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3153 psych > parkinson's > Flashcards

parkinson's Flashcards

1
Q

3 features of PD — pathophysiology

A
  • Lewy bodies
  • degeneration of dopaminergic neurons
  • basal ganglia
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2
Q

lewy bodies

A
  • Accumulation of aggresomes (aggregated proteins)
    • Lewy bodies ~ deposits of a-synuclein and ubiquitin
    • Eosinophilic cytoplasmic inclusions
  • apoptosis
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3
Q

degeneration of dopaminergic neurons, substantia nigra

A
  • Lewy body inclusion in substantia nigra
    • Induce oxidative stress, nitric stress
    • Molecular abnormalities
  • Dysfunction of nigrostriatal pathway
    • Loss of darked region
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4
Q

basal ganglia and motor control

A
  • Affects motor control
  • Involved in action selection
  • Normally inhibit a number of motor systems
    • Substantia nigra-mediated release of inhibition permits a motor system to become active
    • Involves both excitatory D1 and inhibitory D2 receptors
  • Loss of substantia nigra –> no release of inhibition –> hypokinetic state
  • Strong connection to other areas
    • Thalamus, motor cortex etc
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5
Q

indirect vs direct pathways (basal ganglia)

A

DIRECT: hypoactivation of excitatory D1 receptors
* Weaken striatal inhibition of Globus pallidus internal
* Va/VL thalamus excites more motor pathway

INDIRECT: hypoactivation of inhibitory D2 receptors
* Strengthen striatal inhibition of GPe (external)

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6
Q

neurotransmitter deficiency – PD

A
  • Striatal dopaminergic deficiency
    * Extrapyramidal motor sx (tremor, rigidity, bradykinesia)
  • Other neurotransmitters involved
    * Non-motor sx
    * Autonomic, psychiatric, sensory, ocular, gait imbalance
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7
Q

cardinal features of PD

A
  • Tremor at rest
  • Bradykinesia (slowness of movement)
    * micrographia (smaller handwriting)
  • Rigidity (cogwheeling)

postural instability and gait disturbances
* stooped posture, reduced arm swing, masked facial expression

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8
Q

progressives features of PD

A
  • Early yrs of disease: Rate of disability progression marked
  • 10-15yrs after onset: Sig disability
  • Later stage: pt more dependent in their activities of daily living
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9
Q

initial presentation

A
  • Asymmetric
  • +ve response to levodopa/ apomorphine (DA agonists)
  • NOT PRESENT: Postural instability (& falls)
  • NOT PRESENT: Autonomic dysfunction
  • Less rapid progression
  • Impaired olfaction ?

Can conduct neuroimaging

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10
Q

progressed disease

A
  • Unable to perform basic ADLs (or cannot perform safely)
    ○ Mobility (walk, use stairs)
    ○ Feeding self
    ○ Grooming, personal hygiene
    ○ Toileting
    ○ Showering/ bathing
    ○ Continence (bowel, bladder)
  • Choking
  • Pneumonia (from aspiration into lungs)
  • Falls (mobility deficit)
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11
Q

progressive sx of PD

A
  • Motor sx: fluctuations, dyskinesias
  • Non-motor sx (fall, postural instability, postural hypotension, confusion, dementia - PDD, suboptimal nutrition, speech, sleep d/o)
  • PDD: Parkinson’s Disease Dementia
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12
Q

PD timeline

A
  • 20 yr prodrome
    * hyposmia, constipation, bladder disorder
    * sleep d/o, obesity, dep
  • clinical onset
    * unilateral: tremor, rigidity, akinesia
  • II: bilateral disease
  • III: poor balance
  • IV: falls, dependency, cognitive decline
  • V: chair/ bed bound, dementia (PDD)
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13
Q

measurement of disease progression

A
  • Hoehn and Yahr staging
    * prodrome –> I,II,III,IV,V (across 20 yrs)
  • MDS: Unified Parkinson’s Disease Rating Scale (UPDRS)
    * research tool
    * intellect, Activities of daily living, motor exam, complication of therapy (dyskinesia)
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14
Q

dx of PD

A
  • Based on clinical sigs, physical examination, hx taking = 2/3 cardinal signs present
    • Tremor
      ○ Resting, disappears with movement,, incr with stress
    • Rigidity
      ○ Cogwheel rigidity, leadpipe rigidity
    • Bradykinesia
      ○ Weakness, loss of dexterity, loss of facial exp, difficulty getting out of bed/chair, turning (walking), reduced blinking
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15
Q

