Drugs Used in Parkinsonism

and Other Movement Disorders

Dong-Won Kang, M.D., Ph.D.

Department of Clinical Pharmacology,
Anaesthesia, and Critical Care Medicine
UZ-FMHS
Introduction
 ☞ Introduction

Types of Abnormal Movements

Types of Movement Description
Causes / Examples
Tremor • a rhythmic oscillatory movement around a joint
Resting tremor • tremor at rest
• parkinsonism
Postural tremor • occur during maintenance of sustained posture
Intention tremor • occurs during movement
• occurs in patients with a lesion of the brainstem or cerebellum, esp. superior
cerebellar peduncle
• also from toxicity of alcohol or other drugs
Chorea • dance-like, unpatterned movement
• consists of irregular, unpredictable, involuntary muscle jerks that occur in
different parts of the body and impair voluntary activity
Ballismus • particularly violent form of chorea
• Hereditary (Hungtington disease), or as a complication of various medical
disorders
Athetosis / dystonia • a movement characterized by slow, involuntary, convoluted, writhing movements
of the fingers, hands, toes, and feet and in some cases, arms, legs, neck and
tongue / a longer, more sustained form
• may occur with perinatal brain damage, certain drug complication, diverse
neurological disorders. etc.
Tics • sudden coordinated abnormal movements that tend to occur repetitively,
particularly about the face and head, especially in children
Gilles de la Tourette syndrome • characterized by chronic multiple tics
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 ☞ Introduction

Abnormal Movements
Athetosis Chorea

Tic Ballismus

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 ☞ Introduction

Basal Ganglia
Function in Movement, Posture, and Balance

Initiate & • desired movements while filtering

maintain out undesiring movements

Maintain • posture and balance

• motor learning and habit

Helps in formation

Work through • interconnected loops

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 ☞ Introduction
Basal Ganglia
Regulation of Purposeful Movement

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 ☞ Introduction
Basal Ganglia
Dopaminergic System for Movement Control

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 ☞ Introduction

Basal Ganglia: Direct Pathway

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 ☞ Introduction

Basal Ganglia: Indirect Pathway

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 ☞ Introduction

Basal Ganglia
Regulation of Purposeful Movement

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 ☞ Introduction

Functional circuitry
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 ☞ Introduction

Basal Ganglia
Summary: Regulation of Purposeful Movement
Basal ganglia Nuclei Caudate nucleus, putamen, globus pallidus,
subthalamic nucleus, substantia
Function Movement modulation
Pathways Direct Type Excitatory
Pathway Cortex → striatum → globus pallidus interna →
thalamus → motor cortex
Function Increase in motor activity
Indirect Type Inhibitory
Pathway Cortex → striatum → globus pallidus externa
→ subthalamus → globus pallidus interna →
thalamus → motor cortex
Function Decrease in motor activity
Function modulation Nigrostriatal and thalamostriatal pathways
Clinical aspects Hypertonic and dyskinetic (hypokinesia, hyperkinesia)
disorders
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 Movement Disorders
&
Their Pharmacological
Treatment
 ☞ Pharmacotherapy

Parkinson Disease (PD)

Parkinsonism

• a progressive neurological disorder of muscle

movement.
• characterized by
• tremors, muscular rigidity, bradykinesia
• postural instability, and gait abnormality
• idiopathic parkinsonism = PD (paralysis agitans)

Etiology

• correlated with destruction of dopaminergic neurons

in the substantia nigra.
• with a consequent reduction of dopamine actions in
the corpus striatum, parts of the basal ganglia system
that are involved in motor control.

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 ☞ Pharmacotherapy

PD: Etiology

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 ☞ Pharmacotherapy

Basal Ganglia in PD

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 ☞ Pharmacotherapy

PD: Treatment Strategy

Pharmacological Strategy Drug example
➢ Restore dopaminergic activity in basal ganglia
• Exogenous DA replacement • L-DOPA (levodopa)
• Inhibitor of L-DOPAⓟ/DAⓒ metabolism
• ↓ peripheral metabolism by AADC • Carbidopa, benserazide
• ↓ peripheral metabolism by COMT • Tolcapone, entacapone
• ↓ CNS metabolism by COMT • Tolcapone
• ↓ CNS metabolism by MAO-B • Selegiline (low-dose), rasagiline
• DA receptor agonist • Ergot – Bromocriptine, pergolide, lergotrile
• Nonergot – ApomorphineSC, pramipexole,
ropinirole, & rotigotineTD
➢ Antagonize the excitatory effect of cholinergic neurons in basal ganglia
• Muscarinic receptor antagonist • Trihexyphenidyl, benztropine mesylate,
procyclidine, biperiden, orphenadrine
• Diphenhydramine
➢ Mixed
• Alter DA release in the striatum • Amantadine
• Anticholinergic action
• Block NMDA glutamate receptors
AADC: Aromatic L-amino acid decarboxylase, COMT: Catechol-O-methyl transferase, MAO: Monoamine oxidase, SC: subcutaneous, TD: transdermal - 17 -
 ☞ Pharmacotherapy

