Pharmacology of Movement

Question 1

Parkinson’s Pathology

Answer 1

Loss of dopaminergic cells in substantia nigra pars compacta
Lewy bodies in neurones- intracellular formations enriched in the protein alpha-synuclein
GABA inhibitory drive to thalamus becomes stronger

Question 2

Dopamine Transporter (DaT) imaging

Answer 2

Help monitor gradual dopaminergic nigral cell loss

In striatum

Question 3

Cardinal Parkinson’s signs

Answer 3

Resting tremor
Bradykinesia
Rigidity
Gait and postural changes

Question 4

Parkinson’s other changes

Answer 4

Frozen facial expression
Flexed posture
Stop/Start movement
Microphagia
Depression
Sleep disturbance

Question 5

Non-motor features parkinsons

Answer 5

May precede by 12-15 years the onset of atypical Parkinsonian motor symptoms

Question 6

SNCA gene

Answer 6

Used to make alpha-synuclein

Rare SNCA mutations, duplications or triplications cause autosomal dominant familial PD

Question 7

Prevalence PD

Answer 7

2nd most common neurodegenerative disorder
100-180 in 100,000
M > F

Question 8

Mitochondrial toxicity

Answer 8

MPTP= methyl-phenyl-tertrahydropyridine
Compound MPTP can be transformed into metabolite MPP+ which is neurotoxic for dopaminergic neurones
MPP+ taken up into neurone
Causes dysfunction of Complex 1 of the mitochondrial respiratory chain –> increased oxidative stress

Question 9

Oxidative stress

Answer 9

Increased in Parkinson’s
Dopamine is highly oxidizable + its metabolism produces free radicals + oxidation products e.g. H2O2
MAO (b isoform) critically involved in oxidation processes

Question 10

Dopamine biosynthesis

Answer 10

L-tyrosine –> L-Dopa

L-Dopa –> Dopamine

Question 11

Dopaminergic pathways in CNS

Answer 11

Mesocortical
Mesolimbic
Nigrostriatal

Question 12

Dopamine receptors

Answer 12

G protein coupled receptors

Dopamine binds to two types- D1-like and D2-like

Question 13

D1-like receptor subtypes

Answer 13

D1 and D5

Question 14

D2-like receptor subtypes

Answer 14

D2, D3, D4

Question 15

L-Dopa

Answer 15

Biosynthetic precursor

Combined with peripherally acting DOPA decarboxylase inhibitors (carbidopa, benserazide)

Question 16

Dopaminergic agonists

Answer 16

Ropinirole
Pramipexole
Rotigotine- transdermal patch
Apomorphine- infusion
Pergolide
Bromocriptine

Question 17

MAOB inhibitor

Answer 17

Protect residual dopamine against oxidation
Rasagiline
Selegiline

Question 18

Anticholinergic (antimuscarinic) compounds

Answer 18

Dopamine loss leads to hyperactivity of cholinergic cells
Orphenadrine
Procyclidine

Question 19

Amantidine

Answer 19

Inhibits dopamine reuptake

Increases dopamine release

Question 20

COMT inhibitors

Answer 20

Used in combination with L-Dopa to enhance its effects
Entacapone
Tolcapone

Question 21

L-Dopa adverse effects

Answer 21

Nausea/vomiting
Postural hypotension
Psychosis
Impulse-control disorders
Excessive day time sleepiness

Question 22

L-Dopa motor complications

Answer 22

On-off effect
Wearing-off
Dyskinesia
Dystonia

Question 23

Treatment stratergy

Answer 23

Mild- MAO-B inhibitor
Mild/moderate- Dopamine agonist
Moderate/severe- Levodopa + COMTI

Question 24

Human embryonic mesencephalic graft

Answer 24

Graft is functional and releases dopamine

Question 25

Surgical approaches to PD

Answer 25

Stimulation subthalamic nucleus Thalamotomy Pallidotomy DBS - advance PD whose symptoms not adequately controlled by optimised pharmacological therapy

Question 26

Huntington's disease

Answer 26

Autosomal dominant Changes in gene encoding protein huntingtin on chromosome 4 Gene presents with abnormal no. of repeats of glutamine in protein sequence --> abnormal gene contains >36 repeats --> gain of function mutation --> mutated protein aggregates inside cells Major degeneration of striatal neurones and cortical atrophy

Question 27

Huntington's disease pathological changes

Answer 27

Cortical atrophy Prominent striatal degeneration Loss of medium spiny neurones (striato-pallidal and striato-nigral)

Question 28

Huntingtons- mechanisms underlying neurodegeneration

Answer 28

``` Excitotoxicity Loss of neurotrophic factors Accumulation of aggregates of mutant huntingtin protein Dysregulation of transcription Increased oxidative stress ```

Question 29

Huntington's symptoms

Answer 29

``` Choreic (jerky) movements Gait abnormalities Lack of coordination Cognitive impairment- bad attention and memories Sleep disturbance Weight loss Psychiatric disturbances ```

Question 30

Huntington's pharmacological management

Answer 30

Vesicular amine transporter inhibitor- tetrabenazine Antidopaminergic drugs- haloperidol, olanzapine Antidepressant drugs- imipramine, amitriptyline