Levodopa in Parkinson's disease

Levodopa: Neurotoxicity/Neuroprotection, Early/Delayed, Dyskinesia/5HT neurons, Contraindications.

1. Levodopa in
Parkinson's disease
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

2. L-dopa
The Gold Standard
Symptomatic Therapy of PD
Improves All Symptoms
(esp. Bradykinesia)
1968

3. 2015
L-dopa
IR
CR
Levodopa FDA Approval History

4. DDC
1-3%
Two forms are available :
❑1:4 Carbidopa 25mg + Levodopa 100mg
❑1:10Carbidopa 25mg +Levodopa 250mg,
Dopamine is not used because it cannot cross BBB
A. AOral L-dopa
Mechanism of action of Levodopa

5. When combined with a decarboxylase inhibitor, more levodopa reaches the brain.
less drug is required
[so its dose & it side effects].

6. ↑↑Antiparkinsonian
Effect
↓↓Peripheral
Side Effects
↑↑ central DA & ↓↓ Peripheral DA
Peripheral Decarboxylase inhibitors
Carbidopa-Benserazide
dose of L-dopa by 75%
Benefits

7. L-dopa Effects ↓in 3-5 Years ??!!
Better to Reserve L-DOPA
(To old age > 65 yrsor severe disease ??!!)
Recent Guidelines changed this trend
Due to Gradual neuronal degeneration

8. Is Levodopa Neurotoxic?
the Controversy

9. Aminochrome
Neuromelanin
Two-electron reduction
One-electron reduction
L-dopa

10. IS LEVODOPA TOXIC?
YES, NO OR MAYBE?
(Cell culture) & use large conc. L-dopa

11. The ELLDOPA study
(Earlier versus Later LevoDOPA)
Thesymptomshadprogressedmuchless
thanplacebo,inadose-responsemanner.
beta-CIT SPECT sub-study→ “levodopa ↓↓ dopamine
transporter in nigrostriatal N terminals in striatum”??
→ fueled concern about the drug's potential toxicity.
ELLDOPA study failed to change the
treating pattern of PD ??!!
“2004” 2004

12. comparedUPDSscorebetween222PDpatientsrandomly
assignedtoreceivelevodopa(100mg3times/day+
carbidopa25mg)for80weeks(earlystart)and223
receivedplacebofor40weeksfollowedbylevodopa
/carbidopafortheremaining40weeks(delayedstart).
“Levodopa had NOdisease-modifying effect in PD over trial period”
No difference in the severity of symptoms
No difference in rates of dyskinesia or
L-dopa-motor fluctuations
The LEAP study “2019”
(Levodopa in Early Parkinson’s Disease)
2019
Limitationsinclude the absence confirmatory neuroimaging, given the high rate of clinical misdiagnosisin PD. Also, intermediate
dose of levodopa was used and thus the results may differ with a higher or lower dose, longer periods or later start …..??!!
either beneficial or detrimental

13. Also, Canadian guideline for Parkinson disease 2019
2017
Evidence from clinical studies supports that levodopa is not toxic and does not promote nigral cell death ??!!

14. 1.Parkinson Disease (FDA approved)
DOSE : 200-1000 mg orally/day (usually 300-600/d)
2. Parkinsonism (post-encephalitic, CO, Mg poisoning)
3. Restless leg syndrome (off-label)
50 mg orally 1-2 hsbefore bed time with carbidopa
Indications of Levodopa

15. Adverse Drug Reactions (ADR)
of Levodopa

16. DA
Central
1-3 %
Peripheral
99-97%
Peripheral (ADRs)
1.Nausea, Vomiting # PU
2.Postural ↓↓BP
3. Arrhythmia
Central ADRs
1.Psychosis
2.Dyskinesia

17. Domperidone
D2-blocker not cross BBB
“Used for vomiting in Parkinson patient
Vomiting Pathway

18. •Psychosis (CI)
Why?
•Dyskinesia
Why?
Central Side Effects
CNS

19. In Psychosis
↑↑ Dopamine
•Psychosis (CI)
Why?

20. Atypical antipsychotics e.g. Clozapine , Quetiapine??
Treatment L-dopainduced psychosis :
Block D2-receptors mainly
in mesolimbic system

21. Pimavanserin
▪5-HT
2Ainverse agonist
▪FDA 2016for “Parkinson D Psychosis”
▪Well tolerated Atypical Antipsychotic
Nuplazid17, 34mg tab
“Clozapine, Olanzapine, Risperidone” have 5-HT
2Ainverse
agonism with affinity to receptors (DA, α, H, M , ….) → Side effects
-PsychosisinPD,accumulationofcorticalLewybody→lossof5-HTsignalingfrom
dorsalrapheneurons→↑↑↑postsynaptic5-HT
2Areceptors(alsoinAlzh.D)
-TheFDAhadsetApril2021toapprovePimavanserinforDementiaRelatedPsychosis
(phaseIIIHARMONY)
-Pimavanserin can prolong QT interval ………
-Metabolized by CYP3A4 enzyme(with strong CYP3A4 inhibitor .. →↓ dose to 17 mg/ day).
-Not recommended in sever hepatic or renal impairment (Cr Cl <30 mL/min)

22. Risk factors for Psychosis in PD
Intrinsic Factors
1.Dementia (LBD, PDD), or Cognitive decline
2.Duration of PD ↑
3.Depressive Symptoms
4.Advanced age
5.REM sleep Behavioral disorder
Extrinsic Factors
1.Use of Dopaminergic drugs (esp. L-dopa high doses)
2.Polypharmacy (DA-ergic+Anticholinergic)
3.Sleep Deprivation
4.Other RF: infection, metabolic, delirium, Psychoactive D….

