Parkinson's disease (PB) Flashcards

1
Q

steps of conversion of tyrosine to adrenaline

A
tyrosine
L-DOPA
dopamine
noradrenaline
adrenaline
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2
Q

DA receptor families and subtypes

A

D1 receptor family -> excitatory, inc cAMP and Ca

  • D1
  • D5

D2 receptor family -> inhibitory, dec cAMP and Ca

  • D2
  • D3
  • D4
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3
Q

What type of disorder is Parkinsons?

A

degenerative

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4
Q

What causes Parkinsons (basic)?

A

degeneration of dopamine secreting nerve cells

excess free radicals causes degeneration of neurons

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5
Q

What are Lewy bodies?

A

cytoplasmic inclusions in surviving neurons

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6
Q

mechanisms that cause neuron cell death

A

environmental toxins, aging, neuronal metabolism

  • > free radical formation, oxidative stress, excitotoxicity, vulnerable neurons
  • > DNA damage, lipid peroxidation, protein damage
  • > cell death
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7
Q

symptoms of Parkinson’s

A

motor sympyoms (TRAP)

  • tremor
  • rigidity
  • akinesia
  • postural instability

non-motor symptoms

  • neuropsychiatric
  • sleep disturbances
  • autonomic disturbances
  • sensory disturbances
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8
Q

risk factors for Parkinson’s

A

non-smokers, low caffeine drinkers

genetic mutations in gene LRRK-2

mutations in parkin gene

neuroleptic drugs

antiemetics (prochloperazine, metoclopramide)

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9
Q

Where is DA produced?

A

substantia nigra within the basal ganglia

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10
Q

role of basal ganglia

A

co-ordinate performance of well-learnt, voluntary, semi-automatic motor skills and movement sequences

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11
Q

roles of DA

A

cognitive tasks

  • maintaining attention
  • switching focus of attention
  • mood
  • problem solving
  • decision making
  • visual perception
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12
Q

What does progressive denegeration of DA producing neurons lead to formation of?

A

Lewy bodies

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13
Q

When are clinical signs of disease evident?

A

when 80% of DA producing neurons are lost

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14
Q

dopamine acetylcholine balance

A

DA neurons in substantia nigra and corpus striatum

striatum also rich in excitatory ACh neurons that counteract the action of DA

DA ergic system inhibits the ACh system

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15
Q

UK Brain bank disgnostic criteria for PD

A

step 1: diagnosis
- bradykinesa and one of: rest tremor, rigidity, postural instability

step 2: exclusion criteria

  • Hx of repeated strokes, neuroleptic meds, head injury, definite encephalitis
  • presence of atypical features: early falls, supranuclear gaze palsy, ataxia and cerebellar features, early autonomic features, early cognitive decline, poor response to L-dopa

step 3: supportive slinical features (at least 3)
- unilateral onset, rest tremor, evidence of progression, persistent asymmetry, response to L-dopa, L-dopa induced dyskinesias, L-dopa response for 5+yrs, clinical course of 10+yrs

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16
Q

diagnosis of PD

A

based on TRAP (motor symptoms)

can get MRI/CT brain scans

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17
Q

referral time if PD is suspected

A

not >6 weeks normal cases

not >2 weeks in severe/complex cases

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18
Q

differential diagnosis for tremor disorders

A
psychological tremor - anxiety, thyrotoxicosis, fine tremor
essential tremor
dystonic tremor
cerebellar disorders
vascular parkinsonism
drug induced parkinsonism
atypical parkinsonism disorders
dementia with Lewy bodies
functional (non organic)
normal pressure hydrocephalus
others
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19
Q

2 drug types for PD

A
  1. drugs that restore DA levels in nigro striatal DAergic tract
  2. drugs that restore the DA-ACh balance
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20
Q