overall parkinson tx strategies

A
  • incr central DOPA/ dopaminergic transmission (levodopa+DCI, DA)
    * L-tyrosine —> L-dopa (pass through BBB)
    * L-dopa —-> dopamine (DOPA decarboxylase)
  • decr breakdown (COMTi, MAO-Bi)
    * dopamine reuptake by presynaptic neuron
    * enzymes: COMT, MAO-B
  • correct imbalances in other neurotransmitter pathways
    * anticholinergics, NMDA antagonist (glutamate)
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16
Q

tx plan based on onset

A
  • Early/ young onset PD = [Dopamine agonist] > levodopa (dyskinesia)
    • Slower disease progression
    • Features
      ○ < cognitive decline
      ○ Earlier motor complications
      ○ Dystonia (common initial presentation)
  • Late -onset [poor levodopa response]
    • Falls and freezing
    • rapid course
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17
Q

goals of PD management

A
  • Manage sx
  • Maintain function & autonomy

No tx because PD is progressive, no neuroprotection available

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18
Q

levodopa MOA

A

Incr precursor to incr dopamine synthesis
L-dopa –> dopamine (DOPA decarboxylase, MAO, COMT)

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19
Q

concomitant with

A
  • decarboxylase inhibitors: carbidopa/ benserazide
    • Peripheral DCI (Prevent peripheral dopamine SE)
    • Incr dopamine avail in central (convert to dopamine)
    • incr F from 33% –> 75%
    • not cross BBB

75-100mg OD

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20
Q

ratio of sinemet (carbidopa) , Madopar (benserazide)

A

DCI: LEVO

1 : 4 (Sinemet, Madopar)
1 : 10 (Sinemet)

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21
Q

indication for levodopa

A
  • Gold standard – bradykinesia, rigidity
    * less for speech, postural reflex, gait disturbances
  • Efficacious for sx management of early & late PD * but Low dose and Preferable to start at later stage
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22
Q

ADR of levodopa

A
  • ST: NV, postural hypoTENsion, drowsy, hallucination, psychosis
  • LT: motor fluctuations, dyskinesia (3-5yrs of initiate)
    Irreversible
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23
Q

dyskinesia presentation + management

A

○ Involuntary, uncontrolled
○ Twitching, jerking
○ Peak dose dyskinesia (right after admin - due to lowered dyskineisa threshold)
* Reduce dose// use sustained release
○ Dystonia

  • Management:
    * amantadine
    * replace specific dose w/ modified release levodopa
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24
Q

dyskinesia stage of levodopa

A
  • stable phase
    * motor function near normal (reach sx relief threshold)
    * conc fluctuate w/o sx emergence
  • wearing off –> dyskinesia
    * duration of motor response shortens
    * sx appears b. doses (in morning)
  • peak dose dyskinesia
  • on-off phenomenom
    * severe fluctuations
    * Appear at random but related to swings in drug conc
    * Often and normal mobility difficult to achieve
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25
Q

manage wearing-off dyskinesia sx

A
  • Sustained release forms
    • Release levo/DCI over long period 4-6hrs
    • Lower F (dose adj needed)
      ○ IR –> CR: incr dose 25-50%
      ○ CR –> IR: dose decr
    • Reduce morning stiffness (take last dose of day, pt can get through OM)
      ○ No crush, open capsule
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26
Q

DDI of levodopa

A
  • Pyridoxine
    • Cofactor for dopa decarboxylase
      ○ Take levo + DCI
    • HIGH DOSE: Vit B6 (haem issues)/ vit B complex tabs
  • Fe
    • Decr absorption of levo (space out admin)
  • Protein (food, protein powder)
    • Decr absorption of levo (space out admin)
  • Dopamine antagonists
    • Metoclopramide, prochlorperazine
      ○ Switch to domperidone (antiemetic)
    • FGA
    • SGA: risperidone
  • MAOi (within 14d) - incr NE = hypotensive
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27
Q

COMPTi MOA
catechol-O-methyltransferase

A
  • Block COMT conversion of dopamine/ L-DOPA into inactive form (major metaboliser)
  • More levodopa available to enter brain
    ○ Reduce required dose, less SE
    ○ Incr duration of each Levodopa dose
    ○ Beneficial in tx wearing off response

Entacapone, Tolcapone

28
Q

indication of COMPTi

A
  • Adjunct w/ levodopa (decr off-time, enhancer)
    * decr wearing off effects
  • (not monotherapy)
  • Entacapone (selective, reversible), Tolcapone
29
Q

eg of COMTi drugs

A
  • Comtan: entacapone
  • Stalevo: levo + carbidopa + entacapone
    * Reduce pill burden, but hard to titrate
30
Q

