parkinson's Flashcards
3 features of PD — pathophysiology
- Lewy bodies
- degeneration of dopaminergic neurons
- basal ganglia
lewy bodies
- Accumulation of aggresomes (aggregated proteins)
- Lewy bodies ~ deposits of a-synuclein and ubiquitin
- Eosinophilic cytoplasmic inclusions
- apoptosis
degeneration of dopaminergic neurons, substantia nigra
- Lewy body inclusion in substantia nigra
- Induce oxidative stress, nitric stress
- Molecular abnormalities
- Dysfunction of nigrostriatal pathway
- Loss of darked region
basal ganglia and motor control
- 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
indirect vs direct pathways (basal ganglia)
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)
neurotransmitter deficiency – PD
- Striatal dopaminergic deficiency
* Extrapyramidal motor sx (tremor, rigidity, bradykinesia) - Other neurotransmitters involved
* Non-motor sx
* Autonomic, psychiatric, sensory, ocular, gait imbalance
cardinal features of PD
- 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
progressives features of PD
- 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
initial presentation
- 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
progressed disease
- 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)
progressive sx of PD
- 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
PD timeline
- 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)
measurement of disease progression
- 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)
dx of PD
- 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
- Tremor
overall parkinson tx strategies
- 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)
tx plan based on onset
- 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
goals of PD management
- Manage sx
- Maintain function & autonomy
No tx because PD is progressive, no neuroprotection available
levodopa MOA
Incr precursor to incr dopamine synthesis
L-dopa –> dopamine (DOPA decarboxylase, MAO, COMT)
concomitant with
- 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
ratio of sinemet (carbidopa) , Madopar (benserazide)
DCI: LEVO
1 : 4 (Sinemet, Madopar)
1 : 10 (Sinemet)
indication for levodopa
- 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
ADR of levodopa
- ST: NV, postural hypoTENsion, drowsy, hallucination, psychosis
- LT: motor fluctuations, dyskinesia (3-5yrs of initiate)
Irreversible
dyskinesia presentation + management
○ 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
dyskinesia stage of levodopa
- 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
manage wearing-off dyskinesia sx
- 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
DDI of levodopa
- Pyridoxine
- Cofactor for dopa decarboxylase
○ Take levo + DCI - HIGH DOSE: Vit B6 (haem issues)/ vit B complex tabs
- Cofactor for dopa decarboxylase
- 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
- Metoclopramide, prochlorperazine
- MAOi (within 14d) - incr NE = hypotensive
COMPTi MOA
catechol-O-methyltransferase
- 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
indication of COMPTi
- Adjunct w/ levodopa (decr off-time, enhancer)
* decr wearing off effects - (not monotherapy)
- Entacapone (selective, reversible), Tolcapone
eg of COMTi drugs
- Comtan: entacapone
- Stalevo: levo + carbidopa + entacapone
* Reduce pill burden, but hard to titrate
COMPTi ADR
- 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
DDI of COMTi
- Fe, Ca
- MAOi (ok with MAO-Bi)
○ Caution with MAO-Ai - Catecholamine drug
- Warfarin
○ Enhances anticoag effect
MAO-Bi MOA
selegiline, rasagiline
Irreversible inhibit enzyme MAO B from breakdown of dopamine
(MAY) delay nigral brain cell degeneration
Neuroprotective effects
indication of MAO-Bi
- MONOTHERAPY Early stage of PD (Selegiline)
* symptomatic monotherapy - adjunct in later stages
dose of MAO-Bi
- 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
- 5mg OD-BD (2nd dose in afternoon X ON)
- Rasagilin (Azilect)
- Not metabolised to amphetamines
- 0.5-2mg OD
pk of MAO-Bi
- Short t1/2 (1.5 - 4hrs)
- Long duration of action (irreversible + MAO only regenerate in 14-28d)
- Metabolised for selegiline
- Liver –> amphetamines (stimulating)
ADR of MAO-Bi
- heartburn, LOA
- ANX, palpitation, insomnia
- nightmare, visual hallucination
MAO-A vs B
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)
MAO-Bi DDI
- SSRI, SNRI, TCA (need washout)
- Pethidine, tramadol (opioids)
- Linezolid, dextromethorphan
- DA
- Sympatomimetics: nasal decongestants (pseudoephedrine)
- Other MAOi
MAO-Bi FDI
- Tyramine (metabolised by MAO-A, MAO-B): displace NA
○ More NA = hypotension - Fermented food, aged cheese, beer
dopamine receptor agonist MOA
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
indication of DA RA
- 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??
