Parkinson's disease (PB) Flashcards
1
Q
steps of conversion of tyrosine to adrenaline
A
tyrosine L-DOPA dopamine noradrenaline adrenaline
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
3
Q
What type of disorder is Parkinsons?
A
degenerative
4
Q
What causes Parkinsons (basic)?
A
degeneration of dopamine secreting nerve cells
excess free radicals causes degeneration of neurons
5
Q
What are Lewy bodies?
A
cytoplasmic inclusions in surviving neurons
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
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
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)
9
Q
Where is DA produced?
A
substantia nigra within the basal ganglia
10
Q
role of basal ganglia
A
co-ordinate performance of well-learnt, voluntary, semi-automatic motor skills and movement sequences
11
Q
roles of DA
A
cognitive tasks
- maintaining attention
- switching focus of attention
- mood
- problem solving
- decision making
- visual perception
12
Q
What does progressive denegeration of DA producing neurons lead to formation of?
A
Lewy bodies
13
Q
When are clinical signs of disease evident?
A
when 80% of DA producing neurons are lost
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
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
16
Q
diagnosis of PD
A
based on TRAP (motor symptoms)
can get MRI/CT brain scans
17
Q
referral time if PD is suspected
A
not >6 weeks normal cases
not >2 weeks in severe/complex cases
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
19
Q
2 drug types for PD
A
- drugs that restore DA levels in nigro striatal DAergic tract
- drugs that restore the DA-ACh balance
20
Q
DA in nigro striatal tract drugs
A
levodopa and carbidopa/benserazide DA agonists MAO-B inhibitors COMT inhibitors miscellaenous (amantadine)
21
Q
drugs for DA/ACh balance
A
antimuscarinic
22
Q
2 brand/generics of L-dopa
A
Madopar - co-beneldopa
Sinemet - co-careldopa
23
Q
drugs in Madopar (co-beneldopa)
A
L-dopa + benserazide
24
Q
drugs in Sinemet (co-careldopa)
A
L-dopa + carbidopa
25
formulations of Madopar
capsules
dispersible tabs
CR capsules
26
What drug has the highest conc in Madopar/Sinemet?
levodopa is the higher strength
eg. Madopar 62.5mg caps = levodopa 50mg and benserazide 12.5mg
27
What is duodopa?
intestinal gel with 20mg/ml levodopa and 5mg/ml carbidopa
28
examples of dopamine agonists
```
bromocriptine
carbergoline
pergolide
pramiprexole
ropinrole - Requip
rotigotine- Neupro
```
29
subcutaneous DA preparation
apomorphine - APO-go
30
MAO-B inhibitor
selegiline
resagiline
31
COMT inhibitors
entacapone
tolcapone
L-dopa/carbidopa/entacapone - Stalevo
32
antimuscarinics
trihexyphenidyl
orphenadrine
procyclodine- Kemadrin
33
miscellaneous
amantadine
34
most effective med for Parkinsons
levodopa
35
standard release preparations of levodopa
levodope/carbidopa - Sinemet
levodopa/benserazide - Madopar
36
prolonged release preps of levodopa
levodopa/carbidope - Simemet CR
levodopa/benserazide - Madopar CR
37
How are therapeutic/adverse effects got from levodopa?
from its decarboxylation to DA
38
What prevents peripheral breakdown of levodopa?
given with peripheral decarboxylase inhibitor to prevent peripheral break down
- carbidopa
- benserazide
smaller dose of levodopa needed to treat symptoms then
39
What reduces N&V s/e of levodopa?
given with DOPA decarboxylase inhibitor
- carbidopa, benserazide
40
s/e of levodopa if given on own
N&V
cardiac arrhythmias
hypotension
41
How do DOPA decarboxylase inhibitors work?
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
Why does evodope have s/e when given alone?
it is metabolised in peripheral tissue and GIT to give s/e
43
When are best results obtained from levodopa?
in 1st few years
44
What impoevements are seen from using levodopa?
improvement in muscle rigidity and bradykinesia
normal motor functions
45
Why does levodopa become less effective over time?
