parkinson disease Flashcards
What is parkinson disease?
Neurodegenerative, progressive disease
primarily involving the dopamine generating neurones in the substantia nigra
Parkinson disease is characterised by?
1) bradykinesia,
2) rigidity,
3) tremor, and
4) postural instability
First described by ———————
Identified its major symptoms and called it ————–
Research progressed slowly until the ———-
60’s linked the disease to the loss of cells that produce —————-
Development of DA replacement therapies which still remain the mainstay of treatment to this day
British doctor James Parkinson
“the shaking palsy”
1960’s
dopamine (DA)
PD occurs in about ————— and in about ——————
There are also familial cases of early onset PD from age ——————–
There is also a rarer form of juvenile onset PD from age ———–
1% of the population aged 60 years
4% at 80 years.
(age range 21–40 years)
(younger than 21 years of age)
Parkinsonism presents the same kind of clinical symptoms with Parkinson disease. TRUE or FALSE
true
What are the symptoms of parkinsonism
Tremor
bradykinesia
rigidity
what causes the Parkinsonism
DRUGS – Anti psychotics, metaclopramide, TCA, MPTP
Vascular disease
Parkinson plus syndromes (multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Lewy-body dementia)
Trauma
What is the difference between Parkinson clinical symptoms and that of Parkinsonism
Parkinsonism symptoms are reversible
what are the classic TRIAD core diagnostic symptoms of PD
BRADYKINESIA / slowness
RIGIDITY / stiffness / increased tone
TREMOR / pill rolling / 4-6 Hz /resting
AND
Postural instability
what are the initial symptoms of PD
First signs can be mistaken for another condition.
Can be considered by the patient as a normal part of the aging process.
Persistent mild fatigue
Handwriting might become “shaky”
Person might feel unbalanced or have difficulty performing sit-to-stands
Agitation, irritability, & depression
Lack of affect (masked face phenom)
Initial symptoms can go on for years
what are the motor symptoms of PD
Hand tremors - rhythmic back-and-forth motion of the thumb.
Rigidity or resistance to movement
Muscles associated with movement all have opposing muscles - when one is activated, the other is relaxed.
In PD - both sets of muscles remain engaged and contracted - rigidity
Spontaneous movements can become progressively slower and may actually cease - bradykinesia
Impaired balance and coordination - postural instability
- Patients lean unnaturally backward or forward, head down and stooped stance
-Become vulnerable to falls
Physical presentation of PD
Rigidity and trembling of head
Rigidity and trembling of extremities
forward tilt of trunk
Reduced arm swinging
shuffling gait with short steps
List the non motor symptoms
Depression
Emotional Changes (Irritable, pessimistic, fearful, become dependent or isolated)
Memory Loss (slower thought processes) Dementia with Lewy Bodies (DLB)
Swallowing Difficulties
Speech Problems
Bladder/Bowel disorders
Excessive sweating
Sleep Disturbance
what could be causing difficulty in movement in PD, Limb can not be kept still
Degeneration of pigmented neurones in the pars compacta of the substantia nigra.
Lewy Bodies
Degeneration of brainstem nuclei
What are Lewy bodies
They are prominent, composed of insoluble composed of aggregates containing a protein called alpha-synuclein (AS)
Explain Alpha synuclein protein
it is indispensable for life, it is found in nucleus but primarily at the presynaptic terminal
controls neurotransmitters release
The level of expression of alpha synuclein determines whether it can aggregate and form lewy bodies. TRUE or FALSE
TRUE
Explain why expression level of alpha synuclein is important
Expression level of AS very important > increased AS expression > AS aggregation > LBs > death of SN neurons > mutations that lead to increased AS expression > vulnerability to developing PD.
In normal aging, explain AS expression
Normal aging > increased AS expression > inherent vulnerability to develop PD
REFER TO SLIDE 13-16 ON THE PP
explain the neurobiological motor symptoms of PD
The Basal Ganglia
SN neurons produce/release dopamine
Main targets are caudate nucleus and putamen (striatum)
This basal ganglia pathway is involved in regulation of movement (Extrapyramidal Motor System)
Cells of substantia nigra degenerate
Neurons of striatum are no longer well regulated
Results in loss of control of movements – leads to symptoms characteristic of Parkinson’s disease
Explain the neurological non motor symptoms of PD
Apart from DA neurons degenerating, cell death is found in the following brain regions as well:
1.Locus coeruleus degeneration (NA)
Emotional changes
Anxiety
Stress
2. Nucleus Basalis of Meyenert degeneration (Ach)
Memory
Cognition
3. Enteric nervous system neurotransmitter release (GIT)
constipation; swallowing; drooling
what causes Parkinson disease
Majority of cases are of no known cause > Idiopathic PD.
Genetics (alpha synuclein e.g)
Environmental factors (toxins e.g. MPTP)
Oxidative Stress > impairment in energy regulation > cell death
What are the pharmacotherapy strategies for motor symptoms of PD
Dopamine replacement
1.DA receptor activation dopamine receptor agonists
2.Preventing DA breakdown (Mono amine oxidase 3.inhibitors and Catechol-O-Methyl Transferase Inhibitors)
4.Antimuscarinic drugs
REFER TO SLIDE 21
Dopamine replacement
Mainstay of PD first line therapy
Cannot administer DA itself as it does not cross the blood brain barrier (BBB).