ergot derivative (DA agonist)
bromocriptine (NMS, hyperprolact)
cabergoline (0.5mg dostinex)
pergoline (not in sg)
non-ergot derivative DA agonist
ropinirole
pramipexole (IR, SR form)
rotigotine (patch, exemption item)
apomorphine (sc inj not in SG)
PK of DA agonist
- 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
DA agonist cautions
DO NOT USE
Liver impairment (non-ergot ropinirole)
Urine impairment (non-ergot Pramipexole )
DA agonist ADR
- 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
eg DA agonist ADR
- Pergolide (ergot derivative)
* Peritoneal fibrosis
* Cardiac valve regurgitation - Pramipexole, ropinirole (non-ergot):
* Sedation, somnolence, daytime sleepy
NMDA antagonist MOA
N-methyl D-aspartate
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
NMDA antagonist indications
- Manage Levodopa-induced dyskinesias
- Adjunctive
* 2nd dose in afternoon, stimulating (not ON) - NMS, EPSE (tardive dyskinesia - FGA), hyperprolact
caution for NMDA
renal impair (dose reduction)
* CL: renal
ADR of NMDA antagonist
- N, Cognitive impairment (inability to conc)
- light head, confuse
- Hallucinate, insomnia, nightmare
- Livedo reticularis (venule swell from thrombosis –> risk PE)
* Reticulated discoloration of limbs
memantine vs amantadine
- non-competitive inhibitor NMDA
- No good evidence for effect on levodopa-induced dyskinesias
amantadine
* NMDA antagonist, anticholinergic
* upregulate + sensitivity D2 receptors
anticholinergics eg
- Trihexyphenidyl (benzhexol)
- Biperiden
- Orphenadrine
- procyclidine
- benztropine
anticholinergics MOA
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
indication for anticholinergics
- Sx monotherapy
- Adjunct to levodopa
- Tremor, stiffness in PD
- NOT FOR: bradykinesia, dyskinesia sx
ADR of anticholinergics
- Block parasympathetic system (rest, digest):
* Dry mouth, sedation, constipation, urinary retention, delirium, confusion, hallucinations
tx individualised by
age
stage of disease (early vs late)
lvl of activity (type of daily activity)
assoc psychological factors
assoc medical conditions
drug-induced?
pt factors
pharm tx for non-motox sx
- 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)
CAM
- co-enzyme Q10 + vit E (early): safe, ineffective
- creatine (safe, ineffective)
- vit E 1200 IU (neuroprotective??)
- glutathione
- riboflavin
- lipoic acid
- acetyl carnitine
- curcumin
non pharm
- PT
○ Stretching, transfers, posture, walking (add guiding lines) - OT
○ Mobility aids, home & workplace safety - Speech and swallowing
○ Degree pt can swallow (viscosity level) - Surgery
drug-induced parkinsonism presentation
- Difficult to distinguish from PD
- May be underlying iPD (20%)
Bilateral sx
Elderly
Acute, subacute onset
Poor response to levodopa
Uncommon for rest tremor
DIP tx
- onset of DIP ~3mnths
- Tx: withdraw offending drug
* Withdrawal of drug leads to improvement
* 80% of pt, within 8wks - anticholinergics, amantadine ST use
high potential risk of DIP
(decr DA, neurotransmitters)
- DA (D2) receptor blockers
* APS (FGA > SGA high dose) - DA depleters (tetrabenazine, reserpine)
- DA synthesis blockers (a-methyldopa)
- Ca channel antagonist (flunarizine, cinnarizine)
intermediate potential risk of DIP
- SGA
- Ca channel antagonists
* dilitiazem, verapamil - anti-seizure
* VA, PHT, levetiracetam - antiemetic
* metoclopramide, prochlorperazine - mood stabiliers (Li)
motor sx, activities of daily living
levodopa
(some improvement): DA, MAO-Bi
motor complications ADR
levo > DA, MAOBi
ADE
DA > levodopa, MAOBi
(specified ADE: peripheral, central, non-DA)
(levodopa less ADE, but afer 3-5yrs, more complicatd ADE)
