Pharmacotherapy for Parkinson

Disease

Dr.Datten Bangun,MSc,SpFK
&
Dr.Yunita Sari Pane.M.Kes

Dept.Farmakologi & Therapeutik

Fak.Kedokteran USU
MEDAN
What is Parkinsons Disease?
Parkinsons is a brain disorder
Occurs when neurons in a part of the brain called
the substantia niagra die or become impaired
These neurons produce dopamine
Use to be called shaking palsy
* Dr. James Parkinson first
discovered the disease in 1817
* 1960s chemical difference in brain
were identified
* 2000 Michael J. Fox Foundation
 Introduction
Parkinsons disease (PD) is a progressive
neurodegenerative disorder.
It is caused by degeneration of substantia nigra in
the midbrain, and consequent loss of DA-containing
neurons in the nigrostrial pathway.
Two balanced systems are important in the
extrapyramidal control of motor activity at the level of
the corpus striatum and substantia nigra;
1. Acetylcholine
2. Dopamine
 Pathophysiology

Normally Dopamine & Ach neurotransmitters work

together to enable motor neurons to refine
voluntary movement

Parkinson's results from the degeneration of

dopamine-producing nerve cells in the brain,
specifically in the substantia nigra and locus
coeruleus

Clients have lost 80% or more of their dopamine-

producing cells by the time symptoms appear
 Dopamine
Neurochemical that
supports fine motor activity,
blood pressure, focus,
inspiration, intuition,
enthusiasm, and joy, among
other functions.
Dopamine Agonist: Drugs
that copy the effects of the
brain chemical dopamine
and increase the amount of
dopamine that is available
to the brain for use.
 Grippe

Essential of Medical
Pharmacology
5st Ed. (2003)

Factors contributing to degeneration of

nigrostrial DA-ergic neurones causing PD
CAUSES OF EXTRAPYRAMIDAL DISORDERS
Drugs---chlorpromazine
---butyrophenons
---metochlorpramide
---reserpine
ToxinsCO and manganese poisoning
Inherited and metabolic disorders :
wilsons disease
spinocerebellar ataxia
Encephalitis lethargica
Diffuse small vascular disease
Inherited or degenerative disease
huntingtons disease
progressive supra nuclear gaze palsy
{Steel Richardson
The key steps in the synthesis and degradation of dopamine
and the sites of action of various psychoactive substances at the
dopaminergic synapse
In normal conditions
acetylcholine release from the striatum (cholinergic
neurons)is strongly inhibited by dopamine (depleted from
the nigrostriatal neurons).
Joint GABA-ergic neurons then opposite excitatory
function of glutamate neurones connected to the motor
cortex

Neurodegeneration of the dopaminergic neurons

(Subs.nigra)+ loss of dopamine (the striatum) leads to
both hyperactivity of these cholinergic striatal neurons
+ blockade of GABA-ergic cells (Subst.nigra). The result is
an increase in excitatory activity of glutamate + the motor
cortex
muscle rigidity, tremor, hypokinesia
 Objectives of antiparkinsonian
pharmacotherapy
Balancing the dopaminergic/cholinergic system

NEUROTRANSMITTERS

Dopamine > Ach = hyperkinetic

Ach > dopamine =hypokinetic

Maybe restored by two mechanisms:

 How to Balance the dopaminergic/cholinergic
system
A.INCREASE IN DOPAMINERGIC ACTIVITY
(1) dopamine precursors (replacement of dopamine)
(2) MAO-B blockade
(3) increase in dopamine release
(4) blockade of amine neuronal reuptake
(5) dopamine receptors agonists

B. How to treat excitatory function of

cholinergic and glutaminergic neurons?

MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS

 Pharmacological Treatment of
Parkinsons Disease
Goals:
Primary = restore dopamine receptor function.
Secondary = inhibition of muscarinic cholinergic
receptors.

