Antiparkinsonian Drugs (Full Lecture)

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 2
nd
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 D
2receptors.
-Antiemetics (Metoclopramide) block D
2receptors.
-Reserpine, Tetrabenazine (VMATI)depletes DA stores.
-Methyldopa (Aldomet) inhibits DA synthesis.

9. Drug-Induced pseudoparkinsonism
➢Antiemetics
Metoclopramide
Block D
2receptors in BG
➢Antipsychotics
(Typical)Phenothiazinese.g.
Thioridazineand 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-striatedDopaminergic 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 ModulationBradykinesia RigidityTremors
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
AnticholinergicsDopaminergics

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 DADA
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 yrsor 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-dopainduced 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 ptafter 5 yrsuse)

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??)
Peripheralcauses:(kinetic)
-Delayedgastricemptying,(50-90%&..…)
-Dietaryprotein,(compete..)
-Shortplasmat½,(1-2hr)
Centralcauses:(Dynamic)
-PulsatiledeliverytostriatalDAreceptors
-Impairedstoragecapacity,
-AlterationofDAreceptors

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-periodsof 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
-Lividoreticularis
-Tolerance (Rapid)
purple spotting of skin
Amantadine ADRs

58. MAOB inhibitorse.g.
Selegiline

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

60. 1. Monotherapy in Mild early PD esp. in young age
2. Adjuvanttherapy 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. •Metabolizedinto an amphetamine-like
metabolite → InsomniaSelegiline
•No amphetamine-like metabolite
•(No insomnia)
•Once daily,↓ side effect profile, > MAO-B inhibition & >
neuroprotective
Rasagiline

63. COMT inhibitorse.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. Adjuvanttherapy 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-dopaanddopaminergic
drugscannotbeused
becauseDAreceptorsare
blockedbyantipsychotics.
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. IfAnticholinergicsare
contraindicated,Howto
managetremorsand
Drooling?

73. Beta adrenergic blockers e.g. Propranololmay 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. Ifanticholinergicsarecontraindicated
DroolingorSialorrheacanbetreatedLocallyby
botulinumtoxininjections,andsublingualatropine)
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