PD Tx: L-DOPA
Property

• immediate precursor of dopamine

Treatment effects

• obtained in the first few years

• begins to diminish after about 3 or 4 years of
therapy, regardless of the initial therapeutic
response
• does not stop the progression of parkinsonism
• early initiation lowers the mortality rate
• can ameliorate many of the clinical motor features
of parkinsonism, but particularly effective in
relieving bradykinesia and any disabilities resulting
from it.

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 ☞ Pharmacotherapy

PD Tx: Metabolism of L-DOPA

AADC: aromatic L-amino acid decarboxylase, ALDH: aldehyde dehydrogenase, DH: dopamine -hydroxylase,
COMT: catechol-O-methyl transferase, MAO: monoamine oxidase
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 ☞ Pharmacotherapy

PD Tx: L-DOPA & Carbidopa

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 ☞ Pharmacotherapy

PD Tx: L-DOPA
Adverse Effects
GI effects

• anorexia, N/V – occur in 80% of pts given w/o

peripheral DC inhibitor (20% w/ inhibitor) →
domperidone for persistent nausea (CIx –
phenothiazines)

CV effects

• tachycardia, ventricular extrasystoles, AFib (rare)

• postural hypotension – common, tends to
diminish with continuing Tx
• hypertension – in the presence of non-selective
MAOI or with massive doses of levodopa

DC: decarboxylase, CIx: contraindication, AFib: atrial fibrillation, Tx: treatment, MAOI: MAO inhibitor
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 ☞ Pharmacotherapy

PD Tx: L-DOPA
Adverse Effects
Behavioral effects

• Mental effects
• depression, anxiety, agitation, insomnia, somnolence,
sleep attacks, confusion, delusions, hallucinations,
nightmares, euphoria, and changes in mood or
personality
• common in pts with L+C > L only
• Tx
• atypical antipsychotics with low affinity to D2
receptors – clozapine, olanzapine, quetiapine, &
risperidone
• selective 5-HT2A inverse agonist – pimavanserin (for
hallucination & delusion)
• Dopamine dysregulation syndrome
• compulsive use of dopaminergic medication
• more common with dopamine agonists

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 ☞ Pharmacotherapy

PD Tx: L-DOPA
Adverse Effects
Dyskinesias

• dose-related
• occur in up to 80% pts receiving levodopa for
more than 10 years
• m/c – choreoathetosis of the face and distal
extremities
• reflect overactivity of DA in basal ganglia
• may be related to unequal distribution of striatal
DA
• Tx
• reduction of levodopa → may alleviate, but
motor symptoms of parkinsonism worsens
• amantadine, clozapine for troublesome
dyskinesias
m/c: most common
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 PD Tx: L-DOPA: Adverse Effects ☞ Pharmacotherapy

Response fluctuations

• Wearing-off phenomenon
• = end-of-dose akinesia: rigidity and akinesia return rapidly at the end of the
dosing interval
• relate to the timing of levodopa intake as the “buffering capacity” is lost
• Tx
• increasing dose and frequency can improve the situation → limited by the
development of dyskinesias
• RYTARY carbidopa-levodopa ER capsule / DUOPA carbidopa-levodopa
intestinal gel
• On-off phenomenon
• unrelated to the timing of doses
• off-periods of marked akinesia alternate over the course of a few hours with
on-periods of improved mobility but often marked disabling dyskinesias
• most likely to occur in initial well-responders
• by unknown mechanism

Miscellaneous

• Mydriasis
• Blood dyscrasias, positive reaction to the Coombs test
• Brownish discoloration of saliva and urine produced from catecholamine
oxidation
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 ☞ Pharmacotherapy

PD Tx: Inhibitors of Metabolism

• COMT inhibitors – significantly reduce the “wearing-off” symptoms when

combined with levodopa/carbidopa

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 ☞ Pharmacotherapy

PD Tx: Dopamine Receptor Agonists

Property
⚫ important role as first-line therapy for PD
⚫ have D/A substantially longer than that of levodopa
⚫ often used in the Mx of dose-related fluctuations in motor state
⚫ particularly effective in the Tx of pts who have developed on-off
phenomenon / wearing-off phenomenon
⚫ more likely to cause higher incidence of mental disturbances than
levodopa – disorders of impulse control → compulsive gambling,
betting, sexual activity, and other behaviors
Formulations
⚫ Ropinirole & pramipexole
➢ available in once-daily sustained-release formulations
⚫ Rotigotine
➢ transdermal delivery produces stable plasma drug levels over 24h
⚫ Apomorphine
➢ highly emetogenic → use oral trimethobenzamide (CIx – 5-HT3
antagonist, profound hypotension & loss of consciousness)
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 ☞ Introduction

