B12: Neurodegenerative disorder treatment, Nootropic drugs

Question 1

Background:

What is the major neuronal pathway affected in Parkinson’s disease?

Answer 1

Nigrostriatal Pathway

Between dopaminergic neurons of the substantia nigra pars compacta (midbrain) and the dorsal striatum (caudate nucleus + putamen of the basal ganglia)

Plays an important role in movement regulation

Question 2

Background:

What is the general pathogenetic explanation for neuronal damage in neurodegenerative diseases? (2 processes)

Answer 2

1. Excitotoxicity - overfunction of excitatory amino acids (mostly glutamate at NMDA/AMPA receptors)
2. Oxidative Stress

Question 3

Background:

What are some (8) possible causes these neuron-damaging processes?

(Not that important for midterm, just be aware of them for orals…)

Answer 3

1. Autoimmunity
2. Prions
3. Viruses
4. Metabolic Disorders
5. Genetic Inheritance
6. Trauma
7. Arteriosclerosis
8. Inflammatory Disease
9. (Exogenous Excitotoxins - drugs, etc.; not mentioned in slides)

Question 4

Background:

What are 7 important neurodegenerative diseases?

(According to Kato, only Parkinson’s + Alzheimer’s are important for the midterm, but other teacher’s midterms may contain more. Just adding all for oral exam completeness…)

Answer 4

1. Parkinson’s disease - nigrostriatal dopaminergic dysfunction
2. Alzheimer’s - Tau protein and amyloid beta buildup
3. Huntington’s chorea - trinucleotide repeat disorder of HTT gene (4p)
4. Vascular Dementia - due to multiple minor strokes
5. Wilson’s Disease - copper accumulation
6. Multiple Sclerosis - AI demyelination
7. ALS - genetic/trauma-related motor neuron death

Question 5

Background:

We’ve covered DA synthesis enough already, so here a few more specific questions about it…

1. What dietary AA can be converted to tyrosine for DA synth + how?
2. What are the co-factors for the DA synth enyzmes?

(question 2 is probably way too much, but you wanna do the USMLE, don’t you?)

Answer 5

1. Phenylalanine - converted by Phe OHase (absent in PKU) in liver (+ kidney)
2. Tyr OHase uses tetrahydrobiopterin; DOPA decarboxylase uses PLP; (DA B-OHase uses ascorbate AKA vitamin C)

Question 6

Background:

What are Alzheimer’s symptoms?

(Which one appears first?)

Answer 6

1. Short-term memory loss - comes first
2. Apraxia/Dyspraxia - motor execution dysfunction
3. Aphasia/Dysphasia - speech issues (forget words, trouble forming phrases)
4. Long-term memory loss - comes later (w/ worsening motor sx)
5. Behavioral Changes - aggression, irritability, mood fluctuation, etc.
6. Eventually ending in extreme apathy + no movement

Cognitive/emotional/language issues overall can be termed dementia + Alzheimer’s accounts for ~60% of dementia cases.

Question 7

Background:

What are 4 possible reasons/risk factors for Alzheimer’s?

What are 4 theories for Alzheimer’s etiology based on observed pathopysiological changes?

(3 important; 1 disputed)

Answer 7

• Genetic Heritability (50-80%); head injury; depression; hypertension

1. Cholinergic Theory - ↓ hippocampal ACh
2. Amyloid Theory - β-amyloid plaques; amyloid-related protein activates neuronal “death receptors”
3. Tau Hypothesis - intraneuronal fibrillary tangles of Tau protein → death pathway activation; microtubule disintegration; cytoskeletal collapse
4. (Disrupted Biometal Homeostasis - aluminum buildup; disputed)

Question 8

What are 5 groups of medications for Alzheimer’s?

