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parkinson's disease Flashcards

1
Q

what is parkinsonism

A

symptoms similar to PD but have secondary causes

  • drug/toxin - induced
  • vascular (stroke)
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2
Q

possible causes of PD

A

1) age related loss of neurons
2) environmental toxins/insults

  • MPTP-MPP+
  • pesticides, herbicides

3) genetics

  • predispositions to toxins/insults
  • genetic abnormalities
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3
Q

pathophysiology of PD

A
  • failure to clear abnormal/damaged proteins by ubiquitin/proteasome system -> accumulation of misfolded alpha-synuclein -> formation and accumulation of Lewy body (Aggresomes) inside neurons
  • lewy body mediate functional mitochondria failure -> neuron damage and apoptosis - loss of dopaminergic neurons in substantia nigra
  • long term overexpression of alpha-syn (and neuron apoptosis) -> decrease DA neurotransmission -> motor symptoms
  • neuroinflammation -> activation of microglia -> further neuroinflammation and neurodegeneration -> disease progression
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4
Q

clinical presentation of PD - 4 characteristics features

A

TRAP

  • tremor: resting tremor that increases w stress, not caused by events
  • rigidity: muscular rigidity, cogwheel rigidity
  • akinesia: slowness of movement, sense of weakness, loss of dexterity, loss of facial expression, reduced blinking
  • postural instability
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5
Q

PD clinical presentation - initial presentation

A

asymmetric, +ve response to levodopa/apomorphine, sometimes impaired sense of smell

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6
Q

PD clinical presentation as disease progress

A
  • unable to perform basic ADL
  • choking, pneumonia, falls
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7
Q

PD clinical presentation - non motor symptoms

A
  • dementia, depression, psychosis, sleep disorder
  • constipation, GI motility
  • orthostatic hypotension, sialorrhea (drool cuz X swallow)
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8
Q

PD disease progression timeline

A

20 year prodrome

    • 20 yr: constipation, bladder problem
  • -10 yr: sleep disorder, obesity, depression

20 year disease stage

  • I: unilateral TRA
  • II: bilateral
  • III: poor balance
  • IV: falls, dependency, cognitive decline
  • V: chair/bed bound, dementia
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9
Q

classifications of PD

A

1) juvenile - onet PD < 20 yo

  • higher freq of genetically inherited PD

2) early/young onset PD < 40 yo

  • slower disease progression
  • lesser cognitive decline
  • earlier motor complication
  • initial presentation: dystonia
  • use dopamine agonist instead of levodopa
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10
Q

diagnosis of PD

A

1) 2/3 of cardinal signs present (TRAP)
2) neuroimaging

  • MRI for differential diagnosis of other parkinsonism symptoms
  • DAT: differentiate essential tremor and other non-dopamine deficiency aetiologies
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11
Q

measuring of PD disease progression

A

UPDRS

1) non-motor experience of daily living

  • intellectual impairment, depression

2) motor experiences of daily living

  • speech, salivation, swallowing, dressing, hygiene, walking

3) motor examination

  • facial expression, tremor at rest, gait

4) motor complication

  • dyskinesia, clinical fluctuations
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12
Q

general approach to PD treatment

A

1) increase central dopamine and dopaminergic transmission

  • inhibit peripheral conversion of levodopa to dopamine by DOPA-decarboxylase, MAO-B and COM-T then inhibit central conversion of dopamine to homovanillic acid by MAO-B and COM-T

2) correct imbalance in other pathways

  • anticholinergics, NMDA antagonist
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13
Q

non pharmaco for PD

A

1) med review

  • correct levodopa preparations (IR vs CR, sinemet 1:10 vs 1:4)
  • DDI, comorb, timing of administration

2) physiotherapy
3) occupational therapy
4) speech therapy
5) deep brain stimulation (DBS) for advanced PD

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14
Q

types of pharmacological treatment

A

1) levodopa
2) dopamine agonist
3) MAO-B inhibitors
4) catechol-O-methyl transferase inhibitors
5) anticholinergics
6) NMDA antagonist

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15
Q

indication of levodopa

A

1) try to give others first to minimise motor complications unless cannot be controlled or + other agents so can lower dose of levodopa
2) most effective for treating bradykinesia and rigidity, not so for speech, postural reflex and gait disturbances

