Management of parkinson’s disease
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Transcript of Management of parkinson’s disease
• Dopaminergic neuron loss• extensive non dopaminergic pathology
- cholinergic neurons of the nucleus basalis of Meynert.
- norepinephrine neurons of the locus coeruleus
- serotonin neurons in the midline raphe
- neurons in the cerebral cortex, brainstem, spinal cord, and peripheral autonomic nervous system.
Medications available for PD
• Dopamine replacement therapy is the major medical approach.
• Leading unmet need is to stop or slow progression.
• Development of symptoms unresponsive to dopaminergic therapy
levodopa
L dopa- metabolism
L-dopa
• Peripheral decarboxylase inhibitors carbidopa and benserazide.
• Allows fourfold reduction in L-dopa dosage.• Immediate release, controlled release(2/3rd)• Absorption only in small intestine.• H-pylori eradication• Malignant melanoma-intermediary in melanin
synthesis• Elevated plasma homocysteine (methyl group in
COMT)
Dopamine agonists
Dopamine agonists
Dopamine agonists
• Second most powerful
• Lisuride- water soluble, sc.
• Cabergoline-long acting, once a day.
• Rotigotine- transdermal patch
• Apomorphine-sc, intranasal
• Nausea, orthostatic hypotension, edema, sleep attacks,valvulopathy
COMT inhibitors
• Extend half life of levodopa without increasing peak plasma concentration.
• Elevated LFT, diarrohea
COMT inhibitors
MAO inhibitors
MAO -inhibitors
• Cheese effect with MAO A inhibitors
• Not taken with levodopa
• MAO-B safe
• Dual inhibitors-theoretically good
anticholinergics
amantadine
amantadine
• Dopamine release
• Antiglutamate
• Quick onset (2 days)
• Livedo retcularis, edema,visual hallucinations
Therapeutic Principles
• Keep the patient functioning independently as long as possible
• Patients should be encouraged to remain active and mobile
• Individualize therapy
• If therapies are established protective, they should be given priority
Treatment of early stage(mild symptoms,no restriction of activities• Excellent candidates for clinical trials.
• Symptomatic treatment can be delayed
• Neuroprotection—neuro protection
neuro restoration
neuro regeneration
Selegiline and antioxidants
• DATATOP-selegiline and tocopherol• Selegiline delayed symptomatic treatment
by 9 months• Reduced rate of worsening of UPDRS• Decreased risk of freezing• Symptomatic effect vs neuroprotective• Total MAO blockade• Tocopherol -ineffective
• Riluzole Glutamate excitotoxicity Riluzole blocks Vd sodium channel Not effective• Trophic factors GDNF-survival of neurons, dendritic
growth , quantal size immunophilins- ligands primate studies encouraging
• Enhancing mitochondria and energy function-co Q 10 and creatine, not to be futile
• Counteracting inflammation-minocycline, not futile
• Inhibiting apoptosis-rasagiline
• Dopamine agonists-CALM PD
neuroprotection
Treatment of mild stage (interferes with activities)
• Symptomatic treatment.• Degree of disability and age• Severe disease-levodopa, rapid
guaranteed action• Younger patients(<60 yrs),(<70 if mentally
strong)- dopa sparing strategy (DA agonists,
amantadine, anticholinergics) prone to develop motor complications
Dopamine agonists
• Less likely to induce motor complications
• Monotherapy successful for more than 3 years only in 30%.
• Ergots-st anthonys fire, retroperitoneal, pleuro-pericardial fibrosis, valvulopathy
• Non ergots-drowsiness, sleep attacks.
• Nausea, hypotension, leg edema, hallucinations,sedation.
Dopamine agonists
• Start with a tiny dose, bed time dose.• Bromocriptine 1.25,pergolide-0.05,pramipexole-
0.125 for first 3 days, ropinirole 0.25 tid for 1 st week.
• Gradual dose escalation at bromocrptine-1.25 /wk, pergolide-0.125/wk,ropinirole-0.5 /day twice weekly, pramipexole 0.125/2 days for 10 days, then 0.125/day weekly.
• Switching among agonists • 1:1:5:10
=pergolide:pramipexole:ropinirole:bromocriptine
amantadine
• Effective in 2/3 of mildly affected patients ,rapid onset in 2 days
• 100 md bid t1/2 28 hrs, max 400mg.
• Dose reduction in renally impaired
• Short lived effect in advanced stages but adjunctive to levodopa and agonists .
• Reduces l-dopa induced dyskinesias.
anticholinergics
• Monotherapy or adjunctive to l dopa/DA in tremor.
• Start with low doses, trihexyphenydyl 1mg bd, benztropine 0.5mg bd
• Side effects-peripheral and central• >70 yrs, weaker anticholinergic-
diphenhydramine-50mg tid,orphenadrine-50mg tid,,cyclobenzaprine-20mg tid,amitriptyline 25 md tid.
• Advance stages ?
Moderate stage-inadequate response to non levodopa
medications• Rule of thumb-utilize the lowest drug that
brings about symptom reversal.• 10/100,25/100,50/200.• Atleast 50-75 mg of cabidopa is required
for adequate inhibition of peripheral decarboxylase.
