Pharmacology of movement

Question 1

What are Lewy bodies?

Answer 1

intracellular formations enriched in the protein alpha-synuclein

Question 2

What part of the brain is DaT imaging used on? In terms of Parkinson’s, what does this imaging show?

Answer 2

Looks at the striatum

Monitors the dopaminergic nigral cell loss

Question 3

List some of the features/symptoms of Parkinson’s disease.

Answer 3

Frozen facial expression
Flexed posture
Altered (shuffling) gait
Difficulting initiating + stopping movements
Gradual development of micrographia
Non motor features: olfactory dysfunction, depression, sleep disturbance, cognitive dysfunction

Question 4

What is the name of the scoring scale for disability that is commonly used for PD patients?

Answer 4

Schwaband England Activities of Daily Living
100% = independent, no slowness/impairment
0% = vegetative functions (swallowing, bladder + bowel) not functioning

Question 5

List some of the genes implicated in PD.

Answer 5

SNCA
LRRK2
GBA
PARK2 and PARK7
PINK1

Question 6

What is the result of defects in the SNCA gene?

Answer 6

it affects alpha-synuclein
it is a rare defect
duplications or triplications can cause autosomal dominant, familial PD

Question 7

What does MPTP stand for?

Answer 7

Methyl-phenyl-tetrahydropyridine

Question 8

What converts MPTP to MPP and why is this dangerous?

Answer 8

Monoamine oxidase B converts MPTP -> MPP (1-methyl-4-phenylpyridine)
This is dangerous as MPP is neurotoxic for dopaminergic neurones and can cause mitochondrial toxicity
Does this by inhibiting complex I in the mitochondrial respiratory chain - this reduces ATP production

Question 9

Name the 3 main dopaminergic pathways in the CNS.

Answer 9

1. Mesocortical - ventral tegmental area –> prefrontal cortex
2. Nigrostriatal - substantia nigra pars compacta –> dorsal striatum
3. Mesolimbic - ventral tegmental area –> ventral striatum

Question 10

What type of receptors are dopamine receptors?

Answer 10

GPCRs

Question 11

What receptor subtypes belong to the D1 and D2 families respectively?

Answer 11

D1 family = D1, D5

D2 family = D2, D3, D4

Question 12

What is L-Dopa combined with peripherally and why?

Answer 12

DOPA decarboxylase inhibitors (Carbidopa and benserazide)
This prevents the conversion of L-Dopa to dopamine in the periphery (outside CNS)
This prevents adverse effects such as nausea and hypotension

Question 13

Give examples of dopamine agonists.

Answer 13

• ropinirole
• pramipexole
• rotigotine
• pergolide
• bromocriptine
• cabergoline

Question 14

What is the route of administration of rotigotine?

Answer 14

transdermal patch

Question 15

What is the route of administration of apomorphine?

Answer 15

infusion

Question 16

Why might a clinician prescribe MAOB inhibitors to a PD patient?

Answer 16

to preserve residual dopamine against oxidation

Question 17

Give two examples of MAOB inhibitors.

Answer 17

Rasagiline

Selegiline

Question 18

Why might a clinician prescribe anticholinergic/antimuscarininc compounds to a patient with PD?
Give examples of such compounds.

Answer 18

Dopamine loss can lead to hyperactivity in cholinergic cells

Examples = orphendarine, procyclidine, trihexyphenidyl

Question 19

Why might amantadine be an appropriate drug to prescribe to someone with PD?

Answer 19

it inhibits dopamine reuptake and increases dopamine release

Question 20

Give examples of motor complications associated with L-Dopa use.

Answer 20

“on-off” effect
“wearing off”/tolerance
dyskinesia, dystonia

Question 21

On what chromosome is the Huntingtin gene found?

Answer 21

Chromosome 4

Question 22

How is the Huntingtin gene mutated in Huntington’s disease?

Answer 22

gene presents with an abnormal number of repeats of glutamine (CAG codon)
An abnormal gene will contain >36 repeats leading to a GAIN of function (the mutated protein will aggregate inside of cells)

Question 23

What physical changes to the brain occur in Huntington’s?

Answer 23

Cortical atrophy
Striatal degeneration
Loss of medium size spiny neurones

Question 24

What are some of the mechanisms underlying neurodenegeration in Huntington’s?

Answer 24

Excitotoxicity (due to increases glutamate)
Loss of neurotrophic facotrs
Accumulation of aggregates of mutant huntingtin protein
Dysregulation of transcription
Increased oxidative stress
Abnormalities in axonal transport
Synaptic abnormalities

Question 25

List some of the symptoms of Huntington’s.

Answer 25

Choreic movement 
Gait abnormalities 
Lack of coordination 
Cognitive impairment 
Psychiatric disturbances 
Sleep disturbance 
Weight loss

Question 26

When might a COMT-inhibitor be prescribed for Parkinson’s? Give examples of these drugs.

Answer 26

Usually used in combination with L-dopa, so probably prescribed when L-dopa becomes less effective
Examples: tolcapone, entacapone

Question 27

Give examples of non-motor side effects of L-Dopa.

Answer 27

• N+V
• Postural hypotension
• Psychosis
• Impulse-control disorders
• Excessive day time sleepiness

Question 28

What are the different surgical approaches to treating PD?

Answer 28

• stimulation of subthalamic nucleus (DBS)

- pallidotomy/thalamotomy

Question 29

Give example(s) of vesicular amine transporters used to treat Huntington’s.

Answer 29

Tetrabenazine

Question 30

Give example(s) of antidopaminergic/antipsychotic drugs used to treat Huntington’s.

Answer 30

Haloperidol

Olanzapine

Question 31

Give example(s) of antidepressants used to treat Huntington’s.

Answer 31

Imipramine

Amitriptyline