This slide is about neurotransmission of dopamine and drugs used in the treatment of Parkinson's Disease.
It is part of the Presentation by Kityo Robert, A MSc. Pharmacology scholar at Mbarara University of Science and Technology, 2023.
2. Case Study
An 83-year-old woman with Parkinson’s disease is currently being treated with
carbidopa/levodopa, but her Parkinson’s symptoms are worsening. She has
normal liver function and no history of liver disease. Selegiline is added to her
regimen.
(a) Why is levodopa administered with carbidopa?
(b) Why are the symptoms worsening?
(c) How does selegiline help in Parkinson’s disease?
(d) Why Parkinson symptoms with no liver disease?
(e) What if Selegiline isn’t used?
(f) Any alternative therapy available?
3. Objectives:
• Biochemistry of dopamine synthesis, storage, reuptake.
• Dopamine receptors.
• Central dopamine pathways.
• Parkinson’s disease: pathophysiology.
• Physiology of nigrostriatal pathways.
• Pharmacological classes and agents for PD.
4. What is Dopamine(DA)?
• Dopamine is a catecholamine neurotransmitter.
• It is the therapeutic target or a number of important central nervous system
(CNS) disorders, including Parkinson’s disease(PD) and schizophrenia.
• DA is also a precursor or the other catecholamine neurotransmitters
norepinephrine and epinephrine.
• Most abundant in the corpus striatum and the hypothalamus.
Structure
5. • How is Dopamine synthesized?
TH
AADC
Rate determining step
L-
Dopaminergic Neuron
TH – Tyrosine hydroxylase
AADC – Aromatic- L- aminoacid
decarboxylase
Source: Modified from Karen Whalen Lippincott Illustrated Reviews
Pharmacology 2019, Pathophysiologic Basis of Drug Therapy, pp
185.
6. • After DA synthesis, What next? DA synthesis
DA transport and
storage
DA Release
DA Reuptake
DA Metabolism
Storage
Release
Reuptake
Metabolism
MAO – Monoamine oxidase
VMAT – Vesicular monoamine
transporter
DOPAC – Dihydroxy phenylacetic acid
Source: Modified from David E. Golan, Ehrin J. Armstrong et al, Principles of
Pharmacology_ The Pathophysiologic Basis of Drug Therapy, 4th edition, pp
208.
7. • DA Metabolism(contd…)
Dopamine
DOPAC
HVA
3-Methyl tyramine
COMT
MAO /AD
COMT
MAO /AD
COMT – Catechol-O-methyl transferase
AD – Aldehyde dehydrogenase
HVA – Homo vanillic acid
MAO Inhibitor
i.e. selegiline
Urine
8. • Dopamine Receptors
Source: Modified
from David E.
Golan, Ehrin J.
Armstrong et al,
Principles of
Pharmacology_
The
Pathophysiologic
Basis of Drug
Therapy, 4th
edition, pp 210.
9. • Central Dopamine Pathways
Mesocortico/mesolim
bic pathway
Nigrostriatal pathway
Neocortex
Amygdala
Source: Modified from Goodman and Gilman, The Pharmacological Basis of
Therapeutics, 13th Edition, pp 238.
Tuberoinfundibular
pathway
10. • How does dopamine control movement?
Parkinson Disease: Pathophysiology
• The dopaminergic deficit in PD arises from a loss of the neurons in the
substantia nigra pars compacta that provide innervation to the striatum.
• Is based on the finding that the striatal DA content is reduced in excess of
80%, with a parallel loss of neurons from the substantia nigra.
• Its suggested that replacement of DA could restore function.
11. • Parkinson Disease: Clinical overview
• Parkinsonism is a clinical syndrome with four cardinal features:
oBradykinesia (slowness and poverty of movement)
oMuscular rigidity
oResting tremor (which usually abates/stops during voluntary movement)
oImpairment of postural balance, leading to disturbances of gait and to falling
12. • Physiology of nigrostriatal pathway
• Direct pathway:
oThe net effect of stimulation of the direct pathway at the level of the striatum is to
increase the excitatory outflow from the thalamus to the cortex.
• Indirect pathway:
oThe net effect of stimulating the indirect pathway at the level of the striatum is to
reduce the excitatory outflow from the thalamus to the cerebral cortex
13. • Physiology of nigrostriatal pathway(contd…)
Source: Modified from Goodman and
Gilman, The Pharmacological Basis of
Therapeutics, 13th Edition, pp 330.