COMPTi ADR

A
  • Liver dysfunction (Tolcapone affects CYP450)
  • D
  • Urinary discolouration (ORANGE)
  • Visual hallucinations

potentiate dopaminergic effects
* Incr abnormal movements, dykinesia - initiation
* Much milder than Levodopa SE
* decr levodopa dose (reduce dyskineisa in LT)
* hypotension, NV

Dopamine needed to regulate these cycles
- Sensory function
- Sleep/wake funct

31
Q

DDI of COMTi

A
  • Fe, Ca
  • MAOi (ok with MAO-Bi)
    ○ Caution with MAO-Ai
  • Catecholamine drug
  • Warfarin
    ○ Enhances anticoag effect
32
Q

MAO-Bi MOA

A

selegiline, rasagiline
Irreversible inhibit enzyme MAO B from breakdown of dopamine

(MAY) delay nigral brain cell degeneration
Neuroprotective effects

33
Q

indication of MAO-Bi

A
  • MONOTHERAPY Early stage of PD (Selegiline)
    * symptomatic monotherapy
  • adjunct in later stages
34
Q

dose of MAO-Bi

A
  • Selegiline (deprenyl, eldepryl, jumex)
    • 5mg OD-BD (2nd dose in afternoon X ON)
      ○ Liver metabolise to amphetamines (stimulating, no MAO-B effect)
    • DATATOP: has vit E
  • Rasagilin (Azilect)
    • Not metabolised to amphetamines
    • 0.5-2mg OD
35
Q

pk of MAO-Bi

A
  • Short t1/2 (1.5 - 4hrs)
    • Long duration of action (irreversible + MAO only regenerate in 14-28d)
  • Metabolised for selegiline
    • Liver –> amphetamines (stimulating)
36
Q

ADR of MAO-Bi

A
  • heartburn, LOA
  • ANX, palpitation, insomnia
  • nightmare, visual hallucination
37
Q

MAO-A vs B

A

MAO-A: peripheral, NA, 5HT (antidep- reversible RIMA)
MAO-B: central, DA
* MAO regenerates on 14-28d
* Irreversible MAO-B inhibitors (not totally selective, has MAO-A effect too)

38
Q

MAO-Bi DDI

A
  • SSRI, SNRI, TCA (need washout)
  • Pethidine, tramadol (opioids)
  • Linezolid, dextromethorphan
  • DA
  • Sympatomimetics: nasal decongestants (pseudoephedrine)
  • Other MAOi
39
Q

MAO-Bi FDI

A
  • Tyramine (metabolised by MAO-A, MAO-B): displace NA
    ○ More NA = hypotension
  • Fermented food, aged cheese, beer
40
Q

dopamine receptor agonist MOA

A

pramipexole, pergolide, ropinirole

  • act directly on dopamine receptors in brain, reduce PD sx (antiparkinsonian effects)
  • mimic DA action, bind to D2 receptor in basal ganglia
  • prevent/ delay onset of motor complications
41
Q

indication of DA RA

A
  • MONO in Younger PD pt
    • Fewer SE, if sx not as bad use this instead of levo
    • delay levodopa (also has less motor complications)
  • Adjunct to levo for mod-severe pts
    • Manage motor complications by levo
    • Neuroprotective? Disease modifying??
42
Q

ergot derivative (DA agonist)

A

bromocriptine (NMS, hyperprolact)
cabergoline (0.5mg dostinex)
pergoline (not in sg)

43
Q

non-ergot derivative DA agonist

A

ropinirole
pramipexole (IR, SR form)
rotigotine (patch, exemption item)
apomorphine (sc inj not in SG)

44
Q

PK of DA agonist

A
  • F:
    • ERGOT derived < NON-ERGOT derived
    • Extensive 1st pass metabolism
  • T1/2, DOA (>levo)
  • Metabolism (Non-ergot)
    • ropinirole: liver –> inactive metabolites
    • Pramipexole: excrete unchanged in urine
45
Q

DA agonist cautions

DO NOT USE

A

Liver impairment (non-ergot ropinirole)
Urine impairment (non-ergot Pramipexole )

46
Q

DA agonist ADR

A
  • peripheral DA: NV, orthostatic hypoTENsion, oedema
    less motor complications than LEVO
  • central DA: Headache, dizzy, hallucination (visual), somnolence, compulsive behaviours
    more than LEVO
  • non-DA (more risk with ERGOT): fibrosis, valvular HD, cardia arrhythmia
47
Q

eg DA agonist ADR

A
  • Pergolide (ergot derivative)
    * Peritoneal fibrosis
    * Cardiac valve regurgitation
  • Pramipexole, ropinirole (non-ergot):
    * Sedation, somnolence, daytime sleepy
48
Q

