Pharmacology of Movement Flashcards
what does parkinson’s disease histologically look like
- Loss of dopaminergic cells in substantia nigra pars compacta
- And presence in neurones of Lewy bodies ( these are intracellular formation that are enriched in the protein alpha-synuclein)
- These Lewy bodies are also presence in other conditions such as dementia
- There are also losses of cells throughout the nervous system
How can you monitor the loss of dopaminergic nigral cells in parkinsons
- This imaging of the transporter is known as the DAT scan
- The transporter is a marker of dopaminergic projections and can be labelled with SPECT ligands
What are the motor features of parkinsons
Features of the disease
- Resting tremor – specific frequency of around 4-6hz
- Bradykinesia (akinesia)
- Rigidity
They also have
- Difficulty initiating and stopping movement
- Altered gait and postural changes (flexed posture)
Other symtpoms
- Gradual development of micrographia
What are the non motor features of parkinsons
- olfactory dysfunction
- depression
- psychotic symptoms
- cognitive dysfunction
- dementia (late phase)
- sleep disturbance
- autonomic dysfunction
what features of parkinsons arise first normally motor or non motor
non-motor features may precede by 12-15 years the onset of typical parkinsonian motor symptoms, this premotor phase is likely to involve multiple regions of the peripheral and central nervous system
describe the scoring phase of parkinsons
- 100%-Completely independent. Able to do all chores w/o slowness, difficulty, or impairment.
- 90%-Completely independent. Able to do all chores with some slowness, difficulty, or impairment. May take twice as long.
- 80%-Independent in most chores. Takes twice as long. Conscious of difficulty and slowing
- 70%-Not completely independent. More difficulty with chores. 3 to 4X along on chores for some. May take large part of day for chores.
- 60%-Some dependency. Can do most chores, but very slowly and with much effort. Errors, some impossible
- 50%-More dependant. Help with 1/2 of chores. Difficulty with everything
- 40%-Very dependant. Can assist with all chores but few alone
- 30%-With effort, now and then does a few chores alone of begins alone. Much help needed
- 20%-Nothing alone. Can do some slight help with some chores. Severe invalid
- 10%-Totally dependant, helpless
- 0%-Vegetative functions such as swallowing, bladder and bowel function are not functioning. Bedridden.
what protein is associated with parkinsons
protein alpha-synuclein
what gene is associated with parkinson’s disease
- SNCA- codes for the protein alpha-synuclein – increases significantly the risk of developing Parkinson’s
- Duplications, or triplications can cause autosomal dominant familial parkinsons disease
describe how neurotoxins and dopamine receptors can lead to parkinsons
- there can be mitochondrial toxicity
- MPTP this can be transformed into the metabolite MPP+ which is neurotoxic for dopaminergic neurones
- dysfunction of complex I of the mitochondrial respiratory chain can lead to increased oxidative stress
Why is oxidative stress increased in parkinsons disease
- Dopamine is highly oxidizable and its metabolism produces free radicals and oxidation products such as H2O2
- MAO – monoamine oxidase (B isoform) is critically involved in oxidation
processes
describe the pathway of dopamine synthesis
- L tyrosine is made into L dopa via tyrosine hydroxylase
- L dopa is made into dopamine via DOPA decarboxylase
describe the pathway of dopamine being degraded
- MAO coverts dopamine to DOPA
- then COMT coverts DOPA to its inactive form
why is dopamine given as L dopa in a drug
- dopamine does not go straight through the blood brain barrier as it is hydrophilic
- when it is taken in high amounts it also makes you sick
- it is inactivated as well
What type of receptors are dopamine receptors
G protein coupled receptors
name the two dopamine family receptors and there subtypes
- D1-like (D1 family) receptor subtypes: D1 and D5
- D2-like (D2 family) receptor subtypes: D2, D3, D4
describe L dopa and what is it combined with
- L-DOPA (levodopa) is a biosynthetic precursor – is combined with peripherally acting DOPA decaboxylase inhibitors (carbidopa, benserazide)