Antimuscarinic Drugs for Parkinsonism

Drug Usual Daily Dose (mg)
Benztropine mesylate 1–6
Biperiden 2–12
Orphenadrine 150–400
Procyclidine 7.5–30
Trihexyphenidyl 6–20

Therapeutic effects
⚫ may improve
➢ tremor & rigidity
⚫ have little effect on
➢ bradykinesia

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 ☞ Introduction

Combined Effects of Antiparkinson Drugs

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 ☞ Introduction
Summary
Sites of Action of Antiparkinson Drugs

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☞ Introduction

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 ☞ Pharmacotherapy

Huntington Disease (HD)

Property

• an autosomal dominant inherited disorder caused by

an abnormality (expansion of a CAG trinucleotide
repeat that codes for a polyglutamine tract) of the
huntingtin gene on chromosome 4
• characterized by
• progressive chorea and dementia that usually begin
in adulthood

Etiology

• seems to be related to an imbalance of DA, ACh,

GABA, and perhaps other NTs in the BG
• Chorea – results from functional overactivity in
dopaminergic nigrostriatal pathways

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 ☞ Pharmacotherapy

HD: Etiology

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 ☞ Pharmacotherapy

Basal Ganglia in HD

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 ☞ Pharmacotherapy

HD Tx: Symptomatic
To reduce the severity of chorea
⚫ Inhibitors of VMAT2 by depleting central DA
➢ irreversible – reserpine
➢ reversible – tetrabenazine, deutetrabenazine
➢ deutetrabenazine – a selective inhibitor of VMAT2
⚫ Postsynaptic DA receptor blockade
➢ may be helpful
➢ phenothiazines (fluphenazine), butyrophenones (haloperidol)
Symptomatic treatment of mental problems
⚫ depression – fluoxetine, carbamazepine
⚫ paranoia, delusional states, & psychosis – lower dose of

antipsychotics
HD pts exhibiting worsening of involuntary movements as a
result of anxiety or stress
⚫ judicious use of sedative or anxiolytic benzodiazepines

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 ☞ Summary
Defects of Extrapyramidal Motor System
Occurring in PD and HD

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 ☞ Pharmacotherapy

Drugs Used in Various Movement Disorders

Disorders Drugs M/A Effects / Comments
Tics Pimozide*, Block central D2 • Reduce vocal and motor tic
• Tourette fluphenazine, receptors frequency and severity
syndrome haloperidol • Reduce the frequency and
(chronic Tetrabenazine Central DA depletion intensity of tics by about 60%
multiple • *: used 1st line of treatment
tics) Guanfacine, Centrally acting 2-  Motor & vocal tic
clonidine adrenergic • Particularly helpful for
agonists behavioral symptoms, eg.
impulse control disorders
Ballismus Tetrabenazine Central DA depletion • Mx: same as for chorea
Haloperidol, Block central D2
perphenazine receptors
Tardive Tetrabenazine, Central DA depletion
dyskinesia deutetrabenazine,
valbenazine
Phenothiazines, Block central D2 • DA receptor blockade (eg.also
butyrophenones receptors causes dyskinesia,
paradoxically
Tardive Treatment: the same as for tardive dyskinesia
dystonia
Benztropine, Block muscarinic • May be helpful
diphenhydramine, receptors
biperiden
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 ☞ Pharmacotherapy

Drugs Used in Various Movement Disorders

Disorders Drugs M/A Effects / Comments

Athetosis, Levodopa DA restoration • No satisfactory medical

dystonia treatment
• But may respond to dopa-
responsive dystonia
Restless legs • Dopaminergic therapy
syndrome Pramipexole, Long-acting DA • preferred
ropinirole, agonists
Rotigotine skin patch
Levodopa
• Others
Symptoms may resolve with correction of coexisting iron-deficiency anemia.
Diazepam, Various • often effective
clonazepam,
gabapentine, or
opiates
Occ. pts with Trial of diazepam, amantadine, antimuscarinic drugs (high dose), carbamazepine,
dystonia baclofen, haloperidol, or phenothiazines
Blepharo- Often benefit from injection of botulinum toxin into the overactive muscles.
spasm or
torticollis

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