2. • 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.

4. 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

6. levodopa

7. L dopa- metabolism

9. 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)

10. Dopamine agonists

11. Dopamine agonists

12. 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

14. COMT inhibitors
• Extend half life of levodopa without
increasing peak plasma concentration.
• Elevated LFT, diarrohea

15. COMT inhibitors

17. MAO inhibitors

18. MAO -inhibitors
• Cheese effect with MAO A inhibitors
• Not taken with levodopa
• MAO-B safe
• Dual inhibitors-theoretically good

19. anticholinergics

20. amantadine

21. amantadine
• Dopamine release
• Antiglutamate
• Quick onset (2 days)
• Livedo retcularis, edema,visual
hallucinations

23. 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

24. 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

25. 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

26. • 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

27. • 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

28. neuroprotection

30. 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

32. 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.

33. 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

34. 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.

35. 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 ?

37. 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

38. 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.

39. • 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

40. 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

41. 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

42. Sensory and behavioural offs
• Pain
• Akathisia
• Depression
• Anxiety
• Dysphoria
• panic

44. 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

46. 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.

47. 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

48. Dose failures/ no on
• Episodic failure of patient to respond to
each dose.
• Poor gastric emptying.
• Dissolved levodopa/apomorphine
• prokinetics

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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

56. 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

57. 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

58. 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

61. Non motor symptoms

66. dementia

67. psychosis

75. insomnia

76. somnolence

77. Future advances

80. Thank you

81. • 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