Lecture Notes for B. Pharm, Medicinal Chemistry of Purbanchal University Nepal regarding Antiparkinsonics

1. Antiparkinsonics
(Parkinson has no cure as of 2014
Drugs only control symptoms)

2. DEFINITION
Parkinson's disease is degenerative disorder of
the CNS dopaminergic neurons which shows
mainly motor and sometimes cognition (thinking)
related symptoms.
movement-related (motor)
shaking, rigidity, slowness of movement and
difficulty with walking
Cognitive problems
Dementia

3. Causes
• Parkinson is caused due to imbalance of
dopamine(DA) and acetylcholine (Ach)
• Ach and DA need to be balanced for smooth
movement. DA causes muscle relaxation while
Ach causes contraction.
• Reduction of DA, in the basal ganglia results in
imbalance of those two and causes motor
disorders
• In some cases, at later stages of the disease
reduction of Ach which is also involved in learning
and attention leads to dementia

5. Classification
• Anti-Cholinergic drugs: atropine, Benzhexol*
Reduces acetylcholine effects (treatment for tremors in early stages)
• Cholinesterase inhibitors: Rivastigmine
Promotes acetylcholine effects (treatment for dementia in later stages)
• Dopamine precursors: levodopa*
Prodrug of dopamine
• Dopamine decarboxylase inhibitors: Carbidopa, benserazide
Inhibits peripheral metabolic degradation of dopamine
• Catechol-O-methyl Tranferase (COMT) inhibitors:
Entacapone
inhibits COMT based metabolism of Levodopa
• Dopamine agonist: bromocryptin, Amantadine
Promotes dopamine effect in the brain.

6. Anticholinergics
• Anticholinergic medicines block cholinergic nerve
impulses that help control the muscles of the
arms, legs and body by inhibiting binding of
acetylcholine with it’s receptors
• For normal motor or muscle control, the effects
of acetylcholine and dopamine need to be
balanced. In Parkinson dopamine levels decrease
but Acetylcholine levels remain same.
• Anticholinergic medicines decrease levels of
acetylcholine to achieve a closer balance with
dopamine levels.

8. Benzhexol (Trihexyphenidyl)
• It is an antimuscarinic drug that blocks Ach effect on M1
receptor
• In Parkinson DA and Ach levels are imbalanced that causes
motor defects. DA lvls are reduced while Ach lvls remain
constant. Benzhexol lowers Ach levels and maintains the
balance
• Trihexyphenidyl is used for the symptomatic treatment of
Parkinson's disease in mono and combination therapy with
L-Dopa
• Also used to control drooling of children with cerebral palsy
(cebebrum paralysis that effects movement)
• In older patients with Parkinsonism it can increases chances
of dementia since Ach is involved in cognition too

9. Cholinesterase inhibitors
• Cholinesterase inhibitors are designed to increase
levels of acetylcholine, a chemical messenger
involved in memory, judgment and learning,
traits which are lost in dementia stage of
Parkinsonism which only occurs sometimes at a
later stage
• Cholinesterase inhibitors do not stop the
destruction of dopaminergic nerve cells. Their
ability to improve symptoms eventually declines
as brain cell damage progresses.

10. Rivastigmine
• It is a acetylcholinesterase/butyrylcholinesterase
inhibitor used to treat dementia that sometimes
occurs at later stage of Parkinson
• It increases lvl of Ach by blocking it’s degradation
from the enzyme acetyl/butyryl cholinesterase
• This improves cognitive functions like memory
and awareness
• Side effects are mostly nausea and vomiting and
at low doses it is generally safe
• It can sometimes dangerously slow heartbeat in
which case atropine (Ach blocker) is used

11. Which is more hydrophillic or less lipophillic ?
How does brain get glucose from blood
when glucose is not lipophillic at all?

