ic17 parkinson's disease

Question 1

what are the four characteristic features of PD and which are the cardinal sx

Answer 1

TRAP

1. tremor
2. rigidity
3. akinesia (/ bradykinesia)
4. postural instabiity

1,2,3 are cardinal sx

Question 2

what are the components that goes into diagnosing PD and what is the diagnostic criteria for PD

Answer 2

diagnosis made based on clinical signs, physical examination and history

diagnostic criteria is that at least 2 of the 3 cardinal signs must be present

T remor (resting tremor, disappears with movement, incr with stress)
R igidity (cogwheel rigidity, leadpipe rigidity)
A kinesia/bradykinesia (subjective sense of weakness, loss of dexterity, difficulty using kitchen tools, loss of facial expression, reduced blinking, difficulty getting out of chair, difficulty turning while walking)

Question 3

what is the difference between leadpipe and cogwheel rigidity

Answer 3

lead pipe rigidity is constant resistance to movement throughout the whole range of motion while cogwheel rigidity is the resistance that stops and starts when the limb is moved through its range of motion (jerkiness)

Question 4

what are the features at initial presentation of idiopathic PD vs as the disease progresses

Answer 4

initial presentation:
i) asymmetric
ii) positive response to levodopa or apomorphine
iii) postural instability and falls not present
iv) less rapid progression in first 3 yrs
v) autonomic dysfunction not present

disease progresses:
i) unable to perform ADL or perform them safely (mobility, feeding self, grooming and personal hygiene, toileting, showering, continence for bowel and bladder)
ii) choking
iii) pneumonia
iv) falls

Question 5

what is the pathophysiology of PD (how much loss results in clinical sx)

Answer 5

impaired clearing of abnormal or damaged proteins thus leading to failure of toxic protein clearance which result in aggresomes like lewy bodies (alpha-synuclein and ubiquitin) which ultimately causes loss of dopaminergic neurons in substantia nigra and dysfunction of the nigrostriatal path

approx 80% loss of dopaminergic neurons = clinical sx (represented by lightened “dark bands” aka substantia nigra no longer present)

Question 6

how is disease progression of PD measured

Answer 6

1. hoehn and yahr staging
2. MDS-unified parkinson’s disease rating scale (UPDRS)

Question 7

what is the hoehn and yahr staging largely based on (elaborate on the stages)

Answer 7

largely based on mobility

stage 1: sx on one side of body only
stage 2: bilateral sx, no balance impairment
stage 3: impaired postural reflexes, physically independent
stage 4: severe disability, yet still able to walk or stand unassisted
stage 5: wheelchair bound or bedridden

Question 8

what are the components the MDS-UPDRS and UPDRS are measuring

Answer 8

UPDRS:
i) mentation, behaviour and mood (intellect, impairment, depression)
ii) ADL (speech, salivation, swallowing, dressing, hygiene, walking)
iii) motor examination (gait, facial, tremor at rest)
iv) complications of therapy (dyskinesia, clinical fluctuations)

MDS-UPDRS:
i) non motor experiences of daily living (aka all the non motor sx like depression, psychosis etc)
ii) motor experiences of daily living
iii) motor examination
iv) motor complications

Question 9

what is the PD timeline, which kind of sx manifests first

Answer 9

20yr prodrome (where non motor sx manifests first) then reach clinical onset then start 20yr disease stage

Question 10

what are the type of non motor sx of PD

Answer 10

1. dementia
2. depression
3. psychosis
4. rapid eye movement sleep disorder
5. autonomic dysfunction (constipation, GI motility, postural hypotension, sialorrhea aka excessive salivation)
6. fatigue

Question 11

what are the characteristics and features of young onset PD

Answer 11

i) slower disease progression
ii) lesser cognitive decline
iii) earlier motor complications
iv) dystonia is common initial presentation of early onset (vs falls and freezing in late onset)
v) dopamine agonists (pramipexole, pergolide, ropinirole) preferred over levodopa bc of motor complications assoc w levodopa

Question 12

what is “dystonia”

Answer 12

involuntary muscle contraction that causes slow repetitive movements or abnormal postures

