1. Drug-induced Parkinsonism 2. Mechanism of Action of Antiparkinsonian drugs 3. Dopaminergic Drugs -L-dopa - DA agonists - MAOB inhibitors - COMT inhibitors - Amantadine 4. Anticholinergic Drugs 5. Treatment Algorithm

1. Antiparkinsonian Drugs
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

2. 1. Recognize that antiparkinsonian therapy aims to correct the
imbalance involved in the pathophysiology of the disease by
the use of anticholinergic drugs or dopaminergic agents.
2. Discuss the central and peripheral adverse effects of L-dopa.
3. Provide a proper management of Levodopa induced adverse
effects.
4. Predict the role of apomorphine in emergency cases of
sudden immobility
5. Apply the pharmacological basis for proper optimization of L-
dopa therapy via its combination with decarboxylase
inhibitors (e.g. carbidopa), COMT inhibitors (e.g. entacapone),
MAO-B inhibitors (e.g. selegiline) or dopamine agonists

3. Definition
 Parkinsonism is a Progressive
Neurodegenerative disease due
to degeneration of
Nigro-Striatal Dopamine neurons.

4. Epidemiology of PD
▪ The 2nd most common
neurodegenerative disorder
after Alzheimer´s disease.
▪ It affects 1-2 % of the general
population > 65 years.

5. Clinical features
Four cardinal symptoms:
➢ Bradykinesia (essential)
➢ Resting tremor
➢ Muscle rigidity
➢ Postural instability

7. 1- Idiopathic ~ 85% (Parkinson disease ”PD”)
2- Viral encephalitis
3- Vascular (post-stroke) ~ 3%
4- Environmental Toxin (CO or MPTP…….)
5- Drug-Induced ~ 7% - 9%
Causes of Parkinsonism

8. Drug-Induced Parkinsonism:
- Antipsychotics (Typical >Atypical) block D2 receptors.
- Antiemetics (Metoclopramide)  block D2 receptors.
- Reserpine, Tetrabenazine (VMATI) depletes DA stores.
- Methyldopa (Aldomet)  inhibits DA synthesis.

9. Drug-Induced pseudoparkinsonism
➢ Antiemetics
Metoclopramide
Block D2 receptors in BG
➢ Antipsychotics
(Typical) Phenothiazines e.g.
Thioridazine and haloperidol,
Antiemetic
Antipsychotics
Should be used cautiously
Parkinsonian patients

10. Four Dopaminergic Pathways in CNS
In Parkinsonism
↓↓ Dopamine
In Psychosis
↑↑ Dopamine

11. Pathophysiology of PD
 Degeneration of Nigro-striated Dopaminergic fibers
→ ↓ ↓ dopamine & ↑ Acetylcholine in Basal Ganglia
Loss of Smooth, coordinated movement

12. Substantia Nigra
(DA synthesis)
Nigrostriatal DA neurons
Ach
Striatum
Balance
DA
Muscle Tone
(- )
Movement
(+)
Initiation
Modulation
Normal
Basal Ganglia

13. Substantia Nigra
(DA synthesis)
Nigrostriatal DA neurons
Ach
Striatum
Imbalance
DA
Movement Muscle Tone
Initiation
Modulation
Bradykinesia Rigidity
Tremors
Parkinson

14. Ach
DA Imbalance
Antiparkinsonian Drugs
Anti-
cholinergics
Dopaminergic
Drugs
Parkinson D

15. I.  Dopaminergic Activity
1. Levodopa/carbidopa.
2. Dopamine Agonists:
a. Ergot e.g. Bromocriptine
b. Non-ergot e.g. Pramipexole
3. COMT inhibitors e.g. Entacapone.
4. MAOB inhibitors e.g. Selegiline.
5. NMDA-R Blocker e.g. Amantadine
II.  Cholinergic Activity
Benztropine
Trihexyphenidyl
Antiparkinsonian Drugs
Anticholinergics
Dopaminergics

