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
2
Q
Parkinson’s Disease
A
- Lewy Bodies
- Contain ubiquitan and synuclein
3
Q
Alzheimer’s Disease
A
- Neuritic plaques (outside neuron)
- Neurofibrillary tangles (inside neuron)
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)
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
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
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
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
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
10
Q
Levodopa SE
A
- Orthostatic hypotension (increase NE)
- Cardiac stimulation (activitation of beta-adrenergic receptors)
- Vomiting: DA triggering CTZ
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
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
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
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
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
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