DA in nigro striatal tract drugs

A
levodopa and carbidopa/benserazide
DA agonists
MAO-B inhibitors
COMT inhibitors
miscellaenous (amantadine)
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21
Q

drugs for DA/ACh balance

A

antimuscarinic

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22
Q

2 brand/generics of L-dopa

A

Madopar - co-beneldopa

Sinemet - co-careldopa

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23
Q

drugs in Madopar (co-beneldopa)

A

L-dopa + benserazide

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24
Q

drugs in Sinemet (co-careldopa)

A

L-dopa + carbidopa

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25
Q

formulations of Madopar

A

capsules
dispersible tabs
CR capsules

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26
Q

What drug has the highest conc in Madopar/Sinemet?

A

levodopa is the higher strength

eg. Madopar 62.5mg caps = levodopa 50mg and benserazide 12.5mg

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27
Q

What is duodopa?

A

intestinal gel with 20mg/ml levodopa and 5mg/ml carbidopa

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28
Q

examples of dopamine agonists

A
bromocriptine
carbergoline
pergolide
pramiprexole
ropinrole - Requip
rotigotine- Neupro
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29
Q

subcutaneous DA preparation

A

apomorphine - APO-go

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30
Q

MAO-B inhibitor

A

selegiline

resagiline

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31
Q

COMT inhibitors

A

entacapone
tolcapone
L-dopa/carbidopa/entacapone - Stalevo

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32
Q

antimuscarinics

A

trihexyphenidyl
orphenadrine
procyclodine- Kemadrin

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33
Q

miscellaneous

A

amantadine

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34
Q

most effective med for Parkinsons

A

levodopa

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35
Q

standard release preparations of levodopa

A

levodope/carbidopa - Sinemet

levodopa/benserazide - Madopar

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36
Q

prolonged release preps of levodopa

A

levodopa/carbidope - Simemet CR

levodopa/benserazide - Madopar CR

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37
Q

How are therapeutic/adverse effects got from levodopa?

A

from its decarboxylation to DA

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38
Q

What prevents peripheral breakdown of levodopa?

A

given with peripheral decarboxylase inhibitor to prevent peripheral break down

  • carbidopa
  • benserazide

smaller dose of levodopa needed to treat symptoms then

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39
Q

What reduces N&V s/e of levodopa?

A

given with DOPA decarboxylase inhibitor

  • carbidopa, benserazide
40
Q

s/e of levodopa if given on own

A

N&V
cardiac arrhythmias
hypotension

41
Q

How do DOPA decarboxylase inhibitors work?

A

dec levodopa metabolism in peripheral tissues and metabolism in GIT

decarboxylation of levodopa doesn’t occur

more can cross BBB

-> fewer undesirable s/e

42
Q

Why does evodope have s/e when given alone?

A

it is metabolised in peripheral tissue and GIT to give s/e

43
Q

When are best results obtained from levodopa?

A

in 1st few years

44
Q

What impoevements are seen from using levodopa?

A

improvement in muscle rigidity and bradykinesia

normal motor functions

45
Q

Why does levodopa become less effective over time?

A

progressive loss of dopaminergic neurons

down regulation of D1/D2 R on post synaptic terminals

(some patients require reduced doses of levodopa to prevent s/e but inc frequency)

46
Q

dyskinesia

A

excessive and abnormal involuntary movements

47
Q

main s/e with levodopa especially on LT Tx

A

dyskinesia

dose related - higher dose = inc risk

48
Q

What Parkinson’s patients does dyskinesia occur more in?