12. Dopamine precursor
• External DA can’t cross BBB but the prodrug L-
dopa can. L-Dopa is dopamine with acid group to
create an amino acid functional group. The blood
brain barrier has Amino Acid Transporter which
allows penetration of L-dopa, even though L-
Dopa is less lipophillic than DA
• In the brain it gets metabolized into dopamine by
the enzyme DOPA decarboxylase.
• Thus, L-DOPA is used to increase dopamine
concentrations in the brain which is lowered in
Parkinson

14. • It is most preferred and safest drug in
Parkinson
• Metabolism outside the brain can lower the
efficacy of L-Dopa
• Thus L-Dopa is given with carbidopa which
blocks Dopamine decarboxylase mediated
peripheral metabolism and allows high dose
of L-Dopa to penetrate brain. Carbidopa itself
doesn’t penetrate the brain.

16. Carbidopa
• It is a Dopamine decarboxylase inhibitors.
• It’s purpose is to increase efficacy of L-Dopa
by preventing it’s peripheral metabolic
degradation and thus allowing more L-Dopa
to penetrate the brain
• While Dopamine decarboxylase exists both
inside and outside the brain, Carbidopa only
blocks metabolism outside the brain cause it
can’t penetrate the brain.

17. Entacapone
• It is a Catechol-O-methyl Tranferase (COMT)
inhibitors
• Entacapone prevents COMT from
metabolizing L-DOPA into inactive metabolite
3-methoxy-4-hydroxy-L-phenylalanine
(3-OMD) in the periphery.
• Thus more L-Dopa can penetrate the brain
• It itself doesn’t cross BBB

18. Amatidine
• It promotes Dopamine release and prevents
reuptake of dopamine in the CNS
• Exact MOA is not known. It promotes dopamine,
noradrenaline and serotonine and blocks
monoamine oxidase A and NMDA receptors,
• It has amine group with pKa of 10.8. Although
mostly protonated in the blood, the unique cage
structure provides a very high lipophilicity for
good penetration into brain and also prevents
metabolism such that it is excreted from kidney in
unchanged form

19. Benzhexol

20. Levodopa

21. Thank you

22. Review
• In Parkinson neurons that make Dopamine die
• Thus need to supplement dopamine externally
• But Dopamine can’t penetrate the brain (body
makes dopamine in brain itself)
• Thus given in prodrug form- levodopa

23. • Dopamine used for motor functions
• Acetylcholine used for motor and cognitive
functions
• A balance of DA and Ach is needed for proper
movement

24. • Levodopa has an amino group and penetrate
the brain utilizing the amino acid transporters
in the BBB
• After getting inside brain, it is metabolized
into dopa which eventually forms dopamine
• This is a good strategy but it has metabolic
problem

25. • There are 3 enzymes that want to degrade the
levodopa outside brain thus limiting it’s
therapy
They are
• Dopamine decarboxylase
• COMT
• MOA (mono amine oxidase)-B

26. • The solution is to co-administer Levodopa
with drugs that block those enzymes
• Dopamine decarboxylase- Carbidopa
• COMT - Entacapone
• MOA (mono amine oxidase)-B :Selegiline
• Thus more Levodapa can enter the brain

27. Acetylcholine based therapy are also useful
• 1) AntiCholinergics: lower Ach levels prevent tremors
(as balance is reached with preexisting lowered DA lvls)
• 2) Cholinergics: Increasing Ach levels controls dementia
• (Lowering Ach levels might have lead to dementia as
Ach is needed for cognitive function. Thus better to go
with levodopa based therapy)
• Dementia is a cognitive (thinking capacity)defect which
sometimes (not always)occurs in Parkinson at later
stage

28. Especial Topic
Deep Brain Stimulation
A drugless therapeutic wonder for
Parkinson, Alzheimer, Depression and
Dystonia

29. • Imagine curing UNCURABLE DISEASES not with
drugs but just a piece of lead rod nailed into your
brain! (remember brain feels no pain as it has no
pain receptors)
• The lead rod insulated except at the tip and
delivers electrical stimulation to only a targeted
area in brain
• It doesn’t shock the patient or harm other brain
areas
• DBS is FDA approved for Parkinson and in Phase 3
clinical trial for Alzheimer

31. Incredible outcome in Parkinson and Dystonia
Youtube- Andres Lozano- Parkinson's, depression and the switch that might turn them off