SNpc –Substantia nigra pas
compacta
SNpr –Substantia nigra pas
reticulate
Gpe – Globus pallidus externa
Gpi – Globus pallidus interna
STN – Subthalamic nucleus
Glu – Glutamatergic
VA/VL – Ventral anterior and
Ventral lateral
GABA - γ-aminobutyric acid
Ach – Acetyl Choline
Direct pathway
Indirect pathway
14. • What are the strategies for treating Parkinson’s Disease?
• 1st strategy (Levodopa/Carbidopa)
Drug Main action Therapeutic
use
Adverse effects Pharmacokinetic
s
Notes
Levodopa and
Carbidopa
-Levodopa is
converted to DA
by
decarboxylation.
-Carbidopa
increases
availability of DA
to the CNS.
Treatment of
Parkinson’s
disease
• Nausea
• Vomiting
• Hypotension
• Mydriasis
CNS
• Hallucinations
• Mood changes
• Abnormal
movements
(dyskinesia)
• Depression
• Anxiety
• Akinesis(‘wearing
off’)
Administered
Orally
Half-life: 1-3hr
• Most effective.
• Dopamine
doesn’t cross
the Blood-Brain
barrier.
• Carbidopa
inhibits DA
metabolism
with less side
effects.
15. • 2nd Strategy (Dopamine Agonist)
Drug Main action Therapeutic
use
Adverse effects Pharmacokinetic
s
Notes
Pramipexole and
Ropinirole
Apomorphine
D2 and D3
receptor sites
- D4 receptors
- Moderate
affinity for D2,
D3 and D5
- Low affinity for
D1
Treatment of
Parkinson’s
disease
Treatment of
Parkinson’s
disease
• Nausea
• Vomiting
• Hypotension
• Mydriasis
CNS
• Hallucinations
• Mood changes
• Abnormal
movements
(dyskinesia)
• Depression
• Anxiety
• Akinesis(‘wearing
off’)
Oral
administration
Subcutaneous
injection
• Dopamine
agonists delay
motor
complications
and are most
commonly
initiated before
Levodopa to
patients who
have mild
disease and a
young age.
16. • Other DA agonists
oBromocriptine
oPergolide
• Earlier used but now rarely used due to their adverse side effects like
fibrosis of heart valves and valvular heart diseases respectively
17. 3rd Strategy (Inhibitors of Dopamine metabolism)
Source: David E. Golan, Ehrin J. Armstrong et al, Principles
of Pharmacology_ The Pathophysiologic Basis of Drug
Therapy, 4th edition, pp 214.
LNAA – L-Neutral aminoacid transporter
18. • 4th Strategy (NonDopaminergic)
• (a) Antimuscarinic drugs(Muscarinic receptor antagonists)
• Benztropine, Trihexyphenidyl, Diphenyldramine
Source:Bertram katzung - Basic Clinical Pharmacology 15th
(2022), 15th edition, pp 734.
Antimuscarinic agents blocks Ach transmission and help to
correct the imbalance in DA/ACh activity.
Note
• ACh has an opposite activity to that of DA
19. • (b) Amantadine
• Antifungal used for treatment of influenza type-B
• Appears to alter DA release, has anticholinergic properties and blocks NMDA
glutamate receptors
• It is used to treat Levodopa-induced dyskinesia that develop late in the course
of the disease
NMDA: N-methyl-d-aspartate
21. Case Study
An 83-year-old woman with Parkinson’s disease is currently being treated with
carbidopa/levodopa, but her Parkinson’s symptoms are worsening. She has
normal liver function and no history of liver disease. Selegiline is added to her
regimen.
(a) Why is levodopa administered with carbidopa?
(b) Why are the symptoms worsening?
(c) How does selegiline help in Parkinson’s disease?
(d) Why Parkinson symptoms with no liver disease?
(e) What if Selegiline isn’t used?
(f) Any alternative therapy available?
22. REFERENCES
• Rang & Dales Pharmacology, 9th edition.
• Goodman & Gilman’s The Pharmacological Basis of Therapeutics.
• Karen W. Lippincott Illustrated Reviews Pharmacology.
• Bertram katzung - Basic Clinical Pharmacology 15th (2022), 15th
edition