Parkinson I Flashcards
What is Parkinson’s disease characterised by?
- Idiopathic
- Degenerative
- CNS Disorder
with 4 characteristic features:
1. slowness and poverty of movement
2. muscular rigidity
3. resting tremor
4. postural instability
Risk factors of PD
age, obesity, male.
smoking, caffeine, alcohol (reduces risk of PD) -> but doesn’t mean that you do more of it!
What are the cardinal signs required to diagnose PD?
At least 2 out of 3 of them must be present to accurately diagnose PD.
- Tremor
- Rigidity
- Akinesia/bradykinesia
Features of idiopathic PD - at initial presentation
- Asymmetric
- Positive response to levodopa or apomorphine
- Postural instability (and falls) - absent
- Less rapid progression
- Absence of autonomic dysfunction
What are the implications of PD?
- Unable to perform basic ADLs
» E.g. mobility, feeding self, grooming, personal hygiene
» Dysphagia –> pneumonia
» Falls due to gait instability
What is the pathology, cause of PD
Loss of dopaminergic neurons from the substantial nigra (at least 80% for the symptoms to show)
Age-related loss of nutrons
Environmental toxins / insults (MPTP-MPP+, pesticides, herbicides)
Genetics (predisposition to toxins, insults and genetic abnormalities)
What is the Hoehn and Yahr Staging of PD
- Symptoms only occur on one side of the body
- Bilateral symptoms, no balance impairment
- Impaired postural reflexes, physically independent
- Severe disability, yet still able to walk or stand
- Wheelchair bound or bedridden
What is the purpose of using Hoehn and Yahr staging?
- assess mobility
- if on treatment, should be assessed when person is in the “ON” and “OFF” state.
Cognitive impairments and their respective drug names
Dementia - rivastigmine
Psychosis - clozapine, quetiapine, rivastigmine
REM sleep behaviour disorder - clonazepam, melatonin
GI motility - domperidone
Orthostatic hypertension - domperidone, pyridostigmine
Sialorrhoea - atropine drops, botox
fatigue - methylphenidate, modafinil
Early/young onset PD features
- Slower disease progression
- Features
» slower cognitive decline
» earlier motor complications
» dystonia is common initial presentation - dopamine agonists are used in preference to levodopa.
Summary of the identification, diagnosis and prognosis in PD
Suspect Parkinson’s –> referral to specialist –> consider possibility of atypical parkinsonism –> no confirmatory tests available –> predictors of more benign course (younger onset) OR predictors of more rapid course (older onset)
Goals of PD treatment
- manage symptoms
- maintain function and autonomy
Treatment modalities (pharmacological)
- Increased amount of central dopamine, dopaminergic transmission
1) . Levodopa + DCI
2) . Dopamine agonists
3) . MAO-B inhibitors
4) . COMT inhibitors - Correct imbalance in other pathways
5) . Anticholinergics
6) . NMDA antagonists
Treatment modalities (non-pharmacological)
- PT:
- Stretching, transfers, posture, walking - OT:
- Mobility aids, home and workplace safety - Speech and swallowing
- Surgery
Characteristics of levodopa
- Most effective drug for treatment of symptoms
- esp. bradykinesia and rigidity
- less effective for speech, postural reflex and gait disturbances - Dopamine cannot be used as a treatment - it does not cross the blood brain-barrier.
- Peripheral conversion of levodopa to dopamine is catalysed by DOPA decarboxylase, MAO, COMT.
- causes nausea/vomiting, hypotension
Pharmacokinetics of levodopa
- absorbed in proximal part of small intestine
- bioavailability is boosted with the addition of benserazide or carbidopa.
- by an active, saturable carrier system for large, neutral amino acids (e.g. tryptophan)
- absorption decreases with high fat or protein meals
- with addition of DOPA decarboxylase inhibitors, 75mg-100mg of levodopa is required to saturate the dopa decarboxylase.