3 are important, 1 is very vague, 1 is experimental

Answer 8

1. Acetylcholinesterase Inhibitors - Tacrine, Donepezil, Rivastigmine, Galantamine
2. NMDA Antagonists - Memantine
3. NSAIDs - Ibuprofen, Indometacin, (Flurbiprofen)
4. Anti-Oxidants
5. Anti-Amyloid - in trials; amyloid vaccination and mAbs (Bapineuzumab)

Question 9

What are 4 acetylcholinesterase ihibitors for Alzheimer’s?

General side effects?

Specific info for each?

Answer 9

• General Side Effects: cholinomimetic sx, i.e. increased GI motility w/ nausea, vomiting, diarrhea; increased salivation + heart rate

1. Tacrine - older, discontinued; hepatotoxic, nausea, vomit, diarrhea, short DOA
2. Donepezil - not hepatotoxic; (oral)
3. Rivastigmine - not hepatotoxic; longer DOA + high potency; (oral or patch; Kato says specificity for CNS causes fewer side effects)
4. Galantamine - also a weak nAChR agonist (Wiki says allosteric modulator, not agonist)

Question 10

What is the NMDA antagonist used for Alzheimer’s?

Answer 10

Memantine

decreases glutamatergic excitotoxicity

(lots of other receptor effects too… 5-HT3 atg, nAChR atg, D2 ag, sigma ag, but none mentioned by our dept.)

Question 11

What are 3 NSAIDs that are potentially effective in Alzheimer’s? (2 important, one in trials)

What is their possible mechanism of action?

Answer 11

1. Ibuprofen
2. Indometacin
3. Flurbiprofren - in trials

Probably not a COX inhibition effect (because aspirin doesn’t work), but rather a γ secretase inhibition, causing decreased production of amyloid beta 1-42, the form specifically associated with Alzheimer’s

Question 12

Background:

What are the 4 main motor symptoms of Parkinson’s disease?

Answer 12

1. Akinesia / Hypokinesia / Bradykinesia - difficulty starting/stopping movement; slow movement, eventually sometimes no movement
2. Rigidity of the muscles - so-called “cogwheel” rigidity; step-by-step rather than fluid motion
3. Resting Tremor - tremor which abates with voluntary movement; specif 4-6 Hz
4. Postural Instability - often with forward-bent position

• Dx criteria is bradykinesia + at least 1 of the other 3
• Can remember TRAP (K would be better for “-kinesia” but good luck coming up with something for TRKP)

Question 13

Background:

What is the ART classification for Parkinson’s types?

Answer 13

1. Akinetic-Rigid Form - worse prognosis; self-explanatory name…
2. Tremor-Dominant Form - slower progression; less movement inhibition, stronger tremor; anti-muscarinics work well

Question 14

Background:

Describe the nigrostriatal neuronal circuit important in Parkinson’s.

(3 neurons in circuit + pathway out of the circuit)

Answer 14

1. Cholinergic Striatal Neurons - stimulate GABAergic neurons also in striatum
2. GABAergic Striatal Neurons - inhibit SN DA neurons via axons to the SN
3. Dopaminergic Substantia Nigra Neurons - inhibit cholinergic striatal neurons
4. Axons of GABAergic striatal (globus pallidus) neurons run out of the striatum to inhibit the glutamatergic neurons of the subthalamic nucleus, which have some kind of effect on corticospinal tracts controlling skeletal muscles… 1-3 are important for now, 4 is important in distant future neuro classes…

Importance: In Parkinson’s, lack of dopaminergic inhibition from the SN on striatal cholinergic stimulation of striatal GABAergic inhibition means an overall inhibition of this circuit leading to motor dysfunction. I’m so sorry for all this…

Question 15

Background:

What are 4 cognitive/psychiatric/sensory symptoms of Parkinson’s disease?

Answer 15

1. Dementia - impairment of cognition, verbal fluency, visuospatial procession and executive function
2. Depression
3. Anxiety
4. Psychosis
5. Sleep Disturbances - insomnia, nightmares, hallucinations, daytime somnolence, RLS, apnea
6. Sensory Sx - pain, paresthesias, olfactory dysfunction

Question 16

Background:

What are some (7) supportive symptoms in the diagnosis of Parkinson’s?

