Therapeutics - PD

Question 1

What is the aetiology of Parkinson’s disease?

Answer 1

Age related loss of neurons
Env toxin/insults
- MPTP-MPP+
- Pesticides, herbicides

Genetics
- Predisposition to toxins/insults
- Genetic abnormalityies

Drug-induced
-High: Dopamine D2 rece blockers - FGA, SGA, dopamine synth blockers - alpha-methyldopa
-Int: Non-DHP CCB, ASM (valproate, PHT, levetiracetam), antiemetics (prochlorperazine, metoclopramide), mood stabilisers Li
-Low: antiarrhythmics (amiodarone), immunosuppressants, antidepressants, cotrimoxazole, statins, antifungals, hormones

Question 2

What is the pathophysiology of Parkinson’s disease?

Answer 2

Degeneration of dopaminergic neurons in substantia nigra

Misfolded alpha-synuclein forms Lewy body
Long term over xp of alpha-syn decreases DA neurotransmission
Pathological alpha-syn aggregates mediate fnal mitochondrial failure
Mitochondrial failure triggers neuro inflamm (contro to neurotox) –> activation of microglia (to clear cellular debris)

Impaired clearing of abnormal/damaged intracellular proteins by ubiquitin-proteasomal sys
Failure to clear toxic proteins
- Accum –> aggresomes –> cells undergo apoptosis
Lewy bodies ~ aggresome, containing alpha-syn and ubiquitin
- Found in cells esp ard basal ganglia

Question 3

Explain the physiology of dopaminergic activity wrt Parkinson’s disease.

Answer 3

Synthesis
L-tyrosine –> L-dopa (cat by tyrosine hydroxylase)
L-dopa –> dopamine (cat by DOPA decarboxylase)

Breakdown
Dopamine –>–> homovanillic acid (cat by catechol-O-methyltransferase [COMT] & MAO)

Question 4

What are the risk factors of Parkinson’s disease?

Answer 4

Age
Genetics
Male (slight)
Pesticides
Heavy metal exposure
Head trauma
Obesity

Question 5

Describe the epidemiology of Parkinson’s disease?

Answer 5

1% of population aged >60y.o. (global)
0.3% SG population
Slight male prepondrence
No sig diff in prevalence rates bet races
Ave age of onset: early-mid 60s
Young-onset PD: 21-40y.o.
Juvenile onset PD: <20y.o. (higher freq of genetically inherited PD amongst this grp)

Question 6

Describe the principles of pharmacological management of Parkinson’s disease?

Answer 6

Increase central dopamine, dopaminergic transmission:
Levodopa

Dopamine agonists
- Gd for early onset, young pts
- Adjunct to levodopa in mod-severe PD
- Management of motor complications caused by levodopa
- Apomorphine used more as rescue for advanced pts

MAO-B inhib
- Gd for early onset, young pts
- Improvement in UPDRS scores not as great as dopamine agonists or levodopa

COMT inhib
- Never monothera
- Adjunct to levodopa

Correct imbal in other pathways:
Anticholinergics
- Limited use in PD
- Symptomatic control tremor

NMDA rece antagonists: Amantadine
- Adjunct to levodopa
- Management of levodopa induced dyskinesia

Question 7

What are the goals of treatment?

Answer 7

Manage symptoms
Maintain fn & autonomy
No treatment for PD has ever been shown to be neuroprotective

Question 8

What are the non-pharmacological management of Parkinson’s disease?

Answer 8

Physiothera
Occupational thera
Speech thera (softer voice + swallowing difficulties)
Deep brain stimulation

Question 9

What are the signs and symptoms of Parkinson’s disease?

Answer 9

Hypoactivity
Lewy bodies in cells esp ard basal ganglia
Pale substantia nigra

Tremor
Rigidity
Akinesia/bradykinesia
Postural instability
Loss of motor coordination
Postural instability, gait disturbances

Non-motor symptoms
- Autonomic: constipation, GI motility, orthostatic hypotension/HTN, sialorrhea
(manage w peripheral dopamine antagonist, avoid central)
- Psychiatric: depression, psychosis, anxiety
- Sleep disorders
- Sensory
- Ocular
- Suboptimal nutrition

Question 10

Describe the disease progression of PD

Answer 10

Rate of disability progression is most marked in early years of disease
Sig disability 10-15y after onset

Ini:
Assymetric
+ve resp to levodopa or apomorphine
Postural instability & falls not present yet
Less rapid progression
Autonomic dysfn not present
Neuroimaging
- MRI: only for differential Dx of other parkinsonian syndromes
- Single photon emission computed tomography (SPECT) - DA transporter imaging (DaT scan)
Impaired olfaction (not part of diagnostic test run)

Progression:
Unable to perform basic ADLs
Choking (impaired motor fn –> swallowing becomes issue)
Pneumonia (aspiration from swallowing problems)
Falls

Question 11

What are the instruments to measure disease progression?

Answer 11

Hoehn and Yahr staging

Unifief Parkinson’s Disease Rating Scale (UPDRS) and modified UPDRS (MDS-UPDRS)
- Covers non-motor xp of daily living
- Motor xp of daily living
- Motor exam
- Motor complications