Idiopathic PD Flashcards
What is Parkinson’s Disease/ paralysis agitans/ shaking palsy?
- idiopathic
- degenerative
- CNS disorder
What are the 4 characteristic features of PD?
- Slowness and poverty of movement
- Muscular rigidity
- Resting tremor
- Postural instability
What are the 3 cardinal signs that are used for diagnosis of PD?
- Tremor: resting tremor (disappears with movement), inc w stress
- Rigidity: “ratchet”-like stiffness (cogwheel rigidity); also leadpipe rigidity
- Akinesia/bradykinesia: subjective sense of weakness, loss of dexterity, difficulty using kitchen tools, loss of facial expression, reduced blinking, difficulty getting out of bed/chair, difficulty turning while walking
How many cardinal signs must be present to confirm diagnosis of PD?
2 out of 3
Which cardinal sign is not a diagnostic feature?
Postural instability
What are the features at initial presentation of Idiopathic PD?
- Asymmetric
- +VE response to levodopa / apomorphine
- Postural instability (& falls) - not present
- Less rapid progression (rapid is H&Y of 3 in 3 years)
- Autonomic dysfn - not present
- Impaired olfaction (?)
- Neuroimaging ??
What are some morbidity factors caused by Idiopathic PD?
- Unable to perform basic ADLs (or perform them safely)
~ mobility, feeding self, grooming, personal hygiene, toileting, showering/bathing, continence (bowel and bladder) - Dysphagia (leads to pneumonia)
- Falls due to instability (not able to react fast enough)
What is the cause of Idiopathic PD?
- Loss of dopaminergic neurons in substantia nigra: about 80% loss –> clinical smx
- age-related loss of neurons
- env toxin/insults?; MPTP-MPP+, Pesticides, herbicides
- genetics: predisposition to toxins/ insults; genetic abnormalities
When do we use Hoehn and Yahr to measure PD?
- to assess mobility (doesnt measure non-motor smx)
- if on tx, should be assess when the person is in the “ON” and also in the “OFF” state
(dont need to do at every clinic visit)
How to we interpret Hoehn and Yahr? (KIV)
increasing disability; decreasing independence from 1 to 5
1: smx on one side of body only
2: bilateral smx; no balance impairment
3: impaired postural reflexes; physically independent
4: Severe disability, yet still able to walk/ stand or stand unassisted
5: wheelchair bound or bedridden
What are some non-motor smx of PD?
- dementia
- depression
- psychosis
- REM sleep behaviour disorder
- Constipation
- GI motility
- Orthostatic hypotension
- Sialorrhoea (due to dysphagia)
- Fatigue
What are other measurements for PD? KIV
measuring non-motor sx
- UPDRS
- MDS-UPDRS (+non-motor)
How many years before clinical onset does smx occur?
20 year prodrome:
- 20yr hyposmia (lack of smell), constipation, bladder disorder
- 10yr sleep disorder, obesity, depression
What are the features of early/ young onset PD?
- slower disease progression
Features:
- less cognitive decline
- earlier motor complications
- dystonia common initial presentation VS falls & freezing in late-onset
dopamine agonists used in preference to levodopa
- dystonia (muscles contract involuntarily, causing repetitive or twisting movements.)
What are the goals of tx?
Manage smx
Maintain fn and autonomy
no tx for PD has ever been shown to be “neuroprotective”
Which class of drugs inc central dopamine, dopaminergic transmission?
1) levodopa + DCI
2) Dopamine agonists
3) MAO B inhibitors
4) COMT inhibitors
Which class of drugs correct the imbalance in other pathways?
1) Anticholinergics
2) NMDA antagonists
What are some non-pharmacological approaches to PD?
- PT: stretching, transfers, posture, walking
- OT: mobility aids, home and workplace safety
- speech and swallowing
- surgery
When is levodopa most effective?
- esp Bradykinesia and Rigidity
When is levodopa the least effective?
- less effective for speech, postural reflex and gait disturbances
Why dopamine cannot be used as a treatment?
DA doesnt cross BBB
Which enzyme causes a peripheral conversion of levodopa to dopamine?