Question 13

outline the diagnosis algorithm of PD

Answer 13

PD suspected bc of TRAP -> refer to specialist -> consider possibility of atypical PD (poor response too levodopa, symmetrical, early falls, rapid progression, lack of tremor, prominent dysautonomia) -> if not determine if the clinical presentation is (a) predictors of more benign course (young onset, resting tremor) or (b) predictors of more rapid course (older onset, male, postural instability/ freezing gait, assoc comorb, poor levodopa resp, dementia)

Question 14

what are the goals of tx for PD

Answer 14

1. manage sx
2. maintain func and autonomy

note that no PD tx has been shown to be neuroprotective (aka no cure)

Question 15

what are the pharmacotx for PD (drug class and eg. of drugs)

Answer 15

to incr central dopamine and dopaminergic transmission:
i) levodopa + DOPA decarboxylase inhibitor (carbidopa, benserazide)
ii) dopamine agonist (pramipexole, pergolide, ropinirole)
iii) MAO-B inhibitors (selegiline, rasagiline)
iv) COMT inhibitors (entacapone, tolcapone)

to correct imbalance in other pathways
i) anticholinergics (trihexyphenidyl)
ii) NMDA receptor antagonists (amantadine)

Question 16

what are the non pharmacotx

Answer 16

1. physiotherapy (stretching, transfers, posture, walking)
2. occupational therapy (mobility aids, home and workplace safety)
3. speech and swallowing
4. surgery

Question 17

what is levodopa effective in tx

Answer 17

effective in tx sx of PD
i) most effective for bradykinesia and rigidity
ii) less effective for speech, postural reflex and gait imbalances

Question 18

what are the PK features of levodopa (F, absorption considerations, transport system)

Answer 18

F: 33% alone, 75% w carbidopa or benserazide

absorbed in proximal part of small intestine and absorption decr with high fat or high protein meals

transported by an active saturable carrier system for large neutral AA

Question 19

outline the path of levodopa from administration to target site (incl the enzymes acting on levodopa at various sites)

Answer 19

levodopa absorbed through the gut lumen to enter blood and peripheral tissues

in blood and peripheral tissues:
i) levodopa acted on by COMT to form metabolites
ii) levodopa acted on by DOPA decarboxylase to form dopamine
iii) levodopa acted on by MAO-B to form metabolites

in brain:
i) only levodopa passes BBB (dopamine does not)
ii) levodopa acted on by DOPA decarboxylase to form dopamine
iii) levodopa acted on by both COMT and MAO-B to form metabolites
iv) dopamine formed by levodopa conversion is acted on by both COMT and MAO-B to form metabolites

Question 20

do carbidopa and benserazide cross the BBB

Answer 20

no they do not cross the BBB

Question 21

what are the req dosages for carbidopa and benserazide to saturate DOPA decarboxylase (and what is the usual proportions of levodopa:DCI)

Answer 21

75-100mg daily

levodopa:DCI
i) 1:4
ii) 1:10

Question 22

what are the s/e of levodopa

Answer 22

i) N/V
ii) postural hypotension
iii) drowsiness, sudden sleep onset
iv) hallucination, psychosis
v) dyskinesia (within 3-5yr of initiating tx)

Question 23

what are the motor complications of levodopa (outline the trajectory of these motor complications as PD progresses)

Answer 23

1. “on off” phenomenon
   i) ON refers to response to levodopa
   ii) OFF refers to no response to levodopa
   iii) unpredictable and not related to dose or dosing interval
   iv) difficult to control with meds
   v) mechanism unclear
2. “wearing off”
   i) shortened ON time
   ii) effect of levodopa wanes before the end of dosing interval
   iii) assoc w disease progression
   iv) manage with modifying administration times or replace with modified release preparations
3. dyskinesia
   i) refers to involuntary uncontrollable twitching, jerking, peak dose dyskinesia, dystonia
   ii) manage with (a) changing administration freq (incr freq w lower dose) or replace specific doses with modified release (b) adding amantadine

stable phase -> wearing off phase -> dyskinesia -> on off phase

Question 24

what are the benefits and disadvantages of CR levodopa and how to change from IR levodopa to CR levodopa (and vice versa)

Answer 24

benefit:
i) CR designed to release levodopa/MCI over a longer period (4-6hr)
ii) useful for decr stiffness on waking (added on to last dose of the day)

disadvantage: lower F (also not alot of pts will be on CR bc difficult to sustain effect)

