IC16 PD Flashcards
cardinal motor sx of PD (LO)
TRAP
- Tremor at rest
- Rigidity (cogwheel, leadpipe)
- Akinesia/ bradykinesia
- Postural instability (not cardinal sx)
epidemiology of PD
increase with age
decrease with smoking and caffeine
5 non-motor sx of PD (LO)
- cognitive impairment (depression)
- psychiatric sx (depression, psychosis)
- sleep disorders
- autonomic dysfunction (constipation, decrease GI motility, OH, sialorrhoea)
- others (fatigue)
Pathophysiology of PD (LO)
misfolded alpha-synuclein aggregate to form Lewy body which:
1. decrease DA transmission
2. causes mitochondrial failure
3. neuroinflammation through activation of microglial
Result: loss of dopaminergic neurons in the substantia nigra -> cause clinical sx of PD
Dx of PD
any 2 out of 3 cardinal sx
- Tremor at rest (disappear with movements)
- Rigidity (cogwheel/ leadpipe)
- Akinesia (difficulty getting out of bed/chair, difficulty turning while walking)
Idiopathic PD
- asymmetric sx
- +’ve response to levodopa
- postural instability not present initially
- less rapid progression
- autonomic dysfunction not present initially
what neuroimaging is used to dx PD?
SPECT- DaT scan
Effects of poor motor sx in PD
- unable to perform ADL
- choking
- pneumonia/ UTI
- falls
measuring PD progression
Hoehn and Yahr staging, UPDRS
PD timeline
20yrs prodrome, dx usually occurs with first motor sx
early/young onset PD
slower disease progression, < cognitive decline, early motor sx, dystonia in common initially
- dopamine agonist preferred over levodopa
Goals of tx (LO)
manage sx, maintain function and autonomy
- no tx for PD currently
pharmacological treatments (LO)
- levodopa + DCI
- dopamine agonist
- MAOBi
- COMT
- anticholinergics
- NMDA antagonist
why is levodopa first line
most effective in treating motor sx (bradykinesia, rigidity); less effective for speech, postural reflex and gait disturbances
dopamine cannot be used as tx because…
does not cross BBB (only L-DOPA can)
how is levodopa metabolised peripherally?
DOPA carboxylase, MAO, COMT
- peripheral dopamine cause N/V/hypotension
how is levodopa absorbed?
at proximal part of SI by an active saturable carrier system
- low oral F (increases with DCI)
- abs decrease with high fat or protein meals
eg of DCI, MOA, do they cross BBB?
carbidopa, benserazide
- does not cross BBB
- MOA: inhibit peripheral breakdown of levodopa
AE of levodopa
- N/V
- orthostatic hypotension
- drowsiness, sudden sleep onset
- hallucinations, psychosis
- dyskinesia (within 3-5yrs of initiation)
motor complications of levodopa
- on-off phenomenon
- wearing off effect
- dyskinesia
describe on-off phenomenon and mx
response/no response to levodopa
- unpredictable, not related to dose/dosing interval
- mx: difficult to control with meds
describe wearing off effect
effect of levodopa wanes before end of dosing interval
- mx: increase dosing frequency, use extended release formulations
describe peak dose dyskinesia
involuntary, uncontrollable muscle twitching or jerking that occurs at peak dose of levodopa
- mx: add amantadine, use MR levodpa
mx of levodopa motor complications (LO)
- adjust levodopa dose
- change dosing frequency
- explore dosage forms (ER)
- Adjunct meds: DA, MAO-Bi, COMT
Progression of PD and response to levodopa
- stable phase
- wearing off effect
- peak dose dyskinesia (when levodopa dose is increased to overcome wearing off effect)
- on-off fluctuations at the late stage (appears randomly)
Characteristics of sustained released levodopa formulations
- release levodopa slowly over a longer period of time
- lower F
- useful to decrease stiffening on waking (usually overnight dose would been reduced when pt wake up)
- useful to overcome peak dose dyskinesia and wearing off effect
- do not crush or open capsule
levodopa DDI
- pyridoxine (vit B6) - cofactor for DOPA carboxylase, not an issue of DCI is given
- iron - affect absorption (space out)
- fat/protein (food, protein powder) - affect absorption (space out)
- dopamine antagonist (eg antiemetic - metoclopramide, prochlorperazine; FGA; risperidone)
antiemetic of choice in PD
domperidone
eg of dopamine agonist
ropinirole, pramipexole, rotigotine (patch), apomorphine (SC)
MOA of dopamine agonist
act on D2 receptors in basal ganglia, mimic the action of dopamine
PK characteristics of dopamine agonist
- ergot derivative lower F than non-ergot due to first pass metabolism
- longer half life and duration that levodopa
- ropinirole: metabolised by liver (caution in liver impairment)
- pramipexole: excreted largely unchanged in urine (caution in renal failure)
AE of dopamine agonist (peripheral and central)
- peripheral: N/V/ orthosatic hypotension, leg edema
- central: hallucination/psychosis, somnolence, daytime sleepiness, compulsive behaviours (must counsel pt)
- fibrosis and valvular heart disease (more common in ergot derivative DA)
what is the most important counselling point for pt on dopamine agonist?