- Catalysed by DOPA decarboxylase, MAO, COMT
What are the PK of levodopa?
- abs in proximal part of SI
- Levodopa F: ~ 33%
- With benserazide or carbidopa: ~75%
- by an active saturable carrier system for large neutral aa e.g. tryptophan
- Abs dec with high fat or high protein meals (separate by 2 hours)
What is combined with Levodopa?
DOPA decarboxylase inhibitors (DCI)
- Do not cross the BBB (only protect levodopa at peripheral)
75-100mg daily required to saturate dopa decarboxylase
What is the ratio of DCI: levodopa?
DCI: levodopa
- 1:4 (Sinemet, Madopar)
- 1:10 (Sinemet)
What are the adv effects of levodopa?
- N/V
- Orthostatic hypotension
- Drowsiness, sudden sleep onset
- Hallucinations, psychosis
- Dyskinesias - Usual onset: within 3-5 yrs of initiating tx w levodopa
What are some motor complications of levodopa?
- “on-off” phenomenon
- “wearing off”
- dyskinesias
What is the “on-off” phenomenon?
“on-off” phenomenon
- ON: response to levodopa
- OFF: no response to levodopa
- Unpredictable, not related to dose/ dosing interval
- “throwing a light switch”
- Mechanism is unclear
- Difficult to control w meds
What is the “wearing off” effect of levodopa and how do we manage it?
“wearing off”
- Effect of levodopa wanes before the end of the dosing interval
- shortened “ON” time
- associated with disease progression
- Management: Modify times of adm, and/or Replace with modified-release preparations at the appropriate time
What is dyskinesia and how to manage it?
- involuntary, uncontrollable
- twitching, jerking
- peak dose dyskinesia
- dystonia
Management: add amantadine; or replace specific doses with modified-release levodopa
What are the changes in levodopa response associated with progression of PD?
- Early PD
Long duration motor response –> Low incidence of dyskinesia - Moderate PD
Shorter duration motor response –> Increased incidence of dyskinesia - Advanced PD
Short duration motor response –> ‘On’-time consistently associated with dyskinesia
Why are sustained-release forms of levodopa designed?
release levodopa/DCI over a longer period (about 4-6 hours)
SR have Lower F
- dose adjustments may be needed when switching between IR (immediate-release) and CR (controlled-release) forms
- IR to CR: generally inc dose needed (~25-50%)
- CR to IR: generally dec dose needed
What are some precautions/ instructions for sustained-release levodopa?
useful for dec stiffness on waking (to be taken before bedtime)
Sinemet SR/CR - do not crush
Madopar HBS -do not open capsule
What are some DDI/ food-drug interactions that we should monitor/consider for levodopa?
- pyridoxine
- iron
- protein
- antidopaminergic drugs
- nonselective MAOis
What is the concern between Pyridoxine and Levodopa?
Pyridoxine (B6) is a cofactor for dopa decarboxylase
- generally not a problem if levodopa is adm w DCI BUT to be aware of possibility of interactions with:
- high dose of B6 for haematological problems or in high potency Vit B complex tabs
(e. g. Neurobion, vit b4, daneuron)
What is the concern between Iron and Levodopa?
Iron affects abs of levodopa –> space out adm
What is the concern between Protein (food, protein powder) and Levodopa?
Affects abs of levodopa –> space out adm (2 hours apart)
What is the concern between Antidopaminergic drugs and Levodopa?
NO: Metoclopramide, prochlorperazine, 1st gen antipsychotics, risperidone
Antiemetic of choice in PD (for N/V) = DOMPERIDONE
What are the ergot and non-ergot derivatives of dopamine agonists?
Ergot derivatives:
- Bromocriptine
- Cabergoline
- Pergolide (not in SG)
Non-ergot derivatives:
- Ropinirole
- Pramipexole
- Rotigotine (transdermal patch)
- Apomorphine (subcut, injection, not in SG)
What is the MOA of dopamine agonists?
Act on D2 receptors in the basal ganglia
Mimic action of dopamine
What are the PK of dopamine agonists?