Levodopa - adverse effects
- nausea/vomiting
- orthostatic hypotension
- drowsiness
- hallucinations, psychosis
- dyskinesias (usual onset: within 3-5 years of initiating treatmnet with levodopa)
Levodopa - motor complications
- on-off phenomenon
» unpredictable, not related to dosing interval
» difficult to control with meds. - wearing off response
» effect of levodopa wanes before the end of the dosing interval
» shortened “ON” time
» associated with disease progression
» can be managed by modifying time of administration, or giving sustained-release medications. - dyskinesia
» add amantadine, replace specific doses with modified-release levodopa
What are the changes in levodopa response associated with the progression of PD?
Dyskinesia threshold decreases, response threshold moves up, more dose is required to reach the purple zone.
Duration of motor response shortens
“On”-time consistently associated with dyskinesia.
How are levodopa sustained-release forms different from the normal versions
- release levodopa over a longer period
- lower bioavailability
» when switching from IR to CR: dose increment is generally required.
» when switching from CR to IR: dose reduction is required.
Drug interactions with levodopa and their management
1. pyridoxone >> watch out for interactions with B6 2. iron >> space out administration 3. protein >> space out administration 4. antidopaminergic drugs (metoclopramide, prochloperazine, risperidone) 5. non-selective MAOIs
Dopamine agonists
ergot vs non-ergot derivatives
Ergot:
- bromocriptine
- pergolide
Non-ergot:
- ropinirole
- pramiprexole
- rotigotine (transdermal)
- apomorphine (subcut)
MOA of dopamine agonists
Act on dopamine (D2) receptors in the basal ganglia.
Mimic action of dopamine
Pharmacokinetics of dopamine agonists
- Ergot-derived has lower bioavailability than non ergot-derived medications.
- Longer half life and duration of action than levodopa.
- Ropinirole: mainly metabolised by the liver
- Pramiprexole: excreted largely unchanged in the urine
Dopamine agonist side effects (central and peripheral)
Dopaminergic - central
- Hallucinations
- Somnolence
- Compulsive behaviours
Dopaminergic - peripheral
- Nausea, vomiting
- Orthostatic hypotension
- Leg edema
Non-dopaminergic side effects:
- fibrosis
- restrictive valvular heart disease
What are dopamine agonists used for?
- to manage the motor complications brought about by levodopa.
- can be used as monotherapy in young PD patients, or as an adjunctive.
Different formulations of PD drugs for:
- Rotigotine
- Pramiprexole and ropinirole
Rotigotine - patch
Pramiprexole and ropinirole - immediate-release and sustained release formulations
What and where do MAO-B inhibitors inhibit?
- central, dopamine
Can MAO-B inhibitors be used for monotherapy?
Yes
Selegiline vs rasagiline properties
- Both are not entirely selective for MAO-B.
- Selegiline is hepatically metabolised to form amphetamines, rasagiline is not metabolised to form amphetamines.
- Selegiline dose: 5mg OM to BD. Rasagiline dose 0.5-2mg OD
Notable MAO-B drug interactions
- with tyramine-rich foods: cheese reaction
- with other MAOIs: serotonin syndrome
Comparing levodopa, dopamine agonists, and MAO-i.
Motor symptoms: levodopa sees the most improvement in motor symptoms
Activities of daily living: levodopa sees the most improvement in activities of daily living.
Motor complications: levodopa has the most motor complications
Adverse events: dopamine agonists have the most adverse events
Place in therapy for MAO-B
used as monotherapy for the young
Types of COM-T inhibitors and their MOA
entacapone, tolcapone
decrease “off” time
Place in therapy
must be used as adjunct with levodopa.
Entacapone characteristics
- selective, reversible COMT inhibitor
- must be taken at the same time as levodopa
- use with caution in hepatic impairment
- monitoring of LFTs is generally not required
- side effects include: diarrhoea, urine discoloration (orange), dyskinesia, dopaminergic effects (orthostatic hypotension, N/V)
- drug interactions: iron, calcium, warfarin, MAO-I
Tolcapone characteristics
- more potent and longer duration of effect than entacapone
- need for LFTs every 2-4 weeks x 6 months- not registered in Singapore
