Neurodegenerative Disorders Flashcards

1
Q

Neurodegenerative Diseases

A
  • Progressive dysfunction and death of neurons
  • Usually exclude disease of known vascular, toxic, metabolic, infective or autoimmunne origin
  • Pathogenesis: genetic susceptibility, environment, and aging factors are important
  • Abnormal protein accumulation in neurons is a typical feature
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2
Q

Parkinson’s Disease

A
  • Lewy Bodies

- Contain ubiquitan and synuclein

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3
Q

Alzheimer’s Disease

A
  • Neuritic plaques (outside neuron)

- Neurofibrillary tangles (inside neuron)

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4
Q

Degeneration

A
  • Often affects a specific system for a selective vulnerability
  • Protein aggregates represent pathological hallmark lesions
  • Could also originate from misfolded proteins and an inability to clear them (Ubiquitin => proteasome sytstem, autophagy)
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5
Q

Idiopathic Parkinson Disease

A

-Most common
-Loss of substantia nigra dopamine neurons
Other causes: vascular disease, head trauma, tumors, and drug-induced parkinsonis
-Environmental agents: MPTP, illicit byproduct of a meperidine analogue

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6
Q

Lewy Bodies

A
  • Brains of Parkinson’s patients contain Lewy bodies

- Lewy bodies are a normal brain protein (alpha synuclein) that are misfolded and form aggregates

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7
Q

Parkinson’s Mechanism of Dysfunction

A
  • Glu antagonists or GABA agonists have little effect
  • Imbalance in PD is a decrease in dopamine activity with an apparent increase in cholinergic activity
  • Treatment: reverse the imbalance
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8
Q

Ambroxol

A
  • Reduces mucus production in respiratory tract
  • Increases activity of lysosomal enzyme GBA
  • May reduce build-up of excess lipids and proteins like alpha-nuclein
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9
Q

Levodopa

A
  • MoA: increase dopamine in remaining nigrostriatal neurons in caudate nucleus
  • PD treatment
  • Most of L-dopa is convered to DA in the periphery causing its peripheral toxicities
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10
Q

Levodopa SE

A
  • Orthostatic hypotension (increase NE)
  • Cardiac stimulation (activitation of beta-adrenergic receptors)
  • Vomiting: DA triggering CTZ
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11
Q

Carbidopa

A
  • Lodosyn
  • Peripheral decarboxylase inhibitor that doesn’t cross BBB
  • Decreased SE which allows for smaller doses of L-dopa
  • Fixed combos, slow release, and a combination of IR/CR available
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12
Q

L-Dopa Central Toxicities

A
  • Dyskinesias: involuntary chorieform movements
  • Behavioral: hallucinations, confusion, psychotic reactions (atypical antipsychotics may help)
  • ON-OFF Syndrome: long term levodopa therapy SE
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13
Q

ON-OFF Syndrome

A
  • “Off Syndrome”: rapid loss of therapeutic effect between doses
  • “On-Off Syndrome”: rapid fluctuations between the drug working and not working after a single levodopa dose
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14
Q

Dopamine D2 Agonists

A
  • Monotherapy or with L-dopa
  • Ex: Pramipexole (Mirapex) and Rotigotine (Neupro Patch)
  • MoA: Up-regulation of DA2 receptors in stiatum due to love levels of DA released, so better response to D2 agonists
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15
Q

D2 Agonist SE

A
  • Somnolence: falling asleep during daily living and higher hallucination risk
  • N/V (trimethobenzamide for antiemetic therapy)
  • Orthostatic hypotension
  • Hallucinations
  • Don’t stop suddently due to sudden DA withdrawal (anxiety, depression, fatigue)
  • Lower risk of dyskinesias and on/off syndrome
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16
Q

Amantadine

A
  • Symmetrel
  • Used monotherapy or with L-dopa
  • Acts to release DA from nerve terminals
  • Adjunct with L-dopa during on/off periods
17
Q

MAOI

A
  • Monotherapy or with L-dopa
  • Ex: Selegiline (Eldepryl) and Rasagiline (Azilect)
  • Selective irreversible inhibitor to MAO-A
  • LOTS of drug interactions with foods and other drugs
  • SE: N/V, confusion in older adults, hallucinations esp with L-dopa, orthostatic hypotension
18
Q

COMT-I

A
  • Suppresses the metabolism of L-dopa
  • Ex: Tolcapone (Tasmar) and Entacapone (Comtan)
  • Used ONLY as an adjunct to L-dopa
  • Ineffective when given alone
19
Q