Ergot derived: lower F than non-ergot derived, due to extensive first-pass metabolism
Longer t1/2 and DOA than levodopa
(Longer DOA ; prevent delay of dyskinesia, purposeless, not reversible
Dopamine agonists less likely to cause dyskinesia vs levodopa)
Which dopamine agonist needs to be considered for dose adjustment in hepatic impairment?
Ropinirole: mainly metabolised by liver, to inactive metabolites
Which dopamine agonist needs to be considered for dose adjustment in renal impairment?
Pramipexole: excreted largely unchanged in the urine
What are the peripheral adv effects of dopamine agonists?
- N/V
- Orthostatic hypotension
- Leg oedema
What are the central adv effects of dopamine agonists?
- Hallucinations (usually visual > auditory)
- Somnolence, day-time sleepiness
- Compulsive behaviours (gambling, shopping, eating, hypersexuality)
What are some non-dopaminergic adv effects of dopamine agonists?
- Fibrosis
: pulmonary, pericardiac, retro-peritoneal
: may be partially reversible upon withdrawal
: lower risk with non-ergot agents - Valvular heart disease: incidence appears to be greater with ergot-derived agents
fibrosis and valvular heart disease greater w ergot-derived agents
What are the pros and cons of levodopa and dopamine agonists?
dopamine agonists have less motor complications than levodopa BUT
dopamine agonists have more hallucinations, sleep disturbances, leg oedema, and orthostatic hypotension
Is dopamine agonist preferred over levodopa?
- no clinically significant differences in efficacy btw agents
- however, dopamine agonists are freq preferred over levodopa in younger pts: to maximise tx options and delay the onset of levodopa-induced motor complications
Is dopamine agonists used mono or combined?
- monotherapy in young-onset PD
- Adjunct to levodopa in moderate/severe PD
How does dopamine agonist help with the complications of levodopa?
Management of motor complications caused by levodopa
When is the Rotigotine patch used for?
Useful when transferring
Handy for pts not suitable for those cant take things orally,
Nil by mouth, cannot be tube fed
Is it proven that dopamine agonists have neuroprotective effects and have disease modifications?
no
What are some additional points to note for dopamine agonists (KIV?)
- pergolide not registered in SG
- Rotigotine patches: in some countries, the patch required refrigeration. The manufacturer has de-registered Neupro patches in SG –> exemption item
Cabergoline marketed under 2 diff brand names: Dostinex (0.5mg); Cabaser (1mg, 2mg) ; Cabaser not registered in SG
Pramipexole and Ropinirole are available in both IR and SR forms
What are the MAO-B inhibitors?
central, dopamine (HOWEVER, not totally selective for MAO-B)
NOT peripheral, NE and 5HT (MOA-A)
Rate of MAO regeneration: 14-28 days
Which MAO-B inhibitors are irreversible enzyme inhibitors?
Selegiline and Rasagiline
What is unique about the t/2 and DOA of Selegiline and Rasagiline?
Short half life (~1.5-4hrs)
BUT long DOA
Are Selegiline and Rasagiline used mono or combi with levodopa?
- MONOtherapy used for early stages
Is it proven that MAO-B inhibitors have neuroprotective effects?
no
What are the doses of Selegiline and Rasagiline?
Selegiline: 5mg OM to BD (2nd dose in the afternoon)
Rasagiline: 0.5mg to 2mg OD (any time of the day)
Which MAO-B inhibitor is hepatically metabolised to amphetamines which are stimulating and thus have no effect on MAO-B?
Selegiline
Which MAO-B inhibitor is not metabolised to amphetamines?
Rasagiline
What is the problem with the formation of amphetamines?
stimulating and have no effect on MAO-B
What are some DDI interactions with MAO-B inhibitors?
Drug interactions:
- SSRIs, SNRIs, TCAs: washout periods recommended
- Pethidine, tramadol
- Linezolid
- Dextromethorphan
- Dopamine
- Sympathomimetics: nasal decongestants e.g. pseudoephedrine, phenylephrine
- another MAOI
What are some drug-food interactions with MAO-B inhibitors?
Tyramine: metabolised by both MAO-A and MAO-B
No firm guidelines regarding the necessity for dietary restriction
In practice, pts should be advised to avoid such foods
How to use MAO-B inhibitors to manage PD? mono or combi and at which stage of PD is it usually used?
