Pharmacology Parkinson Disease

Question 1

Symptoms of Parkinson Disease

Answer 1

*Progressive disorder

*Rate of disability progression is most marked in the early years
of the disease.

*Significant disability 10-15 years after onset

*At later stages, PD patients become increasingly dependent in
their activities of daily living.

*Motor fluctuation, dyskinesias and non-motor symptoms (eg falls,
postural instability, postural hypotension, confusion, dementia, suboptimal nutrition, speech and sleep disorders) are common at later stages.

Question 2

Motor symptoms of PD

Answer 2

1.Tremor at rest

2.Slowness of movement (bradykinesia)

3.Rigidity (stiffness and resistance)
“cogwheel-like” movements of arms

Postural instability

1/2/3 = Cardinal features of PD

Question 3

Non-motor manifestations of PD

Answer 3

Autonomic, neuropsychiatric, olfactory and sensory

Common in PD as many as 88% of patients have at least one nonmotor symptom and 11% with five nonmotor symptoms

More prominent in later stages of PD

Relatively resistant to, and may be worsened by dopaminergic agents

Cause significant disability

Often neglected in PD management

Question 4

AE of levodopa

Answer 4

Side effects:

– Short term: nausea, vomiting, postural hypotension

– Long term: motor fluctuations and dyskinesia (10%/yr)

– Although levodopa is the most efficacious drug for the symptomatic
management of both early and late Parkinson’s disease, the dose of
levodopa should be kept to the minimum necessary to achieve good
motor function.

Question 5

*** COMT inhibitors - side effects (7)

Answer 5

increase abnormal movements (dyskinesias)

– liver dysfunction (Tolcapone)

– nausea, diarrhea

– urinary discoloration

– visual hallucinations

– daytime drowsiness, sleep disturbances

Question 6

Example of anticholinergics

Answer 6

Trihexyphenidyl (Artane)

Question 7

Anticholinergics advantages

Answer 7

Advantages:

– May be effective in controlling tremor
– Peripherally acting agents may be useful in treating
sialorrhoea

Question 8

AE of anticholinergics (7)

Answer 8

– Side effects (especially in elderly):

– Dry mouth, sedation, constipation, urinary retention, delirium, confusion, hallucinations

Question 9

Dopamine agonists - side
effects

Answer 9

similar to levodopa

– ‘ergot’ derivative - fibrosis

– pedal edema

– somnolence with ropinirole, pramipexole

– arrhythmia

– Pergolide - restrictive valvular heart disease

Question 10

Which medication to use for PD?

Answer 10

Treatment has to be individualised
according to:

–age
–stage of disease
–level of activity
–associated psychological factors
–associated medical conditions
–patient factors

Question 11

Early Symptomatic Disease
without complications:

May not even need oral medications if coping well

More importantly,

– Physiotherapy and exercise regime (stretching, maintain balance and posture)

– Healthy and balanced diet

– Knowledge on disease

– Social support

If oral medications required…

Answer 11

• Anticholinergic agents (eg Artane)

– MAO-B / COM-T inhibitors (eg
Selegiline)

–Dopamine agonists (eg Bromocriptine)

– Levodopa (eg Madopar)

Question 12

Pathophysiology of PD

Answer 12

*Impaired clearing of abnormal/damaged intracellular
proteins by ubiquitin-proteasomal system.

Failure to clear toxic proteins
-> accumulation of aggresomes
-> apoptosis

Lewy bodies ≈ aggresome, containing α-synuclein and ubiquitin

Degeneration of dopaminergic neurons with Lewy body inclusions in substantia nigra, locus ceruleus, cortical association areas, hypothalamic neurons, sympathetic ganglia, parasympathetic neurons, olfactory bulb.

Substantia nigra has dopaminergic projections to basal ganglia

Facilitates and modulates motor movements initiated by motor
cortex

Question 13

Synthesis:
-L-tyrosine
-L-dopa

Answer 13

-> L-dopa (tyrosine
hydroxylase)

-> dopamine (DOPA
decarboxylase)

Question 14

Breakdown:

dopamine

Answer 14

dopamine -> homovanillic acid
(catechol-O-methytransferase,
COMT & monoamine oxidase,
MAO)

Question 15

Strategies for increasing or decreasing dopamine synthesis

Answer 15

1) Increase dopamine synthesis
Levodopa

2) Inhibit dopamine breakdown with
COMT inhibitors

3) Strategy: inhibit dopamine breakdown with MAO-B inhibitors

Strategy: activate dopamine receptors Dopamine agonists

Question 16

Strategy: Increase dopamine synthesis Levodopa

Answer 16

Gold Standard

• First available in 1960s

Madopar HBS, madopar 250, Sinemet 100

• Dopamine precursor, “2-in-1” preparation with peripheral
  decarboxylase inhibitors to prevent side effects due to excess DA
  in PNS (Eg, Levodopa + carbidopa: Sinemet)

**Although levodopa is the most efficacious drug for the symptomatic management of both early and late Parkinson’s disease, the dose of levodopa should be kept to the
minimum necessary to achieve good
motor function.

Question 17

Levodopa + carbidopa:

Answer 17

Sinemet

Question 18

Strategy: inhibit dopamine breakdown with COMT inhibitors

Answer 18

Entacapone (Comtan®) or Tolcapone (Tasmar®)

blocks an enzyme that converts levodopa into an inactive form

more levodopa is available to enter the brain

only effective if used with levodopa

increases duration of each dose of levodopa, beneficial in treating “wearing off” responses

Question 19

Strategy: inhibit dopamine breakdown with
MAO-B inhibitors

Answer 19

E.g., Selegiline (Jumex®)
can be taken by itself

mild antiparkinson activity

inhibits enzyme monoamine oxidase B, interferes
with breakdown of dopamine

laboratory studies suggest that it may delay the nigral brain cell degeneration

Selegiline is efficacious as a symptomatic monotherapy and may be used in early stages of Parkinson’s disease.

Question 20

EG of anticholinergic

Answer 20

Trihexyphenidyl (Artane)

Anticholinergic agents may be used
as symptomatic monotherapy or as
an adjunct to levodopa to treat
tremors and stiffness in Parkinson’s
disease.

Question 21

Strategy: activate dopamine receptors Dopamine agonists

Answer 21

Used since 1970s, adjunct or monotherapy

• Available as
  – Bromocriptine (Parlodel®)
  – Pergolide (Celance®, Permax®)
  – Piribedil (Trivastal Retard®)
  – Ropinirole (Requip®)
  – Pramipexole (Sifrol ®)
• Act directly on dopamine receptors in the brain to reduce the symptoms
  of PD
• Antiparkinsonian effects not superior to levodopa (levodopa still the gold standard)
• Prevent or delay onset of motor complications

Dopamine agonists are efficacious as
symptomatic monotherapy. Dopamine agonists
may also be used as an adjunct to levodopa in the treatment of Parkinson’s disease

In younger Parkinson’s disease patients, therapy should commence first with dopamine agonists rather than levodopa.

Question 22

AE of ropinirole and pramipexole

Answer 22

Dopamine agonist

Somnolence, strong desire for sleep/ sleeping for unusually long periods of time

Question 23

AE of pergolide

Answer 23

restrictive valvular heart disease