NMDA antagonist MOA
N-methyl D-aspartate

A

amantadine
1) enhance release of stored DA
2) inhibit presynaptic uptake of DA
3) anti- glutamatergic activity –> decr activate NMDA receptor –> less cell apoptosis, reduce excitotoxicity

49
Q

NMDA antagonist indications

A
  • Manage Levodopa-induced dyskinesias
  • Adjunctive
    * 2nd dose in afternoon, stimulating (not ON)
  • NMS, EPSE (tardive dyskinesia - FGA), hyperprolact
50
Q

caution for NMDA

A

renal impair (dose reduction)
* CL: renal

51
Q

ADR of NMDA antagonist

A
  • N, Cognitive impairment (inability to conc)
  • light head, confuse
  • Hallucinate, insomnia, nightmare
  • Livedo reticularis (venule swell from thrombosis –> risk PE)
    * Reticulated discoloration of limbs
52
Q

memantine vs amantadine

A
  • non-competitive inhibitor NMDA
  • No good evidence for effect on levodopa-induced dyskinesias

amantadine
* NMDA antagonist, anticholinergic
* upregulate + sensitivity D2 receptors

53
Q

anticholinergics eg

A
  • Trihexyphenidyl (benzhexol)
  • Biperiden
  • Orphenadrine
  • procyclidine
  • benztropine
54
Q

anticholinergics MOA

A

Peripheral acting agents useful in tx sialorrhea (excess saliva flow, tremor): Ach PNS effect - rest, digest

inhibit PNS: selective block ACh receptors in nerve cells

55
Q

indication for anticholinergics

A
  • Sx monotherapy
  • Adjunct to levodopa
    • Tremor, stiffness in PD
    • NOT FOR: bradykinesia, dyskinesia sx
56
Q

ADR of anticholinergics

A
  • Block parasympathetic system (rest, digest):
    * Dry mouth, sedation, constipation, urinary retention, delirium, confusion, hallucinations
57
Q

tx individualised by

A

age
stage of disease (early vs late)
lvl of activity (type of daily activity)
assoc psychological factors
assoc medical conditions
drug-induced?
pt factors

58
Q

pharm tx for non-motox sx

A
  • dementia (AChEi)
  • DEP (DA, SSRI, SNRI)
  • psychosis (APS, AChEi)
  • sleep d/o (BZP, melatonin)
  • autonomic dysfunction
    * constipation (osmotic PEG)
    * GI motility (domperidone, peripheral DA antagonist)
    * ortho hyoTEN (domperidone, vasopressor, AChEi)
    * sialorrhoea (anticholinergic, neurotoxin)
  • fatigue (stimulant)
59
Q

CAM

A
  • co-enzyme Q10 + vit E (early): safe, ineffective
  • creatine (safe, ineffective)
  • vit E 1200 IU (neuroprotective??)
  • glutathione
  • riboflavin
  • lipoic acid
  • acetyl carnitine
  • curcumin
60
Q

non pharm

A
  • PT
    ○ Stretching, transfers, posture, walking (add guiding lines)
  • OT
    ○ Mobility aids, home & workplace safety
  • Speech and swallowing
    ○ Degree pt can swallow (viscosity level)
  • Surgery
61
Q

drug-induced parkinsonism presentation
- Difficult to distinguish from PD
- May be underlying iPD (20%)

A

Bilateral sx
Elderly
Acute, subacute onset
Poor response to levodopa
Uncommon for rest tremor

62
Q

DIP tx

A
  • onset of DIP ~3mnths
  • Tx: withdraw offending drug
    * Withdrawal of drug leads to improvement
    * 80% of pt, within 8wks
  • anticholinergics, amantadine ST use
63
Q

high potential risk of DIP

(decr DA, neurotransmitters)

A
  • DA (D2) receptor blockers
    * APS (FGA > SGA high dose)
  • DA depleters (tetrabenazine, reserpine)
  • DA synthesis blockers (a-methyldopa)
  • Ca channel antagonist (flunarizine, cinnarizine)
64
Q

intermediate potential risk of DIP

A
  • SGA
  • Ca channel antagonists
    * dilitiazem, verapamil
  • anti-seizure
    * VA, PHT, levetiracetam
  • antiemetic
    * metoclopramide, prochlorperazine
  • mood stabiliers (Li)
65
Q

motor sx, activities of daily living

A

levodopa
(some improvement): DA, MAO-Bi

66
Q

motor complications ADR

A

levo > DA, MAOBi

67
Q

ADE

A

DA > levodopa, MAOBi

(specified ADE: peripheral, central, non-DA)
(levodopa less ADE, but afer 3-5yrs, more complicatd ADE)

3153 psych (11 decks)

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