Pharmacology of Movement Disorders Flashcards
Parkinson’s disease is caused by loss of what kind of cells in which part of the brain?
Dopaminergic cells in substantia nigra pars compacta
In Parkinson’s disease (PD) there are Lewy bodies in neurons. What are these?
Intracellular formations enriched in the protein α-synuclein
Main features of PD. (6)
Resting tremor Bradykinesia Rigidity Frozen facial expression Flexed posture Gait changes
What non-motor features are associated with PD? (6)
By how many years do these precede the motor symptoms?
olfactory dysfunction depression psychotic symptoms dementia sleep disturbance autonomic dysfunction
12-15 years
What is the name of the scoring scale for disability?
Schwab and England Activities of Daily Living
How can the gradual dopaminergic nigral cell loss be monitored?
Through dopamine transporter imaging in the striatum
Are most PD cases genetic or sporadic?
What protein are genetic cases linked to?
Sporadic
Alpha synuclein
What is the prevalence and annual incidence of PD?
Is it more prevalent in males or females?
100-180 in 100,000 (0.1-0.18%)
4-20 per 100,000 annually
Males
Methyl-phenyl-tetrahydropyridine (MPTP) is transformed into which metabolite?
How is this harmful?
MPP+
This is neurotoxic for dopaminergic neurons. Dysfunction of complex I of the mitochondrial respiratory chain can lead to increased oxidative stress.
How is oxidative stress linked to PD?
It is increased in PD.
Dopamine is highly oxidisable and its metabolism produces free radicals.
What does MAO(b) stand for? What is it involved in?
Monoamine oxidase (B isoform). Oxidation of dopamine.
L-tyrosine is converted to ____ which is converted to ____. Which enzyme catalyses the second reaction?
L-dopa
Dopamine
L-aromatic amino acid decarboxylase
Dopamine is converted to homovanillic acid in two steps by which two enzymes?
MAO and COMT
What type of receptors are dopamine receptors?
G-protein coupled receptors
There are D1-like and D2-like receptors.
Which 2 receptors make up the D1 family?
Which 3 make up the D2 family?
D1 and D5
D2, D3, D4
What are the five main types of drugs used to treat PD?
- Dopaminergic compounds
- Dopaminergic agonists
- MAOB inhibitors
- Anti-cholingeric compounds
- COMT inhibitors
How do dopaminergic compounds work? Give some examples.
They compensate directly for dopaminergic deficit.
L-dopa/levo-dopa (biosynthetic precursor).
Give some examples of dopaminergic agonists.
Ropinirole, pramipexole, rotigotine (can be used as a transdermal patch), pergolide, bromocriptine, cabergoline…
Apomorphine - given as an infusion.
How do MAOB inhibitors work?
They protect residual dopamine against oxidation.
What kind of drugs are rasagiline and selegiline?
MAOB inhibitors.
Why are anti-cholinergic compounds used for PD treatment? Give some examples.
Dopamine loss leads to hyperactivity of cholinergic cells.
Orphenadrine, procyclidine, trihexyphenidyl.
What are entacapone and tolcapone?
COMT inhibitors. They optimise the effect of L-dopa.
How does amantadine work?
It inhibits dopamine reuptake and increases dopamine release.
Give examples of peripherally acting DOPA decarboxylase inhibitors? Why are these given?
Carbidopa and benserazide.
To maximise the effect of L-dopa on the brain rather than in peripheral tissues.
What are the adverse effects of L-DOPA? (6)
Nausea/vomiting Postural hypotension Psychosis Impulse-control disorders Excessive day-time sleepiness Motor complications (dyskinesia, dystonia, on-off effect)
What is the benefit of dopamine agonists over L-dopa?
No motor complications
What class of drug should be started for a PD patient at diagnosis and has mild motor disability and no cognitive impairment?
MAOB inhibitor
What class of drug should be started for a PD patient at diagnosis that has mild/moderate motor disability and no cognitive impairment?
Dopamine agonist
What class of drug should be started for a PD patient at diagnosis that has moderate/severe motor disability, cognitive impairment and is over the age of 70?
L-dopa and COMT inhibitor.
Name two other treatment approaches for PD.
Human embryonic mesencephalic graft
Deep brain stimulation
What does chorea mean?
Involuntary jerky movements
How is Huntington’s disease inherited?
Which chromosome and which protein are involved?
Autosomal dominant disease
The protein is ‘huntingtin’ on chromosome 4. The mutated protein aggregates inside cells.
Which amino acid has an abnormal number of repeats (36 repeats) in Huntington’s disease?
Glutamine (CAG codon)
What pathological changes are associated with Huntington’s?
Loss of medium spiny neurons
Cortical atrophy
Striatal degeneration
Intranuclear inclusions of huntingtin
What are the symptoms of Huntington’s? (7)
Chorea Gait abnormalities Lack of coordination Cognitive impairment: poor attention, memory difficulties Psychiatric disturbances Sleep disturbance Weight loss
What are the mechanisms underlying neurodegeneration in Huntington’s? (7)
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 is Huntington’s managed?
Tetrabenazine (synaptic vesicular amine transporter inhibitor)
Anti-dopaminergic (antipsychotic) drugs
Antidepressant drugs
Give some examples of anti-dopaminergic drugs.
Haloperidol
Olanzapine
Give some examples of anti-depressant drugs.
Imipramine
Amitriptyline
How does Parkinson’s affect the direct/indirect pathways?
The loss of dopaminergic cells results in an imbalance between the direct and indirect pathways.
