Neuro disorders Flashcards
idiopathic Parkinson’s disease - clinical and non motor features
tremor, lead pipe rigidity, bradykinesia, postural instability
mood changes, pain, cognitive change, urinary symptoms, sleep disorder, sweating
what is the pathology of Parkinson’s?
neurodegeneration, Lewy bodies, loss of pigment, decreased dopamine
what occurs in the basal ganglia circuit in Parkinson’s?
1) loss of dopaminergic neurones in SN results in decreased inhibition of neostriatum
2) loss of inhibition in NS allows increased ACh (excitatory)
3) chain of abnormal signalling causes impaired mobility
describe the catecholamine synthesis pathway
L tyrosine —> LDOPA (via tyrosine hydroxylase) —> dopamine (via DOPA decarboxylase) —> norepinephrine —> epinephrine
what are 2 enzymes involved in the degradation of dopamine?
monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)
what does a DAT scan show?
looking at recycling of dopamine - labelled tracer
not diagnostic but can rule out other problems as normal in drug-induced issues and for tremor symptoms
why is dopamine not used to treat parkinsons?
dopamine cannot cross BBB, LDOPA crosses blood brain barrier via active transport
describe how LDOPA is taken up, the pharmacokinetics and dynamics
must be taken up by dopaminergic neurones in substantial migration to be converted to dopamine
- oral administration, absorbed by active transport in competition with amino acid, wary of high protein meals
- 90% inactivated in intestinal wall by MAO and DOPA decarboxylase
- T1/2 = 2 hours
- 9% converted to dopamine in peripheral tissues via DOPA decarboxylase
- <1% enters CNS as competes with amino acids for active transport across BBB
describe the formulations of LDOPA
used in combination with a peripheral DOPA decarboxylase inhibitor: co-careldopa, co-beneldopa
what are the advantages and disadvantaged of LDOPA?
adv - highly efficacious, low side effects of nausea/anorexia, hypotension, psychosis, tachycardia
disadv - precursor so needs enzyme conversion, long term = loss of efficacy, involuntary movements, motor complications
what are some interactions of LDOPA
- pyridine (vit b6) increases peripheral breakdown of LDOPA
- MAOIs risk hypertensive crisis
- many antipsychotic drugs block dopamine receptors and Parkinsonism is a side effect
dopamine receptor agonists - ergot derived and non ergo, patch and subcutaneous names
ergot - bromocryptin, pergolide, cabergoline
non ergot - ropinrole, pramipexole
patch - rotigotine
subcutaneous - apomorphine
what are the advantages and disadvantages of dopamine receptor agonists?
adv - direct acting, less dyskinesia/motor complications, possible neuroprotection
disadv - less efficacy than LDOPA, impulse control disorders , more psychiatric side effects which are dose limiting and it is expensive
describe impulse control disorders
dopamine dysregulation syndrome
- pathological gambling, hyper sexuality, compulsive shopping, desire to increase dosage, punding
what are the side effects of dopamine receptor agonists?
sedation, hallucinations, confusion, nausea, hypotension
monoamine oxidase B inhibitors - what does monoamine oxidase B do, names
metabolises dopamine, predominates in dopamine-containing regions of the brain so these drugs enhance dopamine
selegiline, rasagaline
COMT inhibitors - names, actions, can it be used alone?
entapacone - doesn’t cross BBB
tolcapone - crosses BBB but mainly effects peripheral
reduces peripheral breakdown of LDOPA to 3-O-methyldopa (3-O-methyldopa competes with LDOPA for active transport into CNS)
no therapeutic effect bone, can use in combination with LDOPA and peripheral decarboxylase inhibitor (stalevo)
have LDOPA sparing effect
prolongs motor response to LDOPA
anticholinergics - names, advantages and disadvantages
trihexyphenidydyl, orphenadrine, procyclidine
adv - treats tremor, not acting via dopamine systems
disadv - no effect on bradykinesia, side effects include confusion, drowsiness, usually anticholinergic s/e
amantadine - possible mechanism, is it useful in PD?
uncertain, possibly enhanced dopamine release, or anticholinergic NMDA inhibition
it is poorly effective, has few side effects, little effect on tremor
in myasthenia gravis, what is the pathophysiology at the synapse?
ACh has difficulty binding due to IgG blockage of the binding site so ACh cholinesterase begins to break it down
what are the clinical signs of myasthenia gravis?
fluctuating, fatiguable, weakness in skeletal muscle
- extraocular muscles commonest presentation
- bulbar involvement cause dysphagia, dysphonia, dysarthria
- limb weakness is proximal symmetric
- respiratory muscle involvement
what are 5 therapeutic interventions used to treat MG?
acetylcholinesterase inhibitors, corticosteroids, steroid sparing (azothioprine), IV immunoglobulin, plasmapharesis
acetylcholinesterase inhibitors - names, mechanism, side effects
pyridostigmine, neostigmine (quicker action, significant cholinergic side effects)
- prevents breakdown of ACh in NMJ so ACh more likely to engage with remaining receptors, side effects = SSLUDGE: salivation, sweating, lacrimation, urinary incontinence, diarrhoea, GI upset, emesis (and miosis)
