Drugs for

PARKINSON’S DISEASE
Dr. Norman Waldron
The UWI School of Nursing, Mona
 CLINICAL FEATURES
Idiopathic in nature
Chronic progressive disability
Characterized by:
Rigidity (hypertonicity ± cogwheel rigidity)
Bradykinesia (slowness of movement & delay in initiating
movement)
Rest tremor: pill – rolling
Postural instability
2
 AETIOLOGY
The normally high concentration of dopamine in
the basal ganglia of the brain is reduced in
Parkinson’s disease.
Dopamine deficiency

Pharmacological, the intent is to restore

dopaminergic activity in the basal ganglia.

February 6, 2021 Drugs for Parkinsonism 3

 DRUGS
Levodopa (L-dopa)
Extracerebral dopa decarboxylase inhibitor
Catechol–O–methyl–transferase inhibitor
Dopamine agonists
Anti-muscarinic drugs
Others:
Amantadine: an antiviral drug
Selegiline: a monoamine oxidase B inhibitor (MAOI)
February 6, 2021 Drugs for Parkinsonism 4
 QUESTION
If the problem is dopamine deficiency.

Why don’t we simply use dopamine to treat

Parkinsonism?

Answer - dopamine itself does not cross the

blood-brain barrier. So, levodopa is used instead.

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February 6, 2021 Drugs for Parkinsonism 6
 LEVODOPA
Levodopa, an amino acid, is the immediate metabolic

precursor of dopamine and norepinephrine.

Levodopa penetrates the blood-brain barrier, where it is

decarboxylated to dopamine in the brain.

February 6, 2021 Drugs for Parkinsonism 7

 MECHANISM OF ACTION
This dopamine replenishes depleted striatal
dopamine and alleviates many of the clinically
features.
However, levodopa is also decarboxylated in the
periphery and very little gets into the brain ~1%.
It improves bradykinesia and rigidity more than
tremor.
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 MECHANISM OF ACTION
However an ingenious way to get around this is to give
levodopa with a/an:

Extracerebral dopa decarboxylase inhibitor.

Catechol – O – methyl – transferase inhibitor

February 6, 2021 Drugs for Parkinsonism 10

Extracerebral dopa decarboxylase inhibitor
Carbidopa (+ levodopa = Madopar®)

Benserazide (+ levodopa = Sinemet®)

This decarboxylase inhibitor protects levodopa from

breakdown in the periphery, allowing more levodopa to
enter the brain ~ 10%, and less worrisome side-effects.
February 6, 2021 Drugs for Parkinsonism 12
 MECHANISM OF ACTION
Inhibition of dopa decarboxylase is associated with
compensatory activation of other pathways of levodopa
metabolism, esp. catechol-O-methyl-transferase (COMT)
and this increases plasma levels of 3-O-methyldopa
(3OMD) a metabolite.
3OMD competes with levodopa for an active carrier
mechanism across the intestinal mucosa and BBB; hence it
produces a poor response to levodopa therapy.
13
February 6, 2021 Drugs for Parkinsonism 14
 MECHANISM OF ACTION
COMT inhibitor prolongs the duration of action of
levodopa by diminishing its peripheral metabolism.
Levodopa clearance is decreased, and relative
bioavailability and half-life of levodopa is thus increased.
Tolcapone
Entacapone: is preferred because it is not associated with
hepatotoxicity

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February 6, 2021 Drugs for Parkinsonism 16
 PHARMACOKINETICS - Levodopa
Rapidly absorbed from the small intestine.
Plasma concentration usually peak between 1-2 hours
after an oral dose.
Half-life 1 – 3 hours.
Excreted by the kidneys; 2/3 of an oral dose appears in
the urine within 8 hours.
Only 1 – 3% of administered levodopa actually enters the
brain. 17
 SIDE EFFECTS
Gastrointestinal: anorexia, nausea and vomiting
(occurs in 80% of patients).

Cardiovascular: arrhythmias, postural hypotension.

Dyskinesias: dose-related, but there is considerable

individual variation in the dose required to produce
them.

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 SIDE EFFECTS
Behavioral changes including: anxiety, agitation,
confusion and mood changes including
depression.

Fluctuations in response:
End-of-dose akinesia

On-off phenomenon
February 6, 2021 Drugs for Parkinsonism 19
 END–OF–DOSE AKINESIA
Certain fluctuation in clinical response to levodopa
occurs with increasing frequency as treatment continues.