Several types of drugs:

Levodopa
Dopamine Receptor Agonists
Monoamine Oxidase Inhibitors (MAOIs).
Catechol-O-Methyltransferase (COMT) inhibitors.
Muscarinic Cholinergic Receptor Antagonists.
Amantidine.
Pharmacological Treatment of
Parkinsons Disease

From: Youdim et al. 2006. Nature Rev Neurosci. 7: 295-309

 1. Enhancement of DA-ergic activity by
drugs which may:
(a) replenish neuronal DA by supplying levodopa,
which
is its natural precursor; administration of DA itself is
ineffective as it does not cross the BBB;
(b) act as DA agonists (bromocriptine, pergolide,
cabergoline, etc.);
(c) prolong the action of DA through selective
inhibition of its metabolism (selegiline);
(d) release DA from stores and inhibit reuptake
(amantadine).
 Central DA-ergic Drugs
Levodopa Levodopa

Dopamine
(-)
Selegiline
MAO-B

(-)
Amantadine Reuptake Amantadine
(+)

Bromocriptine
(+) Pergolide

The Principles of Medical

D2-receptors
Pharmacology (1994)
 Levodopa
Prodrug immediate metabolic precursor of
dopamine.
Levodopa can cross the blood-brain barrier
while dopamine cannot.
CNS enzymatically converted to dopamine by
L-aromatic amino acid decarboxylase.
1-3% of Levodopa actually enters the brain.
Primarily due to extracerebral metabolism.
Extracerebral metabolism can be reduced by
administering a non-BBB permeating peripheral
L-aromatic amino acid decarboxylase inhibitor.
Sinemet = levodopa + carbidopa
Basic & Clinical Pharmacology 10th Ed. (2007)
 Levodopa
Mechanism of Action: restoration of synaptic
concentrations of dopamine.
Activation of post-synaptic D2 receptors = inhibit
adenylyl cyclase = promote voluntary movement via
indirect pathway.
Additional benefit obtained via activation of post-
synaptic D1 receptors = stimulate adenylyl cyclase =
facilitate voluntary movement via direct pathway.
LEVODOPA
(DOPA DihydroOxy-
PhenylAlanine;
(t1/2 1,5 h)
is a natural amino acid
precursor of DA.
The major disadvantage
is the extensive
decarboxylation
of levodopa to DA in
periferal tissues. So that
only 13% of an oral dose
reaches the brain.
 Levodopa
Therapeutic Effectiveness
Best results obtained in first few years of
treatment.
80% of patients show marked initial
improvement (primarily in terms of resolution of
muscle rigidity and bradykinesia).
20% show virtually normal motor function.
Over time, levodopa therapy becomes less
effective
Progressive loss of dopaminergic neurons.
Downregulation of D1/D2 receptors on post-
synaptic terminals.
Some patients require reduced doses of
levodopa to prevent side effects.
 Levodopa Adverse Drug Effects.
Dyskinesias occur in 80% of patients on long-term
levodopa therapy.
Choreiform movements
Dose-related higher doses = increased risk.
Occur more frequently in younger Parkinsons
patients.
Acute side effects related to increased peripheral
concentrations of dopamine.
Nausea
Anorexia treated with peripherally-acting dopamine
antagonist (i.e., Domperidone).
Hypotension particularly in patients on anti-
hypertensives
 Levodopa Adverse Drug Effects
(Cnt.d}
On-off Effect fluctuations in clinical response to
levodopa.
Off = marked akinesia.
On = improved mobility but marked dyskinesia.
Thought to be related to fluctuations in levodopa
plasma concentrations.
Fluctuations can be smoothed out by
incorporating a dopamine receptor agonist into
pharmacotherapy.
Pramipexole.
Ropinirole.
Apomorphine
 . Levodopa Adverse Drug Effects.
Other common side effects:
Confusion.
Insomnia
Nightmares.
Schizophrenic-like syndrome delusions and
hallucinations due to enhanced CNS
concentrations of dopamine.
 2. Dopamine Receptor Agonists.
Pergolide Mesylate (Permax) directly stimulated
both D1 and D2 receptors.
Associated with valvular heart disease (33%).
Loses efficacy over time.

Pramipexole (Mirapex) preferential affinity for

D3 receptor (also D2/D4).
Used primarily in patients with advanced
Parkinsons disease.
Possibly neuroprotective scavenge H2O2.

Ropinirole (Requip) D2 receptor agonist.

Effective as monotherapy in patients with mild
disease.
 2. Dopamine Receptor Agonists.

Bromocriptine (Parlodel) selective D2 receptor

agonist.

Apomorphine potent D1/D2 agonist.

Given via subcutaneous injection to provide
temporary relief of off periods of akinesia.
Short period of effectiveness ( ~ 2 h).
Associated with several side effects (i.e.,
dyskinesias
3. Monoamine Oxidase Inhibitors (MAOIs)
Two types of MAO have been characterized.
MAO-A primarily metabolizes NE and 5-HT.
MAO-B primarily metabolizes dopamine.