16. Dopaminergic Drugs

17. Dopaminergic Drugs
(DA is not used as it cannot cross BBB)
Dopamine

18. 1- Levodopa (L-dopa)
2- Bromocriptine - pramipexole .
3- Amantadine.
4- Selegiline (MAOBI).
5- Entacapone (peripheral COMTI).
Dopaminergic Drugs

19. DA
L-DOPA
DA DA
DA
D2
DA
+
Amantadine
+
Bromocriptine
+
+
Metabolites
MAO B Selegline
- -
COMT
Entacapone - -
Metabolites

21. Levo-dopa

22. L-dopa
The Gold Slandered
Symptomatic Therapy of PD
Improves All Symptoms
(esp. Bradykinesia)

23. Benefits ↓in 3-5 Years
Better to Reserve L- DOPA
(To old age >65 yrs or severe disease ??!!)
Gradual neuronal degeneration

24. 1-3%
DDC
Oral L-dopa A. A

25. When combined with a decarboxylase inhibitor, more levodopa reaches the brain.
less drug is required [so  its dose by 75% &  it side effects].

26. Carbidopa
↑↑Antiparkinsonian
Effect
↓↓Peripheral
Side Effects
↑↑ central DA & ↓↓ Peripheral DA

27. Adverse Drug Reactions (ADR)
of L-dopa

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

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

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

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

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

33. Levodopa-induced Dyskinesia
Abnormal Involuntary movement mostly
choreoathetosis; head, lip or tongue movements

34. Dyskinesia
Why?
(Not Clear, Multiple Theories)
Fluctuation in
dopamine level in BG
↑↑↑ dopamine level in
Basal ganglia (BG)
↑ Glutamate (NMDA-R)
in BG
(50% of pt after 5 yrs use)

35. Levodopa-induced Dyskinesia treated by:
Anti-dyskinesia action
Amantadine
Blocks NMDA receptors
↑↑ dopamine release in BG &
Anticholinergic
Anti-Parkinsonian action (Mild)
↓dose of Sinemet & ↓ Fluctuation use XR …..

36. Other Adverse effects
of Levodopa

37. On-off
Phenomena
wearing off
Phenomena
Motor Fluctuation

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

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

40. 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

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

42. Seligiline
↓ Fluctuation
Prolongs Action
L- dopa
Entacapone
or
Add

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

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

45. • absorbed rapidly from small intestine
• has short half-life (1-2 hrs)
• Protein interferes with its transport into the GIT & CNS.
Levodopa should be taken on empty stomach, 30 min before a meal
Pharmacokinetic of Levodopa

46. 2. Diet Low in Protein ? Why
Nutritional Care in PD
1. Avoid Vit. B6 ? Why
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)

47. Bromocriptine
D2- Agonists
Ergot Nonergot
Pramipexole

48. Bromocriptine
D2- Agonists
Ergot Nonergot
•Vasospasm
•Fibrosis
Pramipexole

49. DA- agonists are first-line
therapy for PD

50. Used in Young & Mild cases
But
Less Dyskinesia
Less Effective than L-dopa

51. Less fluctuation
•Rapid Absorption
•Longer t½.

52. DA- Agonist
Refractory
cases
↓Fluctuations
Sinemet
Plus

53. ➢ Similar to L-dopa:
Hallucination –dyskinesia (Less)
Nausea- postural hypotension
➢ Impulse control disorder (esp. Pramipexol)
➢ Day time sleepiness.
➢ Vasospasm, cardiac & Pulm. Fibrosis
(bromocriptine)
Adverse Effects DA- Agonists

54. Apomorphine
 Potent DA- agonist
 SC “Rescue Therapy" in sever
Off-periods of Akinesia
 It is rapid and more effective
than L-dopa.
 Need antiemetic with it.