name some dopaminergic agonists
ropinirole, pramipexole, rotigotine, pergolide, bromocriptine, cabergoline
What is rotigotine
Rotigotine: dopamine agonist which can be used as transdermal patch – important as the disease progresses and they can no longer swallow
What is apomorphine
dopamine agonist which can be used as an infusion, for major motor fluctuations
name some MAOb inhibitors
• MAOB inhibitors (protect residual dopamine against oxidation)
- rasagiline, selegiline
name some anticholinergic compounds
• Anticholinergic (antimuscarinic) compounds (dopamine loss leads to hyperactivity of cholinergic cells)
- orphenadrine, procyclidine, trihexyphenidyl
what does amantadine do
• Amantadine (inhibits dopamine reuptake, increases dopamine release)
give some examples of COMT inhibitors
• COMT inhibitors (used in combination with L-DOPA, to enhance its effects)
- entacapone, tolcapone
Name the adverse effects of L dopa
- Nausea and vomiting
- Postural hypotension
- Psychosis
- Impulse- control disorders
- Excessive day-time sleepiness
Motor complications
- One off effect – loose efficacy – mobile one moment and then inmobile
- Wearing off (end of dose deterioration)
- Dyskinesia, dystonia
name the initial therapy for early parkinsons disease
L dopa
dopamine agonists
MAOb inhibitors
describe - L dopa - dopamine agonists - MAOb inhibitors in terms of - motor system control - risk of side effects
- L dopa - increases motor system control most 0 increase risk of motor complications and other adverse events
- dopamine agonists - increases motor system control the 2nd most - decrease risk of motor complications but has other adverse effects
- MAOb inhibitors - increases motor system control the least - decrease risk of motor complications but has other adverse effects
describe how a diagnosis of parkinsons is made
- mild motor disability and no cognitive impairment - begin MAOb inhibitor
- mild/moderate motor disability and no cognitive impairment - begin dopamine agonist
- moderate/severe disability and age 70-75+ years or with significant comorbidity including cognitive impairment - begin L Dopa and plus or minus COMT inhibitor
what should parkinsons patient have regular access to
- Monitoring and alteration of medication
- A continuing point of contact
- A reliable source of information
- physiotherapy, speech and language therapy, and occupational therapy should be available, as supportive interventions in the management of these patients
name other treatment for parkinsons
- long term survivial of human embryonic mesencephalic graft in parkisnons disease, - the graft is functional and releases dopamine (after administration of metamphetamine) the dopamine released by the graft can displace the radioalabelled raclopride
what gene defect is in huntingtons disease
associated with changes in the gene encoding the protein huntington on chromosome 4
- The gene presents with an abnormal number of repeats of glutamine (CAG codon) in the protein sequence; abnormal gene contains >36 repeats; the mutation leads to a “gain of function”; the mutated protein aggregates inside cells
What are the pathological changes in huntingtons
- Cortical atrophy and prominent striatal degradation
- Loss of medium size spiny neurones (striato-pallidal and striato-nigral pathways)
What is the mechanism underlying neurodegeneration in huntington’s disease
- Excitotoxicity
- Loss of neurotrophic factors
- Accumulation of aggregates of mutant huntingtin protein
- Dysregulation of transcription
- Increased oxidative stress
- Abnormalities in axonal transport
- Synaptic abnormalities
How long does huntingtons disease take to progress
The disease progresses over about 12-15 years from onset
What are the symptoms of Huntington’s disease
- Choreic movement (early to mid-stage disease)
- Gait abnormalities
- Lack of coordination
- Cognitive impairment: poor attention, memory difficulties
- Psychiatric disturbances
- Sleep disturbance
- Weight loss
what is the pharacological management of Huntington’s disease
- Vesicular amine transporter inhibitor: tetrabenazine- blcoks the concentration of dopamine in vesicles
- Antidopaminergic (antipsychotic) drugs: haloperidol, olanzapine
- Antidepressant drugs: imipramine, amitriptyline
