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
❑ 1:10 Carbidopa 25mg + Levodopa 250mg,
Dopamine is not used because it cannot cross BBB
A. A
Oral 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 yrs or 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)
The symptoms had progressed much less
than placebo, in a dose-response manner.
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. compared UPDS score between 222 PD patients randomly
assigned to receive levodopa (100 mg 3 times /day +
carbidopa 25 mg) for 80 weeks (early start) and 223
received placebo for 40 weeks followed by levodopa
/carbidopa for the remaining 40 weeks (delayed start).
“Levodopa had NO disease-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
Limitations include the absence confirmatory neuroimaging, given the high rate of clinical misdiagnosis in 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 hs before 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-dopa induced psychosis :
Block D2-receptors mainly
in mesolimbic system

21. Pimavanserin
▪ 5-HT2A inverse agonist
▪ FDA 2016 for “Parkinson D Psychosis”
▪ Well tolerated Atypical Antipsychotic
Nuplazid 17, 34mg tab
“Clozapine, Olanzapine, Risperidone” have 5-HT2A inverse
agonism with affinity to receptors (DA, α, H, M , ….) → Side effects
-Psychosis in PD, accumulation of cortical Lewy body →loss of 5-HT signaling from
dorsal raphe neurons → ↑↑↑postsynaptic 5-HT2A receptors (also in Alzh. D)
-The FDA had set April 2021 to approve Pimavanserin for Dementia Related Psychosis
(phase III HARMONY)
- 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. Female gender
4. Young age (?!)
5. Low body weight,
6. Non-tremor dominant
7. Anxiety
8. Severity of motor and functional impairment
9. Striatal asymmetric index (SPECT)
10. Genetic risk score & CSF α-syn (??!!) ….
npj Parkinson’s Disease (2018) 33, Front. Neurol. (2019) 10:477

26. Dyskinesia
Why?
(Not Clear, Multiple Theories)
Fluctuation in DA level &
Pulsatile DA-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
DA release from 5-HT terminals →
Large intermittent surges of
extracellular dopamine → ↑ D1 and
NMDA receptors activity →
Abnormal Synaptic Plasticity →
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??)
Peripheral causes: (kinetic)
- Delayed gastric emptying, (50-90% &..…)
- Dietary protein, (compete..)
- Short plasma t ½ , (1-2 hr)
Central causes: (Dynamic)
- Pulsatile delivery to striatal DA receptors
- Impaired storage capacity,
- Alteration of DA receptors

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. Abrupt withdrawal of levodopa or
dopaminergic drugs may →
neuroleptic malignant syndrome
Which more commonly observed
after treatment with DA-
antagonists as antipsychotics
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)