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Antiparkinson Drugs
Parkinson Disease
Definition
•
•
Disturbance in motor function
Characterized by
o
Rigidity
o
Masked face
o
Stooped posture
o
Gait disturbances
o
Slowing of voluntary movement
o
Pill-rolling tremor
Parkinsonism is not a disease, it is per se a collections of signs
and symptoms of underlying diseases. BUT in a case of
absence in underlying causes (which is the most common),
Parkinsonism is cosidered to be a disease of its own
Antiparkinson Drugs
These line of drugs are use in the intention of relieving the
symptoms of Parkinson Disease
It is either acting by through
• Increasing the level of Dopamine
• Reducing the activity of Acetylcholine
Classification of Drugs
1. Drugs that increase the level and activity of Dopamine
a. L-Dopa/Levodopa
b. Mono Amine Oxidase B (MAOB) Inhibitors
i. Selegiline
ii. Rasagiline
c. Catechol – O – Methyl Transferase (COMT) Inhibitor
i. Tolcapone
ii. Entacapone
d. Dopamine Receptor Agonist
i. Bromocriptine
2. Drugs that decrease the activity of Acetylcholine
a. Anticholinergic Agent
i. Benzatropine
Drugs That Affect the Level and Activity of Dopamine
Drugs
Levodopa/
L-Dopa
• It is biologically
produced by the
human body as
the precursor of
Catholamines
such as
o Norepinephrine
o Epinephrine
o Dopamine
Pharmacokinetic
Mechanism of Action
•
L-Dopa
is
the
precursor of Dopamine; therefore
Absorption
by
administering
L-Dopa with hope it will increase
• Readily absorp orally
the level of Dopamine in the brain
• Bioavailibility is quite low – 25-30% • L-Dopa will be converted into Dopamine in the
Distribution
brain by an enzyme called the Aromatic – L –
• Upon absorption, L-Dopa will be
Amino Acid Decarboxylase/ DOPA
Decarboxylase
either
o
This reaction needs Pyridoxine (Vitamin B6) as
o Converted by the Aromatic –
its cofactor
L- Amino Acid
o Hence L-Dopa is often be given together with
Decarboxylase/ DOPA
supplementary Vitamin B6
Decarboxylase into Dopamine
o But if the Vitamin B6 is given solely without
DOPA Carboxylase inhibitors (discussed below)
at the peripheral nervous
with L-Dopa, it will accelerate the peripheral
system
metabolism of L-Dopa
 Dopamine CANNOT pass
• But, L-Dopa is also being converted into
the Blood Brain Barrier
Dopamine at the peripheral nervous system
o Directly pass the BBB and
o Physiologically Dopamine CANNOT pass the
BBB. In order to pass this peripheral
converted into the Dopamine
metabolism, L-Dopa is given together with
by the same enzyme
DOPA Decarboxylase Inhibitors (DDCI) such as
Metabolism
 Carbidopa
• Metabolize by Aromatic – L –
 Benserazide
Amino Acid Decarboxylase
o DDCI will inhibit the enzyme in the peripheral
nervous system from converting the L-Dopa
• Half life is short; therefore duration
into Dopamine
of action is also short
o This will therefore lead to
Excretion
 Increase the level of L-Dopa that can pass
• Via urine
the BBB



