Pharmacologic management

of Parkinsonism&other
movement disorder

dr. Rohmania Setiarini

Parkinson's Disease

Dopamine

PD belongs to a
group of conditions
called motor system
disorders
1-2% of population
suffer from this
condition
Increases to 4 to 5%
for ages 85 and over
Degeneration of
dopaminergic
neurons in the
substantia nigra.

Symptoms of PD
Primary symptoms of PD:
Tremor
Muscle rigidity
(stiffness or
inflexibility)
Bradykinesia (slowing
of voluntary movement
)
Postural and gait
abnormalities

Causes of PD

DA-ergic neurons in
substantia nigra and
corpus striatum
(nigrostriatal DA-ergic
tract) are destroyed
nigrostriatal DA-ergic tract
- part of the
extrapyramidal system,
responsible for motor
control
80% of DA-eric neurons are
damaged, the symptoms of
Parkinson disease appear.

Causes of PD

DA
ACh

The striatum, is also

rich in excitatory
cholinergic neurons
that counteract the
action of dopamine.
This is the dopamineacetylocholine balance
the dopaminergic
system inhibits the
acetylocholinergic
system.

In Parkinson`s disease
dopaminergic neurons
degenerate in nigro-striatal
dopaminergic tract and the
inhibitory influence of
dopamine on the striatum is
diminished, resulting in
increased activity of
excitatory cholinergic
neurons.

Causes of PD
Parkinson's

disease may result from a

combination of genetic and
environmental factors.
Certain toxins, diseases (viral
encephalitis, small vascular lesions) and
drugs may also cause symptoms similar
to those of PD.
- haloperidol (Haldol)
- chlorpromazine (Thorazine)
- metoclopramide (Reglan)
- prochlorperazine (Compazine)

Risk factors

Age - PD usually affects people over

the age of 50
Genetic factors / Heredity
Sex - Men are more likely to develop
Parkinson's disease than women are.
Exposure to pesticides and
herbicides
Reduced estrogen levels
Reduced folate levels

Treatment of PD

There is no cure for

PD, but a variety of
medications
provide dramatic
relief from the
symptoms

2.

The strategy of
treatment of PD rests
on:
dopamine levels in
nigro-striatal
dopaminergic tract
restoring the correct
dopamineacetylocholine
balance (through
antagonizing the
excitatory effect of
cholinergic neurons)

Drugs used in PD
Drugs,

which restore the dopamine levels in

nigro-striatal dopaminergic tract:
Levodopa (L-dopa) and carbidopa
COMT inhibitors
Dopamine agonists
Amantadine
Selegiline
Drugs, which restore the dopamineacetylocholine balance:
Anticholinergics

Levodopa
the

most effective medication for

Parkinson`s disease.
70-80% of treated Parkinson`s patients are
on levodopa therapy.
Standard release preparations:
- levodopa/carbidopa (Sinemet or
Atamet)
- levodopa/benserazide (Madopar)
Prolonged release preparations:
- levodopa/carbiopa (Sinemet CR)
- levodopa/benserazide (Madopar HBS)

Levodopa
Mechanism of actions:
dopamine doesn't cross
the BBB
Levodopa metabolic
precursor of DA easily
penetrate the BBB into
the CNS.

Levodopa

DOPA-decarboxylase

Dopamine

DOPA decarboxylase
inhibitors

Levodopa combined with DOPA decarboxylase

inhibitors represent a significant improvement
in the treatment of PD.
Carbidopa
Benserazide

a smaller dose of levodopa is needed to treat

symptoms
nausea and vomiting often associated with
levodopa treatment are greatly reduced by the
presence of DOPA decarboxylase inhibitors.

Levodopa
Actions:
Levodopa reduces akinesia and
rigidity, in smallest degree
decreases tremor.
Pharmacokinetics:
well absorbed upon oral
administration.
should be taken on empty
stomach, 45 minutes before a
meal. Foods inhibit the
absorption from the gut of
levodopa and it`s transport into
the CNS.

Drug interaction
B6
MAOI
Levodopa loses therapeutic
efficacy after a long time of
treatment. This means that the
length of time that each dose is
effective begins to decrease,
leading to more frequent doses.

Levodopa
The adverse side effects:
CNS:
- visual and auditory hallucinations,
- mood changes (depression, excitation).
With increased dosing and prolonged use of
levodopa, patients experience:
- dyskinesias (spontaneous, involuntary
movements) and "on-off" periods when the
medication will suddenly and unpredictably
start or stop working.
- insomnia and anxiety.
Peripheral:
- nausea, vomiting
- low blood pressure.

COMT inhibitors

represent a new
class of Parkinson's
medications
they must be taken
as an adjunct with
levodopa/carbidopa

Entacapone (Comtan)
Tolcapone (Tasmar)

COMT inhibitors

Indication:
Tolcapone- reduces
the frequency of the
on-offperiods
(motor fluctuations)
Entacaponesecondary
medication; delays
wearing off by
prolonging
effectiveness of
levodopa (Stalevo)

Side effects:
diarrhea, postural
hypotension,
dyskinesias,
insomnia, nausea,
hallucinations,
anorexia,
constipation .
Tolcapone is
hepatotoxic

Dopamine agonists
They mimic the effects
of dopamine in the
brain
The older used in
combination with
levodopa
The side effects:
similar to those of
levodopa,
although they are less
likely
to cause involuntary
movements (dyskinesia)
and
more likely to cause

Agonists available :
bromocriptine
(Parlodel)
pergolide (Permax)
New drugs:
pramipexole
(Mirapex)
ropinirole (Requip)

The newer used alone, as the firstline; side effects similar to

bromocriptine but they are milder.