IR to CR: incr dose (approx 25-50%)
CR to IR: decr dose

Question 25

what are the ddi for levodopa

Answer 25

1. pyridoxine (vitB): cofactor for DOPA decarboxylase, generally not an issue if levodopa administered with DCI but just need be aware of possible interactions if (a) high dose B6 for hematological problems or (b) high potency vitB complex tabs
2. Fe: affects absorption from levodopa, space out
3. protein: from food, protein powder; affects absorption of levodopa, space out
4. dopamine antagonists: metaclopramide, prochlorperazine, risperidone, FGA
   (antiemetic of choice for PD is domperidone)

Question 26

what are the types of dopamine agonists

Answer 26

1. ergot derivatives (older ver, not really used alr)
   i) bromocriptine
   ii) cabergoline**
   iii) pergolide*
2. non ergot derivatives
   i) pramipexole
   ii) ropinirole
   iii) rotigotine (TD patch)*
   iv) apomorphine (SQ inj)*

*note that these are not in SG; rotigotine became an exemption item
**only dostinex brand avail in SG

Question 27

what is the moa and PK features of dopamine agonists (list the eg. of dopamine agonists)

Answer 27

ergot derivatives: bromocriptine, pergolide, cabergoline
non ergot derivatives: pramipexole, ropinirole, rotigotine, apomorphine

moa: act on dopamine D2 receptor and mimics dopamine

PK:
i) longer halflife and duration of action than levodopa
ii) ergot derived have lower F than non ergot derived due to first pass effect
iii) ropinirole is metabolised in the liver into inactive metabolites
iv) pramipexole is large excreted unchanged in the urine

Question 28

what are the s/e of dopamine agonists (peripheral and central)

Answer 28

peripheral:
i) N/V
ii) postural hypotension
iii) leg edema

central:
i) hallucinations (visual>auditory)
ii) somnolence, day time sleepiness
iii) compulsive behaviours eg. gambling, shopping, eating, hypersexuality *pt edu

ergot derived have these additional s/e:
i) fibrosis (peritoneal, pulmonary, pericardiac) - may be partially reversible upon withdrawal *lower risk with non ergot derived
ii) valvular heart disease

Question 29

what are the key features when comparing dopamine agonists to levodopa

Answer 29

i) lesser motor complications than levodopa
ii) but more hallucinations, sleep disturbances, leg edema, postural hypotension
iii) no clinically significant differences in efficacy
iv) dopamine agonists more preferred in younger pts to maximise tx options and delay onset of levodopa induced motor complications

Question 30

what kind of formulations do pramipexole and ropinirole avail as

Answer 30

IR and SR forms

Question 31

what are the indications for dopamine agonists

Answer 31

1. monotherapy in young onset PD
2. adjunct in moderate to severe PD with levodopa
3. management of motor complications caused by levodopa

Question 32

what are the types of MAOs

Answer 32

MAO-A for 5HT, NE (peripheral)
MAO-B for DA (central)

Question 33

what is the rate of MAO regeneration

Answer 33

14-28d

Question 34

what is the moa and PK features of MAO-BIs (list the eg. of MAO-BIs)

Answer 34

selegiline and rasagiline are MAO-BIs

moa: irreversible selective MAO-B inhibitors (but not totally selective for MAO-B)

PK:
i) short half life of 1.5-4hr but long duration of action
ii) selegiline is hepatically metabolised into amphetamines which are stimulating (thus give last dose latest 4pm if not will have sleep issues) and have no effect on MAO-B
ii) rasagiline is not metabolised into amphetemines (thus not as concerned with sleep issues)

Question 35

what are the indications of MAO-BIs

Answer 35

i) monotherapy for early stages (more commonly for young onset PD)
ii) adjunct for later stages

Question 36

what are the doses for MAO-BIs

Answer 36

selegiline: 5mg OM to BD (second dose in afternoon)
rasagiline: 0.5-2mg QD

Question 37

what are the ddis for MAO-BIs

Answer 37

i) SSRIs, SNRIs, TCAs (wash out period req)
ii) pethidine, tramadol
iii) linezolid
iv) dextrametorphan
v) dopamine
vi) sympatomimetics: nasal decongestants like pseudoephedrine
vii) another MAOI