Tolcapone

A
  • Tasmar
  • Inhibits central AND peripheral COMT
  • Black box: risk of potentiall fatal, acute fulminant liver failure (last line resort)
20
Q

Entacapone

A
  • Comtan
  • Inhibits peripheral COMT
  • Short duration of action
  • No hepatotoxicity
  • Stalevo (entacapone, L-dopa, and carbidopa)
21
Q

Anticholinergics

A
  • Initial monotherapy or adjunct for PD
  • Ex: Trihexyphenydyl (Artane) or Benztropine (Congentin)
  • Overcome cholinergic overactivity from DA imbalance
  • Targets tremors in PD, can also be used for pseudo-PD from 1st gen antipsychotics
  • SE: mental confusion, constipation, urinary retention, blurred vision (limit use)
22
Q

Pimacanserin

A
  • Nuplazid
  • Inverse agonist and antagonist of 5HT2A and 5HT2C receptors (latter has lower affinity)
  • Treats hallucinations and delusions associated with PD psychosis
  • Black Box: increased mortality in elderly patients with dementia-related psychosis
23
Q

Alzheimer Disease

A
  • Progressive over 3-10 years
  • Most common cause of dementia
  • 3 genetic associations: APOE3 (most common), APOE4 allele carriers (common in affected persons), APOE2 (neuroprotective, reduced probability)
  • Occurs in all Down syndrome patients, extra 21 chromosome attributes to aggregation prone AB peptide that can form plaques
24
Q

Genetics + Alzheimers

A
  • APOE4 are prone to high cholesterol and Alzheimers, low fat diets can reduce the risk
  • E2/E3 genotype is most common and found in about 60% of people
  • E2 is rarest form and even only having one copy seems to reduce risk of developing Alzheimers by up to 40%
  • E3 doesn’t seem to influence risk of Alzheimers
  • E4 increases risk of Alzheimers and lowers its age of onset, worse with 2 copies
25
Q

Alzheimers Pathology

A
  • Fewer nerve cells and synapses
  • Plaques, abnormal protein fragment clusters, build up between nerve cells (AB deposition)
  • Dead and dying nerve cells contain tangles (twisted Tau protein strands)
26
Q

AChE Inhibitors

A
  • Loss of cholinergic neurons and transmission within cortex associated with memory loss
  • Inhibition of AChE should improve transmission in functioning neurons
  • Ex: Donepezil (Aricept), Galantamine (Razadyne), Rivastigmine (Exelon)
  • For Mild-Moderate Alzheimer
27
Q

AChE Inhibitor SE

A

DUMBELS

  • Diarrhea, urination, miosis, bradycardia/bronchorrhea/bronchoconstriction, emesis (N/V), lacrimation, salivation
  • Some tolerance develops to these effects
  • Not likely to help agitation or aggression
28
Q

Drug to Avoid + Dementia

A
  • Drugs with high/medium anticholinergic activity
  • Analgesics: Tramadol, Meperidine
  • Anticonvulsants
  • Antidepressants: TCAs, paroxetine
  • Antihistamines: 1st generation
  • Antimuscarinics: Oxybutynin
  • Antiemetics Meclizine, Metoclopramide
  • Antiparkinsonian: Benztropine, Trihexyphenidyl
  • Antipsychotics: 1st generation
  • Anxiolytics: Benzos
  • Muscle Relaxants: Baclofen, Carisoprodol, Cyclobenzoprine, Methocarbamol, Tizanidine
29
Q

Glutamatergic Transmission

A

IMPORTANT FOR

  • Learning and memory
  • Overstimulation of glutamate receptors => neurodegeneration
  • Certain neurons die and release glutamate causing a calcium influx causing more neurons to die
  • Antagonists to NMDA glutamate receptors are neuroprotective
30
Q

Memantine

A
  • Namenda
  • NMDA Receptor Antagonist
  • Prevent or slow rate of memory loss in vascular-associated and Alzheimers dementia
  • For moderate to severe cognitive loss
  • Well tolerated with few adverse events and low DI probabilities
  • SE: confusion, agitation, restlessness
  • High doses => ketamine effects
31
Q

Prevagen

A
  • Contains apoaequorin with three calcium binding sites to regulate intracellular calcium
  • Confers neuroprotection when infused directly into brain
  • Over 2000 AE associated with drug
  • Apoaequorin is broken down by pepsin in the GI
  • Advise patients not to count on prevagen or other memory supplements