Increase the half life of L-Dopa from 50
minutes to 11/2 hours
Indirectly increase the level of Dopamine
in the brain with respect to increase in the
half life
Reduce the effects of hyperdominergic
side effects secondary to increase in
peripheral dopamine level
Adverse Effects
Common side effects
• Hypotension
• Arrythmias
• Nausea
o Reduced by
taking with food
o BUT protein ay
interfere with its
absorption
• Allopecia
• Confusion
• Disorientation
• Anxiety
• Excessive libido
• Somnolence
• Narcolepsy
• Insomnia
Side effects due to
chronic admin
• On-off oscillation
• Resistance
• Dyskinesia
• Dopamine
Dysregulation
Syndrome
• Depletion of
serotonin
Drugs
Mono Amine
Oxidase B
(MAOB) Inhibitors
• Selegiline
• Rasagiline
It is not useful as a
single therapy.
Therefore should
always be given as
adjuvant therapy
Pharmacokinetic
Absorption
• Poorly absorp orally
• But it happens that it increases when taken with high
fat content foods due to its liposolubility
Distribution
• Readily distributed across the body compartments
• 90% bounded to plasma proteins
Metabolism
• Metabolized in the liver through DEMETHYLATION
• This process may be inhibited if Selegiline is given with
Oral Contraceptive (OCP) as OCP may inhibit
demethylation process
o This will increase the plasma level of Selegiline up
to 10-20 folds
o Increase the level of Selegiline in the plasma will
shift its selectivity from only MAOB to both MAOA
and MAOB
 Therefore it will
 Reduce the efficacy of Selegiline
 Leads to Cheese Effect
o Cheese effect is an Hypertensive crisis
due to increase in the level of tyramine
(Tyramine in high in cheese)
o Cheese effect happens due to the nonselectivity of selegiline towards MAO
 MAOA is enzyme that metabolizes
epinephrine, norepinephrine and
serotonin
• Selegiline primary metabolites are
o L-Amphitamine
o L-Methamphitamine
Excretion
• Half life
o After a single dose
 1 ½ hours
o After long admin
 9 hours
• Excreted via urine
Mechanism of Action
• MAOB will deaminate
Dopamine into Homovanillic
acid
• Selegiline will covalently bind
to MAOB and leads to
irreversible inhibition of the
activity of the enzyme
• This will therefore reduce the
metabolism of Dopamine
which leads to
o Increase of level of
Dopamine
o Increase the efficacy of LDopa
•
•
•
•
•
•
Adverse Effects
Dizziness
Dry mouth
Insomnia
Muscle pain
Nausea
Constipation
Severe side effects
• Severe headache
• Tachycardia
• Arrhythmias
• Hallucinations
• Chorea
• Difficulty in
breathing
Drugs
Catechol-OMethyl
Transferase
(COMT) Inhibitors
• Tolcapone
(already
withdrawn off the
market)
• Entacapone
It is not useful as a
single therapy.
Therefore should
always be given as
adjuvant therapy
Dopamine
Receptor Agonist

Bromocriptine
Pharmacokinetic
Absorption
• Readily absorb orally
• Low bioavailibility – 30%
Distribution
• Readily distributed across body
comparments
• Readily passes the BBB
• 99% bound to plasma albumin
Metabolism
• Hepatic CYP450
Excretion
• 90% feaces
• 10% urine
Absorption
 Readily absorp orally
 Low bioavailibility – 28%
Distribution
 Readily distributed in all body
compartments
 Passes the BBB
Metabolism
 Remains unknown
Excretion
 85% feaces
Mechanism of Action
• COMT will metabolize L-Dopa into 3Methoxy-4-Hydroxy-L-Phenylalanine
(3-OMD)in the periphery
• COMT also metabolizes Dopamine into
Homovanillic acid in the brain
• COMT inhibitors are somehow similar to
that of Carbidopa, in a sense that
COMT inhibitors inhibit the activity of
COMT in the periphery as well as in the
brain
o This will therefore
 Reducing peripheral metabolism
of L-Dopa into 3-OMD
 Hence, increasing the level
of L-Dopa reaching the CNS
 Reducing the cerebral
metabolism of Dopamine into
Homovanillic acid
 Therefore increasing the
level and activity of
Dopamine
 Bromocriptine is a potent agonist at
dopamine D2 receptors and various
serotonin receptors
 It also inhibits the release of glutamate,
by reversing the glutamate GLT1
transporter
Other Indications of Bromocriptine
 Hyperprolactineamia
 Galactorrhea
 Amenorrhea
 Type 2 Diabetes Mellitus
o Bromocriptine is fund t reduce
HbA1c up to 0.5% (FDA)
Adverse Effects
Side effects primarily
due to increase level of
L-Dopa
 Dyskinesia
 Hepatotoxicity –
primarily in
Tolcapone
 That’s why it has
been withdrawn
from the market
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Nausea
Orthostatic
hypotension
Headache
Vomiting
Worsening of liver
problems
Drugs That Decrease the Activity of Acetylcholine
Drugs
Anticholinergic
Agents

Benzatropine
Benzatropine is a
drug that is
manufactured
through combining
tropine portion of
Atropine with
Benzohydryl portion
of Diphenhydramine
Pharmacokinetic
Absorption
 Readily absorp orally
o Onset at about 1-2 hours
 But the onset increases drastically to
only minutes if given through I/V or
I/M
Other pharmcokinetic of Benzatropine
are remained largely unknown


Mechanism of Action
Benzatropine is a centrally acting
anticholinergic/antihistamine agent
resulting from the combination of the
tropine portion of the atropine
molecule and the benzohydryl
portion of diphenhydramine
Benzatropine antagonises the effect
of acetylcholine, decreasing the
imbalance between the
neurotransmitters acetylcholine and
dopamine, which may improve the
symptoms of early Parkinson's disease
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Adverse Effects
Dry mouth
Blurred vision
Cognitive changes
Constipation
Urinary retention
Tachycardia
Anorexia