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b2 > pharmacology of movement > Flashcards

pharmacology of movement Flashcards

1
Q

in parkinson’s, what pathway is there a shift to?

A

indirect pathway

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2
Q

describe the pathology seen in parkinson’s?

A
  • loss of dopaminergic cells in SNPC

- presence of Lewy bodies in neurons

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3
Q

what other disease is Lewy bodies found in?

A

dementia with Lewy bodies

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4
Q

what are Lewy bodies?

A

intracellular formations enriched in the protein a-synuclein

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5
Q

what is Dopamine transporter (DaT) imaging used for?

A

used to monitor gradual dopaminergic nigral cell loss

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6
Q

what is the dopamine transporter a marker of?

A

dopaminergic projections - can be labelled with SPECT ligands

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7
Q

what are the features of parkinson’s?

A

resting tremor
bradykinesia
rigidity
frozen facial expression and flexed posture
altered gait and postural changes
difficulty in initiating and stopping movement
gradual development of micrographia

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8
Q

what is the cardinal feature of parkinson’s?

A

bradykinesia

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9
Q

what is bradykinesia?

A

slowness of movement

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10
Q

what is micrographia?

A

small writing that cannot be deciphered

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11
Q

what are non-motor features of parkinson’s?

A 
•	Hyposmia
-       Depression
•	Psychotic symptoms
•	Cognitive dysfunction
•	Dementia (late phase)
•	Sleep disturbance
•	Autonomic dysfunction
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12
Q

what is hyposmia?

A

decreased sense of smell

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13
Q

why are non-motor symptoms useful?

A

Non-motor symptoms can be used to diagnose the condition 12-15 years earlier

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14
Q

what are the main genes involved in Parkinson’s

A

SNCA

LRRK2

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15
Q

what does the SNCA gene control?

A

involves the alpha-synuclein protein

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16
Q

what type of molecule is LRRK2?

A

kinase

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17
Q

what is the most common genetic contributor to PD?

A

LRRK2

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18
Q

what factors cause an increase in prevalence of PD?

A

age

male

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19
Q

what is MPTP?

A

methyl-phenyl-tetrahydropyridine

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20
Q

what is MPTP metabolised into?

A

MPP+

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21
Q

what is the problem with MPP+?

A

neurotoxic for dopaminergic neurons

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22
Q

what dysfunction can lead to increased oxidative stress?

A

Dysfunction of complex I in mitochondrial resp chain

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23
Q

why is increased oxidative stress bad in parkinson’s?

A

• Dopamine is v oxidizable – its metabolism forms free radicals and oxidation products e.g. H2O2
- leads to more monoamine oxidase (B isoform) so there’s less dopamine available

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24
Q

describe the biosynthesis of dopamine?

A

L-tyrosine –> L-Dopa –> dopamine

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25
Q

describe the metabolism of dopamine

A

Dopamine  DOPAC via MAO + aldeyhyde dehydrogenase

DOPAC  Homovanilic acid via COMT

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26
Q

why is L-Dopa given instead of dopamine?

A
  1. Dopamine is broken down and inactivated
  2. Hydrophilic – can pass through the BBB
  3. Dopamine makes you sick in large amounts
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27
Q

why does dopamine make you sick in large amounts?

A

it stimulates dopamine receptors in the chemoreceptor trigger zone outside the BBB  induces vomiting

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28
Q

why does an L-dopa carboxylase inhibitor need to be given with L-Dopa carboxylase?

A

stops L-dopa from being peripherally converted into dopamine

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29
Q

name the dopaminergic pathways in the CNS?

A

nigrostriatal
mesocortical
mesolimbic

30
Q

where is the nigrostriatal pathway?

A

from the SNPC to the striatum

31
Q

where is the mesocortical pathway?

A

ventral tegmental area to the cingulate cortex

32
Q

where is the mesolimbic pathway?

A

ventral tegmental area to the ventral part of the striatum

33
Q

which dopaminergic pathway should be targeted by treatment?

A

nigrostriatal

34
Q

what type of receptors are dopamine receptors?

A

GPCRs

35
Q

what are the 2 main groups of dopamine receptors?

A

D1-like

D2-like

36
Q

what are the D1-like receptors?

A

D1 and D5

37
Q

what are the D2-like receptors?

A

D2, D3 and D4

38
Q

what are the main treatment methods for parkinson’s?

A
  1. Dopaminergic compounds
  2. MOAB inhibitors
  3. Anticholinergic compounds
  4. Amantadine
  5. COMT inhibitors
39
Q

how do dopaminergic compounds help in PD?