Answer 16

1. Unilateral Onset - differs from Parkinsonian syndromes due to drugs, etc.
2. Resting Tremor - in slides… seems like a main criterion to me…
3. Progressive Signs + Symptoms - condition worsens with time
4. Persistent Asymmetry of signs - remains unilateral
5. Levodopa Response - early response to levodopa is excellent
6. Levodopa-Induced Dyskinesias - eventual side effect
7. Long Clinical Course - ≥ 10 years

Some of these are kind of vague… just in here for completeness.

Question 17

Background:

What are some (9) of the autonomic dysfunction symptoms of Parkinson’s disease?

(1st one is probably most important; others are just… uncomfortable)

Answer 17

1. Orthostatic Hypotension - with postural instability = risk for falls/fractures
2. GI impairment - swallowing difficulties, impaired motility, constipation
3. Heat Intolerance
4. Urinary Symptoms - increased frequency + urgency
5. Impotence
6. Increased Secretions - hyperhidrosis, hypersalivation, seborrhea

Question 18

What are the general pharmacological treatment strategies for Parkinson’s disease?

(2 main approaches, 1 with 5 drug categories)

Answer 18

1. Dopamine Side
   
   1. “Substitution” - levodopa w/ carbidopa or benserazide
   2. MAO-B inhibitors - selegiline etc.
   3. Dopamine agonists - bromocriptine, cabergoline etc.
   4. COMT inhibitors - opicapone, etc.
   5. Amantadine - multiple MOAs
2. Acetylcholine Side
   
   1. Central Anti-Cholinergics - benztropine, etc.

Question 19

What drug is used for “substitution” therapy in Parkinson’s?

What is it co-administered with and why?

What are its important pharmacokinetics?

What are its side effects + phenomena seen later in the course of its use?

Answer 19

Levodopa - exogenous L-DOPA supplementation

• co-admin with Carbidopa or Benserazide to partially inhibit peripheral DOPA-decarboxylase + increase levodopa CNS entry
• pharmacokinetics: good oral absorption; half life 1-3 hours
• side effects:
  
  • acute peripheral: nausea, vomiting (abates with time), arrhythmia, orthostatic hypotension
  • acute central: depression, psychoses, anxiety, nightmares
  • chronic phenomena: accelerates disease progression (debatable)
    
    • end-of-dose: short DOA → as effect wears off akinesia may develop
    • on-off phenomenon: see choreoathetoid dyskinesia in “on” and akinesia in “off” phase; normal movement can’t be achieved

Question 20

Considering its side effects…

what 2 treatment strategies are used in relation to levodopa?

(one is simple and more important, other is extra)

Answer 20

1. Levodopa therapy should be started as late as possible in the course of Parkinson’s treatment
2. “Drug holidays” - taking breaks of 2-4 wks from levodopa administration; give amantadine or DA agonists during breaks; immobilization during breaks ↑ risk of thrombophlebitis, PE and aspiration pneumonia; efficacy is questioned

Question 21

What are the dopamine agonists used in Parkinson’s treatment?

(4 older/less used, 3 newer)

What are their advantages, special considerations in administration + side effects?

Answer 21

• Used before levodopa as monotherapy; weaker effects but less therapeutic fluctuation
• Side Effects: similar to levodopa, but stronger psychiatric effects; also constipation, dyspesia + impulse control issues

1. Older Drugs:
   
   • Bromocriptine - ergot derivative; mostly for ↑ PRL now
   • Pergolide (oral); Pramipexole (oral; neuroprotective; D3 specific); Ropinirole (oral; D2 specific)
2. Newer Drugs:
   
   • Cabergoline - ergot derivative; oral; early monotherapy
   • Rotigotine - patch
   • Apomorphine - injection; strong agonist, must give with periphal D2 atg domperidone to decrease vomiting

Question 22

What are the COMT inhibitors used in Parkinson’s treatment?