23. Levodopa-induced Dyskinesia
Abnormal Involuntary movement mostly
choreoathetosis; head, lip or tongue movements
(> 50% of PD patients TTT Levodopa > 5 yrs)

24. 80%
20%
30%
80%
20%
(> 50% of PD patients TTT Levodopa > 5 yrs)
Types of

25. Risk factors for L-dopa induced
Dyskinesia (LID)
1.↑L-dopa dosage (> 300 -400mg/d)
2.↑Treatment duration (Levodopa cumulative exposure)
3.Femalegender
4.Youngage (?!)
5.Low body weight,
6.Non-tremordominant
7.Anxiety
8.Severity of motor and functional impairment
9.Striatal asymmetric index (SPECT)
10.Genetic risk score & CSF α-syn (??!!) ….
npjParkinson’s Disease (2018) 33, Front. Neurol. (2019) 10:477

26. Dyskinesia
Why?
(Not Clear, Multiple Theories)
Fluctuation in DA level &
PulsatileDA-R stimulation
↑↑↑ dopamine level in
Basal ganglia (BG)
↑ Glutamate (NMDA-R) in
BG
Dyskinesia appears with L-dopa only when >80% of N striatal DA neurons are lost
DA Surge
L-dopa

27. (Buspar)
Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats.
Brain (2007), 130, 1819^1833
“False transmitter
mechanism”
Buspirone (Buspar)
5-HT1A agonist
agonist
DAreleasefrom5-HTterminals→
Largeintermittentsurgesof
extracellulardopamine→↑D
1and
NMDA receptorsactivity→
AbnormalSynapticPlasticity→
Dyskinesia.
DA Surge
(Early PD or
Normal)
(Late PD)

28. “FDA approved, 2016”
▪Buspirone
as off-label ?!
5-HT1A agonist-↓ Fluctuation by use XR
….. (in off dyskinesia)
Anti-dyskinesia Drug
“Blocks NMDA-R”

29. Other Adverse effects
of Levodopa

30. On-off
Phenomena
wearing off
Phenomena
Motor Fluctuation

31. Wearing off Phenomena
End-of-dose akinesia: gradual loss of effect (wearing off) before next dose.

32. On-off Phenomena
Sudden unpredictable Random swings from mobility (on) to bradykinesia (off) that
occur before the expected “wearing off”

33. Motor Fluctuation
(Short t
½& fluctuation in L-dopa level??)
Peripheralcauses:(kinetic)
-Delayedgastricemptying,(50-90%&..…)
-Dietaryprotein,(compete..)
-Shortplasmat½,(1-2hr)
Centralcauses:(Dynamic)
-PulsatiledeliverytostriatalDAreceptors
-Impairedstoragecapacity,
-AlterationofDAreceptors

34. On-off
Phenomena
wearing off
Phenomena
Motor Fluctuation
Selegline Entacapone
Adjunct to Sinemet

35. ↓Fluctuation
Prolongs Action
L-dopa
or
Add
Selegiline
Entacapone

36. How to ↓ Fluctuation ??
Sinemet + Selegiline
Sinemet + Entacapone
Sinemet + DA-agonist
↓interval between doses
Sinemet SR(sustained-release)

37. Abruptwithdrawaloflevodopaor
dopaminergicdrugsmay→
neurolepticmalignantsyndrome
Whichmorecommonlyobserved
aftertreatmentwithDA-
antagonistsasantipsychotics
Neuroleptic malignant syndrome
(NMS).
Treated by: cooling and
Dantrolene , Amantadine, bromocriptine
and BZD (diazepam)

38. Contraindications of L-dopa
1. Psychotic patients (↑psychotic illness)
2. Angle-closure Glaucoma (Mydriatic & ↑ Aquas H production)
3. Cardiac Arrhythmia or recent M. infarction (↑ Arrhythmia)
4. Peptic ulcer (↑ GIT bleeding)
5. History of Melanoma or undiagnosed skin lesion
(Levodopa is a precursor of skin Melanin)

39. Drug Interactions with levodopa
3. Antipsychotics ???
(typical e.g. Haloperidol)
1.
2.
(Vit. B6)

40. •Absorbed rapidly from small intestine (64%)
•has short half-life (2-3 hrs)
•Renal excretion ~ 30%
•Protein interferes with its transport into the GIT & CNS.
Levodopa should be taken on empty stomach, 30 min before a meal
Pharmacokinetic of Levodopa

41. 2. Diet Low in Protein? Why
Nutritional Care in PD
1.Avoid Vit. B6 ? Why
BUT clinically !!!.........
3. Levodopa should be taken on empty stomach,
30 min. before meal ? Why
4. Diet rich in fibers & fluid ? Why
to minimize constipation (common in PD)