, surgical
treatment (Thalamotomy or pallidotomy)
were preferred.
Early surgeries were successful withtremors, but failed to relieve other symptoms.
Means of last resort due to high risk of
potential complications.
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S rgical proced res
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Surgical procedures
Perkinsonism Recent advances in neurosurgical
procedures allow for better treatment.
Include stimulation of the thalamus
relieves tremor Stimulation of the subthalamic nuclei,
globus pallidus internus
C/I in atypical Perkinsonism
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Surgery -
Deep Brain Stimulation
Brain pacemaker, sends electrical impulses to
brain to stimulate the subthalamic nucleus.
Improves motor functions and reduce motorcomplications.
Complications include: brain
hemorrhage, seizures, death.
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New Researches
Nicotine
Intake of nicotine has shown to slow the
degeneration of neurons.
Acts similar to levodopa. Melatonin
Serotonin derivative that helps insomnia.
Also shown to cause a reduction inproduction of neurodegenerative radicals.
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