3. Introduction
Paralysis agitans / shaking palsy
James Parkinson
Second most common neurodegenerative disease
Idiopathic > Drug induced
Incidence: 1% in age > 65
2.5% age > 80
Male: Female 2:1
4. Etiology
Unknown
Genetics – Important < 50 year
Autosomal dominant : PARK1, LRRK2
Autosomal recessive : Parkin, PINK1, AJ1
Environmental- Pesticide(similar structure to MPTP)
Protective: cigarettes, caffeine
5. Etiology
Degeneration of dopaminergic neuron in substantia nigra pars compacta
70-80% loss for symptoms
Hallmark – Lewy body
11. Antioxidant role
Substantia nigra pars compacta- high oxidative
Free radical generation by MAO
Glutathione limit this damage
Parkinson: Impaired protection
14. DIAGNOSIS
No lab test
Genetic testing
Neuroimaging
Medication history
15. Treatment goal
Improve motor and non motor symptom
Improve mobility
Minimize side effect and treatment complication
NO DRUG IS NEUROPROTECTIVE
Patient education
20. Complication of L-Dopa therapy
Occur after 5-6 month treatment
End of dose wearing off-
Cause: loss of neuronal storage capacity and short half life of dopamine
Patient dependent on exogenous dopamine
Solution: Increase frequency of administration
Or Add COMT or MAO inhibitor
Dopamine agonist can be added
CONTROLLED RELEASE DOPA
21. Complication of L-Dopa therapy
Delayed on/ no on
Cause: Delayed gastric emptying or decreased absorption
Solution: Give empty stomach
Oral disintegrating tablets
22. Complication of L-Dopa therapy
Freezing
Cause: Sudden inhibition of lower extremity motor function: falls
Solution: Increase dose
Add dopamine agonist
Physiotherapy
Walking aids
23. Complication of L-Dopa therapy
Dyskinesia:
Involuntary choreiform movement
Distinguish form tremor
Cause: Peak DA level- too much dopamine stimulation
Solution: Lower dose
May aggravate Parkinson- so increase frequency or add another drug
24.
25. Complication of L-Dopa therapy
Off period dystonia
Sustained muscle contractions
Cause: waning drug level- early morning
Solution: Bedtime dose- sustained release
28. L- DOPA + Carbidopa
Increase half life of L- dopa
Half life : 1 hour
Carbidopa makes it 1.5 hour
Decrease side effect
Peripheral decarboxylase inhibitor(not cross BBB)
Dose: 10mg TDS
29. COMT inhibitor
Increase central bioavailability of DOPA
Increase half life to 2-2.5 hour
ENTACAPONE- 200 mg max 8 times a day
TOLCAPONE- inhibit both central and peripheral COMT
HEPATOTOXIC
100-200 mg TDS
30. MAO –B Inhibitor
Prolong dopamine activity
Selegiline: 5mg BD
METABOLITE: Amphetamine – anxiety insomnia
High FPM: transdermal patch available
Rasagiline: 0.5- 1mg OD
No such metabolite
Cheese reaction
Serotonin syndrome with TCA
Neuroprotective?
33. Dopamine agonist
Adjuvant to L-Dopa
Mild to moderate PD - may be used as monotherapy
PREFFERED IN YOUNG PATIENT
Old patient – more chance of side effect so avoided
Combination with L- Dopa: increased risk of dyskinesia
Side effects – compulsive behaviors/ gambling
34. Apomorphine
Non ergot DA agonist
Approved as rescue therapy for off period
High First pass metabolism: Subcutaneous
2-6mg
Can cause injection site reaction and orthostatic hypotension
35. Amantadine
Antiviral
Mechanism in Parkinson : ?
Inhibition of NMDA receptor????
Facilitate dopamine release????
300mg/day
Useful in dopamine induced dyskinesia- anti-glutamate mechanism
Side effect: livido reticularis(vasoconstriction)
36. Anticholinergics
Benztropine- 0.5-4mg/day
Trihexyphenidyl – 1-6mg/day
Cause of tremor
Side effect: Blur vision
Constipation
Urinary retention
Dry mouth
Confusion
Sedation
Acetyl choline
Dopamine
NEURODEG DIS: PROGRESSIVE IRR. LOSS OF NEURON
Estrogen protective
Cigg. Inv in dopamine signaling
Coffee neuroprotection
Pathology appears first in ant. Olfactory n. & lower brainstem.
Lewy body : aggregates of alpha synuclein
Eosinophilic cytoplasmic inclusions , in nerve cell
Schematic wiring diagram of the basal ganglia. e striatum is the principal input structure of the basal ganglia and receives excitatory glutamatergic input from many areas of cerebral cortex. e striatum contains projection neurons expressing predominantly D1 or D2 DA receptors, as well as interneurons that use ACh as a neurotransmitter. Out ow from the stria- tum proceeds along two routes. e direct pathway, from the striatum to the SNpr and GPi, uses the inhibitory transmitter GABA. e indirect pathway, from the striatum through the GPe and the STN to the SNpr and GPi, consists of two inhibitory GABA-ergic links and one excitatory Glu projection. e SNpc provides dopaminergic innervation to the striatal neurons, giving rise to both the direct and the indirect pathways, and it regulates the relative activity of these two paths. e SNpr and GPi are the output structures of the basal ganglia and provide feedback to the cerebral cortex through the VA/VL nuclei of the thalamus.
et e ect of stimulation of the direct pathway at the level of the striatum is to increase the excitatory out ow from the thalamus to the cortex
net e ect of stim- ulating the indirect pathway at the level of the striatum is to reduce the excitatory out ow from the thalamus to the cerebral cortex.
DA released in the striatum tends to increase the activ- ity of the direct pathway and reduce the activity of the indirect pathway, whereas the depletion that occurs in PD has the opposite e ect. e net e ect of the reduced dopaminergic input in PD is to increase markedly the inhibitory out ow from the SNpr and GPi to the thalamus and reduce excitation of the motor cortex.
Rigidity- Increased muscle resistance
Cogwheel
Constipation cooz bowel muscle rigid
Involvement of extranigral areas plays an important role in non-motor features & levodopa nonresponsive motor aspects.
Tremor- rhythmic oscillatory movement around a joint
Resting, pin rolling
Bradykinesia – slowness in movement
GENETIC : NOT MUCH USEFUL
NEUROIMAGING FOR OTHER CAUSES
Side effect; nausea, orthostatic hypotension
Not cross transmucosal memb – has to reach duodenum]
Separate dose with protein meal
Drug holiday- risk of neurolept malignant syndrome
10/100 MG TDS
25/100 TDS
Tyramine not metabolized in moa I presence
Gets accumulated
Dispalce NE
HYPERTENSIVE CRISIS
TREATMENT PHENTOLAMINE
SEROTONIN SYNDROME DELIRIUM AGITATION TACHYCARDIA DIARRHOEA
TREATMENT CYPROHEPTADINE
Istradefylline new approval
Ropinirole is metabolized by CYP1A2: Inducer- cigarettes
Inhibitor: Flouroquinolones
