Pharmacotherapy of Parkinson

Disease
Setyo Purwono
Pharmacology & Therapy
Faculty Of Medicine
Universitas Gadjah Mada

Basal Ganglia
The Basal Ganglia Consists of Five Large
Subcortical Nuclei That Participate in Control
of Movement:
Caudate Nucleus
Putamen
Globus Pallidus
Subthalamic Nucleus
Substantia Nigra

The balance of the five large Subcortical Nuclei are

responsible for smooth motor movements
The primary input is from the Cerebral Cortex, and
the output is directed through the thalamus back
to the Prefrontal, Premotor, and Motor Cortex
Neurotransmitters in Basal Ganglia Include
Serotonin, Acetylcholine, GABA, Enkephalin,
Substance P, Glutamate, and Dopamine
Dopamine from Substantia Nigra decreases release
of acetylcholine from striatum.

PARKINSON DISEASE
Parkinson disease (Parkinson's disease, PD) is a
progressive neurodegenerative disorder associated
with a loss of dopaminergic nigrostriatal neurons.
Parkinson disease is recognized as one of the most
common
neurological
disorders,
affecting
approximately 1% of individuals older than 60 years.
Cardinal features include resting tremor, rigidity,
bradykinesia, and postural instability.

Parkinson Disease:
Imbalance primarily between
the excitatory neurotransmitter
Acetylcholine and
inhibitory neurotransmitter Dopamine
in the Basal Ganglia
DA

ACh

 In Parkinson disease, loss of dopaminergic input from

the substantia nigra diminishes activity in the direct
pathway and increases activity in the indirect
pathway;
the net effect is to increase inhibition of the thalamic
nuclei and to reduce excitation of the cortical motor
system.
(Adams and Victors Principles of Neurology ,2005)

Pathophysiology of PD Disease
Cortex

Caudate
nucleus
Corpus
striatum

Putamen

Thalamus

Globus
pallidus

Loss of
dopaminergic
input to
striatum

Degeneration
of neurons in
substantia
nigra pars
compacta

Midbrain

Disrupted
signaling
between
basal
ganglia,
cortex, and
thalamus

Drug Therapy
Drug Therapy Against Parkinson Disease Is Aimed at
Bringing the Basal Ganglia Back to Balance

Decrease Cholinergic Activity Within Basal Ganglia

Activating Dopamine receptors in Substantia Nigra

Antagonize Acetylcholine receptors

Dopamine synthesis

Therapy of PD: levodopa

Late 1950s: LL-dihydroxyphenylalanine (L

(L--DOPA;
levodopa), a precursor of DA that crosses the bloodblood-brain
barrier, could restore brain DA levels and motor
functions in animals treated with catecholamine depleting
drug (reserpine).

First treatment attempts in PD patients with levodopa

resulted in dramatic but shortshort-term improvements; took
years before it become an established and succesfull
treatment.

Still today, levodopa cornerstone of PD treatment;

virtually all the patients benefit.

Agents that Increase Dopamine functions

Increasing the synthesis of dopamine - l-Dopa
Inhibiting the catabolism of dopamine - selegiline
Stimulating the release of dopamine amphetamine
Stimulating the dopamine receptor sites directly bromocriptine & pramipexole
Blocking the uptake and enhancing the release of
dopamine - amantadine

L Dopa- Pharmacokinetics
L Dopa is readily absorbed from GI Tract
Usually large doses must be given since ~1% actually
cross Blood Brain Barrier enters CNS
Large amount of L Dopa has to be given due to First
Pass Effect
L Dopa metabolized by dopa decarboxylase in liver
and periphery to dopamine
Secreted in urine unchanged or conjugated with
glucoronyl sulfate
Most of L Dopa converted in periphery to NE and EPI

Levodopa
Despite risk of complications, still considered gold
standard for treatment of PD symptoms
SE: orthostatic hypotension, dyskinesias, wearing
off, hallucinations, nausea
Most commonly prescribed in combination with
carbidopa
10/100 = 10 mg carbidopa, 100 mg levodopa
25/100 = 25 mg carbidopa, 100 mg levodopa
25/250 = 25 mg carbidopa, 250 mg levodopa

Avoid abrupt discontinuation of drug

Effects of L Dopa on the Symptoms of Parkinson

Disease
L Dopa Fairly Effective in Eliminating Most of the
Symptoms of Parkinson Disease
Bradykinesia and Rigidity Quickly Respond to L Dopa
Reduction in Tremor Effect with Continued Therapy
L Dopa less Effective in Eliminating Postural Instability
and Shuffling Gait Meaning Other Neurotransmitters
Are Involved in Parkinson Disease

Effects of L Dopa on Behavior

In Terms of Behavior, L Dopa Partially Changes
Mood by Elevating Mood, and L Dopa
Increases Patient Sense of Well Being
Significant Number of Patients Get Behavior
Side Effects

Effects of L Dopa on
Cardiovascular System
The Cardiovascular Effects Are Cardiac Stimulation Due to
Beta Adrenergic Effect on Heart
Treat with Propranolol to Block Cardiac Stimulation Effects
Must be careful in treatment of elderly, most will have
underlying cardiovascular problems, can transient
tachycardia, cardiac arrhythmias and hypertension
In Some Individuals, L Dopa produces Orthostatic
Hypotension
Tolerance Will Develop Within Few Weeks