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
dyskinesia
excessive and abnormal involuntary movements
47
main s/e with levodopa especially on LT Tx
dyskinesia
dose related - higher dose = inc risk
48
What Parkinson's patients does dyskinesia occur more in?
younger patients
49
''on-off'' effect with levodopa
- 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
s/e of levodopa
- 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
amtiemetic for N&V from levodopa
domperidone
52
what patients is levodopa c/i in
psychosis
53
PK of levodopa
well absorbed on oral admin
54
How to take levodopa
take on empty stomach 45mins before meal
foods inhibit absorption from gut and its transport into CNS
55
interactions with levodopa
- 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
Uses of DA receptor agonists
```
individual drugs
OR
in combination with levodopa/anticholinergic drugs
OR
patients who can't tolerate levodopa
```
57
How does bromocriptine work?
selective D2 receptor agonist and partial agonist at D1 receptors
58
Howdoes pergolide mesylate work?
directly stimulates both D1 and D2 receptors
59
s/e with DA receprot agonists
associated with cardiac valve fibrosis
loses efficacy over time
60
s/e of DA receptor agonists
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
2 classes of DA R agonists
1. ergot alkaloids - bromocriptine, pergolide
| 2. non-ergot alkaloids - ropinirole, pramipexole, rotigotine
62
Where fo ropinirole and pramipexole work (non-ergot alkaloid DA R agonists)?
affinity for D2 sub classes especially at D2 and D3 receptors
63
advantage of pramipexole
neuroprotective - scavenges H2O2
64
rotigotine (DA R agonist)
- 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
advantages of Rotigotine
patch
- good if compliance is an issue
- oral route unavailable
66
s/e of non-ergot alkaloid DA R agonists
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
Apomorphine
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
s/e with apomorphine
- 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
2 types of MAO
MAO-A - metabolises NA and 5-HT
MAO-B - metabolises DA
70
examples of MAOIs
selegiline
rasagiline
71
How do MAOIs work?
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
What is seligeline metabolised to?
methamphetamine and amphetamine
73
When are MAOIs effective?
in early PD
| - monotherapy or in combination with levodopa
74
How are MAOIs beneficial?
enables reduction in levodopa dose or smoothes the ''on-off'' fluctuations associated with levodopa
metabolite is neuroprotective - desmethylselegiline
75
s/e of MAOIs
- 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
What does COMT stand for?
catechol-O-methyltransferase
77
examples of COMT inhibitors
tolcapone
entacapone
opicapone
78
How do COMT inhibitors work?
inhibit peripheral metabolism of levodopa
may also reduce ''on-off'' fluctuations
79
PK of COMT inhibitors
oral absorption not influenced by food
extensively bound to plasma albumin (98%)
extensively metabolised and eliminated in faeces/urine
80
s/e with COMT inhibitors
- related to inc plasma concs of levodopa
- dyskinesia, nausea, confusion
- diarrhoea, abdominal pain
- orthostatic hypotension
- sleep disorders
- orange urine discolouration
- tolcapine - potentially hepatotoxic
81
dose of rasagiline and selegiline (COMT inhibitors)
rasagiline 1mg daily
selegiline 5mg daily
-> inc to 10mg after 2-4 weeks
82
dose of entacapone
initially 200mg with each dose of levodopa with dopa-decarboxylase inhibitor
max 2g daily
83
dose of tolcapone
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
When are anticholinergics used?
before the introduction of levodopa
85
MOA of anticholinergics
dec activity of Ach
86
use of anticholinergics for PD
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
s/e of anticholinergics
```
constipation
blurred vision
dry mouth
urinary retention
neuropsychiatric symptoms - memory loss, confusion, hallucinations
```
88
Can anticholinergics be used LT?
NO
because of their s/e
89
What type of drug is Amantadine?
antiviral drug
used for Tx of influenza A
90
MOA of amantadine
inc DA release in striatum
has anticholinergic activity
blocks NMDA glutamate R
91
benefits/limitations of amantadine
less efficacy but less s/e than levodopa
little effect on tremor but more effective than anticholinergics against rigidity and bradykinesia
92
s/e of amantadine
```
difficulty concentrating
confusion
insomnia
nightmares
agitation
hallucinatons
leg swelling
dermatological rxns - Livedo reticularis (red/blue skin, worsens when cold)
```
93
When is amantadine used
late stage PD
if pt has problems with dysinesia induced by levodopa
94
Tx regimen for young PD pt
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
Tx regimen for old/frial PD pt
L-dopa
THEN
MAOI
COMT inhibitor
IF DYSKINESIA - reduce L-dopa and add amantadine
SEVERE MOTOR FLUCTUATIONS - SC apomorphine/duodopa