- Improvement in UPDRS scores not as great as with dopamine agonists or levodopa
- monotherapy in early stages, or adjunct in later stages
- more commonly used in early stages of young onset PD
Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more improvement in motor smx
levodopa
Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more improvement in ADLs?
levodopa
Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more motor complications?
levodopa
Among levodopa, dopamine agonists and MAO-B inhibitors, which one has more specific adv effects?
dopamine agonists
In the presence of DCI (Decarboxylase inhibitor), which enzyme is a major metaboliser of levodopa?
COMT
What COMT inhibitors do? MOA?
- decreases “off” time; Useful in wearing off, prolonged effect of levodopa
Is COMT inhibitor used as mono or combi?
Not effective without concurrent levodopa
“protects levodopa”
In animals, shown to inhibit central COMT activity
COMT activity; enters CNS minimally; protects levodopa in the peripheral
What is entacapone?
Selective, reversible COMT inhibitor
TO BE TAKEN AT SAME TIME AS LEVODOPA
What are some DDI to take note of for entacapone?
- iron, calcium chelation
- any catecholamine drug
- enhance anticoagulant effect of warfarin
Not applicable in SG: Avoid concurrent nonselective MAOi (but safe with MAO-B inhibitors, caution with selectiv e MAO-Ai)
What are some side effects of entacapone?
diarrhoea urine discolouration (orange)
Is entacapone “with caution” in hepatic or renal impairment?
hepatic impairment
Do we need to monitor LFTs for Entacapone?
No
What are the 2 forms of Entacapone?
- Comtan: entacapone ONLY
Entacapone only given when you want to longer duration by reducing the conversion of levodopa to dopamine - Stalevo: levodopa, carbidopa, and entacapone (to lengthen DOA)
What are some adv effects of entacapone?
- may cause dyskinesia upon initiation –> may require a dec in levodopa dose (Usually reversible, for a short period of time)
- May also potentiate other dopaminergic effects: orthostatic hypotension, N/V (more sig SE)
What are some common side effects of Anticholinergic drugs?
Dry mouth
constipation
Urinary retention
Blurred vision, confusion
Is the site of action of anticholinergics at CNS or periphery?
CNS
PD is a CNS disorder
Which drugs cannot be used to manage smx of PD?
Peripherally acting agents such as
Ipratropium and Hyoscine N-butylbromide (polar, hydrophilic, doesnt cross BBB)
Tolterodine: bladder issues
What are the 2 anticholinergic drugs used for PD?
- Benztropine (tmax 7h)
- Trihexyphenidyl (tmax 1.3h)
What are NMDA?
NMDA N-methyl-D-asparate
- One of the chemicals associated with neurotoxicity is glutamate
- Glutamate activates NMDA receptor activity which activates processes that encourage cell death
- Inc glutamatergic activity linked to the : development of, and Maintenance of levodopa-induced dyskinesia
What is amantadine?
- NMDA antagonist
- anticholinergic
- upregulates D2 receptors, inc sensitivity of D2 receptors
several proposed MOA
good evidence for an effect on levodopa-induced dyskinesia
Does memantine have a good evidence for an effect on levodopa-induced dyskinesia?
no
How are NMDA antagonists excreted?
Renally excreted - reduce dose in renal impairment
How are the doses like for NMDA antagonists?
Can be stimulating (similar to the formation of amphetamines in MAOB)
- 2nd dose in the afternoon, NOT AT NIGHT
Can amantadine given with memantine?
no, avoid concurrent use with memantine
What are the adv effects of NMDA antagonists?
Nausea, light-headedness, insomnia, confusion, hallucination, livedo reticularis
Is NMDA antagonist mono or combi or adjunctive?
- adjunctive
- managing levodopa-induced dyskinesias
What are some alternative / complementary med we should look out for?
- Co-enzyme Q10 + 200iU vit E in early PD –> safe but not effective
- Creatine for tx of early stage PD –> safe but not effective
- Vit E
- Glutathione
- Ribofalvin
- Lipoic acid
- Acetyl carnitine
- Curcumin