Question 38

what are the fdi for MAO-BIs

Answer 38

key chemical of concern is tyramine (cheese rxn) bc it is metabolised by both MAO-A and MAO-B

thus try to avoid aged cheeses and meat, draft beer, fermented food like sauerkraut and kimbhi, marmite, banana peel, soy sauce bc these foods contain high levels of tyramine

Question 39

compare levodopa, dopamine agonists and MAO-BIs based on their effects on motor sx, ADL, motor complications, s/e

Answer 39

for levodopa:
[motor sx] more improvements
[ADL] more improvements
[motor complications] more complications
[s/e] fewer non motor s/e (sleepiness, hallucinations, impulsive control disorders)

for dopamine agonists:
[motor sx] less improvement
[ADL] less improvement
[motor complications] less complications
[s/e] more non motor s/e

for MAO-BIs:
[motor sx] less improvement
[ADL] less improvement
[motor complications] less complitcations
[s/e] less non motor s/e

Question 40

what is the key idea behind using COMTi (relate to moa and effect of levodopa when given COMTi and list eg. of COMTi)

Answer 40

with DCI like carbidopa and benserazide, the major metaboliser of levodopa is catechol-o-methyl transferase (COMT)

entacapone and tolcapone are COMTis

reduces OFF time of levodopa

Question 41

what is the moa, administration instructions, s/e, ddi, caution of entacapone and what formulations is entacapone avail as

Answer 41

moa: selective reversible COMTi

administration: must be taken at the same time as levodopa

s/e: urinary discolouration (orange), D, note may cause dyskinesia upon initiation, note may potentiate other dopaminergic effects of postural hypotension, N/V

ddi: Fe, Ca, avoid concom non selective MAOIs (but ok with MAO-Bi; caution for selective MAO-Ai), any cathecolamine drug (cathecolamines are epinephrine, norepinephrine and dopamine), enhance anticoagulant effect of warfarin

caution:
i) hepatic impairment (but monitoring of LFTs not required)
ii) to note that may cause dyskinesia upon initiation thus should decr dose of levodopa (which is also good bc can reduce risk of motor complications)

formulations:
i) comtan: entacapone
ii) stalevo: levodopa, carbidopa, entacapone (to decr pill burden)

Question 42

what is the difference between epinephrine and norepinephrine

Answer 42

epinephrine has more effect on heart while norepinephrine has more effect on blood vessels

Question 43

what is the use and s/e of anticholinergics in managing PD (list the eg. of anticholinergics)

Answer 43

trihexyphenidyl and benztropine are anticholinergics

use: limited use in PD, primarily used to control tremor (indicated either as monotx or adjunct to levodopa to control tremors and stiffness)

s/e: anticholinergic s/e (dry mouth, urinary retention, constipation, sedation, confusion, hallucination, delirium

Question 44

what is the rationale behind using an NMDA receptor antagonist

Answer 44

glutamate is the most abundant excitatory NT and is assoc with neurotoxicity and glutamate activates N-methyl-D-aspartate (NMDA) receptor activity which activates the processes that causes cell death

incr glutamatergic activity is also linked to the development and maintenance of levodopa induced dyskinesia

Question 45

what are the moa, s/e, PK features (excretion), caution, indications of amantadine

Answer 45

moa:
1. NMDA receptor antagonist
2. dopamine D2 receptor agonist
3. enhances release of stored dopamine
4. inhibit presynaptic uptake of catecholamine

s/e: N, lightheadedness, insomnia, confusion, livedo reticularis

PK features: excreted renally thus reduce dose in renal impairment

caution: second dose in afternoon and not at night bc can be stimulating, avoid concom use with memantine (also a NMDA receptor antagonist)

indications: monotx ok but more for adjunctive for managing levodopa induced dyskinesia

Question 46

compare between all possible drugs and their effectiveness as (i) monotx (ii) adjunctive tx (iii) tx of motor fluctuations (iv) tx of dyskinesia

Answer 46

1. levodopa + DCI:
   i) +
   ii) -
   iii) +
   iv) -
2. pramipexole/ ropinirole:
   i) +
   ii) +
   iii) +
   iv) -
3. selegiline/ rasagiline:
   i) +
   ii) +
   iii) +
   iv) -
4. entacapone/ tolcapone:
   i) -
   ii) +
   iii) +
   iv) -
5. trihexyphenidyl:
   i) +
   ii) +
   iii) -
   iv) -
6. amantadine:
   i) +
   ii) +
   iii) -
   iv) +

