Pharmacology of Movement Disorders

Question 1

Parkinson’s disease is caused by loss of what kind of cells in which part of the brain?

Answer 1

Dopaminergic cells in substantia nigra pars compacta

Question 2

In Parkinson’s disease (PD) there are Lewy bodies in neurons. What are these?

Answer 2

Intracellular formations enriched in the protein α-synuclein

Question 3

Main features of PD. (6)

Answer 3

Resting tremor
Bradykinesia
Rigidity
Frozen facial expression
Flexed posture
Gait changes

Question 4

What non-motor features are associated with PD? (6)

By how many years do these precede the motor symptoms?

Answer 4

olfactory dysfunction
depression
psychotic symptoms
dementia
sleep disturbance
autonomic dysfunction  

12-15 years

Question 5

What is the name of the scoring scale for disability?

Answer 5

Schwab and England Activities of Daily Living

Question 6

How can the gradual dopaminergic nigral cell loss be monitored?

Answer 6

Through dopamine transporter imaging in the striatum

Question 7

Are most PD cases genetic or sporadic?

What protein are genetic cases linked to?

Answer 7

Sporadic

Alpha synuclein

Question 8

What is the prevalence and annual incidence of PD?

Is it more prevalent in males or females?

Answer 8

100-180 in 100,000 (0.1-0.18%)
4-20 per 100,000 annually
Males

Question 9

Methyl-phenyl-tetrahydropyridine (MPTP) is transformed into which metabolite?
How is this harmful?

Answer 9

MPP+
This is neurotoxic for dopaminergic neurons. Dysfunction of complex I of the mitochondrial respiratory chain can lead to increased oxidative stress.

Question 10

How is oxidative stress linked to PD?

Answer 10

It is increased in PD.

Dopamine is highly oxidisable and its metabolism produces free radicals.

Question 11

What does MAO(b) stand for? What is it involved in?

Answer 11

Monoamine oxidase (B isoform).
Oxidation of dopamine.

Question 12

L-tyrosine is converted to ____ which is converted to ____. Which enzyme catalyses the second reaction?

Answer 12

L-dopa
Dopamine
L-aromatic amino acid decarboxylase

Question 13

Dopamine is converted to homovanillic acid in two steps by which two enzymes?

Answer 13

MAO and COMT

Question 14

What type of receptors are dopamine receptors?

Answer 14

G-protein coupled receptors

Question 15

There are D1-like and D2-like receptors.
Which 2 receptors make up the D1 family?
Which 3 make up the D2 family?

Answer 15

D1 and D5

D2, D3, D4

Question 16

What are the five main types of drugs used to treat PD?

Answer 16

1. Dopaminergic compounds
2. Dopaminergic agonists
3. MAOB inhibitors
4. Anti-cholingeric compounds
5. COMT inhibitors

Question 17

How do dopaminergic compounds work? Give some examples.

Answer 17

They compensate directly for dopaminergic deficit.

L-dopa/levo-dopa (biosynthetic precursor).

Question 18

Give some examples of dopaminergic agonists.

Answer 18

Ropinirole, pramipexole, rotigotine (can be used as a transdermal patch), pergolide, bromocriptine, cabergoline…
Apomorphine - given as an infusion.

Question 19

How do MAOB inhibitors work?

Answer 19

They protect residual dopamine against oxidation.

Question 20

What kind of drugs are rasagiline and selegiline?

Answer 20

MAOB inhibitors.

Question 21

Why are anti-cholinergic compounds used for PD treatment? Give some examples.

Answer 21

Dopamine loss leads to hyperactivity of cholinergic cells.

Orphenadrine, procyclidine, trihexyphenidyl.

Question 22

What are entacapone and tolcapone?

Answer 22

COMT inhibitors. They optimise the effect of L-dopa.

Question 23

How does amantadine work?

Answer 23

It inhibits dopamine reuptake and increases dopamine release.

Question 24

Give examples of peripherally acting DOPA decarboxylase inhibitors? Why are these given?

Answer 24

Carbidopa and benserazide.

To maximise the effect of L-dopa on the brain rather than in peripheral tissues.

Question 25

What are the adverse effects of L-DOPA? (6)

Answer 25

``` Nausea/vomiting Postural hypotension Psychosis Impulse-control disorders Excessive day-time sleepiness Motor complications (dyskinesia, dystonia, on-off effect) ```

Question 26

What is the benefit of dopamine agonists over L-dopa?

Answer 26

No motor complications

Question 27

What class of drug should be started for a PD patient at diagnosis and has mild motor disability and no cognitive impairment?

Answer 27

MAOB inhibitor

Question 28

What class of drug should be started for a PD patient at diagnosis that has mild/moderate motor disability and no cognitive impairment?

Answer 28

Dopamine agonist

Question 29

What class of drug should be started for a PD patient at diagnosis that has moderate/severe motor disability, cognitive impairment and is over the age of 70?

Answer 29

L-dopa and COMT inhibitor.

Question 30

Name two other treatment approaches for PD.

Answer 30

Human embryonic mesencephalic graft | Deep brain stimulation

Question 31

What does chorea mean?

Answer 31

Involuntary jerky movements

Question 32

How is Huntington's disease inherited? | Which chromosome and which protein are involved?

Answer 32

Autosomal dominant disease | The protein is 'huntingtin' on chromosome 4. The mutated protein aggregates inside cells.

Question 33

Which amino acid has an abnormal number of repeats (36 repeats) in Huntington's disease?

Answer 33

Glutamine (CAG codon)

Question 34

What pathological changes are associated with Huntington's?

Answer 34

Loss of medium spiny neurons Cortical atrophy Striatal degeneration Intranuclear inclusions of huntingtin

Question 35

What are the symptoms of Huntington's? (7)

Answer 35

``` Chorea Gait abnormalities Lack of coordination Cognitive impairment: poor attention, memory difficulties Psychiatric disturbances Sleep disturbance Weight loss ```

Question 36

What are the mechanisms underlying neurodegeneration in Huntington's? (7)

Answer 36

``` Excitotoxicity Loss of neurotrophic factors Accumulation of aggregates of mutant huntingtin protein Dysregulation of transcription Increased oxidative stress Abnormalities in axonal transport Synaptic abnormalities ```

Question 37

How is Huntington's managed?

Answer 37

Tetrabenazine (synaptic vesicular amine transporter inhibitor) Anti-dopaminergic (antipsychotic) drugs Antidepressant drugs

Question 38

Give some examples of anti-dopaminergic drugs.

Answer 38

Haloperidol | Olanzapine

Question 39

Give some examples of anti-depressant drugs.

Answer 39

Imipramine | Amitriptyline

Question 40

How does Parkinson's affect the direct/indirect pathways?

Answer 40

The loss of dopaminergic cells results in an imbalance between the direct and indirect pathways.