Neurodegenerative Disorders

Question 1

Neurodegenerative Diseases

Answer 1

• 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

Question 2

Parkinson’s Disease

Answer 2

• Lewy Bodies

- Contain ubiquitan and synuclein

Question 3

Alzheimer’s Disease

Answer 3

• Neuritic plaques (outside neuron)

- Neurofibrillary tangles (inside neuron)

Question 4

Degeneration

Answer 4

• 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)

Question 5

Idiopathic Parkinson Disease

Answer 5

-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

Question 6

Lewy Bodies

Answer 6

• Brains of Parkinson’s patients contain Lewy bodies

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

Question 7

Parkinson’s Mechanism of Dysfunction

Answer 7

• 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

Question 8

Ambroxol

Answer 8

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

Question 9

Levodopa

Answer 9

• 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

Question 10

Levodopa SE

Answer 10

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

Question 11

Carbidopa

Answer 11

• 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

Question 12

L-Dopa Central Toxicities

Answer 12

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

Question 13

ON-OFF Syndrome

Answer 13

• “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

Question 14

Dopamine D2 Agonists

Answer 14

• 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

Question 15

D2 Agonist SE

Answer 15

• 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

Question 16

Amantadine

Answer 16

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

Question 17

MAOI

Answer 17

• 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

Question 18

COMT-I

Answer 18

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

Question 19

Tolcapone

Answer 19

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

Question 20

Entacapone

Answer 20

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

Question 21

Anticholinergics

Answer 21

• 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)

Question 22

Pimacanserin

Answer 22

• 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

Question 23

Alzheimer Disease

Answer 23

• 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

Question 24

Genetics + Alzheimers

Answer 24

• 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

Question 25

Alzheimers Pathology

Answer 25

• 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)

Question 26

AChE Inhibitors

Answer 26

• 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

Question 27

AChE Inhibitor SE

Answer 27

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

Question 28

Drug to Avoid + Dementia

Answer 28

• 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

Question 29

Glutamatergic Transmission

Answer 29

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

Question 30

Memantine

Answer 30

• 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

Question 31

Prevagen

Answer 31

• 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