A

younger patients

49
Q

'’on-off’’ effect with levodopa

A
  • fluctuations in clinical response
  • on = improved mobility but marked dyskinesia
  • off = marked akinesia, absense/loss of power of voluntary movement
  • reated to fluctuations in levodopa plasma concs
  • fluctuations smoothened out by adding DA R agonist
50
Q

s/e of levodopa

A
  • GI disturbances - anorexia, N&V
  • dry mouth
  • postural hypotension
  • drowsiness, sudden onset of sleep
  • dystonia (invol contraction of muscles)
  • dyskinesia
  • chorea (invol movements)
  • neuropsychiatric symptoms - hallucinations, confusion, abnormal dreams, insomnia
51
Q

amtiemetic for N&V from levodopa

A

domperidone

52
Q

what patients is levodopa c/i in

A

psychosis

53
Q

PK of levodopa

A

well absorbed on oral admin

54
Q

How to take levodopa

A

take on empty stomach 45mins before meal

foods inhibit absorption from gut and its transport into CNS

55
Q

interactions with levodopa

A
  • inc risk postural hypotension with antihypertensive drugs
  • risk of hypertensive crisus due to inc catecholamines with MAOIs
  • pyridoxine (vit B6) inc peripheral breakdown of L-dopa
56
Q

Uses of DA receptor agonists

A
individual drugs
OR
in combination with levodopa/anticholinergic drugs
OR
patients who can't tolerate levodopa
57
Q

How does bromocriptine work?

A

selective D2 receptor agonist and partial agonist at D1 receptors

58
Q

Howdoes pergolide mesylate work?

A

directly stimulates both D1 and D2 receptors

59
Q

s/e with DA receprot agonists

A

associated with cardiac valve fibrosis

loses efficacy over time

60
Q

s/e of DA receptor agonists

A

GI disturbances - anorexia, N&V
cardiac arrhythmias
postural hypotension
drowsiness and sudden onset of sleep
dyskinesia
neuropsychoatric symptoms - hallucination, confusion, abnormal dreams, insomnia
pulmonary infiltrates and erythromelagia - Ergot related effects
impulse control disorder - pathological gambling

61
Q

2 classes of DA R agonists

A
  1. ergot alkaloids - bromocriptine, pergolide

2. non-ergot alkaloids - ropinirole, pramipexole, rotigotine

62
Q

Where fo ropinirole and pramipexole work (non-ergot alkaloid DA R agonists)?

A

affinity for D2 sub classes especially at D2 and D3 receptors

63
Q

advantage of pramipexole

A

neuroprotective - scavenges H2O2

64
Q

rotigotine (DA R agonist)

A
  • agonist at all 5 DA receptors
  • used to treat signs/symptoms of early PD
  • admin as once daily transdermal patch
  • gives even PK for 24 hrs
65
Q

advantages of Rotigotine

A

patch

  • good if compliance is an issue
  • oral route unavailable
66
Q

s/e of non-ergot alkaloid DA R agonists

A

GI - N&V
sleepiness and fatigue
marked hypotension
drowsiness, sudden onset of sleep, excessive daytime sleeping
dyskinesia
neuropsychiatric symptoms - hallucinations, confusion, abnormal dreams, insomnia

67
Q

Apomorphine

A

potent DA agonist

high affinity for D4 R

moderate affinity for D2, 3, 5 and some alpha R

low affinity for D1

via SC injection to give temp relief of ‘‘off’’ periods of akinesia, pre-filled pins

short effectiveness - 2hrs

for severe, advances PD, symptoms not controlled

68
Q

s/e with apomorphine

A
  • highly emetogenis, needs pre/post anti-emetics
  • same s/e as other DA agonists
  • prolongs QT interval
  • injection site reaction
  • abuse characteristics, inc dosing - hallucination, dyskineais, abnormal behaviour
69
Q

2 types of MAO

A

MAO-A - metabolises NA and 5-HT

MAO-B - metabolises DA

70
Q

examples of MAOIs

A

selegiline

rasagiline

71
Q

How do MAOIs work?

A

selective, irreversible inhibition of MAO-B

prevent breakdown of natural DA and DA from levodopa

-> inc DA levels in brain

doesn’t inhibit MAO-B

72
Q

What is seligeline metabolised to?

A

methamphetamine and amphetamine

73
Q

When are MAOIs effective?