Amantadine- Symmetrel

antiviral drug

Mechanism of actions:
enhences the syntesis and
release of DA and improve
Dopaminergic neurotransmission.

Actions:
less efficacious than levodopa
but it has fewer side effects
has little effect on tremor but is
more effective than the
anticholinergics against rigitidy
and bradykinesia

Side effects:
difficulty in concentrating
confusion, insomnia
nightmares, agitation
hallucinations
leg swelling

for people in the latter stages

of Parkinson's disease, if they
have problems with
dyskinesia induced by
levodopa

Selegiline- Deprenyl

selective IMAO-B
an adjunct to
levodopa therapy,
prevent the break
down of both naturally
occurring DA and DA
formed from levodopa,
resulting in
dopamine levels in
the brain

has a mild antidepressant effect.

Side effects:
heartburn,
nausea,
dry mouth,
dizziness
risk for severe
hypertension (only at
high doses of drug)

Anticholinergics
the main treatment Adverse effects:
for Parkinson's
blurred vision, dry mouth,
disease before the
urinary retention)
introduction of
levodopa.
mental problems:
Mechanism of
memory loss,
actions:
the activity of Ach confusion
hallucinations.
Actions:
- used as secondary They are not used longadjuvant
term due to their side
medications.
effects.
they
help
control
Biperiden HCL (Akineton), Benztropine mesylate (Cogentin) Procyclidine
tremors in the early
(Kemadrin), Trihexyphenidyl (Artane)
stages of the
disease.

Tremors:

Tremor is an involuntary, rhythmic, oscillatory movement, which can present as

a resting tremor, action tremor, or intention tremor.

Essential tremors
Essential Tremors: most common movement disorder
Occurs at a rate of 5% in the general population.
Frequency increases with age
In many families, ET is inherited in an autosomally dominant pattern. In 30 to
50% of cases.

Medical management:
Popranolol (Inderal) non-selective.
- most well-studied beta-blocker used in the treatment of ET.
- 45% and 75% will show improvement in arm tremor compared with placebo.
- Dosing Standard or Long-acting formulation
- Initiated with 20 mg/d.
- Titrated weekly to an effective dosage, typically 120 mg/d - as 320 mg/d.
Side effects:
- Elderly: may experience symptomatic hypotension or bradycardia.
- Other side effects include impotence, drowsiness, confusion, headache,
depression and exercise intolerance. (Benito-Leon et al, 2007b).
If side effects develop, patients do not usually develop tolerance.
Contraindicated: Asthma, COPD, 2nd degree heart block and Insulin dependent DM.

Medical
Management:
Mechanism of action:
- Central mechanism of action has been suggested for -adrenergic blockers,
but they are not lipid soluble and hence do not cross the bloodbrain barrier.
-- This suggests that the therapeutic effect of -adrenergic blockers might be
mediated, at least in part, by the peripheral -adrenergic receptors.

Other selective beta-antagonists such as nadolol also appear to be effective but

have not been as well studied compared with the nonselective betaantagonist.

Medical Managment
Primidone Anticonvulsant,
- A structural analog of phenobarbital
- It has similar efficacy to propranolol
Dosing:
- The typical starting dose is 25 mg nightly.
- Titrated slowly to avoid side effect
- It may take 6 to 8 weeks for patients to achieve an effective dose
(average 750 mg/d divided into three doses a day)
Side effects:
- Most bothersome: Somnolence and fatigue
- 20% may develop: nausea, drowsiness, and unsteadiness, even
when
starting at very low doses
- Unlike propranolol, the early mild side effects of primidone are
habituating and, therefore, may be tolerated with slow upward
titration in
dose.

Medical Managment
Propranolol and primidone Combination therapy
Greater relief in some patients
Other less well-studied oral agents may be used to treat ET, including
benzodiazepines, topiramate, and gabapentin.
These medications have varying effectiveness.

Medical Managment
Topiramate Topamax, Anticonvulsant
- Shown effective anti-tremor drug in a multicentre, double-blind,
placebo controlled trial of 208 patients with essential tremor. (Ondo
WG et al, neurology 2006)
- Topiramate was associated with a greater improvement in function
and disability than did placebo.
Most common Side effects:
paraesthesias (58 [28%]), weight loss (46 [22%]), and taste
perversion (40 [19%]); other side-effects included nausea, difficulties
in concentration and attention, and somnolence.

Medical Managment
Gabapentin: Neurontin,
anticonvulsant

Mixed results from double-blind, placebo controlled

studies in essential tremor have been reported. (Lyons
KE et al, CNS drugs 2008)

Levetiracetam, Keppra
anticonvulsant

Had a significant anti-tremor effect in one doubleblind, placebo-controlled trial at a single dose of 1000
mg. (Bushara KO, Neurology 2005).
Was not found to be effective in other studies. (Elble

Medical Managment
Diazepam, lorazepam,
clonazepam, alprazolam,
Ameliorating effects on essential
tremors. (Lyons KE, CNS Drugs
2008).

Dystonia
Definition:
- Dystonia is a neurologic disorder dominated by involuntary,
stereotyped, patterned (sustained or spasmodic) contractions
of muscles. These movements frequently cause twisting and
other abnormal movements or postures.
- Causes involuntary simultaneous co-contraction of both
agonist and antagonist muscles, resulting in the twisted
Movements.
- Dystonic contractions are usually sustained at the peak of the
movement, differentiating dystonic contractions from the brief
contractions seen in chorea or myoclonus.