Question 47

what are possible alternative or complement medicines for PD pts but what to note regarding these

Answer 47

note that currently no supplements are proven to have additional clinical benefits but safe to take if pt wishes to but also as PD progresses, pt will probably find it incr harder to swallow so apart from additional pill burden from these supplements, it is also probably harder for them to swallow anyway

i) co-enzyme Q10
ii) creatine
iii) vitE
iv) glutathione
v) riboflavin
vi) lipoic acid
vii) acetyl carnitine
viii) curcumin

Question 48

compare the differences between drug induced parkinsonism (DIP) vs idiopathic parkinson disease (iPD) based on (i) age at onset (ii) sx at onset (iii) onset (iv) course w tx (v) response to causative drug withdrawal (vi) resp to levodopa (vii) other features (viii) tremors at rest (ix) sex (x) freezing (xi) DaT scan (xii) PET/SPECT imaging

Answer 48

DIP:
i) typically in elderly
ii) symmetrical
iii) acute/ subacute (approx 3m within exposure to offending drug)
iv) reversible (not always)
v) variable
vi) poor
vii) orofacial dyskinesia, akathisia
viii) uncommon
ix) more often in females
x) uncommon
xi) normal
xii) normal uptake of presynaptic markers, decr uptake of dopamine receptor ligands

iPD:
i) sixth decade (80-90yo)
ii) asymmetrical
iii) chronic
iv) progressive
v) poor
vi) marked
vii) -
viii) common
ix) more often in males
x) common
xi) abnormal
xii) decr uptake of presynaptic markers, normal uptake of dopamine receptor ligands

Question 49

what does it mean by “uptake of presynaptic markers” vs “uptake of dopamine receptor ligands”

Answer 49

assessing either presynaptic (e.g. dopamine synthesis and storage, transporter density) or postsynaptic terminals (i.e. D2 receptors availability)

in PD, it typically involved degeneration of the dopaminergic nerve terminals thus it is likely that the presynaptic markers would be affected compared to the postsynaptic terminal

Question 50

what does “motor fluctuations” refer to

Answer 50

refers to ON OFF response based on the response to levodopa

Question 51

does withdrawal of causative drug immediately help with DIP

Answer 51

no withdrawal of causative drug is effective in improving sx in 80% of pts and takes approx 8w

Question 52

what are the possible causative drugs of DIP (classify based on risk)

Answer 52

high risk:

i) D2 receptor antagonist: FGA (haloperidol, amisulpride, prochlorperazine), high dose SGA (risperidone, olanzapine, aripirprazole)

ii) DA depleters: tetrabenazine, reserpine

iii) DA synthesis blockers: alpha-methyldopa

iv) Ca channel antagonist (P-channel): flunarizine, cinnarizine

intermediate risk:

i) Ca channel antagonist (L-channel): diltiazem, verapamil

ii) ASM: PHT, VPA, LVT

iii) antiemetics/ gastric motility agents: metoclopramide, prochlorperazine

iv) SGA: ziprasidone

v) mood stabilisers: lithium

low risk:

i) immunosuppressants: ciclosporin, tacrolimus

ii) antiarrhythmics: amiodarone

iii) antidepressants: SSRIs (fluoxetine, sertraline), TCAs (phenalzine), MAOIs (meclobemide)

iv) statins: lovastatin

v) abx: cotrimoxazole

vi) antifungal: amphotericin B

vii) antiviral: acyclovir

viii) hormones: norepinephrine, levothyroxin, medroxyprogesterone

Question 53

how should we manage DIP

Answer 53

prevention is the best treatment, if not use anticholinergics (trihexyphenidyl, benztropine) or NMDA receptor antagonist (amantadine)

Question 54

what is the role of pharmacists

Answer 54

medication review:
i) correct levodopa preparation (check 1:4 or 1:10 and check IR or CR)
ii) can pt swallow pills whole
iii) ddi (dopamine antagonists, antiemetics, SSRIs)
iv) comorbidities and their meds ddi
v) timing (specific administration timings)