A

compensate directly for the dopamine deficit

40
Q

what is the most common dopaminergic compound given in PD?

A

L-Dopa (Levodopa)

Biosynthetic precursor

41
Q

what does L-Dopa need to be combined with?

A

a peripherally acting DOPA decarboxylase inhibitor

42
Q

name DOPA decarboxylase inhibitors

A

carbidopa

benserazide

43
Q

name dopaminergic agonists

A

ropinirole, pramipexole, rotigotine, pergolide, bromocriptine, cabergoline

44
Q

how is rotigotine administered?

A

transdermal patch

45
Q

how is apomorphine administered?

A

infusion for major motor fluctuations

46
Q

how do MAOB inhibitors work?

A

protect residual dopamine against oxidation

47
Q

name MAOB inhibitors

A

Rasagiline, selegiline

48
Q

why should anticholinergic compounds be given in PD?

A

dopamine loss leads to hyperactivity of cholinergic cells

49
Q

name anticholinergic compounds

A

Orphenadrine, procyclidine, trihexyphenidyl

50
Q

why is amantadine given in PD?

A

inhibits dopamine reuptake

increases dopamine release

51
Q

why are COMT inhibitors given in PD?

A

used in combination with L-Dopa to enhance its effects

52
Q

name COMT inhibitors

A

Entacapone, tolcapone

53
Q

list adverse effects of L-Dopa

A
  • Nausea/vomiting
  • Postural hypotension
  • Psychosis
  • Impulse-control disorders
  • Excessive day-time sleepiness
54
Q

what are the motor complications of L-Dopa?

A
  • on-off effect
  • wearing off
  • dyskinesia
  • dystonia
55
Q

what is the on off effect?

A

unpredictable mobility associated with regular intake of L-DOPA

56
Q

what is dyskinesia?

A

uncontrollable involuntary movement

57
Q

what is dystonia?

A

muscles contracting uncontrollably

58
Q

what should PD patients have access to?

A

o monitoring and alteration of medication
o a continuing point of contact
o a reliable source of information

Physiotherapy, speech and language therapy and occupational therapy should be available

59
Q

what are other treatment approaches to PD other than pharmacological treatments?

A
  • human embryonic mesencephalic graft - graft releases dopamine after metamphetamine is given
  • surgical approach
60
Q

what surgical approaches are there to PD?

A
  • stimulation of subthalamic nucleus
  • pallidotomy
  • thalamotomy
  • deep brain stimulation
61
Q

what is a thalamotomy?

A

destruction of part of the thalamus to fix a tremor

62
Q

when is deep brain stimulation used?

A

used in people with advanced PD whose symptoms aren’t controlled by pharmacology therapy

63
Q

what is Huntington’s chorea?

A

involuntary jerky movements

64
Q

what pathology causes Huntington’s?

A

Major degeneration of striatal neurons and cortical atrophy

loss of medium spiny neurons (striato-pallidal and striato-nigral pathways)

65
Q

how is huntington’s inherited?

A

autosomal dominant

66
Q

what gene is affected in huntington’s and what chromosome is this found on?

A

huntingtin gene on chromosome 4

67
Q

how does the affected gene in Huntington’s present?

A

o Genes presents w abnormal number of repeats of glutamine (CAG codon) in the protein sequence – gain of function mutation
- mutated protein aggregates inside cells

68
Q

what are the mechanisms underlying neurodegeneration in huntington’s disease?

A
  • Excitotoxicity
  • Loss of neurotrophic factors
  • Accumulation of aggregates of mutant huntingtin protein
  • Dysregulation of transcription
  • Increased oxidative stress
  • Abnormalities in axonal transport
  • Synaptic abnormalities
69
Q

what are symptoms of HD?

A
  • Choreic movement (early to mid-stage disease)
  • Gait abnormalities
  • Lack of coordination
  • Cognitive impairment: poor attention, memory difficulties
  • Psychiatric disturbances
  • Sleep disturbance
  • Weight loss
70
Q

how long does HD take to progress from onset?

A

12-15 years

71
Q

what is the pharmacological treatment for HD?

A

no treatment - mainly palliative and symptomatic
o Tetrabenazine: inhibitor of vesicular amine transporter
o Haloperidol, Olanzapine: antidopaminergic/antipsychotic drugs
o Imipramine, Amitriptyline: antidepressant drugs.

b2 (5 decks)

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