• If L-dopa , 300 mg/day use 25/100 form.• Carbidopa tablets are available for
vomiting
Immediate release vs extended release
• Rapid response with IR.• Longer half life and lower peak plasma
levels with CR, unpredicatable response.• 2/3-3/4 th of identical dose of IR.• Useful in older patients, less chance of
drowsiness.• Pre bed time dose allows mobility in night.• Mean of 9.3 +_1.8 days to achieve max
response.
• Most common plateau schedule neurologist aim for is 25/100 mg tid.
• Start with low dose 25/100,increase in weekly strengths of 25/100.
• Bradykinesia and rigidity respond well than tremor.
• Increase to 50/200 mg tid before adding agonist.• Before concluding ineffective -2000mg.• As disease progresses, duration of effect
decreases.• Avoid sudden withdrawal
Advanced stage-motor complications,freezing,falls
• All patients should be receiving levodopa therapy or atleast have had a trial of the drug but have not been able to remain on it because of disabling side effects
• Fluctuations and dyskinesias
• Temporal relation to last dose, sensory, motor or behavioural phenomenon
Fluctuations(offs)• Slow wearing off• Sudden off• Random off• Yo-yoing• Delayed on• Dose failure• Weak response at end of
the day• Variation with meals• Sudden transient freezing
Dyskinesias• Peak dose
chorea,ballism,dystonia• Diphasic chorea and
dystonia• Off dystonia• Myoclonus• Simultaneous dyskinesia
and parkinsonism
Sensory and behavioural offs
• Pain
• Akathisia
• Depression
• Anxiety
• Dysphoria
• panic
pathogenesis
• Advance stage of disease,duration and dose of levodopa treatment
• Pharmocokinetic and pharmacodynamic mechanisms
• Altered dopamine storing capacity
• Dopamine receptor super sensitivity and differential sensitivity
• Intermittent levodopa administration
Wearing off
• Adequate dose of levodopa does not last at least 4 hrs
• As plasma levels fall, clinical response also falls• Selegiline, rasagiline-decrease off time by 1.5
hrs• Comt inhibitor-increase on time by 1 hr• CR preparation-starting at night dose and
working forward• Standard preparation closer intervals• Dopamine agonists• Zonisamide and adenosine antagonists.
On and off/random off
• Unrelated to timing of last dose .
• Careful plotting of these off periods.
• Disolved levodopa in carbonated water.
• Subcutaneous/intranasal apomorphine
• 10-15 minutes
Dose failures/ no on
• Episodic failure of patient to respond to each dose.
• Poor gastric emptying.
• Dissolved levodopa/apomorphine
• prokinetics
Delayed on
• Problem in getting an on with first dose in the morning.
• Plasma levels vs low affinity
• Higher morning dose to kick on
• Dissolved levodopa
Weak response at end of the day
• Diurnal variation
• Decreased plasma levels with each dose.
• Increasing afternoon or evening dose
• CR preparation
• DA, amantadine ,anticholinergics
Response variations with meals
• Full meal-delayed gastric emptying, delayed and weaker response
• Empty stomach-rapid response with dyskinesias.
• High protein meals-amino acids interferes with mucosal transport of levodopa.
Non protein meals in morning.
Normal protein meals in night
freezing
• On freezing or off freezing
• Start hesitation, target hesitation, turning hesitation, startle hesitation.
• Selegiline.
• L-threo-dops- precursor of nor epinephrine.
• Botulinum into legs of freezers
Peak dose dyskinesias
• Severity of disease is the major risk factor.• Chorea is more common ,dystonia is more
disabling.• Overdosed state.• Small frequent dose or CR preparation• DA with reduction of l dopa• Amantadine• Clozapine, fluoxetine, propranolol, buspirone,
mirtazapine
Diphasic dyskinesias
• D-I-D phenomenon
• Plasma levels are falling or rising, but not during peak plasma level.
• Predominantly the legs
• Differential sensitivity of receptors
• DA with long duration of action with small levodopa
Off dytonia
• Early morning dystonia
• Pharmacokinetic problem
• Low plasma levels
• CR preparation
• Pergolide
• Dystonia can also be a feature of PD, high dose or low dose
Yo-yo ing
• Combination of fluctuations and dyskinesias
• Plain levodopa without carbidopa
• DA
• Liquefied sinemet-4 tabs of 25/250 in 1 litre of soda-conc 1mg/ml,stored in dark
• Intraduodenal pump
others
• Myoclonus-ominous sign, DLB, levodopa toxicity,methysergide.
• Somatotopically specific dyskinesias-head and neck more sensitive than legs
• Loss of efficacy over time• Falling due to loss of postural reflexes-
keep the patient sufficiently parkinsonian• Surgery-mouth dissolving l- dopa,
apomorphine
time drug meal sleep tremor stifness others 00-1 am 1-2am 2-3am 3-4am 4-5am 5-6am 6-7am 7-8pm 8-9am 9-10am 10-11am 11-12am 12-1pm 1-2pm 2-3pm 3-4pm 4-5pm 5-6pm 6-7pm 7-8pm 8-9pm 9-10pm 10-11pm 11-00pm
Non motor symptoms
dementia
psychosis
insomnia
somnolence
Future advances
Thank you
• The Scientific and clinical basis for treatment of parkinson’s disease-2009 AAN
• Mark stacy-Medical treatment of PD
• Stanley Fahn-Medical treatment of PD