Selegiline (Eldepryl) and Rasagiline.

Selective, irreversible inhibitors of MAO-B.
 3. Selegiline MAO-B Inhibitor
Therapeutic Effectiveness
Effective in early Parkinsons disease (as
monotherapy or in combination with levodopa).
Enables reduction in levodopa dose or may
smooth the on-off fluctuations associated with
levodopa.
Metabolite = Desmethylselegiline
neuroprotective.
 3. Selegiline MAO-B Inhibitor
Adverse Effects
Selectivity for brain MAO-B makes selegiline less
likely to produce ADRs involving peripheral
tyramine (i.e., wine, cheese, and chopped liver
syndrome).
Tyramine = catecholamine releasing agent.
Blocks MAO-A at high doses.
Hypertensive crisis due to peripheral
accumulation of NE.
Fatal hyperthermia may occur when
administered in conjunction with meperidine,
cocaine, or fluoxetine.
 4. Catechol-O-Methyltransferase
(COMT) Inhibitors.

Inhibition of L-aromatic amino acid decarboxylase is

associated with compensatory activation of COMT.
Increased plasma levels of 3-OMD = poor
response to levodopa (competition for active
transporter in the gut and at the BBB?).

Adjunctive therapy in patients treated with

levodopa.
 4. Catechol-O-Methyltransferase
(COMT) Inhibitors.
Tolcapone and Entacapone
Selective COMT inhibitors diminish peripheral
metabolism of levodopa.
May also reduce on-off fluctuations.
Adverse Effects:
Related to increased plasma concentrations of
levodopa.
Include dyskinesias, nausea, and confusion.
Other side effects: diarrhea, abdominal pain,
orthostatic hypotension, sleep disorders,
orange urine discoloration.
Tolcapone potentially hepatotoxic.
2. Reduction of cholinergic activity
by antimuscarinic drugs; this approach is ;
most effective against tremor and rigidity,and
less effective in the treatment of
bradykinesia.
 5. Muscarinic Cholinergic Receptor Antagonists.

Muscarinic Receptors localized to striatal neurons.

Mediate cholinergic tremor
May cause presynaptic inhibition of dopamine
release.

Trihexyphenidyl (Artane) and Benztropine (Cogentin).

Therapeutic Effectiveness
Useful in patients administered neuroleptics as
anti-dopaminergic properties of these drugs
antagonize effects of levodopa.
Improve muscle rigidity and tremor but have little
effect on bradykinesia.

 Adverse Effects
Characterized as atropine-like = dry mouth,
inability to sweat, impaired vision, urinary
retention, constipation, drowsiness,
confusion.
 6. Amantadine (Symmetrel)
Antiviral drug with anti-Parkinsonian properties.

Mechanism of action is unclear

Potentiates dopaminergic function by modifying
synthesis, release, or reuptake of dopamine.

=Therapeutic Effectiveness
Less effective than levodopa or bromocryptine
Therapeutic benefits are short-lived.
Adverse Effects of Amantadine
Primarily CNS = restlessness, depression,
irritability, insomnia, agitation, excitement,
hallucinations, confusion.
Overdoses = acute toxic psychosis.
Others = headache, edema, postural
2. Reduction of cholinergic activity
by antimuscarinic drugs; this approach is ;
most effective against tremor and rigidity,and
less effective in the treatment of
bradykinesia.
 BROMOCRIPTINE
a derivative of ergot (Ergot de savle, Secale cornutum).
It is a D2-receptor agonist, but also a weak alpha-
adrenoceptor anatagonist.
It should be started at very low doses (11,25 mg p.o. at
night), increasing at weekly interval and according to
clinical response.
It is also used for treatment of prolactin-secreting
adenomas, amenorrhea/galactorrhea to
hyperprolactinemia,
to stop lactation, acromegaly.
 ADRs of BROMOCRIPTINE
Nausea and vomiting, which may be
prevented withdomperidone;
postural hypotension (may cause dizziness or
syncope);
after prolonged use
pleural effusion and
-retroperitoneal fibrosis.
 Parkinsons disease
2nd most common
neurodegenerative disease.
Mean onset = 57 years of age.
Affects 1-2% of population over 60
years of age.
Etiology is unknown.
Disease progression is highly
variable.
Can be early onset in some cases.
Objectives of antiparkinsonian
pharmacotherapy is balancing
the dopaminergic/cholinergic system