Effects of L Dopa on
Gastrointestinal System
Very Common Gastrointestinal Effects of L Dopa
Include Nausea, Vomiting, and Anorexia
Probably Due to Stimulation of Chemoreceptor
Trigger Zone (CTZ) in Medulla
Tolerance Develops in a Few Weeks to this Effect
Other GI Disturbances Are Abdominal Pain

Effects of L Dopa on Endocrine

System
L Dopa Conversion to Dopamine
Causes decrease in Prolactin from Stimulation
of Dopamine Receptors in Tubularinfundibular
System

Therapy of PD: limitations of levodopa

Efficacy tends to decrease as the disease progresses.

Chronic treatment associated with adverse events

(motor fluctuations, dyskinesias and neuropsychiatric
problems)
Does not prevent the continuous degeneration of nerve
cells in the subtantia nigra, the treatment being
therefore symptomatic.

Adverse Effects of L Dopa

Some are Irreversible and Dose Dependent
However, Long Term Therapy with L Dopa Not
Associated with Renal or Liver Effects
Early in Therapy, 80% of Patients Have Nausea and
Vomiting Due to Chemoreceptor Trigger Zone
Stimulation
30% of Patients have Orthostatic Hypotension; So
must Carefully Regulate Dose

Adverse effects cont.

See Cardiac Arrhythmia from Stimulation of Adrenergic
Receptors in Heart (Autonomic lecture). Adjust Dose
for People with Cardiac Problems
50% of Patients Have Abnormal Involuntary
Movements; ie. grimacing of face and tongue
movements; slow writhing type of movements (Not
Jerky Movements) in Arm and Face
This Is Due to High Dose of Dopa and Occurs Early in
Therapy at 2 to 4 Weeks
Best Way to Handle Is by Reducing Dose

Long Term Therapy

Behavioral Disturbances in 20 to 25% of Population
Trouble in Thinking (Cognitive Effects)
L Dopa Can Induce:
Psychosis
Confusion
Hallucination
Anxiety
Delusion
Some Individuals develop Hypomania Which Is Inappropriate
Sexual Behavior; "Dirty Old Man", "Flashers"

Side effect Treatment

Treatment Is to reduce Dose and Put Person
on Drug Holiday
Stop All Medication for 3-21 Days and Then
Slowly Reinitiate Therapy to Gradually
increasing doses.

"On/off" Effect
"On/off" Effect Is like a Light Switch ; Without
Warning, All of a Sudden, Person Goes from Full
Control to Complete Reversion Back to Bradykinesia,
Tremor, Etc. Lasting from 30 Minutes to Several
Hours and Then Get Control Again
"On/off" Effect Occurs after usually after 2 or more
years on L Dopa
Related to Denervation Hypersensitivity

 Treat by Giving Small Dose Regiments from 16 to 20

Hours
"On/off" Effect May Be Due to Composite of Amino
Acids That Use Same Dopamine Transportor across
Gastric Mucosa causing extremely low levels of L
Dopa in CNS thereby causing symptoms of
Parkinson Disease to reappear.
Changing diet (to low protein), may cause large
conc of L Dopa in CNS Giving thus producing an 'off'
Effect of Symptoms of Parkinson Disease

Drug Interactions with L Dopa

Vitamin B6 - Vitamin B6 Is a Cofactor for
Decarboxylation of L Dopa; Vitamin B6
Enhances Conversion of L Dopa to Dopamine in
Periphery Making it less Readily for Use in the
CNS
L Dopa Is co-administered with Carbidopa

Drug Interactions cont

Carbidopa Is Antagonistic to Peripheral L Dopa
Decarboxylation
Carbidopa Doesn't Cross Blood Brain Barrier
By co-administering Carbidopa, will decrease
metabolism of L Dopa in GI Tract and Peripheral
Tissues thereby increasing L Dopa conc into CNS;
meaning we can decrease L Dopa dose and also
control the dose of L Dopa to a greater degree.

Drug Interactions cont

Antipsychotic Drugs - Antipsychotic Drugs Block
Dopamine Receptor
Reserpine -Reserpine Depletes Dopamine Storage
Anticholinergics - Used Synergistically with L Dopa as an
Antiparkinson Agent, but Anticholinergics Act to
decrease L Dopa absorption since Anticholinergics have
an effect on gastric emptying time which delays crossing
of GI Membrane by L Dopa

Dopamine Agonists

Bromocriptine
Pramipexole
Ropinirole
Rotigitine
cabergoline, lisuride
apomorphine

Properties of dopaminergic agonists

Drug

D1

dopamine

yes

no

---

apomorphine

yes

no

20 min

bromocriptine

no

yes

2-3 hrs

cabergoline

no

yes

65 hrs

lisuride

no

yes

2-3 hrs

pergolide

yes

yes

21 hrs

piribedil

no

no

2-3 hrs

pramipexole

no

no

6-8 hrs

ropinirole

no

no

3-5 hrs

Ergot

Half
Half--life

Bromocriptine
for Treating Parkinson Disease ;
an Ergotamine derivative,
acts as a Dopamine Receptor Agonist
the Drug Produces Little Response in Patients
That Do Not React to Levodopa

