• 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