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16
Q

levodopa MOA

A
  • increase dopamine synthesis
  • synthetic L-dopa that is converted into dopamine by DOPA decarboxylase, MAO-B, COM-T
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17
Q

DCI (benserazide) for levodopa

A
  • peripheral DOPA-decarboxylase inhibitor to prevent systemic SE from excess DA
  • only L-dopa can cross BBB, dopamine can’t
  • if levodopa converted into dopamine in periphery then can’t cross BBB to take effect
  • so give DCI to ensure levodopa cross BBB then can converted into dopamine to take effect
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18
Q

levodopa formulations

A

1) CR

  • useful for reducing stiffness on waking
  • X rush tablets (sinemet) or open capsule (madopar)

2) dose adjustment required for switching between IR and CR

  • IR -> CR: increase dose by 25 - 50%
  • CR -> IR: reduce dose
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19
Q

levodopa PK

A
  • absorbed in proximal part of small intestines
  • low F but increased w DCI
  • decreased absorption with high fat/protein meal so need to space apart administration from heavy meals
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20
Q

levodopa AE - tldr

A

1) peripheral effects
2) central effects
3) motor effects

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21
Q

levodopa - peripheral effects

A

N/V, orthostatic hypotension

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22
Q

levodopa - central effects

A

hallucination, psychosis, drowsiness, sudden sleep onset

23
Q

levodopa - motor effects

A

1) “on-off” phenomenon

  • switch between response and no response to levodopa
  • usual unpredictable and unrelated to dose/dosing interval

2) “wearing off”

  • effect of levodopa can wear off before end of dosing interval -> shortened response
  • associated with disease progression
  • management: modify administration time or give CR formulation

3) dyskinesia

  • irreversible
  • usual onset within 3 - 5 years of initiation
  • involuntary, uncontrolled twitching/jerking
  • peak dose dyskinesia and dystonia
  • management
    ** reduce dose if peak dose dyskinesia
    ** replace specific doses w modified release
    ** Add amantadine
24
Q

response to levodopa vs progression

A
  • as disease progress there will be more “off” phases so need to increase dose but might have peak dose dyskinesia
25
Q

levodopa DDI

A

1) pyridoxine

  • cofactor for DOPA-decarboxylase
  • increase decarboxylase activity = decrease levodopa bioavailability
  • technically not a problem if give with DCI but possible interactions if
    ** high B6 for haematological problem
    ** high potency Vit B complex tablets

2) iron, protein (food or powder)

  • affect absorption of levodopa so need to space administration apart

3) dopamine antagonist

  • antiemetic (metoclopramide, prochlorperazine) -> use domperidone instead
  • 1st gen antipsychotics
  • risperidone

4) dopamine agonist

  • additive effects
  • ergot derivatives (bromocriptine)
  • non-ergot derivatives (ropinirole, pramipexole, rotigotine, apomorphine)
26
Q

types of dopamine agonist used

A

ropinirole, pramipexole

27
Q

indication for dopamine agonist

A

1) monotherapy in young onset PD
2) adjunct to levodopa in mod/severe PD
3) management of motor complications in PD

28
Q

MOA of dopamine agonist

A

act on dopamine (d2) receptors in basal ganglia, mimic action of dopamine

29
Q

PK of dopamine agonist

A

1) absorption

  • ergot derivatives lower F than non-ergot derivatives cuz extensive first pass
  • longer t1/2 and duration of action than levodopa

2) ropinirole

  • metabolised by liver -> inactive metabolites
  • titrate w caution for liver impairment

3) pramipexole

  • excreted largely unchanged in urine
  • titrate for renal impairment
30
Q

dopamine agonist AE

A

1) peripheral

  • N/V, orthostatic hypotension, leg oedema

2) central

  • hallucination (visual > auditory)
  • somnolence, day-time sleepiness
  • compulsive behaviour

3) non-dopaminergic

  • fibrosis
    ** pulmonary, pericardiac, retro-peritoneal
    ** partially reversible upon withdrawal
    ** more for ergot derivatives
  • valvular heart disease
    ** more for ergot derivatives
  • management
    ** give apomorphine/rotigotine
31
Q

comparison of dopamine agonist with levodopa

A
  • lesser motor complications
  • more hallucinations, sleep disturbances, leg oedema, orthostatic hypotension
  • no difference in efficacy
  • preferred for younger patients to maximise treatment options and delay onset of levodopa induced motor complications
32
Q

types of MAO-B inhibitors

A

selegiline, rasagiline

33
Q

indication for MAO-B inhibitors

A

monotherapy in early stages esp young onset PD, adjunct in later stages

34
Q

MOA for MAO-B inhibitors

A
  • irreversible
  • inhibit MAO-B from catalysing dopamine to homovanillic acid
35
Q