(2 newer, 1 discontinued)

How are they used, what are their advantages + side effects?

Answer 22

Given with DA agonist or levodopa, never monotherapy;

1. Newer Drugs: Entacapone and Opicapone (newest)
   
   • inhibit peripheral COMT only; decrease levodopa-induced dyskinesias
2. Discontinued: Tolcapone
   
   • ​​also acts centrall__y; withdrawn due to hepatotoxicity

Remember Al Capone … (he inhibited the cops… sounds kinda like COMT… and if he was able to operate without the Chicago DA keeping him in line things would have been even worse… ok maybe I’m reaching a bit)

Question 23

What are the 3 MAO-B inhibitors used in Parkinson’s treatment?

When/how are they introduced into treatment?

Important pharmacodynamics/kinetics? Side effects?

(2 from Kato, 1 from slides w/ extra info from Wiki)

Answer 23

​Can be monotherapy at first, levodopa added later

• Selegiline - irreversible; is neuroprotective so also used in Alzheimer’s/depression (↑ superoxide dismutase/catalases + ↓ oxidative stress), but can be degraded to amphetamine derivatives → sleep disturbances
• Rasagiline - irreversible + 10x stronger, but requires sooner levodopa introduction (used if selegiline + levodopa already in use + want stronger MAOI effect); no sleep disturbances
• (Safinamide - reversible; very new; also inhibits Glu release and DAT/SERT; given in akinesia “off” periods of on-off phenomenon)

Question 24

What drug originally used as an anti-viral has therapeutic effects on DA transmission in Parkinson’s?

Mechanisms (4)? Administration? Side effects?

Answer 24

Amantadine - originally an anti-influenza drug

• Mechanisms: enhanced DA transmission (↑ synth/release, ↓ reuptake); NMDA inhibition (↓excitotoxicity); adenosine A_2A-R atg (disinhibits D2 effects); muscarinic atg
• Administration: weak oral absorption; strong as IV but ↑ seizure risk; weaker than levodopa + tolerance develops; used as early monotherapy or in akinetic crisis
• Side Effects: mostly CNS; anxiety, insomnia, difficulty concentrating

Question 25

What are the antimuscarinics used in Parkinson’s treatment?

(7 total, first 3 probably most important)

What type of Parkinson’s are they used for?

Side effects?

(Added a bit of info on some, but for Parkinson’s it seems sufficient to know some examples)

Answer 25

• Used for tremor-dominant Parkinson’s disease or drug-induced Parkinsonism to improve ACh/DA imbalance seen in the disease
• Ineffective for hypokinesia​
• Side Effects​: constipation, tachycardia, xerostomia, urinary retention, blurred vision, etc.

1. Procyclidine - also used in other dystonias
2. Benztropine - also for anti-psychotic EPS
3. Trihexyphenidyl - M1 specific
4. Biperiden; Orphenadrine (older, H1 + many other antagonisms); Dexetimide; Metixene

Question 26

Describe the “therapeutic pyramid” for Parkinson’s treatment.

(Which drugs are used first + which are added later in what order)

Answer 26

Main idea is to delay start of levodopa until as late as possible; antimuscarinics only for tremor-dominant form or drug-induced Parkinsonism

1. First selegiline or rasagiline (or DA agonists, according to slides)
2. Then add amantadine
3. Then add DA agonists (or MAOI if DA agonist was used first, I suppose)
4. Then add levodopa + carbidopa/beserazde
5. Then add opicapone (improves levodopa effect in pts with end-of-dose and on-off phenomena)

(Kato said sometimes opicapone is added at same time as levodopa)

Question 27

PLACEHOLDER

this deck needs info on Huntington’s, vascular dementia, Wilsons and ALS plus nootropics

but it probably wont be other midterm so skipping for now