Drug therapy of

Parkinsonism

Dr. Heethal Jaiprakash

Pharmacology and therapeutics
Email:heethaljaiprakash@imu.edu.my
(Extension-1223)
 Learning outcomes
On completing this lecture, you should be able to:

Classify the groups of drugs used in Parkinson’s disease

Explain the rationale behind the combination of levodopa

and carbidopa

List the adverse effects of levodopa

Define on/off phenomenon and its management

Name the drugs used in drug induced parkinsonism

• It is a neurodegenerative disorder of the
basal ganglia

• Loss of dopaminergic neurons in the

substantia nigra

• Parkinson’s disease is a progressive

disorder of movement, mainly in the elderly.
Dopamine is the oil that keeps the machinery
function smoothly

Dopamine
(oil)

Substantia nigra
(factory)

Basal ganglia – striatum

(machinery)
 Parkinson’s disease- features
• Tremors at rest : diminish
during voluntary activity
• Muscle rigidity(cogwheel
rigidity) : presents as increased
resistance to passive limb
movement
• Hypokinesia or bradykinesia:
voluntary movements are
suppressed
• Gait : short, shuffling gait, They
find it hard to start, and once
they start, they cannot quickly
stop or change direction.
• Dementia: degeneration in
other parts of brain.
 Non-motor symptoms
• Cognitive impairment
• Dementia
• Psychiatric symptoms
• Particularly depression
• Autonomic disturbance
• Sleep disturbances
 Classification of drugs used in parkinsonism
A. Restoring Dopamine in the basal ganglia
1.  synthesis of Dopamine- levodopa
2.  Dopamine breakdown – MAO B inhibitors –
selegiline
COMTinhibitors - entacapone
4.  Release of dopamine - amantadine
5. Dopamine receptor agonist - bromocriptine
B. Antagonizing the excitatory Cholinergic neurons
1. Directly block brain ACh receptors - benztropine
levodopa
 LEVODOPA
– Metabolic precursor of dopamine
– Enhances synthesis of dopamine in the neurons of substantia nigra

Mechanism of action

Levodopa Transported to CNS

Dopamine

Side effects- nausea,

vomiting, Cardiac
Dopamine arrhythmias,
hypotension
• Levodopa decreases rigidity, tremors and
other symptoms

Interactions with Levodopa:

• MAO-A inhibitors potentiate the toxicity of levodopa
• Levodopa+Vitamin B6(Pyridoxine) contraindicated .
WHY????????
Vitamin B6 increases peripheral breakdown
of levodopa and decreases effect of levodopa
Levodopa always combined with carbidopa.
why?????
• Carbidopa is a dopa decarboxylase inhibitor
• Diminishes metabolism of levodopa in GIT and
peripheral tissues
• Lowers dose of levodopa
• Reduces peripheral side effects
 Adverse effects of levodopa

• Peripheral: anorexia, nausea, vomiting,

arrhythmias

• CNS effects: visual and auditory hallucinations,

abnormal involuntary movements(dyskinesias),
mood changes, depression, psychosis and
anxiety, on-off effect
 On and off effect
(wearing off effect)

• Happens in patients receiving long term levodopa

• Unpredictable fluctuations between mobility and
immobility
• Levodopa has short half life hence fluctuations in the
plasma levels are responsible for this affect
• Concomitant use of COMT inhibitors with levodopa can
be helpful
 MAO-B inhibitor : Selegiline

• Selectively inhibits MAO-B

which metabolizes
dopamine.

• High doses- selectivity is

lost and causes
hypertensive crises.

• Reduces dose requirement

of levodopa
 COMT inhibitor- Entacapone
• Selectively and reversibly inhibit COMT
• Entacapone - Increases the brain uptake of
levodopa
• Effective orally
• Useful to smoothen the motor
fluctuations(wearing off)
• Adverse effects: nausea, anorexia, dyskinesia,
hallucination and sleep disorder
 Dopamine receptor agonists
Bromocriptine:
• Ergot derivative and vasoconstrictor
• Dopamine receptor agonist
• Actions are similar to levodopa.
• Caution – CV disease, peripheral vascular
disease
• Side- effects- cardiac problems, pulmonary and
retroperitoneal fibrosis, worsening of
peripheral vasospasm and peptic ulcer.
 Non ergot Dopamine receptor agonists
• Pramipexole, Ropinirole- do not increase
peripheral vasospasm nor cause fibrosis

• Apomorphine: used in “off "phenomenon ,

injectable

• Rotigotine – transdermal delivery once daily

patch

• Use : effective in early Parkinson’s disease

 Amantadine
• Antiviral drug

Mechanism of action in Parkinsonism:

1. increases the release of dopamine
2. blocks cholinergic receptors
3. inhibits the NMDA receptors

Adverse effects:
Restlessness, agitation, confusion, hallucination, toxic
psychosis, hypotension, urinary retention, peripheral
edema, dry mouth

Use: less effective than levodopa ; more effective

than anti -cholinergics in rigidity and bradykinesia
 ANTICHOLINERGIC DRUGS

❖Muscarinic acetylcholine receptor antagonists

❖Examples: benztropine, Trihexyphenidyl,
procyclidine
❖Tremor is more diminished than rigidity or
hypokinesia
❖Commonly used in drug induced extrapyramidal
symptoms( drugs causing parkinsonism-
Phenothiazines, metoclopramide,risperidone etc)
❖Adverse effects :dry mouth, constipation,
impaired vision, urinary retention
 REFERENCES

• Katzung BG, Masters SB, Trevor AJ. Basic and clinical

pharmacology (lange basic science). : McGraw-Hill
Education; 2012.

• Rang HP, Ritter JM, Flower RJ, Henderson G. Rang &

Dale's pharmacology. : Elsevier Health Sciences; 2014.
1. In Parkinsonian patients who have prostatic
hypertrophy, caution should be exercised with the
used of this drug. Which is this drug?
a. Carbidopa
b. Benztropine
c. Amantadine
d. Selegiline
2. A 65-year-old man with parkinsonism is
prescribed entacapone along with levodopa-
carbidopa. How is entacapone useful in this patient?

a. Activates COMT
b. Decreases the formation of 3 OMD
c. Inhibits dopamine uptake
d. Inhibits MAO-B
3. A patient was administered levodopa for his
parkinsonism along with another drug which
reduces the peripheral adverse effects of levodopa.
Which one of the following drugs could have been
administered to reduce the peripheral adverse
effects of levodopa?

a. Amantadine
b. Carbidopa
c. Bromocriptine
d. Entacapone