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