PK of MAO-B inhibitors

A
  • short t1/2 but long duration of action
  • selegiline hepatically metabolised to amphetamines
    ** stimulating so if BD patient need to take 2nd dose in late afternoon to prevent insomnia
    ** no effect on MAO-B
36
Q

SE of MAO-B inhibtiors

A
  • heartburn, loss of appetite
  • anxiety, palpitation, insomnia
  • nightmare, visual hallucination
37
Q

interactions with MAO-B inhibitors

A

drugs

1) SSRI, SNRI, TCAS (serotonergic syndrome, need washout period)
2) pethidine, tramadol
3) linezolid
4) dextromethorphan
5) dopamine, sympathomimetics, another MAOI

food: tyramine

  • cheese effect
  • sympathomimetic effect -> acute HTN w throbbing headache
  • avoid preserved food and aged food if possible
38
Q

types of catechol-O-methyltransferase inhibitors

A

entacapone

39
Q

indication for entacapone

A
  • only adjunct with levodopa + DCI (must be taken at the same time as levodopa)
  • not effective as monotherapy cuz minimal entry into CNS
  • avoid in hepatic impairment
40
Q

entacapone MOA

A
  • selectively and reversibly inhibit COM-T from catalysing dopamine to homovanillic acid -> more levodopa available to enter brain (need dose reduction of levodopa)
41
Q

entacapone SE

A
  • diarrhoea
  • urine discolouration
  • dyskinesia at initiation (need to lower dose)
  • worsen dopaminergic effect (orthostatic hypotension, N/V)
42
Q

entacapone drug interactions

A

1) Fe, Ca
2) avoid concurrent with non-selective MAOi (can give MAO-B selective, caution for MAO-A)
3) any catecholamine drug
4) enhance anticoagulant effect of warfarin

43
Q

types of anticholinergics

A

trihexyphenidyl

44
Q

anticholinergics general

A
  • only used to control tremor if tremor-predominant symptoms
  • anticholinergics SE
  • peripheral acting agents effective for sialorrhea
45
Q

NMDA antagonist - effects of glutamate

A
  • activation of processes that encourage apoptosis of dopaminergic neurons
  • development and maintenance of levodopa induced dyskinesia
46
Q

types of NMDA antagonist

A

amantadine

47
Q

MOA of NMDA antagonist

A
  • inhibit NMDA receptor from being activated by glutamate
  • anticholinergic
  • upregulate/increase sensitivity of dopamine D2 receptors
  • enhanced release of stored dopamine
48
Q

PK of NMDA antagonist

A
  • renally excreted (reduce dose if renal impairment)
  • can be stimulating (2nd dose given afternoon not night)
49
Q

NMDA antagonist SE

A
  • N/V, lightheaded, insomnia, cognitive impairment, hallucination, nightmare
  • livedo reticularis (venule swelling due to thrombosis -> mottled reticulated discolouration of limbs)
50
Q

alternative medications for PD

A

1) safe but not effective: co-enzyme Q-10, creatine
2) others: Vit E, glutathione, riboflavin, lipoic acid, acetyl carnitine, curcumin

51
Q

general drug induced PD

A
  • bilateral symptoms
  • subacute/acute
  • mostly reversible (withdrawal lead to improvement in 8 wks)
  • variable onset, 3 months within exposure to offending agents
  • more common in elderly cuz polypharmacy
  • can use anticholinergics/amantadine
52
Q

high risk drugs for drug induced PD

A

1) dopamine D2 receptor blockers (FGA, SGA)
2) dopamine depleters (tetrabenazine, reserpine)
3) dopamine synthesis blockers (methyldopa)
4) calcium channel antagonist (flunarizine, cinnarizine)

53
Q

intermediate risk for drug induced PD

A

1) ziprasidone
2) calcium channel antagonist (diltiazem, verapamil)
3) antiepileptics (valproate, phenytoin, levetiracetam)
4) antiemetic and gastric motility agents (prochlorperazine, metoclopramide, substituted benzamines)
5) mood stabiliers (lithium)

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