Class notes

Neuropharmacology notes for exam 2 and 3

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Course
(PHAR562)

Institution
McGill University (Mcgillu)

These 2 documents contain information about exam 2 and 3 in that course, Neurodevelopmental disorders and Neurodegeneration disorders, namely: Epilepsy, mechanisms for pain & addiction, Alzheimer's disease, Parkinson's disease, ALS, FTD and SMA.

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Uploaded on December 15, 2023
Number of pages 30
Written in 2023/2024
Type Class notes
Professor(s) Bowie
Contains Materials for exam 2 and exam 3

pharmacology
phar562
parkinsons disease
alzheimers disease
als
lower motor n
amyotrophic lateral sclerosis als
primary lateral sclerosis pls
progressive muscular atrophy pma
upper motor neuron disease

Institution McGill University (Mcgillu)
Education Biology
Course (PHAR562)

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PHAR 562

Neurodegeneration – Motor neuron disease
Vocab

Motor neuron disease
- Impairment in muscle innervation
Spinal Muscular Atrophy
- Early impairment of muscle innervation
Ataxia
- Loss of voluntary movement
Dementia
- Memory and cognitive functions impairment
o AD
o Vascular Dementia
o PD
o HD
o Lewy body dementia
o Trisomy 21
Multiple sclerosis
- Degeneration of myelin sheaths

Anatomy
- Motor unit => basic unit of motor function
o A motor neuron and the group of muscle fibers it innervates
- Upper and lower motor neurons
o Upper
 Derive from motor cortex / brain stem
 Project to lower motor neurons
 Release glutamate on the lower motor neurons as means of
communication
o Lower
 Located in spinal cord
 Innervate muscles and mediates voluntary movement
 Exception cranial nerve is the lower motor neuron with nuclei
located in brainstem as it innervates tongue and eyes
- Motor Neuron Diseases
o Occur when motor neurons become damaged
o Present as muscle weakness
 Muscles are less innervated => loss of control
 May lead to difficulty breathing & swallowing
o UMN diseases may present differently from LMN diseases
 Amyotrophic lateral sclerosis (ALS)
 UMN and LMN are both affected

,PHAR 562

 Most common motor neuron disease
 Dysmorphic disease – weakness that spreads
 Diverse pathology
 Primary Lateral Sclerosis (PLS)
 UMN affected
 Progressive Muscular Atrophy (PMA)
 LMN affected
- Diagnosis
o UMN (upper motor neurons) signs
 Babinski sign – upward response of big toe when stimulated
 Hyperreflexia – hyperactive repeating reflexes
 Spasticity
o LMN
 Muscle atrophy and weakness
 Fasciculations (looks like spasms but it is constant)
 Decreased muscle tone
 Hyporeflexia
o Difficulty diagnosing ALS as there could be both hyperreflexia (UMN) and
hyporeflexia (LMN) – symptoms may mask each other

Amyotrophic Lateral Sclerosis (ALS) – AKA Lou Gehring’s disease or Charcot’s disease
- Amyotrophy => neurogenic atrophy of the muscle
- Lateral sclerosis => hardness of the spinal cord seen when ALS patients are examined at
autopsy
o Caused by the proliferation of astrocytes and scars
- Forms of ALS:
o Classical sporadic
o Familial
o Geographic variant
- Age onset 55-65
o Can start at 45
- Seen in 1-2/100,000 – affecting more males
- 50% patients die within 3 years of onset, 90% die within 5 years
- Usually starts in the limbs, can be very heterogenous
o Can start in face too
- 30% bulbar (medulla oblongata) onset => tongue affected first
o Patients have issues with speech and swallowing
- All muscles are affected in ALS except ocular and bladder
- Respiratory problems are the major discomfort and major cause of death
- Interventions:
o No treatment
o End stage: Breathing tube or non-invasive mechanical ventilation (not easily
accessible since patients are often not mobile)

, PHAR 562

o Pharmacological treatment Riluzole
 Increased life expectancy by a few months

Suggested Disease Mechanism 1: Dying forward hypothesis
Cortical dysfunction and hyperexcitability
- Trans-synaptic glutamatergic excitotoxicity
o Something happens in the cortex triggers the hyperexcitability of motor neurons
leading to increased glutamate in the synaptic cleft leading to toxicity of lower
motor neurons (Dying forward hypothesis)
o Glutamate in the synaptic cleft is normally cleared by pre- and post-synaptic
terminals & by astrocytes that express EAAT2 (Excitatory amino acid transporter 2)
on the surface
 EAAT2
 Glutamate transporter on astrocytes that clear away glutamate
from synaptic cleft
 Decreased in ALS
- Hyperexcitability via NDMAR and AMPAR
o GluR2 deficiency occurs in some ALS patients
 It is required for Ca2+ entry into the cell
o Swelling of motor neurons observed due to an increased Na+ and Cl-, leading to
accumulation of water
- Riluzole
o Reduces cortical hyperexcitability and blocks glutamatergic neurotransmission
through 7 different mechanisms
 Glutamate release from presynaptic terminal inhibited by blocking Na+
and Ca2+ channels (1-2)
 Blocks NMDAR, AMPAR, and Kainate receptors in the postsynaptic
terminal, so that there is less Ca2+ influx (3,4,5)
 Potentiates glutamate uptake by astrocytes via EAAT2 (6)
 Inhibits glutamate release (7)
o Mechanism indicates dying forward mechanism is involved in ALS
 Heterogenous presentation of disease indicates that other mechanisms
may be involved too
- Pharmacology of Riluzole
o ADME
 Absorption: 50mg BID; Bioavailability: 60% oral
 Distribution: 96% bound to plasma protein (increasing its half-life)
 Metabolism: CYP1A2 hydroxylation
 Drug-drug interaction with other CYP1A2 substrates (e.g.,
acetaminophen, caffeine, warfarin)
 Excretion: 95% renal as glucoronides
o Adverse events: Blurred vision, difficulty breathing, weakness, dizziness, GI
discomfort

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