Apomorphine
Structurally similar to dopamine
First synthesized in 1869 from acidic
treatment of morphine (but retains no
opiate properties)
Requires parenteral delivery (but site of
injection greatly influences uptake)
Used as rapid rescue for unpredictable off
periods (onset of action 6 -15 minutes)

Apomorphine
Indications
Acute, intermittent treatment of hypomobility, off
episodes (end-of-dose wearing off and
unpredictable on/off episodes) associated with
advanced PD
As an adjunct to other medications

Contraindicated
In patients who have demonstrated
hypersensitivity to the drug or its ingredients,
such as its preservative metabisulfite

Dopamine Agonists
May be used as initial therapy for patients
with mild disease or as add on therapy for
patients with more severe disease
May delay need for levodopa therapy in
early patients
Later stage patients may be able to decrease
levodopa dosing if DA added
Neuroprotective effect?

Dopamine Agonists
Directly stimulate dopamine receptors
No metabolic conversion required
Longer half-life than levodopa (exception:
apomorphine)
May delay onset of dykinesias or motor
fluctuations

Dopamine agonists
Advantages over levodopa: no need for
biotransformation; no competition with other
substances across intestine
Absorption rate decreased in when patient
has full stomach
Side effects: hallucinations, peripheral
edema, somnolence, compulsive behavior
Ergot alkaloid DA no longer used

Amantadine
Antiviral agent; anti-PD effect found accidentally
Effective for tremor, rigidity and dyskinesias
Actual mechanism of action poorly understood:
perhaps facilitates release of dopamine from
striatal neurons, inhibits presynaptic reuptake of
catacholamines, or creates an NMDA receptor
blockade.
Does have weak DA properties
Decreases glutamatergic output from STN (may
account for anti-dyskinetic effect)

Amantadine
T1/2 is 2-4 hours
Medication is excreted mostly unchanged in the
urine
Side effects may include hypotension, hallucinations,
sedation, dry mouth
Rare side effect unique to amantadine is livido
reticularis patchy discoloration of the skin
(although unsightly, harmless to patient; resolves
with discontinuation of med)

Livido reticularis

MAO Inhibitors - General

MAO-B breaks down dopamine within the CNS
Inhibition of MAO-B increases dopamine
levels and function
Because of increase in dopamine activity
within CNS, potential for increased dopamine
side effects

MAO Inhibitors
Selegeline
At low doses, remains selective for MAO-B
At doses >10 mg, becomes non-selective
Active amphetamine-like metabolite
DATATOP study initally showed reduced need for
levodopa at 9 months; at 3 years need for
levodopa equivalent in all tested groups (no
difference in dyskinesias or wearing off)

 Eldepryl
Selegiline in a conventional oral tablet

Zelapar
Selegiline in an orally dissolving tablet
Avoids metabolism & MAO-A inactivation
in the GI tract

Emsam
Selegiline in a transdermal patch
Avoids metabolism & MAO-A inactivation
in the GI tract
Marketed only for depression, not
Parkinsons disease

COMT Inhibitors
In presence of a decarboxylase inhibitor
(carbidopa), COMT is major metabolizing
enzyme of levodopa
Effect of medication thought to be due to
increased/sustained plasma levels of levodopa
Entacapone and Tolcapone

COMT Inhibitors
General precautions: should not be given
with non-selective MAO inhibitors
May decrease metabolism of epinephrine,
isoproterenol, norepinephrine, dobutamine,
alpha-methyldopa
Will potentiate side effects of levodopa
Tolcapone: Black box warning; liver
monitoring required

Catechol-O-methyltransferase (COMT)
inhibitors

Tolcapone (Tasmar) and Entacapone (Comtan)

Increases the duration of effect of levodopa dose
Can increase peak levels of levodopa
Should be taken with carbidopa/levodopa (not effective
used alone)
Can be most beneficial in treating "wearing off" responses
Can reduce carbidopa/levodopa dose by 20-30%

Anticholinergic agents

Trihexiphenidyl (Artane)
Benztropine mesylate (Cogentin)
Diphenhydramine (Benadryl)
ALL:
Potential benefit for tremor, little or no effect on rigidity or
bradykinesia
Prominent side effects: dry mouth, sedation, mood
changes, mental slowness, blurred vision, increased
intraocular pressure
Contraindicated in patient with prostatic enlargement,
narrow-angle glaucoma, obstructive GI disease

 The Antimuscarinic Agents Are Much less

Efficacious than Levodopa
These Drugs Play Only an Adjuvant Role in
Antiparkinson Therapy
the Actions of Atropine, Scopolamine,
Benztropine, Trihexyphenidyl, and Biperiden
are Similar

Possible Neuroprotection

MAO-B Inhibitors
Antioxidants
CoEnzyme Q10
Dopamine agonists
Levodopa
Estrogen
NMDA antagonists
Neurotrophic factors
Riluzole
others