A

in early PD

- monotherapy or in combination with levodopa

74
Q

How are MAOIs beneficial?

A

enables reduction in levodopa dose or smoothes the ‘‘on-off’’ fluctuations associated with levodopa

metabolite is neuroprotective - desmethylselegiline

75
Q

s/e of MAOIs

A
  • selectivity for brain MAO-B makes selegiline less likely to porcude ADRs involving peripheral tyramine (wine, cheese, chopped liver syndrome)
  • blocks MAO-A at high doses - hypertensive crisis due to peripheral accumulation of NA
  • fatal hyperthermia - can occur when given with meperidine/cocaine/fluoxetine
76
Q

What does COMT stand for?

A

catechol-O-methyltransferase

77
Q

examples of COMT inhibitors

A

tolcapone

entacapone

opicapone

78
Q

How do COMT inhibitors work?

A

inhibit peripheral metabolism of levodopa

may also reduce ‘‘on-off’’ fluctuations

79
Q

PK of COMT inhibitors

A

oral absorption not influenced by food

extensively bound to plasma albumin (98%)

extensively metabolised and eliminated in faeces/urine

80
Q

s/e with COMT inhibitors

A
  • related to inc plasma concs of levodopa
  • dyskinesia, nausea, confusion
  • diarrhoea, abdominal pain
  • orthostatic hypotension
  • sleep disorders
  • orange urine discolouration
  • tolcapine - potentially hepatotoxic
81
Q

dose of rasagiline and selegiline (COMT inhibitors)

A

rasagiline 1mg daily

selegiline 5mg daily

-> inc to 10mg after 2-4 weeks

82
Q

dose of entacapone

A

initially 200mg with each dose of levodopa with dopa-decarboxylase inhibitor

max 2g daily

83
Q

dose of tolcapone

A

tolcapone 100mg TDS (min gap 6hrs)

max dose 200mg TDS

first dose taken with levodopa and dopa-decarb inh

tolcapone only continued if substantial improvement seen after 3 weeks

84
Q

When are anticholinergics used?

A

before the introduction of levodopa

85
Q

MOA of anticholinergics

A

dec activity of Ach

86
Q

use of anticholinergics for PD

A

secondary adjuvant meds

help control tremors in early stages of disease

not used in idiopathic PD - less effective than DA drugs and could cause cognitive impairment

87
Q

s/e of anticholinergics

A
constipation
blurred vision
dry mouth
urinary retention
neuropsychiatric symptoms - memory loss, confusion, hallucinations
88
Q

Can anticholinergics be used LT?

A

NO

because of their s/e

89
Q

What type of drug is Amantadine?

A

antiviral drug

used for Tx of influenza A

90
Q

MOA of amantadine

A

inc DA release in striatum

has anticholinergic activity

blocks NMDA glutamate R

91
Q

benefits/limitations of amantadine

A

less efficacy but less s/e than levodopa

little effect on tremor but more effective than anticholinergics against rigidity and bradykinesia

92
Q

s/e of amantadine

A
difficulty concentrating
confusion
insomnia
nightmares
agitation
hallucinatons
leg swelling
dermatological rxns - Livedo reticularis (red/blue skin, worsens when cold)
93
Q

When is amantadine used

A

late stage PD

if pt has problems with dysinesia induced by levodopa

94
Q

Tx regimen for young PD pt

A

MAOI - rasagaline, selegiline
or
DA agonist (non-ergot)

THEN

L-dopa
COMT inhibitor

IF DYSKINESIA - reduce L-dopa and add amantadine

SEVERE MOTOR FLUCTUATIONS - SC apomorphine/duodopa

95
Q

Tx regimen for old/frial PD pt

A

L-dopa

THEN

MAOI
COMT inhibitor

IF DYSKINESIA - reduce L-dopa and add amantadine

SEVERE MOTOR FLUCTUATIONS - SC apomorphine/duodopa