Neurodegenerative Flashcards
Parkinson’s and Huntington’s are caused by
death of neurons in the extrapyramidal system (substantia nigra and striatum)
Alzheimers is caused by
death of neurons in the cortical and hippocampal neurons
ALS is caused by
degeneration in spinal motor and cortical neurons
Factors that leads to neuron degeneration
- free radicals/oxidative stress
- toxins
- aging
- excess glutamate
- decline in neuronal metabolism
- genetic predisposition
Parkinson’s symptoms
- bradykinesia
- tremors at rest
- muscular rigidity
- abnormal posture
- mask-like face and shuffling gait
- impaired speech
- inability to perform skilled tasks
Parkinsonism
any condition that cuases a combination of the movement abnormalities seen in Parkinson’s disease, especially resulting from loss of dopamine-containing neurons – don’t necessarily have parkinson’s
-meds, head trauma, brain lesions, small strokes
Parkinson’s pathophysiology
- substantia nigra dies (they prod dopa); > 80% of neurons die before symptoms appear
- surviving neurons have Lewy bodies (perturbs fxn) which have a misfolded alpha-synuclein PRO, triggers toxic pathways (ie oxidative stress, synaptic dysfunction, etc.)
- thalamic neurons projecting to cortex are inhibited, net decrease in the excitatory input ot he cortex, disrupts muscle control
Draw Parkinson’s p’way
see
levopoda MOA & downsides
-precursor of DA, able to cross BBB
-orally available, rapidly absorbed via small intest.
-decreases rigidity, tremors, other symptoms
downsides:
-decline in response after 3-5 years
-short half life (1-2 hours)
only 1-3% of drug reaches the brain, rest in metabolized by AAAD
levodopa SE
caused by peripheral conversion of DA to NE
-anorexia, tachycardia, nausea, hypotension
CNS: depression, hallucination, psychosis, anxiety, dyskinesia
carbidopa MOA
syptomatic rx of Parkinson’s esp at advanced stages
- AAAD inhibitor, blocks peripheral metabolism of L-dopa for increased avail in brain
- can reduce dopa dose 4-5x
- reduced SE in periphery
entacapone/tolcapone
inhibitor of COMT, further decreases peripheral metabolism of L-dopa
selegline MOA and SE
adjunt to L-dopa
inhibits MAO B in synapse and pre-synaptic terminal
-decreases production of H202 and neurotoxic free radicals
-orally active, half life 7-9 hours, renal excretion
downside: metabolized to meth and amphetamine –> insomnia
rasagiline
selective inhib of MAO B
not metabolized to amphetamine-like substance
bromocriptine
D2 agonist and d1 partial agonist
-monotherapy early in disease and as an L-dopa adjunct late
-orally active (start slow and build dosage)
SE:
CV: arrhythmias, postural hypotension
Neuro: depression, confusion, hallucinations, sleepiness, impulsivity
GI: N/V
contraindicated with heart/mental probs
ropinirole
d2/d3 agonist
-monotherapy early in disease and as an L-dopa adjunct late
-orally active (start slow and build dosage)
SE:
CV: arrhythmias, postural hypotension
Neuro: depression, confusion, hallucinations, sleepiness, impulsivity
GI: N/V
contraindicated with heart/mental probs
pramipexole
d2/d3 agonist
-monotherapy early in disease and as an L-dopa adjunct late
-orally active (start slow and build dosage)
SE:
CV: arrhythmias, postural hypotension
Neuro: depression, confusion, hallucinations, sleepiness, impulsivity
GI: N/V
contraindicated with heart/mental probs
apomorphine
DA receptor agonist
-acute rx of patients with advanced disease in “off periods”
-admin SQ (NO IV – leads to thrombus formation)
SE: N/V, arrhthmias, postural hypotension, hallucinations, sleepiness
benzotropine/trihexyphenidyl
muscarinic antagonists
-block overstim of receptors
SE: antimuscarinic effects: blurred vision, dry mouth, urinary retention, constipation, aggravation of glaucoma, delirium, psychosis, memory impairment
amantadine
-used to alleviate bradykinesia and rigidity (not tremor) in patients with mild to moderate Parkinson’s prior to initiation of L-Dopa
-blocks muscarinic signaling, but also moderately increases DA release and blocks glutamate NMDA receptors
SE: hallucinations/confusion, nausea, dizziness, rash, antimuscarinic effects
physical changes in brain with Alzheimer’s
-cortex shrivels up, especially in hippocampus
ventricles grow larger
Alzheimer’s potential mechanisms
A-Beta peptides aggregate into various assemblies, some of which impair synapses and dendrites, build up of pathogenic A-Beta could result from increased prod or deficient clearance
microglia could be good or bad depending on their signaling cascades and functions, can release inflammatory mediators and cause further damage
Tau PRO causes neurofibrillary tangles
ApoE4 and tau promote A-Beta induced injury
donepezil/galatamine/rivastigmine/tacrine MOA
blocks catabolism of ACh -increases levels in synaptic clefts -increases ACh signaling modest improvement in some patients -good oral bioavailability -Main diff b/t drugs is half life (donepezil very long) Metabolized by P450 liver enzymes (donepezil, galatamine, tacrine) or plasma cholinesterase (rivastigmine)
SE of donepezile/galatamine/rivastigmine
anorexia, tachycardia, nausea, hypotension, diarrhea
SE of tacrine
hepatotoxicity
memantine
derivative of amatadine
non-competitive antagonist of NMDA receptor, calms hyperactive receptor so that it can then detect signals
-protects neurons from Ca overload that is excitotoxic
-improved ADLs and cognitive fxn
-additive benefits with donepezil
SE: dizziness, h/a, confusion, agitation, constipation
