ic16 parkinsons disease phx management

Question 1

what is mainstay tx for PD and what is it useful/ not useful for

Answer 1

LEVODOPA
(dopamine does not cross BBB, only L-DOPA)

management of bradykinesia and rigidity

less effective for speech, postural reflex, gait disturbances

Question 2

PK levodopa (absorption)

Answer 2

absorbed in proximal small intestine

crosses BBB by an active saturable carrier system for large neutral amino acids

Question 3

[COUNSELLING POINT] + what lowers the absorption of levodopa

Answer 3

decreased absorption
with high fat or high protein meals

take drug on an empty stomach

Question 4

BA of levodopa (and combination products)

Answer 4

33% mono

75% with benserazide and carbidopa

Question 5

PK of DCI?

Answer 5

dopa decarboxylase inhibitors
DO NOT readily cross BBB

Question 6

adverse effects of levodopa

Answer 6

N/V, postural hypotension

CNS: drowsiness, sudden sleep onset, hallucinations, psychosis

dyskinesia (3-5 years of initiation)

Question 7

motor complications of levodopa

Answer 7

associated with disease progression DESPITE optimal dosing therapy of levodopa.

on-off phenomenon

wearing off phenomenon
- effect wanes off before end of dosing interval = shortened ON time = parkinsonism symptoms appear

Question 8

dykinesia of levodopa?

Answer 8

involuntary, uncontrollable,
twitching
dystonia

“choreatic dyskinesia”
despite peak dose (cmax) of levodopa

Question 9

management of motor complications of levodopa

Answer 9

1) adjust levodopa dose = increase dose.
2) change dosing frequency = increase dosing frequency
3) explore dosage forms
4) adjunctive agents: dopamine agonists, MAO-B, COMTi.

Question 10

different dosage forms for levodopa and how to dose adjust from IR formulation

Answer 10

SUSTAINED RELEASE
- release over 4-6 hours

IR -> CR: increase dose by 25-50%
CR -> IR: decrease dose

Question 11

use of SR dosage forms

Answer 11

useful for decreased stiffness on waking.

ie when symptoms reappear in the moring or during the night when the dose wane off

Question 12

drug interactions with levodopa

Answer 12

1) pyridoxine/vitamin b6 (high dose/high potency vit b complex)
- cofactor for dopa decarboxylase

2) iron, protein (food, protein powder)
- affect absorption = space out administration

3) dopamine antagonists
- metoclopramide, prochlorperazine
- FGA
- risperidone?

Question 13

what antiemetic of choice in PD?

Answer 13

DOMPERIDONE
- peripherally acting

Question 14

class and examples of dopamine agonists

Answer 14

ergot derivatives
- bromocrtptine
- pergolide
- cabergoline

non-ergot derivatives
- pramipexole
- ropinirole
- rotigotine (transdermal)
- apomorphine (SQ)

Question 15

moa of dopamine agonist

Answer 15

act on D2 receptors in the basal ganglia

Question 16

PK of dopamine agonists

Answer 16

ergot derived: lower F due to extensive first-pass metabolism

t1/2 and DOA longer than levodopa

Question 17

PK of ropinirole (M)

Answer 17

liver metabolism mainly - caution in hepatic impairment

Question 18

PK of pramipexole (M)

Answer 18

excreted largely unchanged in urine

can be used in hepatic impairment?
caution w/ renal impairments

Question 19

side effect of dopamine agonists

Answer 19

1) DOPAMINERGIC
peripheral:
N/V, orthostatic hypotension, leg oedema

central:
hallucinations (usually visual > auditory)
somnolence, day time sleepiness
compulsive behaviours: gambling, shopping, eating, hypersexuality

2) NON-DOPAMINERGIC (lower risk w non-ergot)
- fibrosis = pulmonary, pericardiac, retro-peritoneal (possible to partially reverse after withdrawal)
- valvular heart disease

Question 20

when should dopamine agonists be used

Answer 20

used in young onset PD patients to maximise tx and delay onset of levodopa induced motor complications
* can also be used to manage the motor complications

monotherapy in young onset

adjunct to levodopa in moderate to severe PD

Question 21

what are the MAOi (and the dosing)

Answer 21

selegiline, rasagiline
irreversible MAO-B inhibitors

selegiline 5mg OM to BD
metabolised to amphetamines = no effect on MAO-B

rasagiline 0.5-2mg OD

Question 22

drug interactions with MAO-B I

Answer 22

SNRI, SSRI, TCA

pethidine, tramadol (opioids)
linezolid
DMP
dopamine
sympathomimetic: pseudoephedrine, phenylephrine

another MAOI

Question 23

counselling for MAOI

Answer 23

AVOID tyramine rich foods eg aged cheese, craft beer, fermented food…

Question 24

place in therapy of MAO in PD

Answer 24

monotherapy in early stages

can also be used as adjunct in late stages

most commonly used in early stages of young onset PD

Question 25

place in therapy of COMT i

Answer 25

only used as adjunct to levodopa,

otherwise not effective

Question 26

entacapone moa

Answer 26

selective reversible inhibitor of COMT

Question 27

how to take Entacapone

Answer 27

take at the same time as levodopa

Question 28

drug interactions with entacapone

Answer 28

iron, calcium

non-selective MAO and MAO-A selective inhibitors

cathecolamine drugs

warfarin = may enhance anticoagulation effect

cathecolamine drugs: dobutamine, dopamine, epinephrine, & isoproterenol

Question 29

SE of entacapone

Answer 29

diarrhoea
urinary discolouration (ORANGE)

WITH LEVODOPA
possible dyskinesia on initiation (lower levodopa dose)
possible potentiation of dopaminergic effects = orthostatic hypotension, N/V

Question 30

caution entacapone

Answer 30

HEPATIC IMPAIRMENT
but no need to monitor LTs

Question 31

place in therapy of anticholinergics? examples of drugs

Answer 31

used primarily to control tremors

benztropine and trihexyphenidyl

Question 32

NMDA antagonists example, used and MOA

Answer 32

AMANTADINE
inhibits NMDA mediated excitotoxicity due to glutamate = dyskinesia (levodopa induced)

possibly used to manage dyskinesia with increased levodopa dosing/ advanced PD where dyskinesia is random

Question 33

MOA of amantadine

Answer 33

dopamine agonist
NMDA receptor agonist
increased released of stored dopamine
inhibit presynaptic uptake of catecholamines (ML)

NMDA antaognist
anticholinergic
upregulation of D2 receptors (WPS)

Question 34

adr of amantadine

Answer 34

livedo reticularis

n/v, insomnia, confusion, hallucination

Question 35

place in therapy of amantadine

Answer 35

used as an adjunctive agent AND
to manage levodopa induced dyskinesia