In some patients, these fluctuation relate to the timing of

levodopa intake (wear-off reaction/ end-of-dose
akinesia).
Modified-release preparations may help with end-of-dose
deterioration.
February 6, 2021 Drugs for Parkinsonism 20
 ON–OFF PHENOMENON
In other instances, fluctuation are unrelated to the timing of
doses (on-off phenomenon)
Typically occurs in patients who responded well initially to
treatment. Patients may benefit from:
Taking medication at more frequently & in smaller doses
The addition of dopamine agonist or a COMT inhibitor to the
drug regime.
Reducing dietary protein
 DRUG INTERACTIONS
Vitamin B6 (pyridoxine) enhances the
extracerebral metabolism of levodopa.

Hypertensive crises may occur if levodopa is

given with MAOIs or within two weeks of its
discontinuation.

Antipsychotics: antagonism of effect of levodopa.

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 CONTRAINDICATIONS
Levodopa should not be given to psychotic patients.
Neuroleptic-induced Parkinsonism.
Closed-angle glaucoma.
Cardiac disease
Patients with active peptic ulcer.
Patients with a history of malignant melanoma or a
suspicious undiagnosed skin lesion
Concomitant use of MAOIs 23
 PREPARATIONS
Sinemet®: contains levodopa and carbidopa in fixed
proportions (10:1 or 4:1)
Madopar®: levodopa to benserazide ratio is constant in
all preparations i.e. 4:1
When levodopa and carbidopa ratio is 10:1 the carbidopa
dose may be insufficient to achieve full inhibition of
extracerebral dopa-decarboxylase.
So a ratio of 4:1 is preferable.
24
 PREPARATIONS
Stalevo®: contains levodopa, carbidopa and
entacapone
4:1 ratio of levodopa to carbidopa combined with 200
mg of entacapone in a standard-release formulation.
• 50 mg / 12.5 mg / 200 mg
• 100 mg / 25 mg / 200 mg
• 150 mg / 37.5 mg / 200 mg

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 SPECIAL NOTE
In considering the use of levodopa in patients with Parkinson’s
disease, it is important to appreciate that the best result are obtained
in the first few years (3-4 years) of treatment.
This is sometimes because the daily dose of levodopa must be
reduced with time in order to avoid side effects at doses that were
well tolerated at the outset.
The reason that adverse effects develop in this way is unclear, but
selective denervation or drug-induced supersensitivity may be
responsible.
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 DOPAMINE AGONISTS
Acts directly on dopamine receptors.

Limited side-effects than levodopa because these

drug affect only certain dopamine receptors.

Examples of dopamine agonist are:

Bromocriptine & pergolide (older agents, rarely used)

Pramipexole and ropinirole (newer agents)

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 PRAMIPEXOLE
Preferential affinity for D2 receptors.

Effective when used as monotherapy for mild

Parkinsonism.

It is rapidly absorbed, reaching peak plasma

concentration in ~ 2 hours.

Excreted largely unchanged in the urine.

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 PRAMIPEXOLE
Initial dose 0.125 mg tid; double the dose after 1
week and again after another week.

Further increments are by 0.75 mg weekly

depending on response and tolerance.

Usual required dose: 0.5 – 1.5 mg t.i.d. daily

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 ROPINIROLE
D2 receptor agonist

Also effective as monotherapy in patients with mild disease.

Initial dose 0.25 mg t.i.d.; increasing total dose by 0.75 mg

weekly increments until the 4th week, then by 1.5 mg.

Usual maintenance dose 2 – 8 mg t.i.d.

Metabolized by the liver.

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PRAMIPEXOLE AND ROPINIROLE
Adverse effects
Postural hypotension Constipation

Fatigue Dyskinesias

Somnolence or insomnia Confusion

Nausea Peripheral oedema

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 DOPAMINE AGONISTS
In May, 2007, the FDA approved:

Rotigotine (Neurpro®), transdermally, providing

continuous dopaminergic stimulation.

The rotigotine patch is applied once a day (Rezak,

2007).

February 6, 2021 Drugs for Parkinsonism

 ANTIMUSCARINIC AGENTS
A number of centrally acting anti-muscarinic
agents are available:
Benztropine mesylate (Cogentin®)

Trihexyphenidyl (benzhexol) (Artane®)

Orphenadrine

Biperiden

Procyclidine 38
 ANTIMUSCARINIC AGENTS
They exert their anti-Parkinson’s effect by
correcting the relative central cholinergic excess
thought to occur in Parkinsonism as a result of
dopamine deficiency.

