Neurodegenerative

Question 1

Parkinson’s and Huntington’s are caused by

Answer 1

death of neurons in the extrapyramidal system (substantia nigra and striatum)

Question 2

Alzheimers is caused by

Answer 2

death of neurons in the cortical and hippocampal neurons

Question 3

ALS is caused by

Answer 3

degeneration in spinal motor and cortical neurons

Question 4

Factors that leads to neuron degeneration

Answer 4

• free radicals/oxidative stress
• toxins
• aging
• excess glutamate
• decline in neuronal metabolism
• genetic predisposition

Question 5

Parkinson’s symptoms

Answer 5

• bradykinesia
• tremors at rest
• muscular rigidity
• abnormal posture
• mask-like face and shuffling gait
• impaired speech
• inability to perform skilled tasks

Question 6

Parkinsonism

Answer 6

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

Question 7

Parkinson’s pathophysiology

Answer 7

• 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

Question 8

Draw Parkinson’s p’way

Answer 8

see

Question 9

levopoda MOA & downsides

Answer 9

-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

Question 10

levodopa SE

Answer 10

caused by peripheral conversion of DA to NE
-anorexia, tachycardia, nausea, hypotension

CNS: depression, hallucination, psychosis, anxiety, dyskinesia

Question 11

carbidopa MOA

Answer 11

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

Question 12

entacapone/tolcapone

Answer 12

inhibitor of COMT, further decreases peripheral metabolism of L-dopa

Question 13

selegline MOA and SE

Answer 13

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

Question 14

rasagiline

Answer 14

selective inhib of MAO B

not metabolized to amphetamine-like substance

Question 15

bromocriptine

Answer 15

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

Question 16

ropinirole

Answer 16

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

Question 17

pramipexole

Answer 17

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

Question 18

apomorphine

Answer 18

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

Question 19

benzotropine/trihexyphenidyl

Answer 19

muscarinic antagonists
-block overstim of receptors
SE: antimuscarinic effects: blurred vision, dry mouth, urinary retention, constipation, aggravation of glaucoma, delirium, psychosis, memory impairment

Question 20

amantadine

Answer 20

-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

Question 21

physical changes in brain with Alzheimer’s

Answer 21

-cortex shrivels up, especially in hippocampus

ventricles grow larger

Question 22

Alzheimer’s potential mechanisms

Answer 22

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

Question 23

donepezil/galatamine/rivastigmine/tacrine MOA

Answer 23

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)

Question 24

SE of donepezile/galatamine/rivastigmine

Answer 24

anorexia, tachycardia, nausea, hypotension, diarrhea

Question 25

SE of tacrine

Answer 25

hepatotoxicity

Question 26

memantine

Answer 26

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