Use levodopa (L-DOPA) > precursor amino acid converted to DA > L-Dopa can cross the BBB and is coveted to DA in the brain.
L-dopa susceptible to degradation by enzyme dopa decarboxylase which is also present in the periphery > potential decrease amounts getting into brain
> administer a preparation that contains L-dopa AND a peripheral dopa decarboxylase inhibitor
> Benzerazide (CO-BENELDOPA)
> Carbidopa (CO-CARELDOPA)
effectively extending the duration of drug action and ensuring that lower doses of L-DOPA can be used minimising peripheral side effects.
explain L-DOPA treatment
Initiated in lowest dose and increased in small increment > minimise off-target effects.
Final dose as low as possible.
Choose most effective dosing intervals to avoid motor fluctuations
Effective in treating bradykinesia and rigidity
Less effective in reducing tremor
Often ineffective in relieving problems related to balance
explain long term L-dopa effectiveness in PD
Initially effective but diminishes with time
Although no change in progression, its early use diminishes mortality
Motor fluctuations > after 4 – 6 and most patients within 10 years
>Fluctuations relate to timing of L-dopa intake
>Termed ON/OFF phenomenon
ON > marked improvement in mobility
OFF > marked akinesia
what are the side effects of L-DOPA. Early SE
Gastrointestinal Side Effects
Cardiovascular Side Effects.
Orthostatic or Postural Hypotension.
Behavioural Side Effects.
Abnormal Involuntary Movements (Dyskinesia)
On-Off symptoms
What are the Dopamine receptor modulators and how do they work
- Amantadine (no longer used nowadays)
Antiviral agent found to have anti-parkinsonian activity
acts by releasing dopamine from intact dopamine terminals in the striatum. - Dopaminergic agonists (first line treatment)
Potentially useful as a first-line treatment option for early PD because they delay the onset of motor fluctuations and dyskinesia.
Act directly on selected DA receptors
Have longer half-lives than L-DOPA reduce peaks and troughs prevent the motor complications in early-stage PD or even reverse motor complications initiated in late-stage PD.
Also allows for concomitant therapy with lower dose of L-dopa in unresponsive patients
Cause fewer motor side effects than L-dopa
Associated with more psychiatric side effects (impulse control; pathological gambling stimulation of DA receptors in reward pathways)
What are the dopamine receptor agonists and explain each of them
1.Bromocriptine
Agonist at D2 receptors
Widely used to PD and endocrine disorders
- Pergolide
Agonist at D1 & D2 receptors
Widely used and potentially more effective than Bromocriptine (increases ON time) allowing decrease in L-dopa dose
Associated with valvular heart disease, so use waning in favour of newer agents
3.Pramipexole
Agonist at D3 receptors
Effective as monotherapy in mild PD
Effective as co-therapy with L-dopa in advanced PD
May lessen affective symptoms of PD
Potentially neuroprotective effect
4.Ropinirole
Selective agonist at D2 receptors
Effective as monotherapy in mild PD
Effective “smoothening” the response to L-dopa
- Apomorphine
Potent DA receptor agonist administered s.c under specialist conditions
Helpful in advanced cases unresponsive to other therapies to refractory motor fluctuations
REFER TO SLIDE 29
List the two types of MAOIs in the brain
1) MAO-A (metabolises NA & 5HT);
2) MAO B (metabolises DA) > inhibit MAO-B > less DA broken down > increase amount of DA in the brain
list and explain MAOIs drugs
1.Selegiline
Irreversible inhibitor of MAO-B
>prevents DA breakdown > prolongs antiparkinsonian effect of L-dopa > lower L-dopa dose can be used.
Minor therapeutic effect on its own
> Used as adjunctive therapy with declining effects of L-dopa in later stages.
2.Rasagiline
More potent than Selegiline
what are the Catechol-O-methyl transferase (COMT) inhibitors
- Entacapone and 2. Tolcapone
Similar pharmacological effects
Prolong the activity of L-dopa by preventing its peripheral breakdown > more L-dopa reaches the brain
>Adjunct therapy to L-dopa in patients experience end of dose off symptoms
what are the Antimuscarinic Drugs for PD and explain why they are used
- Benzotropine; 2. Orphenadrine
In striatum, normally, DA from substantia nigra has inhibitory effect whilst acetylcholine, from local interneurons has excitatory effect on striatal neurons
In PD, the lack of DA and its inhibitory effect results in over excitation by cholinergic neurons
Therefore, drugs which block muscarinic cholinergic receptors can be used to alleviate this imbalance.
Not used in primary PD, only drug-induced PD
what are the pharmacotherapy strategies for non motor symptoms. list each symptom with drug use to treatment them
Depression, psychosis > citalopram, quetiapine and clozapine
dementia > Acetylcholinesterase
Sleep disorders > clonazepam
Restless legs syndrome
Periodic limb movements of sleep
REM sleep behaviour disorder
falls
Autonomic disturbance. > oxybutynin, tolterodine
urinary dysfunction
weight loss, dysphagia.
constipation. > movicol
erectile dysfunction
orthostatic hypotension
excessive sweating
sialorrhoea
List the non medical treatments
Brain Grafts and Stem Cell therapy
Deep Brain Stimulation