They reduce tremor and rigidity but have little

effect on bradykinesia.
February 6, 2021 Drugs for Parkinsonism 39
 ANTIMUSCARINIC AGENTS
Treatment should be started with a low dose of one of
the drugs in this category; the level of the medication
being gradually increased until benefit occurs or adverse
effects limit further increments.

If patients fail to respond to one drug, a trail with another

is certainly warranted and may be successful.

February 6, 2021 Drugs for Parkinsonism 40

 ANTIMUSCARINIC AGENTS:
Side-effects
Drowsiness Confusion

Mental slowness Agitation

Inattention Delusions

Restlessness Hallucinations

Mood changes

February 6, 2021 Drugs for Parkinsonism 41

 ANTIMUSCARINIC AGENTS:
Side-effects
Dryness of mouth Tachycardia

Blurring of vision Increased intraocular

Mydriasis pressure

Urinary retention Palpitations

Nausea and vomiting Tachypnoea

Constipation Cardiac arrhythmias.

Rarely: dyskinesias 42
 ANTIMUSCARINIC AGENTS:
contraindications
Patients with prostatic hyperplasia and
Obstructive GIT disease (e.g. pyloric stenosis)
and
Angle-closure glaucoma
TCA
Antihistamines.
February 6, 2021 Drugs for Parkinsonism 43
 AMANTADINE
Antiviral drug.

Mechanism of action is unclear; but it may potentiate

dopaminergic functions by influencing the release, or
reuptake of dopamine.

Amantadine is less potent than levodopa and its benefits

may be short-lived.

Usual dose 100 mg bid or tid

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AMANTADINE: Pharmacokinetics
Peak concentration are reached 1-4 hrs. after an
oral dose.

Plasma half-live is 2-4 hours.

Most of the drug is excreted unchanged in the

urine.

Tolerance to its effect develop.

February 6, 2021 Drugs for Parkinsonism 45
 AMANTADINE: Side-effects
Restlessness Agitation

Depression Excitement

Irritability Hallucination

Insomnia Confusion

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 AMANTADINE:
Contraindications
Patients with a history of seizures and

Congestive cardiac failure (CCF).

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 AMANTADINE
“Amantadine is most beneficial in the earlier
stages of Parkinson’s disease and appears to
have its greatest impact on tremor.” (Rezak,
2007)

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MONOAMINE OXIDASE B INHIBITOR
Selegiline and rasagiline
It retards the breakdown of dopamine; increasing
levels of dopamine at the synapse.
As a consequence it enhances and prolongs the
antiparkinsonism effect of levodopa
It may reduce mild on-off or wearing-off
phenomenon.
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February 6, 2021 Drugs for Parkinsonism 50
 MAO-B INHIBITOR:
Side effects
Nausea and vomiting Dry mouth and sore throat

Stomatitis Confusion

Hypotension Psychosis

Depression Agitation

Constipation Headache

Diarrhoea
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 SELEGILINE
Standard dose is 5 mg with breakfast and 5 mg
with lunch.

Drug interactions may occur with: TCAs,

Meperidine (Demerol®) and SSRIs.

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 CONCLUSIONS
Initial utilization of levodopa-sparing strategies to
delay the development of motor fluctuations and
minimize dyskinesias has had a major impact on
maintaining long-term symptomatic control with
medications in Parkinson’s disease.

February 6, 2021 Drugs for Parkinsonism 53

 CONCLUSION
It is now well documented that, when
appropriate, dopamine receptor agonists
combined with MAO-B inhibitors, amantadine,
and anticholinergic drugs provide excellent
symptomatic relief for a number of years before
the utilization of levodopa is required

February 6, 2021 Drugs for Parkinsonism 54

 REFERENCES
Craig, C. R., & Stitzel, R. E. (1994). Modern
pharmacology. (4th ed.). Boston: Little,
Brown and Company.

Katzung, B. G. (2001). Basic & clinical

pharmacology. (8th ed.). New York:
McGraw Hill.
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 REFERENCES
Rang, H. P., Dale, M. M. & Ritter, J. M.
(2000). Pharmacology. (4th ed.). Edinburgh:
Churchill Livingstone.

Rezak, M. (2007) Current pharmacotherapeutic

treatment options in Parkinson’s disease.
Disease-A-Month, 53(4).
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