55. Mild Effect
Alone
(Early cases ?!)
With L-dopa
(To ↑ its effect)
Amantadine
↑↑ dopamine release in the striatum
Blocks NMDA receptors, anticholinergic

56. Anti-dyskinesia
Amantadine

57. Livido Reticularis
- Insomnia.
- Hallucination.
- Ankle edema
- Livido reticularis
- Tolerance (Rapid)
purple spotting of skin
Amantadine ADRs

58. MAOB inhibitors e.g.
Selegiline

59. Selective inhibitor of MAO-B 
delays breakdown of nigrostriatal
DA  prolongs L-dopa action  
fluctuation & Neuroprotective
Neuroprotective

60. 1. Monotherapy in Mild early PD esp. in young age
2. Adjuvant therapy with L-dopa to ↓ Fluctuation
and ↑ efficacy
Uses of MAOB inhibitors

61. - Insomnia (selegiline)
- Hallucination.
- Very low risk of cheese reaction (at high dose →loss
selectivity and inhibit both MAOA & MAOB)
MAOB inhibitors ADRs

62. • Metabolized into an amphetamine-like
metabolite → Insomnia
Selegiline
• No amphetamine-like metabolite
• (No insomnia)
• Once daily,↓ side effect profile, > MAO-B inhibition & >
neuroprotective
Rasagiline

63. COMT inhibitors e.g.
Entacapone

64. COMT inhibitor   L-dopa
peripheral metabolism   its
bioavailability & prolongs its
action   fluctuations

65.  Add entacapone to Sinemet
Entacapone
Carbidopa
Prolongs action &  fluctuations

66. Adjuvant therapy with L-dopa to ↑ efficacy &
duration and ↓ Fluctuation esp. wearing-off
Uses of COMT inhibitors

67. ➢ Similar to L-dopa:
 Hallucination –dyskinesia (Less)
 Nausea- postural hypotension
➢ Orange urine (10%).
Not harmful just metabolites excreted
COMT inhibitors ADRs

68. Anti-cholinergic Drugs
Trihexyphenidyl Benztropine

69. Uses of Anticholinergics in
Parkinsonism e.g. Benzotropine
2. Drug Induced Parkinsonism (why?)
e.g. psychotic pts receive antipsychotics esp. Typical AP Haloperidol
1. Parkinson disease (esp. in the young): monotherapy in
mild cases or adjuvants to DA drugs in pts with tremors
& sialorrhea (drooling)

70. L-dopa and dopaminergic
drugs cannot be used
because DA receptors are
blocked by antipsychotics.
L-dopa and dopaminergic
drugs may aggravate the
psychotic disorder of the
patient.

71. Avoid in Elderly (>70 yr)
1. Memory Loss
3. Urine Retention in BPH
2. Hallucinations
It delay gastric emptying   L-dopa absorption

72. If Anticholinergics are
contraindicated, How to
manage tremors and
Drooling?

73. Beta adrenergic blockers e.g. Propranolol may be
used for tremors. (monitor HR & BP)
Increased activation of β adrenoceptors has been implicated in tremor, and management commonly
involves administration of propranolol.

74. If anticholinergics are contraindicated
Drooling or Sialorrhea can be treated Locally by
botulinum toxin injections, and sublingual atropine )
Sublingual atropine

75. NICE guideline , 2017; Canadian guideline , 2019
Initial treatment for early Parkinson disease
Either Levodopa or Dopamine agonists
may be used as a symptomatic treatment for early Parkinson disease

76. Treatment algorithm for
Parkinsonism
NICE guideline , 2017; Canadian guideline , 2019

77. Dementia
Rivastigmine
Functional Disability
5HT2A inverse- agonist
Early mild stages to control certain
symptoms before decline in functioning
Pimavanserin (2016)
Vomiting Domperidone
P Hypotension Midodrine
+ Anticholinergics
NICE guideline , 2017; Canadian guideline , 2019
Intrajejunal levodopa-carbidopa
Functional Disability