compulsive behaviours (gambling, shopping, eating, hypersexuality)
dopamine agonist place in therapy compared to levodpa
less motor sx but more hallucination, slp disturbances, leg edema, OH than levodopa
- preferred over levodopa in younger pt
indications for dopamine agonist in PD
- monotx for young onset PD
- adjunct to levodopa for mod-sev PD
- mx of motor complications caused by levodopa
eg of irreversible MAO-Bi, MOA
selegiline, rasagiline
- MOA: inhibit breakdown of levodopa and domaine in the brain (central)
- not totally selective for MAO-B
MAO-A vs MAO-B
MAO-A: peripheral, NA and 5HT
MAO-B: central, dopamine
can MAO-Bi be used as monotx
yes, in early stage PD
what to take note of when taking selegiline
metabolised into amphetamines (stimulants) - take second dose late afternoon instead of at night (otherwise cannot sleep)
- effect not seen with rasagiline (not metabolised to amphetamine)
MAO-Bi DDI
- SSRI, SNRI, TCA - washout needed
- linezolid
- dopamine
- dextromethorphan
- sympathomimetics: pseudoephedrine
MAO-Bi DFI
tyramine containing foods (cheese, aged meat, preserved/fermented food)
MAO-Bi place in tx
- not as great as DA or levodopa
- monotx in early stages, adjunct in late stage PD
- more commonly used in early stages of young onset PD
selective reversible COMT inhibitors eg
entacapone, tolcapone
can COMT be used as monotx
no, must be taken together with levodopa
- decreases “off” time with levodopa
DDI with COMT
- iron, Ca
- concurrent non-selective MAOi (safe with MAO-Bi)
- catecholamine drugs
- enhance anticoagulant effect of warfarin
SE of COMT inhibitors
diarrhoea, urine discoloration (orange)
Cautions with COMT inhibitors
- hepatic impairments
- may cause dyskinesia upon initiating (decrease levodopa dose)
- potentiates dopaminergic effects (eg OH, N, V)
anticholinergics used in PD
benztropine, trihexyphenidyl (benzhexol)
anticholinergics place in tx for PD
- limited use
- used to control tremor
- has anticholinergic SE
eg NMDA antagonist used in PD and MOA
amantadine
(memantine used in AD)
- MOA: decrease glutamate activity that caused cell death
PK of amantadine
- renally excreted
- can be stimulating (take second dose in afternoon instead of night)
amantadine place in tx for PD
- adjunct
- mx of levodopa induced dyskinesia
AE of amantadine
nausea, light headedness, insomnia, confusion, hallucinations, livedo reticularis
alternative/ complementary medicines
co-enzyme Q10, creatine (not proven effective)
Drug induced PD (LO): how is it different from idiopathic PD
- sx occurs bilaterally (iPD usually unilateral initially)
- withdrawal of drugs leads to improvement
- no resting tremor, acute onset
5 drugs that induce PD
- D2 receptor blockers (FGA, SGA)
- Dopamine depleters (valbenzine, tetrabenzine, reserpine)
- Dopamine synthesis blocker (methyldopa)
- CCB (flunarizine, cinnarizine, diltiazem, verapamil)
- valproate
- antiemetic (prochlorperazine, metoclopramide)
Mx of drug induced PD
- tx: withdraw offending drug
- may not always be reversible
- amantadine and anticholinergics may be used
Non-pharm
physiotherapy, occupational therapy, speech therapy, deep brain stimulation (for advanced PD)
